WO2019241751A1 - Ssao inhibitors and uses thereof - Google Patents

Ssao inhibitors and uses thereof Download PDF

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Publication number
WO2019241751A1
WO2019241751A1 PCT/US2019/037380 US2019037380W WO2019241751A1 WO 2019241751 A1 WO2019241751 A1 WO 2019241751A1 US 2019037380 W US2019037380 W US 2019037380W WO 2019241751 A1 WO2019241751 A1 WO 2019241751A1
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Prior art keywords
alkyl
compound
solvate
pharmaceutically acceptable
acceptable salt
Prior art date
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PCT/US2019/037380
Other languages
French (fr)
Inventor
Nicholas D. Smith
Andrew R. Hudson
Mi Chen
Johnny Y. Nagasawa
Original Assignee
Metacrine, Inc.
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Publication date
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Publication of WO2019241751A1 publication Critical patent/WO2019241751A1/en

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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Definitions

  • SSAO semicarbazide-sensitive amine oxidase
  • SSAO Semicarbazide-sensitive amine oxidase
  • AOC3 amine oxidase, copper containing 3
  • VAP-l vascular adhesion protein 1
  • SSAO is an enzyme that exists both as a membrane-bound and a soluble isoform. It is highly expressed in the lung, aorta, liver and ileum. SSAO has been implicated in the pathogenesis of liver diseases (Weston, C.J. et ah, J Neural. Transm. 2011, 118, 1055-1064).
  • SSAO inhibition is a treatment modality for liver diseases or conditions such as fatty liver disease.
  • SSAO inhibitors and uses thereof.
  • described herein is a compound that has the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, a saturated monocyclic C 2-7 heterocycloalkyl, saturated bridged bicyclic C 2- 9heterocycloalkyl, or saturated spirocyclic C 2- 9heterocycloalkyl, wherein C 2- 6 alkenyl, C 2-6 alkynyl, saturated monocyclic C 2-7 heterocycloalkyl, saturated bridged bicyclic C 2- 9heterocycloalkyl, or saturated spirocyclic C 2-9 heterocycloalkyl are optionally
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , - OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , - N(R U )S(0) 2 R 12 , -C(0)
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3- 6cycloalkyl, C 2- 9heterocycloalkyl, C 6-l0 aryl, Ci.gheteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, -CH 2 -C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 .
  • 6cycloalkyl, -CH 2 -C3-6cycloalkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 . ioaryl, -CH 2 -C 6 -ioaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, and Ci.gheteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, and Ci.gheteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6-i oaryl, and Ci_ 9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2- 9heterocycloalkyl, C 6-i oaryl, and Ci.gheteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2- 9heterocycloalkyl, C 6-i oaryl, and Ci. gheteroaryl are optionally substituted with one, two, or three R 14j ;
  • R is selected from H and Ci -6 alkyl; or R and R together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three R 14k ;
  • R 24 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- gheterocycloalkyl, C 6-i oaryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14n ;
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein Y is -R 1 .
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein Y is -I ⁇ -R 1 .
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein Y is -L 2 -R ⁇
  • a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein Y is -I ⁇ -L ⁇ R 1 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9
  • R 1 is a saturated monocyclic C 2- 7 heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, azetidinyl, and tetrahydropyranyl, wherein pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, azetidinyl, and tetrahydropyranyl are optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 1 is piperidinyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, - CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -R 14a , - OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • q is 0, 1, or 2.
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -, and q is 0, 1, or 2.
  • w 1 , w 2 , w 3 , and w 4 are each independently selected from 1 and 2.
  • w 1 , w 2 , w 3 , and w 4 are each independently selected from 1 and 2.
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 - l oaryl, Ci.gheteroaryl, -R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 - l oaryl, Ci.gheteroaryl, -R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -
  • each R la is independently selected from oxo, Ci -6 alkyl, Ci.gheteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.
  • R 14a gheteroaryl, R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), - OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , - C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , -S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 .
  • Rib is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- gheterocycloalkyl, C 6-i oaryl, Ci.gheteroaryl, R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • R lb is independently selected from H, Ci -6 alkyl, C3 -6 cycloalkyl, and R 14a .
  • each R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C2-9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci.
  • gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)OR 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 , -N(R 18 )S(0) 2 R 19 , -C(0)R 19 , - S(0) 2 R 19 , -S(0) 2 N(R 16 )(R 17 ), and -OC(0)
  • each R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, - CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 - C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • each R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g .
  • each R 9 is independently selected from H and unsubstituted Ci -6 alkyl.
  • each R 12 is independently selected from Ci -6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci. 9 heteroaryl, wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • each R 12 is independently selected from Ci -6 alkyl and Ci -9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • each R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 .
  • each R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from - OH, -NH 2 , and -N(H)CH 3 .
  • Y is -R 2 .
  • R 2 is -C(0)0R 4 , -0C(0)N(R 4 )(R 5 ), - N(R 6 )C(0)N(R 4 )(R 5 ), -N(R 6 )C(0)0R 7 , -N(R 6 )S(0) 2 R 7 , or -CH 2 C(0)N(R 24 )(R 25 ).
  • R 4 is selected from H, Ci -6 alkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.
  • gheteroaryl are optionally substituted with one, two, or three R 14c .
  • R 4 is selected from H, Ci -6 alkyl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 5 is H.
  • R 7 is selected from Ci -6 alkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 6 -i 0 aryl, and Ci.
  • gheteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is selected from Ci -6 alkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 6 -i 0 aryl, and Ci.
  • 9heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 24 is selected from H, Ci -6 alkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.
  • 9heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 25 is H.
  • each R 3 is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 3 is
  • ioaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14b .
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2- 9heterocycloalkyl, Ci -9 heteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , -S(0) 2 N(R 9 )(R 10 ), wherein C ⁇ alkyl, C 2-9 heterocycloalkyl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14b .
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), wherein Ci -6 alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1.
  • n is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
  • n is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
  • X is -CH 2 -.
  • R 20 is H.
  • Z is F.
  • Z is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Cl.
  • Z is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is H.
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
  • the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, or oral administration.
  • the pharmaceutical composition is formulated for administration to a mammal by oral administration.
  • the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
  • described herein is a method of treating a disease or condition in a mammal that would benefit from SSAO inhibition comprising administering a compound as described herein, or pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof.
  • the disease or condition is a liver condition.
  • the compound is administered to the mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
  • described herein is a method of treating or preventing any one of the diseases or conditions described herein comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to a mammal in need thereof.
  • a method for the treatment or prevention of a liver condition in a mammal comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof.
  • the liver condition is amenable to treatment with an SSAO inhibitor.
  • the method further comprises administering a second therapeutic agent to the mammal in addition to the compound described herein, or a pharmaceutically acceptable salt, or solvate thereof.
  • a method of treating or preventing a liver disease or condition in a mammal comprising administering to the mammal a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof.
  • the liver disease or condition is nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD).
  • the non-alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH).
  • the non alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH) and is accompanied by liver fibrosis. In some embodiments, the non-alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH) without liver fibrosis.
  • NASH nonalcoholic steatohepatitis
  • the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day.
  • the compound is administered on a continuous dosing schedule.
  • the compound is
  • any of the aforementioned aspects involving the treatment of a disease or condition are further embodiments comprising administering at least one additional agent in addition to the administration of a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III) described herein, or a pharmaceutically acceptable salt thereof.
  • each agent is administered in any order, including simultaneously.
  • the mammal or subject is a human.
  • compounds provided herein are administered to a human.
  • compounds provided herein are orally administered.
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2- 6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl are optionally substituted with one, two, three, four, or five R la ;
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0
  • R 4 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c ;
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - !oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C2 -6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C2 -6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6.l0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3.6 cycloalkyl, C 2 -9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3.6 cycloalkyl, C 2 -9heterocycloalkyl, C 6.l0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3.6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3.6 cycloalkyl, C 2 -9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-g heterocycloalkyl, -CH2-C 2- 9heterocycloalkyl, C 6 .
  • loaryl, -CH 2 -C 6 -ioaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycl
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R 14j ;
  • R 23 is selected from H and Ci -6 alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14k ;
  • R 24 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14n ;
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2- 6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl are optionally substituted with one, two, three, four, or five R la ;
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0C(0)R
  • R 4 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c ;
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - ioaryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, - OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), - 0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)
  • 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2 - gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci.gheteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci. gheteroaryl are optionally substituted with one, two, or three R 14j ;
  • R is selected from H and Ci -6 alkyl; or R and R together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14k ;
  • R 24 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14n ; n is 0, 1, 2, 3, or 4; and
  • p 0 or 1.
  • SSAO Semicarbazide-sensitive amine oxidase
  • AOC3 amine oxidase, copper containing 3
  • VAP-l vascular adhesion protein 1
  • AOC3 amine oxidase, copper containing 3
  • VAP-l vascular adhesion protein 1
  • AOC3 has two closely related genes in the human genome.
  • AOC1 which corresponds to a diamine oxidase (DAO) found in gut, lung and kidney (Chassande, O. et al., J. Biol. Chem., 1994, 269: 14484-14489) and AOC2, a SSAO with expression in the eye (Imamura, Y. et al., Genomics, 1997, 40: 277-283).
  • AOC4 is a sequence that does not lead to a functional gene product in humans (Schwelberger, H. G. J. Neural Transm.,
  • SSAO has at least two physiological functions.
  • SSAO functions as an amine oxidase in which primary amines may be oxidized to aldehydes, leading to the release of ammonia and hydrogen peroxide upon regeneration of the cofactor 2,4,5-trihydroxy-phenyl-alanyl- quinone (TPQ).
  • Endogenous substrates include methylamine, dopamine and aminoacetone.
  • Aldehyde products generated under high AOC3 levels can be highly reactive, leading to glycation end products which may be regarded as drivers of diabetes associated inflammatory mechanisms (Mathys, K. C. et al., Biochem. Biophys. Res. Commun., 2002, 297: 863-869).
  • hydrogen peroxide produced by SSAO can directly lead to direct cellular damage or be sensed by the tissue as a messenger of inflammation and so lead to further propagation of inflammatory processes.
  • SSAO has cell adhesion activity, with SSAO having been shown to be important for leukocyte rolling, adhesion and transmigration in response to inflammatory stimuli (Salmi et al, Antoxidants and Redox Signaling, 2017). Both activities are associated with inflammatory processes.
  • SSAO was also shown to play a role in extravasation of inflammatory cells from the circulation to sites of inflammation (Salmi M.; Trends Immunol. 2001, 22, 21 1-216).
  • SSAO antibodies have been shown to attenuate inflammatory processes by blocking the adhesion site of the SSAO protein.
  • inhibitors of the amine oxidase activity of SSAO have been found to interfere with leukocyte rolling, adhesion and extravasation and, in a similar manner to SSAO antibodies, exhibit anti-inflammatory properties.
  • SSAO has been implicated in the pathogenesis of liver diseases such as fatty liver disease (Weston, C.J. et al., J Neural. Transm. 2011, 118, 1055-1064).
  • serum SSAO is elevated in patients with fatty liver disease and correlates with histological markers of liver injury.
  • SSAO has been shown to contribute to liver fibrosis in preclinical models induced by chemical injury and diet induction.
  • SSAO knock-out animals, or SSAO inhibition using an antibody are protective in both of these models (Weston et al; J. Clin. Invest., 2015, 125, 2, 501-520).
  • Non-alcoholic fatty liver disease is associated with excessive fat in the liver (steatosis) and in some cases progresses to NASH, which is defined by the histologic hallmarks of inflammation, cell death, and fibrosis.
  • primary NASH is associated with insulin resistance
  • secondary NASH is caused by medical or surgical conditions, or drugs such as, but not limited to, tamoxifen.
  • NASH progresses to advanced fibrosis, hepatocellular carcinoma, or end-stage liver disease requiring liver transplantation.
  • NASH develops as a result of triglyceride (TGs) imbalance.
  • TGs triglyceride
  • dysfunctional adipocytes secrete pro-inflammatory molecules such as cytokines and chemokines leading to insulin resistance and a failure of lipolysis suppression in the adipocytes.
  • this failure of lipolysis suppression leads to a release of free fatty acids (FFAs) into the circulation and uptake within the liver.
  • FFAs free fatty acids
  • over accumulation of FFAs in the form of triglycerides (TGs) in lipid droplets leads to oxidative stress, mitochondrial dysfunction, and upregulation of pro-inflammatory molecules.
  • an SSAO inhibitor disclosed herein is used in the treatment of non alcoholic steatohepatitis (NASH).
  • the SSAO inhibitor reduces NASH the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more.
  • NASH is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%.
  • the level of NASH is relative to the level of NASH in a subject not treated with the SSAO inhibitor.
  • an SSAO inhibitor disclosed herein is used in the treatment of NAFLD.
  • the SSAO inhibitor reduces NAFLD in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more.
  • NAFLD is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%.
  • the level of NAFLD is relative to the level of NAFLD in a subject not treated with the SSAO inhibitor.
  • Hepatocyte ballooning a feature denoting cellular injury, is a feature of NASH.
  • Ballooning is a feature that denotes progressive NAFL (types 3 and 4). The term applies to enlarged, swollen-appearing hepatocytes; the affected cells are often intermixed in areas of steatosis and, in classic steatohepatitis, in the perivenular regions. Hepatocellular ballooning is most commonly noted in regions of H & E-detectable perisinusoidal fibrosis. Ballooned hepatocytes are most easily noted when they contain MH (either typical or poorly formed). Hepatocyte ballooning is a structural manifestation of microtubular disruption and severe cell injury.
  • an SSAO inhibitor disclosed herein reduces liver ballooning in a subject.
  • the SSAO inhibitor reduces liver ballooning in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more.
  • liver ballooning is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%.
  • the liver ballooning is relative to the level of liver ballooning in a subject not treated with the SSAO inhibitor.
  • Compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates thereof, are SSAO inhibitors.
  • SSAO inhibitors and uses thereof. In some aspects, described herein are SSAO inhibitors and uses thereof. In some aspects, described herein are SSAO inhibitors and uses thereof. In some aspects, described herein are SSAO inhibitors and uses thereof.
  • Z is H, F, or Cl
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, a saturated monocyclic C 2.7 heterocycloalkyl, saturated bridged bicyclic C 2-9 heterocycloalkyl, or saturated spirocyclic C 2-9 heterocycloalkyl, wherein C 2- 6 alkenyl, C 2-6 alkynyl, saturated monocyclic C 2- 7heterocycloalkyl, saturated bridged bicyclic C 2-9 heterocycloalkyl, or saturated spirocyclic C 2-9 heterocycloalkyl are optionally
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-l0 aryl, Ci -9 heteroaryl, -R 14a , - OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , - N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cydoalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , - S
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0
  • R 4 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ydoalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c ;
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - ioaryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 .
  • l 0 aryl, -CH 2 -C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R 14j ;
  • R 23 is selected from H and Ci -6 alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14k ;
  • R 24 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14n ;
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • substituents are selected from among a subset of the listed alternatives.
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -.
  • X is -0-.
  • X is -S-.
  • X is - S(0) 2 -.
  • X is -N(R 13 )-.
  • X is -N(H)-.
  • X is -C(R 13 ) 2 -.
  • X is -CH 2 -.
  • Z is H, F, or Cl. In some embodiments, Z is F. In some embodiments,
  • Z is Cl. In some embodiments, Z is H.
  • p is 1. In some embodiments, p is 0.
  • Y is -R 1 . In some embodiments, Y is -I ⁇ -R 1 . In some embodiments,
  • Y is -L 2 -R ⁇ In some embodiments, Y is I ⁇ -L ⁇ R 1 . In some embodiments, Y is -L 2 - I ⁇ -R 1 . In some embodiments, L 1 is -0-. In some embodiments, L 1 is -CH 2 -. In some embodiments, L 2 is -CH 2 -.
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, or four R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, Ci.gheteroaryl, - R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)OR 12 , -N(R u )C(0)OR 12 , -N(R u )
  • R 1 is a saturated monocyclic C 2- 7 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0)
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocycl
  • monocyclic C2-7heterocycloalkyl optionally substituted with one R la and R la is selected from Ci. ealkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and - S(0) 2 R 12 .
  • R 1 is an unsubstituted saturated monocyclic C 2- 7heterocycloalkyl.
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is -S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci -9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 .
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is -C(0)OR 9 . In some embodiments, R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is -C(0)N(R 9 )(R 10 ). In some embodiments,
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is - C(0)C(0)N(R 9 )(R 10 ).
  • R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g .
  • R 9 is independently selected from H and unsubstituted Ci -6 alkyl.
  • R 10 is H. In some embodiment
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl substituted with one R la and R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2-9 heterocycloalkyl, - CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 - C 2-9 heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH2-C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci.
  • gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -N(R 16 )(R 17 ), - C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)R 19 , -S(0) 2 R 19 , and -S(0) 2 N(R 16 )(R 17 ).
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo,
  • Ci -6 alkyl and -C(0)R 12 .
  • -C(0)R 12 In some embodiments,
  • R 1 is a saturated monocyclic C2-7heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, hexahydropyrimidinyl, oxepanyl, thiepanyl, azapanyl, and azocanyl, wherein pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,
  • R 1 is a saturated monocyclic C2-7heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, azetidinyl, and tetrahydropyranyl.
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl wherein the saturated monocyclic C 2- 7heterocycloalkyl is piperidine.
  • R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl optionally substituted with one, two, three, or four R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl, - R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 ,
  • R 1 is a saturated bridged bicyclic C 2- 9 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, C 1-9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )C(0)
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , - C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl optionally substituted with one R la and R la is selected from
  • R 1 is an unsubstituted saturated bridged bicyclic C 2- 9 heterocycloalkyl.
  • R 1 is a saturated bridged bicyclic C2-9heterocycloalkyl substituted with one R la and R la is selected from Ci -6 alkyl, Ci.gheteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)R 12 .
  • R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl substituted with one R la and R la is - S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci.gheteroaryl, wherein Ci -6 alkyl and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 .
  • R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl substituted with one R la and R la is -C(0)OR 9 . In some embodiments, R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl substituted with one R la and R la is -C(0)N(R 9 )(R 10 ). In some embodiments, R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl substituted with one R la and R la is -C(0)C(0)N(R 9 )(R 10 ). In some embodiments, R 9 is independently selected from H and Ci. 6 alkyl optionally substituted with one, two, or three R 14g . In some embodiments, R 9 is
  • R 10 is H.
  • R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl substituted with one R la and R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 1 is a saturated bridged bicyclic C 2- 9heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated bridged bicyclic C 2-9 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated bridged bicyclic C 2- 9 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl optionally substituted with one, two, three, or four R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, Ce-ioaryl, Ci -9 heteroaryl, - R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )C
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)OR 12 , -N(R u )C(0)OR 12 , -N(R u )
  • R 1 is a saturated spirocyclic C 2- 9 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci.gheteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated spirocyclic C2-9heterocycloalkyl optionally substituted with one R la and R la is selected from Ci -6 alkyl, Ci.
  • R 1 is an unsubstituted saturated spirocyclic C 2-9 heterocycloalkyl.
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)R 12 .
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci -9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 .
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)OR 9 . In some embodiments, R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)N(R 9 )(R 10 ). In some embodiments, R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)C(0)N(R 9 )(R 10 ). In some embodiments, R 9 is
  • R 9 is independently selected from H and unsubstituted Ci- 6 alkyl.
  • R 10 is H.
  • R 1 is a saturated spirocyclic C 2-9 heterocycloalkyl substituted with one R la and R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci.
  • Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2-g heterocycloalkyl, C 6.l0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 1 is a saturated spirocyclic C 2-g heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci.gheteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated spirocyclic C 2-g heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated spirocyclic C 2-g heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • Y is -R 2 . In some embodiments, Y is -L 2 -R 2 . In some embodiments, L 2 is -CH 2 -. In some embodiments, R 2 is -C(0)0R 4 , -0C(0)N(R 4 )(R 5 ), -
  • R 2 is -C(0)0R 4 , -0C(0)N(R 4 )(R 5 ), - N(R 6 )C(0)N(R 4 )(R 5 ), -N(R 6 )C(0)0R 7 , -N(R 6 )S(0) 2 R 7 , -C(0)N(R 22 )(R 23 ), or - CH 2 C(0)N(R 24 )(R 25 ).
  • R 2 is -C(0)0R 4 .
  • R 2 is - 0C(0)N(R 4 )(R 5 ).
  • R 2 is -N(R 6 )C(0)N(R 4 )(R 5 ).
  • R 4 is selected from H, Ci -6 alkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 4 is selected from H, Ci -6 alkyl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 5 is H.
  • R 2 is -N(R 6 )C(0)0R 7 .
  • R 2 is -N(R 6 )S(0) 2 R 7 .
  • R 7 is selected from Ci -6 alkyl, C 6- ioaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is selected from Ci -6 alkyl, C 6 -i 0 aryl, and Ci. 9 heteroaryl, wherein Ci -6 alkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is Ci -6 alkyl optionally substituted with one, two, or three R 14e .
  • R 6 is H.
  • R 2 is -C(0)N(R 22 )(R 23 ).
  • R 2 is -CH 2 C(0)N(R 24 )(R 25 ).
  • R 24 is selected from H, Ci. 6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 24 is selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 141 .
  • R 25 is H.
  • R 20 is H. In some embodiments, R 20 is Ci -6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3-
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein C ⁇ alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci- 6 alkyl.
  • the compound has the structure of Formula (la), (la’), (Iaa), (Iaa’), (lab), (lab’), (lac), (lac’), (lad), or (lad’), or a pharmaceutically acceptable salt or solvate thereof:
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -;
  • Z is H, F, or Cl
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -;
  • R la is selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , - C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 , -N(
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • n 0, 1, 2, 3, or 4;
  • p is 0 or 1 ;
  • q 0, 1, or 2;
  • w 1 , w 2 , w 3 , and w 4 are each independently selected from 1 and 2.
  • X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0) 2 -. In some embodiments, X is -N(R 13 )-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R 13 ) 2 -. In some embodiments, X is -CH 2 -.
  • Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H.
  • L 3 is -CH 2 CH 2 -. In some embodiments, L 3 is -CH 2 CH 2 CH 2 -. In some embodiments, L 3 is -CH 2 OCH 2 -. In some embodiments, L 3 is -CH 2 N(H)CH 2 -. In some embodiments, L 3 is -CH 2 N(CH 3 )CH 2 -.
  • q is 0. In some embodiments, q is 1. In some embodiments, q is 2.
  • w 1 , w 2 , w 3 , and w 4 are each 1. In some embodiments, w 1 is 2, and w 2 , w 3 , and w 4 are each 1. In some embodiments, w 1 and w 3 are each 2, and w 2 and w 4 are each 1. In some embodiments, w 2 is 2, and w 1 , w 3 , and w 4 are each 1. In some embodiments, w 1 and w 2 are each 2, and w 3 and w 4 are each 1. [0096] In some embodiments, p is 1. In some embodiments, p is 0.
  • R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 - l oaryl, Ci.gheteroaryl, -R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 ,
  • R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R
  • R la is selected from Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), - C(0)R 12 , and -S(0) 2 R 12 .
  • R la is -C(0)R 12 .
  • R la is - S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci.gheteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 . In some embodiments, R la is -C(0)OR 9 . In some embodiments, R la is - C(0)N(R 9 )(R 10 ). In some embodiments, R la is -C(0)C(0)N(R 9 )(R 10 ).
  • R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g . In some embodiments, R 9 is independently selected from H and unsubstituted Ci- 6 alkyl. In some embodiments, R 10 is H. In some embodiments, R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.
  • gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)OR 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 , -N(R 18 )S(0) 2 R 19 , -C(0)R 19 , - S(0) 2 R 19 , -S(0) 2 N(R 16 )(R 17 ), and -OC(0)
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -
  • R 20 is H. In some embodiments, R 20 is Ci- 6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 , wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein C ⁇ alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci -6 alkyl.
  • the compound has the structure of Formula (Iae) or (Iae’), or a pharmaceutically acceptable salt or solvate thereof:
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -;
  • R 1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C2 -6 alkenyl, C2 -6 alkynyl, C 3- 6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C2 -6 alkenyl, C2- 6alkynyl, C 3-6C ycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C2 -6 alkenyl, C2- 6alkynyl, C 3-6C ycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C2 -6 alkenyl, C2 -6 alkynyl, C 3-6C ycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci -6 alkyl, C2 -6 alkenyl, C2 -6 alkynyl, C 3-6C ycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , - C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0) 2 -. In some embodiments, X is -N(R 13 )-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R 13 ) 2 -. In some embodiments, X is -CH 2 -.
  • Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H.
  • p is 1. In some embodiments, p is 0.
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo and Ci- 6 alkyl.
  • R 20 is H. In some embodiments, R 20 is Ci- 6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3 .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein Ci -6 alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci -6 alkyl.
  • the compound has the structure of Formula (lb), (lb’), (Iba), (Iba’), (Ibb), (Ibb’), (Ibc), (Ibc’), (Ibd), or (Ibd’), or a pharmaceutically acceptable salt or solvate thereof:
  • L 3 is -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 N(H)CH 2 -, or -CH 2 N(CH 3 )CH 2 -;
  • R la is selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -
  • R 8 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • R 9 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • R 10 is selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three
  • R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • R 12 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 14a , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci.
  • 6cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -SR 15 , - N(R 16 )(R 17 ), -C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 , -N(R 18 )
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • q 0, 1, or 2;
  • w 1 , w 2 , w 3 , and w 4 are each independently selected from 1 and 2.
  • L 3 is -CH 2 CH 2 -. In some embodiments, L 3 is -CH 2 CH 2 CH 2 -. In some embodiments, L 3 is -CH 2 OCH 2 -. In some embodiments, L 3 is -CH 2 N(H)CH 2 -. In some embodiments, L 3 is -CH 2 N(CH 3 )CH 2 -.
  • q is 0. In some embodiments, q is 1. In some embodiments, q is 2.
  • w 1 , w 2 , w 3 , and w 4 are each 1.
  • w 1 is 2, and w 2 , w 3 , and w 4 are each 1.
  • w 1 and w 3 are each 2, and w 2 and w 4 are each 1.
  • w 2 is 2, and w 1 , w 3 , and w 4 are each 1.
  • w 1 and w 2 are each 2, and w 3 and w 4 are each 1.
  • R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - l oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 , -N(R U
  • R la is independently selected from halogen, oxo, Ci -6 alkyl, Ci -6 haloalkyl, C 2-9 heterocycloalkyl, Ci -9 heteroaryl, -R 14a , -OR 8 , - C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R la is independently selected from halogen, oxo, Ci -6 alkyl, Ci -6 haloalkyl, C 2-9 heterocycloalkyl, Ci -9 heteroaryl, -R 14a , -OR 8 , - C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R la is selected from Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R la is -C(0)R 12 .
  • R la is -S(0) 2 R 12 .
  • R 12 is independently selected from Ci.
  • R 12 is independently selected from Ci -6 alkyl and Ci. 9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from - OH, -NH 2 , and -N(H)CH 3 . In some embodiments, R la is -C(0)0R 9 . In some embodiments, R la is - C(0)N(R 9 )(R 10 ). In some embodiments, R la is -C(0)C(0)N(R 9 )(R 10 ).
  • R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g . In some embodiments, R 9 is independently selected from H and unsubstituted Ci- 6 alkyl. In some embodiments, R 10 is H. In some embodiments, R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.
  • gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 , -N(R 18 )S(0) 2 R 19 , -C(0)R 19 , - S(0) 2 R 19 , -S(0) 2 N(R 16 )(R 17 ), and -0
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, - CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , - C(0)N(R 16 )(R 17 ), -C(0)R 19 , -S(0) 2 R 19 , and -S(0) 2 N(R 16
  • the compound has the structure of Formula (Ibe) or (Ibe’), or a pharmaceutically acceptable salt or solvate thereof:
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci_ 9 heteroaryl, -R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2.6 alkenyl, C 2-6 alkynyl, C 3.6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 14a , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6-i0 aryl, Ci -9 heteroaryl, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , -C(0)N(R 16 )(R 17 ), - C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)0R 19 , - N(R 18 )C(0)R 19 , -N(R 18 )S(0) 2 R 19
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl; and each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl.
  • R 1 is a saturated monocyclic C 2- 7heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, three, four, or five R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo, Ci -6 alkyl, and -C(0)R 12 .
  • R 1 is a saturated monocyclic C 2-7 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is independently selected from oxo
  • Ci -6 alkyl In some embodiments,
  • the compound has the structure of Formula (Ic) or (Ic’), or a pharmaceutically acceptable salt or solvate thereof:
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -;
  • Z is H, F, or Cl
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl,
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0C(0)R
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , - C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0) 2 -. In some embodiments, X is -N(R 13 )-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R 13 ) 2 -. In some embodiments, X is -CH 2 -.
  • Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H. [00123] In some embodiments, p is 1. In some embodiments, p is 0.
  • each R lb is independently selected from H, halogen, -CN, Ci. 6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C2-9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 ,
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 - l oaryl, Ci -9 heteroaryl, R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • each R lb is independently selected from H, Ci -6 alkyl, C3 -6 cycloalkyl, and R 14a . In some embodiments, each R lb is independently selected from H, Ci. 6 alkyl, and C3-6cycloalkyl. In some embodiments, each R lb is independently selected from H and Ci- 6 alkyl. In some embodiments, each R lb is -CH 3 . In some embodiments, each R lb is
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9 heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 20 is H. In some embodiments, R 20 is Ci -6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3- 6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 , wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein Ci -6 alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci -6 alkyl.
  • the compound has the structure of Formula (Id) or (Id’), or a pharmaceutically acceptable salt or solvate thereof:
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6- i0 aryl, Ci -9 heteroaryl, R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , - S(0)R 12
  • R 8 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • R 9 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ; R 10 is selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three
  • R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • R 12 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 14a , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl.
  • each R lb is independently selected from H, halogen, -CN, Ci. 6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , -C
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6- l oaryl, Ci -9 heteroaryl, R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • each R lb is independently selected from H, Ci -6 alkyl, C3-6cycloalkyl, and R 14a . In some embodiments, each R lb is independently selected from H, Ci. 6 alkyl, and C3 -6 cycloalkyl. In some embodiments, each R lb is independently selected from H and Ci -6 alkyl. In some embodiments, each R lb is -CH 3 . In some embodiments, each R lb is
  • R 14a is independently selected from Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • the compound has the structure of Formula (Ie) or (Ie’), or a pharmaceutically acceptable salt or solvate thereof:
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -;
  • Z is H, F, or Cl
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl,
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0C(0)R
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6-i0 aryl, Ci -9 heteroaryl, -OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , - C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), -0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)N(R 16 )(R 17 ), - N(R 18 )C(0)0R 19 , -N(R 18 )C(0)R 19 ,
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0) 2 -. In some embodiments, X is -N(R 13 )-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R 13 ) 2 -. In some embodiments, X is -CH 2 -.
  • Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H.
  • p is 1. In some embodiments, p is 0.
  • each R lb is independently selected from H, halogen, -CN, Ci. 6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, C 6 - 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , n some embodiments, each R lb is independently selected from H, Ci -6 alkyl, . In some embodiments, each R lb is independently selected from H, Ci. 6 alkyl, and C3-6cycloalkyl. In some embodiments, each R lb is independently selected from H and Ci -6 alkyl. In some embodiments, each R lb is -CH 3 . In some embodiments, each R lb is
  • R 14a is independently selected from Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 20 is H.
  • R 20 is Ci -6 alkyl.
  • R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3- 6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 , wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein Ci -6 alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci- 6 alkyl.
  • the compound has the structure of Formula (If) or (If), or a pharmaceutically acceptable salt or solvate thereof:
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 - l oaryl, Ci.gheteroaryl, R 14a , -OR 8 , -SR 8 , - N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12
  • R 8 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • R 9 is selected from H, Ci -6 alkyl, C 2.6 alkenyl, C 2.6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14g ;
  • R 10 is selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three
  • R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • R 12 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 141 ; each R 14a , R 14f , R 14g , R 14h , and R 141 are each independently selected from halogen, -CN, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- gheterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl.
  • each R lb is independently selected from H, halogen, -CN, Ci. 6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, R 14a , -OR 8 , - SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), - N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R
  • each R lb is independently selected from H, halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - l oaryl, Ci -9 heteroaryl, R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • each R lb is independently selected from H, Ci -6 alkyl, C 3-6 cycloalkyl, and R 14a . In some embodiments, each R lb is independently selected from H, Ci. 6 alkyl, and C 3-6C ycloalkyl. In some embodiments, each R lb is independently selected from H and Ci- 6 alkyl. In some embodiments, each R lb is -CH 3 . In some embodiments, each R lb is
  • R 14a is independently selected from Ci -6 alkyl, C 2- gheterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C 6-l0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C2-9heterocycloalkyl, -CH 2 -C2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • SSAO inhibitors and uses thereof.
  • described herein is a compound that has the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
  • Z is H, F, or Cl
  • L 2 is Ci -6 alkyl
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, C 2- 9heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2- 6 alkynyl, C2-9heterocycloalkyl, or Ci.gheteroaryl are optionally substituted with one, two, three, four, or five R la ;
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, Ci.gheteroaryl, -R 14a , - OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), -N(R U )C(0)0R 12 , -N(R U )C(0)R 12 , - N(R U )S(0) 2 R 12 , -C(0)R 12 ,
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0
  • R 4 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c ;
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - l 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, - OR 15 , -SR 15 , -N(R 16 )(R 17 ), -C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)C(0)N(R 16 )(R 17 ), - 0C(0)N(R 16 )(R 17 ), -N(R 18 )C(0)
  • 6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6C ycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R 14j ; R 23 is selected from H and Ci -6 alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C 2- 9heterocycloalkyl ring optionally substituted with one, two, or three
  • R 24 is selected from H, Ci -6 alkyl, C2 -6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14n ;
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • substituents are selected from among a subset of the listed alternatives.
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -.
  • X is -0-.
  • X is -S-.
  • X is - S(0) 2 -.
  • X is -N(R 13 )-.
  • X is -N(H)-.
  • X is -C(R 13 ) 2 -.
  • X is -CH 2 -.
  • Z is H, F, or Cl. In some embodiments, Z is F. In some embodiments,
  • Z is Cl. In some embodiments, Z is H.
  • p is 1. In some embodiments, p is 0.
  • Y is -R 1 . In some embodiments, Y is -I ⁇ -R 1 . In some embodiments,
  • Y is -L 2 -R ⁇ In some embodiments, Y is I ⁇ -L ⁇ R 1 . In some embodiments, Y is -L 2 - I ⁇ -R 1 . In some embodiments, L 2 is -CH 2 -.
  • R 1 is C 2-6 alkynyl, C 2- 9 heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl are optionally substituted with one, two, three, or four R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, C 1-9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(
  • R 1 is C 2- 6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkynyl, C 2-9 heterocycloalkyl, or Ci. gheteroaryl are optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 .
  • R 1 is C 2-9 heterocycloalkyl optionally substituted with one, two, or three R la and each R la is
  • R 1 is C 2-9 heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci. ealkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and - S(0) 2 R 12 .
  • R 1 is C 2-9 heterocycloalkyl optionally substituted with one R la and R la is selected from Ci -6 alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is unsubstituted C 2- gheterocycloalkyl.
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), - C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)R 12 .
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6C ycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci -9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 . In some embodiments, R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)0R 9 . In some embodiments, R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is - C(0)N(R 9 )(R 10 ).
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)C(0)N(R 9 )(R 10 ).
  • R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g .
  • R 9 is independently selected from H and unsubstituted Ci -6 alkyl.
  • R 10 is H.
  • R 1 is C 2- 9heterocycloalkyl substituted with one R la and R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C2-9heterocycloalkyl, -CH 2 -C 2- gheterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, wherein Ci -6 alkyl, C 2- 9heterocycloalkyl, -CH 2 -C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.
  • gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -N(R 16 )(R 17 ), - C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)R 19 , -S(0) 2 R 19 , and -S(0) 2 N(R 16 )(R 17 ).
  • R 1 is C 2- 9heterocycloalkyl wherein C 2- 9heterocycloalkyl is piperidine.
  • R 1 is Ci -9 heteroaryl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3- 6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)OR 12 , -N(R u )C(0)OR 12 , -
  • R 1 is Ci -9 heteroaryl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • Y is -R 2 . In some embodiments, Y is -L 2 -R 2 . In some embodiments, Y is -L 2 -R 2 . In some
  • L 2 is -CH 2 -.
  • R 2 is -C(0)OR 4 , -0C(0)N(R 4 )(R 5 ), - N(R 6 )C(0)N(R 4 )(R 5 ), -N(R 6 )C(0)0R 7 , -N(R 6 )S(0) 2 R 7 , -C(0)N(R 22 )(R 23 ), or - CH 2 C(0)N(R 24 )(R 25 ).
  • R 2 is -C(0)OR 4 .
  • R 2 is - 0C(0)N(R 4 )(R 5 ).
  • R 2 is -N(R 6 )C(0)N(R 4 )(R 5 ).
  • R 4 is selected from H, Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 4 is selected from H, Ci -6 alkyl, and Ci.gheteroaryl, wherein Ci -6 alkyl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 5 is H.
  • R 2 is -N(R 6 )C(0)0R 7 .
  • R 2 is -N(R 6 )S(0) 2 R 7 .
  • R 7 is selected from Ci -6 alkyl, C 6- l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is selected from Ci -6 alkyl, C 6 -i 0 aryl, and Ci.
  • Ci -6 alkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is Ci -6 alkyl optionally substituted with one, two, or three R 14e .
  • R 6 is H.
  • R 2 is -C(0)N(R 22 )(R 23 ).
  • R 2 is -CH 2 C(0)N(R 24 )(R 25 ).
  • R 24 is selected from H, Ci.
  • R 24 is selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 141 .
  • R 25 is H.
  • R 20 is H. In some embodiments, R 20 is Ci- 6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 , wherein Ci -6 alkyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein C ⁇ alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci -6 alkyl.
  • R 1 is C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2- 6 alkynyl, C 2-9 heterocycloalkyl, or Ci -9 heteroaryl are optionally substituted with one, two, three, four, or five R la ;
  • each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 2-
  • each R 3 is independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)0R 12 , -N(R u )C(0)R 12 , -N(R u )S(0) 2 R 12 , -C(0)R 12 , -S(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -0C(0)R
  • R 4 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-i oaryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c ;
  • R 5 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R 4 and R 5 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14d ;
  • R 6 is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl
  • R 7 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 - ioaryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e ;
  • each R 8 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14f ;
  • each R 9 is independently selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14g ;
  • each R 10 is independently selected from H and Ci -6 alkyl; or R 9 and R 10 , together with the
  • each R 11 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 12 is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - gheterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • each R 13 is independently selected from H, Ci -6 alkyl, and Ci -6 haloalkyl;
  • each R 14a , R 14b , R 14c , R 14d , R 14e , R 14f , R 14g , R 14h , R 14i , R 14j , R 14k , R 141 , R 14m , and R 14n are each independently selected from halogen, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, -CH 2 -C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 .
  • l 0 aryl, -CH 2 -C 6-i oaryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci.
  • each R 15 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 16 is independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • each R 17 is independently selected from H and Ci -6 alkyl; or R 16 and R 17 , together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring;
  • each R 18 is independently selected from H and Ci -6 alkyl
  • each R 19 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl;
  • R 20 is selected from H and Ci -6 alkyl
  • R 21 is selected from H and Ci -6 alkyl
  • R 22 is selected from Ci -6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein C 2-6 alkenyl, C 2-6 alkynyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R 14j ;
  • R 23 is selected from H and Ci -6 alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14k ;
  • R 24 is selected from H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 ;
  • R is selected from H, Ci -6 alkyl, and Ci -6 haloalkyl; or R and R together with the nitrogen to which they are attached, form a C 2-9 heterocycloalkyl ring optionally substituted with one, two, or three R 14m ;
  • R 26 is selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14n ;
  • n 0, 1, 2, 3, or 4;
  • p 0 or 1.
  • X is -0-, -S-, -S(0) 2 -, -N(R 13 )-, or -C(R 13 ) 2 -. In some embodiments, X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0) 2 -. In some
  • X is -N(R 13 )-. In some embodiments, X is -N(H)-. In some embodiments, X is - C(R 13 ) 2 -. In some embodiments, X is -CH 2 -.
  • Z is Cl. In some embodiments, Z is H.
  • p is 1. In some embodiments, p is 0.
  • Y is -R 1 . In some embodiments, Y is -I ⁇ -R 1 . In some embodiments,
  • Y is -L 2 -R ⁇ In some embodiments, Y is I ⁇ -L ⁇ R 1 . In some embodiments, Y is -L 2 - I ⁇ -R 1 . In some embodiments, L 2 is -CH 2 -.
  • R 1 is C 2-6 alkynyl, C 2- gheterocycloalkyl, or Ci.gheteroaryl, wherein C 2-6 alkynyl, C 2- 9heterocycloalkyl, or Ci.gheteroaryl are optionally substituted with one, two, three, or four R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6-i oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R
  • R 1 is C 2- 6 alkynyl, C 2- 9heterocycloalkyl, or Ci -9 heteroaryl, wherein C 2-6 alkynyl, C 2- 9heterocycloalkyl, or Ci. 9 heteroaryl are optionally substituted with one, two, or three R la and each R la is independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6- l oaryl, Ci -9 heteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)
  • R 1 is C 2- 9heterocycloalkyl optionally substituted with one or two R la and each R la is independently selected from oxo, Ci. ealkyl, Ci -9 heteroaryl, -R 14a , -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and - S(0) 2 R 12 .
  • R 1 is C 2- 9heterocycloalkyl optionally substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), - C(0)C(0)N(R 9 )(R 10 ), -C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is unsubstituted C 2- gheterocycloalkyl.
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is selected from C ⁇ alkyl, Ci -9 heteroaryl, -R 14a , -C(0)0R 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), - C(0)R 12 , and -S(0) 2 R 12 .
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)R 12 .
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -S(0) 2 R 12 .
  • R 12 is independently selected from Ci -6 alkyl, C 3- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -i 0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl and Ci -9 heteroaryl, wherein Ci -6 alkyl and Ci -9 heteroaryl are optionally substituted with one, two, or three R 141 .
  • R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 . In some embodiments, R 12 is independently selected from Ci -6 alkyl optionally substituted with one, two, or three R 141 and each R 141 is independently selected from -OH, -NH 2 , and -N(H)CH 3 . In some embodiments, R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)0R 9 . In some embodiments, R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is - C(0)N(R 9 )(R 10 ).
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -C(0)C(0)N(R 9 )(R 10 ).
  • R 9 is independently selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 14g .
  • R 9 is independently selected from H and unsubstituted Ci -6 alkyl.
  • R 10 is H. In some embodiments
  • R 1 is C 2-9 heterocycloalkyl substituted with one R la and R la is -R 14a .
  • R 14a is independently selected from Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2- 9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci.
  • R 14a is independently selected from Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, wherein Ci -6 alkyl, C 2-9 heterocycloalkyl, -CH 2 -C 2-9 heterocycloalkyl, C 6 -i 0 aryl, Ci.
  • heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci -6 alkyl, Ci -6 haloalkyl, Ci -6 alkoxy, Ci -6 haloalkoxy, -OR 15 , -N(R 16 )(R 17 ), - C(0)0R 16 , -C(0)N(R 16 )(R 17 ), -C(0)R 19 , -S(0) 2 R 19 , and -S(0) 2 N(R 16 )(R 17 ).
  • R 1 is C 2- 9heterocycloalkyl wherein C 2- 9heterocycloalkyl is piperidine.
  • R 1 is Ci_ 9 heteroaryl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C 3- 6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , -OR 8 , -SR 8 , -N(R 9 )(R 10 ), - C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -C(0)C(0)N(R 9 )(R 10 ), -OC(0)N(R 9 )(R 10 ), -N(R U )C(0)N(R 9 )(R 10 ), - N(R u )C(0)OR 12 , -N(R u )C(0)OR 12 , -
  • R 1 is Ci -9 heteroaryl optionally substituted with one, two, or three R la and each R la is independently selected from halogen, -CN, Ci -6 alkyl, Ci -6 haloalkyl, C3 -6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci.gheteroaryl, -R 14a , -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , -C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ).
  • Y is -R 2 . In some embodiments, Y is -L 2 -R 2 . In some embodiments, Y is -L 2 -R 2 . In some
  • L 2 is -CH 2 -.
  • R 2 is -C(0)OR 4 , -0C(0)N(R 4 )(R 5 ), - N(R 6 )C(0)N(R 4 )(R 5 ), -N(R 6 )C(0)0R 7 , -N(R 6 )S(0) 2 R 7 , -C(0)N(R 22 )(R 23 ), or - CH 2 C(0)N(R 24 )(R 25 ).
  • R 2 is -C(0)OR 4 .
  • R 2 is - 0C(0)N(R 4 )(R 5 ).
  • R 2 is -N(R 6 )C(0)N(R 4 )(R 5 ).
  • R 4 is selected from H, Ci -6 alkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6.l0 aryl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, C 3-6C ycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14c .
  • R 4 is selected from H, Ci -6 alkyl, and Ci -9 heteroaryl, wherein Ci -6 alkyl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14c .
  • R 5 is H.
  • R 2 is -N(R 6 )C(0)0R 7 .
  • R 2 is -N(R 6 )S(0) 2 R 7 .
  • R 7 is selected from Ci -6 alkyl, C 6 - ! oaryl, and Ci.gheteroaryl, wherein Ci -6 alkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is selected from Ci -6 alkyl, C 6.l0 aryl, and Ci.
  • Ci -6 alkyl, C 6.l0 aryl, and Ci -9 heteroaryl are optionally substituted with one, two, or three R 14e .
  • R 7 is Ci -6 alkyl optionally substituted with one, two, or three R 14e .
  • R 6 is H.
  • R 2 is -C(0)N(R 22 )(R 23 ).
  • R 2 is -CH 2 C(0)N(R 24 )(R 25 ).
  • R 24 is selected from H, Ci.
  • R 24 is selected from H and Ci -6 alkyl optionally substituted with one, two, or three R 141 .
  • R 25 is H.
  • R 20 is H. In some embodiments, R 20 is Ci- 6 alkyl. In some embodiments, R 20 is -CH 3 .
  • n 0.
  • n is 1. In some embodiments, n is 2.
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, C 3- 6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, Ci -9 heteroaryl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -N(R U )C(0)OR 12 , -N(R U )C(0)R 12 , -N(R U )S(0) 2 R 12 , -C(0)R 12 , -S(0) 2 R 12 , - S(0) 2 N(R 9 )(R 10 ), and -OC(0)R 12 , wherein Ci -6 alkyl, C 3-6 cycloalkyl, C 2- 9heterocycloalkyl, C 6 -i 0 aryl, and Ci.gheteroaryl are optionally
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , -N(R 9 )(R 10 ), -C(0)OR 9 , - C(0)N(R 9 )(R 10 ), -C(0)R 12 , -S(0) 2 R 12 , and -S(0) 2 N(R 9 )(R 10 ), wherein C ⁇ alkyl is optionally substituted with one, two, or three R 14b .
  • n is 1 and R 3 is selected from halogen, -CN, Ci -6 alkyl, -OR 8 , and -N(R 9 )(R 10 ).
  • n is 1 and R 3 is halogen.
  • n is 1 and R 3 is Ci -6 alkyl.
  • compounds described herein include, but are not limited to, those described in Table 1.
  • provided herein is a pharmaceutically acceptable salt or solvate of a compound that is described in Table 1.
  • compounds described herein include, but are not limited to, those described in Table 2. TABLE 2
  • compounds described herein are in the form of pharmaceutically acceptable salts.
  • active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein.
  • “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term“pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
  • Handbook of Pharmaceutical Salts Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G.
  • Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms.
  • solubility often is a function of pH
  • selective dissolution in one or another part of the digestive tract is possible, and this capability can be manipulated as one aspect of delayed and sustained release behaviors.
  • the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt.”
  • the compound described herein i.e. free base form
  • the compound described herein is basic and is reacted with an organic acid or an inorganic acid.
  • Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and
  • Organic acids include, but are not limited to, l-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);
  • benzenesulfonic acid benzoic acid; camphoric acid (+); camphor- lO-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecyl sulfuric acid; ethane-l,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid;
  • hippuric acid isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene- 1, 5 -di sulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid ⁇ p ); and undecylenic acid.
  • a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to provide a "pharmaceutically acceptable base addition salt.”
  • the compound described herein is acidic and is reacted with a base.
  • an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
  • compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine.
  • compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
  • Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
  • the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • Solvates of compounds described herein are conveniently prepared or formed during the processes described herein.
  • the compounds provided herein optionally exist in unsolvated as well as solvated forms.
  • sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway.
  • the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
  • the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of
  • Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be
  • incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 Cl.
  • isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half- life or reduced dosage requirements.
  • one or more hydrogen atoms of the compounds described herein is replaced with deuterium.
  • the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
  • the compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
  • the compounds and methods provided herein include all cis, trans, syn, anti,
  • E
  • Z
  • isomers as well as the appropriate mixtures thereof.
  • stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns.
  • compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers.
  • resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
  • diastereomers are separated by separation/resolution techniques based upon differences in solubility.
  • separation of steroisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof.
  • stereoisomers are obtained by stereoselective synthesis.
  • prodrugs refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not.
  • the prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
  • An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the“prodrug”) but then is metabolically hydrolyzed to provide the active entity.
  • a further example of a prodrug is a short peptide
  • a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al ., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard,
  • a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester,
  • a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
  • a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
  • compounds described herein are prepared as alkyl ester prodrugs.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound.
  • Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims.
  • some of the herein-described compounds is a prodrug for another derivative or active compound.
  • a prodrug of the compound disclosed herein permits targeted delivery of the compound to a particular region of the gastrointestinal tract.
  • a prodrug is formed by the formation of a covalent linkage between drug and a carrier in such a manner that upon oral administration the moiety remains intact in the stomach and small intestine.
  • This approach involves the formation of prodrug, which is a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation in the biological environment to release the active drug.
  • Formation of prodrugs has improved delivery properties over the parent drug molecule.
  • the problem of stability of certain drugs from the adverse environment of the upper gastrointestinal tract can be eliminated by prodrug formation, which is converted into parent drug molecule once it reaches into the colon.
  • Site specific drug delivery through site specific prodrug activation may be accomplished by the utilization of some specific property at the target site, such as altered pH or high activity of certain enzymes relative to the non-target tissues for the prodrug-drug conversion.
  • conjugate conjugates include, but are not limited to, azo bond conjugates, glycoside conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates or amino-acid conjugates.
  • the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
  • A“metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
  • the term“active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • the term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
  • cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups.
  • Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • the compounds described herein are rapidly metabolized following absorption from the gastro-intestinal tract to metabolites that have greatly reduced SSAO inhibitor activity.
  • the compounds are rapidly metabolized in plasma.
  • the compounds are rapidly metabolized by the intestines.
  • the compounds are rapidly metabolized by the liver.
  • intermediate 1-1 is reacted to incorporate a suitable amine protecting group.
  • a suitable protecting group is a Boc group to provide intermediate 1-2.
  • suitable conditions include the use of Boc 2 0 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the base is an organic base such as triethylamine.
  • the appropriate solvent is an alcohol solvent such as methanol.
  • the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
  • 1-2 is subjected to suitable conditions to incorporate a primary alcohol protecting group.
  • a suitable protecting group is a silyl protecting group such as /-butyldimethyl silyl (TBS) to provide intermediate 1-3.
  • conditions include the use an appropriate reagent such as TBS-C1 using an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base is imidazole.
  • the appropriate solvent is a chlorinated solvent such as dichloromethane.
  • the suitable temperature is about 0 °C to room temperature and the appropriate amount of time is about 18 hours (overnight).
  • 1-3 is reacted under suitable oxidization conditions to provide intermediate 1-4.
  • the alcohol is oxidized under Swem oxidation conditions using an appropriate reagent such as oxalyl chloride with an appropriate base in an appropriate solvent or solvent mixture at an appropriate temperature and an appropriate amount of time.
  • the appropriate base is an organic base such as triethylamine.
  • the appropriate the solvent is a chlorinated solvent such as dichloromethane.
  • the suitable temperature is about -78 °C to room temperature and the appropriate amount of time is about 2 to 18 hours (overnight).
  • suitable one carbon-homologation conditions include the use of phosphonium reagents.
  • suitable one-carbon-homologation conditions includes pre-treating either (fluoromethyl)triphenylphosphonium bromide or tetrafluorob orate salt with an appropriate base, with an appropriate solvent for an appropriate amount of time at an appropriate temperature before the addition of 1-4.
  • the appropriate base is NaHMDS.
  • the appropriate solvent is an ethereal solvent such as THF.
  • the appropriate temperature and amount of time before addition to 1-4 is about 30 mins at about -20 °C. In some embodiments, after 1-4 is added the reaction is continued for an additional about 2 to 18 hours (overnight) at about room temperature.
  • 1-5 was isolated as mixture of regioisomers. In some embodiments, the regioisomers of 1-5 were separated by flash chromatography under appropriate conditions. In some embodiments, appropriate conditions for separation of the regioisomers was flash chromatography using silica gel, eluting with an appropriate solvent system such as a mixture of hexanes and ethyl acetate.
  • 1-5 is reacted under suitable conditions to remove the alcohol protecting group to provide intermediate 1-6.
  • appropriate conditions include using tetrabutylammonium fluoride in a suitable solvent at an appropriate temperature and amount of time.
  • the appropriate solvent is an ethereal solvent such as THF.
  • the appropriate temperature and time is about 1 to 18 hour (overnight) at about room temperature.
  • further purification via flash chromatography using an appropriate solvent system provide the pure E- or Z-isomers of 1-6.
  • appropriate conditions for separation of the regioisomers was flash chromatography using silica gel, eluting with an appropriate solvent system such as a mixture of hexanes and ethyl acetate.
  • 1-6 is reacted under suitable conditions to provide intermediate 1-7.
  • appropriate conditions include using methanesulfonyl chloride using an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base is an organic base such as triethylamine.
  • the appropriate solvent is acetone.
  • the appropriate temperature and time is about 0 °C and about lh.
  • the reaction mixture is filtered and the filtrate is used directly as a solution of intermediate 1-7 in acetone.
  • 1-7 is reacted under suitable conditions to provide intermediate bromide 1-8.
  • appropriate conditions include using lithium bromide in an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate solvent is acetone.
  • the appropriate temperature and time is about room temperature and about lh.
  • 1-8 is reacted with intermediate 1-9 under suitable conditions to provide intermediate 1-10.
  • 1-9 is 4-(pyrimidin-2-yl)phenol, 4-(pyridin-2- yl)phenol or 4-(lH-pyrazol-l-yl)phenol.
  • 1-9 is 4-(lH-tetrazol-5-yl)phenol, 4- (3-methyl-l,2,4-oxadiazol-5-yl)phenol, 4-(3-isopropyl-l,2,4-oxadiazol-5-yl)phenol, 4-(l -ethyl- 1H- tetrazol-5-yl)-phenol, 4-(5-methyl-l,3,4-oxadiazol-2-yl)phenol, 4-(5-amino-lH-l,2,4-triazol-3- yl)phenol, 4-(5-methyl-l,2,4-oxadiazol-3-yl)phenol, 4-(5-amino-l,3,4-oxadiazol-2-yl)phenol, 4- oxazol-2-yl-phenol, 4-(l,3,4-oxadiazol-2-yl)phenol, 4-(3,5-dimethyl-lH-pyrazol-4-yl)phenol, 4- (lH-pyrazol-4-yl)phenol
  • 1-9 is tert-butyl 4-(4- hydroxyphenyl)piperidine-l-carboxylate, tert-butyl 3-(4-hydroxyphenyl)pyrrolidine-l-carboxylate or tert-butyl 3-(4-hydroxyphenyl)azetidine-l-carboxylate.
  • 1-9 is 2-(4- hydroxyphenyl)-N-isopropyloxazole-4-carboxamide, 4-(3,5-dimethylisoxazol-4-yl)phenol, 4-(3- amino-5-methylisoxazol-4-yl)phenol, 5-(4-hydroxyphenyl)imidazolidine-2,4-dione, 4-(l-isopropyl- lH-pyrazol-4-yl)phenol, 4-(l,3-dimethyl-lH-pyrazol-4-yl)phenol, 3-methyl-4-(3-methyl-lH- pyrazol-4-yl)phenol, 4-(l,4-dimethyl-lH-pyrazol-5-yl)phenol, 4-(4-hydroxyphenyl)tetrahydro-2H- pyran-4-carbonitrile, 4-(3-amino-5-methyl-lH-pyrazol-4-yl)phenol, 4-(3-(tert-butyl)-5-methyl-methyl-methyl-
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
  • intermediate 1-6 is reacted under Mitsunobu reaction conditions with intermediate 1-9 using appropriate reagents in an appropriate solvent or solvent mixture at an appropriate temperature and an appropriate amount of time to provide intermediate 1-10.
  • the appropriate reagents are triphenylphosphine and diisopropyl azodi carboxyl ate.
  • the appropriate solvent is an ethereal solvent such as THF.
  • the appropriate temperature is about 0 °C to about room temperature. In some embodiments, the appropriate amount of time is about 18 hours (overnight).
  • 1-10 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound I- 11.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction is conducted in TFA only.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • 1-10 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound 1-11.
  • intermediate 1-9 used in the preparation of compounds 1-10 described herein are prepared as outlined in Scheme 2.
  • intermediate 11-13 is prepared from halide 11-12 using boron- halogen exchange conditions.
  • Suitable boron-halogen exchange conditions include but are not limited to use of a suitable organometallic reagent and a suitable boron reagent.
  • suitable organometallic reagents include palladium.
  • suitable boron reagents include bis(pinacolato)diboron.
  • suitable palladium- catalyzed boron-halogen exchange conditions include Pd(dppf)Cl 2 with an appropriate base, in an appropriate solvent for an appropriate time and at an appropriate temperature.
  • intermediate 11-13 is reacted with an aromatic halide (R 3 -halide) under suitable metal-catalyzed cross-coupling reaction conditions to provide intermediate 1-9.
  • the aromatic halide is an aromatic chloride, bromide or iodide.
  • the aromatic halide is 2-chloropyrimidine.
  • suitable metal- catalyzed cross-coupling conditions include use of palladium.
  • suitable palladium-catalyzed cross-coupling reaction conditions include Pd(PPh 3 ) 2 Cl2 with an appropriate base, in an appropriate solvent for an appropriate time and at an appropriate temperature.
  • the base is an inorganic base such as Na 2 C0 3.
  • the appropriate solvent is a dioxane/water, or DMF/water mixture.
  • the appropriate temperature is about 50 °C to about 90 °C.
  • the appropriate time is about 0.5 hours to about 18 hours (overnight).
  • the phenol group of intermediate 11-13 is substituted with an appropriate protecting group prior to the metal -catalyzed cross-coupling reaction and subsequently removed under appropriate conditions.
  • halide 11-12 is reacted with a nitrogen-containing heterocycle under suitable metal-catalyzed cross-coupling reaction conditions to provide A -linked intermediate 1-9.
  • the nitrogen-containing heterocycle is l//-pyrazole.
  • suitable metal-catalyzed cross-coupling conditions include use of copper.
  • suitable copper-catalyzed cross-coupling reaction conditions include the use of copper (I) iodide with an appropriate base in an appropriate solvent for an appropriate time and at an appropriate temperature.
  • an appropriate base is an inorganic base such as cesium carbonate.
  • an appropriate solvent is DMF.
  • the appropriate time and appropriate temperature is about 120 °C for about 18 hours (overnight).
  • the phenol group of intermediate 11-13 is substituted with an appropriate protecting group prior to the metal -catalyzed cross-coupling reaction.
  • the protecting group is a methyl group.
  • deprotection conditions include using boron tribromide with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate solvent is a chlorinated solvent such as DCM.
  • the reaction temperature is about 0 °C to about room temperature and the reaction time is about 18 hours (overnight).
  • aryl halide 11-12 is reacted with a boron reagent under suitable metal -catalyzed cross-coupling reaction conditions to directly provide 1-9.
  • the boron reagent is an aromatic boronic acid.
  • the boron reagent is an aromatic boronic ester.
  • the boron reagent is an aromatic pinacolyl boronic ester.
  • suitable metal-catalyzed cross-coupling conditions include palladium.
  • suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl 2 with an appropriate base, with an appropriate solvent for an appropriate time and at an appropriate temperature.
  • the phenol group of intermediate 11-12 is substituted with an appropriate protecting group prior to metal -catalyzed cross-coupling reaction.
  • compound is prepared from appropriate metal-catalyzed cross coupling conditions of halide 11-12 with a tin reagent.
  • halide 11-12 is a bromide.
  • the tin reagent is an aromatic tin reagent.
  • metal -catalyzed cross couplings include Stille palladium-catalyzed cross-coupling conditions.
  • Suitable palladium catalysts for cross-coupling include but are not limited to Pd(PPh 3 ) 4 in a suitable solvent, such as DMF or dioxane, at a suitable temperature for an appropriate amount of time.
  • a suitable temperature is 90 °C to about 100 °C.
  • the appropriate amount of time is about 2 hours to about 18 hours (overnight).
  • compound 1-9 is directly prepared from appropriate metal- catalyzed cross coupling conditions of halide 11-12 with an aromatic compound.
  • halide 11-12 is a bromide.
  • metal-catalyzed cross couplings include C-H activation cross-coupling conditions.
  • C-H activation cross coupling conditions include use of palladium catalysts.
  • Suitable palladium catalysts for cross coupling include but are not limited to Pd(OAc) 2 with a suitable ligand in a suitable solvent, such as dioxane, with an appropriate base at a suitable temperature for an appropriate amount of time.
  • the suitable ligand is a phosphine ligand.
  • the appropriate base is an inorganic base.
  • the suitable temperature is about 50 °C to about 110 °C.
  • the appropriate amount of time is about 2 hours to about 18 hours (overnight).
  • ketone III-l is treated with a base to form an enolate with an appropriate base, in an appropriate solvent, for an appropriate amount of time, at an appropriate temperature.
  • the base is an organic base.
  • the organic base is LiHMDS.
  • enolate formation takes place at about -78 °C.
  • the appropriate solvent is THF.
  • the appropriate time is about one hour.
  • the enolate of ketone III-l is reacted with a suitable electrophile in an appropriate solvent to form enol ether III-2 at the appropriate temperature, for an appropriate amount of time.
  • the electrophile forms a sulfate ester.
  • the electrophile is PhNTf 2 .
  • the appropriate temperature is about -78 °C and the appropriate time is about 2 hours.
  • the reaction is further warmed to a suitable temperature over a suitable period of time. In some embodiments, the suitable temperature is about room temperature for about overnight.
  • a suitable boronic acid is reacted with enol triflate III-2 under suitable metal -catalyzed cross-coupling reaction conditions to provide III-3.
  • suitable metal-catalyzed cross-coupling conditions include palladium.
  • suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl 2 with an appropriate base, with an appropriate solvent for an appropriate time and at an appropriate temperature.
  • the base is an inorganic base.
  • the inorganic base is a carbonate base such as Na 2 C0 3.
  • the appropriate solvent is a dioxane/water mixture.
  • the appropriate time and appropriate temperature is about 6 hours at about 30 °C. In some embodiments, the appropriate time and appropriate temperature is about 1 to about 18 hours at about 80 °C.
  • III-3 is subjected under suitable olefin reduction conditions to provide III-4.
  • suitable reduction conditions include palladium-catalyzed hydrogenation conditions.
  • palladium-catalyzed hydrogenation conditions include use of 10% Pd/C with hydrogen (1 atm) in a suitable solvent, such as MeOH, for an appropriate amount of time at an appropriate temperature. In some embodiments, the appropriate amount of time is about overnight at about rt.
  • the acylation of amine III-7 affords compound III-4.
  • suitable acylation conditions include the use of acetyl acetate with a suitable base, such as K 2 C0 3 , in a suitable solvent, such as dioxane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 2 hours.
  • a suitable base such as K 2 C0 3
  • a suitable solvent such as dioxane
  • the synthetic method further comprises the hydrolysis of the ester intermediate formed in the acylation reaction.
  • suitable ester hydrolysis conditions include the use of a suitable base, such as KOH, in a suitable solvent, such as dioxane/water, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 4 hours to provide III-4.
  • the reaction of amine III-7 with a sulfonyl chloride affords compound III-4.
  • suitable conditions include the use of MsCl in a suitable solvent, such as dichloromethane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 18 hours.
  • X is O
  • the oxygen is also concurrently sulfonated under the reaction conditions.
  • the synthetic method further comprises the hydrolysis of the sulfonate ester intermediate formed in the reaction.
  • suitable sulfonate ester hydrolysis conditions include the use of a suitable base, such as NaOH, in a suitable solvent, such as MeOH/water, for an appropriate amount of time and at a suitable temperature, such as about 80 °C for about 1 hour to provide III-4.
  • a suitable base such as NaOH
  • MeOH/water a suitable solvent
  • suitable temperature such as about 80 °C for about 1 hour to provide III-4.
  • intermediate III-7 is reacted to incorporate a suitable amine protecting group.
  • a suitable protecting group is a Boc group to provide intermediate III-4.
  • suitable conditions include the use of Boc 2 0 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the base is an organic base such as triethylamine.
  • the appropriate solvent is an alcohol solvent such as methanol.
  • the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
  • III-7 is subjected to suitable conditions to incorporate a primary alcohol protecting group.
  • a suitable protecting group is a silyl protecting group such as teoc (2-(trimethylsilyl)ethoxycarbonyl) group, to provide intermediate III-4.
  • conditions include the use of the appropriate silyl-based reagent using an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base is triethylamine.
  • the appropriate solvent is THF.
  • the suitable temperature is about 0 °C to room temperature and the appropriate amount of time is about 18 hours (overnight).
  • III-5 is reacted with intermediate III-4 under suitable conditions to provide intermediate III-6.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
  • III-6 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound III-8.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction is conducted in TFA only.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • III-6 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound III-8.
  • compounds described herein are prepared as outlined in Scheme 4.
  • intermediate III-6 wherein R la is a Boc protecting group
  • intermediate III-6 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV- 1.
  • the appropriate solvent is THF.
  • the reaction temperature is about room temperature and the reaction time is about 18 hours (overnight).
  • intermediate III-6 wherein R la is a teoc (2- (trimethylsilyl)ethoxycarbonyl) group protecting group
  • intermediate III-6 is reacted with tetra-n- butylammonium fluoride in an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-1.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction is conducted in TFA only.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • acylation of amine IV-1 with an acyl chloride affords compound IV-2.
  • Suitable acylation conditions include but are not limited to the use of a suitable base, such as TEA or pyridine in a suitable solvent, such as DCM or toluene, for an appropriate amount of time and at a suitable temperature, such as about room temperature to about 80 °C for about 1 hour to about overnight.
  • a suitable base such as TEA or pyridine
  • a suitable solvent such as DCM or toluene
  • pyridine is used as both the base and the solvent.
  • conditions include the addition of DMAP.
  • reaction of amine IV-1 with a sulfonyl chloride affords compound IV-3.
  • suitable conditions include the use of an alkylsufonyl chloride in a suitable solvent, such as dichloromethane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 18 hours.
  • the alkylation of amine IV-1 with an alkyl halide affords compound IV-4.
  • an appropriate alkyl halide is an alkyl chloride.
  • suitable alkylation conditions include but are not limited to the use of a suitable base, such as TEA or pyridine in a suitable solvent, such as DMF, for an appropriate amount of time and at a suitable temperature, such as about room temperature to about 80 °C for about 1 hour to about overnight.
  • IV-2 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-5.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • IV-3 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-6.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight). [00242] In some embodiments, IV-4 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-7. In some embodiments, the appropriate acid is HC1 or TFA. In some
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
  • intermediate V-l is reacted with methyl carbonochloridate with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound V-2.
  • the appropriate solvent is Et 2 0, dioxane, MeCN, or THF.
  • the reaction temperature is about room temperature and the reaction time is about 2 hours.
  • V-3 is reacted with intermediate V-2 under suitable conditions to provide intermediate V-4.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
  • V-4 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound V-5.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction is conducted in TFA only.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
  • intermediate VI-1 is reacted with a cabamoyl chloride with an appropriate base and an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VI-2.
  • the cabamoyl chloride is methylcarbamic chloride.
  • the appropriate base is triethylamine or pyridine.
  • the appropriate solvent is DCM or DMF.
  • the reaction temperature is about room temperature and the reaction time is about 18 hours.
  • VI-2 is reacted with VI-3 under suitable conditions to provide intermediate VI-4.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
  • VI-2 is reacted with VI-3 under suitable conditions to provide intermediate VI-5.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
  • intermediate VI-5 is reacted with a cabamoyl chloride with an appropriate base and an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VI-4.
  • the cabamoyl chloride is methylcarbamic chloride.
  • the appropriate base is triethylamine or pyridine.
  • the appropriate solvent is DCM.
  • the reaction temperature is about room temperature and the reaction time is about 18 hours.
  • VI-4 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VI-6.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
  • VII-1 is reacted with VII-2 under suitable conditions to provide intermediate VII-3.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
  • VII-3 is subjected to suitable nitro functional group reduction conditions to provide aniline VII-4.
  • suitable nitro reduction conditions include use of iron powder and ammonium chloride in a suitable solvent or solvent mixture, such as ethanol/water, for an appropriate amount of time at an appropriate temperature.
  • the reaction temperature is about 90 °C and the reaction time is about 2 hours.
  • the reaction of aniline VII-4 with a sulfonyl chloride affords compound VII-5.
  • suitable conditions include the use of an alkylsufonyl chloride with a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 18 hours.
  • VII-5 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VII-6.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • a suitable boronic ester VIII-1 is reacted with aryl bromide or idodie VIII-2 under suitable metal-catalyzed cross-coupling reaction conditions to provide VIII-3.
  • suitable metal-catalyzed cross-coupling conditions include palladium.
  • suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf) 2 Cl 2 with an appropriate base, with an appropriate solvent for an appropriate time and at an appropriate temperature.
  • the base is an inorganic base.
  • the inorganic base is a carbonate base such as K 2 C0 3.
  • the appropriate solvent is a dioxane/water mixture.
  • the appropriate time and appropriate temperature is about 1 hour at about 100 °C.
  • VIII-3 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VIII-4.
  • the appropriate acid is TFA.
  • the appropriate solvent is DCM.
  • the reaction temperature is about room temperature and the reaction time is about 1 hour.
  • acylation of amine VIII-4 affords compound VIII-5.
  • suitable acylation conditions include the use of acetic anhydride with a suitable base, such as Et 3 N, in a suitable solvent, such as DCM, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 1 hour.
  • VIII-5 is subjected under suitable olefin reduction conditions to provide VIII-6.
  • suitable reduction conditions include palladium-catalyzed hydrogenation conditions.
  • suitable palladium-catalyzed hydrogenation conditions also concurrently removes the phenol protecting group.
  • the phenol protecting group is a benzyl group.
  • hydrogenation conditions include use of 10% Pd/C with hydrogen (1 atm) in a suitable solvent, such as MeOH, for an appropriate amount of time at an appropriate temperature.
  • a suitable solvent such as MeOH
  • the appropriate amount of time is about overnight at about room temperature.
  • VIII-6 is reacted with intermediate VIII-7 under suitable conditions to provide intermediate VIII-8.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
  • VIII-8 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VIII-9.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction is conducted in TFA only.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • VIII-8 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound VIII-9.
  • IX-1 is reacted with intermediate IX-2 under suitable alkylation conditions to provide intermediate IX-3.
  • appropriate alkylation conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base is sodium hydride.
  • the appropriate solvent is DMF.
  • the reaction temperature is about 0 °C to about room temperature and the reaction time is about 1 hour to about 18 hours (overnight).
  • IX-3 is subjected to suitable benzyl deprotection conditions to provide IX-4.
  • suitable deprotection conditions include palladium-catalyzed hydrogenation conditions.
  • appropriate conditions include using an appropriate palladium catalyst under a suitable pressure of hydrogen with an appropriate solvent or solvent mixture for an appropriate amount of time and at an appropriate temperature.
  • the appropriate palladium catalyst is palladium on carbon.
  • a suitable pressure of hydrogen is about atmospheric pressure to about 50 PSI.
  • the appropriate solvent is methanol.
  • the reaction temperature is about room temperature and the reaction time is about 1 hour to 18 hours (overnight).
  • IX-4 is reacted with intermediate IX-5 under suitable conditions to provide intermediate IX-6.
  • appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature.
  • the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate.
  • the appropriate solvent is THF, DMF or DMA.
  • the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
  • IX-6 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IX-7.
  • the appropriate acid is HC1 or TFA.
  • the appropriate solvent is Et 2 0, dioxane, MeOH, EtOH, EtOAc or DCM.
  • the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
  • IX-6 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound IX-7.
  • compounds are prepared as described in the Examples.
  • Ci-C x includes Ci-C 2 , C 1 -C 3 . . . Ci-C x.
  • a group designated as "C 1 -C 4 " indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, /50-propyl, «-butyl, /.so -butyl, .sfc-butyl, and /-butyl.
  • An“alkyl” group refers to an aliphatic hydrocarbon group.
  • the alkyl group is branched or straight chain.
  • the“alkyl” group has 1 to 10 carbon atoms, i.e. a Ci- Cioalkyl.
  • a numerical range such as“1 to 10” refers to each integer in the given range; e.g.,“1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • an alkyl is a Ci-C 6 alkyl.
  • the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
  • An“alkylene” group refers refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl.
  • an alkylene is a Ci-C 6 alkylene.
  • an alkylene is a Ci-C 4 alkylene.
  • an alkylene comprises one to four carbon atoms (e.g., Ci- C 4 alkylene).
  • an alkylene comprises one to three carbon atoms (e.g., C 1 -C 3 alkylene).
  • an alkylene comprises one to two carbon atoms (e.g., Ci-C 2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises two carbon atoms (e.g., C 2 alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C 2 -C alkylene).
  • Typical alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, - CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and the like.
  • Deuteroalkyl refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.
  • alkenyl refers to a type of alkyl group in which at least one carbon-carbon double bond is present.
  • R is H or an alkyl.
  • an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
  • alkynyl refers to a type of alkyl group in which at least one carbon-carbon triple bond is present.
  • an alkenyl group has the formula -CoC-R, wherein R refers to the remaining portions of the alkynyl group.
  • R is H or an alkyl.
  • an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • Non-limiting examples of an alkynyl group include -CoCH, -CoCCH 3 -CoCCH 2 CH 3 , - CH 2 CoCH.
  • An“alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.
  • alkylamine refers to the -N(alkyl) x H y group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
  • the term“aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer.
  • the term“aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or“heteroaryl” or“heteroaromatic”) groups (e.g., pyridine).
  • the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.
  • the term“carbocyclic” or“carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from“heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.
  • aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some
  • an aryl is a phenyl. In some embodiments, an aryl is a C 6 -C l0 aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • cycloalkyls are spirocyclic or bridged compounds.
  • cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbomyl and bicyclo[l. l. l]pentyl.
  • a cycloalkyl is a C 3 - C 6 cycloalkyl.
  • a cycloalkyl is a monocyclic cycloalkyl.
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2. l]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like
  • halo or, alternatively,“halogen” or“halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
  • haloalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom.
  • a fluoroalkyl is a Ci-C 6 fluoroalkyl.
  • fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
  • a fluoroalkyl is a Ci-C 6 fluoroalkyl.
  • a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g ., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-C 6 heteroalkyl.
  • heteroalkylene refers refers to a divalent heteroalkyl radical.
  • heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
  • heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds.
  • Non-aromatic heterocyclic groups include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
  • the heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl,
  • l]octanyl 3H-indolyl, indolin-2-onyl, isoindolin-l-onyl, isoindoline-l,3-dionyl, 3,4- dihydroisoquinolin-l(2H)-onyl, 3,4-dihydroquinolin-2(lH)-onyl, isoindoline-l,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, lH-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl.
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • a group derived from pyrrole includes both pyrrol-l-yl (A-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both A-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached).
  • the heterocyclic groups include benzo-fused ring systems.
  • at least one of the two rings of a bicyclic heterocycle is aromatic.
  • both rings of a bicyclic heterocycle are aromatic.
  • heteroaryl or, alternatively,“heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
  • Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
  • Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, l,8-naphthyridine, and pteridine.
  • a heteroaryl contains 0-4 N atoms in the ring.
  • a heteroaryl contains 1-4 N atoms in the ring.
  • a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring.
  • a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring.
  • heteroaryl is a Ci-Cgheteroaryl.
  • monocyclic heteroaryl is a Ci-Csheteroaryl.
  • monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
  • bicyclic heteroaryl is a C 6 -C 9 heteroaryl.
  • A“heterocycloalkyl” or“heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur.
  • a heterocycloalkyl is fused with an aryl or heteroaryl.
  • the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
  • heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
  • a heterocycloalkyl is a C2-Cioheterocycloalkyl.
  • a heterocycloalkyl is a C4-Cioheterocycloalkyl.
  • a heterocycloalkyl contains 0- 2 N atoms in the ring.
  • a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
  • bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
  • bond when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
  • moiety refers to a specific segment or functional group of a molecule.
  • Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • optional substituents are independently selected from D, halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , - CH 3 , -CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
  • substituted groups are substituted with one or two of the preceding groups.
  • module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
  • modulator refers to a molecule that interacts with a target either directly or indirectly.
  • the interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof.
  • a modulator is an agonist.
  • administered refers to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
  • co-administration or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • an“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
  • An appropriate“effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

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Abstract

Described herein are compounds that are semicarbazide-sensitive amine oxidase (SSAO) inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in treating or preventing a liver disease or condition.

Description

SSAO INHIBITORS AND USES THEREOF
CROSS-REFERENCE
[0001] This application claims benefit of U.S. Provisional Application No. 62/685,842, filed on June 15, 2018, U.S. Provisional Application No. 62/750,063, filed on October 24, 2018, and U.S. Provisional Application No. 62/795,384, filed on January 22, 2019, all of which are herein incorporated by reference in their entirety.
FIELD OF THE INVENTION
[0002] Described herein are compounds that are semicarbazide-sensitive amine oxidase (SSAO), methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with SSAO activity.
BACKGROUND OF THE INVENTION
[0003] Semicarbazide-sensitive amine oxidase (SSAO) is a member of the semicarbazide- sensitive amino oxidase family, and is also known as AOC3 (amine oxidase, copper containing 3) or VAP-l (vascular adhesion protein 1). SSAO is an enzyme that exists both as a membrane-bound and a soluble isoform. It is highly expressed in the lung, aorta, liver and ileum. SSAO has been implicated in the pathogenesis of liver diseases (Weston, C.J. et ah, J Neural. Transm. 2011, 118, 1055-1064). SSAO inhibition is a treatment modality for liver diseases or conditions such as fatty liver disease.
SUMMARY OF THE INVENTION
[0004] In one aspect, described herein are SSAO inhibitors and uses thereof. In one aspect, described herein is a compound that has the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000002_0001
Formula (III);
wherein:
Figure imgf000002_0002
Figure imgf000003_0001
R1 is C2-6alkenyl, C2-6alkynyl, a saturated monocyclic C2-7heterocycloalkyl, saturated bridged bicyclic C2-9heterocycloalkyl, or saturated spirocyclic C2-9heterocycloalkyl, wherein C2- 6alkenyl, C2-6alkynyl, saturated monocyclic C2-7heterocycloalkyl, saturated bridged bicyclic C2-9heterocycloalkyl, or saturated spirocyclic C2-9heterocycloalkyl are optionally
substituted with one, two, three, four, or five
Figure imgf000003_0002
each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, -R14a, - OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, - N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, R14a, -OR8, - SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, - S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
R2 is -C(0)0R4, -0C(0)N(R4)(R5), -N(R6)C(0)N(R4)(R5), -N(R6)C(0)0R7, -N(R6)S(0)2R7, - S(0)R7, -0C(0)R7, -N(R21)C(0)R22, -S(0)2R22, -S(0)2N(R22)(R23), - S(=0)(=NH)N(R4)(R5), -CH2C(0)N(R24)(R25), -CH2N(R21)C(0)R26, -CH2S(0)2R26, or - CH2S(0)2N(R24)(R25);
each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-l0aryl, Ci.gheteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14b; R4 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14d;
R6 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R7 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- l0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14e;
each R8 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14f;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14g;
each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the
nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h;
each R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
each R13 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R14a, R14b, R14c, R14d, R14e, R14f, R14g, R14h, R14i, R14j, R14k, R141, R14m, and R14n are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, -CH2-C3-6Cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6. loaryl, -CH2-C6-ioaryl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein C^alkyl, C2-6alkenyl, C2-6alkynyl, C3.
6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6. ioaryl, -CH2-C6-ioaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci.
ealkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and - 0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci.gheteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci.gheteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci_9heteroaryl;
R20 is selected from H and Ci-6alkyl;
R21 is selected from H and Ci-6alkyl;
R22 is selected from Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci.gheteroaryl, wherein C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci. gheteroaryl are optionally substituted with one, two, or three R14j;
R is selected from H and Ci-6alkyl; or R and R together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14k;
R24 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R141;
R is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R and R together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14m; R26 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14n;
n is 0, 1, 2, 3, or 4; and
p is 0 or 1.
[0005] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
[0006] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -R1. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -I^-R1. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -L2-R\ In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -I^-L^R1. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -I^-L^R1. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L1 is -0-. In some embodiments is a compound of Formula (III), or a
pharmaceutically acceptable salt or solvate thereof, wherein L1 is -CH2-. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)OR12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a saturated monocyclic C2- 7heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, homomorpholinyl,
thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, hexahydropyrimidinyl, oxepanyl, thiepanyl, azapanyl, and azocanyl, wherein pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, hexahydropyrimidinyl, oxepanyl, thiepanyl, azapanyl, and azocanyl are optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6. loaryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, - N(Ru)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and - 0C(0)R12. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a saturated monocyclic C2-7heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, azetidinyl, and tetrahydropyranyl, wherein pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, azetidinyl, and tetrahydropyranyl are optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci. 6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, Ci.gheteroaryl, -R14a, -OR8, -SR8, - N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is piperidinyl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, - CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -R14a, - OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12.
[0007] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000007_0001
Formula (la).
[0008] In some embodiments is a compound of Formula (la’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000008_0001
Formula (la’).
[0009] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a saturated bridged bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -
Figure imgf000008_0004
[0010] In some embodiments is a compound of Formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000008_0002
Formula (Iaa);
wherein L3 is -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2N(H)CH2-, or -CH2N(CH3)CH2-, and q is 0, 1, or 2.
[0011] In some embodiments is a compound of Formula (Iaa’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000008_0003
Formula (Iaa’);
wherein L3 is -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2N(H)CH2-, or -CH2N(CH3)CH2-, and q is 0, 1, or 2. [0012] In some embodiments is a compound of Formula (lab), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000009_0001
Formula (lab);
wherein L3 is -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2N(H)CH2-, or -CH2N(CH3)CH2-, and q is 0, 1, or 2.
[0013] In some embodiments is a compound of Formula (lab’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000009_0002
Formula (lab’);
wherein L3 is -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2N(H)CH2-, or -CH2N(CH3)CH2-, and q is 0, 1, or 2.
[0014] In some embodiments is a compound of Formula (lac), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000009_0003
Formula (lac);
wherein L3 is -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2N(H)CH2-, or -CH2N(CH3)CH2-, and q is 0, 1, or 2.
[0015] In some embodiments is a compound of Formula (lac’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000010_0001
Formula (lac’);
wherein L3 is -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2N(H)CH2-, or -CH2N(CH3)CH2-, and q is 0, 1, or 2.
[0016] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable
salt or solvate thereof, wherein
Figure imgf000010_0002
Figure imgf000010_0003
[0017] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a saturated spirocyclic C2-9heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, - CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, Ci-9heteroaryl, -R14a, - OR8, -SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12.
[0018] In some embodiments is a compound of Formula (lad), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000010_0004
Formula (lad);
wherein w1, w2, w3, and w4 are each independently selected from 1 and 2.
[0019] In some embodiments is a compound of Formula (lad’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000011_0001
Formula (lad’);
wherein w1, w2, w3, and w4 are each independently selected from 1 and 2.
[0020] In some embodiments is a compound of Formula (Iae), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000011_0002
Formula (Iae);
wherein R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, Ci.gheteroaryl, -R14a, -OR8, -SR8, - N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12.
[0021] In some embodiments is a compound of Formula (Iae’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000011_0003
Formula (Iae’);
wherein R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, Ci.gheteroaryl, -R14a, -OR8, -SR8, - N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. [0022] In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each Rla is independently selected from oxo, Ci-6alkyl, Ci.gheteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each Rla is independently selected from oxo, Ci-6alkyl, and -C(0)R12.
[0023] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable
salt or solvate thereof, wherein
Figure imgf000012_0001
Figure imgf000012_0002
[0024] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable
salt or solvate thereof, wherein
Figure imgf000012_0003
Figure imgf000013_0001
[0025] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein
Figure imgf000013_0002
Figure imgf000013_0003
[0026] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein
Figure imgf000013_0004
Figure imgf000013_0005
[0027] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable
salt or solvate thereof, wherein
Figure imgf000014_0001
Figure imgf000014_0002
In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or
solvate thereof, wherein
Figure imgf000014_0003
each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.
gheteroaryl, R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, - C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each
Rib is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-ioaryl, Ci.gheteroaryl, R14a, -OR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), - C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each Rlb is independently selected from H, Ci-6alkyl, C3-6cycloalkyl, and R14a.
[0028] In some embodiments is a compound of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000014_0004
Formula (Ic).
[0029] In some embodiments is a compound of Formula (Ic’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000015_0003
Formula (Ic’).
[0030] In some embodiments is a compound of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000015_0001
Formula (Ie).
[0031] In some embodiments is a compound of Formula (Ie’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000015_0002
Formula (Ie’).
[0032] In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6.l0aryl, Ci. gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)OR16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), - N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, - S(0)2R19, -S(0)2N(R16)(R17), and -OC(0)R19. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci. ehaloalkoxy, -OR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)R19, -S(0)2R19, and - S(0)2N(R16)(R17). In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R9 is independently selected from H and Ci-6alkyl optionally substituted with one, two, or three R14g. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R9 is independently selected from H and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R10 is H. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R12 is independently selected from Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci. 9heteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R12 is independently selected from Ci-6alkyl and Ci-9heteroaryl, wherein Ci-6alkyl and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141 and each R141 is independently selected from - OH, -NH2, and -N(H)CH3.
[0033] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -R2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -L2-R2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is
Figure imgf000016_0001
CH2S(0)2N(R24)(R25). In some embodiments is a compound of Formula (III), or a
pharmaceutically acceptable salt or solvate thereof, wherein R2 is -C(0)0R4, -0C(0)N(R4)(R5), - N(R6)C(0)N(R4)(R5), -N(R6)C(0)0R7, -N(R6)S(0)2R7, or -CH2C(0)N(R24)(R25). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from H, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.
gheteroaryl are optionally substituted with one, two, or three R14c. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from H, Ci-6alkyl, and Ci-9heteroaryl, wherein Ci-6alkyl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is H. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from Ci-6alkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C6-i0aryl, and Ci.
gheteroaryl are optionally substituted with one, two, or three R14e. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from Ci-6alkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C6-i0aryl, and Ci.
9heteroaryl are optionally substituted with one, two, or three R14e. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is Ci-6alkyl optionally substituted with one, two, or three R14e. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is H. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R24 is selected from H, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.
9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R24 is selected from H and Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R25 is H.
[0034] In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is
independently selected from halogen, -CN, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6. loaryl, Ci-9heteroaryl, -OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6. ioaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14b. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-9heterocycloalkyl, Ci-9heteroaryl, -OR8, -N(R9)(R10), -C(0)0R9, - C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), wherein C^alkyl, C2-9heterocycloalkyl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, -CN, Ci-6alkyl, -OR8, -N(R9)(R10), wherein Ci-6alkyl is optionally substituted with one, two, or three R14b. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -0-. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -S(0)2-. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac),
(lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH2-. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is H. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is Ci-6alkyl. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a
pharmaceutically acceptable salt or solvate thereof, wherein Z is F. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Cl. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is H. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments is a compound of Formula (la), (Iaa), (lab), (lac), (lad),
(Lae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.
[0035] In another aspect, described herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, or oral administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
[0036] In another aspect, described herein is a method of treating a disease or condition in a mammal that would benefit from SSAO inhibition comprising administering a compound as described herein, or pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof. In some embodiments, the disease or condition is a liver condition.
[0037] In some embodiments, the compound is administered to the mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
[0038] In another aspect, described herein is a method of treating or preventing any one of the diseases or conditions described herein comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to a mammal in need thereof.
[0039] In another aspect, described herein is a method for the treatment or prevention of a liver condition in a mammal comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof. In other embodiments, the liver condition is amenable to treatment with an SSAO inhibitor. In some embodiments, the method further comprises administering a second therapeutic agent to the mammal in addition to the compound described herein, or a pharmaceutically acceptable salt, or solvate thereof.
[0040] In another aspect, described herein is a method of treating or preventing a liver disease or condition in a mammal, comprising administering to the mammal a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the liver disease or condition is nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease (NAFLD). In some embodiments, the non-alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH). In some embodiments, the non alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH) and is accompanied by liver fibrosis. In some embodiments, the non-alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH) without liver fibrosis.
[0041] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal.
[0042] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day. In some embodiments, the compound is administered on a continuous dosing schedule. In some embodiments, the compound is
administered on a continuous daily dosing schedule.
[0043] In any of the aforementioned aspects involving the treatment of a disease or condition are further embodiments comprising administering at least one additional agent in addition to the administration of a compound of Formula (la), (Iaa), (lab), (lac), (lad), (Iae), (Ic), (Ie), or (III) described herein, or a pharmaceutically acceptable salt thereof. In various embodiments, each agent is administered in any order, including simultaneously.
[0044] In any of the embodiments disclosed herein, the mammal or subject is a human.
[0045] In some embodiments, compounds provided herein are administered to a human.
[0046] In some embodiments, compounds provided herein are orally administered.
[0047] In another aspect, described herein is a compound that has the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000020_0001
Formula (II);
wherein:
Figure imgf000020_0002
Figure imgf000021_0001
R1 is C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, or Ci-9heteroaryl, wherein C2-6alkenyl, C2- 6alkynyl, C2-9heterocycloalkyl, or Ci-9heteroaryl are optionally substituted with one, two, three, four, or five Rla;
each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-
Figure imgf000021_0002
each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12, wherein C^alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b;
R4 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14d;
R6 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R7 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- !oaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14e;
each R8 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14f;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14g;
each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the
nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h;
each R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R141;
each R13 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R14a, R14b, R14c, R14d, R14e, R14f, R14g, R14h, R14i, R14j, R14k, R141, R14m, and R14n are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, -CH2-C3-6cycloalkyl, C2-gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6. loaryl, -CH2-C6-ioaryl, Ci.gheteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, -CH2-C3-6Cycloalkyl, C2-gheterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6. loaryl, -CH2-C6-ioaryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci.
ealkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and - 0C(0)R19; each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
R20 is selected from H and Ci-6alkyl;
R21 is selected from H and Ci-6alkyl;
R22 is selected from Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R14j;
R 23 is selected from H and Ci-6alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14k;
R24 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
R is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R and R together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14m;
R26 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14n;
n is 0, 1, 2, 3, or 4; and
p is 0 or 1.
[0048] In another aspect, described herein is a compound that has the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000024_0001
Formula (I);
wherein,
Figure imgf000024_0002
R1 is C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, or Ci-9heteroaryl, wherein C2-6alkenyl, C2- 6alkynyl, C2-9heterocycloalkyl, or Ci-9heteroaryl are optionally substituted with one, two, three, four, or five Rla;
each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-
Figure imgf000024_0003
each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b;
R4 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14d;
R6 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R7 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- ioaryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14e;
each R8 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14f;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14g;
each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the
nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h;
each R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
each R13 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R14a, R14b, R14c, R14d, R14e, R14f, R14g, R14h, R14i, R14j, R14k, R141, R14m, and R14n are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, - OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), - 0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, - N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19, wherein Ci. 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci. ealkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and - 0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
R20 is selected from H and Ci-6alkyl;
R21 is selected from H and Ci-6alkyl;
R22 is selected from Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci.gheteroaryl, wherein C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci. gheteroaryl are optionally substituted with one, two, or three R14j;
R is selected from H and Ci-6alkyl; or R and R together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14k;
R24 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R141;
R is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R and R together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14m;
R26 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14n; n is 0, 1, 2, 3, or 4; and
p is 0 or 1.
[0049] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and
modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.
DETAILED DESCRIPTION OF THE INVENTION
[0050] Semicarbazide-sensitive amine oxidase (SSAO) is a member of the semicarbazide- sensitive amino oxidase family, and is also known as AOC3 (amine oxidase, copper containing 3) or VAP-l (vascular adhesion protein 1). SSAO (AOC3) has two closely related genes in the human genome. AOC1 which corresponds to a diamine oxidase (DAO) found in gut, lung and kidney (Chassande, O. et al., J. Biol. Chem., 1994, 269: 14484-14489) and AOC2, a SSAO with expression in the eye (Imamura, Y. et al., Genomics, 1997, 40: 277-283). AOC4 is a sequence that does not lead to a functional gene product in humans (Schwelberger, H. G. J. Neural Transm.,
2007, 1 14: 757-762).
[0051] SSAO has at least two physiological functions. In some cases, SSAO functions as an amine oxidase in which primary amines may be oxidized to aldehydes, leading to the release of ammonia and hydrogen peroxide upon regeneration of the cofactor 2,4,5-trihydroxy-phenyl-alanyl- quinone (TPQ). Endogenous substrates include methylamine, dopamine and aminoacetone.
Aldehyde products generated under high AOC3 levels can be highly reactive, leading to glycation end products which may be regarded as drivers of diabetes associated inflammatory mechanisms (Mathys, K. C. et al., Biochem. Biophys. Res. Commun., 2002, 297: 863-869). In addition, hydrogen peroxide produced by SSAO can directly lead to direct cellular damage or be sensed by the tissue as a messenger of inflammation and so lead to further propagation of inflammatory processes.
[0052] In some cases, SSAO has cell adhesion activity, with SSAO having been shown to be important for leukocyte rolling, adhesion and transmigration in response to inflammatory stimuli (Salmi et al, Antoxidants and Redox Signaling, 2017). Both activities are associated with inflammatory processes.
[0053] SSAO was also shown to play a role in extravasation of inflammatory cells from the circulation to sites of inflammation (Salmi M.; Trends Immunol. 2001, 22, 21 1-216). SSAO antibodies have been shown to attenuate inflammatory processes by blocking the adhesion site of the SSAO protein. In addition, inhibitors of the amine oxidase activity of SSAO have been found to interfere with leukocyte rolling, adhesion and extravasation and, in a similar manner to SSAO antibodies, exhibit anti-inflammatory properties.
[0054] Recently SSAO has been implicated in the pathogenesis of liver diseases such as fatty liver disease (Weston, C.J. et al., J Neural. Transm. 2011, 118, 1055-1064). In some embodiments, serum SSAO is elevated in patients with fatty liver disease and correlates with histological markers of liver injury. In some embodiments, SSAO has been shown to contribute to liver fibrosis in preclinical models induced by chemical injury and diet induction. SSAO knock-out animals, or SSAO inhibition using an antibody are protective in both of these models (Weston et al; J. Clin. Invest., 2015, 125, 2, 501-520).
Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis
[0055] Non-alcoholic fatty liver disease (NAFLD) is associated with excessive fat in the liver (steatosis) and in some cases progresses to NASH, which is defined by the histologic hallmarks of inflammation, cell death, and fibrosis. In some instances, primary NASH is associated with insulin resistance, while secondary NASH is caused by medical or surgical conditions, or drugs such as, but not limited to, tamoxifen. In some cases, NASH progresses to advanced fibrosis, hepatocellular carcinoma, or end-stage liver disease requiring liver transplantation.
[0056] In some instances, NASH develops as a result of triglyceride (TGs) imbalance. For example, dysfunctional adipocytes secrete pro-inflammatory molecules such as cytokines and chemokines leading to insulin resistance and a failure of lipolysis suppression in the adipocytes. In some instances, this failure of lipolysis suppression leads to a release of free fatty acids (FFAs) into the circulation and uptake within the liver. In some cases, over accumulation of FFAs in the form of triglycerides (TGs) in lipid droplets leads to oxidative stress, mitochondrial dysfunction, and upregulation of pro-inflammatory molecules.
[0057] In some embodiments, an SSAO inhibitor disclosed herein is used in the treatment of non alcoholic steatohepatitis (NASH). In some examples, the SSAO inhibitor reduces NASH the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, NASH is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some instances, the level of NASH is relative to the level of NASH in a subject not treated with the SSAO inhibitor.
[0058] In some embodiments, an SSAO inhibitor disclosed herein is used in the treatment of NAFLD. In some examples, the SSAO inhibitor reduces NAFLD in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some cases, NAFLD is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some instances, the level of NAFLD is relative to the level of NAFLD in a subject not treated with the SSAO inhibitor.
Ballooning
[0059] Hepatocyte ballooning, a feature denoting cellular injury, is a feature of NASH.
Ballooning is a feature that denotes progressive NAFL (types 3 and 4). The term applies to enlarged, swollen-appearing hepatocytes; the affected cells are often intermixed in areas of steatosis and, in classic steatohepatitis, in the perivenular regions. Hepatocellular ballooning is most commonly noted in regions of H & E-detectable perisinusoidal fibrosis. Ballooned hepatocytes are most easily noted when they contain MH (either typical or poorly formed). Hepatocyte ballooning is a structural manifestation of microtubular disruption and severe cell injury.
[0060] In some embodiments, an SSAO inhibitor disclosed herein reduces liver ballooning in a subject. In some examples, the SSAO inhibitor reduces liver ballooning in the subject by at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or more. In some instances, liver ballooning is reduced by about 5% to about 50%, by about 5% to about 25%, by about 10% to about 20%, or by about 10% to about 30%. In some instances, the liver ballooning is relative to the level of liver ballooning in a subject not treated with the SSAO inhibitor.
Compounds
[0061] Compounds described herein, including pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates thereof, are SSAO inhibitors.
[0062] In one aspect, described herein are SSAO inhibitors and uses thereof. In some
embodiemnts, described herein is a compound that has the structure of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000029_0001
Formula (III);
wherein,
Figure imgf000029_0002
Z is H, F, or Cl;
Figure imgf000030_0001
R1 is C2-6alkenyl, C2-6alkynyl, a saturated monocyclic C2.7heterocycloalkyl, saturated bridged bicyclic C2-9heterocycloalkyl, or saturated spirocyclic C2-9heterocycloalkyl, wherein C2- 6alkenyl, C2-6alkynyl, saturated monocyclic C2-7heterocycloalkyl, saturated bridged bicyclic C2-9heterocycloalkyl, or saturated spirocyclic C2-9heterocycloalkyl are optionally
substituted with one, two, three, four, or five
Figure imgf000030_0002
each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-l0aryl, Ci-9heteroaryl, -R14a, - OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, - N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cydoalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, R14a, -OR8, - SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, - S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
R2 is -C(0)0R4, -0C(0)N(R4)(R5), -N(R6)C(0)N(R4)(R5), -N(R6)C(0)0R7, -N(R6)S(0)2R7, - S(0)R7, -0C(0)R7, -N(R21)C(0)R22, -S(0)2R22, -S(0)2N(R22)(R23), - S(=0)(=NH)N(R4)(R5), -CH2C(0)N(R24)(R25), -CH2N(R21)C(0)R26, -CH2S(0)2R26, or - CH2S(0)2N(R24)(R25);
each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b;
R4 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cydoalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14d;
R6 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R7 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- ioaryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14e;
each R8 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14f;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14g;
each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the
nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h;
each R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
each R13 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R14a, R14b, R14c, R14d, R14e, R14f, R14g, R14h, R14i, R14j, R14k, R141, R14m, and R14n are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6. loaryl, -CH2-C6-ioaryl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6. l0aryl, -CH2-C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci.
ealkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and - 0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
R20 is selected from H and Ci-6alkyl;
R21 is selected from H and Ci-6alkyl;
R22 is selected from Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R14j;
R 23 is selected from H and Ci-6alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14k;
R24 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
R is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R and R together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14m;
R26 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14n;
n is 0, 1, 2, 3, or 4; and
p is 0 or 1.
[0063] For any and all of the embodiments, substituents are selected from among a subset of the listed alternatives. For example, in some embodiments X is -0-, -S-, -S(0)2-, -N(R13)-, or -C(R13)2-. In some embodiments, X is -0-. In some embodiments, X is -S-. In some embodiments, X is - S(0)2-. In some embodiments, X is -N(R13)-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R13)2-. In some embodiments, X is -CH2-.
[0064] In some embodiments, Z is H, F, or Cl. In some embodiments, Z is F. In some
embodiments, Z is Cl. In some embodiments, Z is H.
[0065] In some embodiments, p is 1. In some embodiments, p is 0.
[0066] In some embodiments, Y is -R1. In some embodiments, Y is -I^-R1. In some
embodiments, Y is -L2-R\ In some embodiments, Y is I^-L^R1. In some embodiments, Y is -L2- I^-R1. In some embodiments, L1 is -0-. In some embodiments, L1 is -CH2-. In some embodiments, L2 is -CH2-.
[0067] In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, or four Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci.gheteroaryl, - R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, - C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)OR12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, R1 is a saturated monocyclic C2- 7heterocycloalkyl optionally substituted with one or two Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one or two Rla and each Rla is independently selected from oxo, Ci-6alkyl, Ci-9heteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is a saturated
monocyclic C2-7heterocycloalkyl optionally substituted with one Rla and Rla is selected from Ci. ealkyl, Ci-9heteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and - S(0)2R12.
[0068] In some embodiments, R1 is an unsubstituted saturated monocyclic C2-7heterocycloalkyl.
[0069] In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl substituted with one Rla and Rla is selected from C^alkyl, Ci-9heteroaryl, -R14a, -C(0)OR9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is a saturated
monocyclic C2-7heterocycloalkyl substituted with one Rla and Rla is -C(0)R12. In some
embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl substituted with one Rla and Rla is -S(0)2R12. In some embodiments, R12 is independently selected from Ci-6alkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl and Ci-9heteroaryl, wherein Ci-6alkyl and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141 and each R141 is independently selected from -OH, -NH2, and -N(H)CH3. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl substituted with one Rla and Rla is -C(0)OR9. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl substituted with one Rla and Rla is -C(0)N(R9)(R10). In some embodiments,
R1 is a saturated monocyclic C2-7heterocycloalkyl substituted with one Rla and Rla is - C(0)C(0)N(R9)(R10). In some embodiments, R9 is independently selected from H and Ci-6alkyl optionally substituted with one, two, or three R14g. In some embodiments, R9 is independently selected from H and unsubstituted Ci-6alkyl. In some embodiments, R10 is H. In some
embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl substituted with one Rla and Rla is -R14a. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6.l0aryl, Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci. ehaloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)OR16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), - 0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and -OC(0)R19. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6.l0aryl, Ci. gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -N(R16)(R17), - C(0)0R16, -C(0)N(R16)(R17), -C(0)R19, -S(0)2R19, and -S(0)2N(R16)(R17).
[0070] In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from oxo, Ci-6alkyl, Ci-9heteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from oxo, Ci-6alkyl, and -C(0)R12. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from oxo,
Ci-6alkyl, and -C(0)R12. In some embodiments,
Figure imgf000035_0001
Figure imgf000035_0002
Figure imgf000036_0001
Figure imgf000036_0002
Figure imgf000036_0003
[0074] In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, hexahydropyrimidinyl, oxepanyl, thiepanyl, azapanyl, and azocanyl, wherein pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, homomorpholinyl,
thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, hexahydropyrimidinyl, oxepanyl, thiepanyl, azapanyl, and azocanyl. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, azetidinyl, and tetrahydropyranyl. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl wherein the saturated monocyclic C2-7heterocycloalkyl is piperidine.
[0075] In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl optionally substituted with one, two, three, or four Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, Ci-9heteroaryl, - R14a, -OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, - C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12. In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12. In some embodiments, R1 is a saturated bridged bicyclic C2- 9heterocycloalkyl optionally substituted with one or two Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, C1-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12. In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl optionally substituted with one or two Rla and each Rla is independently selected from oxo, Ci-6alkyl, Ci-9heteroaryl, -R14a, -C(0)0R9, - C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl optionally substituted with one Rla and Rla is selected from
C(0)R12, and
Figure imgf000037_0001
[0076] In some embodiments, R1 is an unsubstituted saturated bridged bicyclic C2- 9heterocycloalkyl.
[0077] In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl substituted with one Rla and Rla is selected from Ci-6alkyl, Ci.gheteroaryl, -R14a, -C(0)OR9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)R12. In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl substituted with one Rla and Rla is - S(0)2R12. In some embodiments, R12 is independently selected from Ci-6alkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl and Ci.gheteroaryl, wherein Ci-6alkyl and Ci.gheteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141 and each R141 is independently selected from -OH, -NH2, and -N(H)CH3. In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)OR9. In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)N(R9)(R10). In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)C(0)N(R9)(R10). In some embodiments, R9 is independently selected from H and Ci. 6alkyl optionally substituted with one, two, or three R14g. In some embodiments, R9 is
independently selected from H and unsubstituted Ci-6alkyl. In some embodiments, R10 is H. In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl substituted with one Rla and Rla is -R14a. In some embodiments, R14a is independently selected from Ci-6alkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6.l0aryl, Ci-9heteroaryl, wherein Ci-6alkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6.l0aryl, Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci.
ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)OR16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and -OC(0)R19. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i0aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci. ehaloalkoxy, -OR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)R19, -S(0)2R19, and - S(0)2N(R16)(R17).
[0078] In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from oxo, Ci-6alkyl, Ci-9heteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is a saturated bridged bicyclic C2-9heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from oxo, Ci-6alkyl, and -C(0)R12. In some embodiments, R1 is a saturated bridged bicyclic C2- 9heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently
Figure imgf000039_0001
[0080] In some embodiments, R1 is a saturated spirocyclic C2-9heterocycloalkyl optionally substituted with one, two, three, or four Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, Ce-ioaryl, Ci-9heteroaryl, - R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, - C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, R1 is a saturated spirocyclic C2-9heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)OR12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, R1 is a saturated spirocyclic C2- 9heterocycloalkyl optionally substituted with one or two Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, R1 is a saturated spirocyclic C2-9heterocycloalkyl optionally substituted with one or two Rla and each Rla is independently selected from oxo, Ci-6alkyl, Ci.gheteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is a saturated spirocyclic C2-9heterocycloalkyl optionally substituted with one Rla and Rla is selected from Ci-6alkyl, Ci. gheteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12.
[0081] In some embodiments, R1 is an unsubstituted saturated spirocyclic C2-9heterocycloalkyl.
[0082] In some embodiments, R1 is a saturated spirocyclic C2-9heterocycloalkyl substituted with one Rla and Rla is selected from C^alkyl, Ci-9heteroaryl, -R14a, -C(0)OR9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is a saturated spirocyclic C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)R12. In some embodiments, R1 is a saturated spirocyclic C2-9heterocycloalkyl substituted with one Rla and Rla is -S(0)2R12. In some embodiments, R12 is independently selected from Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl and Ci-9heteroaryl, wherein Ci-6alkyl and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141 and each R141 is independently selected from -OH, -NH2, and -N(H)CH3. In some embodiments, R1 is a saturated spirocyclic C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)OR9. In some embodiments, R1 is a saturated spirocyclic C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)N(R9)(R10). In some embodiments, R1 is a saturated spirocyclic C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)C(0)N(R9)(R10). In some embodiments, R9 is
independently selected from H and Ci-6alkyl optionally substituted with one, two, or three R14g. In some embodiments, R9 is independently selected from H and unsubstituted Ci-6alkyl. In some embodiments, R10 is H. In some embodiments, R1 is a saturated spirocyclic C2-9heterocycloalkyl substituted with one Rla and Rla is -R14a. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, wherein Ci. 6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci.
Figure imgf000040_0001
OC(0)R19. In some embodiments, R14a is independently selected from Ci-6alkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, wherein Ci-6alkyl, C2- gheterocycloalkyl, -CH2-C2-gheterocycloalkyl, C6.l0aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci. ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)R19, -S(0)2R19, and -S(0)2N(R16)(R17).
[0083] In some embodiments, R1 is a saturated spirocyclic C2-gheterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from oxo, Ci-6alkyl, Ci.gheteroaryl, -R14a, -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is a saturated spirocyclic C2-gheterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from oxo, Ci-6alkyl, and -C(0)R12. In some embodiments, R1 is a saturated spirocyclic C2-gheterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from oxo, Ci-6alkyl, and -C(0)R12.
Figure imgf000041_0001
, , 6alkyl, and C3-6cycloalkyl. [0085] In some embodiments, Y is -R2. In some embodiments, Y is -L2-R2. In some embodiments, L2 is -CH2-. In some embodiments, R2 is -C(0)0R4, -0C(0)N(R4)(R5), -
Figure imgf000042_0001
CH2S(0)2N(R24)(R25). In some embodiments, R2 is -C(0)0R4, -0C(0)N(R4)(R5), - N(R6)C(0)N(R4)(R5), -N(R6)C(0)0R7, -N(R6)S(0)2R7, -C(0)N(R22)(R23), or - CH2C(0)N(R24)(R25). In some embodiments, R2 is -C(0)0R4. In some embodiments, R2 is - 0C(0)N(R4)(R5). In some embodiments, R2 is -N(R6)C(0)N(R4)(R5). In some embodiments, R4 is selected from H, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c. In some embodiments, R4 is selected from H, Ci-6alkyl, and Ci-9heteroaryl, wherein Ci-6alkyl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c. In some embodiments, R5 is H. In some embodiments, R2 is -N(R6)C(0)0R7. In some embodiments, R2 is -N(R6)S(0)2R7. In some embodiments, R7 is selected from Ci-6alkyl, C6- ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14e. In some embodiments, R7 is selected from Ci-6alkyl, C6-i0aryl, and Ci. 9heteroaryl, wherein Ci-6alkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14e. In some embodiments, R7 is Ci-6alkyl optionally substituted with one, two, or three R14e. In some embodiments, R6 is H. In some embodiments, R2 is -C(0)N(R22)(R23). In some embodiments, R2 is -CH2C(0)N(R24)(R25). In some embodiments, R24 is selected from H, Ci. 6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R24 is selected from H and Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments, R25 is H.
[0086] In some embodiments, R20 is H. In some embodiments, R20 is Ci-6alkyl. In some embodiments, R20 is -CH3.
[0087] In some embodiments, n is 0.
[0088] In some embodiments, n is 1. In some embodiments, n is 2.
[0089] In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, C3-
6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12, wherein Ci-6alkyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10), wherein C^alkyl is optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, and -N(R9)(R10). In some embodiments, n is 1 and R3 is halogen. In some embodiments, n is 1 and R3 is Ci-6alkyl.
[0090] In some embodiments, the compound has the structure of Formula (la), (la’), (Iaa), (Iaa’), (lab), (lab’), (lac), (lac’), (lad), or (lad’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000043_0001
Formula (Iaa);
Figure imgf000043_0002
Formula (lab);
Figure imgf000044_0001
Formula (lac’);
Figure imgf000044_0002
Formula (lad’);
wherein,
X is -0-, -S-, -S(0)2-, -N(R13)-, or -C(R13)2-;
Z is H, F, or Cl;
L3 is -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2N(H)CH2-, or -CH2N(CH3)CH2-; Rla is selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, - S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12, wherein C^alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b;
each R8 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14f;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14g;
each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the
nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h;
each R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
each R13 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R14a, R14b, R14f, R14g, R14h, and R141 are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein Chalky!, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, - N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), - N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, - S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
R20 is selected from H and Ci-6alkyl;
n is 0, 1, 2, 3, or 4;
p is 0 or 1 ;
q is 0, 1, or 2; and
w1, w2, w3, and w4 are each independently selected from 1 and 2.
[0091] In some embodiments, X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0)2-. In some embodiments, X is -N(R13)-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R13)2-. In some embodiments, X is -CH2-.
[0092] In some embodiments, Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H.
[0093] In some embodiments, L3 is -CH2CH2-. In some embodiments, L3 is -CH2CH2CH2-. In some embodiments, L3 is -CH2OCH2-. In some embodiments, L3 is -CH2N(H)CH2-. In some embodiments, L3 is -CH2N(CH3)CH2-.
[0094] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.
[0095] In some embodiments, w1, w2, w3, and w4 are each 1. In some embodiments, w1 is 2, and w2, w3, and w4 are each 1. In some embodiments, w1 and w3 are each 2, and w2 and w4 are each 1. In some embodiments, w2 is 2, and w1, w3, and w4 are each 1. In some embodiments, w1 and w2 are each 2, and w3 and w4 are each 1. [0096] In some embodiments, p is 1. In some embodiments, p is 0.
[0097] In some embodiments, Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, Ci.gheteroaryl, -R14a, -OR8, -SR8, - N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, Rla is selected from Ci-6alkyl, Ci-9heteroaryl, -R14a, -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - C(0)R12, and -S(0)2R12. In some embodiments, Rla is -C(0)R12. In some embodiments, Rla is - S(0)2R12. In some embodiments, R12 is independently selected from Ci-6alkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl and Ci.gheteroaryl, wherein Ci-6alkyl and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141 and each R141 is independently selected from -OH, -NH2, and -N(H)CH3. In some embodiments, Rla is -C(0)OR9. In some embodiments, Rla is - C(0)N(R9)(R10). In some embodiments, Rla is -C(0)C(0)N(R9)(R10). In some embodiments, R9 is independently selected from H and Ci-6alkyl optionally substituted with one, two, or three R14g. In some embodiments, R9 is independently selected from H and unsubstituted Ci-6alkyl. In some embodiments, R10 is H. In some embodiments, Rla is -R14a. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci. gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)OR16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), - N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, - S(0)2R19, -S(0)2N(R16)(R17), and -OC(0)R19. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -
Figure imgf000048_0001
[0098] In some embodiments, R20 is H. In some embodiments, R20 is Ci-6alkyl. In some embodiments, R20 is -CH3.
[0099] In some embodiments, n is 0.
[00100] In some embodiments, n is 1. In some embodiments, n is 2.
[00101] In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10), wherein C^alkyl is optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, and -N(R9)(R10). In some embodiments, n is 1 and R3 is halogen. In some embodiments, n is 1 and R3 is Ci-6alkyl.
[00102] In some embodiments, the compound has the structure of Formula (Iae) or (Iae’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000048_0002
Formula (Iae’);
wherein,
X is -0-, -S-, -S(0)2-, -N(R13)-, or -C(R13)2-;
Z is H, F, or Cl; R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, -R14a, -OR8, - SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, - S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14b;
each R8 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14f;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14g;
each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the
nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h;
each R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R141;
each R13 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R14a, R14b, R14f, R14g, R14h, and R141 are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein C^alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, - N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), - N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, - S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl;
R20 is selected from H and Ci-6alkyl;
n is 0, 1, 2, 3, or 4; and
p is 0 or 1.
[00103] In some embodiments, X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0)2-. In some embodiments, X is -N(R13)-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R13)2-. In some embodiments, X is -CH2-.
[00104] In some embodiments, Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H.
[00105] In some embodiments, p is 1. In some embodiments, p is 0.
[00106] In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from oxo, Ci-6alkyl, Ci-9heteroaryl, -R14a, -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from oxo, Ci-6alkyl, and -C(0)R12. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from oxo, Ci-6alkyl, and -C(0)R12. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from oxo and Ci-6alkyl. In some embodiments,
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000052_0001
Figure imgf000052_0002
[00110] In some embodiments, R20 is H. In some embodiments, R20 is Ci-6alkyl. In some embodiments, R20 is -CH3.
[00111] In some embodiments, n is 0.
[00112] In some embodiments, n is 1. In some embodiments, n is 2.
[00113] In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, C3.
6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10), wherein Ci-6alkyl is optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, and -N(R9)(R10). In some embodiments, n is 1 and R3 is halogen. In some embodiments, n is 1 and R3 is Ci-6alkyl.
[00114] In some embodiments, the compound has the structure of Formula (lb), (lb’), (Iba), (Iba’), (Ibb), (Ibb’), (Ibc), (Ibc’), (Ibd), or (Ibd’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000053_0001
Formula (Iba);
Figure imgf000053_0002
Formula (Ibb);
Figure imgf000054_0001
Formula (Ibc’);
Figure imgf000054_0002
Formula (Ibd’); wherein,
L3 is -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2N(H)CH2-, or -CH2N(CH3)CH2-;
Rla is selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -
N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -
S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
R8 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14f;
R9 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14g;
R10 is selected from H and Ci-6alkyl; or R9 and R10, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three
R14h;
R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R12 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
each R14a, R14f, R14g, R14h, and R141 are each independently selected from halogen, -CN, Ci.
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6.10aiyl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein C^alkyl, C2-6alkenyl, C2-6alkynyl, C3.
6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, - N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), - N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, - S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl; each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
q is 0, 1, or 2; and
w1, w2, w3, and w4 are each independently selected from 1 and 2.
[00115] In some embodiments, L3 is -CH2CH2-. In some embodiments, L3 is -CH2CH2CH2-. In some embodiments, L3 is -CH2OCH2-. In some embodiments, L3 is -CH2N(H)CH2-. In some embodiments, L3 is -CH2N(CH3)CH2-.
[00116] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.
[00117] In some embodiments, w1, w2, w3, and w4 are each 1. In some embodiments, w1 is 2, and w2, w3, and w4 are each 1. In some embodiments, w1 and w3 are each 2, and w2 and w4 are each 1. In some embodiments, w2 is 2, and w1, w3, and w4 are each 1. In some embodiments, w1 and w2 are each 2, and w3 and w4 are each 1.
[00118] In some embodiments, Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, - N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, Rla is independently selected from halogen, oxo, Ci-6alkyl, Ci-6haloalkyl, C2-9heterocycloalkyl, Ci-9heteroaryl, -R14a, -OR8, - C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some
embodiments, Rla is selected from Ci-6alkyl, Ci-9heteroaryl, -R14a, -C(0)OR9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, Rla is -C(0)R12. In some embodiments, Rla is -S(0)2R12. In some embodiments, R12 is independently selected from Ci. 6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl and Ci. 9heteroaryl, wherein Ci-6alkyl and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141 and each R141 is independently selected from - OH, -NH2, and -N(H)CH3. In some embodiments, Rla is -C(0)0R9. In some embodiments, Rla is - C(0)N(R9)(R10). In some embodiments, Rla is -C(0)C(0)N(R9)(R10). In some embodiments, R9 is independently selected from H and Ci-6alkyl optionally substituted with one, two, or three R14g. In some embodiments, R9 is independently selected from H and unsubstituted Ci-6alkyl. In some embodiments, R10 is H. In some embodiments, Rla is -R14a. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci. gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), - N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, - S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6.l0aryl, Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, - CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)R19, -S(0)2R19, and -S(0)2N(R16)(R17).
[00119] In some embodiments, the compound has the structure of Formula (Ibe) or (Ibe’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000057_0001
Formula (Ibe’);
wherein,
R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci_9heteroaryl, -R14a, -OR8, - SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, - S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14g;
each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the
nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h;
each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2.6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
each R14a, R14g, R14h, and R141 are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and - 0C(0)R19, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN,
Figure imgf000058_0001
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl; and each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl.
[00120] In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from oxo, Ci-6alkyl, Ci-9heteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from oxo, Ci-6alkyl, and -C(0)R12. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from oxo, Ci-6alkyl, and -C(0)R12. In some embodiments, R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from oxo
and Ci-6alkyl. In some embodiments,
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000060_0004
Figure imgf000060_0001
Figure imgf000060_0002
some embodiments, the compound has the structure of Formula (Ic) or (Ic’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000060_0003
Formula (Ic);
Figure imgf000061_0001
Formula (Ic’);
wherein:
X is -0-, -S-, -S(0)2-, -N(R13)-, or -C(R13)2-;
Z is H, F, or Cl;
each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl,
C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- i0aryl, Ci-9heteroaryl, R14a, -OR8, -SR8, -
N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -
N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -
S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b;
each R8 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14f;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14g;
each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the
nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h;
each R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R141;
each R13 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R14a, R14b, R14f, R14g, R14h, and R141 are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, - N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), - N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, - S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl;
R20 is selected from H and Ci-6alkyl;
n is 0, 1, 2, 3, or 4; and
p is 0 or 1.
[00121] In some embodiments, X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0)2-. In some embodiments, X is -N(R13)-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R13)2-. In some embodiments, X is -CH2-.
[00122] In some embodiments, Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H. [00123] In some embodiments, p is 1. In some embodiments, p is 0.
[00124] In some embodiments, each Rlb is independently selected from H, halogen, -CN, Ci. 6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, R14a, -OR8, - SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, Ci-9heteroaryl, R14a, -OR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10). In some embodiments, each Rlb is independently selected from H, Ci-6alkyl, C3-6cycloalkyl, and R14a. In some embodiments, each Rlb is independently selected from H, Ci. 6alkyl, and C3-6cycloalkyl. In some embodiments, each Rlb is independently selected from H and Ci-6alkyl. In some embodiments, each Rlb is -CH3. In some embodiments, each Rlb is
independently -R14a. In some embodiments, R14a is independently selected from Ci-6alkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6.l0aryl, Ci-9heteroaryl, wherein Ci-6alkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci.
ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)OR16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and -OC(0)R19. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci.
ehaloalkoxy, -OR15, -N(R16)(R17), -C(0)OR16, -C(0)N(R16)(R17), -C(0)R19, -S(0)2R19, and - S(0)2N(R16)(R17).
[00125] In some embodiments, R20 is H. In some embodiments, R20 is Ci-6alkyl. In some embodiments, R20 is -CH3.
[00126] In some embodiments, n is 0.
[00127] In some embodiments, n is 1. In some embodiments, n is 2.
[00128] In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, -N(R9)(R10), -C(0)0R9, - C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10), wherein Ci-6alkyl is optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, and -N(R9)(R10). In some embodiments, n is 1 and R3 is halogen. In some embodiments, n is 1 and R3 is Ci-6alkyl.
[00129] In some embodiments, the compound has the structure of Formula (Id) or (Id’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000064_0001
Formula (Id’);
wherein:
each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- i0aryl, Ci-9heteroaryl, R14a, -OR8, -SR8, - N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, - S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
R8 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14f;
R9 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14g; R10 is selected from H and Ci-6alkyl; or R9 and R10, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three
R14h;
R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R12 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
each R14a, R14f, R14g, R14h, and R141 are each independently selected from halogen, -CN, Ci.
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein C^alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, - N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), - N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, - S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl; and
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl.
[00130] In some embodiments, each Rlb is independently selected from H, halogen, -CN, Ci. 6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, R14a, -OR8, - SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12. In some embodiments, each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, Ci-9heteroaryl, R14a, -OR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10). In some embodiments, each Rlb is independently selected from H, Ci-6alkyl, C3-6cycloalkyl, and R14a. In some embodiments, each Rlb is independently selected from H, Ci. 6alkyl, and C3-6cycloalkyl. In some embodiments, each Rlb is independently selected from H and Ci-6alkyl. In some embodiments, each Rlb is -CH3. In some embodiments, each Rlb is
independently -R14a. In some embodiments, R14a is independently selected from Ci-6alkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6.l0aryl, Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci.
ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i0aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci.
ehaloalkoxy, -OR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)R19, -S(0)2R19, and - S(0)2N(R16)(R17).
[00131] In some embodiments, the compound has the structure of Formula (Ie) or (Ie’), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000066_0001
Formula (Ie’); wherein,
X is -0-, -S-, -S(0)2-, -N(R13)-, or -C(R13)2-;
Z is H, F, or Cl;
each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl,
C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- i0aryl, Ci-9heteroaryl, R14a, -OR8, -SR8, -
N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -
N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -
S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, Ci-9heteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12, wherein C^alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b;
each R8 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14f;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14g;
each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the
nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h;
each R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
each R13 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R14a, R14b, R14f, R14g, R14h, and R141 are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, - N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), - N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, - S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
R20 is selected from H and Ci-6alkyl;
n is 0, 1, 2, 3, or 4; and
p is 0 or 1.
[00132] In some embodiments, X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0)2-. In some embodiments, X is -N(R13)-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R13)2-. In some embodiments, X is -CH2-.
[00133] In some embodiments, Z is F. In some embodiments, Z is Cl. In some embodiments, Z is H.
[00134] In some embodiments, p is 1. In some embodiments, p is 0.
[00135] In some embodiments, each Rlb is independently selected from H, halogen, -CN, Ci. 6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, R14a, -OR8, - SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6- 14a, -OR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, n some embodiments, each Rlb is independently selected from H, Ci-6alkyl,
Figure imgf000069_0001
. In some embodiments, each Rlb is independently selected from H, Ci. 6alkyl, and C3-6cycloalkyl. In some embodiments, each Rlb is independently selected from H and Ci-6alkyl. In some embodiments, each Rlb is -CH3. In some embodiments, each Rlb is
independently -R14a. In some embodiments, R14a is independently selected from Ci-6alkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci.
ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i0aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci.
ehaloalkoxy, -OR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)R19, -S(0)2R19, and - S(0)2N(R16)(R17)In some embodiments, R20 is H. In some embodiments, R20 is Ci-6alkyl. In some embodiments, R20 is -CH3.
[00136] In some embodiments, n is 0.
[00137] In some embodiments, n is 1. In some embodiments, n is 2.
[00138] In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10), wherein Ci-6alkyl is optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, and -N(R9)(R10). In some embodiments, n is 1 and R3 is halogen. In some embodiments, n is 1 and R3 is Ci-6alkyl.
[00139] In some embodiments, the compound has the structure of Formula (If) or (If), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000070_0001
Formula (If);
wherein,
each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, Ci.gheteroaryl, R14a, -OR8, -SR8, - N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, - S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
R8 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14f;
R9 is selected from H, Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14g;
R10 is selected from H and Ci-6alkyl; or R9 and R10, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three
R14h;
R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R12 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R141; each R14a, R14f, R14g, R14h, and R141 are each independently selected from halogen, -CN, Ci.
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein C^alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, - N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), - N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, - S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl; and
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl.
[00140] In some embodiments, each Rlb is independently selected from H, halogen, -CN, Ci. 6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, R14a, -OR8, - SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, Ci-9heteroaryl, R14a, -OR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10). In some embodiments, each Rlb is independently selected from H, Ci-6alkyl, C3-6cycloalkyl, and R14a. In some embodiments, each Rlb is independently selected from H, Ci. 6alkyl, and C3-6Cycloalkyl. In some embodiments, each Rlb is independently selected from H and Ci-6alkyl. In some embodiments, each Rlb is -CH3. In some embodiments, each Rlb is
independently -R14a. In some embodiments, R14a is independently selected from Ci-6alkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2- gheterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-l0aryl, Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci.
ehaloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i0aryl, Ci.gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci.
ehaloalkoxy, -OR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)R19, -S(0)2R19, and - S(0)2N(R16)(R17)In one aspect, described herein are SSAO inhibitors and uses thereof. In one aspect, described herein is a compound that has the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000072_0001
Formula (I);
wherein,
Figure imgf000072_0002
Z is H, F, or Cl;
L1 is -0-, -S-, -S(=0)-, -S(=0)2-, -S(=0)2NR21-, -S(=0)(=NH)NR21-, -CH2-, -CH=CH-, -CºC-,
-C(=0)-, -C(=0)0-, -0C(=0)-, -0C(=0)0-, -C(=0)NR21-, -NR21C(=0)-, -0C(=0)NR21-, -
NR21C(=0)0-, -NR21C(=0)NR21-, -NR21S(=0)2-, or -N(R21)-;
L2 is Ci-6alkyl;
R1 is C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, or Ci-9heteroaryl, wherein C2-6alkenyl, C2- 6alkynyl, C2-9heterocycloalkyl, or Ci.gheteroaryl are optionally substituted with one, two, three, four, or five Rla;
each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci.gheteroaryl, -R14a, - OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, - N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
Figure imgf000073_0001
each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12, wherein C^alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b;
R4 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14d;
R6 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R7 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- l0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14e;
each R8 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14f;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14g;
each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the
nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h; each R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
each R13 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R14a, R14b, R14c, R14d, R14e, R14f, R14g, R14h, R14i, R14j, R14k, R141, R14m, and R14n are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, - OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), - 0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, - N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19, wherein Ci. 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci. ealkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and - 0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
R20 is selected from H and Ci-6alkyl;
R21 is selected from H and Ci-6alkyl;
R22 is selected from Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R14j; R 23 is selected from H and Ci-6alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three
R14k;
R24 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
R is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R and R together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14m;
R26 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14n;
n is 0, 1, 2, 3, or 4; and
p is 0 or 1.
[00141] For any and all of the embodiments, substituents are selected from among a subset of the listed alternatives. For example, in some embodiments X is -0-, -S-, -S(0)2-, -N(R13)-, or -C(R13)2-. In some embodiments, X is -0-. In some embodiments, X is -S-. In some embodiments, X is - S(0)2-. In some embodiments, X is -N(R13)-. In some embodiments, X is -N(H)-. In some embodiments, X is -C(R13)2-. In some embodiments, X is -CH2-.
[00142] In some embodiments, Z is H, F, or Cl. In some embodiments, Z is F. In some
embodiments, Z is Cl. In some embodiments, Z is H.
[00143] In some embodiments, p is 1. In some embodiments, p is 0.
[00144] In some embodiments, Y is -R1. In some embodiments, Y is -I^-R1. In some
embodiments, Y is -L2-R\ In some embodiments, Y is I^-L^R1. In some embodiments, Y is -L2- I^-R1. In some embodiments, L2 is -CH2-. In some embodiments, R1 is C2-6alkynyl, C2- 9heterocycloalkyl, or Ci-9heteroaryl, wherein C2-6alkynyl, C2-9heterocycloalkyl, or Ci-9heteroaryl are optionally substituted with one, two, three, or four Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, C1-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, R1 is C2- 6alkynyl, C2-9heterocycloalkyl, or Ci-9heteroaryl, wherein C2-6alkynyl, C2-9heterocycloalkyl, or Ci. gheteroaryl are optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6. loaryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, - N(Ru)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and - 0C(0)R12. In some embodiments, R1 is C2-9heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci.
6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6. loaryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, - N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12. In some embodiments, R1 is C2-9heterocycloalkyl optionally substituted with one or two Rla and each Rla is independently selected from oxo, Ci. ealkyl, Ci-9heteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and - S(0)2R12. In some embodiments, R1 is C2-9heterocycloalkyl optionally substituted with one Rla and Rla is selected from Ci-6alkyl, Ci-9heteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is unsubstituted C2- gheterocycloalkyl.
[00145] In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is selected from C^alkyl, Ci-9heteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - C(0)R12, and -S(0)2R12. In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)R12. In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is -S(0)2R12. In some embodiments, R12 is independently selected from Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl and Ci-9heteroaryl, wherein Ci-6alkyl and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141 and each R141 is independently selected from -OH, -NH2, and -N(H)CH3. In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)0R9. In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is - C(0)N(R9)(R10). In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)C(0)N(R9)(R10). In some embodiments, R9 is independently selected from H and Ci-6alkyl optionally substituted with one, two, or three R14g. In some embodiments, R9 is independently selected from H and unsubstituted Ci-6alkyl. In some embodiments, R10 is H. In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is -R14a. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci.
ehaloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), - 0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci. gheteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -N(R16)(R17), - C(0)0R16, -C(0)N(R16)(R17), -C(0)R19, -S(0)2R19, and -S(0)2N(R16)(R17).
[00146] In some embodiments, R1 is C2-9heterocycloalkyl wherein C2-9heterocycloalkyl is piperidine.
[00147] In some embodiments, R1 is Ci-9heteroaryl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), - C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)OR12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, R1 is Ci-9heteroaryl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, -R14a, -OR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10).
[00148] In some embodiments, Y is -R2. In some embodiments, Y is -L2-R2. In some
embodiments, L2 is -CH2-. In some embodiments, R2 is -C(0)OR4, -0C(0)N(R4)(R5), - N(R6)C(0)N(R4)(R5), -N(R6)C(0)0R7, -N(R6)S(0)2R7, -C(0)R7, -C(0)N(R22)(R23), -S(0)2R22, - S(0)2N(R22)(R23), -S(=0)(=NH)N(R4)(R5), -CH2C(0)N(R24)(R25), -CH2S(0)2R26, or - CH2S(0)2N(R24)(R25). In some embodiments, R2 is -C(0)OR4, -0C(0)N(R4)(R5), - N(R6)C(0)N(R4)(R5), -N(R6)C(0)0R7, -N(R6)S(0)2R7, -C(0)N(R22)(R23), or - CH2C(0)N(R24)(R25). In some embodiments, R2 is -C(0)OR4. In some embodiments, R2 is - 0C(0)N(R4)(R5). In some embodiments, R2 is -N(R6)C(0)N(R4)(R5). In some embodiments, R4 is selected from H, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c. In some embodiments, R4 is selected from H, Ci-6alkyl, and Ci.gheteroaryl, wherein Ci-6alkyl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c. In some embodiments, R5 is H. In some embodiments, R2 is -N(R6)C(0)0R7. In some embodiments, R2 is -N(R6)S(0)2R7. In some embodiments, R7 is selected from Ci-6alkyl, C6- l0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14e. In some embodiments, R7 is selected from Ci-6alkyl, C6-i0aryl, and Ci. 9heteroaryl, wherein Ci-6alkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14e. In some embodiments, R7 is Ci-6alkyl optionally substituted with one, two, or three R14e. In some embodiments, R6 is H. In some embodiments, R2 is -C(0)N(R22)(R23). In some embodiments, R2 is -CH2C(0)N(R24)(R25). In some embodiments, R24 is selected from H, Ci. 6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R24 is selected from H and Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments, R25 is H.
[00149] In some embodiments, R20 is H. In some embodiments, R20 is Ci-6alkyl. In some embodiments, R20 is -CH3.
[00150] In some embodiments, n is 0.
[00151] In some embodiments, n is 1. In some embodiments, n is 2.
[00152] In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10), wherein C^alkyl is optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, and -N(R9)(R10). In some embodiments, n is 1 and R3 is halogen. In some embodiments, n is 1 and R3 is Ci-6alkyl.
[00153] In another aspect, described herein is a compound that has the structure of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
Figure imgf000079_0001
Formula (II);
wherein,
Figure imgf000079_0002
R1 is C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, or Ci-9heteroaryl, wherein C2-6alkenyl, C2- 6alkynyl, C2-9heterocycloalkyl, or Ci-9heteroaryl are optionally substituted with one, two, three, four, or five Rla;
each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-
Figure imgf000079_0003
each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14b;
R4 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14d;
R6 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R7 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- ioaryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14e;
each R8 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14f;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14g;
each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the
nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h;
each R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
each R13 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R14a, R14b, R14c, R14d, R14e, R14f, R14g, R14h, R14i, R14j, R14k, R141, R14m, and R14n are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6. loaryl, -CH2-C6-ioaryl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6. l0aryl, -CH2-C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci.
ealkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and - 0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl;
R20 is selected from H and Ci-6alkyl;
R21 is selected from H and Ci-6alkyl;
R22 is selected from Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R14j;
R 23 is selected from H and Ci-6alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14k;
R24 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
R is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R and R together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14m;
R26 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14n;
n is 0, 1, 2, 3, or 4; and
p is 0 or 1.
[00154] In some embodiments X is -0-, -S-, -S(0)2-, -N(R13)-, or -C(R13)2-. In some embodiments, X is -0-. In some embodiments, X is -S-. In some embodiments, X is -S(0)2-. In some
embodiments, X is -N(R13)-. In some embodiments, X is -N(H)-. In some embodiments, X is - C(R13)2-. In some embodiments, X is -CH2-.
[00155] In some embodiments, Z is H, F, or Cl. In some embodiments, Z is F. In some
embodiments, Z is Cl. In some embodiments, Z is H.
[00156] In some embodiments, p is 1. In some embodiments, p is 0.
[00157] In some embodiments, Y is -R1. In some embodiments, Y is -I^-R1. In some
embodiments, Y is -L2-R\ In some embodiments, Y is I^-L^R1. In some embodiments, Y is -L2- I^-R1. In some embodiments, L2 is -CH2-. In some embodiments, R1 is C2-6alkynyl, C2- gheterocycloalkyl, or Ci.gheteroaryl, wherein C2-6alkynyl, C2-9heterocycloalkyl, or Ci.gheteroaryl are optionally substituted with one, two, three, or four Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, R1 is C2- 6alkynyl, C2-9heterocycloalkyl, or Ci-9heteroaryl, wherein C2-6alkynyl, C2-9heterocycloalkyl, or Ci. 9heteroaryl are optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- loaryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, - N(Ru)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and - OC(0)R12. In some embodiments, R1 is C2-9heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci.
6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- i0aryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, - N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, R1 is C2-9heterocycloalkyl optionally substituted with one or two Rla and each Rla is independently selected from oxo, Ci. ealkyl, Ci-9heteroaryl, -R14a, -C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and - S(0)2R12. In some embodiments, R1 is C2-9heterocycloalkyl optionally substituted with one Rla and Rla is selected from C^alkyl, Ci-9heteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), - C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12. In some embodiments, R1 is unsubstituted C2- gheterocycloalkyl.
[00158] In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is selected from C^alkyl, Ci-9heteroaryl, -R14a, -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - C(0)R12, and -S(0)2R12. In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)R12. In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is -S(0)2R12. In some embodiments, R12 is independently selected from Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl and Ci-9heteroaryl, wherein Ci-6alkyl and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments, R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141 and each R141 is independently selected from -OH, -NH2, and -N(H)CH3. In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)0R9. In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is - C(0)N(R9)(R10). In some embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is -C(0)C(0)N(R9)(R10). In some embodiments, R9 is independently selected from H and Ci-6alkyl optionally substituted with one, two, or three R14g. In some embodiments, R9 is independently selected from H and unsubstituted Ci-6alkyl. In some embodiments, R10 is H. In some
embodiments, R1 is C2-9heterocycloalkyl substituted with one Rla and Rla is -R14a. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci.
ehaloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), - 0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19. In some embodiments, R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-i0aryl, Ci. 9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -N(R16)(R17), - C(0)0R16, -C(0)N(R16)(R17), -C(0)R19, -S(0)2R19, and -S(0)2N(R16)(R17).
[00159] In some embodiments, R1 is C2-9heterocycloalkyl wherein C2-9heterocycloalkyl is piperidine.
[00160] In some embodiments, R1 is Ci_9heteroaryl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), - C(0)OR9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)OR12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12. In some embodiments, R1 is Ci-9heteroaryl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, -R14a, -OR8, -N(R9)(R10), -C(0)OR9, -C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10).
[00161] In some embodiments, Y is -R2. In some embodiments, Y is -L2-R2. In some
embodiments, L2 is -CH2-. In some embodiments, R2 is -C(0)OR4, -0C(0)N(R4)(R5), - N(R6)C(0)N(R4)(R5), -N(R6)C(0)0R7, -N(R6)S(0)2R7, -C(0)R7, -C(0)N(R22)(R23), -S(0)2R22, - S(0)2N(R22)(R23), -S(=0)(=NH)N(R4)(R5), -CH2C(0)N(R24)(R25), -CH2S(0)2R26, or - CH2S(0)2N(R24)(R25). In some embodiments, R2 is -C(0)OR4, -0C(0)N(R4)(R5), - N(R6)C(0)N(R4)(R5), -N(R6)C(0)0R7, -N(R6)S(0)2R7, -C(0)N(R22)(R23), or - CH2C(0)N(R24)(R25). In some embodiments, R2 is -C(0)OR4. In some embodiments, R2 is - 0C(0)N(R4)(R5). In some embodiments, R2 is -N(R6)C(0)N(R4)(R5). In some embodiments, R4 is selected from H, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14c. In some embodiments, R4 is selected from H, Ci-6alkyl, and Ci-9heteroaryl, wherein Ci-6alkyl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c. In some embodiments, R5 is H. In some embodiments, R2 is -N(R6)C(0)0R7. In some embodiments, R2 is -N(R6)S(0)2R7. In some embodiments, R7 is selected from Ci-6alkyl, C6- !oaryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14e. In some embodiments, R7 is selected from Ci-6alkyl, C6.l0aryl, and Ci. 9heteroaryl, wherein Ci-6alkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14e. In some embodiments, R7 is Ci-6alkyl optionally substituted with one, two, or three R14e. In some embodiments, R6 is H. In some embodiments, R2 is -C(0)N(R22)(R23). In some embodiments, R2 is -CH2C(0)N(R24)(R25). In some embodiments, R24 is selected from H, Ci. 6alkyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141. In some embodiments, R24 is selected from H and Ci-6alkyl optionally substituted with one, two, or three R141. In some embodiments, R25 is H.
[00162] In some embodiments, R20 is H. In some embodiments, R20 is Ci-6alkyl. In some embodiments, R20 is -CH3.
[00163] In some embodiments, n is 0.
[00164] In some embodiments, n is 1. In some embodiments, n is 2.
[00165] In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -N(RU)C(0)OR12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -OC(0)R12, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, -N(R9)(R10), -C(0)OR9, - C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10), wherein C^alkyl is optionally substituted with one, two, or three R14b. In some embodiments, n is 1 and R3 is selected from halogen, -CN, Ci-6alkyl, -OR8, and -N(R9)(R10). In some embodiments, n is 1 and R3 is halogen. In some embodiments, n is 1 and R3 is Ci-6alkyl.
[00166] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
[00167] In some embodiments, compounds described herein include, but are not limited to, those described in Table 1.
TABLE 1
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
* indicates bridgehead isomer not determined
[00168] In some embodiments, provided herein is a pharmaceutically acceptable salt or solvate of a compound that is described in Table 1.
[00169] In some embodiments, compounds described herein include, but are not limited to, those described in Table 2. TABLE 2
Figure imgf000107_0001
[00170] In some embodiments, provided herein is a pharmaceutically acceptable salt or solvate of a compound that is described in Table 2.
[00171] In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
[00172] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
[00173] The term“pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use , Weinheim/Ziirich: Wiley - VCH/VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms.
Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible, and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
[00174] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt." In some embodiments, the compound described herein (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and
metaphosphoric acid. Organic acids include, but are not limited to, l-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);
benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- lO-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecyl sulfuric acid; ethane-l,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid;
hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene- 1, 5 -di sulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid {p ); and undecylenic acid.
[00175] In some embodiments, a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.
[00176] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to provide a "pharmaceutically acceptable base addition salt." [00177] In some embodiments, the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.
[00178] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.
[00179] The methods and formulations described herein include the use of N- oxides (if
appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.
[00180] In some embodiments, sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
[00181] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of
chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. [00182] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be
incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, 2H, 3H, 13C, 14C, 15N, 180, 170, 35 S, 18F, 36Cl. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half- life or reduced dosage requirements. In some embodiments, one or more hydrogen atoms of the compounds described herein is replaced with deuterium.
[00183] In some embodiments, the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.
[00184] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and/or the separation of stereoisomers by chiral chromatographic columns. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment,
diastereomers are separated by separation/resolution techniques based upon differences in solubility. In other embodiments, separation of steroisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen,“Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.
[00185] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. The prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the“prodrug”) but then is metabolically hydrolyzed to provide the active entity. A further example of a prodrug is a short peptide
(polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
[00186] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al ., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard,
H.“Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and El. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester,
alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphate ester, sugar ester, ether, and the like. In some embodiments, a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group. In some embodiments, compounds described herein are prepared as alkyl ester prodrugs.
[00187] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound.
[00188] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound described herein as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound. In some embodiments, a prodrug of the compound disclosed herein permits targeted delivery of the compound to a particular region of the gastrointestinal tract.
Formation of a pharmacologically active metabolite by the colonic metabolism of drugs is a commonly used“prodrug” approach for the colon-specific drug delivery systems.
[00189] In some embodiments, a prodrug is formed by the formation of a covalent linkage between drug and a carrier in such a manner that upon oral administration the moiety remains intact in the stomach and small intestine. This approach involves the formation of prodrug, which is a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation in the biological environment to release the active drug. Formation of prodrugs has improved delivery properties over the parent drug molecule. The problem of stability of certain drugs from the adverse environment of the upper gastrointestinal tract can be eliminated by prodrug formation, which is converted into parent drug molecule once it reaches into the colon. Site specific drug delivery through site specific prodrug activation may be accomplished by the utilization of some specific property at the target site, such as altered pH or high activity of certain enzymes relative to the non-target tissues for the prodrug-drug conversion.
[00190] In some embodiments, covalent linkage of the drug with a carrier forms a conjugate conjugate. Such conjugates include, but are not limited to, azo bond conjugates, glycoside conjugates, glucuronide conjugates, cyclodextrin conjugates, dextran conjugates or amino-acid conjugates.
[00191] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
[00192] A“metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds. [00193] In some embodiments, the compounds described herein are rapidly metabolized following absorption from the gastro-intestinal tract to metabolites that have greatly reduced SSAO inhibitor activity.
[00194] In additional or further embodiments, the compounds are rapidly metabolized in plasma.
[00195] In additional or further embodiments, the compounds are rapidly metabolized by the intestines.
[00196] In additional or further embodiments, the compounds are rapidly metabolized by the liver.
Synthesis of Compounds
[00197] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.
[00198] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.
[00199] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. The starting materials are available from commercial sources or are readily prepared.
[00200] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed.,
Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An
Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C.
"Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley- VCH, ISBN: 3-527-29871- 1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and
Intermediates: An ETllmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and
"Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
[00201] The compounds described herein are prepared by the general synthetic routes described below in Schemes 1 to 7.
[00202] In some embodiments, intermediates used in the preparation of compounds described herein are prepared as outlined in Scheme 1.
Scheme 1
Figure imgf000114_0001
[00203] In Scheme 1, substituents Y, R3, n and p are as described herein.
[00204] In some embodiments, intermediate 1-1 is reacted to incorporate a suitable amine protecting group. In some embodiments, a suitable protecting group is a Boc group to provide intermediate 1-2. In some embodiments suitable conditions include the use of Boc20 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments the base is an organic base such as triethylamine. In some embodiments the appropriate solvent is an alcohol solvent such as methanol. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00205] In some embodiments, 1-2 is subjected to suitable conditions to incorporate a primary alcohol protecting group. In some embodiments, a suitable protecting group is a silyl protecting group such as /-butyldimethyl silyl (TBS) to provide intermediate 1-3. In some embodiments conditions include the use an appropriate reagent such as TBS-C1 using an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base is imidazole. In some embodiments, the appropriate solvent is a chlorinated solvent such as dichloromethane. In some embodiments, the suitable temperature is about 0 °C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00206] In some embodiments, 1-3 is reacted under suitable oxidization conditions to provide intermediate 1-4. In some embodiments, the alcohol is oxidized under Swem oxidation conditions using an appropriate reagent such as oxalyl chloride with an appropriate base in an appropriate solvent or solvent mixture at an appropriate temperature and an appropriate amount of time. In some embodiments, the appropriate base is an organic base such as triethylamine. In some embodiments, the appropriate the solvent is a chlorinated solvent such as dichloromethane. In some embodiments, the suitable temperature is about -78 °C to room temperature and the appropriate amount of time is about 2 to 18 hours (overnight).
[00207] In some embodiments, 1-4 is reacted under suitable one carbon-homologation conditions to provide 1-5. In some embodiments, suitable one carbon-homologation conditions include the use of phosphonium reagents. In some embodiments, suitable one-carbon-homologation conditions includes pre-treating either (fluoromethyl)triphenylphosphonium bromide or tetrafluorob orate salt with an appropriate base, with an appropriate solvent for an appropriate amount of time at an appropriate temperature before the addition of 1-4. In some embodiments, the appropriate base is NaHMDS. In some embodiments, the appropriate solvent is an ethereal solvent such as THF. In some embodiments, the appropriate temperature and amount of time before addition to 1-4 is about 30 mins at about -20 °C. In some embodiments, after 1-4 is added the reaction is continued for an additional about 2 to 18 hours (overnight) at about room temperature. In some embodiments, 1-5 was isolated as mixture of regioisomers. In some embodiments, the regioisomers of 1-5 were separated by flash chromatography under appropriate conditions. In some embodiments, appropriate conditions for separation of the regioisomers was flash chromatography using silica gel, eluting with an appropriate solvent system such as a mixture of hexanes and ethyl acetate. [00208] In some embodiments, 1-5 is reacted under suitable conditions to remove the alcohol protecting group to provide intermediate 1-6. In some embodiments, appropriate conditions include using tetrabutylammonium fluoride in a suitable solvent at an appropriate temperature and amount of time. In some embodiments, the appropriate solvent is an ethereal solvent such as THF. In some embodiments, the appropriate temperature and time is about 1 to 18 hour (overnight) at about room temperature. In some embodiments, further purification via flash chromatography using an appropriate solvent system provide the pure E- or Z-isomers of 1-6. In some embodiments, appropriate conditions for separation of the regioisomers was flash chromatography using silica gel, eluting with an appropriate solvent system such as a mixture of hexanes and ethyl acetate.
[00209] In some embodiments, 1-6 is reacted under suitable conditions to provide intermediate 1-7. In some embodiments, appropriate conditions include using methanesulfonyl chloride using an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base is an organic base such as triethylamine. In some embodiments, the appropriate solvent is acetone. In some embodiments, the appropriate temperature and time is about 0 °C and about lh. In some embodiments, the reaction mixture is filtered and the filtrate is used directly as a solution of intermediate 1-7 in acetone.
[00210] In some embodiments, 1-7 is reacted under suitable conditions to provide intermediate bromide 1-8. In some embodiments, appropriate conditions include using lithium bromide in an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate solvent is acetone. In some embodiments, the appropriate temperature and time is about room temperature and about lh.
[00211] In some embodiments, 1-8 is reacted with intermediate 1-9 under suitable conditions to provide intermediate 1-10. In some embodiments, 1-9 is 4-(pyrimidin-2-yl)phenol, 4-(pyridin-2- yl)phenol or 4-(lH-pyrazol-l-yl)phenol. In some embodiments, 1-9 is 4-(lH-tetrazol-5-yl)phenol, 4- (3-methyl-l,2,4-oxadiazol-5-yl)phenol, 4-(3-isopropyl-l,2,4-oxadiazol-5-yl)phenol, 4-(l -ethyl- 1H- tetrazol-5-yl)-phenol, 4-(5-methyl-l,3,4-oxadiazol-2-yl)phenol, 4-(5-amino-lH-l,2,4-triazol-3- yl)phenol, 4-(5-methyl-l,2,4-oxadiazol-3-yl)phenol, 4-(5-amino-l,3,4-oxadiazol-2-yl)phenol, 4- oxazol-2-yl-phenol, 4-(l,3,4-oxadiazol-2-yl)phenol, 4-(3,5-dimethyl-lH-pyrazol-4-yl)phenol, 4- (lH-pyrazol-4-yl)phenol, 2-(4-hydroxy-phenyl)-oxazole-4-carboxylic acid ethyl ester, 4-(4H-l,2,4- triazol-3-yl)phenol, ethyl 2-(4'-hydroxyphenyl)-l,3-oxazole-4-carboxylate, 4-[l,3,4]oxadiazol-2-yl- phenol, 4-(l-methyl-lH-l,2,4-triazol-5-yl)phenol, 4-(l-ethyl-lH-l,2,3,4-tetrazol-5-yl)phenol or 4- [5-(trifluoromethyl)-l,2,4-oxadiazol-3-yl]phenol. In some embodiments, 1-9 is tert-butyl 4-(4- hydroxyphenyl)piperidine-l-carboxylate, tert-butyl 3-(4-hydroxyphenyl)pyrrolidine-l-carboxylate or tert-butyl 3-(4-hydroxyphenyl)azetidine-l-carboxylate. In some embodiments, 1-9 is 2-(4- hydroxyphenyl)-N-isopropyloxazole-4-carboxamide, 4-(3,5-dimethylisoxazol-4-yl)phenol, 4-(3- amino-5-methylisoxazol-4-yl)phenol, 5-(4-hydroxyphenyl)imidazolidine-2,4-dione, 4-(l-isopropyl- lH-pyrazol-4-yl)phenol, 4-(l,3-dimethyl-lH-pyrazol-4-yl)phenol, 3-methyl-4-(3-methyl-lH- pyrazol-4-yl)phenol, 4-(l,4-dimethyl-lH-pyrazol-5-yl)phenol, 4-(4-hydroxyphenyl)tetrahydro-2H- pyran-4-carbonitrile, 4-(3-amino-5-methyl-lH-pyrazol-4-yl)phenol, 4-(3-(tert-butyl)-5-methyl-lH- pyrazol-4-yl)phenol, 4-(pyridin-3-yl)phenol, 4-(pyridin-4-yl)phenol, 4-(3-methylpyridin-2- yl)phenol, 4-(pyrimidin-5-yl)phenol, 4-(4,6-dimethylpyrimidin-5-yl)phenol, 4-(4- hydroxyphenyl)tetrahydro-2H-thiopyran l, l-dioxide, 4-(pyrazin-2-yl)phenol, 4-(3 -methyl pyrazin- 2-yl)phenol, 6-(4-hydroxyphenyl)pyridin-3-ol, 6-(4-hydroxyphenyl)nicotinamide, 4-(lH-indazol-7- yl)phenol, 4-(4-hydroxyphenyl)piperidin-2-one, 4-(4-hydroxyphenyl)pyrrolidin-2-one, l-(3-(4- hydroxyphenyl)pyrrolidin-l-yl)ethenone or l-(4-(4-hydroxyphenyl)piperazin-l-yl)ethenone. In some embodiments, appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate. In some embodiments, the appropriate solvent is THF, DMF or DMA. In some embodiments, the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
[00212] In some embodiments, intermediate 1-6 is reacted under Mitsunobu reaction conditions with intermediate 1-9 using appropriate reagents in an appropriate solvent or solvent mixture at an appropriate temperature and an appropriate amount of time to provide intermediate 1-10. In some embodiments, the appropriate reagents are triphenylphosphine and diisopropyl azodi carboxyl ate. In some embodiments, the appropriate solvent is an ethereal solvent such as THF. In some
embodiments, the appropriate temperature is about 0 °C to about room temperature. In some embodiments, the appropriate amount of time is about 18 hours (overnight).
[00213] In some embodiments, 1-10 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound I- 11. In some embodiments, the appropriate acid is HC1 or TFA. In some embodiments, the appropriate solvent is Et20, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight). In some embodiments, 1-10 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound 1-11.
[00214] In some embodiments, intermediate 1-9 used in the preparation of compounds 1-10 described herein are prepared as outlined in Scheme 2. Scheme 2
Figure imgf000118_0001
11-12 11-13 I-9
[00215] In Scheme 2, substituents R3 and n are as described herein.
[00216] In some embodiments intermediate 11-13 is prepared from halide 11-12 using boron- halogen exchange conditions. Suitable boron-halogen exchange conditions include but are not limited to use of a suitable organometallic reagent and a suitable boron reagent. In some embodiments, suitable organometallic reagents include palladium. In some embodiments, suitable boron reagents include bis(pinacolato)diboron. In some embodiments, suitable palladium- catalyzed boron-halogen exchange conditions include Pd(dppf)Cl2 with an appropriate base, in an appropriate solvent for an appropriate time and at an appropriate temperature.
[00217] In some embodiments, intermediate 11-13 is reacted with an aromatic halide (R3-halide) under suitable metal-catalyzed cross-coupling reaction conditions to provide intermediate 1-9. In some embodiments, the aromatic halide is an aromatic chloride, bromide or iodide. In some embodiments, the aromatic halide is 2-chloropyrimidine. In some embodiments, suitable metal- catalyzed cross-coupling conditions include use of palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(PPh3)2Cl2 with an appropriate base, in an appropriate solvent for an appropriate time and at an appropriate temperature. In some embodiments, the base is an inorganic base such as Na2C03. In some embodiments, the appropriate solvent is a dioxane/water, or DMF/water mixture. In some embodiments, the appropriate temperature is about 50 °C to about 90 °C. In some embodiments, the appropriate time is about 0.5 hours to about 18 hours (overnight). In some embodiments, the phenol group of intermediate 11-13 is substituted with an appropriate protecting group prior to the metal -catalyzed cross-coupling reaction and subsequently removed under appropriate conditions.
[00218] In some embodiments, halide 11-12 is reacted with a nitrogen-containing heterocycle under suitable metal-catalyzed cross-coupling reaction conditions to provide A -linked intermediate 1-9. In some embodiments, the nitrogen-containing heterocycle is l//-pyrazole. In some embodiments, suitable metal-catalyzed cross-coupling conditions include use of copper. In some embodiments, suitable copper-catalyzed cross-coupling reaction conditions include the use of copper (I) iodide with an appropriate base in an appropriate solvent for an appropriate time and at an appropriate temperature. In some embodiments, an appropriate base is an inorganic base such as cesium carbonate. In some embodiments, an appropriate solvent is DMF. In some embodiments, the appropriate time and appropriate temperature is about 120 °C for about 18 hours (overnight). In some embodiments, the phenol group of intermediate 11-13 is substituted with an appropriate protecting group prior to the metal -catalyzed cross-coupling reaction. In some embodiments, the protecting group is a methyl group. In some embodiments, deprotection conditions include using boron tribromide with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate solvent is a chlorinated solvent such as DCM. In some embodiments, the reaction temperature is about 0 °C to about room temperature and the reaction time is about 18 hours (overnight).
[00219] In some embodiments, aryl halide 11-12 is reacted with a boron reagent under suitable metal -catalyzed cross-coupling reaction conditions to directly provide 1-9. In some embodiments, the boron reagent is an aromatic boronic acid. In some embodiments, the boron reagent is an aromatic boronic ester. In some embodiments, the boron reagent is an aromatic pinacolyl boronic ester. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl2 with an appropriate base, with an appropriate solvent for an appropriate time and at an appropriate temperature. In some embodiments, the phenol group of intermediate 11-12 is substituted with an appropriate protecting group prior to metal -catalyzed cross-coupling reaction.
[00220] In some embodiments, compound is prepared from appropriate metal-catalyzed cross coupling conditions of halide 11-12 with a tin reagent. In some embodiments, halide 11-12 is a bromide. In some embodiments, the tin reagent is an aromatic tin reagent. In some embodiments, metal -catalyzed cross couplings include Stille palladium-catalyzed cross-coupling conditions.
Suitable palladium catalysts for cross-coupling include but are not limited to Pd(PPh3)4 in a suitable solvent, such as DMF or dioxane, at a suitable temperature for an appropriate amount of time. In some embodiments, the suitable temperature is 90 °C to about 100 °C. In some embodiments, the appropriate amount of time is about 2 hours to about 18 hours (overnight).
[00221] In some embodiments, compound 1-9 is directly prepared from appropriate metal- catalyzed cross coupling conditions of halide 11-12 with an aromatic compound. In some embodiments, halide 11-12 is a bromide. In some embodiments, metal-catalyzed cross couplings include C-H activation cross-coupling conditions. In some embodiments, C-H activation cross coupling conditions include use of palladium catalysts. Suitable palladium catalysts for cross coupling include but are not limited to Pd(OAc)2 with a suitable ligand in a suitable solvent, such as dioxane, with an appropriate base at a suitable temperature for an appropriate amount of time. In some embodiments, the suitable ligand is a phosphine ligand. In some embodiments, the appropriate base is an inorganic base. In some embodiments, the suitable temperature is about 50 °C to about 110 °C. In some embodiments, the appropriate amount of time is about 2 hours to about 18 hours (overnight).
[00222] In some embodiments, intermediates used in the preparation of compounds described herein are prepared as outlined in Scheme 3.
Scheme 3
Figure imgf000120_0001
[00223] In Scheme 3, substituents X, Z, Rla, R3, n, and p are as described herein. In some embodiments, X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
[00224] In some embodiments, ketone III-l is treated with a base to form an enolate with an appropriate base, in an appropriate solvent, for an appropriate amount of time, at an appropriate temperature. In some embodiments, the base is an organic base. In some embodiments, the organic base is LiHMDS. In some embodiments, enolate formation takes place at about -78 °C. In some embodiments, the appropriate solvent is THF. In some embodiments, the appropriate time is about one hour. In some embodiments, the enolate of ketone III-l is reacted with a suitable electrophile in an appropriate solvent to form enol ether III-2 at the appropriate temperature, for an appropriate amount of time. In some embodiments, the electrophile forms a sulfate ester. In some
embodiments, the electrophile is PhNTf2. In some embodiments, the appropriate temperature is about -78 °C and the appropriate time is about 2 hours. In some embodiments, the reaction is further warmed to a suitable temperature over a suitable period of time. In some embodiments, the suitable temperature is about room temperature for about overnight.
[00225] In some embodiments, a suitable boronic acid is reacted with enol triflate III-2 under suitable metal -catalyzed cross-coupling reaction conditions to provide III-3. In some
embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)Cl2 with an appropriate base, with an appropriate solvent for an appropriate time and at an appropriate temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base such as Na2C03. In some embodiments, the appropriate solvent is a dioxane/water mixture. In some embodiments, the appropriate time and appropriate temperature is about 6 hours at about 30 °C. In some embodiments, the appropriate time and appropriate temperature is about 1 to about 18 hours at about 80 °C.
[00226] In some embodiments, III-3 is subjected under suitable olefin reduction conditions to provide III-4. In some embodiments, suitable reduction conditions include palladium-catalyzed hydrogenation conditions. In some embodiments, palladium-catalyzed hydrogenation conditions include use of 10% Pd/C with hydrogen (1 atm) in a suitable solvent, such as MeOH, for an appropriate amount of time at an appropriate temperature. In some embodiments, the appropriate amount of time is about overnight at about rt.
[00227] In some embodiments, the acylation of amine III-7 affords compound III-4. In some embodiments, suitable acylation conditions include the use of acetyl acetate with a suitable base, such as K2C03, in a suitable solvent, such as dioxane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 2 hours. In some embodiments wherein X is O, the oxygen is also concurrently acylated under the acylation reaction conditions.
In some embodiments, the synthetic method further comprises the hydrolysis of the ester intermediate formed in the acylation reaction. In some embodiments, suitable ester hydrolysis conditions include the use of a suitable base, such as KOH, in a suitable solvent, such as dioxane/water, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 4 hours to provide III-4.
[00228] In some embodiments, the reaction of amine III-7 with a sulfonyl chloride affords compound III-4. In some embodiments, suitable conditions include the use of MsCl in a suitable solvent, such as dichloromethane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 18 hours. In some embodiments wherein X is O, the oxygen is also concurrently sulfonated under the reaction conditions. In some embodiments, the synthetic method further comprises the hydrolysis of the sulfonate ester intermediate formed in the reaction. In some embodiments, suitable sulfonate ester hydrolysis conditions include the use of a suitable base, such as NaOH, in a suitable solvent, such as MeOH/water, for an appropriate amount of time and at a suitable temperature, such as about 80 °C for about 1 hour to provide III-4.
[00229] In some embodiments, intermediate III-7 is reacted to incorporate a suitable amine protecting group. In some embodiments, a suitable protecting group is a Boc group to provide intermediate III-4. In some embodiments suitable conditions include the use of Boc20 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments the base is an organic base such as triethylamine. In some embodiments the appropriate solvent is an alcohol solvent such as methanol. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00230] In some embodiments, III-7 is subjected to suitable conditions to incorporate a primary alcohol protecting group. In some embodiments, a suitable protecting group is a silyl protecting group such as teoc (2-(trimethylsilyl)ethoxycarbonyl) group, to provide intermediate III-4. In some embodiments conditions include the use of the appropriate silyl-based reagent using an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base is triethylamine. In some embodiments, the appropriate solvent is THF. In some embodiments, the suitable temperature is about 0 °C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00231] In some embodiments, III-5 is reacted with intermediate III-4 under suitable conditions to provide intermediate III-6. In some embodiments, appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate. In some embodiments, the appropriate solvent is THF, DMF or DMA. In some embodiments, the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
[00232] In some embodiments, III-6 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound III-8. In some embodiments, the appropriate acid is HC1 or TFA. In some
embodiments, the appropriate solvent is Et20, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight). In some embodiments, III-6 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound III-8. [00233] In some embodiments, compounds described herein are prepared as outlined in Scheme 4.
Scheme 4
Figure imgf000123_0001
[00234] In Scheme 4, substituents X, Z, Rla, R3, n, and p are as described herein. In some embodiments, X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
[00235] In some embodiments of intermediate III-6 wherein Rla is a Boc protecting group, intermediate III-6 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV- 1. In some embodiments, the appropriate solvent is THF. In some embodiments, the reaction temperature is about room temperature and the reaction time is about 18 hours (overnight).
[00236] In some embodiments of intermediate III-6 wherein Rla is a teoc (2- (trimethylsilyl)ethoxycarbonyl) group protecting group, intermediate III-6 is reacted with tetra-n- butylammonium fluoride in an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-1. In some embodiments, the appropriate acid is HC1 or TFA. In some embodiments, the appropriate solvent is Et20, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
[00237] In some embodiments, the acylation of amine IV-1 with an acyl chloride affords compound IV-2. Suitable acylation conditions include but are not limited to the use of a suitable base, such as TEA or pyridine in a suitable solvent, such as DCM or toluene, for an appropriate amount of time and at a suitable temperature, such as about room temperature to about 80 °C for about 1 hour to about overnight. In some embodiments, pyridine is used as both the base and the solvent. In some embodiments, conditions include the addition of DMAP.
[00238] In some embodiments, the reaction of amine IV-1 with a sulfonyl chloride affords compound IV-3. In some embodiments, suitable conditions include the use of an alkylsufonyl chloride in a suitable solvent, such as dichloromethane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 18 hours.
[00239] In some embodiments, the alkylation of amine IV-1 with an alkyl halide affords compound IV-4. In some embodiments, an appropriate alkyl halide is an alkyl chloride. In some embodiments, suitable alkylation conditions include but are not limited to the use of a suitable base, such as TEA or pyridine in a suitable solvent, such as DMF, for an appropriate amount of time and at a suitable temperature, such as about room temperature to about 80 °C for about 1 hour to about overnight.
[00240] In some embodiments, IV-2 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-5. In some embodiments, the appropriate acid is HC1 or TFA. In some
embodiments, the appropriate solvent is Et20, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
[00241] In some embodiments, IV-3 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-6. In some embodiments, the appropriate acid is HC1 or TFA. In some
embodiments, the appropriate solvent is Et20, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight). [00242] In some embodiments, IV-4 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IV-7. In some embodiments, the appropriate acid is HC1 or TFA. In some
embodiments, the appropriate solvent is Et20, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
[00243] In some embodiments, compounds described herein are prepared as outlined in Scheme 5.
Scheme 5
Figure imgf000125_0001
[00244] In Scheme 5, substituents X, Z, R3, n, and p are as described herein. In some
embodiments, X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
[00245] In some embodiments, intermediate V-l is reacted with methyl carbonochloridate with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound V-2. In some embodiments, the appropriate solvent is Et20, dioxane, MeCN, or THF. In some embodiments, the reaction temperature is about room temperature and the reaction time is about 2 hours.
[00246] In some embodiments, V-3 is reacted with intermediate V-2 under suitable conditions to provide intermediate V-4. In some embodiments, appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate. In some embodiments, the appropriate solvent is THF, DMF or DMA. In some embodiments, the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
[00247] In some embodiments, V-4 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound V-5. In some embodiments, the appropriate acid is HC1 or TFA. In some embodiments, the appropriate solvent is Et20, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
[00248] In some embodiments, compounds described herein are prepared as outlined in Scheme 6.
Scheme 6
Figure imgf000126_0001
[00249] In Scheme 6, substituents X, Z, R3, n, and p are as described herein. In some
embodiments, X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
[00250] In some embodiments, intermediate VI-1 is reacted with a cabamoyl chloride with an appropriate base and an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VI-2. In some embodiments, the cabamoyl chloride is methylcarbamic chloride. In some embodiments, the appropriate base is triethylamine or pyridine. In some embodiments, the appropriate solvent is DCM or DMF. In some embodiments, the reaction temperature is about room temperature and the reaction time is about 18 hours.
[00251] In some embodiments, VI-2 is reacted with VI-3 under suitable conditions to provide intermediate VI-4. In some embodiments, appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate. In some embodiments, the appropriate solvent is THF, DMF or DMA. In some embodiments, the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
[00252] In some embodiments, VI-2 is reacted with VI-3 under suitable conditions to provide intermediate VI-5. In some embodiments, appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate. In some embodiments, the appropriate solvent is THF, DMF or DMA. In some embodiments, the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
[00253] In some embodiments, intermediate VI-5 is reacted with a cabamoyl chloride with an appropriate base and an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VI-4. In some embodiments, the cabamoyl chloride is methylcarbamic chloride. In some embodiments, the appropriate base is triethylamine or pyridine. In some embodiments, the appropriate solvent is DCM. In some embodiments, the reaction temperature is about room temperature and the reaction time is about 18 hours.
[00254] In some embodiments, VI-4 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VI-6. In some embodiments, the appropriate acid is HC1 or TFA. In some
embodiments, the appropriate solvent is Et20, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
[00255] In some embodiments, compounds described herein are prepared as outlined in Scheme 7.
Scheme 7
Figure imgf000128_0001
VII-5 VII-6
[00256] In Scheme 7, substituents X, Z, R3, n, and p are as described herein. In some
embodiments, X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
[00257] In some embodiments, VII-1 is reacted with VII-2 under suitable conditions to provide intermediate VII-3. In some embodiments, appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate. In some embodiments, the appropriate solvent is THF, DMF or DMA. In some embodiments, the reaction temperature is about 50 °C to about 60 °C and the reaction time is about 18 hours (overnight).
[00258] In some embodiments, VII-3 is subjected to suitable nitro functional group reduction conditions to provide aniline VII-4. In some embodiments, suitable nitro reduction conditions include use of iron powder and ammonium chloride in a suitable solvent or solvent mixture, such as ethanol/water, for an appropriate amount of time at an appropriate temperature. In some embodiments, the reaction temperature is about 90 °C and the reaction time is about 2 hours.
[00259] In some embodiments, the reaction of aniline VII-4 with a sulfonyl chloride affords compound VII-5. In some embodiments, suitable conditions include the use of an alkylsufonyl chloride with a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 18 hours. [00260] In some embodiments, VII-5 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VII-6. In some embodiments, the appropriate acid is HC1 or TFA. In some
embodiments, the appropriate solvent is Et20, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight).
[00261] In some embodiments, intermediates used in the preparation of compounds described herein are prepared as outlined in Scheme 8.
Scheme 8
Figure imgf000129_0001
[00262] In Scheme 8, substituents L3, X, Z, Rla, R3, n, p and q are as described herein. In some embodiments, L3 is -CH2CH2-. In some embodiments, X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1. In some embodiments, q is 1.
[00263] In some embodiments, a suitable boronic ester VIII-1 is reacted with aryl bromide or idodie VIII-2 under suitable metal-catalyzed cross-coupling reaction conditions to provide VIII-3. In some embodiments, suitable metal-catalyzed cross-coupling conditions include palladium. In some embodiments, suitable palladium-catalyzed cross-coupling reaction conditions include Pd(dppf)2Cl2 with an appropriate base, with an appropriate solvent for an appropriate time and at an appropriate temperature. In some embodiments, the base is an inorganic base. In some embodiments, the inorganic base is a carbonate base such as K2C03. In some embodiments, the appropriate solvent is a dioxane/water mixture. In some embodiments, the appropriate time and appropriate temperature is about 1 hour at about 100 °C.
[00264] In some embodiments, VIII-3 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VIII-4. In some embodiments, the appropriate acid is TFA. In some embodiments, the appropriate solvent is DCM. In some embodiments, the reaction temperature is about room temperature and the reaction time is about 1 hour.
[00265] In some embodiments, the acylation of amine VIII-4 affords compound VIII-5. In some embodiments, suitable acylation conditions include the use of acetic anhydride with a suitable base, such as Et3N, in a suitable solvent, such as DCM, for an appropriate amount of time and at a suitable temperature, such as about room temperature for about 1 hour.
[00266] In some embodiments, VIII-5 is subjected under suitable olefin reduction conditions to provide VIII-6. In some embodiments, suitable reduction conditions include palladium-catalyzed hydrogenation conditions. In some embodiments, suitable palladium-catalyzed hydrogenation conditions also concurrently removes the phenol protecting group. In some embodiments, the phenol protecting group is a benzyl group. In some embodiments, palladium-catalyzed
hydrogenation conditions include use of 10% Pd/C with hydrogen (1 atm) in a suitable solvent, such as MeOH, for an appropriate amount of time at an appropriate temperature. In some embodiments, the appropriate amount of time is about overnight at about room temperature.
[00267] In some embodiments, VIII-6 is reacted with intermediate VIII-7 under suitable conditions to provide intermediate VIII-8. In some embodiments, appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate. In some embodiments, the appropriate solvent is THF, DMF or DMA. In some embodiments, the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
[00268] In some embodiments, VIII-8 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound VIII-9. In some embodiments, the appropriate acid is HC1 or TFA. In some
embodiments, the appropriate solvent is Et20, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments the reaction is conducted in TFA only. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight). In some embodiments, VIII-8 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound VIII-9.
[00269] In some embodiments, intermediates used in the preparation of compounds described herein are prepared as outlined in Scheme 9.
Scheme 9
Figure imgf000131_0001
[00270] In Scheme 9, substituents X, Z, R1, R3, n, and p are as described herein. In some embodiments, X is -0-. In some embodiments, Z is F. In some embodiments, n is 0. In some embodiments, p is 1.
[00271] In some embodiments, IX-1 is reacted with intermediate IX-2 under suitable alkylation conditions to provide intermediate IX-3. In some embodiments, appropriate alkylation conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base is sodium hydride. In some embodiments, the appropriate solvent is DMF. In some embodiments, the reaction temperature is about 0 °C to about room temperature and the reaction time is about 1 hour to about 18 hours (overnight).
[00272] In some embodiments, IX-3 is subjected to suitable benzyl deprotection conditions to provide IX-4. In some embodiments, suitable deprotection conditions include palladium-catalyzed hydrogenation conditions. In some embodiments, appropriate conditions include using an appropriate palladium catalyst under a suitable pressure of hydrogen with an appropriate solvent or solvent mixture for an appropriate amount of time and at an appropriate temperature. In some embodiments, the appropriate palladium catalyst is palladium on carbon. In some embodiments, a suitable pressure of hydrogen is about atmospheric pressure to about 50 PSI. In some embodiments, the appropriate solvent is methanol. In some embodiments, the reaction temperature is about room temperature and the reaction time is about 1 hour to 18 hours (overnight).
[00273] In some embodiments, IX-4 is reacted with intermediate IX-5 under suitable conditions to provide intermediate IX-6. In some embodiments, appropriate conditions include using an appropriate base with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature. In some embodiments, the appropriate base in an inorganic base such as cesium carbonate or potassium carbonate. In some embodiments, the appropriate solvent is THF, DMF or DMA. In some embodiments, the reaction temperature is about room temperature to about 90 °C and the reaction time is about 18 hours (overnight).
[00274] In some embodiments, IX-6 is reacted with an appropriate acid with an appropriate solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound IX-7. In some embodiments, the appropriate acid is HC1 or TFA. In some
embodiments, the appropriate solvent is Et20, dioxane, MeOH, EtOH, EtOAc or DCM. In some embodiments, the reaction temperature is about room temperature to about 60 °C and the reaction time is about 2 to about 18 hours (overnight). In some embodiments, IX-6 is treated with HC1 after reaction with TFA to isolate the hydrochloride salt of compound IX-7.
[00275] In some embodiments, compounds are prepared as described in the Examples.
Certain Terminology
[00276] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term“including” as well as other forms, such as“include”,“includes,” and“included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
[00277] As used herein, Ci-Cx includes Ci-C2, C1-C3 . . . Ci-Cx. By way of example only, a group designated as "C1-C4" indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, /50-propyl, «-butyl, /.so -butyl, .sfc-butyl, and /-butyl.
[00278] An“alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the“alkyl” group has 1 to 10 carbon atoms, i.e. a Ci- Cioalkyl. Whenever it appears herein, a numerical range such as“1 to 10” refers to each integer in the given range; e.g.,“1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a Ci-C6alkyl. In one aspect, the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
[00279] An“alkylene” group refers refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a Ci-C6alkylene. In other embodiments, an alkylene is a Ci-C4alkylene. In certain embodiments, an alkylene comprises one to four carbon atoms (e.g., Ci- C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., Ci-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises two carbon atoms (e.g., C2 alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C2-C alkylene). Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, - CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.
[00280] “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.
[00281] The term“alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.
[00282] The term“alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -CºC-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -CºCH, -CºCCH3 -CºCCH2CH3, - CH2CºCH.
[00283] An“alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.
[00284] The term“alkylamine” refers to the -N(alkyl)xHy group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0. [00285] The term“aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer. The term“aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or“heteroaryl” or“heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.
[00286] The term“carbocyclic” or“carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from“heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.
[00287] As used herein, the term“aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some
embodiments, an aryl is a phenyl. In some embodiments, an aryl is a C6-Cl0aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).
[00288] The term“cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbomyl and bicyclo[l. l. l]pentyl. In some embodiments, a cycloalkyl is a C3- C6cycloalkyl. In some embodiments, a cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2. l]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l]heptanyl, and the like
[00289] The term“halo” or, alternatively,“halogen” or“halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
[00290] The term“haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In one aspect, a fluoroalkyl is a Ci-C6fluoroalkyl.
[00291] The term“fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a Ci-C6fluoroalkyl. In some embodiments, a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
[00292] The term“heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g ., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-C6heteroalkyl.
[00293] The term“heteroalkylene” refers refers to a divalent heteroalkyl radical.
[00294] The term "heterocycle" or“heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl,
tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,
homomorpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3. l.0]hexanyl, 3- azabicyclo[4. l.0]heptanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2. l]octanyl, 5- azabicyclo[2. l. l]hexanyl, 6-azabicyclo[3.l. l]heptanyl, 7-azabicyclo[2.2. l]heptanyl, 8- azabicyclo[3.2. l]octanyl, 3H-indolyl, indolin-2-onyl, isoindolin-l-onyl, isoindoline-l,3-dionyl, 3,4- dihydroisoquinolin-l(2H)-onyl, 3,4-dihydroquinolin-2(lH)-onyl, isoindoline-l,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, lH-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C- attached (or C-linked) or A -attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-l-yl (A-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both A-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=0) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.
[00295] The terms“heteroaryl” or, alternatively,“heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.
Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, l,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a Ci-Cgheteroaryl. In some embodiments, monocyclic heteroaryl is a Ci-Csheteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9heteroaryl.
[00296] A“heterocycloalkyl” or“heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
tetrahydrothiopyranyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2, 5-dithionyl, pyrrolidine-2, 5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-Cioheterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-Cioheterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0- 2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring. [00297] The term“oxo” refers to the =0 radical.
[00298] The term“bond” or“single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
[00299] The term“moiety” refers to a specific segment or functional group of a molecule.
Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
[00300] The term“optionally substituted” or“substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -C02H, -C02alkyl, -C(=0)NH2, - C(=0)NH(alkyl), -C(=0)N(alkyl)2, -S(=0)2NH2, -S(=0)2NH(alkyl), -S(=0)2N(alkyl)2, alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, - CN, -NH2, -NH(CH3), -N(CH3)¾ -OH, -C02H, -C02(Ci-C4alkyl), -C(=0)NH2, -C(=0)NH(Ci- C4alkyl), -C(=0)N(Ci-C4alkyl)2, -S(=0)2NH2, -S(=0)2NH(Ci-C4alkyl), -S(=0)2N(Ci-C4alkyl)2, Ci- C alkyl, C3-C6cycloalkyl, Ci-C fluoroalkyl, Ci-C heteroalkyl, Ci-C alkoxy, Ci-C fluoroalkoxy, - SCi-C alkyl, -S(=0)Ci-C alkyl, and -S(=0)2Ci-C alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, - CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).
[00301] The term“acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
[00302] The term“modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
[00303] The term“modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist. [00304] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.
[00305] The terms“co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
[00306] The terms“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate“effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
[00307] The terms“enhance” or“enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term“enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
[00308] The term“pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term“fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that the active ingredients, e.g. a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.
[00309] The terms“kit” and“article of manufacture” are used as synonyms.
[00310] The term“subject” or“patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.
[00311] The terms“treat,”“treating” or“treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
Pharmaceutical compositions
[00312] In some embodiments, the compounds described herein are formulated into
pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975;
Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.
(Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.
[00313] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.
[00314] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.
[00315] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
[00316] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[00317] Pharmaceutical compositions for parenteral administration include aqueous and non- aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[00318] Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[00319] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
[00320] Pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.
[00321] Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
[00322] Pharmaceutical compositions suitable for topical administration include liquid or semi liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation.
[00323] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
[00324] In some embodiments, a compound disclosed herein is formulated in such a manner that delivery of the compound to a particular region of the gastrointestinal tract is achieved. For example, a compound disclosed herein is formulated for oral delivery with bioadhesive polymers, pH-sensitive coatings, time dependent, biodegradable polymers, microflora activated systems, and the like, in order to effect delivering of the compound to a particular region of the gastrointestinal tract.
[00325] In some embodiments, a compound disclosed herein is formulated to provide a controlled release of the compound. Controlled release refers to the release of the compound described herein from a dosage form in which it is incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release
compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations. [00326] Approaches to deliver the intact therapeutic compound to the particular regions of the gastrointestinal tract (e.g. such as the colon), include:
[00327] (i) Coating with polymers: The intact molecule can be delivered to the colon without absorbing at the upper part of the intestine by coating of the drug molecule with the suitable polymers, which degrade only in the colon.
[00328] (ii) Coating with pH-sensitive polymers: The majority of enteric and colon targeted delivery systems are based on the coating of tablets or pellets, which are filled into conventional hard gelatin capsules. Most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as Eudragit® S, more specifically Eudragit® L and Eudragit® S. Eudragit® L100 and S 100 are copolymers of methacrylic acid and methyl methacrylate.
[00329] (iii) Coating with biodegradable polymers;
[00330] (iv) Embedding in matrices;
[00331] (v) Embedding in biodegradable matrices and hydrogels;
[00332] (vi) Embedding in pH-sensitive matrices;
[00333] (vii) Timed release systems;
[00334] (viii) Redox-sensitive polymers;
[00335] (ix) Bioadhesive systems;
[00336] (x) Coating with microparticles;
[00337] (xi) Osmotic controlled drug delivery;
[00338] Another approach towards colon-targeted drug delivery or controlled-release systems includes embedding the drug in polymer matrices to trap it and release it in the colon. These matrices can be pH-sensitive or biodegradable. Matrix-Based Systems, such as multi-matrix (MMX)-based delayed-release tablets, ensure the drug release in the colon.
[00339] Additional pharmaceutical approaches to targeted delivery of therapeutics to particular regions of the gastrointestinal tract are known. Chourasia MK, Jain SK, Pharmaceutical approaches to colon targeted drug delivery systems., J Pharm Pharm Sci. 2003 Jan-Apr;6(l):33-66. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific drug-delivery systems Crit Rev Ther Drug Carrier Syst. 2007;24(2): 147-202. Kumar P, Mishra B. Colon targeted drug delivery systems— an overview. Curr Drug Deliv. 2008 Jul;5(3): 186-98. Van den Mooter G. Colon drug delivery. Expert Opin Drug Deliv. 2006 Jan;3(l): 111-25. Seth Amidon, Jack E. Brown, and Vivek S. Dave, Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches,
A APS PharmSciTech. 2015 Aug; 16(4): 731-741.
[00340] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
Methods of Dosing and Treatment Regimens
[00341] In one embodiment, the compounds described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from administration of an SSAO inhibitor. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
[00342] In some embodiments disclosed herein, are methods of administering an SSAO inhibitor in combination with an additional therapeutic agent.
[00343] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
[00344] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
[00345] In certain embodiments, wherein the patient’s condition does not improve, upon the doctor’s discretion, the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
[00346] In certain embodiments, wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.
[00347] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
[00348] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity ( e.g ., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
[00349] In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
[00350] In one embodiment, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg/kg per body weight.
In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. [00351] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
[00352] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
[00353] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
[00354] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
[00355] In certain instances, it is appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents. [00356] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant ( i.e ., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
[00357] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
[00358] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may be additive of the two therapeutic agents or the patient may experience a synergistic benefit.
[00359] In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like.
Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.
[00360] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.
[00361] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the compound provided herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
[00362] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If
administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
[00363] The compounds described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.
[00364] In some embodiments, an SSAO inhibitor is administered in combination with an additional therapeutic agent for the treatment of a liver disease or condition. In some embodiments, the additional therapeutic agent is selected from an FXR agonist, an ACC inhibitor, and an ASK-l inhibitor, or a combination thereof.
EXAMPLES
[00365] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. [00366] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:
ACN or MeCN acetonitrile
AcOH acetic acid
Ac acetyl
BINAP 2,2'-bis(diphenylphosphino)-l, 1 '-binaphthalene
Bn benzyl
BOC or Boc /c/7-butyl carbamate
t-Bu /c77-butyl
Cy cyclohexyl
DBA or dba dib enzyli deneacetone
DCE dichloroethane (CICH2CH2CI)
DCM dichloromethane (CH2Cl2)
DIPEA or DIEA dii sopropyl ethyl ami ne
DMAP 4-(7V, A'-di m ethyl am i no)pyri dine
DME 1 ,2-dimethoxy ethane
DMF N, A'-di m ethyl form a ide
DMA N, A'-di m ethyl acetam i de
DMSO dimethylsulfoxide
Dppf or dppf 1 , 1 '-bis(diphenylphosphino)ferrocene
EEDQ 2-Ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline eq equivalent(s)
Et ethyl
Et20 diethyl ether
EtOH ethanol
EtOAc ethyl acetate
HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- bjpyridinium 3-oxid hexafluorophosphate
HMPA hexamethylphosphoramide
HPLC high performance liquid chromatography
KHMDS potassium bis(trimethylsilyl)amide
NaHMDS sodium bis(trimethylsilyl)amide
LiHMDS lithium bis(trimethylsilyl)amide
LAH lithium aluminum anhydride LCMS liquid chromatography mass spectrometry
Me methyl
MeOH methanol
MS mass spectroscopy
Ms mesyl
NBS A-bromosuccinimide
NMM A-m ethyl -m orphol i ne
NMP A-methyl-pyrrolidin-2-one
NMR nuclear magnetic resonance
PCC pyridinium chlorochr ornate
Ph phenyl
PPTS pyridium / oluenesulfonate
iPr/i-Pr /.vo-propyl
TBS /er/-butyldimethylsilyl
RP-HPLC reverse phase-high pressure liquid chromatography
TFA trifluoroacetic acid
TEA triethylamine
THF tetrahydrofuran
TLC thin layer chromatography
Intermediate 1
tert- Butyl (2-(bromomethyl)-3-fluoroallyl)carbamate
Figure imgf000150_0001
Intermediate 1
Step 1: terf-Butyl (2,3-dihydroxypropyl)carbamate
[00367] Di-/er/-butyl dicarbonate (264 g, 1.21 mol) was added to a stirred solution of 3- aminopropane-l,2-diol (100 g, 1.10 mol) and triethylamine (111 g, 1.10 mol) in MeOH (2000 mL) and the reaction stirred at room temperature overnight. The mixture was concentrated under reduced pressure and residual solvent removed by azeotrope with toluene to yield the crude material /tvV-butyl (2,3-dihydroxypropyl)carbamate (210 g) as a white solid. 1H NMR (400 MHz, CDCl3) d 5.31 (s, 1H), 3.94-3.68 (m, 3H), 3.66-3.51 (m, 2H), 3.39-3.09 (m, 2H), 1.45 (s, 9H).
Step 2: tert- Butyl (3-((fe/7-butyldiniethylsilyl)oxy)-2-hydroxypropyl)carbainate [00368] A solution of /er/-butyl (2,3-dihydroxypropyl)carbamate (210 g, 1.10 mol) and imidazole (82.2 g, 1.21 mol) in DCM (1500 mL) was cooled to 0°C. /er/-Butyldimethylsilyl chloride (166 g, 1.10 mol) was added to the reaction at 0 °C, the mixture slowly warmed to room temperature and stirred overnight. The mixture was poured into water (1000 ml) and extracted with DCM (1000 mL). The combined organics were washed with water (2x 1000 ml), brine (1000 ml), dried (Na2S04) and concentrated under reduced pressure to yield the crude material tert- butyl (3 -{{tert- butyldimethylsilyl)oxy)-2-hydroxypropyl)carbamate (340 g) as a yellow oil. 1H NMR (400 MHz, CDCI3) d 5.08 (br s, 1H), 3.75-3.65 (m, 1H), 3.63-3.56 (m, 1H), 3.55-3.46 (m, 1H), 3.36-3.26 (m, 1H), 3.12-3.05 (m, 1H), 3.03-2.98 (m, 1H), 1.41 (s, 9H), 0.86 (s, 9H), 0.04 (s, 6H).
Step 3: tert- butyl (3-((fer/-butyldimethylsilyl)oxy)-2-oxopropyl)carbamate
[00369] DMSO (25.6 g, 327 mmol) was added dropwise to a solution of oxalyl chloride (31.2 g, 246 mmol) in DCM (500 mL) at -78 °C and the reaction stirred at -78°C for an additional 1 h. A solution of /er/-butyl (3-((tert-butyldimethylsilyl)oxy)-2-hydroxypropyl)carbamate (50 g, 164 mmol) in DCM (100 mL) was then added dropwise at -78 °C and stirred at -78°C for an additional 1 h. Et3N (82.8 g, 818 mmol) was added dropwise at -78 °C and the reaction warmed to room temperature. The mixture was poured into water (500 ml) and extracted with DCM (2 x 1000 mL). The combined organics were dried (Na2S04), filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (2% ethyl acetate in petroleum ether) gave tert- butyl (3 -((fert-butyl dimethyl silyl)oxy)-2-oxopropyl)carbamate (40 g, 81%) as a yellow oil. 1H NMR (400 MHz, CDCI3) d 5.08 (br s, 1H), 4.21-4.02 (m, 4H), 1.41 (s, 9H), 0.86 (s, 9H), 0.04 (s, 6H).
Step 4: tert- Butyl (2-(((feH-butyldimethylsilyl)oxy)methyl)-3-fluoroallyl)carbamate
[00370] A solution of (fluoromethyl)triphenylphosphonium bromide (29 g, 77.3 mmol) in THF (300 mL) was cooled to -20 °C before the dropwise addition of a 1M NaHMDS solution in THF (206 mL, 206 mmol). The mixture was stirred at -20 °C for 30 min before the addition of a solution of tert- butyl (3-((/er/-butyldimethylsilyl)oxy)-2-oxopropyl)carbamate (15.6 g, 51.5 mmol) in THF (100 mL). The reaction was warmed to room temperature and stirred for 2 h. The reaction mixture was poured into water (1000 mL) and extracted with EtOAc (3x500 mL). The combined organics were washed with brine (2x500 mL), dried (Na2S0 ) and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-2% ethyl acetate in petroleum ether) gave a 4: 1 mixture of E:Z regioisomers of tert- butyl (2-(((/er/-butyldimethylsilyl)oxy)methyl)-3- fluoroallyl)carbamate (22.9 g, 69 %) isolated as a yellow oil. 1H NMR (400 MHz, CDCI3) d 6.61 (d, 0.8H), 6.57 (d, 0.2H), 5.05 (s, 0.2H), 4.90 (s, 0.8H), 4.34-4.09 (m, 2H), 3.90-3.68 (m, 2H), 1.45 (s, 9H), 0.91 (s, 9H), 0.08 (s, 6H). Step 5: terf-Butyl (3-fluoro-2-(h droxymethyl)allyl)carbamate
[00371] 1M TBAF in THF (107 mL, 107 mmol) was added to a solution of a 4: 1 mixture of E:Z isomers of fe/7-butyl (2-(((/er/-butyldimethylsilyl)oxy)methyl)-3-fluoroallyl)carbamate (22.9 g, 71.7 mmol) in THF (200 mL) and the reaction stirred at room temperature for 1 h. The reaction mixture was poured into a saturated ammonium chloride solution (300 mL) and extracted with EtOAc (3x200 mL). The organic layers were combined, washed with brine (2x200 mL), dried (Na2S04) and concentrated under reduced pressure. Purification by flash chromatography using silica gel (375:25:80 hexane: THF: ethyl acetate) gave a 4: 1 mixture of E.Z regioisomers of tert- butyl (3-fluoro-2-(hydroxymethyl)allyl)carbamate (14 g, 80 %) isolated as a yellow oil. 1H NMR (400 MHz, CDCl3): d 6.61 (d, 0.8H), 6.51 (d, 0.2H), 4.93 (s, 1H), 4.29-4.27 (m, 0.4H), 4.05-3.87 (m, 3.6H), 3.74-3.72 (m, 1H), 1.46 (s, 9H).
Step 6: 2-(((ferf-Butoxycarbonyl)amino)methyl)-3-fluoroallyl methanesulfonate
[00372] A solution of a 4: 1 mixture of tert- butyl (3-fluoro-2-(hydroxymethyl)allyl)carbamate (3.0 g, 14.6 mmol) and Et3N (4 mL, 29.2 mmol) in acetone (40 mL) was cooled to 0 °C.
Methanesulfonyl chloride (1.7 mL, 21.9 mmol) was added and the reaction stirred for 1 h. The mixture was filtered and the cake washed with acetone (5 ml) to give a solution of 2 -{{{tert- butoxycarbonyl)amino)methyl)-3-fluoroallyl methanesulfonate in acetone. Yield assumed quantitative (4.14 g).
Step 7: tert- Butyl (2-(bromomethyl)-3-fluoroallyl)carbamate
[00373] Lithium bromide (12.7 g, 146 mmol) was added to a solution of 2 -{{{tert- butoxycarbonyl)amino)methyl)-3-fluoroallyl methanesulfonate (4.14 g, 14.6 mmol) in acetone (50 mL) and the reaction stirred at room temperature for 1 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3x20 mL). The combined organics were washed with brine (2x20 mL), dried (Na2S04) and concentrated under reduced pressure to give the crude product as a 4: 1 mixture of E:Z regioisomers of /er/-butyl (2-(bromomethyl)-3- fluoroallyl)carbamate (3 g) isolated as a yellow oil. 1H NMR (400 MHz, CDCI3) d 6.77 (d, 0.8H), 6.63 (d, 0.2H), 4.76 (s, 1H), 4.08 (d, 0.4H), 4.01 (d, 1.6H), 3.98-3.93 (m, 1.6H), 3.80-3.75 (m, 0.4H), 1.46 (s, 9H); LCMS 212.1 [M+H-/Bu]+.
[00374] The mixture of E:Z regioisomers of tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate may be purified further. For example, a 5 g mixture of /cvV-butyl (2-(bromomethyl)-3- fluoroallyl)carbamate (E/Z= 4: 1) was loaded on ~ 10 g of 100 mesh silica gel. This in turn was put on -400 g of 1000 mesh silica gel, and eluted with n-hexane/THF/EtOAc=75/5/l6 (3.8 L). The collected fractions were monitored by TLC (PE/EtOAc=l : l, KMn04 as color developing agent, Rf=0.5/0.55). After concentration, (E)-tert- butyl (3-fluoro-2-(hydroxymethyl)allyl)carbamate (2.5 g, >95% E by EtNMR) was obtained as a yellow oil.
[00375] Intermediate 1 of different E:Z isomer ratios can be used to prepare the final compounds below. For example, a mixture of 4: 1 E:Z regioisomers of Intermediate 1 can be used with isolation of final compounds to give final compounds of >95% (E) purity. Alternatively, >95% (E)
Intermediate 1 can be used to prepare final compounds of >95% (E) purity.
Compound 1.01 & 1.02
E)-3-Fluoro-2-((4-(pyridin-2-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride (Compound 1.01) & Z)-3-Fluoro-2-((4-(pyridin-2-yl)phenoxy)methyl)prop-2-en-l-amine
Figure imgf000153_0001
Step 1: terf-Butyl (3-fluoro-2-((4-(pyridin-2-yl)phenoxy)methyl)allyl)carbamate
[00376] A mixture of tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (460 mg, 1.72 mmol) 4-(pyri din-2 -yl)phenol (294 mg, 1.72 mmol), K2C03 (711 mg, 5.1 mmol) and DMF (10 mL) was stirred at 60 °C overnight. The mixture was cooled to room temperature. The mixture was poured into water (30 mL) and extracted with EtOAc (3 x40 mL). The organic layers were combined, washed with water (2x20 mL), brine (20 mL), dried (Na2S04), filtered and concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 3/1) to give tert- butyl (3- fluoro-2-((4-(pyridin-2-yl)phenoxy)methyl)allyl)carbamate (500 mg, 81%) as a yellow oil. 1H NMR (400 MHz, CDCl3)a: d 8.65 (d, 1H), 7.95 (d, 2H), 7.77-7.63 (m, 2H), 7.23-7.14 (m, 1H), 7.06-6.96 (m, 2H), 6.75 (d, 0.8H), 6.62 (d, 0.2H), 4.81 (s, 1H), 4.76 (d, 0.4H), 4.50 (d, 1.6H), 3.97 (d, 1.6H), 3.78 (d, 0.4H) 1.42 (s, 9H); LCMS: 359.2 [M+H]+. a NMR is of a mixture of the (E) and (Z) alkene isomers.
Step 2: E)-3-Fluoro-2-((4-(pyridin-2-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride (Compound 1.01) & (Z)-3-Fluoro-2-((4-(pyridin-2-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride (Compound 1.02)
[00377] A mixture of /cvV-butyl (3-fluoro-2-((4-(pyridin-2-yl)phenoxy)methyl)allyl)carbamate (500 mg, 1.40 mmol) and HCl/MeOH (4 M, 3.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated to dryness, and then purified by reverse-phase HPLC (water
(0.05%HCl))/CH3CN) to give (¾)-3-fluoro-2-((4-(pyridin-2-yl)phenoxy)methyl)prop-2-en-l -amine hydrochloride (Compound 1.01) (146 mg, 40%) as a white solid and (Z -3-fluoro-2-((4-(pyridin-2- yl)phenoxy)methyl)prop-2-en-l -amine hydrochloride (Compound 1.02) (45 mg, 12%) as a white solid. Compound 1.01 : 1H NMR (400 MHz, DMSO-i¾): d 8.78-8.70 (m, 1H), 8.39 (s, 3H), 8.29 (t, 1H), 8.24-8.18 (m, 1H), 8.17-8.10 (m, 2H), 7.68 (t, 1H), 7.36 (d, 1H) 7.22 (d, 2H), 4.78 (s, 2H), 3.62 (d, 2H); LCMS: 259.1 [M+H]+. Compound 1.02: 1H NMR (400 MHz, DMSO- d6 ): d 8.74 (d, 1H), 8.47-8.24 (m, 4H), 8.23-8.17 (m, 1H), 8.13 (d, 2H), 7.67 (t, 1H), 7.26 (d, 1H), 7.23 (d, 2H), 4.78 (d, 2H), 3.56 (d, 2H); LCMS: 259.1 [M+H]+.
Compound 1.03 & 1.04
E -2-((4-(l//-Pyrazol-l-yl)phenoxy)methyl)-3-fluoroprop-2-en-l-amine hydrochloride (Compound 1.03) & Z)-2-((4-(l/ -Pyrazol-l-yl)phenoxy)methyl)-3-fluoroprop-2-en-l-amine hydrochloride (Compound 1.04)
Figure imgf000154_0001
Step 1: l-(4-Methoxyphenyl)-l/ -pyrazole
[00378] A mixture of l-iodo-4-methoxybenzene (6.0 g, 25 mmol), lH-pyrazole (3.49 g, 51.3 mmol), Cs2C03 (25 g, 76 mmol), Cul (976 mg, 5.1 mmol) and DMF (100 mL) was heated to 120 °C overnight under N2. The mixture was cooled to room temperature, and then poured into water (150 mL) and filtered. The filtrate was extracted with EtOAc (3 x200 mL). The organic layers were combined, washed with water (2x 100 mL), brine (100 mL), dried (Na2S04), filtered and concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 20/1) to give l-(4-methoxyphenyl)-liT-pyrazole (3.5 g, 78%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.83 (d, 1H), 7.70 (d, 1H), 7.65-7.55 (m, 2H), 7.02-6.92 (m, 2H), 6.44 (t, 1H), 3.84 (s, 3H); LCMS: 175.1 [M+H]+.
Step 2: 4-(l/ -Pyrazol-l-yl)phenol
[00379] To a solution of l-(4-methoxyphenyl)-liT-pyrazole (2.4 g, 13 mmol) in DCM (100 mL) at 0 °C, a solution of BBr3 (10.3 g, 41 mmol) in DCM (50 mL) was added dropwise. The mixture was warmed to room temperature overnight. The mixture was poured into NaHC03 (100 mL) and filtered. The cake was dried in vacuum to give crude product. The crude product was purified by chromatography on silica gel (petroleum ether/EtOAc = 5/1) to give 4-( 1 //-pyrazol - 1 -yl )phenol (1.3 g, 58%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 8.44 (s, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 7.35-7.26 (m, 2H), 6.76-6.66 (m, 2H), 6.37 (t, 1H); LCMS: 161.1 [M+H]+.
Step 3: tert- Butyl (2-((4-(Li/-pyrazol-l-yl)phenoxy)methyl)-3-fluoroallyl)carbamate
[00380] A mixture of tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (370 mg, 1.38 mmol), 4-(liT-pyrazol-l-yl)phenol (221 mg, 1.3 mmol), K2C03 (572.1 mg, 4.1 mmol) and DMF (10 mL) was stirred at 60 °C overnight. The reaction was cooled to room temperature, poured into H20 (30 mL), and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (Petroleum ethenEthyl acetate=20: l 2: 1) to give tert- butyl (2-((4-( 1 //-pyrazol - 1 - yl)phenoxy)methyl)-3-fluoroallyl)carbamate (340 mg, 64%) as a yellow oil. 1H NMR (400 MHz, DMSO-i¾)a: d 8.38 (d, 1H), 7.77-7.70 (m, 2H), 7.68 (d, 1H), 7.09-6.95 (m, 3H), 6.51-6.47 (m, 1H), 4.62 (d, 0.4H), 4.47 (d, 1.6H), 3.77 (d, 1.6H), 3.61 (d, 0.4H), 1.34 (s, 9H); LCMS: 348.3 [M+H]+. a NMR is of a mixture of the (E) and (Z) alkene isomers.
Step 4: (E')-2-((4-(l/ -Pyrazol-l-yl)phenoxy)methyl)-3-fluoroprop-2-en-l-amine (Compound 1.03) & (Z)-2-((4-(l/ -Pyrazol-l-yl)phenoxy)methyl)-3-fluoroprop-2-en-l-amine (Compound 1.04)
[00381] To a solution of /cvV-butyl (2-((4-( 1 //-pyrazol - 1 -yl )phenoxy )methyl )-3 - fluoroallyl)carbamate (340 mg, 0.97 mmol) in DCM (6 mL) at room temperature, TFA (2 mL, 27 mmol) was added for 1 h. The mixture was concentrated to dryness. The residue was co-evaporated with DCM (2 x 20 mL) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3 mL) and then 2M HC1 in diethyl ether (0.5 mL) was added. The precipitate formed was isolated and dried under reduced pressure. The residue was purified by reverse-phase HPLC (water (0.05%HCl)-ACN) to give (//)-2-((4-( 1 //-pyrazol - 1 -yl )phenoxy)methyl )-3 -fl uoroprop-2-en- 1 - amine (Compound 1.03) (111 mg, 45%) as a white solid and (Z)-2-((4-(lif-pyrazol-l- yl)phenoxy)methyl)-3-fluoroprop-2-en-l -amine (Compound 1.04) (5.5 mg, 2%) as a white solid. Compound 1.03: 1H NMR (400 MHz, DMSO-i¾): d 8.40 (d, 1H), 8.33 (s, 3H), 7.81-7.73 (m, 2H), 7.69 (d, 1H), 7.32 (d, 1H), 7.16-7.07 (m, 2H), 6.50 (t, 1H), 4.68 (d, 2H), 3.62-3.60 (m, 2H); LCMS: 248.1 [M+H]+. Compound 1.04: 1H MR (400 MHz, DMSO-i¾): d 8.40 (d, 1H), 8.26 (s, 3H), 7.80-7.72 (m, 2H), 7.69 (d, 1H), 7.21 (d, 1H), 7.16-7.09 (m, 2H), 6.50 (t, 1H), 4.78 (d, 2H), 3.54- 3.52 (m, 2H); LCMS: 248.1 [M+H]+.
Compound 1.05a
(E)-2-((4-(3,5-Dimethyl-Li/-pyrazol-4-yl)phenoxy)methyl)-3-fluoroprop-2-en-l-amine
Figure imgf000155_0001
Step 1: terf-butyl 4-(4-(Benzyloxy)phenyl)-3,5-dimethyl-l//-pyrazole-l-carboxylate
[00382] A mixture of 1 -(benzyl oxy)-4-bromobenzene (2.75 g, 10.5 mmol), (l-(tert- butoxycarbonyl)-3,5-dimethyl-lH-pyrazol-4-yl)boronic acid (2.01 g, 8.4 mmol), palladium acetate (200 mg, 0.89 mmol), SPhos (735 mg, 1.79 mmol), K3P04 (5.33 g, 25.1 mmol), toluene (15 mL), ethanol (7.5 mL), and water (7.5 mL) was degassed 3 times by vacuum-nitrogen cycles and stirred at room temperature for 5.5 h. The reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL) and then brine (100 mL), dried (Na2S04), filtered, and concentrated. The residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give /tvV-butyl 4- (4-(benzyl oxy)phenyl)-3,5-di methyl - 1 //-pyrazol e- 1 -carboxylate (1.91 g, 60%) as a yellow oil. 1H NMR (400 MHz, DMSO-r 6): d 7.51-7.46 (m, 2H), 7.45-7.39 (m, 2H), 7.37-7.32 (m, 1H), 7.22 (d, 2H), 7.10 (d, 2H), 5.14 (s, 2H), 2.37 (s, 3H), 2.13 (s, 3H), 1.37 (s, 9H); LCMS: 401.1 [M+Na]+. Step 2: 4-(4-(Benzyloxy)phenyl)-3, 5-dimethyl- Lif-pyr azole
[00383] Trifuoroacetic acid (6 mL) was added to a mixture of tert- butyl 4-(4-(benzyloxy)phenyl)-
3.5 -di methyl - 1 //-pyrazol e- 1 -carboxyl ate (1.90 g, 5.02 mmol) and DCM (24 mL) at room temperature. The mixture was stirred for 65 min, washed with saturated NaHC03 (2x 100 mL) and then brine (100 mL), dried (Na2S04), filtered, and concentrated to give 4-(4-(benzyloxy)phenyl)-
3.5-dimethyl-l /-pyrazole as a yellow solid (1.34 g, 96%). 1H NMR (400 MHz, DMSO-</6): d 12.2 (s, 1H), 7.50-7.45 (m, 2H), 7.44-7.38 (m, 2H), 7.37-7.32 (m, 1H), 7.19 (d, 2H), 7.04 (d, 2H), 5.12 (s, 2H), 2.18 (s, 3H), 2.13 (s, 3H); LCMS: 279.3 [M+H]+.
Step 3: 4-(3, 5-Dimethyl- l//-pyrazol-4-yl)phenol
[00384] A mixture of 4-(4-(benzyloxy)phenyl)-3,5-dimethyl-l /-pyrazole (1.74 g, 6.25 mmol), 10% Pd/C (182 mg), methanol (25 mL) and THF (25 mL) was stirred under atmosphere of hydrogen (balloon) overnight. The mixture was filtered through Celite, and the filter cake was washed with 1 : 1 THF/methanol (50 mL). 10% Pd/C (201 mg) and acetic acid (2 mL) were added to the filtrate. The mixture was stirred under atmosphere of hydrogen (balloon) overnight. The mixture was filtered through Celite with a methanol rinse (100 mL), and then concentrated. The residue was purified by silica gel chromatography (70-100% EtO Ac/hexanes) to give 4-(3,5- dimethyl-l /-pyrazol-4-yl)phenol (0.95 g, 81%) as a beige foam. 1H NMR (400 MHz, DMSO-i¾): d 9.34 (s, 1H), 7.07 (d, 2H), 6.80 (d, 2H), 2.15 (s, 6H); LCMS: 189.0 [M+H]+.
Step 4: (E)-tert- Butyl (2-((4-(3,5-dimethyl-l//-pyrazol-4-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00385] (E)-tert- Butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (135 mg, 0.50 mmol) in DMF (1 mL) was added to a mixture of 4-(3,5-dimethyl-l /-pyrazol-4-yl)phenol (85 mg, 0.45 mmol) and K2C03 (229 mg, 1.66 mmol) at room temperature. The mixture was stirred overnight, diluted (10 mL EtOAc), washed with 1N NaOH (2x 10 mL) and then brine (10 mL), dried (Na2S04), filtered, and concentrated. The residue was purified by silica gel chromatography (20-60% EtOAc in hexanes) to give (E)-tert- butyl (2-((4-(3, 5-di methyl - 1 //-pyrazol -4-yl)phenoxy)methyl)-3- fluoroallyl)carbamate (130 mg, 77%) as a white foam. 1H MR (400 MHz, DMSO-i¾): d 12.29 (s, 1H), 7.18 (d, 2H), 7.09 (t, 0.8H), 7.06 (d, 1H), 6.99 (d, 2H), 6.81-6.70 (br, 0.2H), 4.45 (d, 2H), 3.78 (d, 2H), 2.16 (s, 6H), 1.35 (s, 9H); LCMS: 376.1 [M+H]+.
Step 5: (E)-tert-butyl (2-((4-(3,5-dimethyl-lH-pyrazol-4-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00386] 4M HC1 in dioxane (0.3 mL) was added to a solution of (E)-tert- butyl (2-((4-(3,5- di m ethyl - 1 //-py razol -4-y 1 )phenoxy)m ethyl )-3 -fl uoroal 1 yl )carbam ate (120 mg, 0.32 mmol), diethyl ether (2 mL), and DCM (1 mL) at room temperature. Methanol (1 mL) was added to the mixture after 5h, and the reaction was stirred overnight. The solvent was removed under reduced pressure and the residue was triturated in DCM (2 mL). The precipitate was collected by filtration with DCM rinse (2 mL) to give (£)-2-((4-(3,5-dimethyl-liT-pyrazol-4-yl)phenoxy)methyl)-3- fluoroprop-2-en-l -amine (98 mg, 98%, HC1 salt) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 8.32 (s, 3H), 7.39 (d, 1H), 7.30 (d, 2H), 7.09 (d, 2H), 4.68 (d, 2H), 3.66-3.58 (m, 2H), 2.27 (s, 6H); LCMS: 276.0 [M+H]+.
[00387] The compounds below were synthesized in a similar manner as described for Compounds 1.01, 1.02, 1.03, 1.04, and l .05a.
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0002
Compound 1.36
(E)-2-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-3, 5-dimethyl- Li7-pyrazol-l- yl)acetamide hydrochloride
Figure imgf000162_0001
Step 1: 2-(4-Bromo-3,5-dimethyl-Li7-pyrazol-l-yl)acetamide
[00388] To a mixture of 4-brom o-3 , 5 -di m ethyl - 1 //-pyrazol e (3.0 g, 17.1 mmol) 2-bromoacetamide (2.84 g, 20.6 mmol) in DMF (60 mL) at 0°C, NaH (1.03 g, 25.7 mmol, 60% purity in mineral oil) was added. The mixture was stirred at 0°C for 30 min. 2-Bromoacetamide (2.84 g, 20.6 mmol) was added at 0 °C and then warmed to room temperature overnight. The mixture was poured into water (180 mL) and filtered. The cake was dried under vacuum to give 2-(4-bromo-3, 5 -dimethyl -1/7- pyrazol-l-yl)acetamide (3 g) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾): d 7.52 (s, 1H), 7.24 (s, 1H), 4.67 (s, 2H), 2.15 (s, 3H), 2.07 (s, 3H); LCMS: 232.0 [M+H]+.
Step 2: 2-(3,5-Dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1/7-pyrazol-l- yl)acetamide
[00389] A mixture of 2-(4-bromo-3,5-dimethyl-l/7-pyrazol-l-yl)acetamide (1.5 g, 6.46 mmol), 4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (6.62 g, 51.7 mmol), Et3N (3.27 g, 32.3 mmol), XPhos (616 mg, 1.29 mmol), Pd2(dba)3 (592 mg, 0.65 mmol), and dioxane (30 mL) was stirred at 100 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature, poured into water (30 mL) and extracted with EtOAc (2 x50 mL). The organic layers were combined, washed with water (2 x30 mL), brine (30 mL), dried (Na2S04), filtered, concentrated and then purified by chromatography on silica gel (petroleum ether/EtOAc = 0/1) to give 2-(3, 5-dimethyl-4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)- l/7-pyrazol-l-yl) acetamide (640 mg, 35%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 6.08 (s, 1H), 5.46 (s, 1H), 4.68 (s, 2H), 2.37 (s, 3H), 2.35 (s, 3H), 1.32 (s, 12H); LCMS: 280.1 [M+H]+.
Step 3: 2-(4-(4-(Methoxymethoxy)phenyl)-3, 5-dimethyl- Lif-pyrazol-l-yl) acetamide
[00390] A mixture of 2-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1 H- pyrazol-l-yl) acetamide (640 mg, 2.29 mmol), l-bromo-4-(methoxymethoxy)benzene (597 mg, 2.75 mmol), K2C03 (951 mg, 6.88 mmol), Pd2(dba)3 (210 mg, 0.23 mmol), XPhos (219 mg, 0.46 mmol), dioxane (30 mL) and H20 (6 mL) was stirred at 100 °C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, poured into water (30 mL) and extracted with EtOAc (2 x50 mL). The organic layers were combined, washed with water (2 x30 mL), brine (30 mL), dried (Na2S04), filtered, concentrated and then purified by chromatography on silica gel (petroleum ether/EtOAc = 10/1) to give 2-(4-(4-(methoxymethoxy )phenyl)-3,5-di methyl - 1 //- pyrazol-l-yl) acetamide (400 mg, 60 %) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.15 (d, 2H), 7.09 (d, 2H), 6.17 (s, 1H), 5.55 (s, 1H), 5.22 (s, 2H), 4.72 (s, 2H), 3.51 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H); LCMS: 290.1 [M+H]+.
Step 4: 2-(4-(4-Hydroxyphenyl)-3, 5-dimethyl- l//-pyrazol-l-yl)acetamide
[00391] A mixture of 2-(4-(4-(Methoxymethoxy)phenyl)-3,5-dimethyl-liT-pyrazol-l-yl) acetamide (400 mg, 1.38 mmol) and 4 M HC1 in THF (30 mL) was stirred at room temperature for 3h. The mixture was concentrated to dryness, dissolved in water (20 mL), adjusted to pH=7 with aq. sat. NaHC03 solution, and then extracted with EtOAc (2 c 50 mL). The organic layers were combined, washed with water (2 c 20 mL), brine (20 mL), dried (Na2S04), filtered, concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 0/1) to give 2-(4-(4- hy droxyphenyl )-3 , 5 -di m ethyl - 1 //-pyrazol - 1 -yl jacetam i de (150 mg, 42%) as a yellow oil. 1H NMR (400 MHz, MeOD-r¾): d 7.16-7.05 (m, 2H), 6.90-6.81 (m, 2H), 4.78 (s, 2H), 2.21 (s, 3H), 2.17 (s, 3H); LCMS: 246.1 [M+H]+.
Step 5: (E)-tert-Bu y\ (2-((4-(l-(2-amino-2-oxoethyl)-3, 5-dimethyl- l//-pyrazol-4- yl)phenoxy)methyl)-3-fluoroallyl)carbamate
[00392] A mixture of 2-(4-(4-hydroxy phenyl )-3 , 5 -di m ethyl - 1 //-pyrazol - 1 -y 1 jacetam i de (150 mg, 0.61 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (197 mg, 0.73 mmol), K2C03 (85 mg, 0.61 mmol) and CH3CN (10 mL) was stirred at 80 °C for 2 h. The mixture was cooled to room temperature, poured into water (20 mL) and extracted with EtOAc (2 x30 mL). The organic layers were combined, washed with water (2 x50 mL), brine (20 mL), dried (Na2S0 ), filtered and concentrated. Purification by prep-TLC gave (E)-tert- butyl (2-((4-(l-(2-amino-2-oxoethyl)-3,5- di m ethyl - 1 //-pyrazol -4-y 1 )phenoxy)tn ethyl )-3 -fl uoroal 1 yl jcarbam ate (170 mg, 57%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.13-7.05 (m, 2H), 6.93-6.86 (m, 2H), 6.71 (d, 1H), 6.10 (s,
1H), 5.45 (s, 1H), 4.73 (s, 1H), 4.65 (s, 2H), 4.41 (d, 2H), 3.95 (d, 2H), 2.17 (s, 3H), 2.15 (s, 3H) 1.39-1.30 (m, 9H); LCMS: 433.2 [M+H]+.
Step 6: (ii)-2-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-3, 5-dimethyl- Lif-pyrazol-l- yl)acetamide hydrochloride
[00393] A mixture of tert-butyl (E)-tert- butyl (2-((4-(l-(2-amino-2-oxoethyl)-3,5-dimethyl-li7- pyrazol-4-yl)phenoxy)methyl)-3-fluoroallyl)carbamate (170 mg, 0.39 mmol), TFA (4.36 g, 38.3 mmol) and DCM (10 mL) was stirred at room temperature for 2 h. The mixture was concentrated to dryness, and then purified by reverse-phase HPLC(water(0.04%HCl)-MeCN) to give (E)-2-(4-(4- ((2-(aminomethyl)-3 -fluoroallyl)oxy)phenyl)-3 , 5 -dimethyl- liT-pyrazol- 1 -yl)acetamide
hydrochloride (79 mg, 61 %) as a white solid. 1H NMR (400 MHz, D20): d 7.23 (d, 2H), 7.04 (d, 1H), 7.03 (d, 2H), 4.96-4.92 (m, 2H), 4.58 (d, 2H), 3.79 (d, 2H), 2.18 (s, 3H), 2.15 (s, 3H); LCMS: 333.2 [M+H]+.
Compound 1.59
(ii)-5-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-l,4-dimethyl-l//-pyrazole-3- carboxamide hydrochloride
Figure imgf000164_0001
Step 1: 5-(4-Bromophenyl)-l,4-dimethyl-l/T-pyrazole-3-carboxylic acid
[00394] A mixture of ethyl 5-(4-bromophenyl)-l,4-dimethyl-pyrazole-3-carboxylate (6.3 g, 19.5 mmol), LiOH.H20 (2.45 g, 58.5 mmol), MeOH (40 mL), THF (40 mL) and H20 (40 mL) was stirred at room temperature for 16 h. The mixture was concentrated to removed MeOH and THF, adjusted to pH=l with 1M HC1 (30 mL) and filtered. The cake was dried under vacuum to give 5- (4-bromophenyl)-l,4-dimethyl-lH-pyrazole-3-carboxylic acid (6 g, crude) as a yellow solid. 1H NMR (400 MHz, CDCI3): d 11.09 (s, 1H), 7.65 (d, 2H), 7.20 (d, 2H), 3.85 (s, 3H), 2.21 (s, 3H); MS: 294.9 [M+H]+.
Step 2: 5-(4-Bromophenyl)-l,4-dimethyl-l/T-pyrazole-3-carbonyl chloride
[00395] To a solution of 5 -(4-bromophenyl)-l,4-dimethyl-pyrazole-3 -carboxylic acid (3.0 g, 10.2 mmol) in DCM (60 mL), (COCl)2 (2.58 g, 20.3 mmol) and DMF (74.3 mg, 1.02 mmol) was added. The mixture was stirred at room temperature for 1 h then concentrated to give 5-(4-bromophenyl)- 1, 4-dimethyl- liT-pyrazole-3 -carbonyl chloride (3.19 g, crude) as a yellow solid. Step 3: 5-(4-Bromophenyl)-l,4-dimethyl-l//-pyrazole-3-carboxamide
[00396] 4M NH3 in THF (120 mL) was added dropwise to a solution of 5-(4-bromophenyl)-l,4- dimethyl-pyrazole-3 -carbonyl chloride (3.19 g, 10.2 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 16 h, filtered and concentrated to give 5-(4-bromophenyl)-l,4- dimethyl-liT-pyrazole-3 -carboxamide (2.6 g, crude) as a white solid. 1H NMR (400 MHz, CDCl3): d 7.75-7.71 (m, 2H), 7.40-7.35 (m, 2H), 7.35 (s, 1H), 7.12 (s, 1H), 3.73 (s, 3H), 2.12 (s, 3H); MS: 294.1 [M+H]+
Step 4: l,4-Dimethyl-5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l//-pyrazole- 3-carboxamide
[00397] To a solution of 5 -(4-bromophenyl)-l,4-dimethyl-pyrazole-3 -carboxamide (1.5 g, 5.10 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.94 g, 7.65 mmol) in dioxane (30 mL), Pd(dppf)Cl2 (373 mg, 0.51 mmol) and KOAc (1.50 g, 15.3 mmol) were added. The mixture was degassed with 3 vacuum-nitrogen cycles and stirred at 100 °C for 6 h under a nitrogen atmosphere. The reaction was cooled to room temperature, poured into water (40 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2S04), filtered, concentrated and then purified by column chromatography (Si02, petroleum ether/ethyl acetate=20/l to 0: 1) to give l,4-dimethyl-5-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)-liT-pyrazole-3 -carboxamide (1.5 g, 86%) as a white solid. 1H NMR (400 MHz, DMSO-r¾): d 7.81 (d, 2H), 7.44 (d, 2H), 7.35 ( s, 1H), 7.12 (s, 1H), 3.74 (s, 3H), 2.13 (s, 3H), 1.32 (s, 12H); MS: 342.2 [M+H]+.
Step 5 : 5-(4-H drox phenyl)- 1 ,4-dimethyl-l/ -pyrazole-3-car boxamide
[00398] To a solution of l,4-dimethyl-5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)- liT-pyrazole-3 -carboxamide (1.5 g, 4.40 mmol) in THF (32 mL), NaB03.4H20 (2.03 g, 13.2 mmol) was added. The mixture was stirred at room temperature for 16 h, poured into water (30 mL) and then extracted with EtOAc (3 x 35 mL). The combined organic layers were washed with brine (2 c 30 mL), dried over Na2S04, filtered, concentrated and then purified by column chromatography (Si02, petroleum ether/ethyl acetate=20/l to 0: 1) to give 5-(4-hydroxyphenyl)-l,4-dimethyl-liT- pyrazole-3 -carboxamide (0.8 g, 79%) as a white solid. 1H NMR (400 MHz, DMSO-r¾): d 9.78 (s, 1H), 7.29 ( s, 1H), 7.21-7.19 (m, 2H), 7.06 (s, 1H), 6.93-6.87 (m, 2H), 3.69 (s, 3H), 2.09 (s, 3H); MS: 232.1 [M+H]+.
Step 6: (E)-tert-Butyl (2-((4-(3-carbamoyl-l,4-dimethyl-lH-pyrazol-5-yl)phenoxy)methyl) 3- fluoroallyl)carbamate [00399] To a solution of 5 -(4-hydroxyphenyl)-l,4-dimethyl-pyrazole-3 -carboxamide (250 mg,
1.08 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (348 mg, 1.30 mmol) in MeCN (10 mL), Cs2C03 (1.06 g, 3.24 mmol) was added. The mixture was stirred at room temperature for 16 h, poured into water (30 mL) then extracted with EtOAc (3 x 35 mL). The combined organic layers were washed with brine (2 c 30 mL), dried over Na2S04, filtered, concentrated and then purified by column chromatography (Si02, petroleum ether/ethyl acetate=30/l to 0: 1) to give (E)-tert- butyl (2-((4-(3-carbamoyl- l ,4-dimethyl- 1 //-pyrazol-5- yl)phenoxy)methyl)-3-fluoroallyl)carbamate (330 mg, 73%) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾): d 7.34-7.30 (m, 3H), 7.10-7.08 (m, 4H), 7.07 (d, 1H), 4.50-4.49 (m, 2H), 3.78 (d, 2H), 3.71 (s, 3H), 2.10 (s, 3H), 1.33 (s, 9H); MS: 419.1 [M+H]+.
Step 7: (ii)-5-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-l, 4-dimethyl- l//-pyrazole-3- carboxamide hydrochloride
[00400] To a solution of (E)-tert- butyl (2-((4-(3 -carbamoyl - 1 , 4-di methyl - l //-pyrazol -5- yl)phenoxy)methyl)-3-fluoroallyl)carbamate (330 mg, 0.79 mmol) in DCM (5 mL), TFA (1.54 g, 13.5 mmol) was added. The mixture was stirred at room temperature for 1 h, concentrated under reduced pressure to dryness and purified by reverse-phase HPLC [water(0.04%HCl)-MeCN] to give (£)-5-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-l,4-dimethyl-liT-pyrazole-3- carboxamide hydrochloride (102 mg, 36%) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 8.46-8.20 (m, 3H), 7.37 (d, 2H), 7.34 (d, 1H), 7.33 (s, 1H), 7.15 (d, 2H), 7.11 (s, 1H), 4.71 (d, 2H), 3.71 (s, 3H), 3.62 (d, 2H), 2.10 (s, 3H); MS:3 l9. l [M+H]+.
Compound 1.61
(E)-3-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-l,4-dimethyl-lH-pyrazole-5- carboxamide hydrochloride
Figure imgf000166_0001
Step 1: Ethyl 4-(4-bromophenyl)-3-methyl-2,4-dioxobutanoate
[00401] Na (3.88 g, 169 mmol) was added in small portion to dry EtOH (180 mL) and stirred until all the sodium had reacted. Diethyl oxalate (30.9 g, 211 mmol) was added followed by dropwise addition of a solution of l-(4-bromophenyl)propan-l-one (18 g, 84.5 mmol) in EtOH (180 mL). The mixture was stirred at room temperature overnight. The mixture was poured into ice-water (500 mL), adjusted to pH=l, and then extracted with EtOAc (2 x500 mL). The organic layers were combined, washed with water (2 x300 mL), brine (300 mL), dried (Na2S04), filtered and concentrated to dryness to give ethyl 4-(4-bromophenyl)-3 -m ethyl-2, 4-dioxobutanoate (27 g, crude) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.84 (d, 2H), 7.65 (d, 2H), 4.98-4.91 (m, 1H), 4.27 (q, 2H), 1.43 (d, 3H), 1.29 (t, 3H); LCMS: 310.8 [M-H] .
Step 2: Ethyl 5-(4-bromophenyl)-l, 4-dimethyl- Li/-pyrazole-3-carboxylate and ethyl 3-(4- bromophenyl)-l, 4-dimethyl- Li/-pyrazole-5-carboxylate
[00402] A mixture of ethyl 4-(4-bromophenyl)-3-methyl-2,4-dioxobutanoate (27 g, 86.2 mmol), methylhydrazine (23.3 g, 202 mmol), and EtOH (300 mL) was stirred at 90 °C overnight. The mixture was cooled to room temperature, concentrated to dryness, and purified by chromatography on silica gel (petroleum ether/EtOAc = 20/1) to give ethyl 3 -(4-bromophenyl )- 1 ,4-di methyl - 1 H- pyrazole-5-carboxylate (5.07 g, 18%) as a yellow solid. 1H NMR (400 MHz, CDCl3) d 7.56 (d, 2H), 7.45 (d, 2H), 4.40 (q, 2H), 4.17 (s, 3H), 2.37 (s, 3H), 1.42 (t, 3H); LCMS: 323.0 [M+H]+; and ethyl 5-(4-bromophenyl)- l , 4-dim ethyl - l //-pyrazole-3 -carboxyl ate (6 3 g, 23%) as a yellow solid. 1H NMR (400 MHz, CDCI3): d 7.63 (d, 2H), 7.17 (d, 2H), 4.42 (q, 2H), 3.80 (s, 3H), 2.16 (s, 3H), 1.41 (t, 3H); LCMS: 323.0 [M+H]+.
Step 3: 3-(4-Bromophenyl)-l,4-dimethyl-l/T-pyrazole-5-carboxylic acid
[00403] A mixture of ethyl 3-(4-bromophenyl)-l,4-dimethyl-lH-pyrazole-5-carboxylate (4.5 g, 13.9 mmol), LiOH.H20 (1.75 g, 41.8 mmol), MeOH (30 mL), THF (30 mL) and H20 (30 mL) was stirred at room temperature overnight. The mixture was concentrated to remove the MeOH and THF, adjusted to pH=l with 1M HC1 and filtered. The cake was dried in vacuum to give 3-(4- bromophenyl)-l,4-dimethyl-li7-pyrazole-5-carboxylic acid (4 g, crude) as a yellow solid. 1H NMR (400 MHz, CDCI3): d 7.57 (d, 2H), 7.48 (d, 2H), 4.42 (q, 3H), 2.43 (s, 3H); LCMS: 295.0 [M+H]+.
Step 4: 3-(4-Bromophenyl)-l,4-dimethyl-l/T-pyrazole-5-carbonyl chloride
[00404] To a solution of 3-(4-bromophenyl)-l,4-dimethyl-liT-pyrazole-5-carboxylic acid (2.0 g, 6.78 mmol), DMF (49.5 mg, 0.68 mmol) in DCM (20 mL) at room temperature, (COCl)2 (1.72 g, 13.6 mmol) was added. The mixture was stirred at room temperature for 2 h then concentrated to dryness to give 3-(4-bromophenyl)-l , 4-di methyl -l //-pyrazole-5-carbonyl chloride (2.12 g, crude) as a yellow solid.
Step 5: 3-(4-Bromophenyl)-l,4-dimethyl-l/T-pyrazole-5-carboxamide
[00405] A solution of 3-(4-bromophenyl)-l,4-dimethyl-liT-pyrazole-5-carbonyl chloride (2.12 g, 6.76 mmol) in DCM (20 mL) was added to a solution of 4M N¾ in THF (100 mL) at 0°C. The mixture was warmed to room temperature overnight. The mixture was concentrated to dryness to give 3-(4-bromophenyl)-l,4-dimethyl-liT-pyrazole-5-carboxamide (1.9 g, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-r¾): d 7.82-7.79 (m, 2H), 7.65 (d, 2H), 7.55 (d, 2H), 3.91 (s, 3H), 2.23 (s, 3H); LCMS: 294.0 [M+H]+. Step 6: l,4-Dimethyl-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l//-pyrazole- 5-carboxamide
[00406] A mixture of 3-(4-bromophenyl)-l,4-dimethyl-li7-pyrazole-5-carboxamide (1.6 g, 5.44 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.07 g, 8.16 mmol), Pd(dppf)Cl2 (398 mg, 0.54 mmol), KOAc (1.60 g, 16.3 mmol) and dioxane (30 mL) was stirred at 100 °C for 5 h under a nitrogen atmosphere. The mixture was cooled to room temperature, poured into water (50 mL), filtered and then extracted with EtOAc (2 x 80 mL). The organic layers were combined, washed with water (2 c 550 mL), brine (50 mL), dried (Na2S04), filtered, concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 1/5) to give l,4-dimethyl-3-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-li7-pyrazole-5-carboxamide (1.35 g, 73%) as a yellow solid. 1H NMR (400 MHz, DMSO-r¾): d 7.85-7.81 (m, 2H), 7.75 (d, 2H), 7.64 (d, 2H), 3.93 (s, 3H), 2.25 (s, 3H), 1.31 (s, 12H); LCMS: 342.1 [M+H]+.
Step 7: 3-(4-Hydroxyphenyl)-l,4-dimethyl-l//-pyrazole-5-carboxamide
[00407] A mixture of l,4-dimethyl-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-liT- pyrazole-5-carboxamide (800 mg, 2.34 mmol) NaB03.4H20 (1.08 g, 7.03 mmol) and THF (20 mL) was stirred at room temperature overnight. The mixture was poured into water (30 mL) and extracted with EtOAc (2 O mL). The organic layers were combined, washed with water (2 M0 mL), brine (30 mL), dried (Na2S04), filtered and concentrated to give 3-(4-hydroxyphenyl)-l,4- dimethyl-liT-pyrazole-5-carboxamide (450 mg, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-r¾): d 9.50 (s, 1H), 7.74-7.71 (m, 2H), 7.38 (d, 2H), 6.82 (d, 2H), 3.91 (s, 3H), 2.19 (s, 3H); LCMS: 232.1 [M+H]+.
Step 8: (E)-tert- Butyl (2-((4-(5-carbamoyl- 1,4-dimethyl- l//-pyrazol-3-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00408] A mixture of 3-(4-hydroxyphenyl)-l,4-dimethyl-liT-pyrazole-5-carboxamide (200 mg, 0.86 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (255 mg, 0.95 mmol), Cs2C03 (845 mg, 2.59 mmol), and MeCN (10 mL) was stirred at room temperature overnight. The mixture was poured into water (30 mL) and extracted with EtOAc (2 M0 mL). The organic layers were combined, washed with water (2 x20 mL), brine (20 mL), dried (Na2S04), filtered and concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 1/1) to give (E)-tert- butyl (2-((4-(5-carbamoyl-l,4-dimethyl-liT-pyrazol-3-yl)phenoxy)methyl)-3- fluoroallyl)carbamate (300 mg, 83 %) as a yellow solid. 1H NMR (400 MHz, DMSO-r¾): d 7.76- 7.73 (m, 2H), 7.50 (d, 2H), 7.06 (d, 1H), 7.02 (d, 2H), 4.47 (d, 2H), 3.86 (s, 3H), 3.78 (d, 2H), 2.20 (s, 3H), 1.38 (s, 9H); LCMS: 419.3 [M+H]+. Step 9 : (ii)-3-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)- 1 ,4-dimethyl- l//-pyrazole-5- carboxamide hydrochloride
[00409] TFA (4.62 g, 40.5 mmol) was added to a solution of (E)-tert- butyl (2-((4-(5-carbamoyl- 1 ,4-di methyl - 1 //-pyrazol -3 -y 1 )phenoxy)rn ethyl )-3 -fl uoroal 1 y 1 )carbam ate (400 mg, 0.96 mmol) in DCM (10 mL) at room temperature and the reaction stirred at room temperature for 2 h. The mixture was concentrated to dryness and then purified by reverse-phase HPLC (water (0.04%HCl)- MeCN) to give (E)-3-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-l,4-dimethyl-liT-pyrazole-5- carboxamide hydrochloride (150 mg, 49 %) as a white solid. 1H NMR (400 MHz, D20) d 7.45 (d, 2H), 7.06 (d, 1H), 7.03 (d, 2H), 4.60 (d, 2H), 3.92-3.76 (m, 5H), 2.11 (s, 3H); LCMS: 319.1
[M+H]+.
Compound 1.63
(ii)-6-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-5-(trifluoromethyl)nicotinamide hydrochloride
Figure imgf000169_0001
Step 1: 6-Hydroxy-5-(trifluoromethyl)nicotinonitrile
[00410] To a solution of 5-iodo-3-(trifluoromethyl)pyridin-2-ol (4.0 g, 13.8 mmol) in DMF (50 mL), CuCN (2.48 g, 27.7 mmol) was added. The mixture was degassed with 3 vacuum-nitrogen cycles and stirred at 120 °C for 16 h. The reaction was cooled to room temperature, poured into water (60 mL), diluted with 3 M HC1 (30 mL) then extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (2 c 60 mL), dried over Na2S04, filtered, and concentrated to give 6-hydroxy-5-(trifluoromethyl)nicotinonitrile (2.5 g, crude) as an oil. 1H NMR (400 MHz, CDCI3): d 8.03 (s, 2H); MS: 189.0 [M+H]+.
Step 2: 6-Bromo-5-(trifluoromethyl)nicotinonitrile
[00411] To a solution of 6-hydroxy-5-(trifluoromethyl)pyridine-3-carbonitrile (2.5 g, 13.3 mmol), POBr3 (4.57 g, 16.0 mmol) in ACN (10 mL), Na2ITP04 (981 mg, 6.91 mmol) was added. The mixture was stirred at 80 °C for 16 h under a nitrogen atmosphere. The reaction was cooled to room temperature, poured into water (40 mL) then extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (2 c 40 mL), dried over Na2S04, filtered, concentrated, and then purified by prep-TLC (Si02, petroleum ether/ethyl acetate = 5: 1) to give 6-bromo-5- (trifluoromethyl)nicotinonitrile (1.3 g, 39%) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 9.14 (d, 1H), 8.89 (d, 1H). Step 3: 6-(4-H droxyphenyl)-5-(trifluoromethyl)nicotinonitrile
[00412] To a solution of 6-bromo-5-(trifluoromethyl)pyridine-3-carbonitrile (1.3 g, 5.2 mmol), (4- hydroxyphenyl)boronic acid (857 mg, 6.22 mmol) in dioxane (26 mL) and H20 (6.5 mL),
Pd(dppf)Cl2 (417 mg, 0.57 mmol) and Cs2C03 (5.06 g, 15.5 mmol) were added. The mixture was degassed with 3 vacuum -nitrogen cycles and stirred at 100 °C for 3 h. The reaction was cooled to room temperature, poured into water (40 mL) then extracted with EtOAc (3 x 45 mL). The combined organic layers were washed with brine (2 c 30 mL), dried over Na2S04 , filtered, concentrated, and then purified by prep-TLC (Si02, petroleum ether/ethyl acetate=5/l) to give 6-(4- hydroxyphenyl)-5-(trifluoromethyl)nicotinonitrile (1.0 g, 73%) as a white solid. 1H NMR (400 MHz, DMSO-£¾): d 9.98 (s, 1H), 9.28 (s, 1H), 8.86 (s, 1H), 7.40 (d, 2H), 6.89-6.87 (m, 2H);
LCMS: 265.0 [M+H]+.
Step 4: 6-(4-H droxyphenyl)-5-(trifluoromethyl)nicotinic acid
[00413] To a solution of 6-(4-hydroxyphenyl)-5-(trifluoromethyl)pyridine-3-carbonitrile (1.0 g, 3.78 mmol) in EtOH (10 mL) and H20 (10 mL), NaOH (454 mg, 11.4 mmol) was added. The mixture was stirred at 100 °C for 16 h then concentrated, adjusted to pH=l with 1M HC1 (10 mL) and filtered. The cake was dried under vacuum to give 6-(4-hydroxyphenyl)-5- (trifluoromethyl)nicotinic acid (1 g, crude) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 14.32 (s, 1H), 9.93 (s, 1H), 9.28 (s, 1H), 8.53 (s, 1H), 7.39 (d, 2H), 6.88-6.86 (m, 2H); LCMS:
284.0 [M+H]+.
Step 5: 6-(4-H droxyphenyl)-5-(trifluoromethyl)nicotinamide
[00414] To a solution of 6-(4-hydroxyphenyl)-5-(trifluoromethyl)pyridine-3-carboxylic acid (400 mg, 1.41 mmol) in DMF (16 mL), HOBt (229 mg, 1.69 mmol), EDCI (528 mg, 2.75 mmol), TEA (1.43 g, 14.12 mmol) and NH4Cl (378 mg, 7.06 mmol) were added. The mixture was stirred at room temperature for 16 h, then poured into water (30 mL) and extracted with EtOAc (3 x 35 mL). The combined organic layers were washed with brine (2 c 30 mL), dried over Na2S04, filtered, concentrated, and then purified by prep-TLC (Si02, petroleum ether/ethyl acetate= 0: 1) to give 6- (4-hydroxyphenyl)-5-(trifluoromethyl)nicotinamide (230 mg, 58%) as a yellow oil. 1H NMR (400 MHz, DMSO-£¾): d 9.85 (s, 1H), 9.27 (s, 1H), 8.61 (s, 1H), 8.39 (s, 1H), 7.81 (s, 1H), 7.36 (d, 2H), 6.87-6.85 (m, 2H); LCMS: 283 [M+H]+.
Step 6: (E)-tert-Bu y\ (2-((4-(5-carbamoyl-3-(trifluoromethyf)pyridin-2-yl)phenoxy)methyl)-3- fluoroallyl)carbamate [00415] To a solution of 6-(4-hydroxyphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (230 mg, 0.81 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (262 mg, 0.98 mmol) in MeCN (8 mL), Cs2C03 (797 mg, 2.44 mmol) was added. The mixture was stirred at room temperature for 16 h, then poured into water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 c 30 mL), dried over Na2S04, filtered, concentrated, and then purified by prep-TLC (Si02, petroleum ether/ethyl acetate= 0: 1) to give (//)- tert- butyl (2-((4-(5-carbamoyl-3-(trifluoromethyl)pyridin-2-yl)phenoxy)methyl)-3- fluoroallyl)carbamate (160 mg, 42%) as a yellow oil. 1H NMR (400 MHz, DMSO-i¾): d 9.29 (s, 1H), 8.63 (s, 1H), 8.42 (s, 1H), 7.84 (s, 1H), 7.46 (d, 2H), 7.08 (d, 1H), 7.07 (d, 2H), 4.50 (d, 2H), 3.79 (d, 2H), 1.34 (s, 9H); MS: 470.2 [M+H]+.
Step 7 : (ii)-6-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-5-(trifluoromethyl)nicotinamide hydrochloride
[00416] To a solution of (E)-tert- butyl (2-((4-(5-carbamoyl-3-(trifluoromethyl)pyridin-2- yl)phenoxy)methyl)-3-fluoroallyl)carbamate (160 mg, 0.34 mmol) in DCM (5 mL), TFA (3.08 g, 27.0 mmol) was added. The mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to dryness and purified by reverse-phase HPLC [water (0. l%TFA)-MeCN] Before lyophilization, the mixture was diluted by ~5 mL of 1M HC1, and stirred at room temperature for 10 min. (£)-6-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-5-
(trifluoromethyl)nicotinamide hydrochloride (55 mg, 38%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-£¾): d 9.31 (s, 1H), 8.65 (s, 1H), 8.48 (s, 1H), 8.43-8.27 (m, 3H), 7.86 (s, 1H), 7.48 (d, 2H), 7.35 (d, 1H), 7.13 (d, 2H), 4.72 (d, 2H), 3.62 (d, 2H); MS: 370.0 [M+H]+.
Compound 1.64
(E)-6-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-/V-methyl-5- (trifluoromethyl)nicotinamide hydrochloride
Figure imgf000171_0001
Step 1: 6-(4-Hydroxyphenyl)-5-(trifluoromethyl)nicotinoyl chloride
[00417] To a solution of 6-(4-hydroxyphenyl)-5-(trifluoromethyl)pyridine-3-carboxylic acid (450 mg, 1.59 mmol), DMF (11.6 mg, 0.16 mmol) in DCM (10 mL), (COCl)2 (403 mg, 3.18 mmol) was added. The mixture was stirred at 50 °C for 1 h then concentrated to give 6-(4-hydroxyphenyl)-5- (trifluoromethyl)nicotinoyl chloride (479 mg, crude) as a yellow solid.
Step 2 : 6-(4-h dr oxyphenyl)-/V-methyl-5-(tr ifluoromethy 1 )n icotina m ide [00418] To a mixture of methanamine hydrochloride (322 mg, 4.76 mmol) in DCM (10 mL), Et3N (1.61 g, 15.9 mmol) was added followed by 6-(4-hydroxyphenyl)-5-(trifluoromethyl)nicotinoyl chloride (479 mg, 1.59 mmol) in DCM (2 mL). The mixture was stirred at 30 °C for 16 h, poured into water (30 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (2 c 30 mL), dried over Na2S04, filtered, concentrated, and then purified by prep-TLC (Si02, petroleum ether/ethyl acetate= 0: 1) to give 6-(4-hydroxyphenyl)-/V-methyl-5- (trifluoromethyl)nicotinamide (100 mg, 21%) as a yellow solid. 1H NMR (400 MHz, DMSO-r¾): d 9.85 (s, 1H), 9.23 (s, 1H), 8.89 (s, 1H), 8.58 (d, 1H), 7.36 (d, 2H), 6.87-6.85 (m, 2H), 2.85 (d, 3H); LCMS: 297.1 [M+H]+.
Step 3: (E)-tert- Butyl (3-fluoro-2-((4-(5-(methylcarbamoyl)-3-(trifluoromethyl)pyridin-2- yl)phenoxy)methyl)allyl)carbamate
[00419] To a solution of 6-(4-hydroxyphenyl)-/V-methyl-5-(trifluoromethyl)pyridine-3- carboxamide (100 mg, 0.34 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (109 mg, 0.41 mmol) in MeCN (5 mL), Cs2C03 (330 mg, 1.01 mmol) was added. The mixture was stirred at room temperature for 3 h, poured into water (20 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over Na2S04, filtered, concentrated, and then purified by prep-TLC (Si02, petroleum ether/ethyl acetate= 0: 1) to give (E)-tert- butyl (3-fluoro-2-((4-(5-(methylcarbamoyl)-3-(trifluoromethyl)pyridin-2- yl)phenoxy)methyl)allyl)carbamate (100 mg, 61 %) as a yellow solid. 1H NMR (400 MHz, DMSO-r¾): d 9.25 (s, 1H), 8.90 (d, 1H), 8.60 (s, 1H), 7.46 (d, 2H), 7.08 (d, 1H), 7.07 (d, 2H), 4.50 (d, 2H), 3.79 (d, 2H), 2.85 (d, 3H), 1.34 (s, 9H); LCMS:484. l [M+H]+.
Step 4: (ii)-6-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-/V-methyl-5- (trifluoromethyl)nicotinamide hydrochloride
[00420] To a solution of (E)-tert- butyl (3-fluoro-2-((4-(5-(methylcarbamoyl)-3- (trifluoromethyl)pyridin-2-yl)phenoxy)methyl)allyl)carbamate (100 mg, 0.21 mmol) in DCM (5 mL), TFA (3.08 g, 27.0 mmol) was added. The mixture was stirred at room temperature for 1 h, concentrated under reduced pressure to dryness and then purified by reverse-phase HPLC
[water(0.04%HCl)-MeCN] to give (E)-6-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-/V- methyl-5-(trifluoromethyl)nicotinamide hydrochloride (33 mg, 38 %) as a yellow solid. 1H MR (400 MHz, DMSO-r¾): d 9.27 (s, 1H), 8.98 (d, 1H), 8.62 (s, 1H), 8.31-8.11 (m, 3H), 7.49 (d, 2H), 7.35(d, 1H), 7.11-7.13 (m, 2H), 4.70 (d, 2H), 3.64 (d, 2H), 2.85 (d, 3H); LCMS: 384.1 [M+H]+. Compound 1.65
(ii)-2-((4-(3-Cyclopropyl-5-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-3-fluoroprop-2-en-l- amine
Figure imgf000173_0001
Step 1: 3-Cyclopropyl-5-methyl-l/ -pyr azole
[00421] A mixture of l-cyclopropylbutane-l,3-dione (8.0 g, 63.4 mmol), NH2-NH2.H2O (3.81 g, 76.1 mmol), 4A molecular sieves (16 g) and EtOH (80 mL) was stirred at 80 °C overnight. The mixture was cooled to room temperature, filtered and concentrated to dryness to give 3- cyclopropyl-5-methyl-liT-pyrazole (6 g, crude) as a yellow oil. 1H NMR (400 MHz, CDCI3): d 5.61 (s, 1H), 2.19 (s, 3H), 1.83-1.81 (m, 1H), 0.90-0.78 (m, 2H), 0.67-0.55 (m, 2H); LCMS: 123.1
[M+H]+.
Step 2: 4-Bromo-3-cyclopropyl-5-methyl-l/ -pyrazole
[00422] A mixture of 3-cyclopropyl-5-methyl-li7-pyrazole (1.70 g, 13.9 mmol), NBS (2.48 g,
13.9 mmol) and DMF (15 mL) was evacuated and purged with nitrogen three times then stirred at room temperature for lh under nitrogen. The reaction mixture was poured into water (15 mL) and then extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with water (2 x l5 mL), brine (l5mL), dried over Na2S04, filtered, concentrated, and purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=l/l) to give 4-bromo-3-cyclopropyl-5- m ethyl- liT-pyrazole (850 mg, 30%) as a white oil. 1H NMR (400 MHz, CDCI3) d 10.2-8.4 (m, 1H), 2.21 (s, 3H), 1.86-1.84 (m, 1H), 1.0-0.9 (m, 2H), 0.9-0.8 (m, 2H); LCMS: 201.0 [M+H]+.
Step 3: tert- Butyl 4-bromo-3-cyclopropyl-5-methyl-l/ -pyrazole-l-carboxylate
[00423] A solution of 4-brom o-3 -cy cl opropyl -5 -m ethyl - 1 //-py razol e (850 mg, 4.23 mmol), di- /er/-butyl dicarbonate (1.01 g, 4.65 mmol) and DMAP (103 mg, 0.85 mmol) in THF (20 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water (20 mL) and then extracted with EtOAc (2 x20 mL).The combined organic layers were washed with water (2 x20 mL), brine (20 mL), and dried over Na2S04, filtered, concentrated and purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=5/l) to give tert- butyl 4-bromo-3- cyclopropyl-5-methyl- l //-pyrazole- 1 -carboxyl ate (670 mg, 53%) as an oil. 1H MR (400 MHz, CDCI3) d 2.47 (s, 3H), 1.89-1.88 (m, 1H), 1.62 (s, 9H), 1.1-1.0 (m, 2H), 1.0-0.9 (m, 2H); LCMS:
244.9 [M+H-56]+ .
Step 4: tert- Butyl 3-cyclopropyl-4-(4-hydroxyphenyl)-5-methyl-l/ -pyrazole-l-carboxylate [00424] A solution of tert-butyl 4-brom o-3 -cy d opropy 1 -5 -m ethyl - 1 //-pyrazol e- 1 -carboxyl ate (400 mg, 1.33 mmol), (4-hydroxyphenyl)boronic acid (220 mg, 1.59 mmol), K2C03 (55 l mg, 3.98 mmol), Pd2(dba)3 (122 mg, 0.13 mmol), XPhos (127 mg, 0.27 mmol) in dioxane (20 mL) and H20 (4 mL) was heated at 100 °C for l .5h. The reaction mixture was cooled to room temperature, poured into water (20 mL) and then extracted with EtOAc (2 x20 mL). The combined organic layers were washed with water (2^20 mL), brine (45 mL), dried over Na2S04, filtered, concentrated and purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=5/l) to give tert- butyl 3-cyclopropyl-4-(4-hydroxyphenyl)-5-methyl-lH-pyrazole-l-carboxylate (400 mg, 96%) as a red solid. 1H NMR (400 MHz, CDCl3) d 7.18 (d, 2H), 6.90 (d, 2H), 2.41 (s, 3H), 1.8-1.7 (m, 1H), 1.63 (s, 9H), 1.1-1.0 (m, 2H), 0.9-0.8 (m, 2H); LCMS: 337.1 [M+Na]+.
Step 5: (E')-tert-Butyl 4-(4-((2-(((tert-butox carbonyl)amino)methyl)-3- fluoroallyl)oxy)phenyl)-3-cyclopropyl-5-methyl-l//-pyrazole-l-carboxylate
[00425] A solution of tert- butyl 3-cyclopropyl-4-(4-hydroxyphenyl)-5-methyl-li7-pyrazole-l- carboxylate (350 mg, 1.11 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (358 mg, 1.34 mmol), Cs2C03 (1.09 g, 3.34 mmol) and acetonitrile (35 mL) was stirred at room temperature for 1.5 h. The reaction mixture was poured into water (30 mL) and then extracted with EtOAc (2 x30 mL).The combined organic layers were washed with water (2 x30 mL), brine (25ml), dried over Na2S04, filtered, concentrated and purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=3/l) to give (E)-tert- butyl 4-(4-((2-(((tert- butoxycarbonyl)amino)methyl)-3-fluoroallyl)oxy)phenyl)-3-cyclopropyl-5-methyl-lH-pyrazole-l- carboxylate (350 mg, 63%) as a yellow oil. 1H NMR (400 MHz, CDCl3) d 7.19-7.18 (m, 2H), 7.17- 7.16 (m, 2H), 6.90 (d, 1H), 4.66 (d, 1H), 4.4 (d, 2H), 4.0-3.9 (m, 2H), 2.32 (s, 3H), 1.56 (s, 10H), 1.35 (s, 9H), 1.0-0.9 (m, 2H), 0.8-0.7 (m, 2H); LCMS: 502.2 [M+H]+.
Step 6: (ii)-2-((4-(3-Cyclopropyl-5-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-3-fluoroprop-2-e n-l-amine
[00426] (E)-tert- butyl 4-(4-((2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoroallyl)oxy)phenyl)-3- cyclopropyl-5-methyl-lH-pyrazole-l-carboxylate (350 mg, 0.70 mmol) was added into 4 M HC1 in EtOAc (15 mL). The mixture was stirred at room temperature for 3.5 h under nitrogen. The mixture was concentrated to dryness and then purified by reverse-phase HPLC (water (0.04%HCl)-MeCN) to give (E)-2-((4-(3-Cyclopropyl-5-methyl-lH-pyrazol-4-yl)phenoxy)methyl)-3-fluoroprop-2-en-l- amine (56 mg, 26%) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 8.3-8.2 (m, 3H), 7.34 (d, 2H), 7.33 (d, 1H), 7.09 (d, 2H), 4.7-4.6 (m, 2H), 3.7-3.6 (m, 2H), 2.22 (s, 3H), 1.9-1.8 (m, 1H), 1.0- 0.8 (m, 4H): LCMS:302.2 [M+H]+. [00427] The compounds below were synthesized in a similar manner as described for compound 1.65.
Figure imgf000175_0002
Compound 2 and Compound 2.01
E -3-Fluoro-2-((4-(piperidin-4-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride (Compound 2) and (Z)-3-Fluoro-2-((4-(piperidin-4-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride (Compound 2.01)
Figure imgf000175_0001
Step 1: terf-Butyl 4-(4-hydroxyphenyl)piperidine-l-carboxylate
[00428] To a solution of 4-(piperidin-4-yl)phenol (1 g, 5.64 mmol) and triethylamine (1.14 g, 11.2 mmol) in DCM (10 mL) at 0°C, was added dropwise a solution of BOC20 (1.35 g, 6.2 mmol) in DCM (2 mL). The mixture was warmed to room temperature overnight. The mixture was poured into water (15 mL) and extracted with DCM (2x 15 mL). The organic layers were combined, washed with water (2x 10 mL), brine (10 mL), dried (Na2S04), filtered and concentrated and then purified by chromatography on silica gel (petroleum ether/EtOAc = 10/1) to give tert- butyl 4-(4- hydroxyphenyl)piperidine-l-carboxylate (803 mg, 51%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.07 (d, 2H), 6.79 (d, 2H), 5.27 (s, 1H), 4.31-4.21 (m, 2H), 2.82-2.74 (m, 2H), 2.62-2.55 (m, 1H), 1.79 (d, 2H), 1.68-1.43 (m, 11H); LCMS: 278.2 [M+H]+. Step 2: terf-Butyl 4-(4-((2-(((fert-butoxycarbonyl)amino)methyl)-3-fluoroallyl)oxy)phenyl) piperidine-l-carboxylate
[00429] A mixture of tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (460 mg, 1.72 mmol), /er/-butyl 4-(4-hydroxyphenyl)piperidine-l-carboxylate (476 mg, 1.72 mmol), K2C03 (711 mg,
5.15 mmol) and DMF (10 mL) was stirred at 60 °C overnight under a nitrogen atmosphere. The mixture was cooled to room temperature, poured into water (30 mL) and extracted with EtOAc (3 x40 mL). The organic layers were combined, washed with water (2x20 mL), brine (20 mL), dried (Na2S04), filtered, concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 20/1) to give tert- butyl 4-(4-((2-(((/er/-butoxycarbonyl)amino)methyl)-3- fluoroallyl)oxy) phenyl)piperidine-l-carboxylate (360 mg, 45%) as a yellow oil. 1H NMR (400 MHz, CDCl3)a: d 7.05 (d, 2H), 6.70 (d, 2H), 6.70 (d, 0.6H), 6.61 (d, 0.4H), 4.77-4.71 (m, 1H), 4.61 (d, 0.8H), 4.35 (d, 1.2H), 4.28-4.04 (m, 2H), 3.92 (d, 1.2H), 3.69 (d, 0.8H), 2.75-2.69 (m, 2H), 2.55-2.48 (m, 1H), 1.79-1.71 (m, 2H), 1.61 -1.26 (m, 20H); LCMS: 465.3 [M+H]+. a NMR is of a mixture of the ( E) and (Z) alkene isomers.
Step 3: E -3-Fluoro-2-((4-(piperidin-4-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride (Compound 2) and (Z)-3-Fluoro-2-((4-(piperidin-4-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride (Compound 2.01)
[00430] A mixture of tert- butyl 4-(4-((2-(((/er/-butoxycarbonyl)amino)methyl)-3-fluoroallyl)oxy) phenyl)piperidine-l-carboxylate (360 mg, 0.77 mmol) and 4M HC1 in MeOH (2.0 mL) was stirred at room temperature for 1 h. The mixture was concentrated to dryness, and then purified by reverse- phase HPLC (water (0. l%TFA)-CH3CN) to give the TFA salt, which was exchanged with 3M HC1 to give (¾)-3-fluoro-2-((4-(piperidin-4-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride (Compound 2) (32 mg, 15%) as a yellow solid and (Z)-3-fluoro-2-((4-(piperidin-4- yl)phenoxy)methyl)prop-2-en-l -amine hydrochloride (Compound 2.01) (32 mg, 15%) as a yellow solid. Compound 2: 1H NMR (400 MHz, DMSO-r ): d 8.97 (s, 2H), 8.27 (s, 3H), 7.31 (d, 1H), 7.21-7.12 (m, 2H), 6.96 (d, 2H), 4.60 (s, 2H), 3.57 (d, 2H), 3.35-3.21 (m, 2H), 3.02-2.87 (m, 2H), 2.83-2.71 (m, 1H), 1.94-1.71 (m, 4H); LCMS: 265.2 [M+H]+. Compound 2.01 : 1H NMR (400 MHz, DMSO-r¾): 9.01 (s, 2H), 8.28 (s, 3H), 7.21 (d, 1H), 7.16 (d, 2H), 6.97 (d, 2H), 4.72 (s, 2H), 3.53 (d, 2H), 3.34-3.20 (m, 2H), 2.99-2.85 (m, 2H), 2.82-2.72 (m, 1H), 1.91-1.76 (m, 4H); LCMS: 265.2 [M+H]+.
Compound 2.02
(ii)-l-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)piperidin-l-yl)ethanone
hydrochloride
Figure imgf000177_0001
Step 1: 4-(l-Acetylpiperidin-4-yl)phenyl acetate
[00431] To a mixture of 4-(piperidin-4-yl)phenol (1.5 g, 8.4 mmol) and K2C03 (2 g, 14.4 mmol) in dioxane (20 mL) and H20 (20 mL), was added acetyl acetate dropwise (0.79 mL, 8.5 mmol), and then stirred at room temperature for 2 h. The reaction mixture was diluted with H20 (40 mL), and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated under reduced pressure to give 4-(l-acetylpiperidin-4- yl)phenyl acetate (1.5 g, crude) as a white solid. LCMS: 262.2 [M+H]+.
Step 2: l-(4-(4-Hydroxyphenyl)piperidin-l-yl)ethanone
[00432] A mixture of 4-(l-acetylpiperidin-4-yl)phenyl acetate (1.5 g, 5.7 mmol), KOH (1.6 g, 28 mmol), dioxane (10 mL) and H20 (10 mL) was stirred at room temperature for 4 h. The reaction mixture concentrated under reduced pressure to removed organic solvent then diluted with H20 (5 mL) and was adjusted to pH=l with 3M HC1. This was then filtered, the cake was dried under vacuum and then triturated with EtOAc (10 mL) to give l-(4-(4-hydroxyphenyl)piperidin-l- yl)ethanone (550 mg, 43%) as a white solid. 1H NMR (400 MHz, DMSO-r¾): d 9.17 (s, 1H), 7.01 (d, 2H), 6.67 (d, 2H), 4.49 (d, 1H), 3.88 (d, 1H), 3.08 (t, 1H), 2.69-2.52 (m, 2H), 2.01 (s, 3H), 1.74- 1.51 (m, 2H), 1.50-1.47 (m, 1H), 1.36-1.33 (m, 1H); LCMS: 220.1 [M+H]+.
Step 3: tert- Butyl (E)-(2-((4-(l-acetylpiperidin-4-yl)phenoxy)methyl)-3-fluoroallyl)carbamate
[00433] A mixture of l-(4-(4-hydroxyphenyl)piperidin-l-yl)ethanone (339 mg, 1.5 mmol), tert- butyl (E)-2-(bromomethyl)-3-fluoroallyl)carbamate (415 mg, 1.55 mmol), K2C03 (641 mg, 4.6 mmol) and DMF (11 mL) was stirred at 60 °C overnight. The reaction mixture was quenched with H20 (30 mL), and then extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (Petroleum ethenEthyl acetate=l0: l 1 : 1) to give tert- butyl (£)-( 2-((4-(l- acetylpiperidin-4-yl)phenoxy)methyl)-3-fluoroallyl)carbamate (400 mg, 59%) as a yellow oil. 1H NMR (400 MHz, DMSO-r¾): d 7.14 (d, 2H), 6.97 (d, 1H), 7.08-6.99 (m, 1H), 6.93-6.83 (m, 2H), 4.57-4.47 (m, 1H), 4.39 (d, 2H), 3.94-3.85 (m, 1H), 3.74 (d, 2H), 3.09-3.08 (m, 1H), 2.71-2.63 (m, 1H), 2.61-2.52 (m, 1H), 2.02 (s, 3H), 1.74-1.70 (m, 2H), 1.61-1.36 (m, 2H), 1.34 (s, 9H); LCMS: 407.3 [M+H]+. Step 4: (£')-l-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)piperidin-l-yl)ethanone hydrochloride (Compound 2.02)
[00434] A mixture of /er/-butyl (L’)-(2-((4-( 1 -acetyl pi peri din-4-yl)phenoxy)m ethyl )-3- fluoroallyl)carbamate (400 mg, 0.98 mmol), TFA (27 mmol, 2 mL) and DCM (6 mL) was stirred at room temperature for 1 h. The mixture was concentrated to dryness. The residue was co-evaporated with DCM (2 x 20 mL) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3.0 mL) and then 2M HC1 in diethyl ether (0.5 mL) was added. The precipitate formed was isolated and dried under reduced pressure. The residue was purified by reverse-phase HPLC (water (0.05%HCl)-CH3CN) to give (//)- l -(4-(4-((2-(ami nomethyl )-3-fluoroallyl)oxy)phenyl)pi peri din-1 - yl)ethanone hydrochloride (199 mg, 65%) as a white solid. 1H NMR (400 MHz, DMSO-r¾): d 8.26 (s, 3H), 7.28 (d, 1H), 7.17 (d, 2H), 6.92 (d, 2H), 4.59 (d, 2H), 4.51 (d, 1H), 3.89 (d, 1H), 3.58 (m, 2H), 3.16-3.03 (m, 1H), 2.76-2.64 (m, 1H), 2.61-2.52 (m, 1H), 2.02 (s, 3H), 1.80-1.67 (m, 2H), 1.55-1.52 (m, 1H), 1.40-1.36 (m, 1H); LCMS: 307.1 [M+H]+.
Compound 2.03
(£')-3-Fluoro-2-((4-(l-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride
Figure imgf000178_0001
Step 1: 4-(l-(Methylsulfonyl)piperidin-4-yl)phenyl methanesulfonate
[00435] To a solution of 4-(piperidin-4-yl)phenol (1.5 g, 8.46 mmol) in DCM (20 mL) at room temperature, was added /V-ethyl-/V-isopropylpropan-2-amine (25 mmol, 4.4 mL) and MsCl (1.3 mL, 17 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with H20 (30 mL) and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2^20 mL), dried (Na2S04), filtered, concentrated under reduced pressure to give 4-(l- (methylsulfonyl)piperidin-4-yl)phenyl methanesulfonate (1.1 g, crude) as a yellow solid. LCMS: 334.0 [M+H]+.
Step 2: 4-(l-(Methylsulfonyl)piperidin-4-yl)phenol
[00436] A mixture of 4-(l-(methylsulfonyl)piperidin-4-yl)phenyl methanesulfonate (1.1 g, 3.3 mmol), NaOH (1 g, 25 mmol), MeOH (15 mL) and H20 (10 mL) was stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove organic solvent, then diluted with water (5 mL) and was adjusted to pH=l with aqueous 3 M HC1. The suspension was filtered, the cake was dried in vacuum, and then triturated with EtOAc (10 mL) to give 4-(l-(methylsulfonyl)piperidin-4-yl)phenol (400 mg, 47%) as a yellow solid. 1H NMR (400 MHz, DMSO-£¾): d 9.19 (s, 1H), 7.04 (d, 2H), 6.69 (d, 2H), 3.64 (d, 2H), 2.88 (s, 3H), 2.77-2.73 (m, 2H), 2.50-2.46 (m, 1H), 1.81 (d, 2H), 1.63-1.57 (m, 2H); LCMS: 256.1 [M+H]+.
Step 3: tert- Butyl (E)-(3-fluoro-2-((4-(l-(methylsulfonyl)piperidin-4- yl)phenoxy)methyl)allyl)carbamate
[00437] A mixture of tert- butyl (£)-(2-(bromomethyl)-3-fluoroallyl)carbamate (415 mg, 1.55 mmol), 4-(l-(methylsulfonyl)piperidin-4-yl)phenol (395 mg, 1.55 mmol), K2C03 (641 mg, 4.64 mmol) and DMF (11 mL) was stirred at 60 °C overnight. The reaction was cooled to room temperature, quenched with H20 (30 mL), and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (Petroleum ether :Ethyl acetate=l0: l 2: 1) to give tert- butyl (£)-(3-fluoro-2-((4-(l-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)allyl)carbamate (430 mg, 62%) as a white solid. 1H NMR (400 MHz, DMSO-i¾): 5 7.17 (d, 2H), 6.99 (d, 1H), 7.05-7.03 (m, 1H), 6.88 (d, 2H), 4.40 (d, 2H), 3.74 (d, 2H), 3.66-3.64 (m, 2H), 2.88 (s, 3H), 2.84-2.73 (m, 2H), 2.62-2.54 (m, 1H), 1.84-1.81 (m, 2H), 1.64-1.61 (m, 2H), 1.34 (s, 9H); LCMS: 443.3 [M+H]+.
Step 4: (£')-3-Fluoro-2-((4-(l-(methylsulfonyl)piperidin-4-yl)phenoxy)methyl)prop-2-en-l- amine hydrochloride (Compound 2.03)
[00438] A mixture of /cvV-butyl (£)-(3-fluoro-2-((4-(l-(methylsulfonyl)piperidin-4- yl)phenoxy)methyl)allyl)carbamate (430 mg, 0.97 mmol), TFA (2 mL, 27 mmol) and DCM (6 mL) was stirred at room temperature for 1 h. The mixture was concentrated to dryness. The residue was co-evaporated with DCM (2 x 20 mL) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3.0 mL) and then ethereal 2M HC1 in diethyl ether (0.5 mL) was added. The precipitate formed was isolated and dried under reduced pressure. The residue was purified by reverse-phase HPLC (water (0.05%HCl)-CH3CN) to give (E)-3-fluoro-2-((4-(l- (methylsulfonyl)piperidin-4-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride (113 mg, 33%) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 8.24 (s, 3H), 7.29 (d, 1H), 7.20 (d, 2H), 6.94 (d, 2H), 4.60 (d, 2H), 3.66 (d, 2H), 3.58 (s, 2H), 2.89 (s, 3H), 2.84-2.74 (m, 2H), 2.64-2.53 (m, 1H), 1.84-1.81 (m, 2H), 1.64-1.61 (m, 2H); LCMS: 343.1 [M+H]+.
Compound 2.04 & Compound 2.05
E)-Methyl 4-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)piperidine-l-carboxylate hydrochloride (Compound 2.04) & (Z)- Methyl 4-(4-((2-(aminomethyl)-3- fluoroallyl)oxy)phenyl)piperidine-l-carboxylate hydrochloride (Compound 2.05)
Figure imgf000180_0001
Step 1: 2-(Trimethylsilyl)ethyl 4-(4-hydroxyphenyl)piperidine-l-carboxylate
[00439] To a solution of 4-(piperidin-4-yl)phenol (1 g, 5.64 mmol) and Et3N (1.14 g, 11.3 mmol) in THF (10 mL) at 0°C, 2,5-dioxopyrrolidin-l-yl (2-(trimethylsilyl)ethyl) carbonate (1.46 g, 5.6 mmol) was added. The mixture was warmed to room temperature overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (2x30 mL). The organic layers were combined, washed with water (2x20 mL), brine (20 mL), dried (Na2S04), filtered and concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 20/1) to give 2- (trimethylsilyl)ethyl 4-(4 hydroxyphenyl)piperidine-l-carboxylate (1.16 g, 63% ) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.01 (d, 2H), 6.74 (d, 2H), 5.13 (s, 1H), 4.36-4.09 (m, 4H), 2.85- 2.74 (m, 2H), 2.55 (t, 1H), 1.76 (d, 2H), 1.63-1.42 (m, 2H), 1.02-0.93 (m, 2H), 0.6 (s, 9H); LCMS: 344.1 [M+Na]+.
Step 2: 2-(Trimethylsilyl)ethyl 4-(4-((2-(((terf-butoxycarbonyl)amino)methyl)-3- fluoroallyl)oxy)phenyl)piperidine-l-carboxylate
[00440] A mixture of tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (391 mg, 1.46 mmol), 2-(trimethylsilyl)ethyl 4-(4 hydroxyphenyl)piperidine-l-carboxylate (468 mg, 1.46 mmol) K2C03 (604 mg, 4.37 mmol) and DMF (10 mL) was stirred at 50°C overnight. The mixture was cooled to room temperature, poured into water (30 mL) and extracted with EtOAc (3 x30 mL).The organic layers were combined, washed with water (2x20 mL), brine (20 mL), dried (Na2S04), filtered and concentrated and then purified by chromatography on silica gel (petroleum ether/EtOAc = 5/1) to 2-(trimethylsilyl)ethyl 4-(4-((2-(((/er/-butoxycarbonyl)amino)methyl)-3- fluoroallyl)oxy)phenyl)piperidine-l-carboxylate (400 mg, 53%) as a yellow solid. 1H NMR (400 MHz, CDCl3)a: d 7.06 (d, 2H), 6.90-6.75 (m, 2H), 6.70 (d, 0.85H), 6.61 (d, 0.15H), 4.73-4.68 (m, 1H), 4.63 (d, 0.3H), 4.37 (d, 1.7H), 4.31-4.09 (m, 4H), 3.95 (d, 1.7H), 3.71 (d, 0.3H), 2.79-2.68 (m, 2H), 2.65-2.48 (m, 1H), 1.76 (d, 2H), 1.61-1.46 (m, 2H), 1.36 (s, 9H), 1.06-0.92 (m, 2H), 0.00 (s, 9H); LCMS: 509.2 [M+H]+. a NMR is of a mixture of the ( E) and (Z) alkene isomers.
Step 3: tert- Butyl (3-fluoro-2-((4-(piperidin-4-yl)phenoxy)methyl)allyl)carbamate
[00441] A mixture of 2-(trimethylsilyl)ethyl 4-(4-((2-(((/er/-butoxycarbonyl)amino)methyl)-3- fluoroallyl)oxy)phenyl)piperidine-l-carboxylate (400 mg, 0.78 mmol), TBAF (1 M in THF, 2 mL) and THF (10 mL) was stirred at room temperature overnight. The mixture was concentrated to dryness to give /cvV-butyl (3-fluoro-2-((4-(piperidin-4-yl)phenoxy)methyl)allyl)carbamate (300 mg, crude) as a yellow oil. LCMS: 365.3 [M+H]+.
Step 4: Methyl 4-(4-((2-(((terf-butoxycarbonyl)amino)methyl)-3 fluoroallyl)oxy)phenyl) piperidine-l-carboxylate
[00442] To a solution of /er/-butyl (3-fluoro-2-((4-(piperidin-4-yl)phenoxy)methyl)allyl)carbamate (286 mg, 0.78 mmol), triethylamine (397 mg, 3.92 mmol) in DCM (10 mL) at 0°C, was added methyl chloroformate (222 mg, 2.3 mmol). The mixture was warmed to room temperature overnight, poured into water (10 mL) and extracted with DCM (2x 10 mL). The organic layers were combined, washed with water (2x 10 mL), brine (10 mL), dried (Na2S04), filtered, concentrated and then purified by chromatography on silica gel (petroleum ether/EtOAc = 5/1) to give methyl 4-(4- ((2-(((/er/-butoxycarbonyl)amino)methyl)-3 fluoroallyl)oxy)phenyl) piperidine-l-carboxylate (160 mg, 48%) as a yellow oil. 1H NMR (400 MHz, CDCl3)a: d 7.04 (d, 2H), 6.86-6.73 (m, 2H), 6.68 (d, 1H), 4.75-4.38 (m, 1H), 4.61 (d, 0.3H), 4.35 (d, 1.7H), 4.27-4.23 (m, 2H), 3.92 (d, 1.7H), 3.69-3.62 (m, 3.3H), 2.83-2.75 (m, 2H), 2.54 (t, 1H), 1.74 (d, 2H), 1.61-1.50 (m, 2H), 1.34 (s, 9H); LCMS: 423.3 [M+H]+. a NMR is of a mixture of the (//) and ( Z) alkene isomers.
Step 5: (E)-Methyl 4-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)piperidine-l-carboxylate hydrochloride (Compound 2.04) and (Z)-Methyl 4-(4-((2-(aminomethyl)-3- fluoroallyl)oxy)phenyl)piperidine-l-carboxylate hydrochloride (Compound 2.05)
[00443] A mixture of methyl 4-(4-((2-(((/er/-butoxycarbonyl)amino)methyl)-3
fluoroallyl)oxy)phenyl) piperidine-l-carboxylate (160 mg, 0.37 mmol) in 4M HC1 in MeOH (2.0 mL) was stirred at room temperature for 1 h. The mixture was concentrated to dryness, and then purified by reverse-phase HPLC (water (0.05%HCl)-CH3CN) to give (//(-methyl 4-(4-((2- (aminomethyl)-3-fluoroallyl)oxy)phenyl)piperidine-l-carboxylate hydrochloride (Compound 2.04) (50.2 mg, 41%,) as a white solid and ((Z)-methyl 4-(4-((2-(aminomethyl)-3- fluoroallyl)oxy)phenyl)piperidine-l-carboxylate hydrochloride (Compound 2.05) (15 mg, 12% yield) as a white solid. Compound 2.04: 1H MR (400 MHz, DMSO-i¾): d 8.20 (s, 3H), 7.29 (d, 1H), 7.18 (d, 2H), 6.92 (d, 1H), 4.59 (d, 2H), 4.12-4.05 (m, 2H), 3.65-3.53 (m, 5H), 2.98-2.81 (m, 2H), 2.71-2.58 (m, 1H), 1.72 (d, 2H), 1.52-1.46 (m, 2H); 323.1 [M+H]+. Compound 2.05: 1H NMR (400 MHz, DMSO-i¾): 8.16 (s, 3H), 7.20 (d, 1H), 7.18 (d, 2H), 7.00-6.89 (m, 2H), 4.70 (d, 2H), 4.15-4.05 (m, 2H), 3.61 (s, 3H), 3.51 (d, 2H), 2.98-2.75 (m, 2H), 2.73-2.60 (m, 1H), 1.72 (d, 2H), 1.52-1.46 (m, 2H); LCMS: 323.1 [M+H]+. Compound 2.06 & Compound 2.07
(E)-2-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)piperidin-l-yl)acetic acid
hydrochloride (Compound 2.06) & (Z)-2-(4-(4-((2-(Aminomethyl)-3- fluoroallyl)oxy)phenyl)piperidin-l-yl)acetic acid hydrochloride (Compound 2.07)
Figure imgf000182_0001
Step 1: terf-Butyl 2-(4-(4-((2-(((fe/7-butoxycarbonyl)amino)methyl)-3- fluoroallyl)oxy)phenyl)piperidin-l-yl)acetate
[00444] To a solution of /er/-butyl (3-fluoro-2-((4-(piperidin-4-yl)phenoxy)methyl)allyl)carbamate (300 mg, 0.82 mmol) and K2C03 (227 mg, 1.65 mmol) in DMF (5 mL) at room temperature was added /er/-butyl 2-bromoacetate (192 mg, 0.98 mmol) and the reaction mixture stirred at room temperature overnight. The reaction was quenched with H20 (30 mL) and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (petroleum ether: ethyl
acetate=50: l 2: 1) to give tert- butyl 2-(4-(4-((2-(((/er/-butoxycarbonyl)amino)methyl)-3- fluoroallyl)oxy)phenyl)piperidin-l-yl)acetate (180 mg, 40%) as a yellow oil. 1H NMR (400 MHz, CDCl3)a: d 7.15 (d, 2H), 6.89-6.82 (m, 2H), 6.73 (d, 0.8H), 6.61 (d, 0.2H), 4.78 (br s, 1H), 4.68 (d, 0.2H), 4.43 (d, 1.8H), 4.00 (d, 1.8H), 3.76 (d, 0.2H), 3.17 (s, 2H), 3.07 (d, 2H), 2.51-2.40 (m, 1H), 2.29-2.26 (m, 2H), 1.91-1.75 (m, 4H), 1.49 (s, 9H), 1.42 (s, 9H); LCMS: 479.2 [M+H]+. a NMR is of a mixture of the ( E) and (Z) alkene isomers.
Step 2: (ii)-2-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)piperidin-l-yl)acetic acid hydrochloride (Compound 2.06) & (Z)-2-(4-(4-((2-(Aminomethyl)-3- fluoroallyl)oxy)phenyl)piperidin-l-yl)acetic acid hydrochloride (Compound 2.07)
[00445] To a solution of /cvV-butyl 2-(4-(4-((2-(((/er/-butoxycarbonyl)amino)methyl)-3- fluoroallyl)oxy)phenyl)piperidin-l-yl)acetate (180 mg, 0.37 mmol) in DCM (6 mL) at room temperature, was added TFA (27 mmol, 2 mL) and the reaction stirred for 1 h. The mixture was concentrated to dryness. The residue was co-evaporated with DCM (2 x 20 mL) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3 mL) and then 2M HC1 in diethyl ether (0.2 mL) was added. The precipitate formed was isolated and dried under reduced pressure. The residue was purified by reverse-phase HPLC (water (0.05%HCl)-CH3CN) to give (L’)-2-(4-(4-((2-(ami nomethyl )-3-fluoroallyl)oxy)phenyl)piperidin- l -yl)acetic acid hydrochloride (Compound 2.06) (55 mg, 40%) as a white solid and (Z)-2-(4-(4-((2-(aminomethyl)-3- fluoroallyl)oxy)phenyl)piperidin-l-yl)acetic acid hydrochloride (Compound 2.07) (4.9 mg, 3%) as a yellow solid. Compound 2.06: 1H NMR (400 MHz, DMSO-i¾): d 8.32 (s, 3H), 7.28 (d, 1H), 7.26- 7.11 (m, 2H), 6.97 (d, 2H), 4.62 (d, 2H), 4.14 (s, 2H), 3.57 (s, 4H), 3.21 -3.18 (m, 2H), 2.78-2.72 (m, 1H), 2.09-1.85 (m, 4H); LCMS: 323.1 [M+H]+. Compound 2.07: 1H NMR (400 MHz, DMSO- de): d 10.19 (s, 1H), 8.30 (s, 3H), 7.20 (d, 1H), 7.19 (d, 2H), 6.97 (d, 2H), 4.73 (d, 2H), 4.15 (s,
2H), 3.60-3.49 (m, 4H), 3.21-3.18 (m, 2H), 2.78-2.72 (m, 1H), 2.09-1.87 (m, 4H); LCMS: 323.1 [M+H]+.
Compound 2.08
(ii)-2-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)piperidin-l-yl)acetamide
hydrochloride
Figure imgf000183_0001
Step 1: terf-Butyl (E)-(2-((4-(l-(2-amino-2-oxoethyl)piperidin-4-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00446] To a solution of /er/-butyl (£)-(3-fluoro-2-((4-(piperidin-4- yl)phenoxy)methyl)allyl)carbamate (300 mg, 0.82 mmol) and K2C03 (227 mg, 1.65 mmol) in DMF (5 mL) at room temperature was added 2-bromoacetamide (136 mg, 0.98 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched with H20 (30 mL) and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (3 x20 mL), dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (petroleum ethenethyl acetate=20: l DCM: MeOH=0: l) to give tert- butyl (E)-(2-((4-(l-(2-amino-2-oxoethyl)piperidin- 4-yl)phenoxy)methyl)-3-fluoroallyl)carbamate (160 mg, 41%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.14 (d, 3H), 6.91-6.84 (m, 2H), 6.77 (d, 1H), 5.59 (s, 1H), 4.79 (s, 1H), 4.43 (d, 2H), 4.00 (d, 2H), 3.07-2.96 (m, 4H), 2.51-2.43 (m, 1H), 2.33-2.26 (m, 2H), 1.87-1.82 (m, 2H), 1.78- 1.73 (m, 2H), 1.42 (s, 9H); LCMS: 422.1 [M+H]+.
Step 2: (£')-2-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)piperidin-l-yl)acetamide hydrochloride
[00447] To a solution of /cvV-butyl (£)-(2-((4-(l-(2-amino-2-oxoethyl)piperidin-4- yl)phenoxy)methyl)-3-fluoroallyl)carbamate (160 mg, 0.37 mmol) in DCM (6 mL) at room temperature, TFA (27 mmol, 2 mL) was added. The mixture was stirred at room temperature 1 h. The mixture was concentrated to dryness. The residue was co-evaporated with DCM (2 x 20 mL) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3.0 mL) and then 2.0M HC1 in diethyl ether (0.2 mL) was added. The precipitate formed was isolated and dried under reduced pressure. The residue was purified by reverse-phase HPLC (water (0. l%TFA)-CH3CN) to give the TFA salt, which was exchanged with 3M HC1 to give (/f)-2-(4-(4-((2-(ami nomethyl )-3- fluoroallyl)oxy)phenyl)piperidin-l-yl)acetamide hydrochloride (42 mg, 34%) as a yellow solid. 1H NMR (400 MHz, DMSO-r¾): d 9.92 (s, 1H), 8.36 (s, 3H), 8.07 (s, 1H), 7.68 (s, 1H), 7.28 (d, 1H), 7.27-7.07 (m, 2H), 6.97 (d, 2H), 4.63 (d, 2H), 3.91 (s, 2H), 3.68-3.39 (m, 4H), 3.25-3.10 (m, 2H), 2.77-2.71 (m, 1H), 2.08-1.83 (m, 4H); LCMS: 322.1 [M+H]+.
Compound 2.09
(ii)-4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-/V-methylpiperidine-l-carboxamide hydrochloride
Figure imgf000184_0001
Step 1: E)-tert- uiy\ (3-fluoro-2-((4-(l-(methylcarbamoyl)piperidin-4- yl)phenoxy)methyl)allyl)carbamate
[00448] To a solution of (E)-tert- butyl (3-fluoro-2-((4-(piperidin-4- yl)phenoxy)methyl)allyl)carbamate (500 mg, 1.37 mmol) and Et3N (1.9 mL, 13.7 mmol) in DCM (10 mL) at 0 °C, was added methylcarbamic chloride (641 mg, 6.86 mmol). The mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was poured into water (30 mL), and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (Petroleum ethenEthyl acetate=50: l 1 : 1) to give (E)-tert- butyl (3-fluoro-2-((4-(l- (methylcarbamoyl)piperidin-4-yl)phenoxy)methyl)allyl)carbamate (130 mg, 20%) as a yellow oil. 1H NMR (400 MHz, DMSC ,): 5 7.13-7.11 (m, 2.5H), 7.05-7.03 (m, 1H), 6.89-6.85 (m, 2.5H), 6.39-6.38 (m, 1H), 4.39 (d, 2H), 4.05-4.03 (m, 2H), 3.73 (d, 2H), 2.72-2.63 (m, 2H), 2.62-2.58 (m, 1H), 2.57 (d, 3H), 1.68-1.65 (m, 2H), 1.47-1.36 (m, 2H), 1.33 (s, 9H); LCMS: 422.1 [M+H]+.
Step 2: (ii)-4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-/V-methylpiperidine-l- carboxamide hydrochloride
[00449] To a solution of (E)-tert- butyl (3-fluoro-2-((4-(l-(methylcarbamoyl)piperidin-4- yl)phenoxy)methyl)allyl)carbamate (130 mg, 0.31 mmol) in DCM (6 mL) at room temperature, was added TFA (2 mL, 27.01 mmol), and the reaction mixture was stirred for 1 h. The mixture was concentrated to dryness. The residue was co-evaporated with DCM (2 x 20 mL) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3 mL) and then 2.0M HC1 in diethyl ether (0.2 mL) was added. The precipitate formed was isolated and dried under reduced pressure. The residue was purified by reverse-phase HPLC (water (0.04%HCl)-CH3CN) to give (E)-4-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-/V-methylpiperidine-l -carboxamide hydrochloride (49 mg, 49%) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 8.26 (s, 3H), 7.28 (d, 1H), 7.15 (d, 2H), 6.92 (d, 2H), 6.71 (br s, 1H), 4.59 (d, 2H), 4.05 (d, 2H), 3.58 (d, 2H), 2.77- 2.66 (m, 2H), 2.65-2.58 (m, 1H), 2.57 (s, 3H), 1.68 (d, 2H), 1.46-1.36 (m, 2H); LCMS: 322.2
[M+H]+.
Compound 2.10
(ii)-4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)piperidine-l-carboxamide
hydrochloride
Figure imgf000185_0001
Step 1: (ii)-ferf-Butyl (2-((4-(l-carbamoylpiperidin-4-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00450] A mixture of (E)-tert- butyl (3-fluoro-2-((4-(piperidin-4- yl)phenoxy)methyl)allyl)carbamate (1.0 g, 2.74 mmol), urea (181 mg, 3.0 mmol) and dioxane (20 mL) was combined and then the mixture was stirred at 120 °C overnight. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (Petroleum ethenEthyl acetate=50: l 1 : 1) to give (E)-tert- butyl (2-((4- (1 -carbarn oylpiperidin-4-yl)phenoxy)methyl)-3-fluoroallyl)carbamate (250 mg, 22%) as a yellow oil. 1H NMR (400 MHz, DMSC ,): d 7.13-7.11 (m, 2.5H), 7.04 (br s, 1H), 6.86 (d, 2.5H), 5.90 (br s, 2H), 4.39 (d, 2H), 4.09-4.03 (m, 2H), 3.73 (d, 2H), 2.73-2.67 (m, 2H), 2.62-2.56 (m, 1H), 1.68- 1.66 (m, 2H), 1.48-1.38 (m, 2H), 1.33 (s, 9H); LCMS: 408.1 [M+H]+.
Step 2: (E')-4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)piperidine-l-carboxamide hydrochloride
[00451] To a solution of (E)-tert- butyl (2-((4-(l-carbamoylpiperidin-4-yl)phenoxy)methyl)-3- fluoroallyl)carbamate (250 mg, 0.61 mmol) in DCM (6 mL) at room temperature, was added TFA (2 mL, 27 mmol) and the reaction mixture was stirred for 1 h. The mixture was concentrated to dryness. The residue was co-evaporated with DCM (2 x 20 mL) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3.0 mL) and then 2.0M HC1 in diethyl ether (0.5 mL) was added. The precipitate formed was isolated and dried under reduced pressure. The residue was purified by reverse-phase HPLC (water (0.1% HCl)-CH3CN) to give (£)-4-(4-((2-(aminomethyl)-3- fluoroallyl)oxy)phenyl)piperidine-l -carboxamide hydrochloride (60 mg, 31%) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 8.27 (s, 3H), 7.28 (d, 1H), 7.16 (d, 2H), 6.92 (d, 2H), 4.59 (d, 2H), 4.05 (d, 2H), 3.58 (d, 2H), 2.75-2.66 (m, 2H), 2.67-2.57 (m, 1H), 1.68 (d, 2H), 1.47-1.37 (m, 2H); LCMS: 308.1 [M+H]+.
[00452] The compounds below were synthesized in a similar manner as described for Compounds
2-2.10.
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0002
Compound 2.35
(E)-3-Fluoro-2-((4-(l-(pyridin-2-yl)piperidin-4-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride
Figure imgf000188_0001
Step 1: E)-tert- uiy\ (3-fluoro-2-((4-(l-(pyridin-2-yl)piperidin-4- yl)phenoxy)methyl)allyl)carbamate
[00453] To a solution of (E)-tert- butyl (3-fluoro-2-((4-(piperidin-4- yl)phenoxy)methyl)allyl)carbamate (200 mg, 0.55 mmol), 2-bromopyridine (347 mg, 2.20 mmol) in dioxane (8 mL), BINAP (68 mg, 0.11 mmol), Pd2(dba)3 (50 mg, 0.054 mmol), and Cs2C03 (715 mg, 2.20 mmol) were added. The mixture was degassed with 3 vacuum-nitrogen cycles and stirred at 140 °C for 16 h under a nitrogen atmosphere. The reaction was cooled to room temperature, poured into water (20 mL) then extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (3 c 20 mL), dried over Na2S04 filtered and concentrated to dryness to give (E)- /ert-butyl (3-fluoro-2-((4-(l-(pyridin-2-yl)piperidin-4-yl)phenoxy)methyl)allyl)carbamate (102 mg, crude) as a yellow oil. LCMS: 442.2 [M+H]+.
Step 2: (ii)-3-Fluoro-2-((4-(l-(pyridin-2-yl)piperidin-4-yl)phenoxy)methyl)prop-2-en-l-amine hydrochloride
[00454] (E)-tert- Butyl (3-fluoro-2-((4-(l-(pyri din-2 -yl)piperidin-4- yl)phenoxy)methyl)allyl)carbamate (102 mg, 0.23 mmol) was taken up in 4M HC1 in EtOAc (10 mL) and stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to dryness and purified by reverse-phase HPLC [water (0.04%HCl)-MeCN] to give (E)-3-fluoro-2- ((4-(l-(pyridin-2-yl)piperidin-4-yl)phenoxy)methyl)prop-2-en-l -amine hydrochloride (50 mg,
55%) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾): d 8.44-8.43 (m, 3H), 8.05-7.97 (m, 2H), 7.48 (d, 1H), 7.27 (d, 1H), 7.21-7.19 (d, 2H), 6.97-6.90 (m, 3H), 4.63 (d, 2H), 4.51-4.48 (m, 2H), 3.55 (d, 2H), 3.31-3.29 (m, 2H), 2.89-2.87 (m, 1H), 1.90-1.89 (m, 2H), 1.69-1.66 (m, 2H); LCMS: 342.1 [M+H]+.
Compound 2.41
(E)-l-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-4-methylpiperidin-l-yl)ethanone hydrochloride
Figure imgf000189_0001
Step 1: l-Benzyl-4-methylenepiperidine
[00455] 2.5 M n- BuLi in hexanes (22.0 mL, 55 mmol) was added dropwise at 0 °C to a solution of methyltriphenylphosphonium bromide (18.8 g, 52.8 mmol) in THF (100 mL) and the mixture warmed to room temperature. A solution of l-benzylpiperidin-4-one (10 g, 52.8 mmol) in THF (50 mL) was added at room temperature and the mixture was stirred at room temperature for 9 h. The reaction mixture was diluted by adding n-hexane (80 mL) at room temperature, stirred for 1 h and filtered. The filtrate was concentrated under reduced pressure to give l-benzyl-4-methylene- piperidine (7.5 g, 76%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.33-7.20 (m, 5H), 4.59 (s, 2H), 3.46 (s, 2H), 2.40-2.38 (m, 4H), 2.26-2.12 (m, 4H); LCMS: 188.2 [M+H]+.
Step 2: 4-(l-Benzyl-4-methylpiperidin-4-yl)phenol
[00456] A mixture of l-benzyl-4-methylene-piperidine (6.50 g, 34.7 mmol), phenol (32.7 g, 347 mmol) and TfOH (98 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water (50 mL), then extracted with EtOAc (3 x50 mL). The combined organic layers were washed with brine (2 x50 mL), dried over Na2S04, filtered, concentrated, and then purified by reverse-phase HPLC (water(0. l%TFA)-ACN) to give 4-(l-benzyl-4-methylpiperidin-4-yl)phenol (0.7 g, 14%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.32-7.21 (m, 5H), 7.09 (d, 2H),
6.70 (d, 2H), 3.52 (s, 2H), 2.65-2.38 (m, 4H), 2.14-2.03 (m, 2H), 1.74-1.70 (m, 2H), 1.14 (s, 3H); LCMS: 282.1 [M+H]+.
Step 3: 4-(4-Methylpiperidin-4-yl)phenol
[00457] To a solution of 4-(l-benzyl-4-methylpiperidin-4-yl)phenol (700 mg, 2.49 mmol) in EtOAc (20 mL) at room temperature lOwt % Pd/C (500 mg) was added under nitrogen. The suspension was degassed under vacuum and purged with hydrogen three times. The mixture was stirred under hydrogen (20psi) at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure to give 4-(4-methylpiperidin-4-yl)phenol (450 mg, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾): 7.11 (d, 2H), 6.70 (d, 2H), 2.75-2.66 (m, 2H), 2.64-2.56 (m, 2H), 1.87-1.82 (m, 2H), 1.58-1.51 (m, 2H), 1.11 (s, 3H); LCMS: 192.1 [M+H]+.
Step 4: 4-(l-Acetyl-4-methylpiperidin-4-yl)phenyl acetate
[00458] To a solution of 4-(4-methylpiperidin-4-yl)phenol (450 mg, 2.35 mmol) in dioxane (10 mL) and H20 (10 mL) at room temperature, K2C03 (975 mg, 7.06 mmol) and acetic anhydride (721 mg, 7.06 mmol) were added at room temperature. The mixture was stirred at room
temperature for 3 h. The reaction mixture was poured into water (20 mL), then extracted with EtOAc (3 x25 mL). The combined organic layers were washed with brine (2 x25 mL), dried over Na2S04 filtered and concentrated under reduced pressure to give crude 4-(l-acetyl-4- methylpiperidin-4-yl)phenyl acetate (500 mg) as a yellow solid. LCMS: 276.1 [M+H]+.
Step 5: l-(4-(4-Hydroxyphenyl)-4-methylpiperidin-l-yl)ethanone
[00459] To a solution of 4-(l-acetyl-4-methylpiperidin-4-yl)phenyl acetate (500 mg, 1.82 mmol) in dioxane (10 mL) and H20 (10 mL) at room temperature, potassium hydroxide (509 mg, 9.08 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was concentrated to remove dioxane, adjusted to pH~2 with 3M HC1 (-10 mL) and filtered. The cake was dried under vacumm to give l-(4-(4-hydroxyphenyl)-4-methylpiperidin-l-yl)ethanone (400 mg) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 9.17 (s, 1H), 7.15 (d, 2H), 6.71 (d, 2H), 3.48-3.40 (m, 2H), 3.39-3.22 (m, 2H), 2.07-1.76 (m, 5H), 1.69-1.44 (m, 2H), 1.16 (s, 3H); LCMS: 234.1 [M+H]+.
Step 6: (E)-tert-Bu y\ (2-((4-(l-acetyl-4-methylpiperidin-4-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00460] To a solution of l-(4-(4-hydroxyphenyl)-4-methylpiperidin-l-yl)ethanone (200 mg, 0.86 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (276 mg, 1.03 mmol) in MeCN (10 mL) was added K2C03 (355 mg, 2.57 mmol) at room temperature. The mixture was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature, poured into water (20 mL) then extracted with EtOAc (3 x25 mL). The combined organic layers were washed washed with brine (2 x25 mL), dried over Na2S04 filtered, concentrated under reduced pressure, and then purified by prep-TLC (Si02, petroleum ether/ethyl acetate = 1/1) to give (E)-tert- Butyl (2-((4-(l- acetyl-4-methylpiperidin-4-yl)phenoxy)methyl)-3-fluoroallyl)carbamate (260 mg, 72 %) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾): d 7.28 (d, 2H), 7.12 (s, 1H), 7.00 (d, 1H), 6.90 (d, 2H), 4.40 (d, 2H), 3.75 (d, 2H), 3.49-3.41 (m, 2H), 3.39-3.24 (m, 2H), 1.99-1.85 (m, 5H), 1.69-1.52 (m, 2H), 1.33 (s, 9H), 1.18 (s, 3H); LCMS: 421.2 [M+H]+.
Step 7: (£')-l-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-4-methylpiperidin-l- yl)ethanone hydrochloride
[00461] A mixture of (E)-tert- butyl (2-((4-(l-acetyl-4-methylpiperidin-4-yl)phenoxy)methyl)-3- fluoroallyl)carbamate (260 mg, 0.62 mmol) and 4M HC1 in EtOAc (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to dryness, and then purified by reverse-phase HPLC (water(0.04%HCl)-MeCN)to give (E)- 1-(4-(4-((2- (aminomethyl)-3-fluoroallyl)oxy)phenyl)-4-methylpiperidin-l-yl)ethanone hydrochloride (113 mg, 51 %) as a red solid. 1H NMR (400 MHz, DMSO-i¾): d 8.39 (br s, 3H), 7.30 (d, 2H), 7.28 (d, 1H), 6.95 (d, 2H), 4.62 (d, 2H), 3.57 (d, 2H), 3.52-3.41 (m, 2H), 3.32 (s, 2H), 1.99-1.91 (m, 4H), 1.93- 1.84 (m, 1H), 1.71-1.51 (m, 2H), 1.18 (s, 3H); LCMS: 321.2 [M+H]+.
[00462] The compound below was synthesized in a similar manner as described for Compound 2.41.
Figure imgf000192_0002
Compound 2.43
(ii)-l-(3-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-8-azabicyclo[3.2.1]octan-8- yl)ethanone
Figure imgf000192_0001
Step 1: tert-Butyl 3-(4-(benzyloxy)phenyl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate
[00463] A mixture of 1 -(benzyl oxy)-4-bromobenzene (2.5 g, 9.5 mmol), tert-butyl 3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2. l]oct-2-ene-8-carboxylate (3.82 g, 11.4 mmol) , Pd(dppf)2Cl2 (388 mg, 0.48 mmol), K2C03 (3.94 g, 28.5 mmol) in dioxane (27 mL) and H20 (3 mL) was degassed, purged with nitrogen and the mixture was stirred at 100 °C for lh under a nitrogen atmosphere. The mixture was cooled to room temperature then poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, concentrated, and then purified by silica gel chromatography (hexanes/ethyl acetate) to give tert-butyl 3-(4- (benzyloxy)phenyl)-8-azabicyclo[3.2. l]oct-2-ene-8-carboxylate (3.01 g, 83%) as a white solid, 1H NMR (400 MHz, DMSO): d 7.4 (m, 7H), 6.97 (d, 2H), 6.4 (d, 1H); 5.10 (s, 2H), 4.35 (m, 1H); 4.21 (m, 1H ), 2.90 (m, 1H); 2.58 (m, 1H), 2.21 (m, 1H); 1.85 (m, 2H); 1.60 (m, 1H), 1.35 (s, 9H);
LCMS: 235.9 [M+H]+.
Step 2: 3-(4-(benzyloxy)phenyl)-8-azabicyclo[3.2.1]oct-2-ene
[00464] To a solution of tert-butyl 3-(4-(benzyloxy)phenyl)-8-azabicyclo[3.2. l]oct-2-ene-8- carboxylate (1.06 g, 2.71 mmol) in DCM (15 mL) at room temperature was added TFA (2 mL, 27 mmol) and the resulting mixture was stirred for 1 h. The mixture was concentrated to dryness. Diethyl ether was added. A precipitate formed which was filtered and washed with a small amount of ether and dried under reduced pressure to give 3-(4-(benzyloxy)phenyl)-8-azabicyclo[3.2. l]oct- 2-ene TFA salt (689 mg, 87%) as a white solid. 1H NMR (400 MHz, DMSO): d 8.9 (s, 2H) 7.4 (m, 7H), 6.9 (d, 2H), 6.3 (d, 1H), 5.10 (s, 2H), 4.3 (m, 1H), 4.2 (m, 1H), 2.9 (m, 1H), 2.6 (m, 1H),
2. l(m, 3H), 1.8 (m, 1H); LCMS: 292.0 [M+H]+. Step 3: l-(3-(4-(benzyloxy)phenyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)ethanone
[00465] To a stirred solution of 3-(4-(benzyloxy)phenyl)-8-azabicyclo[3.2. l]oct-2-ene TFA salt (405 mg, 1.0 mmol) and Et3N (0.28 ml, 2 mmol) in DCM (5 mL) at 0°C was added acetic anhydride dropwise (99.3 ul, 1.05 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with H20 and brine, organics concentrated under reduced pressure to give l-(3-(4-(benzyloxy)phenyl)-8-azabicyclo[3.2. l]oct-2- en-8-yl)ethenone (333 mg, crude) as a white solid. 1H NMR (400 MHz, DMSO): 7.4 (m, 7H), 6.8 (d, 2H), 6.2 (m, 1H), 4.9-4.8 (m, 1H), 4.3 (m, 1H); 3.1-2.8 (m, 1H), 2.3 (m, 1H), 2.1 (m, 2H), 2.0 ( m, 2H), 1.98 (s, 3H), 1.9 (m, 1H ), 1.7 (m, 1H); LCMS: 334.2 [M+H]+.
Step 4: l-(3-(4-hydroxyphenyl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone
[00466] l-(3-(4-(benzyloxy)phenyl)-8-azabicyclo[3.2. l]oct-2-en-8-yl)ethenone (333 mg, 1 mmol) was dissolved in methanol (20 mL) and flask evacuated and purged with nitrogen. l0wt%
Palladium on carbon (106 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at room temperature overnight. The reaction mixture was evacuated and purged with nitrogen. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (106 mg, 43%) as an off-white solid. LCMS: 246.0 [M+H]+.
Step 5: (ii)-l-(3-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-8-azabicyclo[3.2.1]octan-8- yl)ethanone
[00467] l-(3-(4-hydroxyphenyl)-8-azabicyclo[3.2. l]octan-8-yl)ethanone (106 mg, 0.43 mmol) was reacted in a manner similar to l-(4-(4-Hydroxyphenyl)-4-methylpiperidin-l-yl)ethanone in the preparation of compound 2.41 to yield the title compound as a mixture of exo:endo isomers isolated as a white powder (122 mg, 85%). LCMS: 333.2 [M+H]+.
[00468] The compounds below were synthesized in a similar manner as described in the preceding examples.
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0002
Compound 2.80
(E)-l-(8-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-3-azabicyclo [3.2.1] octan-3- yl)ethanone hydrochloride
Figure imgf000198_0001
Step 1: 3-Benzyl-8-(4-(methoxymethoxy)phenyl)-3-azabicyclo[3.2.1]octan-8-ol
[00469] To a solution of l-bromo-4-(methoxymethoxy)benzene (1.0 g, 4.61 mmol) in THF (40 mL) at -78°C, n- BuLi (2.5 M in «-hexane, 1.9 mL) was added under a nitrogen atmosphere. The mixture was stirred at -78°C for 0.5 h. A solution of 3-benzyl-3-azabicyclo[3.2. l]octan-8-one (661 mg, 3.07 mmol) in THF (10 mL) was added at -78°C under a nitrogen atmosphere and warmed to room temperature overnight. The reaction mixture was poured into water (35 mL) and then extracted with EtOAc (2 x 35 mL). The combined organic layers were washed with H20 (35 mL), brine (35 mL), dried over Na2S04, filtered, concentrated, and then purified by column
chromatography (Si02, Petroleum ether/Ethyl acetate=3/l) to give 3-benzyl-8-(4- (methoxymethoxy)phenyl)-3-azabicyclo[3.2. l]octan-8-ol (800 mg, 74%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.44 (d, 2H), 7.41-7.37 (m, 2H), 7.34-7.31 (m, 2H), 7.26-7.22 (m, 1H), 7.03 (d, 2H), 5.19 (s, 2H), 3.62 (s, 2H), 3.49 (s, 3H), 2.89 (d, 2H), 2.67-2.58 (m, 2H), 2.40 (m, 2H), 1.81 (d, 2H), 1.52-1.38 (m, 3H); LCMS: 354.1 [M+H]+.
Step 2 : 8-(4-(Methoxymethoxy)phenyl)-3-azabic clo [3.2.1] octan-8-ol
[00470] A solution of 3-benzyl-8-(4-(methoxymethoxy)phenyl)-3-azabicyclo[3.2. l]octan-8-ol (800 mg, 2.26 mmol) and Pd(OH)2/C (400 mg, 0.57 mmol, 20% purity) in EtOAc (20 mL) was stirred at 50°C overnight under 50 PSI of hydrogen. The reaction mixture was cooled to room temperature, filtered through celite pad, and concentrated to give 8-(4-(methoxymethoxy)phenyl)- 3-azabicyclo[3.2. l]octan-8-ol (800 mg, crude) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.43 (d, 2H), 7.04 (d, 2H), 5.19 (s, 2H), 3.55 (d, 2H), 3.49 (s, 3H), 2.69-2.60 (m, 2H), 2.36-2.32 (m, 2H), 1.61-1.51 (m, 4H); LCMS: 264.2 [M+H]+.
Step 3: l-(8-Hydroxy-8-(4-(methoxymethoxy)phenyl)-3-azabicyclo[3.2.1]octan-3-yl)ethanone
[00471] A mixture of 8-(4-(methoxymethoxy)phenyl)-3-azabicyclo[3.2. l]octan-8-ol (800 mg, 3.04 mmol), acetic anhydride (930 mg, 9.11 mmol), TEA (615 mg, 6.08 mmol) and dioxane (20 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was poured into water (30 mL) and then extracted with EtOAc (2 x20 mL). The combined organic layers were washed with H20 (30 mL), brine (40 mL), dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02, Petroleum ether/ethyl acetate=0/l) to give 1- (8-hydroxy-8-(4-(methoxymethoxy)phenyl)-3-azabicyclo[3.2. l]octan-3-yl)ethanone (590 mg, 64%) as a yellow solid. 1H NMR (400 MHz, CDCf): d 7.44 (d, 2H), 7.05 (d, 2H), 5.19 (s, 2H), 4.30-4.23 (m, 1H), 3.97-3.90 (m, 1H), 3.49 (s, 3H), 3.48-3.40 (m, 2H), 2.54-2.44 (m, 2H), 2.13 (s, 3H), 1.52 (m, 4H); LCMS: 306.1 [M+H]+.
Step 4: l-(8-(4-Hydroxyphenyl)-3-azabicyclo[3.2.1]octan-3-yl)ethanone
[00472] A mixture of l-(8-hydroxy-8-(4-(methoxymethoxy)phenyl)-3-azabicyclo[3.2. l]octan-3- yl)ethanone (490 mg, 1.60 mmol), TFA (1.83 g, 16.1 mmol), triethylsilane (933 mg, 8.02 mmol), in DCE (50 mL) was stirred at 70°C for 5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water (30 mL), and then extracted with EtOAc (2 x50 mL). The combined organic layers were washed with H20 (50 mL), brine (50 mL), and dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=0/l) to give l-(8-(4-hydroxyphenyl)-3-azabicyclo[3.2. l]octan-3-yl)ethanone (290 mg, 74%) as yellow solid. LCMS: 246.2 [M+H]+.
Step 5: (E)-tert- Butyl (2-((4-(3-acetyl-3-azabicyclo[3.2.1]octan-8-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00473] A mixture of l-(8-(4-hydroxyphenyl)-3-azabicyclo[3.2. l]octan-3-yl)ethanone (290 mg, 1.18 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (380 mg, 1.42 mmol),
Cs2C03 (1.16 g, 3.55 mmol), and MeCN (20 mL) was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was poured into water (30 mL) and then extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with H20 (30 mL), brine (40 mL), dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=0/l) to give (E)-tert- butyl (2-((4-(3 -acetyl-3- azabicyclo[3.2. l]octan-8-yl)phenoxy)methyl)-3-fluoroallyl)carbamate (200 mg, 39%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.21 (d, 2H), 6.91 (d, 2H), 6.77 (d, 1H), 4.71-4.67 (m, 1H), 4.45 (m, 2H), 4.10 (m, 1H), 4.02 (m, 2H), 3.43-3.41 (m, 1H), 3.36-3.29 (m, 1H), 3.07-2.95 (m, 2H), 2.75-2.71 (m, 2H), 2.01 (s, 3H), 1.98-1.88 (m, 2H), 1.76-1.66 (m, 2H), 1.42 (s, 9H); LCMS: 433.1 [M+H]+.
Step 6: (£')-l-(8-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-3-azabicyclo[3.2.1]octan-3- yl)ethanone hydrochloride
[00474] To a solution of (E)-tert- butyl (2-((4-(3-acetyl-3-azabicyclo[3.2. l]octan-8- yl)phenoxy)methyl)-3-fluoroallyl)carbamate (200 mg, 0.46 mmol) in DCM (5 mL) at room temperature, TFA (2 mL) was added. The mixture was stirred at room temperature for lh. The mixture was concentrated to dryness, purified by reverse-phase HPLC (water (0.04%HCl)-MeCN) to give (£)-l-(8-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-3-azabicyclo[3.2. l]octan-3- yl)ethanone hydrochloride (53 mg, 34%) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 8.17 (s, 3H), 7.31 (d, 1H), 7.29 (d, 2H), 6.99 (d, 2H), 4.60 (d, 2H), 3.87-3.84 (m, 1H), 3.61 (d, 2H), 3.39-3.32 (m, 1H), 3.24-3.21 (m, 1H), 2.99-2.96 (m, 1H), 2.76-2.69 (m, 3H), 1.93-1.78 (m, 5H), 1.69-1.61 (m, 1H), 1.53-1.44 (m, 1H); LCMS: 333.2 [M+H]+.
Compound 2.81
(E)-l-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-4-(hydroxymethyl)piperidin-l- yl)ethanone hydrochloride
Figure imgf000200_0001
Step 1: Ethyl l-benzyl-4-(4-bromophenyl)piperidine-4-carboxylate
[00475] A mixture of ethyl 2-(4-bromophenyl)acetate (30 g, 123 mmol), Af-benzyl -2-chl oro-A-(2- chloroethyl)ethanamine (34.4 g, 148 mmol), potassium 2-methylpropan-2-olate (48.5 g, 432 mmol), and DMF (100 mL) was stirred at 70 °C for 8 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water (75 mL), and then extracted with EtOAc (2 x75 mL). The combined organic layers were washed with H20 (75 mL), brine (75 mL), dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02, Petroleum ether/Ethyl acetate =1/1) to give ethyl l-benzyl-4-(4-bromophenyl)piperidine-4- carboxylate (11.2 g, 23%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.41 (d, 2H), 7.28-7.16 (m, 7H), 4.25-4.15 (m, 2H), 3.44 (s, 2H), 2.77 (d, 2H), 2.53-2.46 (m, 2H), 2.14 (m, 2H), 1.94-1.85 (m, 2H), 1.14 (s, 3H); LCMS: 402.2 [M+H]+. Step 2: Ethyl l-benzyl-4-(4-hydroxyphenyl)piperidine-4-carboxylate
[00476] A mixture of ethyl l-benzyl-4-(4-bromophenyl)piperidine-4-carboxylate (10 g, 12.4 mmol), KOH (3.48 g, 31.1 mmol), di-/er/-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[l, l'- biphenyl]-2-yl)phosphine (956 mg, 0.99 mmol), Pd2(dba)3 (1.13 g, 0.62 mmol), H20 (12 mL) and dioxane (120 mL) was stirred at 100 °C overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water (150 mL), and then extracted with EtOAc (2 x l50 mL). The combined organic layers were washed with H20 (150 mL), brine (150 mL), dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02, Petroleum ether/Ethyl acetate =1/1) to give ethyl l-benzyl-4-(4-hydroxyphenyl)piperidine-4- carboxylate (3.5 g, 41%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.31 (d, 2H), 7.29-7.21 (m, 5H), 6.77 (d, 2H), 5.10-4.78 (m, 1H), 4.13 (q, 2H), 3.48 (s, 2H), 2.87-2.76 (d, 2H), 2.57-2.49 (d, 2H), 2.22-2.13 (m, 2H), 1.99-1.87 (m, 2H), 1.17 (t, 3H); LCMS: 340.2 [M+H]+.
Step 3: 4-(l-Benzyl-4-(hydroxymethyl)piperidin-4-yl)phenol
[00477] To a solution of ethyl l-benzyl-4-(4-hydroxyphenyl)piperidine-4-carboxylate (3.5 g, 10.3 mmol) in THF (300 mL) at 0 °C, L1AIH4 (783 mg, 20.6 mmol) was slowly added and the reaction stirred at room temperature overnight. The reaction mixture was poured into water (200 mL) and then extracted with EtOAc (2 c 200 mL). The combined organic layers were washed with H20 (200 mL), brine (200 mL), dried over Na2S04, filtered, and concentrated to give 4-(l-benzyl-4- (hydroxymethyl)piperidin-4-yl)phenol (3.5 g, crude) as a yellow oil. 1H NMR (400 MHz, CDCI3): d 7.35-7.28 (m, 5H), 7.14 (d, 2H), 6.84 (d, 2H), 3.58 (s, 2H), 3.43 (s, 2H), 2.83-2.73 (m, 2H), 2.39- 2.30 (m, 2H), 2.20-2.12 (d, 2H), 1.96-1.86 (m, 2H); LCMS: 298.1 [M+H]+.
Step 4: 4-(4-(Acetoxymethyl)-l-benzylpiperidin-4-yl)phenyl acetate
[00478] A mixture of 4-(l-benzyl-4-(hydroxymethyl)piperidin-4-yl)phenol (3.5 g, 11.8 mmol), acetic anhydride (3.60 g, 35.3 mmol), NaOH (2.35 g, 58.9 mmol) and dioxane (80 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (75 mL) and then extracted with EtOAc (2 x75 mL). The combined organic layers were washed with H20 (75 mL), brine (75 mL), dried over Na2S04, filtered, concentrated, and then purified by column
chromatography (Si02, DCM/MeOH=lO/l) to give 4-(4-(acetoxymethyl)-l-benzylpiperidin-4- yl)phenyl acetate (1.6 g, 36%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.35-7.27 (m, 7H), 7.06 (d, 2H), 4.03 (s, 2H), 3.43 (s, 2H), 2.65-2.56 (m, 2H), 2.28-2.23 (m, 5H), 2.19-2.11 (d, 2H), 2.00-1.94 (m, 2H), 1.93 (s, 3H); LCMS: 382.3 [M+H]+. Step 5: 4-(4-(Acetoxymethyl)piperidin-4-yl)phenyl acetate
[00479] A mixture of 4-(4-(acetoxymethyl)-l-benzylpiperidin-4-yl)phenyl acetate (1.0 g, 2.62 mmol), Pd(OH)2 (0.4 g, 2.85 mmol, 20 % purity) in EtOAc (50 mL) was stirred at 50 °C overnight under 50 PSI of hydrogen. The reaction mixture was filtered through a celite pad and then concentrated to give 4-(4-(acetoxymethyl)piperidin-4-yl)phenyl acetate (1.0 g, crude) as an oil. 1H NMR (400 MHz, DMSO-r¾): d 7.20 (d, 2H), 6.74 (d, 2H), 4.02 (s, 2H), 3.15-3.01 (m, 2H), 2.96- 2.75 (m, 2H), 2.21-2.02 (m, 4H), 1.96 (s, 3H), 1.92 (s, 3H); LCMS: 292.1 [M+H]+.
Step 6: 4-(4-(Acetoxymethyl)-l-acetylpiperidin-4-yl)phenyl acetate
[00480] A mixture of 4-(4-(acetoxymethyl)piperidin-4-yl)phenyl acetate (1.0 g, 4.82 mmol), acetic anhydride (2.46 g, 24.1 mmol), Et3N (4.88 g, 48.3 mmol), and DCM (30 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (40 mL) and then extracted with EtOAc (2 x40 mL). The combined organic layers were washed with H20 (40 mL), brine (40 mL), dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02, DCM/MeOH=lO/l) to give 4-(4-(acetoxymethyl)-l-acetylpiperidin-4-yl)phenyl acetate (450 mg, 28%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.36 (d, 2H), 7.12 (d, 2H), 4.22-4.14 (m, 1H), 4.08-4.00 (m, 2H), 3.66 -3.58 (m, 1H), 3.28-3.18 (m, 1H), 3.08-2.98 (m, 1H), 2.31 (s, 3H), 2.27-2.17 (m, 2H), 2.08 (s, 3H), 1.99 (s, 3H), 1.91-1.79 (m, 2H); LCMS: 382.1 [M+H]+.
Step 7 : l-(4-(Hydroxymethyl)-4-(4-hydroxyphenyl)piperidin-l-yl)ethanone
[00481] A mixture of 4-(4-(acetoxymethyl)-l-acetylpiperidin-4-yl)phenyl acetate (450 mg, 1.35 mmol), Li OH (97 mg, 4.05 mmol), MeOH (5 mL), THF (5 mL), and H20 (5 mL) was stirred at room temperature overnight. The mixture was concentrated to dryness and then purified by reverse- phase HPLC (water (0.04%HCl) - MeCN) to give l-(4-(hydroxymethyl)-4-(4- hydroxyphenyl)piperidin-l-yl)ethanone (150 mg, 40%) as a white solid. 1H NMR (400 MHz, DMSO- d): d 9.22 (s, 1H), 7.14 (d, 2H), 6.72 (d, 2H), 4.63-4.56 (m, 1H), 4.01-3.91 (m, 1H), 3.61- 3.52 (m, 1H), 3.26-3.22 (m, 2H), 3.06-2.96 (m, 1H), 2.75-2.66 (m, 1H), 1.97-1.91 (s, 5H), 1.80- 1.59 (m, 2H); LCMS: 250.1 [M+H]+.
Step 8: (E)-tert- Butyl (2-((4-(l-acetyl-4-(hydroxymethyl)piperidin-4-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00482] A mixture of l-(4-(hydroxymethyl)-4-(4-hydroxyphenyl)piperidin-l-yl)ethanone (100 mg, 0.40 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (129 mg, 0.48 mmol), Cs2C03 (392 mg, 1.20 mmol) and MeCN (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (25 mL) and then extracted with EtOAc (2 x25 mL). The combined organic layers were washed with H20 (25 mL), brine (25 mL), dried over Na2S04, filtered, concentrated, and then purified by prep-TLC (Si02, DCM/MeOH=lO/l) to give ( E)-tert - butyl (2-((4-(l-acetyl-4-(hydroxymethyl)piperidin-4-yl)phenoxy)methyl)-3-fluoroallyl)carbamate (100 mg, 57%) as a yellow oil. 1H NMR (400 MHz, CDCI3): d 7.31-7.27 (m, 2H), 6.96 (d, 2H), 6.76 (d, 1H), 5.31 (s, 1H), 4.84-4.72 (m, 1H), 4.46 (d, 2H), 4.20-4.11 (m, 1H), 4.06-3.97 (m, 2H), 3.65-3.52 (m, 3H), 3.27-3.17 (m, 1H), 3.06-2.95 (m, 1H), 2.26-2.15 (m, 2H), 2.08 (s, 3H), 1.85- 1.70 (m, 2H), 1.42 (s, 9H); LCMS: 437.3 [M+H]+.
Step 9: (£')-l-(4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-4-(hydroxymethyl)piperidin- l-yl)ethanone hydrochloride
[00483] To a solution of (E)-tert- butyl (2-((4-(l-acetyl-4-(hydroxymethyl)piperidin-4- yl)phenoxy)methyl)-3-fluoroallyl)carbamate (100 mg, 0.23 mmol) in DCM (20 mL) at room temperature, TFA (4 mL) was added and stirred at room temperature for 3 h. The mixture was concentrated to dryness then purified by reverse-phase HPLC (water(0.04%HCl)-MeCN) to give (/',)- 1 -(4-(4-((2-(aminom ethyl )-3-fluoroallyl)oxy)phenyl)-4-(hydroxymethyl)pi peri din- 1 - yl)ethanone hydrochloride (44 mg, 57%) as a white solid. 1H NMR (400 MHz, DMSO-<7(5): d 8.36- 8.09 (m, 3H), 7.31 (d, 1H), 7.29 (d, 2H), 6.95 (d, 2H), 4.69-4.60 (m, 3H), 4.01-3.91 (m, 1H), 3.67- 3.52 (m, 3H), 3.34-3.22 (s, 2H), 3.09-2.94 (m, 1H), 2.80-2.69 (m, 1H), 2.10-1.88 (m, 5H), 1.86- 1.73 (m, 1H), 1.72-1.59 (m, 1H); LCMS: 337.2 [M+H]+.
Compound 2.82
(ii)-8-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-3-azabicyclo[3.2.1]octane-3- carboxamide hydrochloride
Figure imgf000203_0001
Step 1 : 8-Hydroxy-8-(4-(methoxymethoxy)phenyl)-3-azabicyclo [3.2.1] octane-3-carboxamide
[00484] A mixture of 8-(4-(methoxymethoxy)phenyl)-3-azabicyclo[3.2. l]octan-8-ol (700 mg, 2.66 mmol), urea (798 mg, 13.3 mmol) in dioxane (25 mL) was stirred at 120 °C overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water (30 mL), and then extracted with EtOAc (3 x30 mL). The combined organic layers were washed with H20 (30 mL), brine (30 mL), dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02, DCM/MeOH=lO/l) to give 8-hydroxy-8-(4- (methoxymethoxy)phenyl)-3-azabicyclo[3.2. l]octane-3-carboxamide (540 mg, 66%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.45 (d, 2H), 7.05 (d, 2H), 5.31 (s, 1H), 5.19 (s, 2H), 4.50 (s, 2H), 3.69-3.65 (m, 4H), 3.49 (s, 3H), 2.53-2.51 (m, 2H), 1.63-1.58 (m, 2H), 1.57-1.51 (m, 2H); LCMS: 307.2 [M+H]+. Step 2 : 8-(4-H droxyphenyl)-3-azabicyclo [3.2.1] octane-3-car boxamide
[00485] A mixture of 8-hydroxy-8-(4-(methoxymethoxy)phenyl)-3-azabicyclo[3.2. l]octane-3- carboxamide (540 mg, 1.76 mmol), triethylsilane (1.02 g, 8.81 mmol), and TFA (20 mL) was stirred at 70 °C for 4 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated to dryness, poured into water (30 mL), and then extracted with EtOAc (2 x30 mL). The combined organic layers were washed with H20 (30 mL), brine (40 mL), dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02,
DCM/MeOH=lO/l) to give 8-(4-hydroxyphenyl)-3-azabicyclo[3.2. l]octane-3-carboxamide (300 mg, 69%) as a white solid; LCMS: 247.1 [M+H]+.
Step 3: (E)-tert-Bnty\ (2-((4-(3-carbamoyl-3-azabicyclo[3.2.1]octan-8-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00486] A solution of 8-(4-hydroxyphenyl)-3-azabicyclo[3.2. l]octane-3-carboxamide (250 mg, 1.02 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (327 mg, 1.22 mmol), and Cs2C03 (992 mg, 3.05 mmol) in MeCN (25 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (30 mL), and then extracted with EtOAc (2 x30 mL). The combined organic layers were washed with H20 (30 mL), brine (40 mL), dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02, DCM/MeOH=lO: l) to give (E)-tert- butyl (2-((4-(3-carbamoyl-3-azabicyclo[3.2. l]octan-8-yl)phenoxy)methyl)-3- fluoroallyl)carbamate (300 mg, 68%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.20 (d, 2H), 6.91 (d, 2H), 6.75 (d, 1H), 4.86-4.72 (m, 1H), 4.45 (m, 2H), 4.33-4.31 (m, 2H), 4.01 (m, 2H), 3.46- 3.37 (m, 2H), 3.25-3.21 (m, 2H), 3.06-3.00 (m, 1H), 2.75-2.70 (m, 2H), 1.99-1.90 (m, 2H), 1.84- 1.81 (m, 2H), 1.42 (s, 9H); LCMS: 434.3 [M+H]+.
Step 4: (ii)-8-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-3-azabicyclo [3.2.1] octane-3- carboxamide hydrochloride
[00487] To a solution of (E)-tert- butyl (2-((4-(3-carbamoyl-3-azabicyclo[3.2. l]octan-8- yl)phenoxy)methyl)-3-fluoroallyl)carbamate (300 mg, 0.69 mmol) in DCM (10 mL) at room temperature, TFA (4 mL) was added and stirred at room temperature for 1.5 h. The mixture was concentrated to dryness and then purified by reverse-phase HPLC (water(0.04%HCl)-MeCN) to give (£)-8-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-3-azabicyclo[3.2. l]octane-3- carboxamide hydrochloride (119 mg, 50%) as a white solid. 1H NMR (400 MHz, DMSO-r¾): d 8.20-8.02 (m, 3H), 7.32 (d, 1H), 7.30-7.24 (d, 2H), 7.01-6.96 (d, 2H), 5.76-5.63 (s, 2H), 4.66-4.49 (m, 2H), 3.65-3.58 (m, 2H), 3.38-3.36 (m, 2H), 2.98-2.83 (m, 3H), 2.70-2.66 (m, 2H), 1.91-1.79 (m, 2H), 1.69-1.53 (d, 2H); LCMS: 334.3 [M+H]+. Compound 2.83
l-(7-(4-(((ii)-2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-3-oxa-9-azabicyclo[3.3.1]nonan-9- yl)ethanone trifluoroacetate
Figure imgf000205_0001
Step 1: l-Bromo-4-(methoxymethoxy)benzene
[00488] To a solution of 4-bromophenol (50 g, 289 mmol) in DMF (500 mL) at 0°C, NaH (23.1 g, 578 mmol, 60% purity) was added. The mixture was stirred at 0°C for 1 h. MOM-C1 (58.1 g, 722 mmol) was added at 0°C and the reaction warmed to room temperature overnight. The mixture was poured into water (1L) and extracted with EtOAc (2 x 800 mL). The organic layers were combined, washed with H20 (1 L), brine (1.5 L), dried (Na2S04), filtered, concentrated, and then purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=5/l) to give l-bromo-4- (methoxymethoxy)benzene (55 g, 88%) as an oil. 1H NMR (400 MHz, CDCl3): d 7.49 (d, 2H), 6.93 (d, 2H), 5.15 (s, 2H), 3.47 (s, 3H).
Step 2: 9-Benzyl-7-(4-(methoxymethoxy)phenyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol
[00489] To a solution of Mg (1.12 g, 46.1 mmol) and LiCl (1.95 g, 46.07 mmol) in THF (60 mL) at room temperature, 1 M DIBAL-H in toluene (0.58 mL) was added and stirred at room
temperature for 30 min. l-Bromo-4-(methoxymethoxy)benzene (5.0 g, 23.0 mmol) was added dropwise at room temperature and then stirred at room temperature for 2 h. A solution of 9-benzyl- 3-oxa-9-azabicyclo[3.3. l]nonan-7-one (1.3 g, 5.62 mmol) in THF (60 mL) was added dropwise at room temperature and then stirred at room temperature overnight. The mixture was poured into aqueous sat. NH4Cl (200 mL) and filtered through celite pad. The filtrate was extracted with EtOAc (2 x300 mL). The organic layers were combined, washed with water (2 x l00 mL), brine (100 mL), dried (Na2S04), filtered, concentrated, and then purified by chromatography on silica gel (petoleum ether/EtOAc = 5/1) to give 9-benzyl-7-(4-(methoxymethoxy)phenyl)-3-oxa-9- azabicyclo[3.3. l]nonan-7-ol (1.2 g, 28%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) d 7.61- 747 (m, 2H), 7.44-7.13 (m, 5H), 7.00-6.91 (m, 2H), 5.12 (s, 2H), 3.81-3.70 (m, 2H), 4.03-3.69 (m, 4H), 3.32 (s, 3H), 3.28 (s, 2H), 2.79-2.71 (m, 2H), 1.61-1.51 (m, 2H). LCMS: 370.2 [M+H]+.
Step 3: 7-(4-(Methoxymethoxy)phenyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol
[00490] To a solution of Pd/C (300 mg, 10% purity) in EtOAc (50 mL) at room temperature, 9- benzyl-7-(4-(methoxymethoxy)phenyl)-3-oxa-9-azabicyclo[3.3. l]nonan-7-ol (1.8 g, 4.87 mmol) was added. The mixture was stirred at 50°C under 50 psi of hydrogen for 32 h. The mixture was cooled to room temperature and then filtered through celite pad. The filtrate was concentrated to give 7-(4-(methoxymethoxy)phenyl)-3-oxa-9-azabicyclo[3.3. l]nonan-7-ol (1.15 g, crude) as a yellow solid. 1H NMR (400 MHz, CDCl3) d 7.48 (d, 2H), 6.95 (d, 2H), 5.10 (s, 2H), 3.96-3.81 (m, 4H), 3.41 (s, 3H), 3.06 (d, 2H), 2.37 (dd, 2H), 1.96 (d, 2H); LCMS: 280.2 [M+H]+.
Step 4: l-(7-Hydroxy-7-(4-(methoxymethoxy)phenyl)-3-oxa-9-azabicyclo [3.3.1] nonan-9- yl)ethanone
[00491] To a solution of 7-(4-(methoxymethoxy)phenyl)-3-oxa-9-azabicyclo[3.3. l]nonan-7-ol (750 mg, 2.68 mmol), Et3N (815 mg, 8.05 mmol) in DCM (10 mL) at room temperature, Ac20 (411 mg, 4.03 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was poured into water (20 mL) and extracted DCM (2 x30 mL).The organic layers were combined, washed with water (2 x lO mL), brine (10 mL), dried (Na2S04), filtered, concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 0/1) to give l-(7- hydroxy-7-(4-(methoxymethoxy)phenyl)-3-oxa-9-azabicyclo[3.3. l]nonan-9-yl)ethanone (360 mg, 42%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.43-7.34 (m, 2H), 7.01-6.89 (m, 2H), 6.59 (s, 1H), 5.10 (s, 2H), 4.75-4.71 (m, 1H), 3.96-3.91 (m, 3H), 3.76 (dt, 2H), 3.41 (s, 3H), 2.43-2.25 (m, 2H), 2.07 (s, 3H), 2.03 (br d, 1H), 1.93 (br d, 1H); LCMS: 322.1 [M+H]+.
Step 5: l-(7-(4-hydroxyphenyl)-3-oxa-9-azabicyclo[3.3.1]non-6-en-9-yl)ethanone
[00492] To a solution of l-(7-hydroxy-7-(4-(methoxymethoxy)phenyl)-3-oxa-9- azabicyclo[3.3. l]nonan-9-yl)ethanone (360 mg, 1.12 mmol) and Et3SiH (651 mg, 5.60 mmol) in DCM (10 mL) at room temperature, TFA (1.28 g, 11.2 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated to remove the organic solvent and poured into aqueous sat. NaHC03 (30 mL) and extracted with DCM (2 x30 mL). The organic layers were combined, washed with water (2 x20 mL), brine (20 mL), dried (Na2S04), filtered, and concentrated to give l-(7-(4-hydroxyphenyl)-3-oxa-9-azabicyclo[3.3. l]non-6-en-9-yl)ethanone (250 mg, crude) as a yellow solid. LCMS: 260.1 [M+H]+.
Step 6: l-(7-(4-Hydroxyphenyl)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)ethanone
[00493] A mixture of l-(7-(4-hydroxyphenyl)-3-oxa-9-azabicyclo[3.3. l]non-6-en-9-yl)ethanone (250 mg, 964 umol), Pd/C (100 mg, 10% purity) and MeOH (20 mL) was stirred at room
temperature overnight under 50 psi of hydrogen. The mixture was filtered through a celite pad. The filtrate was concentrated to dryness to give l-(7-(4-hydroxyphenyl)-3-oxa-9- azabicyclo[3.3. l]nonan-9-yl)ethanone (200 mg, crude) as a yellow oil. 1H NMR (400 MHz, MeOD-i¾): d 6.98 (d, 2H), 6.61 (d, 2H), 4.58 (d, 1H), 4.03 (d, 1H), 3.64-3.56 (m, 2H), 3.55-3.48 (m, 1H), 3.42 (dd, 1H), 2.26-2.13 (m, 2H), 2.12-2.01 (m, 4H), 1.85-1.68 (m, 2H); LCMS: 262.2 [M+H]+. Step 7: terf-butyl ( E -2-((4-(9-acetyl-3-oxa-9-azabicyclo [3.3.1] nonan-7-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00494] A mixture of l-(7-(4-hydroxyphenyl)-3-oxa-9-azabicyclo[3.3. l]nonan-9-yl)ethanone (250 mg, 0.96 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (308 mg, 1.15 mmol), Cs2C03 (935 mg, 2.87 mmol), and MeCN (10 mL) was stirred at room temperature overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x30 mL). The organic layers were combined, washed with water (2 x20 mL), brine (20 mL), dried (Na2S04), filtered, concentrated, and then purified by prep-TLC (petroleum ether/EtOAc = 0 /l) to give tert- butyl ((A)-2-((4-(9-acetyl -3 -oxa-9-azabi cyclop 3 1 ]nonan-7-yl)phenoxy)methyl)-3-fluoroallyl (carbarn ate (200 mg, 47%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.11 (d, 2H), 6.78 (d, 2H), 6.66 (d, 1H), 4.75-4.70 (m, 2H), 4.35 (d, 2H), 3.98-3.84 (m, 3H), 3.69-3.59 (m, 2H), 3.57-3.45 (m, 2H), 2.38-2.25 (m, 1H), 2.23-2.11 (m, 2H), 2.08 (s, 3H), 1.95-1.83 (m, 1H), 1.76 (dt, 1H), 1.41-1.26 (m, 9H); LCMS: 449.3 [M+H]+.
Step 8: l-(7-(4-(((£')-2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-3-oxa-9- azabicyclo [3.3.1] nonan-9-yl)ethanone trifluoroacetate
[00495] To a solution of ((E)-2-((4-(9-acetyl-3-oxa-9-azabicyclo[3.3. l]nonan-7- yl)phenoxy)methyl)-3-fluoroallyl)carbamate (200 mg, 0.45 mmol) in DCM (10 mL) at room temperature, TFA (3.08 g, 27.0 mmol) was added. The mixture was stirred at 25°C for 2 h. The mixture was purified by by reverse-phase HPLC (water(0. l%TFA)-MeCN) to give l-(7-(4-(((£)-2-
(aminomethyl)-3-fluoroallyl)oxy)phenyl)-3-oxa-9-azabicyclo[3.3. l]nonan-9-yl)ethanone trifluoroacetate (45 mg, 29%) as a white solid. 1H NMR (400 MHz, D20): d 7.27 (d, 2H), 7.05 (d,
1H), 6.95 (d, 2H), 4.65-4.53 (m, 3H), 4.19 (d, 1H), 3.81 (s, 2H), 3.76-3.61 (m, 3H), 3.55 (d, 1H),
2.43-2.26 (m, 2H), 2.25-2.09 (m, 4H), 1.85-1.69 (m, 2H); LCMS: 349.2 [M+H]+.
Compound 2.93
7-(4-(((E)-2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-3-oxa-9-azabicyclo[3.3.1]nonane-9- carboxamide hydrochloride
Figure imgf000207_0001
Step 1: 7-Hydroxy-7-(4-(methoxymethoxy)phenyl)-3-oxa-9-azabicyclo[3.3.1]nonane-9- carboxamide
[00496] A mixture of 7-(4-(methoxymethoxy)phenyl)-3-oxa-9-azabicyclo[3.3. l]nonan-7-ol (550 mg, 1.97 mmol), urea (1.18 g, 19.7 mmol) and dioxane (30 mL) was stirred at 120 °C overnight. The mixture was cooled to room temperature, poured into water (60 mL) and extracted with EtOAc (2 x lOO mL). The organic layers were combined, washed with water (2 x50 mL), brine (50 mL), dried (Na2S04), filtered, concentrated, and then purified by chromatography on silica gel
(petroleum ether/EtOAc = 0/1) to give 7-hydroxy-7-(4-(methoxymethoxy)phenyl)-3-oxa-9- azabicyclo[3.3. l]nonane-9-carboxamide (400 mg, 63%) as a yellow oil. 1H NMR (400 MHz, CDCl3) d 7.46 (d, 2H), 6.99 (d, 2H), 6.64 (s, 1H), 5.16 (s, 2H), 4.69 (s, 2H), 4.15-3.94 (m, 4H), 3.93-3.83 (m, 2H), 3.47 (s, 3H), 2.49 (dd, 2H), 1.97 (d, 2H); LCMS: 323.2 [M+H]+.
Step 2: 7-(4-hydroxyphenyl)-3-oxa-9-azabicyclo[3.3.1]non-6-ene-9-carboxamide
[00497] To a solution of 7-hydroxy-7-(4-(methoxymethoxy)phenyl)-3-oxa-9- azabicyclo[3.3. l]nonane-9-carboxamide (400 mg, 1.24 mmol), Et3SiH (721 mg, 6.20 mmol) in DCM (20 mL) at room temperature, TFA (1.41 g, 12.41 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated to dryness, dissolved in DCM (50 mL) and then washed with sat.aq. NaHCO, (2 x50 mL), washed with water (2 x 10 mL), brine (10 mL), dried (Na2S04), filtered, and concentrated to give 7-(4-hydroxyphenyl)-3-oxa-9- azabicyclo[3.3. l]non-6-ene-9-carboxamide (300 mg, crude) as a yellow solid. 1H NMR (400 MHz, CD3OD) d 7.29 (d, 2H), 6.74 (d, 2H), 6.10 (d, 1H), 4.63-4.16 (m, 2H), 3.92 (d, 1H), 3.78 (dd, 1H), 3.73-3.55 (m, 4H), 3.03-2.87 (m, 1H), 2.53 (d, 1H); LCMS: 261.0 [M+H]+.
Step 3: 7-(4-Hydroxyphenyl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxamide
[00498] A mixture of 7-(4-hydroxyphenyl)-3-oxa-9-azabicyclo[3.3. l]non-6-ene-9-carboxamide (300 mg, 1.15 mmol), Pd/C (30 mg, 10% purity) and MeOH (20 mL) was stirred at room temperature under 50 PSI of hydrogen overnight. The mixture was filtered though celite pad and then concentrated to give 7-(4-hydroxyphenyl)-3-oxa-9-azabicyclo[3.3. l]nonane-9-carboxamide (300 mg, crude) as a yellow solid. 1H NMR (400 MHz, DMSO-r¾) d 9.28 (s, 1H), 6.99 (m, 2H), 6.69 (m, 2H), 6.06 (s, 2H), 4.19-4.08 (m, 1H), 3.54 (d, 2H), 3.41 (d, 2H), 3.16-3.14 (m, 1H), 2.06 (m, 3H), 1.66-1.55 (m, 2H); LCMS: 263.1 [M+H]+.
Step 4:terf-Butyl ((ii)-2-((4-(9-carbamoyl-3-oxa-9-azabicyclo[3.3.1]nonan-7- yl)phenoxy)methyl)-3-fluoroallyl)carbamate
[00499] A mixture of 7-(4-hydroxyphenyl)-3-oxa-9-azabicyclo[3.3. l]nonane-9-carboxamide (100 mg, 0.38 mmol), (E)-fer/-butyl(2-(bromomethyl)-3-fluoroallyl)carbamate (153 mg, 0.57 mmol), Cs2C03 (745 mg, 2.29 mmol), and MeCN (20 mL) was stirred at room temperature overnight. The mixture was concentrated to dryness and then purified by reverse-phase HPLC (water(0.04%HCl)- MeCN) to give tert- butyl ((E)-2-((4-(9-carbamoyl-3-oxa-9-azabicyclo[3.3. l]nonan-7- yl)phenoxy)methyl)-3-fluoroallyl)carbamate (100 mg, 55%) as a yellow oil .1H NMR (400 MHz, CDCI3): d 7.20 (d, 2H), 6.86 (d, 2H), 6.74 (d, 1H), 4.83-4.72 (m, 1H), 4.54 (s, 2H), 4.43 (d, 2H), 4.01-3.91 (m, 2H), 3.72-3.63 (m, 4H), 2.54-2.42 (m, 1H), 2.34-2.23 (m, 2H), 1.93-1.82 (m, 2H), 1.42 (s, 9H); LCMS: 450.3 [M+H]+.
Step 5: 7-(4-(((E)-2-(Aminomethyl)-3-fliioroallyl)oxy)phenyl)-3-oxa-9- azabicyclo [3.3.1] nonane-9-carboxamide hydrochloride
[00500] To a solution of /er/-butyl ((E)-2-((4-(9-carbamoyl-3-oxa-9-azabicyclo[3.3. l]nonan-7- yl)phenoxy)methyl)-3-fluoroallyl)carbamate (100 mg, 0.22 mmol) in DCM (10 mL) at room temperature, TFA (4 mL) was added and stirred at room temperature for lh. The mixture was concentrated to dryness and then purified by reverse-phase HPLC (water (0.l%TFA)-MeCN) to give 7-(4-(((E)-2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)-3-oxa-9-azabicyclo[3.3. l]nonane-9- carboxamide trifluoroacetate (119 mg, 50%) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 8.03-7.92 (m, 3H), 7.22-7.14 (m, 2H), 7.06 (d, 1H), 6.93 (d, 2H), 6.07 (s, 2H), 4.56-4.52 (m, 2H), 4.30-3.92 (m, 2H), 3.67-3.49 (m, 4H), 3.43 (d, 2H), 2.30-2.22 (m, 1H), 2.14-2.04 (m, 2H), 1.68- 1.57 (m, 2H); LCMS: 350.2 [M+H]+.
Compound 3 & Compound 3.01
(E)-Methyl (4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)carbamate hydrochloride (Compound 3) & (Z)-Methyl (4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)carbamate hydrochloride (Compound 3.01)
Figure imgf000209_0001
Step 1: Methyl (4-hydroxyphenyl)carbamate
[00501] To a solution of 4-aminophenol (6.0 g, 54 mmol) in THF (60 mL) and C¾CN (60 mL) at room temperature, was added dropwise methyl carbonochloridate (2.60 g, 27 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated and dissolved in EtOAc (100 mL), and then washed with water (3x50 mL). The organic layer dried (Na2S04), filtered and concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 5/1) to give methyl (4-hydroxyphenyl)carbamate (2.0 g, 21%) as a yellow solid. 1H NMR (400 MHz, CDCI3): d 7.14 (d, 2H), 6.70 (d, 2H), 6.39 (s, 1H), 4.90 (s, 1H), 3.69 (s, 3H); LCMS: 168.1
[M+H]+.
Step 2: tert- butyl (3-fluoro-2-((4-((methox carbonyl)amino)phenoxy)methyl)allyl)car hamate [00502] A mixture of tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (370 mg, 1.38 mmol), methyl (4-hydroxyphenyl)carbamate (230 mg, 1.38 mmol), K2C03 (572 mg, 4.14 mmol) and DMF (10 mL) was stirred at 60 °C overnight. The reaction was cooled to room temperature, then quenched with H20 (30 mL), and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (petroleum ether/ethyl acetate=20: l 2: 1) to give tert- butyl (3-fluoro- 2-((4-((methoxycarbonyl)amino)phenoxy)methyl)allyl (carba ate (290 mg, 54%) as a yellow oil. 1H NMR (400 MHz, DMSO-r¾)a: d 9.42 (s, 1H), 7.33 (d, 2H), 7.05 (s, 1H), 6.96 (d, 0.8H), 6.93- 6.83 (m, 2H), 6.85 (d, 0.2H), 4.51 (d, 0.4H), 4.37 (d, 1.6H), 3.73 (d, 1.6H), 3.58 (d, 0.4H), 3.63 (s, 3H), 1.34 (s, 9H); LCMS: 355.3 [M+H]+. a NMR is of a mixture of the ( E) and (Z) alkene isomers. Step 3: (E)-Methyl (4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)carbamate hydrochloride (Compound 3) & (Z)-Methyl (4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)carbamate hydrochloride (Compound 3.01)
[00503] To a solution of methyl tert- butyl-(3-fluoro-2-((4-
((methoxycarbonyl)amino)phenoxy)methyl)allyl)carbamate (290 mg, 0.81 mmol) in DCM (6 mL) at room temperature, was added TFA (2 mL, 27 mmol) and the resulting mixture was stirred for 1 h. The mixture was concentrated to dryness. The residue was co-evaporated with DCM (2 x 20 mL) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3.0 mL) and then 2.0M HC1 in diethyl ether (0.5 mL) was added. The precipitate formed was isolated and dried under reduced pressure. The residue was purified by reverse-phase HPLC (water (0.05%HCl)-CH3CN) to give (£)-m ethyl (4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)carbamate hydrochloride
(Compound 3) (95 mg, 45%) and (Z)- methyl (4-((2-(aminomethyl)-3- fluoroallyl)oxy)phenyl)carbamate hydrochloride (Compound 3.01) (19 mg, 8%) as a white solid. Compound 3 : 1H NMR (400 MHz, DMSO-r¾): d 9.48 (s, 1H), 8.27 (s, 3H), 7.43-7.27 (m, 2H), 7.28 (d, 1H), 6.97-6.88 (m, 2H), 4.57 (d, 2H), 3.63 (s, 3H), 3.57 (d, 2H); LCMS: 255.1 [M+H]+.
Compound 3.01 : 1H NMR (400 MHz, DMSO-r¾): d 9.48 (s, 1H), 8.18 (s, 3H), 7.36 (d, 2H), 7.19 (d, 1H), 6.98-6.88 (m, 2H), 4.68 (d, 2H), 3.64 (s, 3H), 3.51 (m, 2H); LCMS: 255.1 [M+H]+.
[00504] The compounds below were synthesized in a similar manner as described for Compounds 3 and 3.01.
Figure imgf000210_0001
Figure imgf000211_0002
Compound 4
(E)-4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl methylcarbamate hydrochloride
Figure imgf000211_0001
Step 1: 4-Hydroxyphenyl methylcarbamate
[00505] A mixture of hydroquinone (5 g, 45 mmol), methyl carbamic chloride (12.7 g, 136 mmol) and pyridine (50 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to dryness, then diluted with H20 (100 mL), and extracted with EtOAc (3x 100 mL). The organic layers were combined, washed with brine (2x50 mL), dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (Petroleum ethenEthyl acetate=20: l 2:1) to give 4-hydroxyphenyl methylcarbamate (2 g, 23%) as a yellow solid. 1H NMR (400 MHz, DMSO-r¾): d 9.30 (s, 1H), 7.50-7.36 (m, 1H), 6.92-6.81 (m, 2H), 6.75-6.66 (m, 2H), 2.63 (d, 3H); LCMS: 166.2 [M-H]+.
Step 2: tert- Butyl (E)-(3-fluoro-2-((4-h droxyphenoxy)methyl)allyl)carbamate
[00506] A mixture of /tvV-butyl (£)-(2-(bromomethyl)-3-fluoroallyl)carbamate (340 mg, 1.27 mmol), 4-hydroxyphenyl methylcarbamate (211 mg, 1.27 mmol), K2C03 (525 mg, 3.8 mmol) and DMF (10 mL) was stirred at 55 °C overnight. The reaction was cooled to room temperature, then quenched with H20 (30 mL), and extracted with EtOAc (3x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated, and purified by prep-TLC (petroleum ether/ethyl acetate=l/l) to give /er/-butyl (E)-(3-fluoro-2-((4- hydroxyphenoxy)methyl)allyl)carbamate (100 mg, 21%) as a white solid. 1H NMR (400 MHz, CDCl3): d 6.72 (d, 1 H), 6.81-6.73 (m, 4H), 5.12 (s, 1H), 4.82 (s, 1H), 4.37 (d, 2H), 4.00 (d, 2H), 1.44 (s, 9H); LCMS: 319.9 [M+Na]+. Step 3: terf-Butyl (E)-(3-fluoro-2-((4-((methylcarbamoyl)oxy)phenoxy)methyl)allyl)carbamate
[00507] To a solution of /cvV-butyl (£)-(3-fluoro-2-((4-hydroxyphenoxy)methyl)allyl)carbamate (100 mg, 0.33 mmol) and Et3N (468 uL, 3.36 mmol) in DCM (5 mL), was added methyl carbamic chloride (157 mg, 1.68 mmol), and then stirred at room temperature overnight. The reaction was quenched with H20 (30 mL) and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated, and purified by prep-TLC (petroleum ether/ethyl acetate=l/l) to give /er/-butyl (E)-(3-fluoro-2-((4- ((methylcarbamoyl)oxy)phenoxy)methyl)allyl)carbamate (75 mg, 48%) as a white solid. 1H NMR (400 MHz, CDCl3): d 7.04 (d, 2H), 6.88 (d, 2H), 6.74 (d, 1H), 4.94 (s, 1H), 4.77 (s, 1H), 4.42 (d, 2H), 4.00 (d, 2H), 2.89 (d, 3H), 1.43 (s, 9H); LCMS: 377.1 [M+Na]+.
Step 4: (ii)-4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl methylcarbamate hydrochloride
[00508] A mixture of /tvV-butyl (£)-(3-fluoro-2-((4-
((methylcarbamoyl)oxy)phenoxy)methyl)allyl)carbamate (65 mg, 0.18 mmol) and 4M HC1 in Et20 (2.0 mL) was stirred at room temperature for 7 h. The reaction mixture was filtered, and the filter cake was dried to give (£)-4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl methylcarbamate hydrochloride (26 mg, 53%) as a white solid. 1H NMR (400 MHz, DMSO-r ): d 8.19 (s, 3H), 7.58- 7.49 (m, 1H), 7.30 (d, 1H), 7.05-6.87 (m, 4H), 4.59 (d, 2H), 3.60 (m, 2H), 2.64 (d, 3H); LCMS: 255.1 [M+H]+.
Compound 5
(ii)-/V-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)propane-2-sulfonamide hydrochloride
Figure imgf000212_0001
Step 1: terf-Butyl (£)-(3-fluoro-2-((4-nitrophenoxy)methyl)allyl)carbamate
[00509] A mixture of 4-nitrophenol (326 mg, 2.35 mmol), /ert-butyl (£)-(2-(bromomethyl)-3- fluoroallyl)carbamate (630 mg, 2.35 mmol), K2C03 (974 mg, 7.05 mmol) and DMF (15 mL) was stirred at 55 °C overnight. The reaction was cooled to room temperature, then quenched with H20 (30 mL), and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated, and then purified by silica gel
chromatography (petroleum ether: ethyl acetate=20: l 10: 1) to give tert- butyl (E)-(3-fluoro-2-((4- nitrophenoxy)methyl)allyl)carbamate (600 mg, 78%) as a white solid. 1H NMR (400 MHz, CDCl3): d 8.21 (d, 2H), 6.99 (d, 2H), 6.78 (d, 1H), 4.76 (s, 1H), 4.55 (d, 2H), 4.01 (d, 2H), 1.41 (s, 9H); LCMS: 271.2 [M+H-56]+. Step 2: terf-Butyl (£)-2-((4-aminophenoxy)methyl)-3-fluoroallyl)carbamate
[00510] A mixture of tert- butyl (E)-(3-fluoro-2-((4-nitrophenoxy)methyl)allyl)carbamate (500 mg, 1.53 mmol), NH4Cl (409 mg, 7.66 mmol), EtOH (6 mL) and H20 (2 mL) was heated to 90 °C, then Fe power (427 mg, 7.66 mmol) was added. The mixture was stirred at 90 °C for 2 h, and then cooled to room temperature. The reaction mixture was filtered and concentrated under reduced pressure to give fe/V-butyl (£)-(2-((4-aminophenoxy)methyl)-3-fluoroallyl)carbamate (530 mg, crude) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 6.86-6.74 (m, 4H), 6.73 (d, 1H), 4.81 (s, 1H), 4.37 (d, 2H), 3.99 (d, 2H), 1.43 (s, 9H); LCMS: 319.3 [M+Na]+.
Step 3: terf-Butyl (E)-3-fluoro-2-((4-(l- methylethylsulfonamido)phenoxy)methyl)allyl)carbamate
[00511] To a solution of /tvV-butyl (£)-(2-((4-aminophenoxy)methyl)-3-fluoroallyl)carbamate (530 mg, 1.79 mmol) and Et3N (17.8 mmol, 2.49 mL) in DCM (10 mL) at 0 °C, was added propane-2- sulfonyl chloride (1 mL, 8.94 mmol),. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with H20 (30 mL), and extracted with EtOAc (3 x20 mL). The organic layers were combined, washed with brine (2x20 mL), dried (Na2S04), filtered, concentrated, and purified by silica gel chromatography (petroleum ethenethyl acetate=50: l 2: 1) to give /tvV-butyl (/7)-(3-fluoro-2-((4-( l -methyl ethyl sulfonamido)phenoxy)methyl)allyl (carbamate (300 mg, 32%) as a yellow oil. 1H NMR (400 MHz, CDCI3): d 7.23 - 7.16 (m, 2H), 6.90 - 6.86 (m, 2H), 6.74 (d, 1H), 6.28 (s, 1H), 4.75 (s, 1H), 4.42 (d, 2H), 4.00 (s, 2H), 3.29 - 3.18 (m, 1H), 1.42 (s, 9H), 1.39 (d, 6H); LCMS: 425.3 [M+Na]+.
Step 4: (ii)-/V-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)propane-2-sulfonamide hydrochloride
[00512] To a solution of /tvV-butyl (A)-(3-fluoro-2-((4-(l- methylethylsulfonamido)phenoxy)methyl)allyl)carbamate (300 mg, 0.74 mmol) in DCM (6 mL) at room temperature was added TFA (22 mmol, 1.67 mL), and the mixture stirred for 1 h. The mixture was concentrated to dryness. The residue was co-evaporated with DCM (2 x 20 mL) to remove trifluoroacetic acid. The resulting oil was taken up in ethyl acetate (3 mL) and then 2.0M HC1 in diethyl ether (0.5 mL) was added. The precipitate formed was isolated and dried under reduced pressure. The residue was purified by reverse-phase HPLC (water (0.05%HCl)-CH3CN) to give (/'/)-A' f-(4-((2-(ami nomethyl )-3-fluoroallyl)oxy)phenyl)propane-2-sulfonamide hydrochloride
(46 mg, 20%) as a yellow solid. 1H NMR (400 MHz, DMSO-r¾): d 9.51 (s, 1H), 8.26 (s, 3H), 7.29 (d, 1H), 7.22-7.10 (m, 2H), 7.00-6.88 (m, 2H), 4.58 (d, 2H), 3.58 (m, 2H), 3.17-3.01 (m, 1H), 1.22 (d, 6H); LCMS: 303.1 [M+H]+. [00513] The compounds below were synthesized in a similar manner as described in the preceding examples.
Figure imgf000214_0001
Figure imgf000215_0002
Compound 9.02
( E -4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)tetrahydro-2//-pyran-4-carboxamide h ydrochloride
Figure imgf000215_0001
Step 1: Ethyl 4-(4-bromophenyl)tetrahydro-2/ -pyran-4-carboxylate
[00514] Under an argon atmosphere, NaH (4.11 g, 103 mmol, 60% purity) was added to a solution of ethyl 2-(4-bromophenyl)acetate (10 g, 41.1 mmol) in anhydrous DMF (200 mL) at 0°C. The resulting mixture was stirred at 0°C for 0.5 h. l-bromo-2-(2-bromoethoxy)ethane (9.5 g, 41.1 mmol) was added and then stirred at 0°C for 1 h. NaH (4.11 g, 103 mmol, 60% purity) was added, and the reaction stirred at 0°C for an additional 1 h. The resulting mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with ethyl acetate (3 x50 mL). The combined organic layers were washed with water (2 x50 mL), brine (50 mL), dried over Na2S04, filtered
concentrated, and then purified by column chromatography (Si02, petroleum ether: ethyl
acetate=5 : l) to give ethyl 4-(4-bromophenyl)tetrahydro-2//-pyran-4-carboxylate (5 2 g? 40%) as a yellow oil. 1H MR (400 MHz, CDCI3): d 7.43 (d, 2H), 7.22 (d, 2H), 4.17 (q, 2H), 3.95 (t, 2H),
3.58 (t, 2H), 2.52 (d, 2H), 1.96 (t, 2H), 1.21 (t, 3H); LCMS: 312.9 [M+H]+.
Step 2: Ethyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)tetrah dro-2//-pyran- 4-carboxylate
A mixture of ethyl 4-(4-bromophenyl)tetrahydropyran-4-carboxylate (4.5 g, 14.4 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3.65 g, 14.4 mmol), KOAc (2.82 g, 28.7 mmol) and l,4-dioxane (60 mL) was evacuated-purged with nitrogen three times. Pd(dppf)Cl2 (526 mg, 0.72 mmol) was added and the mixture stirred at 1 l0°C overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water (80 mL) and then extracted with EtOAc (3 x30 mL). The combined organic layers were dried over Na2S0 , filtered, concentrated, and purified by column chromatography (Si02, petroleum ether/ethyl acetate=30/l) to give ethyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2i7-pyran-4- carboxylate (3.5 g, 68%) as a white solid. 1H NMR (400 MHz, CDCl3): d 7.80 (d, 2H), 7.38 (d, 2H), 4.13 (q, 2H), 3.93 (d, 2H), 3.59 (t, 2H), 2.61-2.45 (m, 2H), 2.08-1.92 (m, 2H), 1.31 (s, 12H), 1.18 (t, 3H); LCMS: 361.3 [M+H]+.
Step 3: Ethyl 4-(4-h droxyphenyl)tetrah dro-2//-pyran-4-carboxylate
[00515] To a solution of ethyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)tetrahydro-2//-pyran-4-carboxylate (4.0 g, 11.1 mmol) in THF (100 mL) at 0 °C, NaB03.4H20 (10.3 g, 66.6 mmol) was added and the reaction warmed to room temperature overnight. The reaction mixture was poured into water (100 mL), and then extracted with EtOAc (3 c50 mL). The combined organic layers were dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=3/l) to give ethyl 4-(4- hydroxyphenyl)tetrahydro-2//-pyran-4-carboxylate (2.0 g, 72%) as a white solid. 1H NMR (400 MHz, CDCl3): d 7.25 (d, 2H), 6.83 (d, 2H), 4.86 (s, 1H), 4.14 (q, 2H), 3.93 (d, 2H), 3.57 (t, 2H), 2.51 (d, 2H), 2.02-1.89 (m, 2H), 1.19 (t, 3H); LCMS: 251.2 [M+H]+.
Step 4: (E)- Ethyl 4-(4-((2-(((tert-butox carbonyl)amino)methyl)-3 fluoroallyl)oxy)phenyl) tetrahydro-2//-pyran-4-carboxylate
[00516] To a solution of ethyl 4-(4-hydroxyphenyl)tetrahydropyran-4-carboxylate (400 mg, 1.60 mmol) in MeCN (10 mL) at room temperature was added (E) -ter t-butyl (2-(bromomethyl)-3- fluoroallyl) carbamate (643 mg, 2.40 mmol) and K2C03 (663 mg, 4.79 mmol). The mixture was stirred at 80°C overnight under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with EtOAc (3 x 15 mL). The combined organic layers were dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=2: l) to give (E)-e thyl 4-(4-((2-(((tert- butoxycarbonyl)amino)methyl)-3-fiuoroallyl)oxy)phenyl)tetrahydro-2//-pyran-4-carboxylate
Figure imgf000216_0001
mg, 86%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.31 (d, 2H), 6.89 (d, 2H), 6.74 (d, 1H), 4.75-4.68 (m, 1H), 4.44 (d, 2H), 4.18-4.13 (m, 2H), 4.00 (d, 2H), 3.95-3.89 (m, 2H), 3.57 (t, 2H), 2.57-2.45 (m, 2H), 2.02-1.84 (m, 2H), 1.42 (s, 9H), 1.19 (t, 3H); LCMS: 338.2 [M+H-l00]+.
Step 5: E)-4-(4-((2-(((terf-Butox carbonyl)amino)methyl)-3-fluoroallyl)oxy)phenyl) tetrahydro-2//-pyran-4-carboxylic acid
[00517] To a solution of (E)-e thyl 4-(4-((2-(((tert-butoxycarbonyl)amino)methyl)-3- fluoroallyl)oxy)phenyl)tetrahydro-2//-pyran-4-carboxylate ^QQ 1 37 mmol) in MeOH (7.5
Figure imgf000216_0002
mL) and THF (15 mL), was added 1M NaOH solution (7 mL). The mixture was stirred at 60°C overnight. The reaction mixture was cooled to room temperature, concentrated to remove the organic solvent, adjusted to pH~5 with 3M aqueous HC1 and extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried over Na2S0 , filtered, concentrated and purified by prep- TLC (Si02, petroleum ether:ethyl acetate=l : l) to give (E)-4-(4-((2-(((tert- butoxycarbonyl)amino)methyl)-3-fluoroallyl)oxy)phenyl) tetrahydro-2//-pyran-4-carboxylic acid (400 mg, 71%) as a white solid. 1H NMR (400 MHz, CDCl3): d 7.33 (d, 2H), 6.89 (d, 2H), 6.74 (d, 1H), 4.47-4.43 (m, 2H), 4.01-3.95 (m, 2H), 3.92 (d, 2H), 3.62 (t, 2H), 2.49 (d, 2H), 1.97 (t, 2H),
1.41 (s, 9H). LCMS: 432.3[M +Na]+.
Step 6: (E)-tert- Butyl (2-((4-(4-carbamoyltetrah dro-2//-pyran-4-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00518] To a solution of E)-4-(4-((2-(((/er/-Butoxycarbonyl)amino)methyl)-3- fluoroallyl)oxy)phenyl) tetrahydro-2//-pyran-4-carboxylic acid (300 mg, 0.73 mmol) and K2C03 (405 mg, 2.93 mmol) in toluene (15 mL), chloromethylene(dimethyl)ammonium chloride (188 mg, 1.47 mmol) was added. The reaction mixture was stirred at room temperature for 3 h under a nitrogen atmosphere, filtered and added to a saturated ammonia solution in toluene (15 mL) (NH3 was bubbled into a solution of toluene at 0°C for 30 minutes) at 0°C. The mixture was warmed to room temperature for lh. The reaction mixture was concentrated to dryness and then purified by prep-TLC (Si02, pretroleum ether/ethyl acetate=l : l) to give (E)-tert- butyl (2-((4-(4- carbamoyltetrahydro-2H-pyran-4-yl)phenoxy)methyl)-3-fluoroallyl)carbamate (80 mg, 25%) as a white solid. 1H NMR (400 MHz, CDCl3): d 7.3 l(d, 2H), 6.93 (d, 2H), 6.75 (d, 1H), 5.21 (s, 2H), 4.86-4.67 (m, 1H), 4.45 (d, 2H), 4.00 (d, 2H), 3.83-3.76 (m, 4H), 2.37 (d, 2H), 2.12-2.03 (m, 2H),
1.42 (s, 9H); LCMS: 409.4 [M+H]+.
Step 7 : ' '£ -4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)tetrahydro-2/ -pyran-4-carboxa mide hydrochloride
[00519] (E)-tert- butyl (2-((4-(4-carbamoyltetrahydro-2H-pyran-4-yl)phenoxy)methyl)-3 - fluoroallyl)carbamate (60 mg, 0.15 mmol) was stirred in 4 M HC1 in EtOAc (15 mL) at room temperature for 1 h under a nitrogen atmosophere. The mixture was concentrated to dryness and then purified by reverse-phase HPLC (water(0.04%HCl)-MeCN) to give (E)- 4-(4-((2-
(aminomethyl)-3-fluoroallyl)oxy)phenyl)tetrahydro-2//-pyran-4-carboxamide hydrochloride (38 mg, 55%) as a white solid. 1H NMR (400 MHz, DMSO-i¾): d 8.23 (s, 3H), 7.42 (d, 2H), 7.29 (d, 1H), 7.15 (s, 1H), 6.99-6.90 (m, 3H), 4.60 (d, 2H), 3.84-3.65 (m, 2H), 3.58 (d, 2H), 3.46 (t, 2H), 2.40 (d, 2H), 1.85-1.68 (m, 2H); LCMS: 309.2[M+H]+.
[00520] The compound below was synthesized in a similar manner as described for compound 9.02.
Figure imgf000218_0002
Compound 10
(E)-l-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)benzyl)pyrrolidin-2-one hydrochloride
Figure imgf000218_0001
Step 1: l-(4-(Benzyloxy)benzyl)pyrrolidin-2-one
[00521] NaH (172 mg, 4.30 mmol, 60% purity) was added to a solution of pyrrolidin-2-one (219 mg, 2.58 mmol) in DMF (10 mL) at 0°C and stirred at 0°C for 0.5 h. l-(Benzyloxy)-4- (chloromethyl)benzene (500 mg, 2.15 mmol) was added and the reaction warmed to room temperature for 1.5 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (Na2S04), filtered, concentrated, and then purified by column chromatography (petroleum ether/ethyl acetate = 50: 1 2: 1) to give l-(4- (benzyloxy)benzyl) pyrrolidin-2-one (500 mg, 83 %) as a yellow solid. 1H NMR (400MHz, CDCl3) d 7.50-7.29 (m, 5H), 7.17 (d, 2H), 6.92 (d, 2H), 5.05 (s, 2H), 4.39 (s, 2H), 3.25 (t, 2H), 2.43 (t, 2H), 2.02-1.92 (m, 2H); LCMS: 282.1 [M+H]+.
Step 2: l-(4-H droxybenzyl)pyrrolidin-2-one
[00522] A mixture of l-(4-(benzyloxy)benzyl)pyrrolidin-2-one (500 mg, 1.78 mmol) and l0wt% Pd/C (100 mg) in MeOH (20 mL) was stirred at room temperature for lh under 15 PSI hydrogen. The mixture was filtered through a Celite pad. The filtrate was concentrated to dryness to give l-(4- hydroxybenzyl)pyrrolidin-2-one (350 mg, crude) as a black brown oil. 1H NMR (400 MHz, MeOD) d 6.94 (d, 2H), 6.71 (d, 2H), 4.30 (s, 2H), 3.29-3.26 (m, 2H), 2.38 (t, 2H), 2.03-1.88 (m, 2H);
LCMS: 192.1 [M+H]+.
Step 3: (ii)-tert-Butyl (3-fluoro-2-((4-((2-oxopyrrolidin-l- yl)methyl)phenoxy)methyl)allyl)carbamate
[00523] A mixture of l-(4-hydroxybenzyl)pyrrolidin-2-one (200 mg, 1.05 mmol), (£)-tert-butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (366 mg, 1.37 mmol), K2C03 (435 mg, 3.15 mmol) and MeCN (10 mL) was stirred at 80 °C overnight. The reaction mixture was cooled to room
temperature, poured into water (30 mL) and extracted with EtOAc (3 x 20 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried (Na2S04), filtered, concentrated and purified by silica gel chromatography (Petroleum ethenEthyl acetate=50: l 0: 1 to DCM:MeOH = 10: 1 ) to give (£)-tert-butyl (3-fluoro-2-((4-((2-oxopyrrolidin-l- yl)methyl)phenoxy)methyl)allyl)carbamate (350 mg, 88%) as a yellow oil. 1H NMR (400MHz, CDCI3) d 7.17 (d, 2H), 6.87 (d, 2H), 6.74 (d, 1H), 4.81-4.77 (m, 1H), 4.43 (d, 2H), 4.39 (s, 2H), 4.00 (d, 2H), 3.34 (t, 2H), 2.43 (t, 2H), 2.04-1.92 (m, 2H), 1.42 (s, 9H); LCMS: 379.2 [M+H]+.
Step 4: (ii)-l-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)benzyl)pyrrolidin-2-one hydrochloride
[00524] A mixture of (£)-tert-butyl (3-fluoro-2-((4-((2-oxopyrrolidin-l- yl)methyl)phenoxy)methyl)allyl)carbamate (300 mg, 0.79 mmol) and 4 M HC1 in EtOAc (10 mL) was stirred at room temperature for 0.5 h. The mixture was concentrated to dryness and then purified by reverse-phase HPLC (water (0.04%HCl)-MeCN) to give (E)-l-(4-((2-(aminomethyl)-3- fluoroallyl)oxy)benzyl)pyrrolidin-2-one hydrochloride (153 mg, 69%) as a yellow solid. 1H NMR (400MHz, DMSO-d6) d 8.31 (br s, 3H), 7.30 (d, 1H), 7.16 (d, 2H), 6.96 (d, 2H), 4.61 (d, 2H), 4.29 (s, 2H), 3.58 (d, 2H), 3.19 (t, 2H), 2.26 (t, 2H), 1.92-1.85 (m, 2H); LCMS: 279.1 [M+H]+.
[00525] The compounds below were synthesized in a similar manner as described for compound 10
Figure imgf000219_0002
Compound 10.02
(ii)-4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)benzyl)morpholin-3-one hydrochloride
Figure imgf000219_0001
Step 1: 4-(4-(Benzyloxy)benzyl)morpholin-3-one
[00526] To a solution of morpholin-3-one (261 mg, 2.58 mmol) in DMF (10 mL) at 0 °C, NaH (172 mg, 4.30 mmol, 60% purity) was added and stirred for 0.5 h. The mixture was warmed to room temperature and 1 -(benzyl oxy)-4-(chloromethyl)benzene (500 mg, 2.15 mmol) added. The mixture was stirred at room temperature for 1.5 h. The reaction mixture was carefully poured into water (30 mL), and then extracted with EtOAc (3 x40 mL). The combined organic layers were washed with brine (2 x30 mL), dried over Na2S04, filtered, concentrated, and then purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=l0/l to 1/1) to give 4-(4- (benzyloxy)benzyl)morpholin-3-one (550 mg, 86%) as a white solid. 1H NMR (400 MHz, DMSO- d6 ): d 7.45-7.43 (m, 2H), 7.40-7.37 (m, 2H), 7.34-7.32 (m, 1H), 7.19 (d, 2H), 6.98 (d, 2H), 5.08 (s, 2H), 4.46 (s, 2H), 4.08 (s, 2H), 3.79-3.76 (m, 2H), 3.22-3.19 (m, 2H); LCMS: 297.9 [M+H]+.
Step 2: 4-(4-Hydroxybenzyl)morpholin-3-one [00527] A mixture of 10 wt% Pd/C (500 mg), MeOH (10 mL), and 4-(4-
(benzyloxy)benzyl)morpholin-3-one (550 mg, 1.85 mmol) was stirred at room temperature for 1 h under hydrogen (50 psi). The reaction mixture was filtered through celite pad and the filtrate was concentrated under reduced pressure to give 4-(4-hydroxybenzyl)morpholin-3-one (340 mg) as a white solid. 1H NMR (400 MHz, DMSO-r/6): d 7.05 (d, 2H), 6.71 (d, 2H), 4.40 (s, 2H), 4.07 (s,
2H), 3.78-3.75 (m, 2H), 3.20-3.17 (m, 2H); LCMS: 207.9 [M+H]+.
Step 3: (E)-tert- Butyl (3-fluoro-2-((4-((3-oxomorpholino)methyl)phenoxy) methyl)allyl) carbamate
[00528] To a solution of 4-(4-hydroxybenzyl)morpholin-3-one (200 mg, 0.97 mmol), ( E)-tert - butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (311 mg, 1.16 mmol) in acetonitrile (8 mL) at room temperature, K2C03 (400 mg, 2.90 mmol) was added. The mixture was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with EtOAc (3 x25 mL). The combined organic layers were washed with brine (2 x25 mL), dried over Na2S04 filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=20/l to 1/1) to give (//)- /er/-butyl (3-fluoro-2-((4-((3-oxomorpholino)methyl)phenoxy) methyl)allyl) carbamate (300 mg, 79%) as a yellow solid. 1H NMR (400 MHz, CDCl3): d 7.20 (d, 2H), 6.87 (d, 2H), 6.74 (d, 1H), 4.83-4.74 (m, lH), 4.56 (s, 2H), 4.43 (d, 2H), 4.23 (s, 2H), 4.00 (d, 2H), 3.83 (t, 2H), 3.25 (t, 2H), 1.42 (s, 9H); LCMS: 395.1 [M+H]+.
Step 4: (£)-4-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)benzyl)morpholin-3-one hydrochloride
[00529] A mixture of (E)-tert- butyl (3-fluoro-2-((4-((3-oxomorpholino)methyl)phenoxy) methyl)allyl) carbamate (300 mg, 0.760 mmol) and 4M HC1 in EtOAc (10 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to dryness and then purified by prep LCMS (water(0.04%HCl)-MeCN) to give (E)-4-(4-((2-(aminomethyl)-3- fluoroallyl)oxy)benzyl)morpholin-3-one hydrochloride (132 mg, 51%) as a yellow solid. 1H NMR (400 MHz, DMSO-r/e): d 8.43 (s, 3H), 7.28 (s, 1H), 7.20 (d, 2H), 6.97 (d, 2H), 4.64 (d, 2H), 4.47 (s, 2H), 4.08 (s, 2H), 3.79-3.76 (m, 2H), 3.56 (d, 2H), 3.21 (t, 2H); MS:295. l [M+H]+.
[00530] The compounds below were synthesized in a similar manner as described for compound 10 02
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0002
Compound 10.48
(S,E)-l-(l-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)ethyl)piperidin-2-one
Figure imgf000224_0001
Step 1: (A)-5-Chloro-/V-(l-(4-methoxyphenyl)ethyl)pentanamide
[00531] Diethylisopropylamine (1.7 mL, 9.76 mmol) and 5-chloropentanoyl chloride (0.65 mL, 5.03 mmol) were added to a solution of (ri)-l-(4-methoxyphenyl)ethanamine.(500 mg, 3.31 mmol) and DCM (15 mL) at 0 °C. The reaction mixture was stirred for lh, diluted with DCM (10 ml), washed with saturated NaHC03 solution (20 mL) and brine (20 mL), dried (Na2S04), filtered, and then concentrated. The residue was purified by silica gel chromatography (10-50% EtOAc in hexanes) to give (ri)-5-chloro-/V-(l-(4-methoxyphenyl)ethyl)pentanamide (773 mg, 87%) as a yellow solid. 1H NMR (400 MHz, DMSO-i¾): d 8.18 (d, 1H), 7.20 (d, 2H), 6.88 (d, 2H), 4.92-4.82 (m, 1H), 3.73 (s, 3H), 3.63 (t, 2H), 2.12 (t, 2H), 1.73-1.55 (m, 4H), 1.30 (d, 3H); LCMS: 291.8 [M+Na]+.
Step 2: (A)-l-(l-(4-Methoxyphenyl)ethyl)piperidin-2-one
[00532] Sodium hydride (60% in mineral oil, 140 mg, 3.50 mmol) was added to a solution of ( S )- 5-chloro-/V-(l-(4-methoxyphenyl)ethyl)pentanamide (770 mg, 2.86 mmol) and DMF (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4 h, quenched with a saturated NaHCO, solution (10 mL), diluted with EtOAc (50 mL) and then washed with water (50 mL) brine (50 mL). The organic layer was dried (Na2S04), filtered, and concentrated. The residue was purified by silica gel chromatography (10-60% EtOAc in hexanes) to give (ri)-l-(l-(4- methoxyphenyl)ethyl)piperidin-2-one (510 mg, 76%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-£¾): d 7.17 (d, 2H), 6.90 (d, 2H), 5.85 (q, 1H), 3.74 (s, 3H), 3.14-3.05 (m, 1H), 2.72-2.64 (m, 1H), 2.32-2.25 (m, 2H), 1.72-1.61 (m, 3H), 1.57-1.48 (m, 1H), 1.30 (d, 3H); LCMS: 255.9 [M+Na]+.
Step 3: (A)-l-(l-(4-Hydroxyphenyl)ethyl)piperidin-2-one
[00533] 1M Boron tribromide in DCM (4.0 mL, 4.0 mmol) was added to a solution of (A)-l-(l-(4- methoxyphenyl)ethyl)piperidin-2-one (473 mg, 2.03 mmol) in DCM (7 mL) at -78 °C. The reaction mixture was stirred at 0 °C for lh, re-cooled to -78 °C, quenched with MeOH (4 mL), and then warmed to room temperature. The solution was washed with saturated NaHC03 solution (10 mL) and then brine (10 mL), dried (Na2S04), filtered and then concentrated to give (ri)-l-(l-(4- hydroxyphenyl)ethyl)piperidin-2-one (430 mg, 97%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-r¾): d 9.44 (s, 1H), 7.05 (d, 2H), 6.72 (d, 2H), 5.81 (q, 1H), 3.12-3.02 (m, 1H), 2.73-2.64 (m, 1H), 2.32-2.25 (m, 2H), 1.70-1.60 (m, 3H), 1.57-1.45 (m, 1H), 1.36 (d, 3H);
[00534] LCMS: 241.9 [M+Na]+.
Step 4: (S,E)-l-(l-(4-((2-(aminomethyl)-3-fluoroallyl)oxy)phenyl)ethyl)piperidin-2-one
[00535] S)-l-(l-(4-Hydroxyphenyl)ethyl)piperidin-2-one (430 mg, 1.96 mmol) was reacted in a manner similar to 4-(4-hydroxybenzyl)morpholin-3-one in the preparation of compound 10.02 to yield the title compound as a white powder (450 mg, 75 %). LCMS: 307.0 [M+H]+.
[00536] The compound below was synthesized in a similar manner as described for compound
10.48.
Figure imgf000225_0001
[00537] The compounds below were synthesized in a similar manner as described in the preceding examples.
Figure imgf000225_0002
Figure imgf000226_0002
Compound 13
E -l-(6-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-2-azaspiro[3.3]heptan-2-yl)ethanone trifluoroacetate
Figure imgf000226_0001
Step 1: terf-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate
[00538] A mixture of /er/-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (9.0 g, 42.2 mmol), PPh3 (22.1 g, 84.4 mmol), I2 (16.1 g, 63.3 mmol), imidazole (8.6 g, 127 mmol) and toluene (450 mL) was stirred at 120 °C for 2 h. The mixture was cooled to room temperature, poured into water (500 mL) and extracted with EtOAc (2 x500 mL). The organic layers were combined, washed with water (2 x500 mL), brine (500 mL), dried (Na2S04), filtered, concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 20/1) to give tert- butyl 6-iodo- 2-azaspiro[3.3]heptane-2-carboxylate (10 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3): d 4.29 (q, 1H), 3.95 (s, 2H), 3.92 (s, 2H), 2.97-2.86 (m, 2H), 2.76-2.65 (m, 2H), 1.42 (s, 9H); LCMS: 267.9 [M+H-56]+.
Step 2: tert- Butyl 6-(4-(benzyloxy)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate
[00539] A mixture of (4-(benzyloxy)phenyl)boronic acid (706 mg, 3.09 mmol), (l S,2S)-2- aminocyclohexanol (18 mg, 0.15 mmol), Nil2 (48 mg, 0.15 mmol) and i-PrOH (5 mL) was taken up into a microwave tube at room temperature. The mixture was capped under nitrogen. 1M NaHMDS in THF (3.1 mL) was added, the mixture stirred for 30 min at room temperature before the addition of a solution of /er/-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 1.55 mmol) in i- PrOH (2 mL). The sealed tube was heated at 100 °C for 1 h in a microwave. The mixture was cooled to room temperature and concentrated to remove the organic solvent. The residue was dissolved in EtOAc (125 mL) and washed with water (2 x50 mL), brine (50 mL), dried (Na2S04), filtered, concentrated and then purified by chromatography on silica gel (petroleum ether/EtOAc = 10/1) to give te/V-butyl 6-(4-(benzyloxy)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate (230 mg, 20%) as a white solid. 1H NMR (400 MHz, CDCI3): d 7.48-7.29 (m, 5H), 7.11 (d, 2H), 6.94 (d,
2H), 5.07 (s, 2H), 4.07 (s, 2H), 3.86 (s, 2H), 3.35 (q, 1H), 2.63-2.53 (m, 2H), 2.31-2.21 (m, 2H), 1.47 (s, 9H): LCMS: 324.1 [M+H-56]+. The reaction was conducted fourteen times in a similar manner to provide sufficient material for subsequent reactions.
Step 3: 6-(4-(Benzyloxy)phenyl)-2-azaspiro [3.3] heptane
[00540] To a mixture of /er/-butyl 6-(4-benzyloxyphenyl)-2-azaspiro[3.3]heptane-2-carboxylate (800 mg, 2.11 mmol) in DCM (10 mL) at room temperature, TFA (4.62 g, 40.5 mmol) was added and stirred at room temperature for 2 h. The mixture was concentrated to dryness. The residue was dissolved in DCM (50 mL) and washed with aq. saturated NaHC03 solution (2 x30 mL), water (2 x30 mL), brine (30 mL), dried (Na2S04), filtered, and concentrated to dryness to give 6-(4- (benzyloxy)phenyl)-2-azaspiro[3.3]heptane (500 mg, crude) as a yellow oil. 1H NMR (400 MHz, CDCI3): d 7.39-7.19 (m, 5H), 7.00 (d, 2H), 6.84 (s, 2H), 5.14-5.01 (m, 1H), 4.97 (s, 2H), 3.84 (s, 2H), 3.63 (s, 2H), 3.31-3.17 (m, 1H), 2.60-2.46 (m, 2H), 2.20-2.08 (m, 2H); MS: 280.2 [M+H]+.
Step 4: l-(6-(4-(Benzyloxy)phenyl)-2-azaspiro[3.3]heptan-2-yl)ethanone
[00541] To a solution of 6-(4-(benzyloxy)phenyl)-2-azaspiro[3.3]heptane (500 mg, 1.79 mmol) TEA (1.04 g, 10.3 mmol) in DCM (10 mL) at 0°C, acetyl acetate (365 mg, 3.58 mmol) was added. The mixture was warmed to room temperature overnight. The mixture was washed with water (2 x5 mL), brine (5 mL), dried (Na2S04), filtered, concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 0/1) to give l-(6-(4-(benzyloxy)phenyl)-2- azaspiro[3.3]heptan-2-yl)ethanone (400 mg, 70%) as yellow oil. 1H NMR (400 MHz, CDCI3): d 7.52-7.30 (m, 5H), 7.12 (d, 2H), 6.94 (d, 2H), 5.07 (s, 2H), 4.25 (s, 1H), 4.15 (s, 1H), 4.01 (s, 1H), 3.95 (s, 1H), 3.46-3.27 (m, 1H), 2.70-2.52 (m, 2H), 2.37-2.21 (m, 2H), 1.89 (d, 3H); LCMS: 322.1 [M+H]+
Step 5: l-(6-(4-hydroxyphenyl)-2-azaspiro[3.3]heptan-2-yl)ethanone
[00542] A mixture of l-(6-(4-(benzyloxy)phenyl)-2-azaspiro[3.3]heptan-2-yl)ethanone (400 mg, 1.24 mmol), 10 wt% Pd/C (100 mg) and MeOH (30 mL) was stirred at room temperature for 2 h under 15 psi of hydrogen. The mixture was filtered through celite pad and the filtrate was concentrated to dryness to give l-(6-(4-hydroxyphenyl)-2-azaspiro[3.3]heptan-2-yl)ethanone (250 mg, crude) as a yellow oil. 1H NMR (400 MHz, DMSO-i¾) d 9.26 (br s, 1H), 7.00 (d, 2H), 6.69 (d, 2H), 4.21 (s, 1H), 4.03 (s, 1H), 3.93 (s, 1H), 3.72 (s, 1H), 3.27-3.18 (m, 1H), 2.49-2.41 (m, 2H), 2.21-2.11 (m, 2H), 1.73 (d, 3H); LCMS: 232.2 [M+H]+.
Step 6: (E)-tert- butyl (2-((4-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)phenoxy)methyl)-3- fluoroallyl)carbamate
[00543] A mixture of l-(6-(4-hydroxyphenyl)-2-azaspiro[3.3]heptan-2-yl)ethanone (200 mg, 0.86 mmol), (E)-tert- butyl (2-(bromomethyl)-3-fluoroallyl)carbamate (278 mg, 1.04 mmol) Cs2C03 (845 mg, 2.59 mmol) and MeCN (10 mL) was stirred at room temperature overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x20 mL).The organic layers were combined, washed with water (2 x lO mL), brine (10 mL), dried (Na2S04), filtered, concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 0/1) to gi ve(E)-tert- butyl (2-((4-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)phenoxy)methyl)-3-fluoroallyl)carbamate (300 mg, 81%) as a yellow oil. 1H NMR (400 MHz, CDCl3): d 7.02 (d, 2H), 6.78 (d, 2H), 6.66 (d, 1H), 4.75-4.58 (m, lH),4.35 (d, 2H), 4.15 (s, 1H), 4.07 (s, 1H), 3.98 (s, 1H), 3.92 (d, 2H), 3.89 (s, 1H), 3.36-3.22 (m, 1H), 2.56-2.44 (m, 2H), 2.28-2.12 (m, 2H), 1.79 (d, 3H), 1.37 (s, 9H); LCMS:4l9.2
[M+H]+.
Step 7: E -l-(6-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-2-azaspiro[3.3]heptan-2- yl)ethanone trifluoroacetate
[00544] To a solution of (E)-tert- butyl (2-((4-(2-acetyl-2-azaspiro[3.3]heptan-6- yl)phenoxy)methyl)-3-fluoroallyl)carbamate (300 mg, 0.72 mmol) in DCM (5 mL), TFA (2 mL)was added and stirred at room temperature for 2 h under a nitrogen atmosphere. The mixture was concentrated to dryness, and then purified by reverse-phase HPLC (water (0. l%TFA)-MeCN) to give (E)- \ -(6-(4-((2-( Ami nomethyl )-3-fluoroallyl)oxy)phenyl)-2-azaspiro[3 3 ]heptan-2- yl)ethanone trifluoroacetate (112 mg, 48%) as a white solid. 1H NMR (400 MHz, D20): d 7.19 (d, 2H), 7.03 (d, 1H), 6.94 (d, 2H), 4.55 (d, 2H), 4.30 (s, 1H), 4.07 (s, 1H), 4.05 (s, 1H), 3.84 (s, 1H), 3.79 (d, 2H), 3.39-3.26 (m, 1H), 2.52-2.48 (m , 2H), 2.26-2.15 (m, 2H), 1.78 (d, 3H); LCMS: 319.1 [M+H]+.
Compound 13.01
E -(6-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-2-azaspiro[3.3]heptan-2-yl)(l- (trifluoromethyl)cyclopropyl)methanone trifluoroacetate
Figure imgf000228_0001
Step 1 : (6-(4-(Benzyloxy)phenyl)-2-azaspiro [3.3] heptan-2-yl)(l-(trifluoromethyl)
cyclopropyl)methanone
[0001] A mixture of 6-(4-(benzyloxy)phenyl)-2-azaspiro[3.3]heptane (450 mg, 1.61 mmol), 1- (trifluoromethyl)cyclopropanecarboxylic acid (298 mg, 1.93 mmol), EDCI (618 mg, 3.22 mmol), HOBt (435 mg, 3.22 mmol) TEA (978 mg, 9.66 mmol), and DCM (10 mL) was stirred at room temperature overnight. The mixture was washed with water (5 mL), brine (5 mL), dried over Na2S04, filtered, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 2/1) to give (6-(4-(benzyloxy)phenyl)-2-azaspiro[3.3]heptan-2-yl)(l-(trifluoromethyl)
cyclopropyl)methanone (540 mg, 81%) as a yellow oil. 1H NMR (400 MHz,CDCl3): d 7.42-7.23 (m, 5H), 7.02 (d, 2H), 6.85 (d, 2H), 4.98 (s, 2H), 4.39-4.32 (m, 1H), 4.23 -4.12 (m, 2H), 3.99-3.80 (m, 1H), 3.29 (q, 1H), 2.56-2.45 (m, 2H), 2.27-2.15 (m, 2H), 1.13 (s, 4H); LCMS: 416.1 [M+H]+.
Step 2: (6-(4-Hydroxyphenyl)-2-azaspiro[3.3]heptan-2-yl)(l-(trifluoromethyl)
cyclopropyl)methanone
[0002] A mixture of (6-(4-(benzyloxy)phenyl) -2-azaspiro[3.3]heptan-2-yl)(l-(trifluoromethyl) cyclopropyl)methanone (600 mg, 1.44 mmol), 10 wt% Pd/C (100 mg) and MeOH (50 mL) was stirred at room temperature under 15 psi of hydrogen for 2 h. The mixture was filtered through celite pad, concentrated to dryness to give crude product (6-(4-hydroxyphenyl)-2- azaspiro[3.3]heptan-2-yl) (l-(trifluorom ethyl) cyclopropyl)methanone (400 mg, crude) as a yellow oil. 1H NMR (400 MHz, DMSO-i¾): d 9.23 (br s, 1H), 7.00 (d, 2H), 6.68 (d, 2H), 4.39-4.35 (m,
1H), 4.25-3.97 (m, 2H), 3.93-3.73 (m, 1H), 3.28-3.18 (m, 1H), 2.49-2.43 (m, 2H), 2.28-2.10 (m, 2H), 1.25-1.07 (m, 4H); LCMS: 326.1 [M+H]+.
Step 3: (E)-tert- Butyl (3-fluoro-2-((4-(2-(l-(trifluoromethyl)cyclopropanecarbonyl)-2- azaspiro[3.3]heptan-6-yl)phenoxy)methyl)allyl)carbamate
[0003] A mixture of (6-(4-hydroxyphenyl)-2-azaspiro[3.3]heptan-2-yl) (l-(trifluorom ethyl) cyclopropyl)methanone (250 mg, 0.77 mmol), (E)-tert- butyl (2-(bromomethyl)-3- fluoroallyl)carbamate (247 mg, 0.92 mmol), Cs2C03 (751 mg, 2.31 mmol) and MeCN (10 mL) was stirred at room temperature overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (2 x20 mL). The organic layers were combined, washed with water (2 x 10 mL), brine (10 mL), dried (Na2S04), filtered, concentrated, and then purified by chromatography on silica gel (petroleum ether/EtOAc = 2/1) to give (E)-tert- butyl (3-fluoro-2-((4-(2-(l- (trifluoromethyl)cyclopropanecarbonyl)-2-azaspiro[3.3]heptan-6- yl)phenoxy)methyl)allyl)carbamate (280 mg, 71%) as yellow oil. 1H NMR (400MHz, CDCl3): d 7.08 (d, 2H), 6.85 (d, 2H), 6.73 (d, 1H), 4.84-4.65 (m, 1H), 4.49-4.40 (m, 3H), 4.27-4.12 (m, 2H), 4.02-3.91 (m, 3H), 3.36 (t, 1H), 2.58 (t, 2H), 2.34-2.23 (m, 2H), 1.42 (s, 9H), 1.20 (s, 4H); LCMS: 535.2 [M+Na]+.
Step 4: E -(6-(4-((2-(Aminomethyl)-3-fluoroallyl)oxy)phenyl)-2-azaspiro[3.3] heptan-2-yl)(l- (trifluoromethyl)cyclopropyl)methanone trifluoroacetate
[0004] A mixture of(E)-/er/-butyl (3-fluoro-2-((4-(2-(l-(trifluoromethyl)cyclopropanecarbonyl)-2- azaspiro[3.3]heptan-6-yl)phenoxy)methyl)allyl)carbamate (280 mg, 0.55 mmol), TFA (0.8 mL) and DCM (2 mL) was stirred at room temperature for 2 h. The mixture was concentrated to dryness and then purified by reverse-phase HPLC (water(0. l%TFA)-MeCN) to give (E)-( 6-(4-((2- (aminomethyl)-3-fluoroallyl)oxy)phenyl)-2-azaspiro[3.3]heptan-2-yl)(l-
(trifluoromethyl)cyclopropyl)methanone trifluoroacetate (76 mg, 33%) as a yellow solid. 1H NMR (400 MHz, D20) d 7.19 (d, 2H), 7.11 (d, 1H), 6.92 (d, 2H), 4.55 (d, 2H), 4.51 (s, 1H), 4.29 (s, 1H), 4.13 (s, 1H), 3.92 (s, 1H), 3.79 (s, 2H), 3.39-3.28 (m, 1H), 2.59-2.46 (m, 2H), 2.29-2.17 (m, 2H), 1.29-1.18 (m, 2H), 1.12-1.09 (m, 2H); LCMS: 413.1 [M+H]+.
Example A-l: Parenteral Pharmaceutical Composition
[00545] To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous), 1-1000 mg of a compound described herein, or a
pharmaceutically acceptable salt or solvate thereof, is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. A suitable buffer is optionally added as well as optional acid or base to adjust the pH. The mixture is incorporated into a dosage unit form suitable for
administration by injection.
Example A-2: Oral Solution
[00546] To prepare a pharmaceutical composition for oral delivery, a sufficient amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is added to water (with optional solubilizer(s), optional buffer(s) and taste masking excipients) to provide a 20 mg/mL solution.
Example A-3: Oral Tablet
[00547] A tablet is prepared by mixing 20-50% by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100-1000 mg.
Example A-4: Oral Capsule
[00548] To prepare a pharmaceutical composition for oral delivery, 1-1000 mg of a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
[00549] In another embodiment, 1-1000 mg of a compound described herein, or a
pharmaceutically acceptable salt thereof, is placed into a size 4 capsule, or a size 1 capsule (hypromellose or hard gelatin) and the capsule is closed. Example A-5: Topical Gel Composition
[00550] To prepare a pharmaceutical topical gel composition, a compound described herein, or a pharmaceutically acceptable salt thereof, is mixed with hydroxypropyl celluose, propylene glycol, isopropyl myristate and purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
Example B-l: Human semicarbazide-sensitive amine oxidase (SSAO) assay
Test Compounds
[00551] Compounds were dissolved in DMSO to provide a Concentration Response Curve (CRC; at 500 times the final concentration) over a range of 6-10 dilutions.
Assay
[00552] Recombinant Human SSAO/VAP-1/AOC3 (R&D systems; Catalog # 3957-AO) was used to screen compound potency in vitro, according to previously described methods (J Pharmacol Exp Ther. 2013 Nov; 347(2):365-74). SSAO enzyme was suspended in 50 mM HEPES buffer to a working concentration of 2.5 pg/ml and 40 pL of this enzyme mixture was then added to each well of a F16 Black Maxisorp 96 well Plate (Nunc, Catalog # 475515). Ten microliters of each test compound (at 5 times the final concentration) were added to each well, resulting in a final well volume of 50 pL of the enzyme and inhibitor mixture. The compounds were preincubated with the enzyme for 30 minutes at 37°C, prior to the addition of a 40 pL volume of Amplex Ultra Red (l25uM AUR; Molecular Probes, Catalog # A36006)/Horseradish peroxidase (2.5U/ml HRP; Sigma-Aldrich Catalog # P8375) oxidase detection reagent containing cytochrome C (7.5 pM; Sigma-Aldrich Catalog # C7752). Cytochrome C was included in the AUR/HRP detection mixture to reduce the background fluorescence that can occur via the spontaneous redox reaction between AUR and HRP. The SSAO enzyme reaction was then initiated by adding 10 pL of the SSAO substrate, benzylamine (Sigma-Aldrich Catalog # B5136), and SSAO activity was measured in kinetic mode over a 30 -120 minute sampling period (excit. 544nm; emit 590nm; cut off 570nm; medium gain) to obtain IC50 values for enzyme activity in each treatment well.
[00553] Representative data for exemplary compounds disclosed herein is presented in Table 3.
TABLE 3
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
where‘++++’ means IC50 <0.01 uM; where‘+++’ means 0.01 uM< IC50 <0.1 uM; where‘++’ means 0.1 uM< IC50 <1.0 uM; where‘+’ means 1.0 uM< IC50 <10.0 uM; * indicates bridgehead isomer not determined.
Example B-2: Mouse semicarbazide-sensitive amine oxidase (SSAO) Assay
[00554] Recombinant Mouse SSAO/VAP-1/AOC3 (R&D systems; Catalog # 6107-AO) can be used to screen compound selectivity in vitro. The Mouse SSAO assay can be run in the same manner as described for the human SSAO assay.
Example B-3: Human diamine oxidase (DAO) enzyme assay
[00555] Inhibition of recombinant human DAO (R& D systems; Catalog # 8298-AO) activity can be used to screen compound selectivity in vitro. The human DAO assay can be run in the same manner as described for the human SSAO assay, with the exception that putrescine (Sigma-Aldrich Catalog # P5780) and aminoguanidine bicarbonate (Sigma-Aldrich Catalog # 109266-100G) can be used as the substrate and positive control, respectively.
Example B-4: Human monoamine oxidase A and B assays [00556] Inhibition of recombinant human MAO-A (Sigma- Aldrich Catalog# M7316) and MAO-B (Sigma- Aldrich Catalog# M7441) can be used to screen compound selectivity in vitro. The MAO- A and MAO-B assays can be run in the same manner as described above for the human SSAO assay, with tyramine (Sigma-Aldrich Catalog # T2879) and benzylamine (Sigma-Aldrich Catalog # B5136) being used as the substrates for MAO-A and MAO-B, respectively. The positive controls for MAO-A and MAO-B can be clorgyline (Sigma-Aldrich Catalog# M3778) and mofegiline (MedChem Express Catalog# HY-16677A), respectively.
Example B-5: Human lysyl oxidase (LOX) assay
[00557] Recombinant human lysyl oxidase (LOX) can be isolated from concentrated conditioned media (CCM) of cells that transiently or stably overexpress the human LOX enzyme. Once isolated, the CCM can be concentrated using a centrifugation column with 10 kDa molecular weight cut-off (MWCO). Inhibition of LOX activity can then be tested suing the same fluorescence readout as for SSAO with the exception that the l,5-diaminopentane can be used as the LOX substrate and b-aminopropionitrile (Sigma-Aldrich Catalog # A3134) used as positive control. Example B-6: Peroxide scavenging/Amplex ultra red interference assay
[00558] A counter assay can be run to assess compound interference with the AUR enzyme and to identify compounds that might scavenge H202 directly, leading to a false positive readout regarding SSAO enzyme inhibition. To do this, H202 solution can be added to compound and the AUR mixture, in the absence of SSAO enzyme, and the effects on H202-induced fluorescence can then be measured. The peroxide scavenger compound N-Acetyl-L-cysteine (NAC: Sigma-Aldrich Catalog # A7250) and the enzyme catalase (Sigma-Aldrich Catalog# Cl 345), which catalyzes the degradation of H202 into H20 and 02, can be used as positive controls in this interference assay. Example B-7: Compound Oxidation Assay
[00559] Because the SSAO compounds are mechanism-based inhibitors, the potential for compound turnover by SSAO/VAP-l can be assessed to determine the substrate propensity of the compounds relative to background (dimethyl sulfoxide only). The assay can be run in a similar manner as that described for the SSAO enzyme assay. Briefly, compounds can be incubated with recombinant human SSAO enzyme, in the absence of benzylamine substrate, and oxidase activity can be measured for 30 - 120 min after addition of the AUR/HRP mixture.
Example B-8: Rat pharmacodynamic model
[00560] SSAO activity can be measured using a modification of previously described methods (J Pharmacol Exp Ther. 2013 Nov;347(2):365-74). To measure compound activity in vivo, rats can be orally administered with compounds at predetermined concentrations. Animals can then be killed after 2-48 hours for collection of plasma, abdominal fat, liver and other tissues of interest. Tissue samples can be homogenized in HES buffer (20mM HEPES,l50mM NaCl, lmM EDTA, lmM EGTA with 1% triton X100, IX protease and phosphatases inhibitor, pH 7.4). For tissues, homogenates can then be centrifuged at 10,000 c g for 30 min at 4°C and the supernatants collected for the fluorometric measurement of SSAO activity. Plasma can be assayed directly. When measuring SSAO activity, pargyline can be included in the assay buffer to inhibit any potential endogenous monoamine oxidase A and B which could interfere with the assay. SSAO activity in the plasma and tissue homogenates can then be analyzed as described in the in vitro methods for human SSAO.
Example B-9: Mouse pharmacodynamic model
[00561] SSAO activity can be measured using a modification of previously described methods (J Pharmacol Exp Ther. 2013 Nov;347(2):365-74). To measure compound activity in vivo, mice can be orally administered with compounds at predetermined concentrations. Animals can then be killed after 2-48 hours for collection of plasma, abdominal fat and other tissues of interest. Tissue samples can be homogenized in HES buffer (20mM HEPES, lmM EDTA, sucrose 250 mM, IX protease and phosphatases inhibitor, pH 7.4). Homogenates can then be centrifuged at 2000 c g for 5 -10 min at 4°C and the supernatants collected and diluted 1 :5 in assay buffer (0.1 M sodium phosphate buffer, pH7.2) for the fluorometric measurement of SSAO activity. When measuring SSAO activity from tissue, pargyline can be included in the assay buffer to inhibit any potential endogenous monoamine oxidase A and B which could interfere with the assay. SSAO activity in the plasma and tissue homogenates can then be analyzed as described in the in vitro methods for human SSAO.
Example B-10: Rat Carbon tetrachloride (CCl4)-induced Liver fibrosis model
[00562] Analysis of the use of SSAO inhibitors to treat liver fibrosis can be performed using the CCU-induced liver fibrosis model. To do this, Sprague-Dawley rats can be dosed with vehicle (olive oil) or CCl4 (1-2 pL/g (1 : 1 in olive oil); 2 times per week) by oral gavage (PO) for a period of 4-8 weeks to induce liver injury and fibrosis. Rats can then be dosed with inhibitors either: 1) in a preventative manner from day 0 onward or 2) in a therapeutic manner, starting 2 or 4 weeks after the initiation of CC14 dosing. At the end of the study period, plasma and tissue can be harvested to determine drug concentrations, SSAO activity, liver enzymes and liver fibrosis, inflammation and pro-fibrotic gene or protein expression in both the vehicle and drug-treated groups.
Example B-ll: Mouse Carbon tetrachloride (CCl4)-induced Liver fibrosis model
[00563] Analysis of the use of SSAO inhibitors to treat liver fibrosis can be performed using the CCl4-induced liver fibrosis model. To do this, C57BL/6 mice can be dosed with vehicle (olive oil) or CC14 (0.5pL/g; 2 times per week) by oral gavage (PO) for a period of 3 week to induce liver injury and fibrosis. Following the 3 week induction period, mice can then be dosed, therapeutically, with SSAO inhibitors for an additional 3 weeks (therapeutic dosing). At the end of the 6 week study period, plasma and tissue can be harvested to determine drug concentrations, SSAO activity, liver enzymes and liver fibrosis, inflammation and pro-fibrotic gene or protein expression in both the vehicle and drug-treated groups.
Example B-12: NASH liver fibrosis model
[00564] Analysis of the use of SSAO inhibitors to treat liver steatosis/inflammation/fibrosis can be performed using rodent high fat diet-induced models of non-alcoholic steatohepatitis (NASH). To test the use of SSAO inhibitors in NASH, mouse NASH models can be run as previously described {World J Hepatol 2016 June 8; 8(16): 673-684).
Example B-13: Lipopolysaccharide (LPS) airway inflammation model
[00565] To assess the use of SSAO inhibitors on inflammation, mice can undergo pulmonary challenge with LPS to induce inflammatory cell infiltration and cytokine production. To do this, mice can be administered with vehicle or SSAO inhibitor by oral gavage, 1-2 h prior to LPS challenge. Inflammation can then be induced by oropharyngeal instillation of vehicle (phosphate- buffered saline) or LPS. Six hours later, mice can be killed and bronchoalveolar lavage (BAL) fluid collected for recovery of airway luminal cells and cytokine analysis. To isolate BAL, the trachea can be cannulated and lavaged with 1.0 mL heparinized (10 U/ml) saline. An aliquot of the lavage can then be reserved for total and differential white cell counts and the remaining fluid can be centrifuged and the supernatants used to measure cytokines.
Example B-14: Mouse bleomycin lung fibrosis model
[00566] Briefly, lung fibrosis can be induced by oropharyngeal instillation of bleomycin
(Blenoxane, Henry Schein Catalog# 1045785) To do this, mice can be anesthetized with isoflurane (5% in 100% 02) and then be hung on a board by their teeth in a reclined position. Bleomycin (BLM; 1-5.0 U/kg) can be delivered by oropharyngeal instillation whereby BLM is dripped onto the vocal chords (2.5pL/g volume) facilitating aspiration. SSAO compounds can be administered prior to BLM challenge (preventative dosing) or at different timepoints after BLM challenge (therapeutic dosing). The route and frequency of dosing can be based on previously determined pharmacokinetic properties for each compound in mice. At various timepoints after BLM challenge (i.e. 7-28 days), mice can killed for analysis of lung inflammation and cytokine release, pulmonary vascular leakage and lung fibrosis.
[00567] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS WHAT IS CLAIMED IS:
1. A compound having the structure of Formula (III):
Figure imgf000237_0001
Formula (III);
wherein:
Figure imgf000237_0002
R1 is C2-6alkenyl, C2-6alkynyl, a saturated monocyclic C2-7heterocycloalkyl, a saturated bridged bicyclic C2-9heterocycloalkyl, or a saturated spirocyclic C2-9heterocycloalkyl, wherein C2- 6alkenyl, C2-6alkynyl, saturated monocyclic C2-7heterocycloalkyl, saturated bridged bicyclic C2-9heterocycloalkyl, or saturated spirocyclic C2-9heterocycloalkyl are optionally
substituted with one, two, three, four, or five
Figure imgf000237_0003
each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-l0aryl, Ci-9heteroaryl, -R14a, - OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, - N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12;
each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cydoalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, R14a, -OR8, - SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10),
Figure imgf000238_0001
each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14b;
R4 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14c;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R4 and R5, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14d;
R6 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R7 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- !oaryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14e;
each R8 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14f;
each R9 is independently selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14g; each R10 is independently selected from H and Ci-6alkyl; or R9 and R10, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14h;
each R11 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R12 is independently selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R141;
each R13 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R14a, R14b, R14c, R14d, R14e, R14f, R14g, R14h, R14i, R14j, R14k, R141, R14m, and R14n are each independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, -CH2-C3-6Cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6. loaryl, -CH2-C6.10aiyl, Ci-9heteroaryl, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, - S(0)2N(R16)(R17), and -0C(0)R19, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6. l0aryl, -CH2-C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci.
ealkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), - C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), -N(R18)C(0)0R19, - N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and - 0C(0)R19;
each R15 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl;
each R16 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl;
each R17 is independently selected from H and Ci-6alkyl; or R16 and R17, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring;
each R18 is independently selected from H and Ci-6alkyl;
each R19 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, C2- gheterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl;
R20 is selected from H and Ci-6alkyl;
R21 is selected from H and Ci-6alkyl; R22 is selected from Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6-l0aryl, and Ci-9heteroaryl, wherein C2-6alkenyl, C2-6alkynyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R14j;
R 23 is selected from H and Ci-6alkyl; or R 22 and R 23 together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14k;
R24 is selected from H, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141;
R is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or R and R together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R14m;
R26 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6Cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14n;
n is 0, 1, 2, 3, or 4; and
p is 0 or 1;
or a pharmaceutically acceptable salt or solvate thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -R1.
3. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -iAR1.
4. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -iAR1.
5. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is iAlAR1.
6. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -iAlAR1.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate
thereof, wherein L1 is -0-.
8 The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate
thereof, wherein L1 is -CH2-.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci. 6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -R14a, - OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, - N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12.
10. The compound of any one of claims 1-9, wherein R1 is a saturated monocyclic C2- 7heterocycloalkyl selected from pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,
tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,
homopiperidinyl, hexahydropyrimidinyl, oxepanyl, thiepanyl, azapanyl, and azocanyl, wherein pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, hexahydropyrimidinyl, oxepanyl, thiepanyl, azapanyl, and azocanyl are optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, - S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12.
11. The compound of any one of claims 1-10, wherein R1 is a saturated monocyclic C2- 7heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, azetidinyl, and tetrahydropyranyl, wherein pyrrolidinyl, piperidinyl, morpholinyl, homomorpholinyl, thiomorpholinyl, piperazinyl, azetidinyl, and tetrahydropyranyl are optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)0R9, - C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12.
12. The compound of any one of claims 1-11, wherein R1 is piperidinyl optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci. 6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -R14a, - OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, - N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12.
13. The compound of claim 2 or 12, or a pharmaceutically acceptable salt or solvate thereof,
having the structure of Formula (la):
Figure imgf000242_0001
Formula (la).
14. The compound of claim 13, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (la’):
Figure imgf000242_0002
Formula (la’).
15. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate
thereof, wherein R1 is a saturated bridged bicyclic C2-9heterocycloalkyl, wherein the saturated bridged bicyclic C2-9heterocycloalkyl is optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), - N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, - S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12.
16. The compound of claim 2 or 15, or a pharmaceutically acceptable salt or solvate thereof,
having the structure of Formula (Iaa):
Figure imgf000242_0003
Formula (Iaa); wherein L3 is -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2N(H)CH2-, or -CH2N(CH3)CH2-, and q is 0, 1, or 2.
17. The compound of claim 16, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Iaa’):
Figure imgf000243_0001
Formula (Iaa’).
18. The compound of claim 2 or 15, or a pharmaceutically acceptable salt or solvate thereof,
having the structure of Formula (lab):
Figure imgf000243_0002
Formula (lab);
wherein L3 is -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2N(H)CH2-, or -CH2N(CH3)CH2-, and q is 0, 1, or 2.
19. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (lab’):
Figure imgf000243_0003
Formula (lab’).
20. The compound of claim 2 or 15, or a pharmaceutically acceptable salt or solvate thereof,
having the structure of Formula (lac):
Figure imgf000244_0001
Formula (lac);
wherein L3 is -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2N(H)CH2-, or -CH2N(CH3)CH2-, and q is 0, 1, or 2.
21. The compound of claim 20, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (lac’):
Figure imgf000244_0002
Formula (lac’).
22. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate
Figure imgf000244_0003
23. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate
thereof, wherein R1 is a saturated spirocyclic C2-9heterocycloalkyl, wherein the saturated spirocyclic C2-9heterocycloalkyl is optionally substituted with one, two, or three Rla and each Rla is independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.10aiyl, Ci-9heteroaryl, -R14a, -OR8, -SR8, -N(R9)(R10), -C(0)0R9, - C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), - N(Ru)C(0)0R12, -N(Ru)C(0)R12, -N(Ru)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, - S(0)2N(R9)(R10), and -0C(0)R12.
24. The compound of claim 2 or 23, or a pharmaceutically acceptable salt or solvate thereof,
having the structure of Formula (lad):
Figure imgf000245_0001
Formula (lad);
wherein w1, w2, w3, and w4 are each independently selected from 1 and 2.
25. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (lad’):
Figure imgf000245_0002
Formula (lad’).
26. The compound of claim 4, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Iae):
Figure imgf000245_0003
Formula (Iae);
wherein R1 is a saturated monocyclic C2-7heterocycloalkyl optionally substituted with one, two, three, four, or five Rla and each Rla is independently selected from halogen, oxo, -CN, Ci. 6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -R14a, - OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, - N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12.
27. The compound of claim 26, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Iae’):
Figure imgf000245_0004
Formula (Iae’).
28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein each Rla is independently selected from oxo, Ci-6alkyl, Ci-9heteroaryl, -R14a, - C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), -C(0)R12, and -S(0)2R12.
29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein each Rla is independently selected from oxo, Ci-6alkyl, and -C(0)R12.
30. The compound of any one of claims 1-8 and 26-28, or a pharmaceutically acceptable salt or
solvate thereof, wherein
Figure imgf000246_0001
Figure imgf000246_0002
31. The compound of any one of claims 1-8 and 26-28, or a pharmaceutically acceptable salt or
solvate thereof, wherein
Figure imgf000246_0003
Figure imgf000247_0001
32. The compound of any one of claims 1-8 and 26-27, or a pharmaceutically acceptable salt or solvate thereof, wherein
Figure imgf000247_0002
Figure imgf000247_0003
33. The compound of any one of claims 1-8 and 26-27, or a pharmaceutically acceptable salt or
solvate thereof, wherein
Figure imgf000248_0001
Figure imgf000248_0002
34. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate
thereof, wherein
Figure imgf000248_0003
each Rlb is independently selected from H, halogen, -
CN, Ci-6alkyl, Ci-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6.l0aryl, Ci-9heteroaryl, R14a, -OR8, -SR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)C(0)N(R9)(R10), - OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, -N(RU)C(0)R12, - N(RU)S(0)2R12, -C(0)R12, -S(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12.
35. The compound of claim 34, or a pharmaceutically acceptable salt or solvate thereof, wherein each Rlb is independently selected from H, halogen, -CN, Ci-6alkyl, Ci-6haloalkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, R14a, -OR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)R12, -S(0)2R12, and -S(0)2N(R9)(R10).
36. The compound of claim 35, or a pharmaceutically acceptable salt or solvate thereof, wherein each Rlb is independently selected from H, Ci-6alkyl, C3-6cycloalkyl, and R14a.
37. The compound of any one of claims 34-36, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ic):
Figure imgf000248_0004
Formula (Ic).
38. The compound of claim 37, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ic’):
Figure imgf000249_0001
Formula (Ic’).
39. The compound of any one of claims 34-38, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ie):
Figure imgf000249_0002
Formula (Ie).
40. The compound of claim 39, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ie’):
Figure imgf000249_0003
Formula (Ie’).
41. The compound of any one of claims 1-31 and 34-40, or a pharmaceutically acceptable salt or solvate thereof, wherein each R14a is independently selected from Ci-6alkyl, C2- gheterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6.l0aryl, Ci_9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci. ealkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -SR15, -N(R16)(R17), -C(0)0R16, - C(0)N(R16)(R17), -C(0)C(0)N(R16)(R17), -0C(0)N(R16)(R17), -N(R18)C(0)N(R16)(R17), - N(R18)C(0)0R19, -N(R18)C(0)R19, -N(R18)S(0)2R19, -C(0)R19, -S(0)2R19, -S(0)2N(R16)(R17), and -0C(0)R19.
42. The compound of claim 41, or a pharmaceutically acceptable salt or solvate thereof, wherein each R14a is independently selected from Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, C6-i0aryl, Ci.gheteroaryl, wherein Ci-6alkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -OR15, -N(R16)(R17), -C(0)0R16, -C(0)N(R16)(R17), -C(0)R19, -S(0)2R19, and -S(0)2N(R16)(R17).
43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt or solvate thereof, wherein each R9 is independently selected from H and Ci-6alkyl optionally substituted with one, two, or three R14g.
44. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein each R9 is independently selected from H and unsubstituted Ci-6alkyl.
45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof, wherein each R10 is H.
46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt or solvate thereof, wherein each R12 is independently selected from Ci-6alkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141.
47. The compound of claim 46, or a pharmaceutically acceptable salt or solvate thereof, wherein each R12 is independently selected from Ci-6alkyl and Ci-9heteroaryl, wherein Ci-6alkyl and Ci. 9heteroaryl are optionally substituted with one, two, or three R141.
48. The compound of claim 47, or a pharmaceutically acceptable salt or solvate thereof, wherein each R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141.
49. The compound of claim 48, or a pharmaceutically acceptable salt or solvate thereof, wherein each R12 is independently selected from Ci-6alkyl optionally substituted with one, two, or three R141 and each R141 is independently selected from -OH, -NH2, -N(H)CH3, OMe, and C02H.
50. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -R2.
51. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is -L2-R2.
52. The compound of claim 50 or claim 51, or a pharmaceutically acceptable salt or solvate
Figure imgf000250_0001
53. The compound of any one of claims 50-52, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -C(0)0R4, -0C(0)N(R4)(R5), -N(R6)C(0)N(R4)(R5), -N(R6)C(0)0R7, - N(R6)S(0)2R7, or -CH2C(0)N(R24)(R25).
54. The compound of any one of claims 50-53, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from H, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- l0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c.
55. The compound of any one of claims 50-54, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from H, Ci-6alkyl, and Ci-9heteroaryl, wherein Ci-6alkyl, and Ci-9heteroaryl are optionally substituted with one, two, or three R14c.
56. The compound of any one of claims 50-55, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is H.
57. The compound of any one of claims 50-53, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R14e.
58. The compound of claim 57, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from Ci-6alkyl, C6.l0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C6-i0aryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R14e.
59. The compound of claim 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is Ci-6alkyl optionally substituted with one, two, or three R14e.
60. The compound of any one of claims 50-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is H.
61. The compound of any one of claims 50-53, or a pharmaceutically acceptable salt or solvate thereof, wherein R24 is selected from H, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- l0aryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R141.
62. The compound of claim 61, or a pharmaceutically acceptable salt or solvate thereof, wherein R24 is selected from H and Ci-6alkyl optionally substituted with one, two, or three R141.
63. The compound of claim 61 or claim 62, or a pharmaceutically acceptable salt or solvate
thereof, wherein R25 is H.
64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, -CN, Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, Ci-9heteroaryl, -OR8, -SR8, -N(R9)(R10), - C(0)0R9, -C(0)N(R9)(R10), -OC(0)N(R9)(R10), -N(RU)C(0)N(R9)(R10), -N(RU)C(0)0R12, - N(Ru)C(0)R12, -N(RU)S(0)2R12, -C(0)R12, -S(0)2R12, -S(0)2N(R9)(R10), and -0C(0)R12, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-i0aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14b.
65. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, -CN, Ci-6alkyl, C2- 9heterocycloalkyl, Ci-9heteroaryl, -OR8, -N(R9)(R10), -C(0)0R9, -C(0)N(R9)(R10), -C(0)R12, - S(0)2R12, -S(0)2N(R9)(R10), wherein Ci-6alkyl, C2-9heterocycloalkyl, and Ci.gheteroaryl are optionally substituted with one, two, or three R14b.
66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3 is independently selected from halogen, -CN, Ci-6alkyl, -OR8, - N(R9)(R10), wherein Ci-6alkyl is optionally substituted with one, two, or three R14b.
67. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
68. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
69. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -0-.
71. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -S(0)2-.
72. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -CH2-.
73. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is H.
74. The compound of any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is Ci-6alkyl.
75. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is F.
76. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is Cl.
77. The compound of any one of claims 1-74 or a pharmaceutically acceptable salt or solvate thereof, wherein Z is H.
78. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
79. The compound of any one of claims 1-77, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.
80. A compound selected from:
Figure imgf000253_0001
pharmaceutically acceptable salt or solvate thereof.
81. A compound selected from:
Figure imgf000254_0001
IJ53
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
acceptable salt or solvate thereof.
82. A compound selected from:
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000260_0002
pharmaceutically acceptable salt or solvate thereof.
83. A compound selected from:
Figure imgf000260_0003
Figure imgf000261_0001
84. A pharmaceutical composition comprising a compound of any one of claims 1-83, or a
pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
85. The pharmaceutical composition of claim 84, wherein the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
86. The pharmaceutical composition of claim 84, wherein the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.
87. A method of treating or preventing a liver disease or condition in a mammal, comprising
administering to the mammal a compound of any one of claims 1-83, or a pharmaceutically acceptable salt or solvate thereof.
88. The method of claim 87, wherein the liver disease or condition is nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD).
89. The method of claim 87, wherein the liver disease or condition is nonalcoholic steatohepatitis (NASH).
90. The method of claim 87, wherein the liver disease or condition is nonalcoholic steatohepatitis (NASH) and is accompanied by liver fibrosis.
91. The method of claim 87, wherein the liver disease or condition is nonalcoholic steatohepatitis (NASH) without liver fibrosis.
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