WO2010090680A1 - Substituted oxindole cb2 agonists - Google Patents

Substituted oxindole cb2 agonists Download PDF

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Publication number
WO2010090680A1
WO2010090680A1 PCT/US2009/067981 US2009067981W WO2010090680A1 WO 2010090680 A1 WO2010090680 A1 WO 2010090680A1 US 2009067981 W US2009067981 W US 2009067981W WO 2010090680 A1 WO2010090680 A1 WO 2010090680A1
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Prior art keywords
dioxane
spiro
indol
cyclopropylmethyl
heteroaryl
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PCT/US2009/067981
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French (fr)
Inventor
Minsheng Zhang
Boyd Lynn Harrison
Charles J. Stanton Iii
Lisa Marie Havran
Dan Chaekoo Chong
Wayne Everett Childers
Steven Victor O'neil
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Wyeth Llc
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Publication of WO2010090680A1 publication Critical patent/WO2010090680A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • CBl and CB2 receptors two subtypes of the cannabinoid receptor, both belong to the G-protein- coupled receptor (GPCR) superfamily.
  • GPCR G-protein- coupled receptor
  • the CBl receptor is predominantly expressed in brain to mediate inhibition of transmitter release and affects many neurological and psychological phenomena, such as mood, appetite, emesis control, memory, spatial coordination muscle tone, and analgesia, as described by Goutopoulos et al., m the publication Pharmacol Ther (2002) 95:103.
  • the CB2 receptor is primarily expressed in immune cells to modulate immune response. Activation of the CB2 receptor is known to induce analgesic effects in inflammatory models involved in neurodegeneration diseases, and plays a role in the maintenance of bone density and progression of atherosclerotic lesions.
  • CB2 agonists are potential drug candidates for reducing pain (such as chronic inflammatory pain, post surgical pain, neuropathic pain, and bone pain) and for treating a host of diseases including osteoarthritis, atherosclerosis, osteoporosis, and cancer (e.g., glioma), as described by Malan et al., m the publication Pain (2001) 93:239. Accordingly, there is an ongoing need for new and improved compounds that modulate the CB2 receptor and can function as therapeutics for the treatment of various CB2 receptor-modulated diseases and disorders such as pain. The invented compounds disclosed herein provide a solution to this need.
  • the invention relates to a compound of Formula I:
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more of the above-described substituted oxindole compounds of the invention, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner.
  • the invention in another aspect, relates to a method of treating a CB2-mediated disorder by administering to a subject in need of this treatment a therapeutically effective amount of one or more of the compounds described above.
  • CB2-mediated disorders include, but are not limited to, pain (such as chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pam), osteoarthritis, atherosclerosis, osteoporosis, and cancer (e.g., glioma).
  • the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in therapy.
  • the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in the treatment of a CB2-mediated disorder such as pain (e.g., chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, or cancer (e.g., glioma).
  • a CB2-mediated disorder such as pain (e.g., chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, or cancer (e.g., glioma).
  • the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for use in the treatment of one or more CB2-mediated disorders.
  • the present invention provides substituted oxindole compounds, that function as CB2 agonists, of Formula I:
  • R 1 is selected from -(CH 2 ) n R a , -CH(OH)R a , -CH(OR b )R a , and -C(O)R a , or is selected from OR a , SR a , SOR a , SO 2 R" and NR a R b ;
  • R 2 and R 3 are independently selected from H, halogen, OH, 0R a , 0WR a , Ci -6 alkyl, and WCi -6 alkyl, wherein Ci_ 6 alkyl or 0R a , is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3 _ 8 cycloalkyl, C 6 .io aryl and C 4 _io heteroaryl; or R 2 and R 3 , together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 .
  • R 4 is independently selected from H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 - I o aryl, C 4 _i 0 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone and -(CH 2 ) n -Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, Ci. 6 haloalkyl, C 3 .
  • R a and R b are independently selected from H, Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 2 _ 6 alkenyl, C 2 . 6 alkynyl, C 6- io aryl, C 4 . 10 heteroaryl, C 3 . 8 cycloalkyl, C 3 . 8 heterocycloalkyl, C 3 . 8 heterocycloalkenyl C 7 - 14 arylalkyl, C 4 .
  • halogen is selected from F, Cl, Br and I; and at each occurrence, n is 0, 1, 2, or 3.
  • the invented compounds selected from: 5'-benzoyl-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(2-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 1'- (cyclopropylmethyl)-5'-(3-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(4-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[2-(trime), 1,3
  • the invented compounds are certain substituted oxindole compounds of Formula I:
  • R 1 is selected from -Y-R a , -Y-Cy and -Y-Ar;
  • Y is a divalent carbon radical selected from -(CH 2 ) n -, -CH(OH)-, -CH(OR a )-, and -C(O)-, or Y is a heteroatom selected from O, S, SO, SO 2 and NR a R b ;
  • Ar is independently selected from C 6 .io aryl, C 4 . 10 heteroaryl, C 7 . 14 arylalkyl and C 4 . 14 heteroarylalkyl, wherein each of said C ⁇ -io aryl, C 440 heteroaryl, C 744 arylalkyl or C 444 heteroarylalkyl is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , 0R a -W, C 1 - 5 alkyl, C w W-alkyl, C w haloalkyl, C 3 . 8 cycloalkyl, C 3 . 8 W-cycloalkyl, -C(O)-CL 6 alkyl, - C(0)-C 6 _io aryl, C 6 _i 0 aryl and C4.10 heteroaryl;
  • Cy is independently selected from C 3 . 8 cycloalkyl, C 3 _ 8 heterocycloalkyl, C 3 . 8 heterocycloalkenyl, C 4 . 12 W-cycloalkyl, C 4 . 12 W-heterocycloalkyl and C 3 . 8 W-heterocycloalkenyl, wherein each of said C 3 . ? cycloalkyl, C 3 . 8 heterocycloalkyl, C 3 . 8 heterocycloalkenyl, C 4 . 12 W-cycloalkyl, C 4 _i 2 W-heterocycloalkyl or C 3 .
  • W-heterocycloalkenyl is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , 0R a -W, C M alkyl, C w W-alkyl, d. 6 haloalkyl, C 3 . 8 cycloalkyl, C 3 . 8 W- cycloalkyl, -C(O)-Ci. 6 alkyl, -C(O)-Ce- I o aryl, C 6 _io aryl and C 4 . 10 heteroaryl; at each occurrence W is a linker selected from -(CH 2 ) n - and -C(O)-;
  • R 2 and R 3 are independently selected from H, halogen, OH, 0R a , 0R a -W, Ci -6 alkyl, Ci. 6 W-alkyl, wherein Ci_ 6 alkyl or 0R a , is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, Ci_s haloalkyl, C 3 . 8 cycloalkyl, C 6-I o aryl and C 4 .
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl or C 5 -C 7 oxy cycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci. 6 alkyl, Ci. 6 haloalkyl, C 3 . 8 cycloalkyl, C 6-I o aryl and C 4 . 10 heteroaryl;
  • R 4 is independently selected from H, Ci- 6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C 6 -Io aryl, C4-10 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone and -(CH 2 ) n -Ci_ 6 haloalkyl, wherein each of said Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6- io aryl, C 4 .
  • heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci. 6 alkyl, Ci. 6 haloalkyl, C 3 . 8 cycloalkyl, C 6-I o aryl and C 4 _io heteroaryl; at each occurrence, R a is independently selected from H, Ci_e alkyl, Ci.
  • Ci_ 6 haloalkyl C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ci_ 6 haloalkyl, C ⁇ -io aryl, C 4 . 10 heteroaryl, C 3 . 8 cycloalkyl, C 3 _ 8 heterocycloalkyl, C 3 _ 8 heterocycloalkenyl C 7 _i 4 arylalkyl, C 4 _i 4 heteroarylalkyl, C 5- ⁇ cycloalkylalkyl and C 5- ⁇ heterocycloalkylalkyl, wherein said Ci -6 alkyl, Ci -6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C ⁇ -io aryl, C4-10 heteroaryl, C 3 .
  • the invented compounds are substituted oxindole compounds of Formula I:
  • R 1 is selected from -(CH 2 ) n R a , -CH(OH)R a , -CH(OR b )R a , and -C(O)R a , or is selected from OR a , SR a , SOR a , SO 2 R a and NR a R b ;
  • R 2 and R 3 are independently selected from H, halogen, OH, OR a , 0WR a , Ci -6 alkyl, and WCi -6 alkyl, wherein Ci_ 6 alkyl or OR a , is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, OR a , Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3 . 8 cycloalkyl, C 6 .io aryl and C 4 .
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, Ci_ 6 haloalkyl, C 3 . 8 cycloalkyl, C 6-I o aryl and C4.10 heteroaryl;
  • R 4 is independently selected from H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 - I o aryl, C 4 _i 0 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone and -(CH 2 ) n -Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, OR a , Ci -6 alkyl, Ci. 6 haloalkyl, C 3 .
  • R a and R b are independently selected from H, Ci -6 alkyl, Ci -6 haloalkyl, C 2 - 6 alkenyl, C 2 . 6 alkynyl, C 6- io aryl, C 4 . 10 heteroaryl, C 3 . 8 cycloalkyl, C 3-8 heterocycloalkyl, C 3-8 heterocycloalkenyl C 7 - 14 arylalkyl, C 4 .
  • halogen is selected from F, Cl, Br and I; and at each occurrence, n is 0, 1, 2, or 3.
  • R 1 is -N(R a )R b ;
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxy cycloalkyl, C 5 . 7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, OR a , Ci_ 6 alkyl, C 3 . 8 cycloalkyl, C 6 .io aryl and C 4 .
  • R 4 is independently selected from H, Ci - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 3 . 8 cycloalkyl, WC 3 . 8 cycloalkyl, C 6 .
  • w aryl C 4-I0 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone and -(CH 2 ) n -Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, OR a , Ci_ 6 alkyl, C 3 . 8 cycloalkyl, C 6 .io aryl and C 4-I o heteroaryl.
  • R 1 is -N(R a )R b and at least one of R a and R b are hydrogen or R a and R b , together with the N atom to which they are attached, join to form a 4-6 memebered heterocycloalkyl ring.
  • R 1 is a methylene radical -(CH 2 ) n - further attached to substituents selected from C ⁇ -io aryl, C 4-I0 heteroaryl, benzodioxanyl, oxazolidinonyl, -(CH 2 ) n -Ci_ 6 haloalkyl, C 3 . 8 cycloalkyl and Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, OR a , Ci_ 6 alkyl, and Ci_ 6 haloalkyl, C 3 . 8 cycloalkyl, WC 3 . 8 cycloalkyl, C 6 . 10 aryl and C 4 . 10 heteroaryl.
  • R 1 is -OR a ;
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 - C 7 oxy cycloalkyl, Cs_ 7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, C 3 .
  • R 4 is independently selected from H, Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 _i 0 aryl, C 6- I 0 heteroaryl, -(CH2) n -benzodioxane, -(C ⁇ ) n - oxazolidinone, -(CH2) n -Ci_6 haloalkyl, -(C ⁇ ) n - C 3 .
  • Ci_ 6 haloalkyl each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 . 8 cycloalkyl, C 6-I0 aryl and C 4-I0 heteroaryl.
  • R 1 is -0-, substituted with substituents selected from d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6-I0 aryl, C 4-I0 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n -oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 .
  • R 4 is independently selected from H, Cr 6 alkyl, C 6-I0 aryl, C 4-I0 heteroaryl, -(C ⁇ ) n - C 3 . 8 cycloalkyl, -(C ⁇ ) n - C 3 . 8 heterocycloalkyl, -(C ⁇ ) n - Ci -6 haloalkyl, -(CH 2 ) n - and Ci -6 haloalkyl.
  • R 1 is -SR a ;
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 - C 7 oxy cycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, OR a , Ci_6 alkyl, C3-8 cycloalkyl, C ⁇ -io aryl and C 4 .
  • R 4 is independently selected from H, d-e alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 -io aryl, C 4 . 10 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone, -(CH 2 ) n -Ci_ 6 haloalkyl, -(CH 2 ) n - C 3 .
  • R 1 is -S-, substituted with substituents selected from Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C ⁇ -io aryl, C 4 . 10 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 Voxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a , Ci- 6 alkyl, C 3 . 5 cycloalkyl, C 6- io aryl and C 4 .
  • R 4 is independently selected from H, Ci- 6 alkyl, C 6 _io aryl, C 4 . 10 heteroaryl, -(CH 2 ) n - C 3 . 8 cycloalkyl, -(CH 2 ) n - C 3 . 8 heterocycloalkyl, -(CH 2 V Ci -6 haloalkyl, -(CH 2 ) n - and Q -6 haloalkyl.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, C 3 . 8 cycloalkyl, C 6 .io aryl and C 4 .
  • R 4 is independently selected from H, Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 -Io aryl, C 4 _io heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ),,- oxazolidinone, -(CH 2 ) n -Ci_ 6 haloalkyl, - (CH 2 ) n - C 3 _ 8 cycloalkyl and Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 . 8 cycloalkyl, C 6 _i 0 aryl and C4-10 heteroaryl.
  • R 4 is independently selected from H, C r6 alkyl, C 6 _i 0 aryl, C 4 - I0 heteroaryl, -(CHz) n - C 3 _ 8 cycloalkyl, -(CH 2 V C 3 _ 8 heterocycloalkyl, -(CH 2 V Ci -6 haloalkyl, -(CH 2 V and Ci -6 haloalkyl.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 .
  • R 4 is independently selected from H, Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6- io aryl, C4.10 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 V oxazolidinone, -(CH 2 V C 1 - 6 haloalkyl, -(CH 2 ) n - C 3 .
  • Ci -6 haloalkyl each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, C 3 _ 8 cycloalkyl, C 6 - I o aryl and C 4 . 10 heteroaryl.
  • R 4 is independently selected from H, Ci-6 alkyl, C 6 _io aryl, C4.10 heteroaryl, -(CH 2 V C3.8 cycloalkyl, -(CH 2 ) n - C3.8 heterocycloalkyl, -(CH 2 ) n - Ci- 6 haloalkyl, -(CH 2 ) n - and Ci_ 6 haloalkyl.
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 . 8 cycloalkyl, C 6 -io aryl and C 4 .
  • R 4 is independently selected from H, Ci - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 _io aryl, C 4 _io heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 V oxazolidinone, -(CH 2 ) n -Ci_ 6 haloalkyl, - (CH 2 V C 3 - 8 cycloalkyl and Ci_ 6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci_ 6 alkyl, C 3 . 8 cycloalkyl, C 6 _i 0 aryl and C4.10 heteroaryl.
  • R 4 is independently selected from H, Cr 6 alkyl, C 640 aryl, C 4 - 10 heteroaryl, -(CH 2 V C 3 . 8 cycloalkyl, -(CH 2 V C 3 . 8 heterocycloalkyl, -(CH 2 ) n - Ci. 6 haloalkyl, -(CH 2 V and Ci_ 6 haloalkyl.
  • R 4 is -(CH 2 ) n -C 3 . 7 cycloalkyl or C 6- io aryl and C 4-I0 heteroaryl, wherein each of C 6 _io aryl and C 4- I 0 heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, 0R a , Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6- I 0 aryl, C 640 heteroaryl, -(CH 2 VCi -6 haloalkyl, -(CH 2 V, Ci -6 haloalkyl, C 3 . 8 cycloalkyl, C 6-I0 aryl and C 6-I0 heteroaryl.
  • R 4 is -(CH 2 )-cyclopropyl, 0R a , C 6 -I 0 aryl, C 4- I 0 heteroaryl, substituted C 6 -I 0 aryl, or substituted C 4-I0 heteroaryl.
  • R 4 is C 6-I0 aryl or C 6-I0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a and Ci -6 alkyl.
  • R a is Ci -6 haloalkyl.
  • halogen or halogen OfCi -6 haloalkyl is fluoro. 20.
  • R a is CF 3 or OCF 3 .
  • R 1 is -CH(0H)R a ;
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 . 8 cycloalkyl, C 6- I 0 aryl and C 4 .
  • R 4 is independently selected from H, Ci - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 -Io aryl, C 4 _io heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 V oxazolidinone, -(CH 2 ) n -Ci.
  • Ci -6 haloalkyl - (CH 2 ) n - C 3 _ 8 cycloalkyl and Ci -6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, OR a , Ci_ 6 alkyl, C3-8 cycloalkyl, C 6- I 0 aryl and C4.10 heteroaryl.
  • R 1 is -CH(OH)-, substituted with substituents selected from Cr 6 alkyl, C 2 - 6 alkenyl, C 2 -e alkynyl, C 6 _io aryl, C 4 .
  • R 4 is -(CH 2 ) n -C 3 . 7 cycloalkyl, C 6 _i 0 aryl or C 4-I0 heteroaryl, wherein each of C 6-I o aryl and C 4-I0 heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, 0R a , Cr 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6-I0 aryl, C 6 .
  • R 4 is -(CH 2 )-cyclopropyl, 0R a , C 6-I0 aryl, C 4-I0 heteroaryl, substituted C 6-I0 aryl, or substituted C 4-I0 heteroaryl.
  • R 4 is C 6- io aryl or C 6-I0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a and Ci -6 alkyl.
  • R a is Ci -6 haloalkyl.
  • halogen or halogen OfCi -6 haloalkyl is fluoro.
  • R a is CF 3 or OCF 3 .
  • R 1 is -CH(OR b )R a ;
  • R 2 and R 3 together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 -C 7 oxycycloalkyl, C 5 . 7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 .
  • R 4 is independently selected from H, Ci - 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 .io aryl, C4.10 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 V oxazolidinone, -(CH 2 VCi -6 haloalkyl, - (CH 2 V C 3 _ 8 cycloalkyl and Ci -6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 . 8 cycloalkyl, C 6-I0 aryl and C 4-I0 heteroaryl.
  • R 1 is -CH(OR a )-, substituted with substituents selected from d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6-I0 aryl, C 4- io heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n -oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a , Ci -6 alkyl, C 3 .
  • R 4 is independently selected from H, Cr 6 alkyl, C 6-I0 aryl, C 4-I0 heteroaryl, -(CH 2 V C 3 . 8 cycloalkyl, -(CH 2 V C 3 . 8 heterocycloalkyl, -(CH 2 ) n - Ci -6 haloalkyl, -(CH 2 V and Ci -6 haloalkyl.
  • R 1 is -(CH 2 V; R 2 and R 3 , together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C 5 - C 7 oxy cycloalkyl, C 5 . 7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, OR a , Ci_6 alkyl, C3-8 cycloalkyl, C 6- I 0 aryl and C 4 .
  • R 4 is independently selected from H, d-e alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6 -io aryl, C 4 _io heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 ) n - oxazolidinone, -(CH 2 ) n -Ci_ 6 haloalkyl, -(CH 2 ) n - C 3 .
  • R 1 is -(CH 2 ) n -, substituted with substituents selected from Ci - 6 alkyl, C 2 -e alkenyl, C 2 - 6 alkynyl, C ⁇ -io aryl, C 4-I0 heteroaryl, -(CH 2 ) n -benzodioxane, -(CH 2 Voxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a , Ci- 6 alkyl, C 3 .
  • R 4 is independently selected from H, Ci- 6 alkyl, C 6-I0 aryl, C 4 . 10 heteroaryl, -(CH 2 ) n - C 3 _ 8 cycloalkyl, -(CH 2 ) n - C 3 _ 8 heterocycloalkyl, -(CH 2 V Ci -6 haloalkyl, -(CH 2 ) n - and Q -6 haloalkyl.
  • R 4 is -(CH 2 ) n -C 3 . 7 cycloalkyl or C 6 -io aryl and C 6 -io heteroaryl, wherein each of C 6-I0 aryl and C 6-I0 heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, 0R a , Ci- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, C 6-I0 aryl, C 4-I0 heteroaryl, -(CH 2 VCi -6 haloalkyl, -(CH 2 V, Ci_ 6 haloalkyl, C 3 . 8 cycloalkyl, C 6-I0 aryl and C 4 _i 0 heteroaryl.
  • R 4 is -(CH 2 )-cyclopropyl, 0R a , C 6-I0 aryl, C 4-I0 heteroaryl, substituted C 6 .io aryl, or substituted C 4-I0 heteroaryl.
  • R 4 is C 6-I0 aryl or C 4-I0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0R a and Ci -6 alkyl.
  • R a is Ci -6 haloalkyl.
  • halogen or halogen of Ci -6 haloalkyl is fluoro.
  • R a is CF 3 or OCF 3 .
  • substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci -6 alkyl” is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • the compounds of the invention are stable. As used herein "stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
  • alkyl is meant to refer to a saturated hydrocarbon group, which is straight-chained or branched.
  • Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n- propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
  • alkenyl refers to an alkyl group having one or more double carbon-carbon bonds.
  • Example alkenyl groups include ethenyl, propenyl, and the like.
  • alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds.
  • Example alkynyl groups include ethynyl, propynyl, and the like.
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 , and the like.
  • aryl refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups comprise from 6 to about 20 carbon atoms, including comprising from 6 to 10 carbon atoms.
  • arylalkyl refers to an alkyl group substituted by an aryl group.
  • Examplary arylalkyl groups include, but are not limited to, benzyl and phenethyl.
  • cycloalkyl refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles.
  • cycloalkyl groups comprise from 3 to 20 carbon atoms, including comprising from 3 to 14 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms or 3 to 6 carbon atoms. Cycloalkyl groups can further comprise 0, 1 or 2 double bonds and'or 0, 1, or 2 triple bonds.
  • cycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like.
  • a cycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion.
  • One or more ring- forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent.
  • Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
  • cycloalkylalkyl refers to an alkyl group substituted by a cycloalkyl group.
  • An examplary cycloalkylalkyl group includes, but is not limited to cyclopentylmethyl and cyclohexylmethyl.
  • heteroaryl refers to an aromatic heterocycle comprising at least one heteroatom ring member selected from sulfur, oxygen and nitrogen.
  • Heteroaryl groups include monocyclic and fused, polycyclic (e.g., heteroaryl comprising 2, 3 or 4 fused rings) systems. Any ring- forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety or can be functionalized to form an N-functionalized group (e.g. N-alkyl or N-aryl).
  • heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazmyl, furyl, quinolyl, isoquinolyl, thienyl, lmidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purmyl, carbazolyl, benzimidazolyl, indolinyl, and the like.
  • the heteroaryl group comprises from 3 to 20 carbon atoms, and in further embodiments comprises from about 4 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 6 to about 10 ring-forming atoms. In some embodiments, the heteroaryl group comprises from 1 to 4 heteroatoms, including comprising from 1 to 3 heteroatoms or 1 to 2 heteroatoms.
  • heteroarylalkyl refers to an alkyl group substituted by a heteroaryl group.
  • An example of a heteroarylalkyl group is pyridylmethyl.
  • heterocycloalkyl refers to a non-aromatic heterocycle where one or more of the ring-forming atoms comprises a heteroatom selected from O, N and S.
  • heterocycloalkenyl refers to a partially-unsaturated heterocycle or a heterocycle comprising at least one unsaturated bonding of carbon atoms or carbon and heteroatoms, where one or more of the ring- forming atoms comprises a heteroatom selected from O, N and S.
  • Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles.
  • heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholmo, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidmyl, thiazolidinyl, imidazolidinyl, and the like.
  • heterocycloalkyl moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles.
  • a heterocycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non- aromatic portion.
  • moieties where one or more ring-forming atoms is substituted by 1 or 2 oxo or sulfido groups.
  • the heterocycloalkyl group comprises from 4 to 20 carbon atoms, and in further embodiments from 5 to 10 carbon atoms. In some embodiments, the heterocycloalkyl group comprises 5 to 20, 5 to 14, 5 to 12, or 5 to 10 ring-forming atoms. In some embodiments, the heterocycloalkyl group further comprises 1 to 4 heteroatoms, including comprising from 1 to 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group further comprises 0 to 2 double bonds. In some embodiments, the heterocycloalkyl group comprises 0 to 2 triple bonds.
  • heterocycloalkylalkyl refers to an alkyl group substituted by a heterocycloalkyl group.
  • halo or halogen includes fluoro, chloro, bromo, and iodo.
  • haloalkyl refers to an alkyl group substituted by one or more halogen atoms.
  • haloalkyl groups examples include CF3 and CF 2 CF3.
  • alkoxy refers to an -O-alkyl group.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present invention that comprise asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1,2,4-triazole, IH- and 2H- isoindole, and IH- and 2H- pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • compound as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted.
  • the compounds of the invention, and salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions comprising at least 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which comprises a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the compounds of the present invention can be prepared from readily available starting materials in a variety of ways known to one skilled in the art of organic synthesis. For example, they can be synthesized via the reaction pathways and techniques as described below.
  • Certain invented benzyl amine compounds 5 were prepared according to Scheme 1.
  • 5-Nitroisatin (1) was converted to the corresponding cyclic acetal 2 using 1,3 -propanediol and/>-TsOH in benzene.
  • Alkylation of the oxindole nitrogen with organohalides produced nitro acetal compound 3.
  • Reduction of the NO 2 group to the corresponding amine compound 4 was accomplished by catalytic hydrogenation using H 2 A 0% Pd/C.
  • Functionalization of the amine 4 with benzaldehydes under reductive amination conditions produced invented benzyl amine compounds 5.
  • Scheme 2
  • Certain invented 5 -Aryl amine compounds 6 were prepared from amine compounds 4 using aryl boronic acids, copper acetate, amine bases such as Et 3 N in aprotic solvents, such as CH2CI2, as summarized in Scheme 2.
  • Certain invented disubstituted amino compounds were prepared according to Scheme 3.
  • Amine compound 4 was protected as the trifluoroacetamide compound 7 by treatment with trifluoroacetic anhydride and Et 3 N in CH 2 CI 2 .
  • Alkylation of the nitrogen of compound 7 with organohalides produced compound 8, which can be deprotected under basic conditions to provide deprotected compound 9.
  • Invented compounds (10) were then prepared from aryl boronic acids, copper acetate, amine bases such as Et 3 N in aprotic solvents such as CH2CI2.
  • Certain invented sulfides, sulfoxides and sulfone compounds (17 and 19, respectively) were prepared according to Scheme 5.
  • 5-Iodo-isatin (14) was converted to the corresponding cyclic acetal compounds 15 using 1,3 -propanediol or ethylene glycol and/?-TsOH in benzene with heating.
  • Aryl sulfide compounds 16 were prepared from corresponding compounds 15 using aryl thiols, in the presence of CuI and ethylene glycol in isopropanol (Org Lett. 2002, 4, 3517) or CoCl 2 (dppe), zinc and pyridine in acetonitrile (Org. Lett 2006, 8, 5613).
  • N-Alkyl oxmdole compounds 17 or 19, respectively were prepared from corresponding compounds 16 or 18 using organohahdes and K 2 CO 3 in DMF with heating.
  • Corresponding N-Aryl oxmdole compounds 17 or 19 were prepared from respective compounds 16 or 18 using aryl boronic acids, copper acetate, amine bases such as EtrN in aprotic solvents such as CH 2 Cl 2 .
  • TIP S -protected thiol compounds 20 were prepared from protected 5-iodoisatin compound 15 by the treatment with appropriate triisopropylthiols, KH and Pd(PPl ⁇ ) 4 in THF (J.Med. Chem. 2001, 44, 4393).
  • Aryl sulfide compounds were prepared from compound 20 using appropriate aryl iodides in the presence of CuI and ethylene glycol in isopropanol. Oxidation, arylation or alkylation to respective compounds 17 or 19, can be accomplished, as summarized in Scheme 5.
  • 5-Aryl ether compounds (25) were prepared according to the procedure of Scheme 7.
  • 5-methoxyisatin (20) was converted to compound 22 via alkylation with cyclopropylmethyl bromide followed by demethylation of compound 21 with boron tribromide in dichloromethane.
  • Compound 22 was then converted to compound 23 with 1,3 -propanediol and j>-TsOH in toluene.
  • Reaction of compound 23 with an iodonium tetrafluoroborate salt (24) in presence of copper and triethylamine in dichloromethane produced invented 5-Aryl ether compounds 25.
  • reaction of compound 23 with a substituted fluoropyridine (27) in presence of cesium carbonate in dichloromethane also produced other invented 5-Aryl ether compounds (26).
  • Certain invented substituted oxmdole compounds (32) were prepared according to the procedure of Scheme 8. Thus 5-iodoisatm (27) was converted to acetal compound (28) with 1,3-propanediol an ⁇ p- TsOH m toluene. Alkylation of Nl was accomplished using organohalides with CS 2 CO 3 m DMF at 60 0 C, and produced N-functionalized ketone componds (29). Carbonylation of N-functionalized compounds 29 in presence of substituted boronic acid, carbon monoxide and dichloro-bis- triphenylphosphinepallidium in toluene produced ketone compounds (30). Sodium borohydride reduction of ketone compounds 30 produced hydroxyl compounds (31). Deoxygenation of hydroxyl compounds 31 with triethylsilane and trifluoroacetic acid in dichloromethane produced methylene bridged compounds (32).
  • oxindole compounds 38 were synthesized by reaction of N-functionalized compounds 33 with an appropriate borate 37 in DMF in presence of tetrakis(triphenylphosphine)palladium and sodium carbonate. Subsequent catalytic hydrogenation of the alkene group in compound 38 in a Parr apparatus at 40 psi of hydrogen produced the other invented 1, 3, 5-substituted oxindole compounds 39.
  • Conventional synthetic reagents and conditions were employed in accordance with methods for preparing compounds of the invention. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, however, alteration of such conditions may be determined and adjusted by persons skilled in the art.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • HPLC high performance liquid chromatograpy
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection of certain functional groups attached to the oxoindole core of the invented compounds, and selection of appropriate protecting groups may be determined by one skilled in the art.
  • the chemistry of protecting groups is described, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991.
  • Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures, which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art.
  • An example method includes fractional recrystallization using a "chiral resolving acid" which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The selection of a suitable elution solvent composition may be determined by one skilled in the art.
  • Compounds of this invention are able to interact with the CB2 receptor and therefore modulate the receptor's activity.
  • modulate is meant to refer to an ability to increase or decrease activity of an the receptor. Modulation can occur in vitro or in vivo. Modulation can further occur in a cell. Accordingly, compounds of the invention can be used in methods of modulating the activity of the CB2 receptor, by contacting the receptor with one or more of the compounds or compositions described herein. As used herein, the term “contacting” refers to bringing together of indicated moieties in an in vitro system or an in vivo system.
  • contacting includes the administration of a compound of the present invention to an individual or patient, such as a human, as well as, for example, introducing a compound of the invention into a sample comprising a cellular or purified preparation of the receptor.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the compounds of the present invention can act as CB2 receptor agonists.
  • these compounds can be used to treat CB2-mediated disorders, such as CB2 agonists are potential drug candidates for reducing treating pain (e.g., chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, and cancer (e.g., glioma).
  • the treatment includes administration of a therapeutically effective amount of one or more of the invented 3-substituted oxindole compounds described above to a patient in need thereof.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • the term "treating" or “treatment” refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • Examplary cancers treatable by the invented compounds herein include, but are not limited to, glioma, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, cancer of the kidney, liver cancer, lung cancer, nasopharygeal cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, MFH/fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma, multiple myeloma, lymphoma, adult T cell leukemia, acute myelogenous leukemia, chronic myeloid leukemia, glioblastoma, astrocytoma, melanoma, mesothelioma, or WiIm' s tumor, and the like.
  • One or more additional pharmaceutical agents or treatment methods can be used in combination with the compounds of the present invention for treatment of the diseases, disorders or conditions described herein.
  • one or more of the above-described 3-substituted oxindole compounds can be used together with an anti-inflammatory agent, an anti-cancer agent, an analgesic, or other therapeutic agent useful in treating pain, cancer, osteoarthritis, atherosclerosis, osteoporosis or other disease.
  • the agents or therapies can be administered together -with the compounds of the invention (e.g., combined into a single dosage form), or the agents or therapies and may be administered simultaneously or sequentially by separate routes of administration.
  • the compounds of the invention can be administered in the form of pharmaceutical compositions, which is a combination of a compound of the invention, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral.
  • Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which comprise, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments comprising, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to an average particle size of less than 200 mesh. If the active compound is substantially water- soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. an average particle size of about 40 mesh.
  • the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by methods described in International Patent Application No. WO 2002/000196.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit comprising a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount.
  • the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above comprising from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may comprise suitable pharmaceutically acceptable excipients as described supra, and in some embodiments, the compositions are administered by an oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices, which deliver the formulation in an appropriate manner.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous earner prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution comprising about 0.1 to about 10% w/v (weight/volume) of the compound for parenteral adminstration. Some typical dose ranges are from about 1 mg/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • kits useful for example, in the treatment or prevention of diseases, such as pain or cancer and other diseases referred to herein, which include one or more containers comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt thereof.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and'or guidelines for mixing the components, can also be included in the kit.
  • Analytical LC/MS Samples were analyzed on an Agilent LC-1100-MSD.
  • the mass spectrometer utilized to confirm the integrity of the compound, was a single quadrapole mass filter scanning from 100-1000 Da.
  • the PDA used to assess compound purity, monitors 254, 215, 230, 280, and 300 nm wavelengths. The compound purity was reported at 254 nm unless stated otherwise.
  • the HPLC mobile phase flow rate was 0.8 ml/mm.
  • Eluent A was 0.1 % HCO 2 H in water and eluent B was 0.1 % HCO 2 H in ACN.
  • HPLC mobile phase gradient w r as initiated at 100% eluent A followed by a linear increase to 100% eluent B in 2.5 minutes. The gradient was held at 100% eluent B for an additional 1.5 minutes (total time 4.0 minutes). The HPLC rapidly equilibrated the column back to 100% eluent A for an additional 1.5 minutes for subsequent injections. The total HPLC/MS run time was 5.5 minutes. Compounds were diluted to ⁇ 1.0 mg/niL in DMSO. The analysis injection volume was 5 ⁇ L. The HPLC column used was a Thermo Electron Corporation, Aquasil Cl 8, 50 x 2.1 mm, 5 ⁇ m particle size. Preparative reverse-phase HPLC (RP-HPLC):
  • Step 2 r-(cyclopropylmethyl)-5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(r//)-one
  • reaction mixture was then stirred at 80° C and exposed to an atmosphere of carbon monoxide via a balloon. After stirring overnight, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, then washed with H 2 O, followed by brine. The organic layer was dried over Na 2 S ⁇ 4 , concentrated and purified by flash chromatography on silica gel to afford product as a white solid (0.7 Ig, 75%).
  • reaction mixture was then stirred at 80° C under an atomosphere of carbon monoxide via balloon. After stirring overnight, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, washed with H 2 O, then followed by brine. The organic layer was dried over Na 2 SO 4 , concentrated and purified by flash chromatography on silica gel to afford product as a white solid (0.22g, 72%).
  • Example 113 A procedure similar to that of Example 113, using different aryl boronic acids for the N-arylation described in step 1, and different aryl boronic acids for the carbonylation described in step 2, provided Examples 114-134.
  • the compounds and their analytical data are shown in Table 4.
  • Example 135 5'-[(2-fluorophenyl)(hydroxy)methyl]-r-phenylspiro[l,3-dioxane-2,3'-indol]-2'(r//)-one
  • Example 135 A procedure similar to that of Example 135, using Examples 114-134 (see Table 4), provided Examples 136-155. The compounds and their analytical data are shown in Table 5.
  • Example 156 A procedure similar to that of Example 156, using Examples 136-155, provided Examples 157- 175. The compounds and their analytical data are shown m Table 6.
  • reaction mixture was then stirred at 80° C under an atmosphere of carbon monoxide via balloon. After stirring overnight, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, then washed with H 2 O, followed by b ⁇ ne. The organic layer was dried over Na 2 S ⁇ 4 , concentrated and then purified by flash chromatography on silica gel to afford product as a brown solid (1.2Og, 43%).
  • reaction mixture was allowed to slowly warm to room temperature. After stirring overnight, TLC analysis indicated that reaction had neared completion, so reaction mixture was quenched with sat. NH 4 Cl and was stirred for 30 minutes. This mixture was then extracted with EtOAc, and organic layers were combined, washed with brine, dried over
  • Examples 186-200 were prepared from 5'-amino4'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2'(l ⁇ )-one and the appropriate aldehyde according to the procedure for Example 185.
  • the title compound (0.05Og, 48%) was prepared from 5'-amino-l'-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one using a procedure similar to that of Example 1, using 2 equivalents of cyclohexanecarbaldehyde in Step 4.
  • 1 H NMR 400 MHz, DMSO-d ⁇ : consistent; MS (ES + ) m/z (M+H).
  • Step 3 N-(I '-butyl-2 '-oxo-1 ',2 '-dihydrospiro[l,3-dioxane-2,3 '-indolJ-S '-yl)-2,2,2- trifluoro-N-methylacetamide
  • r-(Cyclopropylmethyl)-5'-[niethylammo]spiro[l,3-dioxane-2,3'-mdol]- 2'(l'H)-one was prepared from 5'-amino-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-mdol]-2'(rH)-one using a procedure similar to that of Example 198.
  • Step 2 5'-(Phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one
  • Step 2 5'-(Phenylthio)spiro[l,3-dioxolane-2,3'-indol]-2'(l'H)-one
  • Examples 214-216 were prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]- 2'(l'H)-one and the appropriate boronic acid according to the procedure for Example 203.
  • Table 8 Compounds Prepared According to the Procedure of Example 203
  • Examples 217-219 were prepared from 5'-(phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(l ⁇ )-one and the appropriate boronic acid according to the procedure for Example 203.
  • Examples 220-249 were prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l ⁇ )- on and the appropriate boronic acid according to the procedure for Example 203.
  • Examples 254-260 were prepared from 1 '-(cyclopropylmethyl)-5'-iodospiro[l ,3-dioxane-2,3'- indol]-2'(l'H)-one and the appropriate substituted thiopheols according to the procedure for Example 252, and oxidized to the sulfones according to the procedure for Example 253.
  • Examples 262-271 were prepared from l'-(cyclopropylmethyl)-5'-iodospiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one and the appropriate substituted thiophenols according to the procedure for Step 2 of Example 207, and oxidized to the sulfones according to the procedure for Example 208.
  • Table 12 Compounds Prepared According to the Procedure of Examples 207 and 208.
  • Examples 272-275 were prepared from l'-(cyclopropylmethyl)-5'-iodospiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one and the appropriate substituted thiophenols according to the procedure for Step 2 of Example 207.
  • Examples 277 and 278 were prepared from Example 273 and 275 respectively according to the procedure for Example 208.
  • Step 2 l '-fCyclopwpylmethyljS'-fpyridin-S-ylsulfanyljspirollJ-dioxane ⁇ J'-indolJ- 2'(l 'H)-one
  • Examples 280-294 were prepared from l'-(cyclopropylmethyl)-5'-
  • Examples 295-310 were prepared by oxidizing the corresponding sulfides (prepared in Examples ) according to the procedure for Example 208.
  • Step 2 1 '-(cyclopropylmethyl)-5'-hydroxyspiro[l,3-dioxane-2,3 '-indol]-2'(l 'H)-one
  • N-cyclopropylmethyl-5-methoxyisatin was dissolved in dichloromethane (60 mL), treated with neat boron tribromide (3.0 mL, 31.7 mmol) and stirred at ambient temperature for 1 hour.
  • the reaction mixture was diluted with dichloromethane ( 100 mL) and extracted from 1.0 N HCl. The organic layer was dried over sodium sulfate and then concentrated to dryness. The residue was dissolved in toluene (200 mL), treated with 1,3 -propanediol (6.O mL, 83.0 mmol) and toluenesulfonic acid (1.0 g, 5.25 mmol).
  • reaction mixture was loaded directly to a flash chromatography column and purified with ethyl acetate/hexanes (0-50% gradient elution) to provide 1'- (cyclopropylmethyl)-5'-(4-methoxyphenoxy) spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one (0.025 g, 18%) as a dark oil.
  • reaction mixture was loaded directly to a flash chromatography column and then purified with ethyl acetate/hexanes (0-50% gradient elution) to provide 1'- (cyclopropylmethyl)-5'-(phenoxy)spiro[l,3-dioxane-2,3'-indol]-2'(r/7)-one (107.0 mg, 42 %, dark oil).
  • Examples 314-318 were prepared from l '-(cyclopropylmethyl)-5'-hydroxyspiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one and the appropriately substituted 4-fTuoropyridines according to the procedure for Example 313.
  • Table 17 Compounds Prepared According to the Procedure of Example 313
  • Step l r-(2-Chloro-4-nitrophenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(r//)-one
  • Examples 330-335 were prepared from 5'-[(4-methoxyphenyl)thio]spiro[l ,3-dioxane-2,3'-mdol]-
  • Examples 336-341 were prepared from 5'-(py ⁇ dm-4-ylsulfonyl)spiro[l,3-dioxolane-2,3'-mdol]- T(VH)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized m Table 13.
  • Table 19 Compounds Prepared According to the Procedure of Example 179, step 2.
  • Examples 342-357 were prepared from 5'-[(4-methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l '//)-one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 20.
  • Examples 358-360 were prepared from 5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one and the appropriate trifluoromethoxy thiophenol using a procedure similar to that of Example 201, step 2 and summarized in Table 21.
  • Examples 361-363 were prepared from 5'- ⁇ [2-(trifluoromethoxy)phenyl]sulfanyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 22.
  • Examples 364-366 were prepared from 5'- ⁇ [3-(trifluoromethoxy)phenyl]sulfanyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 23.
  • Table 23 Compounds Prepared According to the Procedure of Example 179, step 2.
  • Examples 367-369 were prepared from 5'- ⁇ [4-(trifluoromethoxy)phenyl]sulfanyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(l ⁇ )- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 24.
  • Examples 373-378 were prepared from 5'- ⁇ [2-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(l 'H)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 26.
  • Examples 379-384 were prepared from 5'- ⁇ [3-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(l '//)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 27.
  • Examples 385-390 were prepared from 5'- ⁇ [4-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 28.
  • Examples 393-398 were prepared from 5'-[(3-fluorophenyl)sulfanyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 29.
  • Table 29 Compounds Prepared According to the Procedure of Example 179, step 2.
  • Examples 399-428 were prepared from 5'-[(3-fluorophenyl)sulfonyl]spiro[l ,3-dioxane-2,3'- indol]-2'(l '//)-one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 30.
  • Examples 429-440 were prepared from 5'-(py ⁇ din-4-ylsulfonyl)spiro[l ,3-dioxolane-2,3'-indol]-
  • Examples 441-451 were prepared from 5'- ⁇ [3-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 32.
  • Examples 452-455 were prepared from 5'- ⁇ [2-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 33.
  • Examples 456-458 were prepared from 5'- ⁇ [4-(trifluoromethoxy)phenyl]sulfonyl ⁇ spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 34.
  • Table 34 Compounds Prepared According to the Procedure of Example 197.
  • Examples 459-472 were prepared from 5'-(pyndm-4-ylsulfon>l)spiro[l,3-dioxane-2,3'-mdol]- 2'( 17/)-one and the appropriate boromc acid using a procedure similar to that of Example 197, step 2 and summarized in Table 35.
  • Examples 473-500 were prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 36.
  • the title compound (0.056g, 34%) was prepared from 5'-[(4-methoxyphenyl)sulfonyl]spiro[l ,3- dioxane-2,3'-mdol]-2'(rH)-one and 3,4 difhioronitrobenzene using a procedure similar to that of step 1 of example 319.
  • 1 H NMR 400 MHz, DMSO-d6): consistent; MS (ESI + ) m/z 515.0 (M+H).
  • Examples 504-531 were prepared from 5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(17/)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 37.
  • the title compound (0.055g, 83%) was prepared from 5'-(phenylsulfonyi)spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one and 4-(2-chloroethyl)morpholine hydrochloride using a procedure similar to that of Example 179, step 2.
  • 1 H NMR 400 MHz, DMSO-d6): consistent; MS (ESI + ) m/z 459.1 (M+H).
  • the title compound (0.058g, 86%) was prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one and 4-bromo-2-methylbutan-2-ol (EP78704) using a procedure similar to that of Example 179, step 2.
  • 1 H NMR 400 MHz, DMSO-d6): consistent; MS (ESI + ) m/z 432.1 (M+H).
  • Examples 545-548 were prepared from prepared from 5'-(pyridin-2-ylsulfanyl)spiro[l,3- dioxolane-2,3'-indol]-2'(l T H)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and are summarized in Table 38.
  • Examples 552-554 were prepared from 5'-[(3-fluorophenyl)sulfonyl]spiro[l ,3-dioxane-2,3'- mdol]-2'(l ⁇ )-one and the appropriate lodo-pyndme using a procedure similar to that of Example 540 and are summarized m Table 39 Table 39: Compounds Prepared According to the Procedure of Example 540.
  • Examples 555-557 were prepared from 5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(l ⁇ )- one and the appropriate bromomethyl pyridine using a procedure similar to that of Example 179, step 2 and are summarized in Table 40.
  • Table 40 Compounds Prepared According to the Procedure of Example 179, step 2.
  • 2,3'-indol]-2'(l ⁇ )-one (0.108g, 83%) (Example 339) were prepared from l'-propyl-5'-(pyridin-4- ylsulfanyl)spiro[l,3-dioxolane-2,3'-indol]-2'(l ⁇ )-one using a procedure similar to that of Example 551.
  • Example 559 5'-[(2-Chloro-4-fluorophenyl)sulfanyl]-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)- one
  • Examples 560-565 were prepared from r-(cyclopropylmethyl)-5'-[(triisopropylsilyl)sulfanyl]spiro[l,3- dioxane-2,3'-indol]-2'(l'H)-one and the appropriate commercially available or synthesized, according to procedures described in Tetrahedron. 2005, 61, 4779-4784 or WO 2006/004533, substituted aryl or heteroaryl iodides and according to the procedure for Step 2 of Example 201 and are summarized in Table 41.
  • Examples 567-573 were oxidized to the sulfones according to the procedure for Example 202 and are summarized in Table 42.
  • Examples 577-604 were prepared from 5'-(py ⁇ din-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-mdol]-
  • Example 606 5'-(Pyridin-3-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one
  • Examples 608-632 were prepared from 5'-(pyridin-3-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one and the appropriate substituted boronic acids using a procedure similar to that of Example 197 and summarized in Table 44.
  • Table 44 Compounds Prepared According to the Procedure of Example 197.
  • Step l 5 [2-(trifluoromethyl)benzoyl] spiro[ 1 ,3 -dioxane-2,3 '-indol]-2'( 177)-one
  • Step 2 1 '-(2-fluorobenzyl)-5'- ⁇ [2-(trifluoromethyl)phenyl]carbonyl ⁇ spiro[l ,3-dioxane-2,3'-indol]-2'( 1 ⁇ )-one
  • Examples 636 - 656 were prepared from different benzyl bromides by using a procedure similar to that of Example 635 and summarized in Table 45.
  • Table 45 Compounds Prepared According to the Procedure of Example 635.
  • Examples 658-678 were prepared from Examples 636-656 by using a procedure similar to that of Example 657 and are summarized in Table 46.
  • Examples 679-695 were prepared from Examples 658-677 by using a procedure similar to that of Example 678 and are summarized in Table 47.
  • Table 47 Compounds Prepared According to the Procedure of Example 678.
  • CHO Kl cells expressing the human CBl or CB2 receptor were cultured at 37° C, m Ham's F12 (Invitrogen 21765-037 or equivalent) containing 10% fetal bovine serum (US biotechnologies or the equivalent), 100 ⁇ g/ml penicillin and 100 ⁇ g/ml streptomycin (Gibco 10131-035), 400 ⁇ g/ml G418 (Gibco 10131-035).
  • Adherent cell culture cells were maintained by seeding at 2-3 x 10 6 cells m 30 mL medium m a
  • cells were thawed at 37° C, added to 15 mL complete medium, cent ⁇ fuged at 1200 rpm for 2 minutes The cell pellet was resuspended m 5 ml medium and then added to a T 175 containing 25 ml of medium. Frozen cells were also thawed as above and maintained m culture by adding the resuspended cells to 100 ml of medium m a sterilized 250 mL Erlenmeyer flask that was gassed with 5% CO 2 , capped, and placed on an orbital shaker at low RPM (50-100).
  • cAMP Assay Cells were lifted from the plate with dissociation buffer cent ⁇ fuged and resuspended m a small volume of PBS. Cells were plated (15,000/well; 96 well plate, 7,500/well; 384 well plate) and incubated m the presence of 10 ⁇ M forskolm and compound m Krebs bicarbonate buffer (118 mM NaCl, 5 mM KCl, 1 2 mM MgSO 4 , 2.4 mM CaCl 2 1.2 mM KH 2 PO 4 25 mM NaHCO 3 11.1 mM glucose) at 37 0 C for 30 minutes.
  • compound m Krebs bicarbonate buffer 118 mM NaCl, 5 mM KCl, 1 2 mM MgSO 4 , 2.4 mM CaCl 2 1.2 mM KH 2 PO 4 25 mM NaHCO 3 11.1 mM glucose
  • cAMP content was determined using the HitHunter cAMP XS assay (Discoverx 90-0041, 90-0041 L).
  • Discoverx 90-0041, 90-0041 L For the antagonist assay, compound is incubated m the presence of 10 ⁇ M forskolm and 10OnM WIN-55212-2 at 37 0 C for 30 minutes.
  • the HitHunter assay was performed according to the manufacturer's instructions. Briefly, 20 ⁇ L cAMP antibody/lysis mix (1:1 ratio) were added to stimulated cells and incubated at room temperature for 1 hour. 20 ⁇ L of cAMP XS ED reagent was added and incubated at room temperature for 1 hour. 20 ⁇ L of cAMP XS EA reagent and 20 ⁇ L of CL substrate (1 part Galacton-Star, 5 parts Emerald-II, 19 parts substrate diluent) were added and then incubated at room temperature for 3 hours. Chemilummescence was read on a Victor II at 1 s/well. A standard curve was also established with cAMP concentrations ranging from 10 10 to 10 5 M, diluted m Krebs.
  • IC 50 and EC 50 values were calculated using P ⁇ sm GraphPad using a 4-parameter logistic equation.
  • An active agonist displays greater than 40% inhibition of cAMP.
  • An antagonist typically displays greater than 40% reversal of 100 nM WIN55212-2 response.
  • CHO Kl cells expressing the human CBl or CB2 receptor were cultured at 37 0 C, in Ham's F12 (Invitrogen 21765-037 or equivalent) containing 10% fetal bovine serum (US biotechnologies or equivalent), 100 ⁇ g/mL penicillin and 100 ⁇ g/mL streptomycin (Gibco 10131-035), 400 ⁇ g/mL G418 (Gibco 10131-035).
  • Cells were harvested from plates by scraping in a small volume of ice-cold 20 mM HEPES, 2OmM EDTA, pH 7.5. The cells were homogenized and pelleted by centrifugation at 100,000 g for 30 minutes at 4° C. Membranes were resuspended at a concentration of 1- 5mg/mL.
  • Membranes were incubated in 0.5 mL binding buffer (50 mM Tris pH 5.7, 2.5 mM EDTA pH 8.0, 0.25% essentially fatty acid free BSA (Sigma A6003)) in the presence of 4 nM [ 3 H] SR141716 (CBl antagonist) or 0.6 nM [ 3 H] CP 55,940 (non-selective agonist) nM and cold displacing ligand for 1 hour at 3O 0 C.
  • the assay was terminated by filtration on a brandel harvester through Whatman GFB filter paper, previously soaked in 0.15% polyethyleneamine. Samples were washed with 4 x 5 mL ice cold binding buffer and radioactivity was determined by liquid scintillation counting. Non-specific binding values were determined by either 1 ⁇ M CP 55, 940 or 1 ⁇ M WIN 55212-2.

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Abstract

Provided are substituted compounds, or pharmaceutically acceptable salts thereof, wherein: R1 is selected from -(CH2)nRa, -CH(OH)Ra, -CH(ORb)Ra, and -C(O)Ra, or is selected from ORa, SRa, SORa, SO2Ra and NRaRb; R2 and R3 are independently selected from H, halogen, OH, ORa, OWRa, C1-6 alkyl, and WC 1-6 alkyl, wherein C1-6 alkyl or ORa, is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, ORa, C1-6 alkyl, C1-6 haloalkyl, C3-8cycloalkyl, C6-10 aryl and C4-10 heteroaryl; or R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, C1-6alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C6-10aryl and C4-10 heteroaryl; R4 is independently selected from H.C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6-10 aryl, C4-10 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone and -(CH2)n-C1-6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, ORa, C1-6 alkyl, C1-6 haloalkyl, C3.8 cycloalkyl, WC3.8 cycloalkyl, C6-10 aryl and C4.10 heteroaryl; which are agonists of the CB2 receptor, pharmaceutical compositions containing the same, and methods of treatment related to CB2-mediated disorders (eg., pain, cancer etc.) using the substituted oxindole compounds and compositions described herein.

Description

SUBSTITUTED OXINDOLE CB2 AGONISTS
BACKGROUND
CBl and CB2 receptors, two subtypes of the cannabinoid receptor, both belong to the G-protein- coupled receptor (GPCR) superfamily. The CBl receptor is predominantly expressed in brain to mediate inhibition of transmitter release and affects many neurological and psychological phenomena, such as mood, appetite, emesis control, memory, spatial coordination muscle tone, and analgesia, as described by Goutopoulos et al., m the publication Pharmacol Ther (2002) 95:103. The CB2 receptor is primarily expressed in immune cells to modulate immune response. Activation of the CB2 receptor is known to induce analgesic effects in inflammatory models involved in neurodegeneration diseases, and plays a role in the maintenance of bone density and progression of atherosclerotic lesions. It has been known that CB2 agonists are potential drug candidates for reducing pain (such as chronic inflammatory pain, post surgical pain, neuropathic pain, and bone pain) and for treating a host of diseases including osteoarthritis, atherosclerosis, osteoporosis, and cancer (e.g., glioma), as described by Malan et al., m the publication Pain (2001) 93:239. Accordingly, there is an ongoing need for new and improved compounds that modulate the CB2 receptor and can function as therapeutics for the treatment of various CB2 receptor-modulated diseases and disorders such as pain. The invented compounds disclosed herein provide a solution to this need.
SUMMARY OF THE INVENTION In one aspect, the invention relates to a compound of Formula I:
Figure imgf000002_0001
I or pharmaceutically acceptable salt thereof, wherein the variables are defined herein.
In another aspect, the invention relates to a pharmaceutical composition comprising one or more of the above-described substituted oxindole compounds of the invention, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner.
In another aspect, the invention relates to a method of treating a CB2-mediated disorder by administering to a subject in need of this treatment a therapeutically effective amount of one or more of the compounds described above. CB2-mediated disorders include, but are not limited to, pain (such as chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pam), osteoarthritis, atherosclerosis, osteoporosis, and cancer (e.g., glioma).
In another aspect, the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in therapy. In another aspect, the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in the treatment of a CB2-mediated disorder such as pain (e.g., chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, or cancer (e.g., glioma). In another aspect, the invention relates to a compound of the invention, or pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for use in the treatment of one or more CB2-mediated disorders.
The details of one or more embodiments of the invention are set forth in the accompanying description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides substituted oxindole compounds, that function as CB2 agonists, of Formula I:
Figure imgf000003_0001
I or pharmaceutically acceptable salts thereof, wherein:
R1 is selected from -(CH2)nRa, -CH(OH)Ra, -CH(ORb)Ra, and -C(O)Ra, or is selected from ORa, SRa, SORa, SO2R" and NRaRb;
R2 and R3 are independently selected from H, halogen, OH, 0Ra, 0WRa, Ci-6 alkyl, and WCi-6 alkyl, wherein Ci_6 alkyl or 0Ra, is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, Ci_6 haloalkyl, C3_8 cycloalkyl, C6.io aryl and C4_io heteroaryl; or R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, Ci_6 haloalkyl, C3.8 cycloalkyl, C6-Io aryl and C4.10 heteroaryl;
R4 is independently selected from H, d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-Io aryl, C4_i0 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone and -(CH2)n-Ci_6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, Ci.6 haloalkyl, C3.8 cycloalkyl, WC3-8 cycloalkyl, C6-io aryl and C4.10 heteroaryl; at each occurrence W is -(CH2)n- or -C(O)-; at each occurrence, Ra and Rb are independently selected from H, Ci_6 alkyl, Ci_6 haloalkyl, C2_6 alkenyl, C2.6 alkynyl, C6-io aryl, C4.10 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl C7-14 arylalkyl, C4.14 heteroarylalkyl, C5.12 cycloalkylalkyl and C5.12 heterocycloalkylalkyl, each of which is optionally substituted with ORa, cyano, amino, halo,
Figure imgf000004_0001
alkyl, C6. 10 aryl, C4-I0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl C7-I4 arylalkyl, C4.14 heteroarylalkyl, C5.12 cycloalkylalkyl and C5.12 heterocycloalkylalkyl; at each occurrence, halogen is selected from F, Cl, Br and I; and at each occurrence, n is 0, 1, 2, or 3.
According to one embodiment, the invented compounds selected from: 5'-benzoyl-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(2-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 1'- (cyclopropylmethyl)-5'-(3-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(4-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[2-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[3-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethy^-S'-fS-Ctrifluoromethy^benzoyllspirofl^-dioxane^^'-indoll^Xr/O-one, 1'- (cyclopropylmethy^-S'-^^trifluoromethy^benzoyljspirofl^-dioxane^^'-indoll^Xr/O-one, 1'- (cyclopropylmethyl)-5'-(2-methoxybenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 1'- (cyclopropylmethyl)-5 '-(3 -methoxybenzoyl)spiro[ 1 ,3-dioxane-2,3 '-indol] -2'( 1 '//)-one, 1 '- (cyclopropylmethyl)-5'-(4-methoxybenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(2- chlorobenzoyl)-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(3-chlorobenzoyl)-l'- (cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-(4-chlorobenzoyl)-l'-
(cyclopropylmethyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 '//)-one, 1 '-(cyclopropylmethyl)-5'-(3- methylbenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(4- methylbenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'-[3- (trifluoromethoxy)benzoyl]spiro[l ,3-dioxane-2,3'-indol]-2'(l Η)-one, 1 '-(cyclopropylmethyl)-5'-[4- (trifluoromethoxy)benzoyl]spiro[l ,3-dioxane-2,3'-indol]-2'(l 77)-one, 1 '-(cyclopropylmethyl)-5'-(3- furoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(3-thienylcarbonyl)spiro[l,3- dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2-methylbenzoyl)spiro[l,3-dioxane-2,3'- indol]-2'(l '//)-one, 1 '-(cyclopropylmethyl)-5'-[4-fluoro-2-(trifluoromethyl)benzoyl]spiro[l ,3-dioxane- 2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)-5'-[5-fluoro-2-(trifluoromethyl)benzoyl]spiro[l,3- dioxane-2,3'-indol]-2'(l'//)-one, 5'-[4-chloro-2-(trifluoromethyl)benzoyl]-l'-
(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2,3- difluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one, l'-(cyclopropylmethyl)-5'-(2,5- difluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(3-chloro-4-fiuorobenzoyl)-l'- (cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2,3- dichlorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'-(2,5- dichlorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(3,4- dichlorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2,3- dimethoxybenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'-(2-methoxy-5- methylbenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-(5-chloro-2-methoxybenzoyl)-l'- (cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylniethyl)-5'-(5-fluoro-2- methoxybenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2,3- dimethylbenzoyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l 77)-one, 1 '-(cyclopropylmethyl)-5'-(2,6- dimethylbenzoyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l 77)-one, 5'-(5-chloro-2-methylbenzoyl)-l '- (cyclopropylmethyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 '//)-one, 1 '-(cyclopropylmethyl)-5'-[2- (trifluoromethoxy)benzoyl]spiro[l ,3-dioxane-2,3'-indol]-2'(l 77)-one, 1 '-(cyclopropylmethyl)-5'-(2,4- difluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'-(2,6- dimethoxybenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'- [hydroxy(phenyl)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'-[(2- fluorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'-[(3- fluorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'-[(4- fluorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 2-[5'-{hydroxy[2- (trifluoromethyl)phenyl]methyl}-2'-oxospiro[l,3-dioxane-2,3'- indol]-l'(2'H)-yl]benzonitrile, (-)-2-[5'- {(S)-hydroxy[2-(trifluoromethyl)phenyl]methyl}-2'-oxospiro[l,3-dioxane- 2,3'-indol]-l'(2'H)- yljbenzonitrile, (+)2-[5'-{(R)-hydroxy[2-(trifluoromethyl)phenyl]methyl}-2'-oxospiro[l,3-dioxane- 2,3'- indol]-l'(2'H)-yl]benzonitrile, (+)-r-(3,4-difluorophenyl)-5'-{(R)-hydroxy[2-(trifluoromethyl)phenyl]- methyl}spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, (-)-l'-(3,4-difluorophenyl)-5'-{(S)-hydroxy[2- (trifluoromethyl)phenyl] -methyl} spiro [ 1 ,3 -dioxane-2,3 '-indol]-2'( 1 'H)-one, 1 '-(cyclopropylmethyl)-5'- { 1 - hydroxy- 1 - [2 -(trifluoromethyl)phenyl] ethyl } spiro [ 1 ,3 -dioxane-2 ,3 '-indol] -2 '( 1 Η)-one, 1 '-(3 ,4- difluorophenyl)-5'-{l-hydroxy-l-[2-(trifluoromethyl)phenyl]ethyl}spiro[l,3-dioxane-2,3'-indol]-2'(rH)- one, r-(cyclopropylmethyl)-5'-{hydroxy[2-(trifluoromethyl)phenyl]methyl}spiro[l,3-dioxane-2,3'-indol]- 2'(r//)-one, r-(cyclopropylmethyl)-5'-{hydroxy[3-(trifluoromethyl)phenyl]methyl}spiro[l,3-dioxane- 2,3'-indol]-2'(l'//)-one, r-(cyclopropylmethyl)-5'-{hydroxy[4-(trifluoromethyl)phenyl]methyl}spiro[l,3- dioxane-2,3'-indol]-2'(l'//)-one, r-(cyclopropylmethyl)-5'-[hydroxy(2-methoxyphenyl)methyl]spiro[l,3- dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)-5'-[hydroxy(3-methoxyphenyl)methyl]spiro[l,3- dioxane-2,3'-indol]-2'(l'//)-one, r-(cyclopropylmethyl)-5'-[hydroxy(4-methoxyphenyl)methyl]spiro[l,3- dioxane-2,3'-indol]-2'(l'//)-one, 5'-[(2-chlorophenyl)(hyώOxy)methyl]-l'-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(r//)-one, 5'-[(3-chlorophenyl)(hyώOxy)methyl]-r-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(l'//)-one, 5'-[(4-chlorophenyl)(hyώOxy)methyl]-l'-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(l'//)-one, r-(cyclopropylmethyl)-5'-[hydroxy(3-methylphenyl)methyl]spiro[l,3- dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)-5'-[hydroxy(4-methylphenyl)methyl]spiro[l,3- dioxane-2,3'-indol]-2'(l '//)-one, 1 '-(cyclopropylmethyl)-5'- {hydroxy[3- (trifluoromethoxy)phenyl]methyl}spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'- {hydroxy[4-(trifluoromethoxy)phenyl]methyl}spiro[l,3-dioxane-2,3'-indol]-2'(r/7)-one, 1'- (cyclopropylmethyl)-5'-[3-furyl(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[hydroxy(3-thienyl)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[hydroxy(2-methylphenyl)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-{[4-fluoro-2-(trifluoromethyl)phenyl](hydroxy)methyl}spiro[l,3-dioxane-2,3'- indol]-2'(l 77)-one, 1 '-(cyclopropylmethyl)-5'- { [5-fluoro-2-
(trifluoromethyl)phenyl](hydroxy)methyl}spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-{[4-chloro-2- (trifluoromethyl)phenyl](hydroxy)methyl}-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)- one, r-(cyclopropylmethyl)-5'-[(2,3-difluorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]- 2'( 17/)-one, 1 '-(cyclopropylmethyl)-5 '-[(2,5 -difluorophenyl)(hydroxy)methyl] spiro[ 1 ,3 -dioxane-2,3 '- indol]-2'(l'//)-one, 5'-[(3-chloro-4-fluorophenyl)(hydroxy)methyl]-r-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(l Η)-one, 1 τ-(cyclopropylmethyl)-5'-[(2,3- dichlorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one, l'-(cyclopropylmethyl)-5'- [(2,5-dichlorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1 '-(cyclopropylmethyl)- 5 '- [(3,4-dichlorophenyl)(hydroxy)methyl] spiro [ 1 ,3 -dioxane-2,3 '-indol] -2'( 177)-one, 1 '- (cyclopropylmethyl)-5'-[(2,3-dimethoxyphenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)- one, r-(cyclopropylmethyl)-5'-[hydroxy(2-methoxy-5-methylphenyl)methyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one, 5'-[(5-chloro-2-methoxyphenyl)(hydroxy)methyl]-r-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(l 7/)-one, 1 '-(cyclopropylmethyl)-5'-[(5-fluoro-2- methoxyphenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'- [(2,3-dimethylphenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)- 5'-[(2,6-dimethylphenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-[(5-chloro-2- methylphenyl)(hydroxy)methyl]-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-{hydroxy[2-(trifluoromethoxy)p]ienyl]methyl}spiro[l,3-dioxane-2,3'-indol]- 2'(l'//)-one, l'-(cyclopropylmethyl)-5'-[(2,4-difluorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one, 5'-benzyl-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'/7)-one, 1'- (cyclopropylmethyl)-5'-[2-(trifluoromethyl)benzyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(2-fluorobenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(3-fluorobenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(4-fluorobenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[3-(trifluoromethyl)benzyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[4-(trifluoromethyl)benzyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(2-methoxybenzyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l '//)-one, 1 '- (cyclopropylmethyl)-5'-(3-methoxybenzyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l '//)-one, 1 '-
(cyclopropylmethyl)-5'-(4-methoxybenzyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, 5'-(2-chlorobenzyl)- r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-(3-chlorobenzyl)-l'- (cyclopropylmethyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 '//)-one, 5'-(4-chlorobenzyl)-l '- (cyclopropylmethyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 '//)-one, 1 '-(cyclopropylmethyl)-5'-(3- methylbenzyl)spiro[ 1 ,3 -dioxane-2,3 '-indol]-2'( 177)-one, 1 '-(cyclopropylmethyl)-5 '-(4- methylbenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r/T)-one, l'-(cyclopropylmethyl)-5'-[4- (trifluoromethoxy)benzyl]spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'-(3- thienylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'-(2- methylbenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r/f)-one, l'-(cyclopropylmethyl)-5'-[4-fluoro-2- (trifluoromethyl)benzyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)-5'-[5-fluoro-2- (trifluoromethyl)benzyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-[4-chloro-2- (trifluoromethyl)benzyl] - 1 '-(cyclopropylmethyl)spiro [ 1 ,3 -dioxane-2,3'-indol]-2'( 17/)-one, 1 '- (cyclopropylmethyl)-5'-(2,3-difluorobenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'-
(cyclopropylmethyl)-5'-(2,5-difluorobenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(3-chloro-4- fluorobenzyl)-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'- (2,3-dichlorobenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)-5'-(2,5- dichlorobenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(3,4- dichlorobenzyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 '//)-one, 1 '-(cyclopropylmethyl)-5'-(2,3- dimethoxybenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)-5'-(2-methoxy-5- methylbenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(5-chloro-2-methoxybenzyl)-l'- (cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(5-fluoro-2- methoxybenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)-5'-(2,3- dimethylbenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-(5-chloro-2-methylbenzyl)-r- (cyclopropylmethyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 '//)-one, 1 '-(cyclopropylmethyl)-5'-[2- (trifluoromethoxy)benzyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)-5'-(2,4- difluorobenzyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l Η)-one, r-phenyl-5'-[2-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5 '-benzoyl-1 '-phenylspiro [ 1 ,3-dioxane-2,3 '-indol]-2'( 1 '//)-one, 5'-(2-fluorobenzoyl)- 1 '-phenylspiro [1,3- dioxane-2,3'-indol]-2'(l'//)-one, 5'-(2-methoxybenzoyl)-r-phenylspiro[l,3-dioxane-2,3'-indol]-2'(r//)- one, 5'-(2-chlorobenzoyl)-l'-phenylspiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(2-methylbenzoyl)-l'- phenylspiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 2-(5'-benzoyl-2'-oxospiro[l,3-dioxane-2,3'-indol]- l'(2'//)-yl)benzonitrile, 2-[5'-(2-fluorobenzoyl)-2'-oxospiro[l,3-dioxane-2,3'-indol]-l'(2'//)- yljbenzonitrile, 2-{2'-oxo-5'-[2-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-r(2'/7)- yl}benzonitrile, 2-[5'-(2-methoxybenzoyl)-2'-oxospiro[l,3-dioxane-2,3'-indol]-r(2'//)-yl]benzonitrile, 2- [5'-(2-chlorobenzoyl)-2'-oxospiro[l,3-dioxane-2,3'-indol]-l'(2'//)-yl]benzonitrile, 5'-benzoyl-l'-(3,4- difluorophenyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(3,4-difluorophenyl)-5'-(2- fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(3,4-difluorophenyl)-5'-[2- (trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(3,4-difluorophenyl)-5'-(2- methoxybenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(2-chlorobenzoyl)-l'-(3,4- difluorophenyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(3,4-difluorophenyl)-5'-(2- methylbenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(2,5-difluorophenyl)-5'-[2- (trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(2-chlorobenzoyl)-l'-(2,5- difluorophenyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(3-thienyl)-5'-[2-
(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(2-chlorobenzoyl)-l'-(3- thienyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 2-[5'-(2-methylbenzoyl)-2'-oxospiro[l,3-dioxane-2,3'- indol]- 1 '(2'//)-yl]benzonitrile, 5'-benzoyl-l'-(3,3,3-tπfluoropropyl)spiro[l,3-dioxane-2,3'-mdol]-2'(l'//)-one, l'-propyl-5'-[2- (tnfluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(3,4-Difluorophenyl)-5'- phenethylspiro[[l,3]dioxane-2,3'-mdolm]-2'-one, 5'-(Benzylammo)-l'-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-mdol]-2'(l 'H)-one, 1 '-(Cyclopropylmethyl)-5'-[(2-furylmethyl)ammo]spiro[l ,3-dioxane-2,3'- mdol]- 2'(l'H)-one, r-(Cyclopropylmethyl)-5'-[(2-thienylmethyl)amino]spiro[l,3-dioxane-2,3'-mdol]- 2'( 1 'H)-one, 5'- { [(5-Chloro-2-thienyl)methyl]ammo} -1 '-(cyclopiopylmethyl)spiro[ 1 ,3-dioxane- 2,3'- mdol]-2'(l'H)-one, 5'-{[(2-Butyl-l-benzofuran-3-yl)methyl]ammo}-r-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-mdol]-2'(lΗ)-one, 5'-[(4-Chlorobenzyl)ammo]-r-(cyclopropylmethyl)spiro[l,3-dioxane- 2,3'-mdol]- 2'(l'H)-one, r-(Cyclopropylmethyl)-5'-[(4-methoxybenzyl)ammo]spiro[l,3-dioxane-2,3'- mdol]- 2'(l'H)-one, r-(Cyclopropylmethyl)-5'-[(4-methylbenzyl)ammo]spiro[l,3-dioxane-2,3'-mdol]- 2'(l'H)-one, r-(Cyclopropylmethyl)-5'-[(3,4-dichlorobenzyl)ammo]spiro[l,3-dioxane-2,3'- mdol]-2'(rH)- one, 5'-[(3-Chlorobenzyl)ammo]-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-mdol]- 2'(lΗ)-one, 1'- (Cyclopropylmethyl)-5'-{[4-(tπfluoromethyl)benzyl]ammo}spiro[l,3-dioxane- 2,3'-mdol]-2'(rH)-one, 5'- {[4-Chloro-3-(tπfluoromethyl)benzyl]amino}-r-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-mdol]- 2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(l-naphthylmeth>l)ammo]spiro[l,3-dioxane-2,3'- mdol]-2'(l'H)- one, r-(Cyclopropylmethyl)-5'-[(2,3-dihydro-l,4-benzodioxm-6- ylmethyl)ammo]spiro[l,3-dioxane-2,3'- mdol]-2'(l Η)-one, 1 '-(Cyclopropylmethyl)-5'-[(4-fluorobenzyl)amino]spiro[l ,3-dioxane-2,3'-mdol]- 2'( 1 'H)-one, 5'-[(I -Benzothiophen-2-ylmethyl)ammo]-l '-(cyclopropylmethyl)spiro[ 1 ,3-dioxane- 2,3'- mdol]-2'(l'H)-one, 5'-[Bis(cyclohexylmethyl)amino]-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- mdol]-2'(l'H)- one, r-(Cyclopropylmethyl)-5'-(dimethylammo)spiro[l,3-dioxane-2,3'-mdol]-2'(rH)-one, l'-Butyl-5'- (methylamino)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'- [methyl(phenyl)amino]spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-pipendin-l- ylspiro[l,3-dioxane-2,3'-mdol]-2'(l'H)-one, 5'-(Phenylthio)spiro[l,3-dioxane-2,3'-mdol]-2'(l'H)-one, 5'- (Phenylsulfinyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 5'-(Phenylsulfonyl)spiro[l,3-dioxane-2,3'- mdol]-2'(l'H)-one, 5'-(Phenylthio)spiro[l,3-dioxolane-2,3'-mdol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'- (phenylthio)spiro[l,3-dioxolane-2,3'-mdol]-2'(l'H)-one, 5'-(Phenylsulfonyl)spiro[l,3-dioxolane-2,3'- mdol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-mdol]- 2'(l'H)- one, r-Phenyl-5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(l'H)-one, 5'-(Phenylsulfonyl)-l'-[3- (tnfluoromethyl)phenyl]spiro[l,3-dioxolane-2,3'- mdol]-2'(l'H)-one, l'-(3,4-Difluorophenyl)-5'-
(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-mdol]-2'(l'H)-one, l'-Phenyl-5'-(phenylthio)spiro[l,3-dioxane- 2,3'-mdol]-2'(l'H)-one, l'-Phenyl-5'-(phenylthio)spiro[l,3-dioxane-2,3'-mdol]-2'(l'H)-one, l'-(3,4- Difluorophenyl)-5'-(phenylthio)spiro[l,3-dioxane-2,3'-mdol]-2'(l'H)-one, l'-Phenyl-5'- (phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 5'-(Phenylsulfonyl)-l'-[3- (tπfluoromethyl)phenyl]spiro[ 1 ,3-dioxane-2,3 '-mdol] - 2'(I 'H)-one, 1 '-(3 ,4-difluorophenyl)-5 '- (phenylsulfonyl)spiro[l ,3-dioxane-2,3'-mdol]-2'(l 'H)-one, l'-(2,5-difluorophenyl)-5'- (phenylsulfonyl)spiro[l ,3-dioxane-2,3'-mdol]-2'(l 'H)-one, l'-(3-fluorophenyl)-5'- (phenylsulfonyl)spiro[l ,3-dioxane-2,3'-mdol]-2'(l 'H)-one, l'-(3,5-dichlorophenyl)-5'- (phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, l'-(3-chloro-4-fluorophenyl)-5'- (phenylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l 'H)-one, l'-(4-chlorophenyl)-5'- (phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 5'-(phenylsulfonyl)-l'-[2- (trifluoromethyl)phenyl]spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, l'-(2-methoxyphenyl)-5'- (phenylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l 'H)-one, l'-(4-fluorophenyl)-5'- (phenylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l 'H)-one, l'-(2,3-diflιiorophenyl)-5'- (phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'- (phenylsulfmyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 5'-(Phenylthio)-l '-(2,2,2- trifluoroethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-(phenylthio)spiro[l,3- dioxane-2,3'-indol]-2'(l'H)-one, r-(Cyclopropylmethyl)-5'-[(2-fluorophenyl)sulfonyl]spiro[l,3-dioxane- 2,3'- indol]-2'(lΗ)-one, r-(Cyclopropylmethyl)-5'-[(2-methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 5'-[(2-Chlorophenyl)sulfonyl]-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]- 2'(l'H)-one, 5'-[(3-Chlorophenyl)sulfonyl]-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2'(rH)- one, r-(Cyclopropylmethyl)-5'-[(2-methylphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(lΗ)-one, 1'- (Cyclopropylmethyl)-5'-[(3-fluorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(rH)-one, 1'- (Cyclopropylmethyl)-5'-[(4-fluorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(lΗ)-one, 1'- (Cyclopropylmethyl)-5'- { [2-(trifluoromethyl)phenyl]sulfmyl} spiro[ 1 ,3- dioxane-2,3'-indol]-2'( l'H)-one, r-(Cyclopropylmethyl)-5'-[(2,5-dichlorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 5'- [(4-Chlorophenyl)sulfonyl]-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2'(lΗ)-one, 1'- (Cyclopropylmethyl)-5'-[(3-methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(rH)-one, 1'- (Cyclopropylmethyl)-5'-[(3,4-dichlorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(3-methylphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(4-methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(rH)-one, 5'-(l,3- Benzothiazol-2-ylsulfonyl)-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5 '- [(3 ,4-difluorophenyl)sulfonyl] spiro[ 1 ,3 -dioxane-2,3 '- indol] -2'( 1 Η)-one, 1 '- (Cyclopropylmethyl)-5'-(pyridin-4-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-(pyridin-4-ylthio)spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one, 1'- (Cyclopropylmethyl)-5'-[(3,4-dichloiOphenyl)thio]spiro[l,3-dioxane-2,3'- indol]-2'(l 'H)-one, 1 '- (Cyclopropylmethyl)-5'-[(3,4-difluorophenyl)thio]spiro[l ,3-dioxane-2,3'- indol]-2'(l 'H)-one, 1 '-
(Cy clopropylmethyl)-5 '- { [3 -(trifluoromethyl)phenyl] sulfanyl } spiro [1,3- dioxane-2 ,3 '-indol] -2 '( 1 'H)-one, r-(Cyclopropylmethyl)-5'-(pyridin-2-ylsulfanyl)spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one, 1'- (Cyclopropylmethyl)-5 '-(pyridin-4-ylsulfmyl)spiro [ 1 ,3 -dioxane-2,3 '-indol]- 2'(I 'H)-one, 1 '- (Cyclopropylmethyl)-5 '-(pyridin-2-ylsulfmyl)spiro [ 1 ,3 -dioxane-2,3 '-indol]- 2'(I 'H)-one, 1 '- (Cyclopropylmethyl)-5'-[(3,4-difluorophenyl)sulfinyl]-spiro[l,3-dioxane-2,3'- indol]-2'(lΗ)-one, 1'- (Cyclopropylmethyl)-5'-(pyridin-3-ylsulfanyl)spiro[l ,3-dioxane-2,3'-indol]- 2'(I 'H)-one, 1 '- (Cyclopropylmethyl)-5'-[(4-methylphenyl)sulfanyl]spiro[l ,3-dioxane-2,3'- indol]-2'(l 'H)-one, 1'- (CyclopropylmethyO-S'-l^-^rifluoromethy^phenylJsulfanyllspirofl^- dioxane^^'-indolJ^^l'^-one, 5'-[(3-Chloro-4-fluorophenyl)sulfanyl]-l '-(cyclopropylmethyl)spiro[l ,3-dioxane- 2,3'-indol]-2'(lΗ)-one, 5τ-[(6-Chloropyridin-3-yl)sulfanyl]-r-(cyclopropylmethyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5 '-(naphthalen- 1 -ylsulfanyl)spiro [1 ,3 -dioxane-2,3 '- indol] -2'(I 'H)-one, 1 '- (Cyclopropylmethyl)-5'-(thiophen-2-ylsulfanyl)spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(5-methyl-2-thienyl)thio]spiro[l ,3-dioxane-2,3'- indol]-2'(l Η)-one, 5'-[(5- Acetyl-2-thienyl)thio]-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 5'-[(2- Chloropyridin-4-yl)thio]-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(3,5-dichloiOphenyl)thio]spiro[l,3-dioxane-2,3'- indol]-2'(l 'H)-one, 1 '- (Cyclopropylmethyl)-5'-[(3,5-dichloropyridin-4-yl)thio]spiro[l,3-dioxane- 2,3'-indol]-2'(rH)-one, 1'- (Cyclopropylmethyl)-5'-[(2,4-dichlorophenyl)thio]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(2,5-dichlorophenyl)thio]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 5'-[(4- Chloro^-fluorophenyl^hioJ-l'^cyclopropylmethy^spirofl^-dioxane^^'- indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(2,4-difluorophenyl)thio]spiro[l ,3-dioxane-2,3'- indol]-2'(l Η)-one, 1 '- (CyclopropylmethyO-S'^pyridin-S-ylsulfony^spirofl^-dioxane^^'-indol]- 2'(l'H)-one, 1'- (Cy clopropylmethyl)-5 '- { [3 -(trifluoromethyl)phenyl] sulfonyl } spiro [1,3- dioxane-2 ,3 '-indol] -2 '( 1 'H)-one, r-(Cyclopropylmethyl)-5'-[(4-methylphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 1'- (Cy clopropylmethyl)-5 '- { [4-(trifluoromethyl)phenyl] sulfonyl } spiro [1,3- dioxane-2 ,3 '-indol] -2 '( 1 'H)-one, 5'-[(3-Chloro-4-fluorophenyl)sulfonyl]-r-(cyclopropylmethyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, 5'-[(6-Chloropyridin-3-yl)sulfonyl]-l'-(cyclopropylmetliyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5 '-(naphthalen- 1 -ylsulfonyl)spiro [ 1 ,3 -dioxane-2,3 '- indol] -2'( 1 'H)-one, 1 '- (Cyclopropylmethyl)-5'-(thiophen-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(5-methyl-2-thienyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 5'-[(5- Acetyl^-thieny^sulfonylJ-l'-^yclopropylmethy^spirofl^-dioxane^^'- indolJ^^rH^one, 5'-[(2- Chloropyridin-4-y l)sulfonyl] - 1 '-(cy clopropylmethyl)spiro [ 1 ,3-dioxane- 2 ,3 '-indol] -2 '( 1 'H)-one, 1 '- (Cyclopropylmethyl)-5'-[(3,5-dichlorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 1'-
(Cyclopropylmethyl)-5'-[(3,5-dichloiOpyridin-4-yl)sulfonyl]spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(2,4-dichlorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 5'-[(4- Chloro-2-fluorophenyl)sulfonyl]-r-(cyclopropylmethyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, 1'- (Cy clopropylmethyl)-5 '- [(2 ,4-difluorophenyl)sulfonyl] spiro [ 1 ,3 -dioxane-2,3 '- indol] -2'(I 'H)-one, 1 '- (Cyclopropylmethyl)-5'-(4-methoxyphenoxy)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-(4-methoxyphenoxy)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(2,6-difluoropyridin-4-yl)oxy]spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one, 1'- (Cyclopropylmethyl)-5'-[(2,3,5,6-tetrafluoropyridin-4-yl)oxy]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-[(3-Chloro-2,5,6-trifluoropyridin-4-yl)oxy]-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]- 2'(VH)-onQ, r-(Cyclopropylmethyl)-5'-[(3,5-difluoro-2,6-dimethoxypyridin-4-yl)oxy]spiro[l,3-dioxane- 2,3'-indol]-2'(l'//)-one, 5'-[(3-Chloro-5-fluoro-2,6-dimethoxypyridin-4-yl)oxy]-l'- (cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(Cyclopropylmethyl)-5'-[(2,3,5- trifluoro-6-methoxypyridin-4-yl)oxy]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one and pharmaceutically acceptable salts thereof.
According to one embodiment, the invented compounds are certain substituted oxindole compounds of Formula I:
Figure imgf000011_0001
I or pharmaceutically acceptable salts thereof, wherein:
R1 is selected from -Y-Ra, -Y-Cy and -Y-Ar;
Y is a divalent carbon radical selected from -(CH2)n-, -CH(OH)-, -CH(ORa)-, and -C(O)-, or Y is a heteroatom selected from O, S, SO, SO2 and NRaRb;
Ar is independently selected from C6.io aryl, C4.10 heteroaryl, C7.14 arylalkyl and C4.14 heteroarylalkyl, wherein each of said Cβ-io aryl, C440 heteroaryl, C 744 arylalkyl or C444 heteroarylalkyl is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, 0Ra-W, C1-5 alkyl, Cw W-alkyl, Cw haloalkyl, C3.8 cycloalkyl, C3.8 W-cycloalkyl, -C(O)-CL6 alkyl, - C(0)-C6_io aryl, C6_i0 aryl and C4.10 heteroaryl;
Cy is independently selected from C3.8 cycloalkyl, C3_8 heterocycloalkyl, C3.8 heterocycloalkenyl, C4.12 W-cycloalkyl, C4.12 W-heterocycloalkyl and C3.8 W-heterocycloalkenyl, wherein each of said C3.? cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl, C4.12 W-cycloalkyl, C4_i2 W-heterocycloalkyl or C3.8 W-heterocycloalkenyl, is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, 0Ra-W, CM alkyl, Cw W-alkyl, d.6 haloalkyl, C3.8 cycloalkyl, C3.8 W- cycloalkyl, -C(O)-Ci.6 alkyl, -C(O)-Ce-Io aryl, C6_io aryl and C4.10 heteroaryl; at each occurrence W is a linker selected from -(CH2)n- and -C(O)-;
R2 and R3 are independently selected from H, halogen, OH, 0Ra, 0Ra-W, Ci-6 alkyl, Ci.6 W-alkyl, wherein Ci_6 alkyl or 0Ra, is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, Ci_s haloalkyl, C3.8 cycloalkyl, C6-Io aryl and C4.10 heteroaryl; or R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl or C5-C7 oxy cycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci.6 alkyl, Ci.6 haloalkyl, C3.8 cycloalkyl, C6-Io aryl and C4.10 heteroaryl;
R4 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-Io aryl, C4-10 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone and -(CH2)n-Ci_6 haloalkyl, wherein each of said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C4.10 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci.6 alkyl, Ci.6 haloalkyl, C3.8 cycloalkyl, C6-Io aryl and C4_io heteroaryl; at each occurrence, Ra is independently selected from H, Ci_e alkyl, Ci.6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_6 haloalkyl, Cβ-io aryl, C4.10 heteroaryl, C3.8 cycloalkyl, C3_8 heterocycloalkyl, C3_8 heterocycloalkenyl C7_i4 arylalkyl, C4_i4 heteroarylalkyl, C5-^ cycloalkylalkyl and C5-^ heterocycloalkylalkyl, wherein said Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, Cβ-io aryl, C4-10 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl C7-U arylalkyl, C4.14 heteroarylalkyl, C5-^ cycloalkylalkyl or C5.12 heterocycloalkylalkyl, is optionally substituted with ORa, cyano, amino, halo, C\.e alkyl, Ce-io aryl, C4.10 heteroaryl, C3.8 cycloalkyl, C3.? heterocycloalkyl, C3.8 heterocycloalkenyl C7-i4 arylalkyl, C4.14 heteroarylalkyl, C5.12 cycloalkylalkyl and C5.12 heterocycloalkylalkyl; halogen is selected from F, Cl, Br and I; and n is 0, 1, 2, or 3.
According to a separate embodiment, the invented compounds are substituted oxindole compounds of Formula I:
Figure imgf000012_0001
I or pharmaceutically acceptable salts thereof, wherein:
R1 is selected from -(CH2)nRa, -CH(OH)Ra, -CH(ORb)Ra, and -C(O)Ra, or is selected from ORa, SRa, SORa, SO2Ra and NRaRb;
R2 and R3 are independently selected from H, halogen, OH, ORa, 0WRa, Ci-6 alkyl, and WCi-6 alkyl, wherein Ci_6 alkyl or ORa, is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, Ci_6 haloalkyl, C3.8 cycloalkyl, C6.io aryl and C4.10 heteroaryl; or R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, Ci_6 haloalkyl, C3.8 cycloalkyl, C6-Io aryl and C4.10 heteroaryl;
R4 is independently selected from H, d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-Io aryl, C4_i0 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone and -(CH2)n-Ci_6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, ORa, Ci-6 alkyl, Ci.6 haloalkyl, C3.8 cycloalkyl, WC3-8 cycloalkyl, C6-io aryl and C4.10 heteroaryl; at each occurrence W is -(CH2)n- or -C(O)-; at each occurrence, Ra and Rb are independently selected from H, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2.6 alkynyl, C6-io aryl, C4.10 heteroaryl, C3.8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 heterocycloalkenyl C7-14 arylalkyl, C4.14 heteroarylalkyl, C5.12 cycloalkylalkyl and C5.12 heterocycloalkylalkyl, each of which is optionally substituted with ORa, cyano, amino, halo, Ci_6 alkyl, C6. 10 aryl, C4-I0 heteroaryl, C3.8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl C7-I4 arylalkyl, C4.14 heteroarylalkyl, C5.12 cycloalkylalkyl and C5.12 heterocycloalkylalkyl; at each occurrence, halogen is selected from F, Cl, Br and I; and at each occurrence, n is 0, 1, 2, or 3.
In some embodiments, R1 is -N(Ra)Rb; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxy cycloalkyl, C5.7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3.8 cycloalkyl, C6.io aryl and C4.10 heteroaryl; and R4 is independently selected from H, Ci -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.8 cycloalkyl, WC3.8 cycloalkyl, C6.w aryl, C4-I0 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone and -(CH2)n-Ci_6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3.8 cycloalkyl, C6.io aryl and C4-Io heteroaryl.
In some embodiments, R1 is -N(Ra)Rb and at least one of Raand Rb are hydrogen or Raand Rb, together with the N atom to which they are attached, join to form a 4-6 memebered heterocycloalkyl ring.
In some embodiments, R1 is a methylene radical -(CH2)n- further attached to substituents selected from Cβ-io aryl, C4-I0 heteroaryl, benzodioxanyl, oxazolidinonyl, -(CH2)n-Ci_6 haloalkyl, C3.8 cycloalkyl and Ci_6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, and Ci_6 haloalkyl, C3.8 cycloalkyl, WC3.8 cycloalkyl, C6. 10 aryl and C4.10 heteroaryl.
In some embodiments, R1 is -ORa; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5- C7 oxy cycloalkyl, Cs_7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6_io aryl and C4-I0 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6_i0 aryl, C6-I0 heteroaryl, -(CH2)n-benzodioxane, -(C^)n- oxazolidinone, -(CH2)n-Ci_6 haloalkyl, -(C^)n- C3.8 cycloalkyl and Ci_6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6-I0 aryl and C4-I0 heteroaryl.
In some embodiments, R1 is -0-, substituted with substituents selected from d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-I0 aryl, C4-I0 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6-I0 aryl and C4-I0 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C6-I0 aryl, C4-I0 heteroaryl, -(C^)n- C3.8 cycloalkyl, -(C^)n- C3.8 heterocycloalkyl, -(C^)n- Ci-6 haloalkyl, -(CH2)n- and Ci-6 haloalkyl. In some embodiments, R1 is -SRa; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5- C7 oxy cycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3-8 cycloalkyl, Cβ-io aryl and C4.10 heteroaryl; and R4 is independently selected from H, d-e alkyl, C2-6 alkenyl, C2-6alkynyl, C6-io aryl, C4.10 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone, -(CH2)n-Ci_6 haloalkyl, -(CH2)n- C3.8 cycloalkyl and C\.e haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6_io aryl and C4_i0 heteroaryl.
In some embodiments, R1 is -S-, substituted with substituents selected from Cr6 alkyl, C2-6 alkenyl, C2-6alkynyl, Cβ-io aryl, C4.10 heteroaryl, -(CH2)n-benzodioxane, -(CH2Voxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.5 cycloalkyl, C6-io aryl and C4.10 heteroaryl; and R4 is independently selected from H, Ci-6 alkyl, C6_io aryl, C4.10 heteroaryl, -(CH2)n- C3.8 cycloalkyl, -(CH2)n- C3.8 heterocycloalkyl, -(CH2V Ci-6 haloalkyl, -(CH2)n- and Q-6 haloalkyl.
In some embodiments, R1 is -S(=O)Ra; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6.io aryl and C4.10 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-Io aryl, C4_io heteroaryl, -(CH2)n-benzodioxane, -(CH2),,- oxazolidinone, -(CH2)n-Ci_6 haloalkyl, - (CH2)n- C3_8 cycloalkyl and Ci_6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6_i0 aryl and C4-10 heteroaryl.
In some embodiments, R1 is -S(=0)-, substituted with substituents selected from d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C4.10 heteroaryl, -(CH2)n-benzodioxane, -(CH2Voxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6.io aryl and C4.10 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C6_i0 aryl, C4-I0 heteroaryl, -(CHz)n- C3_8 cycloalkyl, -(CH2V C3_8 heterocycloalkyl, -(CH2V Ci-6 haloalkyl, -(CH2V and Ci-6 haloalkyl.
In some embodiments, R1 is -S(=O)(O)Ra; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6-Io aryl and C4-10 heteroaryl; and R4 is independently selected from H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-io aryl, C4.10 heteroaryl, -(CH2)n-benzodioxane, -(CH2V oxazolidinone, -(CH2V C1-6 haloalkyl, -(CH2)n- C3.8 cycloalkyl and Ci-6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3_8 cycloalkyl, C6-Io aryl and C4.10 heteroaryl.
In some embodiments, R1 is -S(=0)(0)-, substituted with substituents selected from Cr6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6-I0 aryl, C4-10 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.? cycloalkyl, C6-I0 aryl and C4.10 heteroaryl; and R4 is independently selected from H, Ci-6 alkyl, C6_io aryl, C4.10 heteroaryl, -(CH2V C3.8 cycloalkyl, -(CH2)n- C3.8 heterocycloalkyl, -(CH2)n- Ci-6 haloalkyl, -(CH2)n- and Ci_6 haloalkyl.
In some embodiments, R1 is -C(=O)Ra; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6-io aryl and C4.10 heteroaryl; and R4 is independently selected from H, Ci -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6_io aryl, C4_io heteroaryl, -(CH2)n-benzodioxane, -(CH2V oxazolidinone, -(CH2)n-Ci_6 haloalkyl, - (CH2V C3-8 cycloalkyl and Ci_6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6_i0 aryl and C4.10 heteroaryl.
In some embodiments, R1 is -C(=0)- , substituted with substituents selected from Cp6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cβ-io aryl, C4.10 heteroaryl, -(CH2)n-benzodioxane, -(CH2Voxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.? cycloalkyl, C6-io aryl and C4.10 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C640 aryl, C4-10 heteroaryl, -(CH2V C3.8 cycloalkyl, -(CH2V C3.8 heterocycloalkyl, -(CH2)n- Ci.6 haloalkyl, -(CH2V and Ci_6 haloalkyl.
In some embodiments, R4 is -(CH2)n-C3.7 cycloalkyl or C6-io aryl and C4-I0 heteroaryl, wherein each of C6_io aryl and C4-I0 heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, 0Ra, Cr6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-I0 aryl, C640 heteroaryl, -(CH2VCi-6 haloalkyl, -(CH2V, Ci-6 haloalkyl, C3.8 cycloalkyl, C6-I0 aryl and C6-I0 heteroaryl.
In some embodiments, R4 is -(CH2)-cyclopropyl, 0Ra, C6-I0 aryl, C4-I0 heteroaryl, substituted C6-I0 aryl, or substituted C4-I0 heteroaryl.
In some embodiments, R4 is C6-I0 aryl or C6-I0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra and Ci-6 alkyl.
In some embodiments, Ra is Ci-6 haloalkyl.
In some embodiments, halogen or halogen OfCi-6 haloalkyl is fluoro. 20. In some embodiments, Ra is CF3 or OCF3.
In some embodiments, R1 is -CH(0H)Ra; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6-I0 aryl and C4.10 heteroaryl; and R4 is independently selected from H, Ci -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-Io aryl, C4_io heteroaryl, -(CH2)n-benzodioxane, -(CH2V oxazolidinone, -(CH2)n-Ci.6 haloalkyl, - (CH2)n- C3_8 cycloalkyl and Ci-6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3-8 cycloalkyl, C6-I0 aryl and C4.10 heteroaryl.
In some embodiments, R1 is -CH(OH)-, substituted with substituents selected from Cr6 alkyl, C2- 6 alkenyl, C2-e alkynyl, C6_io aryl, C4.10 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3_s cycloalkyl, C6-I0 aryl and C4_io heteroaryl; and R4 is independently selected from H, Ci-6 alkyl, C640 aryl, C4-I0 heteroaryl, -(CH2V C3-8 cycloalkyl, -(CH2V C3-8 heterocycloalkyl, -(CH2)n- Ci_6 haloalkyl, -(CH2V and Ci_6 haloalkyl.
In some embodiments, R4 is -(CH2)n-C3.7 cycloalkyl, C6_i0 aryl or C4-I0 heteroaryl, wherein each of C6-Io aryl and C4-I0 heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, 0Ra, Cr6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-I0 aryl, C6.w heteroaryl, -(CH2VCi-6 haloalkyl, -(CH2V, Ci-6 haloalkyl, C3_8 cycloalkyl, C6-I0 aryl and C6-I0 heteroaryl.
In some embodiments, R4 is -(CH2)-cyclopropyl, 0Ra, C6-I0 aryl, C4-I0 heteroaryl, substituted C6-I0 aryl, or substituted C4-I0 heteroaryl.
In some embodiments, R4 is C6-io aryl or C6-I0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra and Ci-6 alkyl.
In some embodiments, Ra is Ci-6 haloalkyl.
In some embodiments, halogen or halogen OfCi-6 haloalkyl is fluoro.
In some embodiments, Ra is CF3 or OCF3.
In some embodiments, R1 is -CH(ORb)Ra; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6-I0 aryl and C4-I0 heteroaryl; and R4 is independently selected from H, Ci -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6.io aryl, C4.10 heteroaryl, -(CH2)n-benzodioxane, -(CH2V oxazolidinone, -(CH2VCi-6 haloalkyl, - (CH2V C3_8 cycloalkyl and Ci-6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6-I0 aryl and C4-I0 heteroaryl.
In some embodiments, R1 is -CH(ORa)-, substituted with substituents selected from d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-I0 aryl, C4-io heteroaryl, -(CH2)n-benzodioxane, -(CH2)n-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6-I0 aryl and C4-I0 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C6-I0 aryl, C4-I0 heteroaryl, -(CH2V C3.8 cycloalkyl, -(CH2V C3.8 heterocycloalkyl, -(CH2)n- Ci-6 haloalkyl, -(CH2V and Ci-6 haloalkyl. In some embodiments, R1 is -(CH2V; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5- C7 oxy cycloalkyl, C5.7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3-8 cycloalkyl, C6-I0 aryl and C4.10 heteroaryl; and R4 is independently selected from H, d-e alkyl, C2-6 alkenyl, C2-6alkynyl, C6-io aryl, C4_io heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone, -(CH2)n-Ci_6 haloalkyl, -(CH2)n- C3.8 cycloalkyl and C\.e haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6_io aryl and C4_i0 heteroaryl.
In some embodiments, R1 is -(CH2)n-, substituted with substituents selected from Ci -6 alkyl, C2-e alkenyl, C2-6alkynyl, Cβ-io aryl, C4-I0 heteroaryl, -(CH2)n-benzodioxane, -(CH2Voxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.5 cycloalkyl, C6-I0 aryl and C6-Io heteroaryl; and R4 is independently selected from H, Ci-6 alkyl, C6-I0 aryl, C4.10 heteroaryl, -(CH2)n- C3_8 cycloalkyl, -(CH2)n- C3_8 heterocycloalkyl, -(CH2V Ci-6 haloalkyl, -(CH2)n- and Q-6 haloalkyl.
In some embodiments, R4 is -(CH2)n-C3.7 cycloalkyl or C6-io aryl and C6-io heteroaryl, wherein each of C6-I0 aryl and C6-I0 heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, 0Ra, Ci-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6-I0 aryl, C4-I0 heteroaryl, -(CH2VCi-6 haloalkyl, -(CH2V, Ci_6 haloalkyl, C3.8 cycloalkyl, C6-I0 aryl and C4_i0 heteroaryl.
In some embodiments, R4 is -(CH2)-cyclopropyl, 0Ra, C6-I0 aryl, C4-I0 heteroaryl, substituted C6.io aryl, or substituted C4-I0 heteroaryl.
In some embodiments, R4 is C6-I0 aryl or C4-I0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra and Ci-6 alkyl.
In some embodiments, Ra is Ci-6 haloalkyl.
In some embodiments, halogen or halogen of Ci-6 haloalkyl is fluoro.
In some embodiments, Ra is CF3 or OCF3.
At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. It is further intended that the compounds of the invention are stable. As used herein "stable" refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. As used herein, the term "alkyl" is meant to refer to a saturated hydrocarbon group, which is straight-chained or branched. Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n- propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An alkyl group can contain from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Example alkenyl groups include ethenyl, propenyl, and the like.
As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Example alkynyl groups include ethynyl, propynyl, and the like. As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents.
Example haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, and the like.
As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl groups comprise from 6 to about 20 carbon atoms, including comprising from 6 to 10 carbon atoms.
As used herein, "arylalkyl" refers to an alkyl group substituted by an aryl group. Examplary arylalkyl groups include, but are not limited to, benzyl and phenethyl.
As used herein, "cycloalkyl" refers to non-aromatic carbocycles including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems, including spirocycles. In some embodiments, cycloalkyl groups comprise from 3 to 20 carbon atoms, including comprising from 3 to 14 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms or 3 to 6 carbon atoms. Cycloalkyl groups can further comprise 0, 1 or 2 double bonds and'or 0, 1, or 2 triple bonds. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, pentene, hexane, and the like. A cycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non-aromatic portion. One or more ring- forming carbon atoms of a cycloalkyl group can be oxidized, for example, having an oxo or sulfido substituent. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
As used herein, a "cycloalkylalkyl" group refers to an alkyl group substituted by a cycloalkyl group. An examplary cycloalkylalkyl group includes, but is not limited to cyclopentylmethyl and cyclohexylmethyl.
As used herein, a "heteroaryl" group refers to an aromatic heterocycle comprising at least one heteroatom ring member selected from sulfur, oxygen and nitrogen. Heteroaryl groups include monocyclic and fused, polycyclic (e.g., heteroaryl comprising 2, 3 or 4 fused rings) systems. Any ring- forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety or can be functionalized to form an N-functionalized group (e.g. N-alkyl or N-aryl). Examples of heteroaryl groups include without limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazmyl, furyl, quinolyl, isoquinolyl, thienyl, lmidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purmyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group comprises from 3 to 20 carbon atoms, and in further embodiments comprises from about 4 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 6 to about 10 ring-forming atoms. In some embodiments, the heteroaryl group comprises from 1 to 4 heteroatoms, including comprising from 1 to 3 heteroatoms or 1 to 2 heteroatoms.
As used herein, a "heteroarylalkyl" group refers to an alkyl group substituted by a heteroaryl group. An example of a heteroarylalkyl group is pyridylmethyl.
As used herein, "heterocycloalkyl" refers to a non-aromatic heterocycle where one or more of the ring-forming atoms comprises a heteroatom selected from O, N and S. As used herein, "heterocycloalkenyl" refers to a partially-unsaturated heterocycle or a heterocycle comprising at least one unsaturated bonding of carbon atoms or carbon and heteroatoms, where one or more of the ring- forming atoms comprises a heteroatom selected from O, N and S. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) ring systems as well as spirocycles. Examplary "heterocycloalkyl" groups include, but are not limited to, morpholino, thiomorpholmo, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-l,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidmyl, thiazolidinyl, imidazolidinyl, and the like. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles. A heterocycloalkyl group having one or more fused aromatic rings can be attached though either the aromatic or non- aromatic portion. Also included in the definition of heterocycloalkyl are moieties where one or more ring-forming atoms is substituted by 1 or 2 oxo or sulfido groups. In some embodiments, the heterocycloalkyl group comprises from 4 to 20 carbon atoms, and in further embodiments from 5 to 10 carbon atoms. In some embodiments, the heterocycloalkyl group comprises 5 to 20, 5 to 14, 5 to 12, or 5 to 10 ring-forming atoms. In some embodiments, the heterocycloalkyl group further comprises 1 to 4 heteroatoms, including comprising from 1 to 3, or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group further comprises 0 to 2 double bonds. In some embodiments, the heterocycloalkyl group comprises 0 to 2 triple bonds.
As used herein, "heterocycloalkylalkyl" refers to an alkyl group substituted by a heterocycloalkyl group.
As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo. As used herein, "haloalkyl" refers to an alkyl group substituted by one or more halogen atoms.
Examples of haloalkyl groups include CF3 and CF2CF3.
As used herein, "alkoxy" refers to an -O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that comprise asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, IH- and 3H-imidazole, IH-, 2H- and 4H- 1,2,4-triazole, IH- and 2H- isoindole, and IH- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
The term, "compound," as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted.
All compounds, and pharmaceuticaly acceptable salts thereof, are also meant to include solvated or hydrated forms.
In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions comprising at least 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which comprises a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
Synthesis
The compounds of the present invention can be prepared from readily available starting materials in a variety of ways known to one skilled in the art of organic synthesis. For example, they can be synthesized via the reaction pathways and techniques as described below.
Scheme 1
Figure imgf000021_0001
Figure imgf000021_0002
Certain invented benzyl amine compounds 5 were prepared according to Scheme 1. 5-Nitroisatin (1) was converted to the corresponding cyclic acetal 2 using 1,3 -propanediol and/>-TsOH in benzene. Alkylation of the oxindole nitrogen with organohalides produced nitro acetal compound 3. Reduction of the NO2 group to the corresponding amine compound 4 was accomplished by catalytic hydrogenation using H2A 0% Pd/C. Functionalization of the amine 4 with benzaldehydes under reductive amination conditions produced invented benzyl amine compounds 5. Scheme 2
Figure imgf000022_0001
Certain invented 5 -Aryl amine compounds 6 were prepared from amine compounds 4 using aryl boronic acids, copper acetate, amine bases such as Et3N in aprotic solvents, such as CH2CI2, as summarized in Scheme 2.
Scheme 3
Figure imgf000022_0002
Certain invented disubstituted amino compounds were prepared according to Scheme 3. Amine compound 4 was protected as the trifluoroacetamide compound 7 by treatment with trifluoroacetic anhydride and Et3N in CH2CI2. Alkylation of the nitrogen of compound 7 with organohalides produced compound 8, which can be deprotected under basic conditions to provide deprotected compound 9. Invented compounds (10) were then prepared from aryl boronic acids, copper acetate, amine bases such as Et3N in aprotic solvents such as CH2CI2.
Scheme 4
Figure imgf000023_0001
Other invented 5-amino compounds (10) were also prepared according to Scheme 4. 5-Iodo- or 5-bromo isatin compounds 11 were converted to the corresponding cyclic acetal compounds 12 using 1,3- propanediol andp-TsOH in benzene. Alkylation of the oxindole nitrogen of compounds 12 with organohalides produced compounds 13. Amidation was accomplished via Buchwald amination conditions with an amine in the presence of a catalyst, such as Pd2(dba)3 and a ligand such as cymap, to provide other examples of invented 5-amino compounds 10.
Scheme 5
Figure imgf000023_0002
16
Figure imgf000023_0003
Certain invented sulfides, sulfoxides and sulfone compounds (17 and 19, respectively) were prepared according to Scheme 5. 5-Iodo-isatin (14) was converted to the corresponding cyclic acetal compounds 15 using 1,3 -propanediol or ethylene glycol and/?-TsOH in benzene with heating. Aryl sulfide compounds 16 were prepared from corresponding compounds 15 using aryl thiols, in the presence of CuI and ethylene glycol in isopropanol (Org Lett. 2002, 4, 3517) or CoCl2(dppe), zinc and pyridine in acetonitrile (Org. Lett 2006, 8, 5613). Oxidation to corresponding sulfoxide or sulfone compounds (18) was accomplished with m-CPBA. N-Alkyl oxmdole compounds 17 or 19, respectively were prepared from corresponding compounds 16 or 18 using organohahdes and K2CO3 in DMF with heating. Corresponding N-Aryl oxmdole compounds 17 or 19 were prepared from respective compounds 16 or 18 using aryl boronic acids, copper acetate, amine bases such as EtrN in aprotic solvents such as CH2Cl2.
Scheme 6
Figure imgf000024_0001
Other invented sulfides and sulfone compounds 17 and 19, respectively, were alternately prepared according to Scheme 6. TIP S -protected thiol compounds 20 were prepared from protected 5-iodoisatin compound 15 by the treatment with appropriate triisopropylthiols, KH and Pd(PPl^)4 in THF (J.Med. Chem. 2001, 44, 4393). Aryl sulfide compounds were prepared from compound 20 using appropriate aryl iodides in the presence of CuI and ethylene glycol in isopropanol. Oxidation, arylation or alkylation to respective compounds 17 or 19, can be accomplished, as summarized in Scheme 5.
Scheme 7
Figure imgf000025_0001
Certain invented 5-Aryl ether compounds (25) were prepared according to the procedure of Scheme 7. 5-methoxyisatin (20) was converted to compound 22 via alkylation with cyclopropylmethyl bromide followed by demethylation of compound 21 with boron tribromide in dichloromethane. Compound 22 was then converted to compound 23 with 1,3 -propanediol and j>-TsOH in toluene. Reaction of compound 23 with an iodonium tetrafluoroborate salt (24) in presence of copper and triethylamine in dichloromethane produced invented 5-Aryl ether compounds 25.
Alternatively, reaction of compound 23 with a substituted fluoropyridine (27) in presence of cesium carbonate in dichloromethane also produced other invented 5-Aryl ether compounds (26).
Scheme 8
Figure imgf000026_0001
32 36
Certain invented substituted oxmdole compounds (32) were prepared according to the procedure of Scheme 8. Thus 5-iodoisatm (27) was converted to acetal compound (28) with 1,3-propanediol anάp- TsOH m toluene. Alkylation of Nl was accomplished using organohalides with CS2CO3 m DMF at 60 0C, and produced N-functionalized ketone componds (29). Carbonylation of N-functionalized compounds 29 in presence of substituted boronic acid, carbon monoxide and dichloro-bis- triphenylphosphinepallidium in toluene produced ketone compounds (30). Sodium borohydride reduction of ketone compounds 30 produced hydroxyl compounds (31). Deoxygenation of hydroxyl compounds 31 with triethylsilane and trifluoroacetic acid in dichloromethane produced methylene bridged compounds (32).
Alternatively, other substituted oxindole compounds (36) were prepared as shown in Scheme 8. Oxindole compound (28) was converted to compound (33) via reaction with appropriate arylboronic acids in presence of copper acetate, triethylamine and 4 A molecular sieves in dichloromethane. Carbonylation of compound 33 in presence of substituted boronic acids, carbon monoxide and dichloro-bis- triphenylphosphinepallidium in toluene produced ketone compounds (34). Sodium borohydride reduction of ketone compounds 34 produced hydroxyl compounds (35). Deoxygenation of hydroxyl compounds 35 with triethylsilane and trifluoroacetic acid in dichloromethane produced methylene bridged compounds (36).
Scheme 9
Figure imgf000027_0001
Other invented substituted oxindole compounds (39) were synthesized according to Scheme
9. Thus oxindole compounds 38 were synthesized by reaction of N-functionalized compounds 33 with an appropriate borate 37 in DMF in presence of tetrakis(triphenylphosphine)palladium and sodium carbonate. Subsequent catalytic hydrogenation of the alkene group in compound 38 in a Parr apparatus at 40 psi of hydrogen produced the other invented 1, 3, 5-substituted oxindole compounds 39. Conventional synthetic reagents and conditions were employed in accordance with methods for preparing compounds of the invention. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, however, alteration of such conditions may be determined and adjusted by persons skilled in the art.
The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection of certain functional groups attached to the oxoindole core of the invented compounds, and selection of appropriate protecting groups may be determined by one skilled in the art. The chemistry of protecting groups is described, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991.
The reactions of the processes described herein can be carried out in suitable solvents, which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures, which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.
Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallization using a "chiral resolving acid" which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The selection of a suitable elution solvent composition may be determined by one skilled in the art.
Methods of Use
Compounds of this invention are able to interact with the CB2 receptor and therefore modulate the receptor's activity. The term "modulate" is meant to refer to an ability to increase or decrease activity of an the receptor. Modulation can occur in vitro or in vivo. Modulation can further occur in a cell. Accordingly, compounds of the invention can be used in methods of modulating the activity of the CB2 receptor, by contacting the receptor with one or more of the compounds or compositions described herein. As used herein, the term "contacting" refers to bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a compound of the invention with the CB2 receptor includes the administration of a compound of the present invention to an individual or patient, such as a human, as well as, for example, introducing a compound of the invention into a sample comprising a cellular or purified preparation of the receptor.
As used herein, the term "individual" or "patient," used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
The compounds of the present invention can act as CB2 receptor agonists. Thus, these compounds can be used to treat CB2-mediated disorders, such as CB2 agonists are potential drug candidates for reducing treating pain (e.g., chronic inflmmartory pain, post surgical pain, neuropathic pain, bone pain), osteoarthritis, atherosclerosis, osteoporosis, and cancer (e.g., glioma). The treatment includes administration of a therapeutically effective amount of one or more of the invented 3-substituted oxindole compounds described above to a patient in need thereof. As used herein, the phrase "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
As used herein, the term "treating" or "treatment" refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
Examplary cancers treatable by the invented compounds herein include, but are not limited to, glioma, bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck cancer, cancer of the kidney, liver cancer, lung cancer, nasopharygeal cancer, ovarian cancer, pancreatic cancer, prostate cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, MFH/fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma, multiple myeloma, lymphoma, adult T cell leukemia, acute myelogenous leukemia, chronic myeloid leukemia, glioblastoma, astrocytoma, melanoma, mesothelioma, or WiIm' s tumor, and the like.
Combination Therapy
One or more additional pharmaceutical agents or treatment methods can be used in combination with the compounds of the present invention for treatment of the diseases, disorders or conditions described herein. For example, one or more of the above-described 3-substituted oxindole compounds can be used together with an anti-inflammatory agent, an anti-cancer agent, an analgesic, or other therapeutic agent useful in treating pain, cancer, osteoarthritis, atherosclerosis, osteoporosis or other disease. The agents or therapies can be administered together -with the compounds of the invention (e.g., combined into a single dosage form), or the agents or therapies and may be administered simultaneously or sequentially by separate routes of administration.
Pharmaceutical Formulations and Dosage Forms
When employed as pharmaceuticals, the compounds of the invention can be administered in the form of pharmaceutical compositions, which is a combination of a compound of the invention, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction by balloon catheter or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
This invention also includes pharmaceutical compositions, which comprise, as the active ingredient, one or more of the compounds of the invention above in combination with one or more pharmaceutically acceptable carriers. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments comprising, for example, up to 10 % by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to an average particle size of less than 200 mesh. If the active compound is substantially water- soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. an average particle size of about 40 mesh.
The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by methods described in International Patent Application No. WO 2002/000196.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit comprising a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above comprising from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may comprise suitable pharmaceutically acceptable excipients as described supra, and in some embodiments, the compositions are administered by an oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices, which deliver the formulation in an appropriate manner. The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous earner prior to administration. The pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts. The therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution comprising about 0.1 to about 10% w/v (weight/volume) of the compound for parenteral adminstration. Some typical dose ranges are from about 1 mg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
Kits
The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of diseases, such as pain or cancer and other diseases referred to herein, which include one or more containers comprising a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, or pharmaceutically acceptable salt thereof. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and'or guidelines for mixing the components, can also be included in the kit.
The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters, wrhich can be changed or modified to yield essentially the same results. The compounds of the Examples were found to be CB2 agonists according to one or more of the assays provided herein.
EXAMPLES
Analytical LC/MS: Samples were analyzed on an Agilent LC-1100-MSD. The mass spectrometer, utilized to confirm the integrity of the compound, was a single quadrapole mass filter scanning from 100-1000 Da. The PDA, used to assess compound purity, monitors 254, 215, 230, 280, and 300 nm wavelengths. The compound purity was reported at 254 nm unless stated otherwise. The HPLC mobile phase flow rate was 0.8 ml/mm. Eluent A was 0.1 % HCO2H in water and eluent B was 0.1 % HCO2H in ACN. The HPLC mobile phase gradient wras initiated at 100% eluent A followed by a linear increase to 100% eluent B in 2.5 minutes. The gradient was held at 100% eluent B for an additional 1.5 minutes (total time 4.0 minutes). The HPLC rapidly equilibrated the column back to 100% eluent A for an additional 1.5 minutes for subsequent injections. The total HPLC/MS run time was 5.5 minutes. Compounds were diluted to ~1.0 mg/niL in DMSO. The analysis injection volume was 5 μL. The HPLC column used was a Thermo Electron Corporation, Aquasil Cl 8, 50 x 2.1 mm, 5 μm particle size. Preparative reverse-phase HPLC (RP-HPLC):
Compounds were in dissolved in 2 niL of 1 : 1 DMSO:MeCN, filtered through a 0.45 μm GMF, and purified on a Gilson HPLC, using a Phenomenex LUNA Cig column: 60 mm x 21.2 mm I.D., 5 μm particle size: with ACNZH2O (containing 0.2% TFA) gradient elution (95:5 H2O:MeCN to 10:90 H2OMeCN; 8 minutes running time.
Example 1 S'-benzoyl-l'-^yclopropylmethy^spiroIl^-dioxane-l^'-indoll-lXl'/^-one
Figure imgf000034_0001
Step 1
5'-Iodospiro[[l,3]dioxane-2,3'-indolin]-2'-one
Figure imgf000034_0002
A stirred mixture containing 5-iodoisatin (4.06 g, 14.9 mmol), 1,3-propanediol (3.23 mL, 44.6 mmol) and p-toluene sulfonic acid monohydrate (0.565 g, 2.97 mmol) in benzene (149 mL) was heated at reflux temperature for 15 hours. The reaction was cooled to room temperature, washed with saturated aqueous NaHCO3 (3 x), then dried (Na2SO4) and concentrated. The crude product was purified on RediSep silica eluting with a 0 to 100% EtOAc/hexane linear gradient to give 4.00 g (81%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): consistent.
Step 2 r-(cyclopropylmethyl)-5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(r//)-one
Figure imgf000034_0003
5'-Iodospiro[[l,3]dioxane-2,3'-indolin]-2'-one (5.1Og, 15.40mmol) was dissolved in DMF (150 mL) under a N2 atmosphere. To this solution was added Cs2CO3 (15.06g, 46.21mmol) and cyclopropylmethyl bromide (4.48mL, 46.21mmol), and this mixture was heated to 6O0 C. After stirring for 1 hour, TLC indicated reaction was complete, so reaction mixture was diluted with EtOAc, then washed with H2O, followed by brine. The organic layer was dried over Na2SO4, then concentrated and purified by flash chromatography on silica gel to afford product as a white solid (5.5Og, 93%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 385.9 (M+H). Step 3 5'-benzoyl-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one
Figure imgf000035_0001
l'-(cyclopropylmethyl)-5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one (LOOg, 2.59mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.054g, 0.078mmol), K2CO3 (1.07g, 7.77mmol), and phenyl boronic acid (0.35g, 2.86mmol) were added to a flask fitted with a reflux condenser, a septum inlet, and a magnetic stir bar. The flask was flushed with carbon monoxide and then charged with toluene (20 niL). The mixture was then stirred at 80° C and exposed to an atmosphere of carbon monoxide via a balloon. After stirring overnight, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, then washed with H2O, followed by brine. The organic layer was dried over Na2Sθ4, concentrated and purified by flash chromatography on silica gel to afford product as a white solid (0.7 Ig, 75%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 364.1 (M+H).
A procedure similar to that of Example 1, using different boronic acids, provided Examples 2 - 39. The compounds and their analytical data are shown in Table 1.
Table 1: Compounds Prepared According to the Procedure of Example 1.
Figure imgf000035_0002
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0002
Example 40 r-(cyclopropylmethyl)-5?-[hydroxy(phenyl)methyl]spiro[l,3-dioxane-2,3?-indol]-2'(r//)-one
Figure imgf000038_0001
5'-benzoyl-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one (0.3Og, 0.83mmol) was dissolved in THF (8 mL) and to this solution was added NaBH4 (0.031g, 0.826mmol). After stirring for 1 hour, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, then washed with H2O, followed by brine. The organic layer was dried over Na2SO4, then concentrated and purified by flash chromatography on silica gel to afford product as a white solid (0.29g, 96%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 366.1 (M+H). A procedure similar to that of Example 40, using Examples 2-39 (see Table 1), provided Examples 41-77. The compounds and their analytical data are shown in Table 2.
Table 2: Compounds Prepared According to the Procedure of Example 40.
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0002
Example 78 5'-benzyl-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one
Figure imgf000042_0001
r-(cyclopropylmethyl)-5'-[hydroxy(phenyl)metriyl]spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one (0.24g, 0.66mmol) was dissolved in methylene chloride (6 mL) and was then treated with Et3SiH (0.12mL, 0.72mmol). This solution was cooled to O0 C and then TFA (0.15mL, 1.97mmol) was added dropwise. TLC analysis confirmed reaction was complete immediately after the addition of TFA, so the reaction mixture was treated with NaHCO3, and then diluted with methylene chloride. The organic layer was separated, washed with brine, then dried over Na2SO4 and purified by flash chromatography on silica gel to afford product as a colorless oil (0.15g, 66%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 350.1 (M+H).
A procedure similar to that of Example 78, using Examples 41-77, provided Examples 79- 112.
The compounds and their analytical data are shown in Table 3.
Table 3: Compounds Prepared According to the Procedure of Example 78.
Figure imgf000042_0003
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0003
Example 113 l'-phenyl-5'-[2-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one
Figure imgf000045_0001
Step I
5 '-iodo-1 '-phenylspiro[l,3-dioxane-2,3 '-indolJ-2 '(I 'H)-one
Figure imgf000045_0002
5'-Iodospiro[[l,3]dioxane-2,3'-indolin]-2'-one (2.5Og, 7.55mmol), phenylboronic acid (2.76g,
22.65mmol), Cu(OAc)2 (2.74g, 15.10mmol), and 4 Angstrom molecular sieves (3.0Og) were stirred together in CH2Cl2 (75 mL). To this stirring solution was added Et3N (3.25mL, 22.65mmol) and this mixture was allowed to stir overnight. TLC analysis indicated reaction had occurred, although starting material still persisted after 48 hours of stirring. Reaction was stopped, diluted with CH2Cl2 and then filtered through celite. The organic layer was washed with NaHCO3, followed by brine, then was dried over Na2SOzI, concentrated, and purified by flash chromatography on silica gel to afford product as a white solid (1.82g, 59%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) mlz 407.9 (M+H). Step 2
1 '-phenyl-5 '-[2-(trifluoromethyl)benzoylJspiro[l,3-dioxane-2,3 '-indolJ-2 '(I Η)-one
Figure imgf000046_0001
5'-iodo-l'-phenylspiro[l,3-dioxane-2,3'-indol]-2'(rH)-one (0.28g, 0.68mmol), trans- dichlorobis(triphenylphosphine)palladium(II) (0.014g, 0.020mmol), K2CO3 (0.282g, 2.04mmol) and 2- (trifluoromethyl)-phenylboronic acid (0.15 Ig, 0.82mmol), were added to a flask fitted with a reflux condenser, a septum inlet, and a magnetic stir bar. The flask was flushed with carbon monoxide and then charged with toluene (20 mL). The mixture was then stirred at 80° C under an atomosphere of carbon monoxide via balloon. After stirring overnight, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, washed with H2O, then followed by brine. The organic layer was dried over Na2SO4, concentrated and purified by flash chromatography on silica gel to afford product as a white solid (0.22g, 72%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 454.1 (M+H).
A procedure similar to that of Example 113, using different aryl boronic acids for the N-arylation described in step 1, and different aryl boronic acids for the carbonylation described in step 2, provided Examples 114-134. The compounds and their analytical data are shown in Table 4.
Table 4: Compounds Prepared According to the Procedure of Example 113.
Figure imgf000046_0002
Figure imgf000047_0001
Example 135 5'-[(2-fluorophenyl)(hydroxy)methyl]-r-phenylspiro[l,3-dioxane-2,3'-indol]-2'(r//)-one
Figure imgf000048_0001
5T-(2-fluorobenzoyl)-r-phenylspiro[l,3-dioxane-2,3'-indol]-2T(rH)-one (0.16g, 0.39mmol) was dissolved in TΗF (4 mL) and to this solution were added NaBH4 (0.044g, 1.17mmol). After stirring for 1 hour, TLC analysis indicated the reaction to be complete, so reaction mixture was diluted with EtOAc, then washed with H2O, followed by brine. The organic layer was dried over Na2SO4, concentrated and then purified by flash chromatography on silica gel to afford product as a white solid (0.1 Og, 65%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 406.2 (M+H).
A procedure similar to that of Example 135, using Examples 114-134 (see Table 4), provided Examples 136-155. The compounds and their analytical data are shown in Table 5.
Table 5: Compounds Prepared According to the Procedure of Example 135.
Figure imgf000048_0002
Figure imgf000049_0001
th1enyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one (M+.)
5 '- [hydroxy (2 -methylphenyl)methyl] - 1 '- (ES) m/z 402.2
155 phenylspirof 1 ,3 -dioxane-2,3 '-mdol]-2'( 177)-one (M+Η)
Example 156 5?-(2-fluorobenzyl)-l?-phenylspiro[l,3-dioxane-2,3'-indol]-2?(l'H)-one
Figure imgf000050_0001
5'-[(2-fluorophenyl)(hydroxy)methyl]-l'-phenylspiro[l,3-dioxane-2,3'-indol]-2'(l'H)-oiie (0.090g,
0.22mmol) was dissolved in methylene chloπde (2 mL) and was then treated with Et3SiH (39μL, 0.24mmol). The mixture was cooled to 0° C and then TFA (0.49μL, 0.66mmol) was added dropwise. TLC analysis confirmed the reaction was complete after 0.5 hour, so the reaction mixture was treated with NaHCO3, and then diluted with methylene chloπde. The organic layer was separated, washed with bπne, then dried over Na2SC^ and purified by flash chromatography on silica gel to afford product as a colorless oil (0.058g, 67%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 390 1 (M+H).
A procedure similar to that of Example 156, using Examples 136-155, provided Examples 157- 175. The compounds and their analytical data are shown m Table 6.
Table 6: Compounds Prepared According to the Procedure of Example 156.
Figure imgf000050_0002
Figure imgf000051_0001
Example 176 5?-benzoyl-r-(3,3,3-trifluoropropyl)spiro[l,3-dioxane-2,3?-indol]-2?(r//)-one
Figure imgf000052_0001
Step I
5 '-benzoylspiro[l,3-dioxane-2,3 '-indolJ-2 '(I 'H)-one
Figure imgf000052_0002
5'-Iodospiro[[l,3]dioxane-2,3'-indolin]-2'-one (3.0Og, 9.06mmol), trans-dichlorobis- (triphenylphosphine)palladium(II) (0.19g, 0.27mmol), K2CO3 (3.75g, 27.18mmol), and phenyl boronic acid (1.33g, 10.87mmol) were added to a flask fitted with a reflux condenser, a septum inlet, and a magnetic stir bar. The flask was flushed with carbon monoxide and then charged with toluene (90 mL). The mixture was then stirred at 80° C under an atmosphere of carbon monoxide via balloon. After stirring overnight, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, then washed with H2O, followed by bπne. The organic layer was dried over Na2Sθ4, concentrated and then purified by flash chromatography on silica gel to afford product as a brown solid (1.2Og, 43%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 364.1 (M+H).
Step 2
5 '-benzoyl-1 '-(3,3,3-triβuoropropyl)spiro[l,3-dioxane-2,3 '-indol]-2 '(I Η)-one
Figure imgf000052_0003
5'-benzoylspiiO[l,3-dioxane-2,3'-indol]-2'(177)-one (O.lOg, 0.28mmol) was dissolved in DMF (3.0OmL) under a N2 atmosphere. To this solution was added Cs2CO3 (0.27g, 0.83mmol) and 1- trifluoromethylpropyl iodide (0.096mL, 0.83mmol), and this mixture was heated to 6O0C. After stirring for 2 days, TLC indicated reaction was still not complete (-40% product), however, reaction was stopped regardless. Reaction mixture was diluted with EtOAc, then washed with H2O, followed by brine. The organic layer was dried over Na2SO^ concentrated and then purified by flash chromatography on silica gel to afford product as a white solid (0.044g, 39%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 406.1 (M+H). Example 177 l'-propyl-5'-[2-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3Mndol]-2'(17^-one
Figure imgf000053_0001
Step I
5 '-[2-(triflιιoromethyl)benzoyl]spiro[l,3-dioxane-2,3 '-indol]-2 '(I ϋ)-one
Figure imgf000053_0002
5'-Iodospiro[[l,3]dioxane-2,3'-indolin]-2'-one (4.0Og, 12.08mmol), trans-dichlorobis- (triphenylphosphine)palladium(II) (0.25g, 0.36mmol), K2CO3 (5.0Og, 36.21mmol), and 2-
(trifluoromethyl)-phenylboronic acid (2.66g, 14.50mmol) were added to a flask fitted with a reflux condenser, a septum inlet, and a magnetic stir bar. The flask was flushed with carbon monoxide and then charged with toluene (120 mL). The mixture was then stirred at 8O0C under an atmosphere of carbon monoxide via balloon. After stirring overnight, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, then washed with H2O, followed by brine. The organic layer was dried over Na2Sθ4, concentrated and then purified by flash chromatography on silica gel to afford product as a white solid (1.94g, 43%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 376.0 (M- H).
Example 178
r-(3,4-Difluorophenyl)-5'-phenethylspiro[[l,3]dioxane-2,3'-indolin]-2'-one
Figure imgf000053_0003
Step l
1 '-(3,4-Difluorophenyl)-5 '-iodospiro[[l,3Jdioxane-2,3 '-indolin]-2 '-one
Figure imgf000054_0001
A suspension consisting of 5'-iodospiro[[l,3]dioxane-2,3'-indolin]-2'-one (1.9 g, 5.7 mmol), 3,4- difluoro-phenylboronic acid (1.8 g, 11.5 mmol), Et3N (2.4 mL, 17 mmol), Cu(OACh (2.1 g, 11.5 mmol), and 4 A molecular sieves (2.5 g) in CH2Cl2 (100 mL) was stirred at room temperature for 24 hours. The reaction mixture was diluted with CH2CIz and then treated with aqueous NaHCO3. The organic layer was separated, filtered, concentrated, and then purified by flash chromatography on silica gel (5:1 hexane/EtOAc) to yield 2.1 g of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): consistent; MS (ES+) m/z 443.0 (M+H).
Step 2
(E)-I '-(3,4-Difluorophenyl)-5 '-styrylspiro[[l,3]dioxane-2,3 '-indolinJ-2 '-one
Figure imgf000054_0002
A suspension consisting of l'-(3,4-Difluorophenyl)-5'-iodospiro[[l,3]dioxane-2,3'-indolin]-2'-one (89 mg, 0.2 mmol), (E)-4,4,5,5-tetramethyl-2-styryl-l,3,2-dioxaborolane (184 mg, 0.8 mmol), Pd(Ph3P)4 (46 mg, 0.04 mmol), and 2 M Na2CO3 (1 mL, 2 mmol) in 3 mL of DMF was stirred at 50° C for 12 hours. The reaction mixture was diluted with EtOAc and then washed with water and brine. The organic layer was dried (MgSO4), filtered, concentrated, and then purified by flash chromatography on silica gel (hexane/EtOAc) to yield 75 mg of the title compound as a tan solid. 1H NMR (400 MHz, CDCl3): consistent; MS (ES+) m/z 419.1 (M+H). Step 3
1 '-(3,4-Difluorophenyl)-5 '-phenethylspiro[[l,3Jdioxane-2,3 '-indolinJ-2 '-one
Figure imgf000055_0001
A solution consisting of (E)-I '-(3,4-Difluorophenyl)-5'-styiylspiro[[l,3]dioxane-2,3'-indolm]-2'- one (45 mg, 0.11 mmol) in 10 mL of EtOAc was treated with 10% Pd/C and hydrogenated at 40 psi in a Parr reactor for 2 hours. The suspension was filtered, concentrated, and then purified by flash chromatography on silica gel (CH2CU) to yield 39 mg of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): consistent; MS (ES+) m/z 421.1 (M+H).
Example 179
(-)-2-[5'-{(S)-hydroxy[2-(trifluoromethyl)phenyl]methyl}-2'-oxospiro[l,3-dioxane- 2,3'-indol]- r(2Η)-yl]benzonitrile
Figure imgf000055_0002
Step 1
5 '-Iodospirof[l,3Jdioxane-2,3 '-indolin]-2 '-one
Figure imgf000055_0003
A stirred mixture containing 5-iodoisatin (4.06 g, 14.9 mmol), 1,3 -propanediol (3.23 mL, 44.6 mmol) and p-toluene sulfonic acid monohydrate (0.565 g, 2.97 mmol) in benzene (149 mL) was heated at reflux temperature for 15 hours. The reaction was cooled to room temperature, then washed with saturated aqueous NaHCO3 (3x), dried (Na2SO4) and concentrated. The crude product was purified on RediSep silica eluting with a 0 to 100% EtOAc/hexane linear gradient to give 4.00 g (81%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): consistent.
Step 2
2-(5 '-iodo-2 '-oxospirofl,3-dioxane-2,3 '-indolj-l '(2 'H)-yl)benzonitrile
Figure imgf000056_0001
5'-Iodospiro[[l,3]dioxane-2,3'-indolin]-2'-one (20.0Og, 60.40mmol) was dissolved in DMF (100.0OmL) under a N2 atmosphere. To this solution was added NaH (60%: 2.9Og, 72.48mmol) and this solution was stirred for 0.5 hour, after which the nitrile was added (19.66mL, 181.20mmol). This reaction mixture was heated to 125° C and was stirred overnight. After stirring for overnight, TLC analysis
(hexane:EtOAc: : 1 : 1) indicated reaction was nearly complete, so reaction mixture was diluted with EtOAc, washed with NaHCO3, followed by H2O. Aqueous layers were re-extracted with EtOAc, and organic layers were combined, washed with brine, then dried over Na2SO4, concentrated and purified by flash chromatography on silica gel to afford the product as a white solid (17.Og, 65%). 1H NMR (400 MHz5 CDCl3): consistent; MS (ES) m/z 432.9 (M+H).
Step 3
2-{2 -øxø-5 '-[2-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3 '-indolj-l '(2 'H)- ylfbenzonitrile
Figure imgf000056_0002
2-(5'-iodo-2'-oxospiro[l,3-dioxane-2,3'-indol]-l'(2'H)-yl)benzonitrile (16.5Og, 38.18mmol), trans- dichlorobis(triphenylphosphine)palladium(II) (0.803g, 1.15mmol), K2CO3 (15.82g, 114.54mmol), and boronic acid (8.43g, 45.82mmol) were added to a flask fitted with a reflux condenser, a septum inlet, and a magnetic stir bar. The flask was flushed with carbon monoxide and then charged with toluene (20 mL). The mixture was then stirred at 80° C under an atmosphere of carbon monoxide via balloon. After stirring overnight, TLC analysis (hexane:EtOAc::l:l) indicated reaction to be complete, so reaction mixture was diluted with EtOAc, washed with H2O, followed by brine. The organic layer was dried over Na2SO4, concentrated and then purified by flash chromatography on silica gel to afford the product as a white solid (16.8g, 92%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 479.1 (M+H).
Step 4
2-[5 '-{hydroxy[2-(trifluoromethyl)phenyl]methyl}-2 '-oxospiro[l,3-dioxane-2,3 '- indol]-l '(2 'H)- yljbenzonitrile
Figure imgf000057_0001
2- {2 '-oxo-5 '- [2 -(trifluoromethyl)benzoyl] spiro [1,3 -dioxane-2 ,3 '-indol] - 1 '(2'H)- yl } benzonitrile (6.4Og, 13.37mmol) was dissolved in THF (100.0OmL) and was then treated with NaBH4 (l.Olg, 26.73mmol). After stirring overnight, LC/MS analysis indicated reaction to be -75% product and 25% starting material (along with other impurities), so reaction mixture was quenched with NaHCO3, and was stirred for 0.5 hour. The reaction mixture was then extracted with EtOAc, washed with H2O, followed by brine. The organic layer was dried over Na2SO4, concentrated and then purified by flash chromatography on silica gel to afford the product (75% product and 25% starting material) as an off-white solid as a racemate (2.5Og). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 481.2 (M+H).
Step 5
2-[5 '-{(S)-hydroxy[2-(trifluoromethyl)phenyl]methyl}-2 '-oxospiro[l,3-dioxane- 2,3 '-indolj-l '(2 'H)- yljbenzonitrile
Figure imgf000057_0002
The racemate, 2-[5'-{hydroxy[2-(trifluoromethyl)phenyl]methyl}-2'-oxospiro[l,3-dioxane-2,3'- indol]-l'(2'H)-yl]benzonitrile, (6.5Og) was preparatively isolated using a Luna™ CN, 5 x 25 cm column, utilizing a mobile phase of 30% EtOH in hexane. The enantiomers of the main component were then preparatively isolated using a Chiralpak AD-H, 2 x 25 cm column, utilizing a mobile phase of 15% MeOH in CO2. The desired peak (peak 2) eluted at 6.272 minutes. 1H NMR (400 MHz, CDCl3): consistent; MS (ESI) m/z 503.0 (M+Na). αD = -37.0.
Example 180
(+)2-[5?-{(R)-hydroxy[2-(trifluoromethyl)phenyl]methyl}-2?-oxospiro[l,3-dioxane- 2,3?-indol]- r(2Η)-yl]benzonitrile
Figure imgf000057_0003
The racemate from Example 179, Step 4, 2-[5'-{hydroxy[2-(trifluoromethyl)phenyl]methyl}-2'- oxospiro[l,3-dioxane-2,3'- indol]-r(2'H)-yl]benzonitrile, (6.5Og) was preparatively isolated using a Luna™ CN, 5 x 25 cm column, utilizing a mobile phase of 30% EtOH in hexane. The enantiomers of the main component were then preparatively isolated using a Chiralpak AD-H, 2 x 25 cm column, utilizing a mobile phase of 15% MeOH in CO2. The desired peak (peak 1) eluted at 5.727 minutes. 1H NMR (400 MHz, CDCl3): consistent; MS (ESI) m/z 503.0 (M+Na). αD = +36.2.
Example 181
(+)-r-(3,4-difluorophenyl)-5'-{(R)-hydroxy[2-(trifluoromethyl)phenyl]-methyl}spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one
Figure imgf000058_0001
The racemate from Example 147, r-(3,4-difluorophenyl)-5'-{hydroxy[2- (trifluoromethyl)phenyl]methyl}spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, was separated, and the enantiomers of the main component were then preparatively isolated using a Chiralcel™ AS, 2 x 25 cm column, utilizing a mobile phase of 10% EtOH in hexane. The desired peak (peak 1) eluted at 6.306 minutes. 1H NMR (400 MHz, CDCl3): consistent; MS (ESI) m/z 492.1 (M+H).
Example 182
(-)-l'-(3,4-difluorophenyl)-5'-{(S)-hydroxy[2-(trifluoromethyl)phenyl]-methyl}spiro[l,3-dioxane- 2,3'-indol]-2'(lΗ)-one
Figure imgf000058_0002
The racemate from Example 147, l'-(3,4-difluorophenyl)-5'-{hydroxy[2- (trifluoromethyl)phenyl]methyl}spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, was separated, and the enantiomers of the main component were then preparatively isolated using a Chiralcel AS, 2 x 25 cm column, utilizing a mobile phase of 10% EtOH in hexane. The desired peak (peak 2) eluted at 9.164 min. 1H NMR (400 MHz, CDCl3): consistent; MS (ESI) m/z 492.1 (M+H). Example 183 l?-(cyclopropylmethyl)-5?-{l-hydroxy-l-[2-(trifluoromethyl)phenyl]ethyl}spiro[l,3-dioxane-2,3?- indol]-2'(l'H)-one
Figure imgf000059_0001
The compound from Example 5, lτ-(cyclopropylmethyl)-5'-[2-(1τifluoromethyl)- benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one, (0.25g, 0.58mmol) was dissolved in THF (6.0OmL) and cooled to -78° C. Once cooled, a methyl Grignard reagent (3.0M in diethyl ether; 0.2ImL, 0.64mmol) was added drop wise until completion, and reaction mixture was allowed to slowly warm to room temperature. After stirring overnight, TLC analysis indicated that reaction had neared completion, so reaction mixture was quenched with sat. NH4Cl and was stirred for 30 minutes. This mixture was then extracted with EtOAc, and organic layers were combined, washed with brine, dried over Na2SO4, concentrated and then purified by flash chromatography on silica gel to afford product as an off-white solid (0.19, 71 %). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) ink 448.1 (M+H).
Example 184 l'-(3,4-difluorophenyl)-5'-{l-hydroxy-l-[2-(trifluoromethyl)phenyl]ethyl}spiro[l,3-dioxane-2,3'- indol]-2?(lΗ)-one
Figure imgf000059_0002
The compound from Example 126, l'-(3,4-difluorophenyl)-5'-[2- (trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, (0.4Og, 0.82mmol) was dissolved in
THF (8 mL) and cooled to -78° C. Once cooled, a methyl Grignard reagent (3.0M in diethyl ether;
0.3OmL, 0.90mmol) was added drop wise until completion, and reaction mixture was allowed to slowly warm to room temperature. After stirring overnight, TLC analysis indicated that reaction had neared completion, so reaction mixture was quenched with sat. NH4Cl and was stirred for 30 minutes. This mixture was then extracted with EtOAc, and organic layers were combined, washed with brine, dried over
Na2SO4, concentrated and then purified by flash chromatography on silica gel to afford product as a white solid (0.16, 39%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 506.1 (M+H). Example 185 5'-(Benzylamino)-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one
Step 1
5 '-nitrospiro[l,3-dioxane-2,3 '-indol]-2 '(I 'H)-one
Figure imgf000060_0001
To a solution of 5'-nitroisatin (16.0 g, 83.27 mmol, 1 eq.) in benzene (300 niL) was added 1, 3 propanediol (20 mL, 276.7 mmol, 3.32 equivalents) and p-TsOH (3.112 g, 16.36 mmol, 0.2 equivalents). The reaction was heated to reflux temperature with a Dean-Stark trap for 3.5 hours. The reaction was cooled to room temperature, poured into H2O and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, then filtered, concentrated in vacuo, and purified on silica gel eluting with a 25 to 50% EtOAc/hexane to give 20.0 (75%) of the title compound as a yellow solid.
Step 2
1 '-(cyclopropylmethyl)-5 '-nitrospiro[l,3-dioxane-2,3 '-indolJ-2 '(I 'H)-one
To a solution of 5'-nitrospiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one (3.263 g, 13.04 mmol, 1 eq.) in acetone (120 mL) was added K2CO3 (4.600 g, 33.28 mmol, 2.55 equivalents) and cyclopropylmethyl bromide (1.9 mL, 19.6 mmol, 1.5 equivalents). The reaction was heated at reflux 2 hours. The reaction was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, concentrated in vacuo, and then purified on RediSep™ silica gel eluting with a 0 to 100% EtOAc/hexane linear gradient to give 3.586 (80%) of the title compound as a light yellow solid. Step 3
5 '-amino-1 '-(cyclopropylmethyl)spiro[l,3-dioxane-2,3 '-indol]-2 '(I 'H)-one
Figure imgf000061_0001
To a slurry of 10% PdC (0.420 g) in EtOAc was added a solution of 1 '-(cyclopropylmethyl)-5'- nitrospiro[l,3-dioxane-2, 3'-indol]-2'(l'H)-one (3.586 g, 103.53 mmol, 1 equivalent) in EtOAc (80 niL) and the mixture was hydrogenated at 50 psi for 2 hours. It was filtered though a Celite and silica, concentrated in vacuo, and then purified on RediSep silica gel eluting with a 0 to 100% EtOAc/hexane linear gradient to give 2.700 (93%) of the title compound as a light brown solid.
Step 4
5 '-(Benzylamino)-! '-(cyclopropylmethyl)spiro[l,3-dioxane-2,3 '-indolJ-2 '(I 'H)-one
Figure imgf000061_0002
To a of 5'-amino-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one (0.101 g, 0.37 mmol, 1 equivalent) in MeOH (3 mL) was added benzaldehyde (0.050 mL, 0.45 mmol, 1.2 equivalents), HOAc (0.020 mL, 0.36 mmol, 1 eq) and NaCNBH3 (0.043 g, 0.68 mmol, 1.8 equivalents) The reaction was stirred for at room temperature for 1 hour, poured into saturated NaHCO3 solution and water and then extracted with CH2Cl2. The combined organic extracts were concentrated and the crude product was purified on RediSep silica gel eluting with a 0 to 100% EtOAc/hexane linear gradient to give 0.108 g, (80%) of the title compound as a sticky, foamy oil. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) mlz 365.2 (M+H).
Examples 186-200 were prepared from 5'-amino4'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2'(l Η)-one and the appropriate aldehyde according to the procedure for Example 185.
Table 7: Compounds Prepared According to the Procedure of Example 185
Figure imgf000062_0001
Figure imgf000063_0003
Example 201
S'-IBis^yclohexylmethyOaminol-l'-^yclopropylmethylJspiroIl^-dioxane^^'- indol]-2'(l'H)-one
Figure imgf000063_0001
The title compound (0.05Og, 48%) was prepared from 5'-amino-l'-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one using a procedure similar to that of Example 1, using 2 equivalents of cyclohexanecarbaldehyde in Step 4. 1H NMR (400 MHz, DMSO-dό): consistent; MS (ES+) m/z (M+H).
Example 202 l'-(Cyclopropylmethyl)-5'-(dimethylamino)spiro[l,3-dioxane-2,3'-indol]-2!(l'H)-one
Figure imgf000063_0002
The title compound (0.288g, 97 %) was prepared from 5'-amino-l'-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(l'H)-one using a procedure similar to that of Example 1, using 2 equivalents of formaldehyde in Step 4. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z 303.2 (M+H). Example 203 5'-Anilino-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one
Figure imgf000064_0001
A solution consisting of 5'-amino-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-mdol]-2'(lΗ)- one (0.091 g, 0.33 mmol), PhB(OH)2 (0.120 g, 0.98 mmol, 3 equivalents), Et3N (0.140 niL, 1.0 mmol, 3 equivalents), Cu(OAc)2 (0.121 g, 0.66 mmol, 2.0 equivalents), and 4 A molecular sieves (-0.250 g) in CH2Cl2 (4 mL) was stirred at room temperature for 24 hours. The reaction mixture was diluted with CH2Cl2 and treated with aqueous NaCl. The organic layer was separated, filtered, then concentrated and purified by RediSep silica gel eluting with a 0 to 100% EtOAc/hexane linear gradient to give 0.048 g (41%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z 351.1 (M+H).
Example 204 r-Butyl-5?-(methylamino)spiro[l,3-dioxane-2,3?-indol]-2?(lΗ)-one
Step l
5 '-Amino- 1 '-butyl spiro[l,3-dioxane-2,3 '-indol]-2 '(I 'H)-one
Figure imgf000064_0002
5'-Amino-l '-butyl spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one was prepared from 5-nitroisatin in a procedure similar to that of Example 1, Steps 1-3. Step 2
N-(I '-butyl-2 '-oxo-1 ',2 '-dihydrospiro[l,3-dioxane-2,3 '-indolJ-5 '-yl)-2,2,2- trifluoroacetamide
Figure imgf000065_0001
To a solution of 5 '-amino- 1 '-butyl spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one (0.164 g, 0.59 mmol,
1 equivalent) in CH2Cl2 (4 niL) was added Et3N (0.160 mL, 1.95 mmol, 1.95 equivalents) and TFAA (0.110 mL, 0.78 mmol, 1.32 equivalents) and stirred at room temperature for 10 minutes. The reaction mixture was diluted with CH2Cl2 and treated with aqueous NaCl. The organic layer was separated, then dried over MgSO4, concentrated and purified by RediSep silica gel eluting with a 0 to 100% EtOAc/hexane linear gradient to give 0.218 g, (99%) of n-(l'-butyl-2'-oxo-r,2'-dihydrospiro[l,3- dioxane-2,3'-mdol]-5'-yl)-2,2,2- trifluoroacetamide (0.218 g, 99%) as a white solid. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES") m/z 371.1 (M-H).
Step 3 N-(I '-butyl-2 '-oxo-1 ',2 '-dihydrospiro[l,3-dioxane-2,3 '-indolJ-S '-yl)-2,2,2- trifluoro-N-methylacetamide
Figure imgf000065_0002
To a solution of n-(r-butyl-2'-oxo-r,2'-dihydrospiro[l,3-dioxane-2,3'-indol]-5'-yl)-2,2,2- trifluoroacetamide) (0.190 g, 0.51 mmol, 1 equivalent) in acetone (5 mL) was added K2CO3 (0.160 g, 1.16 mmol, 2.27 equivalents) and MeI (0.090 mL, 1.45 mmol, 2.8 equivalents) and the reaction was heated at 50° C overnight. The reaction mixture was poured into water and then extracted with EtOAc. The organic layer was separated, dried over MgSO4, concentrated and then purified by RediSep silica gel eluting with a 0 to 100% EtOAc/hexane linear gradient to give 0.187 g, (95%) of n-(l'-butyl-2'-oxo-l',2'- dihydrospiro[l,3-dioxane-2,3'-indol]-5'-yl)-2,2,2- trifluoro-N-methylacetamide (0.187 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z 387.2 (M+H).
Step 4
1 '-Butyl-5 '-(methylamino)spiro[l,3-dioxane-2,3 '-indol]-2 '(I 'H)-one
Figure imgf000066_0001
To a solution of of n-(l'-butyl-2'-oxo-l',2'-dώydrospiro[l,3-dioxane-2,3'-mdol]-5'-yl)-2,2,2- tπfluoro-N-methylacetamide (0.160 g, 0.4 mmol, 1 equivalent) m MeOH (8 niL) was added 1 NaOH (1.5 niL, 1.5 mmol, 3.5 equivalents) and heated at reflux temperature for 20 minutes. The reaction mixture poured into water and extracted with EtOAc. The organic layer was separated, dried over MgSO/t, concentrated and then purified by RediSep silica gel elutmg with a 0 to 100% EtOAc/hexane linear gradient to give 0.117 g (100%) of the title compound as a sticky yellow oil. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z
Example 205 l'-CCyclopropylmethylJ-S'-Imethy^pheny^aminolspiroIl^-dioxane-Z^'-indol]- 2?(l'H)-one
Step I
I '-(Cyclopropylmethyl)-5 '-[methylaminoJspirofl,3-dioxane-2,3 '-indolj- 2 '(I 'H)-one
Figure imgf000066_0002
r-(Cyclopropylmethyl)-5'-[niethylammo]spiro[l,3-dioxane-2,3'-mdol]- 2'(l'H)-one was prepared from 5'-amino-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-mdol]-2'(rH)-one using a procedure similar to that of Example 198.
Step 2
1 '-(Cyclopropylmethyl)-5 '-[methyl(phenyl)aιninoJspiro[l,3-dioxane-2,3 '-indolj- 2 '(I 'H)-one
Figure imgf000066_0003
The title compound (0.097 g, 76%) was prepared from l'-(cyclopropylmethyl)-5'- [methylammo]spiro[l,3-dioxane-2,3'-mdol]- 2'(l'H)-one using a procedure similar to that of Example 197. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z 365.2 (M+H). Example 206 r-(Cyclopropylmethyl)-5'-piperidin-l-ylspiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one
Step 1
5 '-Bromo-1 '-(cyclopropylmetlιyl)spiro[l,3-dioxane-2,3 '-indolJ-2 '(I 'H)-one
Figure imgf000067_0001
5'-Bromo-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one was prepared from 5- bromo-isatin using a procedure similar to that of Example 179, Steps 1 and 2.
Step 2
1 '-(Cyclopropylmethyl)-5'-piperidin-l-ylspiro[l,3-dioxane-2,3 '-indol]-2'(l 'H)-one
Figure imgf000067_0002
To a solution of 5'-bromo-l'-(cyclopropylmetriyl)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one (0.147 g, 0.43 mmol, 1 equivalent) in dry tetrahydrofuran (3 mL) was added piperidine (0.07 mL, 0.71 mmol, 1.6 equivalents), sodium t-butoxide (0.075 g, 0.78 mmol, 1.8 eq.) and 2-dicyclohexylphosphino-2'-(N,N- dimethylamino)biphenyl (CYMAP, 0.012 g, 0.03 mmol, 0.07 equivalent). Nitrogen was bubbled through the resulting solution for 5 minutes and then bis(dibenzylideneacetone)palladium (0) (Pd2(dba)3, 0.033 g, 0.04 mmol, 0.09 equivalent) was added. The resulting mixture was stirred at reflux temperature under nitrogen for 1 hour. It was then cooled to room temperature, diluted with diethyl ether and then filtered through a plug of celite. After concentration, the residue was purified by RediSep silica gel eluting with a 0 to 100% EtOAc/hexane linear gradient to give 0.067 g, (46%) of the title compound as a sticky yellow oil. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z 343.2 (M+H).
Example 207
5'-(Phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one Step l
Figure imgf000068_0001
5'-Iodospiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one was prepared from 5-iodo-isatin using a procedure similar to that of Example 185, Step 1.
Step 2 5'-(Phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one
Figure imgf000068_0002
To a solution of 5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(rH)-one (0.334 g, 1.00 mmol, 1 eq.) in dry isopropanol (5 mL) was added thiophenol (0.110 mL, 1.07 mmol, 1.0 equivalent), ethylene glycol (0.110 ml, 1.97 mmol, 2 equivalents), potassium carbonate (0.278 g, 2.00 mmol, 2 equivalents) and copper(I) iodide (0.019 g, 0.1 mmol, 0.1 equivalent). The resulting mixture was stirred at 80° C overnight. LC/MS indicated a 2/1 mixture of product to starting material. Additional thiophenol (0.050 mL, 0.5 mmol, 0.5 equivalent) and copper (I) iodide (0.020 g, 0.1 mmol, 0.1 equivalent) was added and the reaction was heated at 80° C for 3 days. It was then cooled to room temperature, poured into water and extracted with EtOAc. After concentration, the residue was purified by RediSep silica gel eluting with a O to 100% EtO Ac/hexane linear gradient to give 0.314 g, (100%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES") m/z 312.1 (M-H).
Example 208
5'-(Phenylsulfmyl)spiro [l,3-dioxane-2,3 '-indol] -2 '(I Η)-one
To a solution of 5'-(phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one (0.115 g, 0.37 mmol, 1 equivalent) in CH2CI2 (5 mL) was added m-CPBA (0.0825 g, 0.37 mmol, 1 equivalent). The reaction was stirred at room temperature for 30 minutes and then partitioned between saturated NaHCθ3 and CH2CU. The organic layer was separated, concentrated and the residue was then purified by RediSep silica gel eluting with a O to 100% EtOAc/hexane linear gradient to give 0.119 g, (98%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES") m/z 328.1 (M-H). Example 209 SHPhenylsulfonyl^piroIl^-dioxane^'-indolH'ClΗHne
Figure imgf000069_0001
The title compound (0.047 g, 85%) was prepared from 5'-(phenylthio)spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one using a procedure similar to that of Example 208, using 2 equivalents of m-CPBA. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES") m/z 344.0 (M-H).
Example 210 5'-(Phenylthio)spiro[l,3-dioxolane-2,3'-indol]-2'(lΗ)-one
Step I
5 '-Iodospiro[l,3-dioxolane-2,3 '-indolJ-2 '(I Η)-one
Figure imgf000069_0002
5'-Iodospiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one was prepared from 5-iodo-isatin and ethylene glycol using a procedure similar to that of Example 185, Step 1.
Step 2 5'-(Phenylthio)spiro[l,3-dioxolane-2,3'-indol]-2'(l'H)-one
Figure imgf000069_0003
The title compound (0.327 g, 86%)was prepared from 5'-iodospiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one using a procedure similar to that of Example 207, Step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES") m/z 298.1 (M-H).
Example 211 r-(Cyclopropylmethyl)-5?-(phenylthio)spiro[l,3-dioxolane-2,3'-indol]-2?(lΗ)-one
Figure imgf000069_0004
The title compound (0.067 g, 56%)was prepared from 5'-(phenylthio)spiro[l,3-dioxolane-2,3'- indol]-2'(l'H)-one, using a procedure similar to that of Example 185, Step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z 354.1 (M+H).
Example 212 5'-(Phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(l'H)-one
Figure imgf000070_0001
The title compound (0.065 g, 58%) was prepared from 5'-(phenylthio)spiro[l,3- dioxolane-2,3'-indol]-2'(l'H)-one using a procedure similar to that of Example 209. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES") m/z 330.0 (M-H).
Example 213 l'-(Cyclopropylmethyl)-5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]- 2'(l'H)-one
Figure imgf000070_0002
The title compound (0.058 g, 100%) was prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxolane- 2,3'-indol]-2'(l'H)-one using a procedure similar to that of Example 185, Step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z 386.0 (M+H).
Examples 214-216
Figure imgf000070_0003
Examples 214-216 were prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]- 2'(l'H)-one and the appropriate boronic acid according to the procedure for Example 203. Table 8: Compounds Prepared According to the Procedure of Example 203
Figure imgf000071_0002
MS (APPI )
Examples 217-219
Figure imgf000071_0001
Examples 217-219 were prepared from 5'-(phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one and the appropriate boronic acid according to the procedure for Example 203.
Table 9: Compounds Prepared According to the Procedure of Example 203
Figure imgf000071_0003
Example 220-249
Figure imgf000072_0001
Examples 220-249 were prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)- on and the appropriate boronic acid according to the procedure for Example 203.
Table 10: Compounds Prepared According to the Procedure of Example 203
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0003
MS (APPI+)
Example 250 r-(Cyclopropylmethyl)-5'-(phenylsulfinyl)spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one
Figure imgf000075_0001
The title compound (0.091 g, 91%) was prepared from 5'-(phenylsulfinyl)spiro[l,3- dioxane-2,3'-indol]-2'(lΗ)-one using a procedure similar to that of Example 185, Step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z 384.0 (M+H).
Example 251 5'-(Phenylthio)-l'-(2,2,2-trifluoroethyl)spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one
Figure imgf000075_0002
The title compound (0.070 g, 80%) was prepared from 5'-(phenylthio)spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one and 2,2,2-trifluoroethyl tπfluoromethanesulfonate using a procedure similar to that of Example 185, Step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (APPI+) m/z 396 (M+H). Example 252 r-(Cyclopropylmethyl)-5'-(phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one
Figure imgf000076_0001
To a solution of l'-(cyclopropylmetliyl)-5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one (0.1 g,
0.26 mmol, 1 equivalent) in dry acetonitrile (3 niL) was added CoCl2(dppe) (0.0 Ig, 0.18 mmol, 0.7 equivalent), Zn (0.025 g, 0.39 mmol 1.5 equivalents), pyridine (0.021 mL, 0.26 mmol 1 equivalent) and thiophenol (0.027 mL, 0.26 mmol 1 equivalent) . The reaction was heated at 110°C overnight. The reaction was cooled to room temperature, diluted with CH2Cl2, then filtered through celite. The filtrate was concentrated and the residue was purified on silica gel column eluting with a 10 to 30%
EtOAc/hexane to give 0.071g (74%) of the title compound as clear oil. 1H NMR (400 MHz, DMSO-d6): consistent; MS (EI+) m/z 367 (M+H).
Example 253 l'-(Cyclopropylmethyl)-5l-(phenylsulfonyl)spiro[l,3-dioxane-2,3l-indol]-2l(l'H)-one
Figure imgf000076_0002
To a solution of r-(cyclopropylmethyl)-5'-(phenylthio)spiro[l,3-dioxane-2,3l-indol]-2τ(lΗ)-one (0.051 g, 0.14 mmol, 1 equivalent) in CH2Cl2 (3 mL) was added potassium permanganate and Montmorillonite KlO mixture (0.1 Ig, 0.69 mmol, 5 equivalents). The reaction was stirred at rt for 5.5 hours. The reaction was diluted with CH2Cl2 and then filtered through celite. The filtrate was concentrated and the residue was purified on silica gel column eluting with a 10 to 70% EtOAc/hexane to give 0.039g (71%) of the title compound as a viscous, colorless oil. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z 400.1 (M+H).
Examples 254-260 were prepared from 1 '-(cyclopropylmethyl)-5'-iodospiro[l ,3-dioxane-2,3'- indol]-2'(l'H)-one and the appropriate substituted thiopheols according to the procedure for Example 252, and oxidized to the sulfones according to the procedure for Example 253.
Figure imgf000077_0001
Table 11 : Compounds Prepared According to the Procedure of Examples 252 and 253.
Figure imgf000077_0002
Example 261 l'^Cyclopropylmethy^-S'-ftl-^rifluoromethy^phenylJsulfinylJspirofl^- dioxane-l^'- indol]-2'(lΗ)-one
Figure imgf000078_0001
The title compound (0.012g, 10%) was prepared from l'-(cyclopropylmethyl)-5'-iodospiro[l,3- dioxane-2,3'-indol]-2'(lΗ)-one using 1 equivalent of 2-(tπfluoromethyl)-benzenethiol according to the procedure for example 252, and oxidized to the sulfoxide according to the procedure for example 253. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z 452.0 (M+H).
Examples 262-271 were prepared from l'-(cyclopropylmethyl)-5'-iodospiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one and the appropriate substituted thiophenols according to the procedure for Step 2 of Example 207, and oxidized to the sulfones according to the procedure for Example 208.
Figure imgf000078_0002
Table 12: Compounds Prepared According to the Procedure of Examples 207 and 208.
Figure imgf000079_0001
Example 272 r-(Cyclopropylmethyl)-5'-(pyridin-4-ylthio)spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one
Figure imgf000080_0001
The title compound (0.103g, 74%) light yellow solid, was prepared from 1 '-(cyclopropylmethyl)- 5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one using 1.1 eq. of 4-mercaptopyridine according to the procedure for Step 2 of Example 207. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ES+) m/z 369.1 (M+H).
Examples 272-275 were prepared from l'-(cyclopropylmethyl)-5'-iodospiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one and the appropriate substituted thiophenols according to the procedure for Step 2 of Example 207.
Figure imgf000080_0002
Table 13: Compounds Prepared According to the Procedure for Step 2 of Example 207.
Figure imgf000080_0003
Example 276 r-(Cyclopropylmethyl)-5?-(pyridin-4-ylsulfinyl)spiro[l,3-dioxane-2,3?-indol]- 2?(lΗ)-one
Figure imgf000081_0001
The title compound (0.097g, 51 %) light yellow solid, was prepared from Example 272 using a procedure similar to that of Example 208. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 385.1 (M+H).
Examples 277 and 278 were prepared from Example 273 and 275 respectively according to the procedure for Example 208.
Figure imgf000081_0002
Table 14: Compounds Prepared According to the Procedure for Example 208.
Figure imgf000081_0003
Example 279 r-(Cyclopropylmethyl)-5'-(pyridin-3-ylsulfanyl)spiro[l,3-dioxane-2,3'-indol]- 2'(lΗ)-one
Step I
I '-(cyclopropylmethyl)-5 '-[(triisopropylsilyl)sulfanyl]spiro[l,3-dioxane-2,3 '-indol]-2 '(I 'H)-one
Figure imgf000082_0001
To a suspension of KH (0.06 g, 1.43 mmol, 1.1 equivalents) in THF (3 mL) at 5° C was added triisopropylsilanelthiol (0.27g, 1.43 mmol, 1.1 equivalents) over 15 minutes. The reaction was stirred at 5° C for 1 hour, then warmed to rt for 1 hour. The clear solution was added to a solution of 1'- (cyclopropylmethyl)-5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one (0.5 g, 1.3 mmol, 1 equivalent) and (PPh3)4Pd (0.1 g, 0.86 mmol, 0.07 equivalent) in THF (4 ml) and then heated at 70 0C for 1 hour. After cooling, the reaction mixture was diluted with ether, washed with brine and then dried with MgSθ4. The filtrate was concentrated and the residue was purified on 4Og Isco silica gel column eluting with 0 to 10% EtOAc/hexane to give 0.44 Ig (76%) of the title compound as a viscous light yellow oil. (J.Med Chem. 2001, 44, 4393). 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 448.2 (M+H).
Step 2 l '-fCyclopwpylmethyljS'-fpyridin-S-ylsulfanyljspirollJ-dioxane^J'-indolJ- 2'(l 'H)-one
Figure imgf000082_0002
The title compound (0.052g, 56%) clear oil, was prepared from l'-(cyclopropylmethyl)-5'- [(triisopropylsilyl)sulfanyl]spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one using a procedure similar to that of Step 2 of Example 207. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 369.1 (M+H).
Examples 280-294 were prepared from l'-(cyclopropylmethyl)-5'-
[(triisopropylsilyl)sulfanyl]spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one and the appropriate substituted aryl or heteroaryl iodides according to the procedure for Step 2 of Example 207.
Figure imgf000082_0003
Table 15: Compounds Prepared According to the Procedure for Step 2 of Example 207.
Figure imgf000083_0001
Figure imgf000084_0002
Examples 295-310 were prepared by oxidizing the corresponding sulfides (prepared in Examples ) according to the procedure for Example 208.
Figure imgf000084_0001
Table 16: Compounds Prepared According to the Procedure for Example 208.
Figure imgf000085_0001
Figure imgf000086_0002
Example 311 r-(Cyclopropylmethyl)-5?-(4-methoxyphenox>)spiro[l,3-dioxane-2,3?-indol]-2'(rH)-one
Step I N-cyclopropylmethyl-5-methoxyisatin
Figure imgf000086_0001
5-Methoxyisatm (3.6 g, 15.6 mmol, 1 equivalent) was dissolved m DMF (50 mL) and treated with cesium carbonate (8.0 g, 24.6mmol, 1.6 equivalents) and cyclopropylmethyl bromide (2.8 g, 20.7 mmol, 1.33 equivalents). The mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with ethyl acetate (50 mL), extracted and washed with brine (100 mL x 3), then dried over sodium sulfate and concentrated under reduced pressure. Chromatography with ethyl acetate/hexanes (0- 70% gradient elution) afforded n-cyclopropylmethyl-5-methoxyisatm. The product was used m the following reaction.
Step 2 1 '-(cyclopropylmethyl)-5'-hydroxyspiro[l,3-dioxane-2,3 '-indol]-2'(l 'H)-one
Figure imgf000087_0001
N-cyclopropylmethyl-5-methoxyisatin was dissolved in dichloromethane (60 mL), treated with neat boron tribromide (3.0 mL, 31.7 mmol) and stirred at ambient temperature for 1 hour. The reaction mixture was diluted with dichloromethane ( 100 mL) and extracted from 1.0 N HCl. The organic layer was dried over sodium sulfate and then concentrated to dryness. The residue was dissolved in toluene (200 mL), treated with 1,3 -propanediol (6.O mL, 83.0 mmol) and toluenesulfonic acid (1.0 g, 5.25 mmol). The mixture was stirred at reflux temperature under a Dean-Stark apparatus for 20 hours. The reaction mixture was then concentrated under reduced pressure and purified by chromatography with ethyl acetate/hexanes (0-70% gradient elution) to afford l '-(cyclopropylmethyl)-5'-hydroxyspiro[l,3-dioxane-2,3'-indol]- 2'(l 'H)-one (1.0 g) as a dark solid.
Step 3
1 '-(Cyclopropylmethyl)-5'-hydroxyspiro[l,3-dioxane-2,3 '-indol]-2 '(I 'H)-one
Figure imgf000087_0002
r-(Cyclopropylmethyl)-5'-hydroxyspiro[l,3-dioxane-2,3'-indol]-2'(rH)-one (0.1 g, 0.36 mmol, 1 equivalent) and 4-anisoliodonium tetrafluoroborate (0.230 g, 0.71 mmol, 1.97 equivalents) were dissolved in dichloromethane (5.0 mL), treated with copper powder (0.110 g, 1.17 mmol, 3.25 equivalents) and triethylamine (0.1 mL, 0.72 mmol, 2 equivalents). The mixture was stirred at ambient temperature in dark for 24 hours. The reaction mixture was loaded directly to a flash chromatography column and purified with ethyl acetate/hexanes (0-50% gradient elution) to provide 1'- (cyclopropylmethyl)-5'-(4-methoxyphenoxy) spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one (0.025 g, 18%) as a dark oil. MS (ES), m/z: 382.2.
Example 312 l'-(Cyclopropylmethyl)-5'-(4-methoxyphenoxy)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one
Figure imgf000087_0003
l'-(cyclopropylmethyl)-5'-hydroxyspiro[l,3-dioxane-2,3'-indol]-2'(l 'H)-one (0.200 g, 0.73 mmol, 1 equivalent) and diphenyliodonium tetrafluoroborate (0.500 g, 1.36 mmol, 1.86 equivalent) were dissolved in dichloromethane (5.0 mL), treated with copper powder (0.200 g, 2.13 mmol, 2.91 equivalents) and triethylamine (0.1 mL, 0.72 mmol, 1 equivalents). The mixture was stirred at ambient temperature in dark for 20 hours. The reaction mixture was loaded directly to a flash chromatography column and then purified with ethyl acetate/hexanes (0-50% gradient elution) to provide 1'- (cyclopropylmethyl)-5'-(phenoxy)spiro[l,3-dioxane-2,3'-indol]-2'(r/7)-one (107.0 mg, 42 %, dark oil). MS (ES), m/z: 352.1.
Example 313 r-(Cyclopropylmethyl)-5?-[(2,6-difluoropyridin-4-yl)oxy]spiro[l,3-dioxane-2,3?-indol]-2'(rH)-one
Figure imgf000088_0001
l'-(Cyclopropylmethyl)-5'-hydroxyspiro[l,3-dioxane-2,3"-indol]-2'(l Η)-one (0.040 g, 0.14 mmol, 1 equivalent) and 2,4,6-trifluoropyridine (0.038 g, 0.028 mmol, 2 equivalents) were dissolved in DMF (2.0 mL), treated with potassium carbonate (0.100 g, 0.72 mmol, 5.1 equivalents) and stirred at ambient temperature for 5 hours. The reaction mixture was extracted with ethyl acetate (100 mL) from brine (100 mL) and followed by washing with brine (50 mL x 2). The organic layers were combined and then dried with sodium sulfate. Flash chromatography with ethyl acetate/hexanes (0-50% gradient elution) provided l'-(cyclopropylmethyl)-5'-[(2,6-difluoropyridin-4-yl)oxy]spiro[l,3-dioxane-2,3'-indol]- 2'(11H)-OiIe (0.037 g, 69%) as a dark solid. MS (ES), m/z: 389.1.
Example 314-318
Figure imgf000088_0002
Examples 314-318 were prepared from l '-(cyclopropylmethyl)-5'-hydroxyspiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one and the appropriately substituted 4-fTuoropyridines according to the procedure for Example 313. Table 17: Compounds Prepared According to the Procedure of Example 313
Figure imgf000089_0003
Example 319
r-CZ-ChlorophenyO-S'-CphenylsulfonyOspiroIl^-dioxolane^^'-indolJ-ZXr/^-one
Figure imgf000089_0001
Step l r-(2-Chloro-4-nitrophenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(r//)-one
Figure imgf000089_0002
To a solution of 5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(r//)-one (0.106 g, 0.32 mmol) in acetone (10 ml) was added cesium carbonate (0.266 g, 0.82 mmol) and 2-chloro-l-fluoro-4- nitrobenzene (0.108 g, 0.614 mmol). The reaction was heated at 65° C for 3 hours (until starting material was consumed, as determined by TLC). The reaction was cooled, then poured into water and extracted with EtOAc. The combined organic extracts were dried over MgSθ4, filtered, concentrated in vacuo, and purified on RediSep™ silica gel eluting with a 0 to 100% EtOAc/hexane linear gradient to give 0.069g (44%) of the title compound as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 487.0 (M+H).
Step 2
1 '-(4-Amino-2-chlorophenyl)-5 '-(phenylsulfonyl)spiro [ 1 ,3-dioxolane-2,3 '-indol] -2'( 177)-one
Figure imgf000090_0001
To a solution of l'-(2-chloro-4-nitrophenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]- 2'(17/)-one (0.063 g, 0.13 mmol) in EtOAc (2 ml) and EtOH (3 ml) was added tin chloride -dihydrate (0.106 g, 0.47 mmol) and the reaction was heated at 70° C over night. After cooling, 2 mL saturated NaHCO3 solution and celite was added and the reaction was stirred for 5 minutes. The solids were then filtered and washed with EtOAc. The organics were washed with brine, dried over MgSθ4, filtered and concentrated in vacuo. The crude material was purified on RediSep silica gel eluting with a 0 to 100% EtOAc/hexane linear gradient to give 0.05Og (85%) of the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 457.0 (M+H).
Step 3
r-(2-Chlorophenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(l'//)-one
Figure imgf000090_0002
To a slurry of r-(4-amino-2-chlorophenyl)-5'-(phenylsιιlforiyl)spiro[l,3-dioxolane-2,3'-indol]-2'(r//)-one (0.043 g, 0.09 mmol) in water (2 ml) and cone. HCl (1 ml) was added ethanol (2 ml) and TFA (2 ml). Sodium nitrite (0.010 g, 0.15 mmol) in water (0.5 ml) was added. The reaction was heated briefly (5 min) to 50° C and then stirred at room temperature for 90 minutes. Water was then added and the reaction was extracted with EtOAc. The organics were concentrated to a small volume and neutralized with saturated NaHCC>3 solution and solid NaHCθ3. This solution was extracted with EtOAc, dried over MgSθ4 and concentrated. The crude material was purified on RediSep silica gel eluting with a 0 to 100% EtOAc/hexane linear gradient to give 0.02Og (50%) of the title compound as a light yellow solid.
1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 442.0 (M+H).
Example 320 r-(2-Chloro-4-nitrophenyl)-5?-(phenylsulfonyl)spiro[l,3-dioxane-2,3?-indol]-2'(r//)-one
Figure imgf000091_0001
The title compound (0.422 g, 73%) was prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one using a procedure similar to that of step 1 of Example 319. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 523.0 (M+Na).
Example 321 l'-(4-Amino-2-chlorophenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one
Figure imgf000091_0002
The title compound (0.355 g, 91%) was prepared from l'-(2-chloro-4-nitroprienyl)-5'- (phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(17/)-one using a procedure similar to that of step 2 of example 319. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 471.0 (M+H).
Example 322 5'-(Pyridin-4-ylthio)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one
Figure imgf000092_0001
The title compound (0.940 g, 96%) was prepared from 5'-iodospiro[l,3-dioxane-2,3'-indol]- 2'(17/)-one and 4-mercaptopyridine using a procedure similar to that of Example 201, step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 315.0 (M+H).
Example 323
5'-(Pyridin-4-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(177)-one
Figure imgf000092_0002
The title compound (0.040 g, 18%) was prepared from 5'-(pyridin-4-ylthio)spiro[l,3-dioxane-2,3'-indol]- 2'(17/)-one using a procedure similar to that of Example 203. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 347.0 (M+H).
Example 324 5'-(Pyridin-4-ylthio)spiro[l,3-dioxolane-2,3'-indol]-2'(r^)-one
Figure imgf000092_0003
The title compound (2.154 g, 76%) was prepared from 5'-iodospiro[l,3-dioxolane-2,3'-indol]-2'(r//)-one and 4-mercaptopyridine using a procedure similar to that of Example 201, step 2. 1H NMR (400 MHz,
DMSO-d6): consistent; MS (ESI+) m/z 301.0 (M+H). Example 325
5'-(Pyridin-4-ylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(ri/)-one
Figure imgf000093_0001
The title compound (0.069 g, 61%) was prepared from 5'-(pyridin-4-ylthio)spiro[l,3-dioxolane- 2,3'-indol]-2'(rH)-one using a procedure similar to that of Example 203. 1H NMR (400 MHz, DMSO- d6): consistent; MS (ESI+) m/z 333.0 (M+H).
Example 326 5?-[(4-Methoxyphenyl)thio]spiro[l,3-dioxane-2,3?-indol]-2?(rH)-one
Figure imgf000093_0002
The title compound (4.085 g, 98%) was prepared from 5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(r//)-one and 4-methoxybenzenethiol using a procedure similar to that of Example 201, step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 344.1 (M+H).
Example 327 5'-[(4-Methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3'-indol]-2'(r/0-one
Figure imgf000093_0003
The title compound (2.612 g, 96%) was prepared from 5'-[(4-methoxyphenyl)thio]spiro[l,3-dioxane-2,3'- indol]-2'(lΗ)-one using a procedure similar to that of Example 203. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 376.0 (M+H).
Example 328 5'-(phenylsulfonyl)-r-pyridin-3-ylspiro[l,3-dioxane-2,3'-indol]-2'(r//)-one
Figure imgf000094_0001
The title compound (0.035 g, 59%) was prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(17/)-one and 3 -pyridine boronic acid using a procedure similar to that of Example 197. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 423.0 (M+H).
Example 329 5'-(Phenylsulfonyl)-l'-pjridin-4-ylspiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one
Figure imgf000094_0002
The title compound (0.017 g, 29%) was prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(17/)-one and 4-pyndme boronic acid using a procedure similar to that of Example 197. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 423.0 (M+H).
Examples 330-335
Figure imgf000094_0003
Examples 330-335 were prepared from 5'-[(4-methoxyphenyl)thio]spiro[l ,3-dioxane-2,3'-mdol]-
2'(17/)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 12. Table 18: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000095_0002
Examples 336-341
Figure imgf000095_0001
Examples 336-341 were prepared from 5'-(pyπdm-4-ylsulfonyl)spiro[l,3-dioxolane-2,3'-mdol]- T(VH)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized m Table 13. Table 19: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000096_0002
Examples 342-357
Figure imgf000096_0001
Examples 342-357 were prepared from 5'-[(4-methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l '//)-one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 20.
Table 20: Compounds Prepared According to the Procedure of Example 197.
Figure imgf000097_0001
Figure imgf000098_0002
Example 358-360
Figure imgf000098_0001
Examples 358-360 were prepared from 5'-iodospiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one and the appropriate trifluoromethoxy thiophenol using a procedure similar to that of Example 201, step 2 and summarized in Table 21.
Table 21 : Compounds Prepared According to the Procedure of Example 201, step 2.
Figure imgf000098_0003
Examples 361-363
Figure imgf000099_0001
Examples 361-363 were prepared from 5'-{[2-(trifluoromethoxy)phenyl]sulfanyl}spiro[l,3- dioxane-2,3'-indol]-2'(rH)- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 22.
Table 22: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000099_0003
Examples 364-366
Figure imgf000099_0002
Examples 364-366 were prepared from 5'-{[3-(trifluoromethoxy)phenyl]sulfanyl}spiro[l,3- dioxane-2,3'-indol]-2'(rH)- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 23. Table 23: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000100_0002
Examples 367-369
Figure imgf000100_0001
Examples 367-369 were prepared from 5'-{[4-(trifluoromethoxy)phenyl]sulfanyl}spiro[l,3- dioxane-2,3'-indol]-2'(lΗ)- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 24.
Table 24: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000101_0002
Example 370-372
Figure imgf000101_0001
Examples 370-372 were prepared from the appropriate 5'-
{[(Trifluoromethoxy)phenyl]sulfanyl}spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one using a using a procedure similar to that of Example 203 and summarized in Table 25. Table 25 : Compounds Prepared According to the Procedure of Example 203.
Figure imgf000101_0003
Examples 373-378
Figure imgf000102_0001
Examples 373-378 were prepared from 5'-{[2-(trifluoromethoxy)phenyl]sulfonyl}spiro[l,3- dioxane-2,3'-indol]-2'(l 'H)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 26.
Table 26: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000102_0002
Examples 379-384
Figure imgf000103_0001
Examples 379-384 were prepared from 5'-{[3-(trifluoromethoxy)phenyl]sulfonyl}spiro[l,3- dioxane-2,3'-indol]-2'(l '//)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 27.
Table 27: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000103_0002
Examples 385-390
Figure imgf000104_0001
Examples 385-390 were prepared from 5'-{[4-(trifluoromethoxy)phenyl]sulfonyl}spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 28.
Table 28: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000104_0002
Example 391
5W(3-Fluorophenyl)sulfanyl]spiro[l,3-dioxane-2,3Mndol]-2'(17/)-one
Figure imgf000105_0001
The title compound (4.039 g, 100%) was prepared from 5'-iodospiro[l,3-dioxane-2,3'-indol]- 2'(17/)-one and 3-fluorothiophenol using a procedure similar to that of Example 201, step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI") m/z 330.0 (M-H).
Example 392 5'-[(3-Fluorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one
Figure imgf000105_0002
The title compound (2.251 g, 81%)was prepared from 5'-[(3-fluorophenyl)sulfanyl]spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one using a procedure similar to that of Example 203. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESF) m/z 362.0 (M-H).
Examples 393-398
Figure imgf000105_0003
Examples 393-398 were prepared from 5'-[(3-fluorophenyl)sulfanyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 29. Table 29: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000106_0002
Examples 399-428
Figure imgf000106_0001
Examples 399-428 were prepared from 5'-[(3-fluorophenyl)sulfonyl]spiro[l ,3-dioxane-2,3'- indol]-2'(l '//)-one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 30.
Table 30: Compounds Prepared According to the Procedure of Example 197.
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0002
Examples 429-440
Figure imgf000109_0001
Examples 429-440 were prepared from 5'-(pyπdin-4-ylsulfonyl)spiro[l ,3-dioxolane-2,3'-indol]-
2'( 17/)-one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 31.
Table 31 : Compounds Prepared According to the Procedure of Example 197.
Figure imgf000110_0001
Figure imgf000111_0002
Examples 441-451
Figure imgf000111_0001
Examples 441-451 were prepared from 5'-{[3-(trifluoromethoxy)phenyl]sulfonyl}spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 32.
Table 32: Compounds Prepared According to the Procedure of Example 197.
Figure imgf000112_0001
Examples 452-455
Figure imgf000113_0001
Examples 452-455 were prepared from 5'-{[2-(trifluoromethoxy)phenyl]sulfonyl}spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 33.
Table 33: Compounds Prepared According to the Procedure of Example 197.
Figure imgf000113_0003
Examples 456-458
Figure imgf000113_0002
Examples 456-458 were prepared from 5'-{[4-(trifluoromethoxy)phenyl]sulfonyl}spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one one and the appropriate boronic acid using a procedure similar to that of Example 197 and summarized in Table 34. Table 34: Compounds Prepared According to the Procedure of Example 197.
Figure imgf000114_0002
Examples 459-472
Figure imgf000114_0001
Examples 459-472 were prepared from 5'-(pyndm-4-ylsulfon>l)spiro[l,3-dioxane-2,3'-mdol]- 2'( 17/)-one and the appropriate boromc acid using a procedure similar to that of Example 197, step 2 and summarized in Table 35.
Table 35: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000115_0001
Examples 473-500
Figure imgf000116_0001
Examples 473-500 were prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)- one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 36.
Table 36: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000117_0001
Figure imgf000118_0001
(phenylsulfonyl)spiro[ 1 ,3 -dioxane-2,3 '-mdol] - (M+Η) 2'(11H)-OIIe l'-[4-(Difluoromethoxy)benzyl]-5'-
520.1
500 (phenylsulfonyl)spiro[ 1 ,3 -dioxane-2,3 '-mdol] - 0.037 (M+Η) 2'(1'H)-OiIe
Example 501 l'-(2-Fluoro-4-nitrophenyl)-5?-[(4-methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3?-indol]-21(l?//)-one
Figure imgf000119_0001
The title compound (0.056g, 34%) was prepared from 5'-[(4-methoxyphenyl)sulfonyl]spiro[l ,3- dioxane-2,3'-mdol]-2'(rH)-one and 3,4 difhioronitrobenzene using a procedure similar to that of step 1 of example 319. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 515.0 (M+H).
Example 502 l'-(2-Fluoro-4-nitrophenyl)-5'-[(4-methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3'-indol]-21(l'//)-one
Figure imgf000119_0002
The title compound (0.045g, 92%) was prepared from r-(2-fluoro-4-nitrophenyl)-5'-[(4- methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one using a procedure similar to that of step 2 of example 319. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI ) m/z 485.1 (M+H).
Example 503 l'-[4-(Dimethylamino)-2-fluorophenyl]-5'-[(4-methoxyphenyl)sulfonyl]spiro[l,3- dioxane-2,3'- indol]-2'(l'H)-one
Figure imgf000120_0001
The title compound (0.005g, 12%) was prepared from r-(4-amino-2-fluorophenyl)-5'-[(4- methoxyphenyl)sulfonyl]spiro[l,3-dioxane- 2,3'-indol]-2'(l'//)-one and methyl iodide (5 eq.) using a procedure similar to that of Example 179, step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) mlz 513.1 (M+H).
Examples 504-531
Figure imgf000120_0002
Examples 504-531 were prepared from 5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(17/)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and summarized in Table 37.
Table 37: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000121_0001
Figure imgf000122_0001
Example 532 r-(2-Morpholin-4-ylethyl)-5T-(phenylsulfonyl)spiro[l,3-dioxane-2,3?-indol]-2?(l?H)-one
Figure imgf000123_0001
The title compound (0.055g, 83%) was prepared from 5'-(phenylsulfonyi)spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one and 4-(2-chloroethyl)morpholine hydrochloride using a procedure similar to that of Example 179, step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 459.1 (M+H).
Example 533 l'-(2-Chloro-4-nitrophenyl)-5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one
Figure imgf000123_0002
The title compound (0.132, 60%) was prepared from 5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l Η)-one using a procedure similar to that of step 1 of example 319. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 502.0 (M+H).
Example 534 l'-(4-Amino-2-chlorophenyl)-5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one
Figure imgf000123_0003
The title compound (0.101, 90%) was prepared from r-(2-chloro-4-nitrophenyl)-5'-(pyridin-2- ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l 77)-one using a procedure similar to that of step 2 of example 319. 1H NMR (400 MHz, DMSO-dό): consistent; MS (ESI+) m/z 472.0 (M+H).
Example 535 l'-(3-Hydroxy-3-methylbutyl)-5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one
Figure imgf000124_0001
The title compound (0.058g, 86%) was prepared from 5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'- indol]-2'(l'//)-one and 4-bromo-2-methylbutan-2-ol (EP78704) using a procedure similar to that of Example 179, step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 432.1 (M+H).
Example 536
5?-(Phenylsulfonyl)-r-(pyridin-2-yl)spiro[l,3-dioxane-2,3?-indol]-2?(rH)-one
Figure imgf000124_0002
To a solution of 25% sodium methoxide (0.079 ml, 0.347 mmol) m DMSO (2 ml) was added oxazolidin-2-one (0.010 g, 0.115 mmol) and copper(I) iodide (0.010 g, 0.053 mmol) and the reaction was stirred at room temperature for 1 hour. 5'-(Phenylsulfonyl)spiro[l,3-dioxane-2,3'-mdol]-2'(177)-one (0.080 g, 0.232 mmol) and 2-bromopyπdme (0.029 ml, 0.301 mmol) were added and the reaction was heated at 120° C over night. The reaction was then cooled, poured into water with a small amount of bπne and extracted w/ EtOAc. The combined organics were dried over MgSθ4 and concentrated. The crude mixture was purified on RediSep™ silica gel elutmg with a 0 to 100% EtOAc/hexane linear gradient to give 0.045g (46%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 423.1 (M+H).
Example 537 l'-(3-Hydroxy-3-methylbutyl)-5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(ll//)-one
Figure imgf000124_0003
The title compound (0.043g, 96%) was prepared from 5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane- 2,3'-indol]-2'(rH)-one and 4-bromo-2-methylbutan-2-ol (EP78704) using a procedure similar to that of Example 179, step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 433.1 (M+H).
Example 538 r-(Pyridin-2-yl)-5'-(pyridin-2-ylsulfanyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'^)-one
Figure imgf000125_0001
The title compound (0.071g, 71%) was prepared from 5'-(pyridin-2-ylsulfanyl)spiro[l,3-dioxane- 2,3'-indol]-2'(177)-one using a procedure similar to that of Example 536. 1H NMR (400 MHz, DMSO- d6): consistent; MS (ESI+) m/z 392.1 (M+H).
Example 539 r-(Pyridin-3-yl)-5'-(pyridin-2-ylsulfanyl)spiro[l,3-dioxane-2,3'-indol]-2'(r/0-one
Figure imgf000125_0002
The title compound (0.035g, 35%) was prepared from 5'-(pyridin-2-ylsulfanyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l TH)-one and 3-iodopyridine using a procedure similar to that of Example 536. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 392.1 (M+H).
Example 540 r-(Pyridin-4-yl)-5'-(pyridin-2-ylsulfanyl)spiro[l,3-dioxane-2,3'-indol]-2'(r/7)-one
Figure imgf000125_0003
To a solution of 5'-(pyridin-2-ylsulfanyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one (0.080 g, 0.254 mmol) in dioxane (2 ml) was added potassium phosphate (0.108 g, 0.509 mmol) N,N-dimethylethane-l,2- diamine (9.14 μl, 0.102 mmol), 4-iodopyridine (0.104 g, 0.509 mmol) and copper(I) iodide (0.019 g, 0.102 mmol). The reaction mixture was purged with N2 for 15 minutes and then heated at 110° C over night. After cooling, the solids were filtered off and washed with EtOAc. The filtrate was concentrated and the crude mixture was purified on RediSep™ silica gel ehiting with a 0 to 100% EtOAc/hexane + 1 % Et3N linear gradient to give 0.053g (53%) of the title compound as a off-white solid. 1H NMR (400 MHz, DMSO-dό): consistent; MS (ESI+) m/z 392.1 (M+H).
Example 541 r-(Pyridin-2-yl)-5?-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3?-indol]-2?(r//)-one
Figure imgf000126_0001
The title compound (0.029g, 100%) was prepared from l'-(pyridm-2-yl)-5'-(pyridin-2- ylsulfanyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one using a procedure similar to that of Example 203. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 424.1 (M+H).
Example 542 r-(Pyridin-3-yl)-5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one
Figure imgf000126_0002
The title compound (0.007g, 31%) was prepared from r-(pyridin-3-yl)-5'-(pyridin-2- ylsulfanyl)spiro[l,3-dioxane-2,3'-indol]-2'(177)-one using a procedure similar to that of Example 203. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 424.1 (M+H).
Example 543 r-(l-Oxidopyridin-3-yl)-5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'/r)-one
Figure imgf000127_0001
The title compound (O.OOόg, 26%) was also isolated from the reaction described in Example 542. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 440.1 (M+H).
Example 544 5'-(Pyridin-2-ylsulfanyl)spiro[l,3-dioxolane-2,3'-indol]-2'(l'/7)-one
Figure imgf000127_0002
The title compound (0.673g, 59%) was prepared from 5'-iodospiro[l,3-dioxolane-2,3'-indol]- 2'(l'H)-one and 2-mercaptopyridine using a procedure similar to that of Example 201, step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 301.0 (M+H).
Examples 545-548
Figure imgf000127_0003
Examples 545-548 were prepared from prepared from 5'-(pyridin-2-ylsulfanyl)spiro[l,3- dioxolane-2,3'-indol]-2'(l TH)-one and the appropriate alkylating agent using a procedure similar to that of Example 179, step 2 and are summarized in Table 38.
Table 38: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000128_0003
Example 549 5'-(Pyridin-2-ylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(l'H)-one
Figure imgf000128_0001
The title compound (0.631g, 86 %) was prepared from 5'-(pyπdm-2-ylsulfanyl)spiro[l,3- dioxolane-2,3'-indol]-2'(l'//)-one using a procedure similar to that of Example 203. 1H NMR (400 MHz, DMSO-dό): consistent; MS (ESI+) m/z 333.1 (M+H)
Example 550 r-^yclopropylmethyO-S'-Cpyridin^-ylsulfonyOspiroIl^-dioxolane-Z^'-indoll-ZXl'HJ-one
Figure imgf000128_0002
The title compound (0.029g, 100 %) was prepared from 5'-(pyπdin-2-ylsulfon\l)spiro[l,3-dioxolane-2,3'- indol]-2'(l'//)-one using a procedure similar to that of Example 179, step 2. 1H NMR (400 MHz, DMSO- d6): consistent, MS (ESI+) m/z 387.1 (M+H).
Example 551 r-(Pyridin-4-yl)-5'-(pjridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'/?)-one
Figure imgf000129_0001
To a solution of r-(pyπdin-4-yl)-5'-(pyπdin-2-ylsulfanyl)spiro[l,3-dioxane-2,3'-mdol]-2τ(rH)- one (0.044 g, 0.112 mmol) m DCM (5 ml) was added TFA (0.200 ml) and 30% hydrogen peroxide (0.035 ml, 0.309 mmol) and the reaction was stirred at rt for 4h. Saturated sodium bisulfite solution was then added, the mixture was stirred 15mm. and then extracted w/ EtOAc. The organic extracts were stirred with saturated NaHCO3 to neutralize The organics were separated, dried over MgSO4 and concentrated. The crude mixture was purified on RediSep silica gel elutmg with a 0 to 100% EtOAc/hexane + 1% Et3N linear gradient to give 0.014g (29%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO- d6): consistent, MS (ESI+) m/z 424.1 (M+H).
Examples 552-554
Figure imgf000129_0002
Examples 552-554 were prepared from 5'-[(3-fluorophenyl)sulfonyl]spiro[l ,3-dioxane-2,3'- mdol]-2'(lΗ)-one and the appropriate lodo-pyndme using a procedure similar to that of Example 540 and are summarized m Table 39 Table 39: Compounds Prepared According to the Procedure of Example 540.
Figure imgf000130_0002
Examples 555-557
Figure imgf000130_0001
Examples 555-557 were prepared from 5'-(pyridin-2-ylsulfonyl)spiro[l,3-dioxolane-2,3'-indol]-2'(lΗ)- one and the appropriate bromomethyl pyridine using a procedure similar to that of Example 179, step 2 and are summarized in Table 40. Table 40: Compounds Prepared According to the Procedure of Example 179, step 2.
Figure imgf000131_0003
Examples 558
5'-[(l-Oxidopyridin-4-yl)sulfonyl]-r-propylspiro[l,3-dioxolane-2,3'-indol]- 2'(r//)-one
Figure imgf000131_0001
The title compound (0.022g, 16 %) and l'-propyl-5'-(pyridin-4-ylsulfonyl)spiro[l,3-dioxolane-
2,3'-indol]-2'(lΗ)-one (0.108g, 83%) (Example 339) were prepared from l'-propyl-5'-(pyridin-4- ylsulfanyl)spiro[l,3-dioxolane-2,3'-indol]-2'(lΗ)-one using a procedure similar to that of Example 551. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 391.1 (M+H).
Example 559 5'-[(2-Chloro-4-fluorophenyl)sulfanyl]-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)- one
Figure imgf000131_0002
The title compound (0.012g, 64%) was prepared as a clear oil from l'-(cyclopropylmethyl)-5'- [(triisopropylsilyl)sulfanyl]spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one using a procedure similar to that of Step 2 of Example 201. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 420.1 (M+H).
Examples 560-565
Figure imgf000132_0001
Examples 560-565 were prepared from r-(cyclopropylmethyl)-5'-[(triisopropylsilyl)sulfanyl]spiro[l,3- dioxane-2,3'-indol]-2'(l'H)-one and the appropriate commercially available or synthesized, according to procedures described in Tetrahedron. 2005, 61, 4779-4784 or WO 2006/004533, substituted aryl or heteroaryl iodides and according to the procedure for Step 2 of Example 201 and are summarized in Table 41.
Table 41 : Compounds Prepared According to the Procedure of Example 201, step 2.
Figure imgf000132_0002
Examples 566
S'-ICl-Chloro-^fluorophenyOsulfonyll-r-^yclopropylmethyOspiroIl^-dioxane-l^'-indoll-lXl'H)- one
Figure imgf000133_0001
The title compound (0.089g, 69%) was prepared as a white solid from 5'-[(2-chloro-4- fluorophenyl)sulfanyl]-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one using a procedure similar to that of Example 202. 1H NMR (400 MHz, DMSO-dό): consistent; MS (ESI+) mlz 452.0 (M+H).
Examples 567-573
Figure imgf000133_0002
Examples 567-573 were oxidized to the sulfones according to the procedure for Example 202 and are summarized in Table 42.
Table 42: Compounds Prepared According to the Procedure of Example 202.
Figure imgf000134_0002
Example 574
5?-(Pyridin-2-ylsulfanyl)spiro[l,3-dioxane-2,3?-indol]-2?(lΗ)-one
Figure imgf000134_0001
The title compound (0.377g, 80%) was prepared from 5'-(phenylthio)spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one using a procedure similar to that of Example 201, step 2. 1H NMR (400 MHz, DMSO- d6): consistent; MS (ESI+) m/z 313.0 (M+H). Example 575
5'-(Pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one
Figure imgf000135_0001
The title compound (0.404g, 73%) was prepared from 5'-(pyπdm-2-ylsulfanyl)spiro[l ,3-dioxane-
2,3'-mdol]-2'(l'H)-one using a procedure similar to that of Example 202. 1H NMR (400 MHz, DMSO- d6): consistent; MS (ESI+) m/z 347.1 (M+H).
Example 576 r-Phenyl-5?-(pyridin-2-ylsulfonyl)spiro[l,3-dioxane-2,3?-indol]-2?(lΗ)-one
Figure imgf000135_0002
The title compound (0.089g, 72%) was prepared from 5'-(pyπdm-2-ylsulfonyl)spiro[l,3-dioxane- 2,3'-mdol]-2'(l 'H)-one and phenyl boronic acid using a procedure similar to that of Example 197. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 423.0 (M+H).
Examples 577-604
Figure imgf000135_0003
Examples 577-604 were prepared from 5'-(pyπdin-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-mdol]-
2'(l'H)-one and the appropriate substituted boronic acids using a procedure similar to that of Example 197 and are summarized m Table 43.
Table 43: Compounds Prepared According to the Procedure of Example 197.
Figure imgf000136_0001
Figure imgf000137_0001
Example 605 5'-(Pyridin-3-ylsulfanyl)spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one
Figure imgf000138_0001
The title compound (0.974g, 71%) was prepared as a white solid from 5'-
[(taisopropylsilyl)sulfanyl]spiro[l,3-ώoxane-2,3'-indol]-2'(lΗ)-one using a procedure similar to that of Example 201 step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) m/z 315.0 (M+H).
Example 606 5'-(Pyridin-3-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one
Figure imgf000138_0002
The title compound (0.17g, 20%) was prepared from 5'-(pyndm-3-ylsulfanyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one using a procedure similar to that of Example 202. 1H NMR (400 MHz, DMSO- d6): consistent; MS (ESI+) m/z 347.0 (M+H).
Example 607 l'-(2-Methoxyphenyl)-5'-(pyridin-3-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one
Figure imgf000138_0003
The title compound (0.030g, 23%) was prepared from 5'-(pyπdm-3-ylsulfonyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one and 2-methoxy -phenyl boronic acid using a procedure similar to that of Example 197. 1H NMR (400 MHz, DMSO-dό): consistent; MS (ESI+) m/z 453.1 (M+H).
Examples 608-632
Figure imgf000139_0001
Examples 608-632 were prepared from 5'-(pyridin-3-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one and the appropriate substituted boronic acids using a procedure similar to that of Example 197 and summarized in Table 44. Table 44: Compounds Prepared According to the Procedure of Example 197.
Figure imgf000139_0002
Figure imgf000140_0001
Example 633
r-(Cyclopropylmethyl)-5'-{[5-(trifluoromethyl)pyridin-2-yl]sulfanyl}spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one
Figure imgf000141_0001
The title compound (0.193g, 74 %) was prepared as a clear oil from l'-(cyclopropylmethyl)-5'- iodospiro[l,3-dioxane-2,3'-indol]-2'(rH)-one and 5-(trifTuoromethyl)pyridine-2-thiol using a procedure similar to that of Example 201 step 2. 1H NMR (400 MHz, DMSO-d6): consistent; MS (ESI+) mlz 437.1 (M+H).
Example 634 r-(Cyclopropylmethyl)-5'-{[4-fluoro-2-(trifluoromethyl)phenyl]sulfinyl}spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one
Figure imgf000141_0002
The title compound (0.012g, 10%) was prepared as a white solid from l'-(cyclopropylmethyl)-5'- {[4-fluoro-2-(trifluoromethyl)phenyl]sulfanyl}spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one using a procedure similar to that of Example 202. 1H NMR (400 MHz, DMSO-dό): consistent; MS (ESI+) m/z 470.0 (M+H).
Example 635 l?-(2-fluorobenzyl)-5'-{[2-(trifluoromethyl)phenyl]carbonyl}spiro[l,3-dioxane-2,3?-indol]-2?(lΗ)- one
Figure imgf000141_0003
Step l 5 '- [2-(trifluoromethyl)benzoyl] spiro[ 1 ,3 -dioxane-2,3 '-indol]-2'( 177)-one
Figure imgf000141_0004
5'-Iodospiro[[l,3]dioxane-2,3'-indolin]-2'-one (4.0Og, 12.08mmol), trans- dichlorobis(triphenylphosphine)palladium(II) (0.25g, 0.36mmol), K2CO3 (5.0Og, 36.21mmol), and 2- (trifTuoromethyl)-phenylboronic acid (2.66g, 14.50mmol) were added to a flask fitted with a reflux condenser, a septum inlet, and a magnetic stir bar. The flask was flushed with carbon monoxide and then charged with toluene (1200.0OmL). The mixture was then stirred at 80° C under a balloon of carbon monoxide. After stirring overnight, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, washed with H2O, followed by brine. Organic layer was dried over Na2Sθ4, concentrated and purified by flash chromatography on silica gel to afford product as a white solid (1.94g, 43%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 376.0 (M-H). Step 2 1 '-(2-fluorobenzyl)-5'- { [2-(trifluoromethyl)phenyl]carbonyl} spiro[l ,3-dioxane-2,3'-indol]-2'( 1 Η)-one
Figure imgf000142_0001
The compound 5'-[2-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one (0.3Og, 0.80mmol) was dissolved in DMF (5.0OmL) under a N2 atmosphere. To this solution was added
Cs2CO3(0.79g, 2.41mmol) and 2-flurobenzyl bromide (0.29mL, 2.41mmol), and this mixture was stirred at room temperature. After stirring for 1 hour, TLC indicated reaction was complete. Reaction mixture was diluted with EtOAc, washed with H2O, followed by brine. Organic layer was dried over Na2SO4, concentrated and purified by flash chromatography on silica gel to afford product as a white solid (0.28g, 72%). 1H NMR (400 MHz, CDCl3): consistent; MS (ES) m/z 486.1 (M+H).
Examples 636-656
Examples 636 - 656 were prepared from different benzyl bromides by using a procedure similar to that of Example 635 and summarized in Table 45. Table 45 : Compounds Prepared According to the Procedure of Example 635.
Figure imgf000142_0002
Figure imgf000143_0001
Figure imgf000144_0002
Example 657 l'-benzyl-5'-{hydroxy[2-(trifluoromethyl)phenyl]methyl}spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one
Figure imgf000144_0001
The compound l'-benzyl-5'-{[2-(triiluoromethyl)phenyl]carbonyl}spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one one (0.24g, 0.5 lmmol) was dissolved in THF (5.0OmL) and to this solution was added NaBH4 (0.039g, 1.54mmol). After stirring for 1 hour, TLC analysis indicated reaction to be complete, so reaction mixture was diluted with EtOAc, washed with H2O, followed by brine. Organic layer was dried over Na2SO4, concentrated and purified by flash chromatography on silica gel to afford product as a white solid (0.12g, 50%). 1H NMR (400 MHz, CDCl3): consistent; MS (ESI) mlz 470.2 (M+H).
Examples 658-677
Examples 658-678 were prepared from Examples 636-656 by using a procedure similar to that of Example 657 and are summarized in Table 46.
Table 46: Compounds Prepared According to the Procedure of Example 657.
Figure imgf000145_0001
Figure imgf000146_0001
Example 678 l'-benzyl-5'-[2-(trifluoromethyl)benzyl]spiro[l,3-dioxane-2,3'-indol]-2l(l'H)-one
Figure imgf000147_0001
The compound 1 '-benzyl-5 '- {hydroxy [2-(trifluoromethyl)phenyl]methyl} spiro[ 1 ,3 -dioxane-2,3 '- indol]-2'(l'H)-one(0.098g, 0.21mmol) was dissolved in methylene chloride (3.0OmL) and was then treated with Et3SiH (0.04OmL, 0.25mmol). This solution was cooled to 0° C before the drop wise addition of TFA (0.047mL, 0.63mniol). TLC analysis confirmed reaction was complete immediately after the addition of TFA, so reaction mixture was treated with NaHCO3, and diluted with methylene chloride. Organic layer was separated, washed with brine, dried over Na2SO4 and purified by flash chromatography on silica gel to afford product as a clear, colorless oil (0.38g, 40%). 1H NMR (400 MHz, CDCl3): consistent; MS (ESI) m/z 454.1 (M+H).
Examples 679-695
Examples 679-695 were prepared from Examples 658-677 by using a procedure similar to that of Example 678 and are summarized in Table 47. Table 47 : Compounds Prepared According to the Procedure of Example 678.
Figure imgf000147_0002
Figure imgf000148_0001
Example A
Functional Assessment of Human CB2 and CBl Cannabinoid Receptor Activity
Cell Culture
CHO Kl cells expressing the human CBl or CB2 receptor were cultured at 37° C, m Ham's F12 (Invitrogen 21765-037 or equivalent) containing 10% fetal bovine serum (US biotechnologies or the equivalent), 100 μg/ml penicillin and 100 μg/ml streptomycin (Gibco 10131-035), 400 μg/ml G418 (Gibco 10131-035). Adherent cell culture cells were maintained by seeding at 2-3 x 106 cells m 30 mL medium m a
T175.
For assays using frozen aliquots of cells, cells were thawed at 37° C, added to 15 mL complete medium, centπfuged at 1200 rpm for 2 minutes The cell pellet was resuspended m 5 ml medium and then added to a T 175 containing 25 ml of medium. Frozen cells were also thawed as above and maintained m culture by adding the resuspended cells to 100 ml of medium m a sterilized 250 mL Erlenmeyer flask that was gassed with 5% CO2, capped, and placed on an orbital shaker at low RPM (50-100).
cAMP Assay Cells were lifted from the plate with dissociation buffer centπfuged and resuspended m a small volume of PBS. Cells were plated (15,000/well; 96 well plate, 7,500/well; 384 well plate) and incubated m the presence of 10 μM forskolm and compound m Krebs bicarbonate buffer (118 mM NaCl, 5 mM KCl, 1 2 mM MgSO4, 2.4 mM CaCl2 1.2 mM KH2PO4 25 mM NaHCO3 11.1 mM glucose) at 370 C for 30 minutes. cAMP content was determined using the HitHunter cAMP XS assay (Discoverx 90-0041, 90-0041 L). For the antagonist assay, compound is incubated m the presence of 10 μM forskolm and 10OnM WIN-55212-2 at 37 0C for 30 minutes.
The HitHunter assay was performed according to the manufacturer's instructions. Briefly, 20 μL cAMP antibody/lysis mix (1:1 ratio) were added to stimulated cells and incubated at room temperature for 1 hour. 20 μL of cAMP XS ED reagent was added and incubated at room temperature for 1 hour. 20 μL of cAMP XS EA reagent and 20 μL of CL substrate (1 part Galacton-Star, 5 parts Emerald-II, 19 parts substrate diluent) were added and then incubated at room temperature for 3 hours. Chemilummescence was read on a Victor II at 1 s/well. A standard curve was also established with cAMP concentrations ranging from 10 10 to 105 M, diluted m Krebs.
Analysis of Results
For agonists activating Gi coupled receptors (i.e. those which couple to the inhibition of cAMP formation) results were expressed as % inhibition of forskolm stimulated cAMP levels. Raw chemiluminescent data was converted to pMol cAMP using the standard curve and then % inhibition calculated as follows:
1 - ( Forskolin - Test ) x lOO
Forskolin
IC50 and EC50 values were calculated using Pπsm GraphPad using a 4-parameter logistic equation. An active agonist displays greater than 40% inhibition of cAMP. An antagonist typically displays greater than 40% reversal of 100 nM WIN55212-2 response.
EC5Q values and binding constants for selected inventive compounds are provided in Table 48 below.
Table 48
Figure imgf000150_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Example B
Assessment of Compound Affinity at the Human CB2 and CBl Cannabinoid Receptors
Cell Culture and Membrane Preparation
CHO Kl cells expressing the human CBl or CB2 receptor were cultured at 37 0C, in Ham's F12 (Invitrogen 21765-037 or equivalent) containing 10% fetal bovine serum (US biotechnologies or equivalent), 100 μg/mL penicillin and 100 μg/mL streptomycin (Gibco 10131-035), 400 μg/mL G418 (Gibco 10131-035).
Cells were harvested from plates by scraping in a small volume of ice-cold 20 mM HEPES, 2OmM EDTA, pH 7.5. The cells were homogenized and pelleted by centrifugation at 100,000 g for 30 minutes at 4° C. Membranes were resuspended at a concentration of 1- 5mg/mL.
Radioligand Binding Assay
30 μg Membranes were incubated in 0.5 mL binding buffer (50 mM Tris pH 5.7, 2.5 mM EDTA pH 8.0, 0.25% essentially fatty acid free BSA (Sigma A6003)) in the presence of 4 nM [3H] SR141716 (CBl antagonist) or 0.6 nM [3H] CP 55,940 (non-selective agonist) nM and cold displacing ligand for 1 hour at 3O0C. The assay was terminated by filtration on a brandel harvester through Whatman GFB filter paper, previously soaked in 0.15% polyethyleneamine. Samples were washed with 4 x 5 mL ice cold binding buffer and radioactivity was determined by liquid scintillation counting. Non-specific binding values were determined by either 1 μM CP 55, 940 or 1 μM WIN 55212-2.
Analysis of Results
IC5O values are calculated using GraphPad by fitting to a 1 or 2 site-binding model. Ki values are calculated from the apparent IC5O values using the Cheng-Prussof equation: Ki = IC50
1+ ([L]ZKd) where [L] = concentration of free radioligand and Kd = dissociation constant of radioligand for the receptor.
Compounds in this invention were found to have CB2 IC50S ranging from 0.062 to 20 μM.
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I:
Figure imgf000170_0001
I or pharmaceutically acceptable salts thereof, wherein:
R1 is selected from -(CH2)nRa, -CH(OH)Ra, -CH(ORb)Ra, and -C(O)Ra, or is selected from OR", SRa, SORa, SO2Ra and NRaRb;
R2 and RJ are independently selected from H, halogen, OH, 0Ra, 0WRa, Ci_6 alkyl, and WC i-6 alkyl, wherein C]_6 alkyl or 0Ra, is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, Ci_6 haloalkyl, C3.8 cycloalkyl, C6.io aryl and C4.10 heteroaryl; or R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci.6 alkyl, Ci. 6 haloalkyl, C3_8 cycloalkyl, C6-Io aryl and C4_io heteroaryl;
R4 is independently selected from H, Cr6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6-Io aryl, C4-10 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone and -(CH2)n-Ci_6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, d.6 alkyl, d.6 haloalkyl, C3.8 cycloalkyl, WC3.8 cycloalkyl, C6. 10 aryl and C4.10 heteroaryl; at each occurrence W is -(CH2)n- or -C(O)-; at each occurrence, Ra and Rb are independently selected from H, Ci_6 alkyl, C1.6 haloalkyl, C2.6 alkenyl, C2_6 alkynyl, C6_i0 aryl, C4.10 heteroaryl, C3_8 cycloalkyl, C3.8 heterocycloalkyl, C3.g heterocycloalkenyl C7.14 arylalkyl, C4.14 heteroarylalkyl, C5.12 cycloalkylalkyl and C5_i2 heterocycloalkylalkyl, each of which is optionally substituted with 0Ra, cyano, amino, halo, Ci_6 alkyl, C6-Io aryl, C4.10 heteroaryl, C3_8 cycloalkyl, C3.8 heterocycloalkyl, C3.8 heterocycloalkenyl C7.14 arylalkyl, C4.14 heteroaiylalkyl, C5.12 cycloalkylalkyl and C5_i2 heterocycloalkylalkyl; at each occurrence, halogen is selected from F, Cl, Br and I; and at each occurrence, n is 0, 1, 2, or 3.
2. The compound of claim 1, wherein R1 is -N(Ra)Rb; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5_7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3.8 cycloalkyl, C6_i0 aryl and C4_i0 heteroaryl; and R4 is independently selected from H, d-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3.8 cycloalkyl, WC3_8 cycloalkyl, Cβ-io aryl, C4_io heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone and -(CH2)n-Ci_6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6-Io aryl and C4_io heteroaryl.
3. The compound of claim 2, wherein R1 is -N(Ra)Rb and at least one of Raand Rb are hydrogen or Raand Rb, together with the N atom to which they are attached, join to form a 4-6 memebered heterocycloalkyl ring.
4. The compound of claim 2, wherein R1 is a methylene radical -(CH2)n- further attached to substituents selected from C6_i0 aryl, C4-I0 heteroaryl, benzodioxanyl, oxazolidinonyl, - (CH2)n-Ci_6 haloalkyl, C3.g cycloalkyl and Ci_6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, and Ci_6 haloalkyl, C3.8 cycloalkyl, WC3.8 cycloalkyl, C6_i0 aryl and C4_i0 heteroaryl.
5. The compound of claim 1, wherein R1 is -ORa; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6.io aryl and C6.io heteroaryl; and R4 is independently selected from H, d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6.io aryl, C4-I0 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone, -(CH^-C^ haloalkyl, -(CH2V C3_8 cycloalkyl and Ci_6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6.io aryl and C4_i0 heteroaryl.
6. The compound of claim 5, wherein R1 is -0-, substituted with substituents selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ce-io aryl, C4-I0 heteroaryl, -(CH2)n-benzodioxane, - (CH2)n-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3-8 cycloalkyl, C6-I0 aryl and C4.10 heteroaryl; and R4 is independently selected from H, d-6 alkyl, C6.w aryl, C4-I0 heteroaryl, -(CH2)n- C3.8 cycloalkyl, -(CH2)n- C3.8 heterocycloalkyl, -(CH2)n-Ci_6 haloalkyl, - (CH2V- and C1^ haloalkyl.
7. The compound of claim 1, wherein R1 is -SRa; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3.8 cycloalkyl, C6.io aryl and C4-I0 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6_i0 aryl, C4-I0 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone, -(CH2)n-Ci_6 haloalkyl, -(CH2)n- C3.8 cycloalkyl and Ci_e haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Q-6 alkyl, C3.8 cycloalkyl, C6-Io aryl and C4-I0 heteroaryl.
8. The compound of claim 7, wherein R1 is -S-, substituted with substituents selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-I0 aryl, C4-I0 heteroaryl, -(CH2)n-benzodioxane, - (CH2)n-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6_i0 aryl and C4-I0 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C6.io aryl, C4-I0 heteroaryl, -(CH2)n- C3.8 cycloalkyl, -(CH2)n- C3.8 heterocycloalkyl, -(CH2)n-Ci.6 haloalkyl, - (CH2V- and Ci_6 haloalkyl.
9. The compound of claim 1, wherein R1 is -S(=O)Ra; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxycycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6-I0 aryl and C4-I0 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C2-6 alkenyl, C2-ealkynyl, C6- 10 aryl, C4-I0 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone, -(CH2)n-Ci.6 haloalkyl, -(CH2)n- C3.8 cycloalkyl and Ci-6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6-I0 aryl and C4-I0 heteroaryl.
10. The compound of claim 9, wherein R1 is -S(=O)-, substituted with substituents selected from Cr6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6.10 aryl, C4.10 heteroaryl, -(CH2)n- benzodioxane, -(CH2)n-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3.8 cycloalkyl, C6.io aryl and C4_i0 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C6_i0 aryl, C4.10 heteroaryl, -(CH2)n- C3.8 cycloalkyl, -(CH2)n- C3.8 heterocycloalkyl, -(CH2)n-Ci_6 haloalkyl, -(CH2)n- and Ci.6 haloalkyl.
11. The compound of claim 1 , wherein R1 is -S(=O)(O)Ra; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5_7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1 , 2, or 3 substituents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3_8 cycloalkyl, C6_io aryl and C4_i0 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6. 10 aryl, C4_io heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone, -(CH2)n-Ci.6 haloalkyl, -(CH2)n- C3.8 cycloalkyl and Ci.6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, ORa, C]-6 alkyl, C3_8 cycloalkyl, C6_io aryl and C4_io heteroaryl.
12. The compound of claim 11, wherein R1 is -S(=O)(O)-, substituted with substituents selected from d-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6_io aryl, C4_i0 heteroaryl, -(CH2)n- benzodioxane, -(CH2)n-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, ORa, Ci-6 alkyl, C3.8 cycloalkyl, C6_io aryl and C4_io heteroaryl; and R4 is independently selected from H, d-6 alkyl, Ce-io aryl, C4-I0 heteroaryl, -(CH2)n- C3.8 cycloalkyl, -(CH2)n- C3.8 heterocycloalkyl, -(CH2)n-Ci_6 haloalkyl, -(CH2)n- and Ci-6 haloalkyl.
13. The compound of claim 1, wherein R1 is -C(=O)Ra; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, ORa, Ci-6 alkyl, C3.8 cycloalkyl, C6_i0 aryl and C4_i0 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C2-6 alkenyl, C2-ealkynyl, C6. 10 aryl, C4_io heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone, -(CH2)n-Ci.6 haloalkyl, -(CH2)n- C3.8 cycloalkyl and Ci-6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6.10 aryl and C4-I0 heteroaryl.
14. The compound of claim 13, wherein R1 is -C(=O)- , substituted with substituents selected from Cr6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6-I0 aryl, C4-Io heteroaryl, -(CH2)n- benzodioxane, -(CH2)n-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3_8 cycloalkyl, C6-Io aryl and C4-I0 heteroaryl; and R4 is independently selected from H, d-6 alkyl, C6-I0 aryl, C4-I0 heteroaryl, -(CH2)n- C3.8 cycloalkyl, -(CH2)n- C3.8 heterocycloalkyl, -(CH2)n-Ci_6 haloalkyl, -(CH2V and Ci_6 haloalkyl.
15. The compound of claim 13, wherein R4 is -(CH2)n-C3.7 cycloalkyl or C6-Io aryl and C6. io heteroaryl, wherein each of C6-I0 aryl and C4-Io heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, ORa, Cr6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-I0 aryl, C4-I0 heteroaryl, -(CH2VCi-6 haloalkyl, -(CH2V, Ci-6 haloalkyl, C3.8 cycloalkyl, C6-Io aryl and C4-I0 heteroaryl.
16. The compound of claim 13, wherein R4 is -(CH2)-cyclopropyl, ORa, C6-I0 aryl, C4-I0 heteroaryl, substituted C6-I0 aryl, or substituted C4-I0 heteroaryl.
17. The compound of claim 13, wherein R4 is C6-I0 aryl or C4-I0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, ORa and Ci_6 alkyl.
18. The compound of claim 17, wherein Ra is Ci.6 haloalkyl.
19. The compound of claim 17, wherein halogen or halogen of Ci_6 haloalkyl is fluoro.
20. The compound of claim 17, wherein Ra is CF3 or OCF3.
21. The compound of claim 1 , wherein R1 is -CH(OH)Ra; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3.8 cycloalkyl, C6-I0 aryl and C4-I0 heteroaryl; and R4 is independently selected from H, d-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6. io aryl, C4-10 heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone, -(CH2)n-Ci-6 haloalkyl, -(CH2)n- C3.8 cycloalkyl and C\.6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, ORa, Ci_6 alkyl, C3.8 cycloalkyl, Cβ-io aryl and C4.10 heteroaryl.
22. The compound of claim 21, wherein R1 is -CH(OH)-, substituted with substituents selected from d-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6_io aryl, C4.10 heteroaryl, -(CH2)n- benzodioxane, -(CH2)n-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6-Io aryl and C4_i0 heteroaryl; and R4 is independently selected from H, d-6 alkyl, C6_io aryl, C4-I0 heteroaryl, -(CH2)n- C3.8 cycloalkyl, -(CH2)n- C3.8 heterocycloalkyl, -(CH2)n-Ci_6 haloalkyl, -(CH2)n- and d.6 haloalkyl.
23. The compound of claim 21, wherein R4 is -(CH2)n-C3.7 cycloalkyl, C6-I0 aryl or C6-io heteroaryl, wherein each of Cβ-io aryl and C4.10 heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, 0Ra, Cr6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6.io aryl, C4-I0 heteroaryl, -(CH2)n-Ci_6 haloalkyl, -(CH2)n-, C1^ haloalkyl, C3.8 cycloalkyl, C6.10 aryl and C4-I0 heteroaryl.
24. The compound of claim 21, wherein R4 is -(CH2)-cyclopropyl, ORa, C6.10 aryl, C4-I0 heteroaryl, substituted C6.io aryl, or substituted C4-I0 heteroaryl.
25. The compound of claim 21, wherein R4 is C6_i0 aryl or C4_i0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra and C\.e alkyl.
26. The compound of claim 25, wherein Ra is
Figure imgf000175_0001
haloalkyl.
27. The compound of claim 25, wherein halogen or halogen of C\.6 haloalkyl is fluoro.
28. The compound of claim 25, wherein Ra is CF3 or OCF3.
29. The compound of claim 1 , wherein R1 is -CH(ORb)Ra; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3-8 cycloalkyl, Cβ-io aryl and C4-10 heteroaryl; and R4 is independently selected from H, Cr6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6. 10 aryl, Gno heteroaryl, -(CH2)n-benzodioxane, -(CH2)n- oxazolidinone, -(CH2)n-Ci.6 haloalkyl, -(CH2)n- C3.8 cycloalkyl and Ci.6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6-io aryl and C4.10 heteroaryl.
30. The compound of claim 29, wherein R1 is -CH(ORb)-, substituted with substituents selected from d-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6.io aryl, C4.10 heteroaryl, -(CH2)n- benzodioxane, -(CH^-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, Cβ-io aryl and C4.10 heteroaryl; and R4 is independently selected from H, Ci-6 alkyl, C6-Io aryl, C4.10 heteroaryl, -(CH2)n- C3.8 cycloalkyl, -(CH2)n- C3.8 heterocycloalkyl, -(CH2)n-Ci_6 haloalkyl, -(CH2V and Ci-6 haloalkyl.
31. The compound of claim 1 , wherein R1 is -(CH2In-; R2 and R3, together with the carbon atom to which they are attached, join to form a ring selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, C5-C7 oxycycloalkyl, C5.7 dioxy cycloalkyl and oxazolidinyl ring, each ring optionally substituted with 1, 2, or 3 substituents independently selected from halogen, CN, OH, 0Ra, Ci_6 alkyl, C3.8 cycloalkyl, C6-Io aryl and C4_i0 heteroaryl; and R4 is independently selected from H, d-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6. 10 aryl, C4_io heteroaryl, -(CH2)n-benzodioxane, -(CH2V oxazolidinone, -(CH2)n-Ci.6 haloalkyl, -(CH2)n- C3.8 cycloalkyl and Ci-6 haloalkyl, each of which is optionally substituted with 1, 2, or 3 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3.8 cycloalkyl, C6-io aryl and C4.10 heteroaryl.
32. The compound of claim 31 , wherein R1 is -(CH2V, substituted with substituents selected from d-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C6.io aryl, C4.10 heteroaryl, -(CH2)n- benzodioxane, -(CH2)n-oxazolidinone, each of which is optionally substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, 0Ra, Ci-6 alkyl, C3_8 cycloalkyl, C6-IO aryl and C4_i0 heteroaryl; and R4 is independently selected from H, Ci -6 alkyl, C6-io aryl, C4-I0 heteroaryl, -(CH2V C3.8 cycloalkyl, -(CH2)n- C3.8 heterocycloalkyl, -(CH2VCi-6 haloalkyl, -(CH2V and Ci_6 haloalkyl.
33. The compound of claim 31, wherein R4 is -(CH2)n-C3.7 cycloalkyl or C6-I0 aryl and C4. 10 heteroaryl, wherein each of C6-Io aryl and C4.10 heteroaryl is substituted with 1-4 substituents selected from H, CN, OH, 0Ra, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-I0 aiyl, C4.10 heteroaryl, -(CH2)n-Ci_6 haloalkyl, -(CH2)n-, Ci-6 haloalkyl, C3.8 cycloalkyl, C6-I0 aryl and C6-I0 heteroaryl.
34. The compound of claim 31 , wherein R4 is -(CH2)-cyclopropyl, ORa, C6-Io aryl, C6-io heteroaryl, substituted C6.io aryl, or substituted C4.10 heteroaryl.
35. The compound of claim 31, wherein R4 is C6-I0 aryl or C4-I0 heteroaryl substituted with 1, 2, 3 or 4 substitutents independently selected from halogen, CN, OH, ORa and Ci-6 alkyl.
36. The compound of claim 35, wherein Ra is Ci_6 haloalkyl.
37. The compound of claim 35, wherein halogen or halogen of Ci_6 haloalkyl is fluoro.
38. The compound of claim 35, wherein Ra is CF3 or OCF3.
39. A compound selected from: 5'-benzoyl-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2T(l'H)-one, r-(cyclopropylmethyl)-5'-(2-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]- 2'(177)-one, l'-(cyclopropylmethyl)-5'-(3-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)- one, r-(cyclopropylmethyl)-5'-(4-fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[2-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)-5'-[3-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)- one, 1 '-(cyclopropylmethyl)-5 '- [3 -(trifluoromethyl)benzoyl] spiro [ 1 ,3 -dioxane-2 ,3 '-indol] - T(VH)-one, r-(cyclopropylmethyl)-5'-[4-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'- indol]-2'(l 77)-one, 1 '-(cyclopropylmethyl)-5'-(2-methoxybenzoyl)spiro[l ,3-dioxane-2,3'- indol]-2'(rH)-one, 1 '-(cyclopropylmethyl)-5'-(3-methoxybenzoyl)spiro[l ,3-dioxane-2,3'- indol]-2'(l TH)-one, 1 '-(cyclopropylmethyl)-5'-(4-methoxybenzoyl)spiro[l ,3-dioxane-2,3'- indol]-2'(l'H)-one, 5'-(2-chlorobenzoyl)-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]- 2'(l'//)-one, 5'-(3-chlorobenzoyl)-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]- 2'(l'//)-one, 5'-(4-chlorobenzoyl)-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]- 2'(lΗ)-one, l'-(cyclopropylmethyl)-5'-(3-methylbenzoyl)spiro[l,3-dioxane-2,3'-indol]- 2\VH)-one, l'-(cyclopropylmethyl)-5'-(4-methylbenzoyl)spiro[l,3-dioxane-2,3'-mdol]- T(VH)-one, r-(cyclopropylmethyl)-5'-[3-(trifluoromethoxy)benzoyl]spiro[l,3-dioxane-2,3'- indol]-2'( 1 'H)-one, 1 '-(cyclopropylmethyl)-5 '- [4-(trifluoromethoxy)benzoyl] spiro [1,3- dioxane-2,3'-indol]-2'(l 'H)-one, 1 '-(cyclopropylmethyl)-5'-(3-furoyl)spiro[l ,3-dioxane-2,3'- indol]-2'(rH)-one, r-(cyclopropylmethyl)-5'-(3-thienylcarbonyl)spiro[l,3-ώoxane-2,3'- mdol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2-methylbenzoyl)spiro[l,3-dioxane-2,3'-mdol]- 2'(177)-one, r-(cyclopropylmethyl)-5'-[4-fluoro-2-(tnfluoromethyl)benzoyl]spiro[l,3- dioxane-2,3'-mdol]-2'(l 'H)-one, 1 '-(cyclopropylmethyl)-5'-[5-fluoro-2- (tnfluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-mdol]-2'(lΗ)-one, 5'-[4-chloro-2- (tπfluoromethyl)benzoyl]- 1 '-(cyclopropylmethyl)spiro[ 1 ,3 -dioxane-2,3 '-mdol] -2'(I '//)-one, r-(cyclopropylmethyl)-5'-(2,3-difluorobenzoyl)spiro[l,3-dioxane-2,3'-mdol]-2'(rΗ)-one, 1'- (cyclopropylmethyl)-5'-(2,5-difluorobenzoyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, 5'-(3- chloro-4-fluorobenzoyl)-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(2,3-dichlorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(2,5-dichlorobenzoyl)spiro[l,3-dioxane-2,3'-uidol]-2'(l'/f)-one, 1'- (cyclopropylmethyl)-5 '-(3,4-dichlorobenzoyl)spiro[ 1 ,3 -dioxane-2,3 '-mdol]-2'( 1 '//)-one, 1 '- (cyclopropylmethyl)-5'-(2,3-dimethoxybenzoyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(2-methoxy-5-methylbenzoyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)- one, 5'-(5-chloro-2-methoxybenzoyl)-l '-(cyclopropylmethyl)spiro[l ,3 -dioxane-2,3 '-mdol] - 2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(5-fluoro-2-methoxybenzoyl)spiro[l,3-dioxane-2,3'- mdol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2,3-dimethylbenzoyl)spiro[l,3-dioxane-2,3'- mdol]-2'(r/7)-one, l'-(cyclopropylmethyl)-5'-(2,6-dimethylbenzoyl)spiro[l,3-dioxane-2,3'- mdol]-2'(l '//)-one, 5'-(5-chloro-2-methylbenzoyl)-l '-(cyclopropylmethyl)spiro[l ,3-dioxane- 2,3'-mdol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-[2-(tnfluoromethoxy)benzoyl]spiro[l,3- dioxane-2,3'-mdol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2,4-difluorobenzoyl)spiro[l,3- dioxane-2,3'-mdol]-2'(l '//)-one, 1 '-(cyclopropylmethyl)-5'-(2,6-dimethoxybenzoyl)spiro[l ,3- dioxane-2,3'-mdol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-[hydiOxy(phenyl)metliyl]spiro[l,3- dioxane-2,3'-mdol]-2'(l '//)-one, 1 '-(cyclopropylmethyl)-5'-[(2- fluorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 1'- (cyclopropylmethyl)-5'-[(3-fluorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-mdol]- 2'(I '//)-one, 1 '-(cyclopropylmethyl)-5'-[(4-fluorophenyl)(hydroxy)methyl]spiro[l ,3-dioxane- 2,3'-mdol]-2'(l'//)-one, 2-[5'-{hydroxy[2-(tπfluoromethyl)phenyl]methyl}-2'-oxospiro[l,3- dioxane-2,3'- mdol]-l'(2Η)-yl]benzomtπle, (-)-2-[5'-{(S)-hydroxy[2- (tπfluoromethyl)phenyl]methyl}-2'-oxospiro[l,3-dioxane- 2,3'-indol]-l'(2'H)-yl]benzonitrile, (+)2-[5'-{(R)-hydroxy[2-(tπfluoromethyl)phenyl]methyl}-2'-oxospiro[l,3-dioxane- 2,3'- mdol]-l '(2Η)-yl]benzomtπle, (+)-l '-(3,4-difluorophenyl)-5'- {(R)-hydroxy[2- (tπfluoromethyl)phenyl]-methyl} spiro[ 1 ,3 -dioxane-2,3 '-mdol] -2'( 1 'H)-one, (-)- 1 '-(3 ,4- difluorophenyl)-5'-{(S)-hydroxy[2-(tπfluoiOmethyl)phenyl]-methyl}spiro[l,3-dioxane-2,3'- mdol]-2'( 1 'H)-one, 1 '-(cyclopropylmethyl)-5 '- { 1 -hydroxy- 1 - [2- (tnfluoromethyl)phenyl]ethyl}spiro[l,3-dioxane-2,3'-mdol]-2'(l'H)-one, l'-(3,4- difluorophenyl)-5'- { 1 -hydroxy- 1 - [2-(trifluoromethyl)phenyl] ethyl} spiro[ 1 ,3-dioxane-2,3 '- indol]-2'(l'H)-one, l'-(cyclopropylmethyl)-5'-{hydroxy[2- (trifluoromethyl)phenyl]methyl}spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cy clopropylmethyl)-5 '- {hydroxy [3 -(trifluoromethyl)phenyl]methyl } spiro [1,3 -dioxane-2 ,3 '- indol]-2'(l Η)-one, 1 '-(cyclopropylmethyl)-5'- {hydroxy[4- (trifluoromethyl)phenyl]methyl}spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[hydroxy(2-methoxyphenyl)methyl]spiro[l,3-dioxane-2,3'-indol]- 2'(lΗ)-one, r-(cyclopropylmethyl)-5'-[hydroxy(3-methoxyphenyl)methyl]spiro[l,3-dioxane- 2,3'-indol]-2'( 1 H)-one, 1 '-(cyclopropylmethyl)-5'-[hydroxy(4- methoxyphenyl)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-[(2- chlorophenyl)(hydroxy)methyl]-l '-(cyclopropylmethyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l 'H)- one, 5 '- [(3-chlorophenyl)(hydroxy)methyl]- 1 '-(cyclopropylmethyl)spiro [ 1 ,3-dioxane-2,3 '- indol]-2'(r//)-one, 5'-[(4-chlorophenyl)(hydroxy)methyl]-r-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(l '//)-one, 1 '-(cyclopropylmethyl)-5'-[hyώOxy(3- methylphenyl)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'- [hydroxy(4-methylphenyl)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-{hydroxy[3-(trifluoromethoxy)phenyl]methyl}spiro[l,3-dioxane-2,3'- indol]-2'(l Η)-one, 1 '-(cyclopropylmethyl)-5'- {hydroxy[4- (trifluoromethoxy)phenyl]methyl}spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[3-furyl(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[hydroxy(3-thienyl)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)-5'-[hydroxy(2-methylphenyl)methyl]spiro[l,3-dioxane-2,3'-indol]- 2'(lΗ)-one, l'-(cyclopropylmethyl)-5'-{[4-fluoro-2-
(trifluoromethyl)phenyl](hydroxy)methyl}spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-{[5-fluoro-2-(triiluoromethyl)phenyl](hydroxy)methyl}spiro[l,3- dioxane-2,3'-indol]-2'(l'//)-one, 5'-{[4-chloro-2-(trifluoromethyl)phenyl](hydroxy)methyl}- l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'- [(2,3 -difluorophenyl)(hydroxy)methyl] spiro [1 ,3-dioxane-2,3 '-indol] -2'(I '//)-one, 1 '- (cyclopropylmethyl)-5'-[(2,5-difluorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]- T[VH)-OXiQ, 5'-[(3-chloro-4-fluorophenyl)(hydroxy)methyl]-l '-(cyclopropylmethyl)spiro[l ,3- dioxane-2,3'-indol]-2'(l '//)-one, 1 '-(cyclopropylmethyl)-5'-[(2,3- dichlorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[(2,5 -dichlorophenyl)(hydroxy)methyl]spiro[ 1 ,3 -dioxane-2,3 '-indol] - T[YH)-OTYQ, r-(cyclopropylmethyl)-5'-[(3,4-dichlorophenyl)(hydroxy)methyl]spiro[l,3- dioxane-2,3'-indol]-2'(l '//)-one, 1 '-(cyclopropylmethyl)-5'-[(2,3- dimethoxyphenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r/7)-one, 1'- (cy clopropylmethy l)-5 '- [hydroxy (2 -methoxy-5 -methylphenyl)methyl] spiro [ 1 ,3 -dioxane-2 ,3 '- mdol]-2'(l'//)-one, 5'-[(5-chloro-2-methoxyphenyl)(hydroxy)methyl]-l'- (cyclopropylmethyl)spiro[l,3-dioxane-2,3'-mdol]-2'(177)-one, l'-(cyclopropylmethyl)-5'-[(5- fluoro-2-methoxyphenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[(2,3-dimethylphenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-indol]- 2'(177)-one, r-(cyclopropylmethyl)-5'-[(2,6-dimethylphenyl)(hydroxy)metriyl]spiro[l,3- dioxane-2,3'-indol]-2'(r//)-one, 5'-[(5-chloro-2-methylphenyl)(hydroxy)methyl]-r- (cyclopropylmethyl)spiro[ 1 ,3-dioxane-2,3'-mdol]-2'( 1 Η)-one, 1 '-(cyclopropylmethyl)-5'- {hydroxy[2-(tπfluoromethoxy)phenyl]methyl}spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[(2,4-difluorophenyl)(hydroxy)methyl]spiro[l,3-dioxane-2,3'-mdol]- 2'(l'//)-one, 5'-benzyl-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[2-(tπfluoromethyl)benzyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, r-(cyclopropylmethyl)-5'-(2-fluorobenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(3-fluorobenzyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 Η)-one, 1 '- (cyclopropylmethyl)-5'-(4-fluorobenzyl)spiro[ 1 ,3-dioxane-2,3'-indol]-2'( 1 '/7)-one, 1 '- (cyclopropylmethyl)-5'-[3-(tπfluoromethyl)benzyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'^cyclopropylmethy^-S'-^-^rifluoromethy^benzylJspirofl^-dioxane^^'-indol]^^!'//)- one, 1 '-(cyclopropylmethyl)-5'-(2-methoxybenzyl)spiro[ 1 ,3-dioxane-2,3'-mdol]-2'( 1 '//)-one, 1 '-(cyclopropylmethyl)-5 '-(3 -methoxybenzyl)spiro[ 1 ,3 -dioxane-2,3 '-indol]-2'( 1 '//)-one, 1 '- (cyclopropylmethyl)-5'-(4-methoxybenzyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, 5'-(2- chlorobenzyl)-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, 5'-(3- chlorobenzy^-r^cyclopropylmethyOspirofl^-dioxane^^'-mdolJ^Xr/^-one, 5'-(4- chlorobenzyl)-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(3-methylbenzyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(4-methylbenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[4-(tπfluoromethoxy)benzyl]spiro[l,3-dioxane-2,3'-mdol]-2'(r//)- one, r-(cyclopropylmethyl)-5'-(3-thienylmethyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-(2-methylbenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 1'- (cyclopropylmethyl)-5'-[4-fluoro-2-(tπfluoromethyl)benzyl]spiro[l,3-dioxane-2,3'-indol]- 2'(177)-one, 1 '-(cyclopropylmethyl)-5'-[5-fluoro-2-(tπfluoromethyl)benzyl]spiro[l ,3-dioxane- 2,3'-mdol]-2'( 1 '#)-one, 5'-[4-chloro-2-(tπfluoromethyl)benzyl]-l '-
(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, l'-(cy clopropylmethy l)-5 '-(2,3- difluorobenzyl)spiro[l,3-dioxane-2,3'-mdol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2,5- difluorobenzyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, 5'-(3-chloro-4-fluorobenzyl)-l'- (cyclopropylmethyl)spiro[l,3-dioxane-2,3'-mdol]-2'(r//)-one, l'-(cy clopropylmethy l)-5 '-(2,3- dichlorobenzyl)spiro[l,3-dioxane-2,3'-mdol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2,5- dichlorobenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'-(3,4- dichlorobenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2,3- dimethoxybenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(cyclopropylmethyl)-5'-(2- methoxy-5-methylbenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-(5-chloro-2- methoxybenzyl)-l '-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l Η)-one, 1 '- (cyclopropylmethy^-S'^S-fluoro^-methoxybenzy^spirofl^-dioxane^^'-indoll^Xr/ft-one, r-(cyclopropylmethyl)-5'-(2,3-dimethylbenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'- (5-chloro-2-methylbenzyl)-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(cyclopropylmethyl)-5'-[2-(trifluoromethoxy)benzyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)- one, r-(cyclopropylmethyl)-5'-(2,4-difluorobenzyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-phenyl-5'-[2-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-benzoyl-l'-phenylspiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(2-fluorobenzoyl)-l'- phenylspiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(2-methoxybenzoyl)-r-phenylspiro[l,3- dioxane-2,3'-indol]-2'(l'//)-one, 5'-(2-chlorobenzoyl)-r-phenylspiro[l,3-dioxane-2,3'-indol]- 2'(l'i7)-one, 5'-(2-methylbenzoyl)-l'-phenylspiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 2-(5'- benzoyl-2'-oxospiro[l,3-dioxane-2,3'-indol]-r(2'//)-yl)benzonitrile, 2-[5'-(2-fluorobenzoyl)- 2'-oxospiro[l,3-dioxane-2,3'-indol]-l'(2'//)-yl]benzonitrile, 2-{2'-oxo-5'-[2- (trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-r(2'/7)-yl}benzonitrile, 2-[5'-(2- methoxybenzoyl)-2'-oxospiro[ 1 ,3 -dioxane-2,3 '-indol]- 1 '(2'//)-yl]benzonitrile, 2- [5'-(2- chlorobenzoyl)-2'-oxospiro[l,3-dioxane-2,3'-indol]-l'(2'//)-yl]benzonitrile, 5'-benzoyl-l'-(3,4- difluorophenyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(3,4-difluorophenyl)-5'-(2- fluorobenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(3,4-difluorophenyl)-5'-[2- (trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(3,4-difluoroplienyl)-5'- (2-methoxybenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'-(2-chlorobenzoyl)-l'-(3,4- difluorophenyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(3,4-difluorophenyl)-5'-(2- methylbenzoyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, l'-(2,5-difluorophenyl)-5'-[2- (trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(r/7)-one, 5'-(2-chlorobenzoyl)-l'- (2,5-difluorophenyl)spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(3-thienyl)-5'-[2- (trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, 5'-(2-chlorobenzoyl)-l'- (3-thienyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 2-[5'-(2-methylbenzoyl)-2'-oxospiro[l,3- dioxane-2,3'-indol]- 1 '(2'//)-yl]benzonitrile,
5'-benzoyl-l '-(3,3,3-trifluoropropyl)spiro[l,3-dioxane-2,3'-indol]-2'(l '//)-one, 1 '- propyl-5'-[2-(trifluoromethyl)benzoyl]spiro[l,3-dioxane-2,3'-indol]-2'(r//)-one, l'-(3,4- Difluorophenyl)-5'-phenethylspiro[[l,3]dioxane-2,3'-indolin]-2'-one, 5'-(Benzylamino)-l'- (cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(2- furylmethyl)amino]spiro[l ,3-dioxane-2,3'-mdol]- 2'(I 'H)-one, 1 '-(Cyclopropylmethyl)-5'-[(2- thienylmethyl)amino]spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one, 5'-{[(5-Chloro-2- thienyl)methyl]amino}-l'-(cyclopropylmethyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, 5'- { [(2-Butyl-l -benzofuran-3 -yl)methyl]amino } - 1 '-(cyclopropylmethyl)spiro[ 1,3- dioxane-2,3 '- indol]-2'( 1 Η)-one, 5'-[(4-Chlorobenzyl)amino]-l '-(cyclopropylmethyl)spiro[ 1 ,3-dioxane-2,3'- indol]- 2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(4-methoxybenzyl)amino]spiro[l,3-dioxane- 2,3'-indol]- 2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(4-methylbenzyl)amino]spiro[l,3- dioxane-2,3'-indol]- 2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(3,4- dichlorobenzyl)amino]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 5'-[(3- Chlorobenzyl)amino]-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one, 1'- (Cyclopropylmethyl)-5 '- { [4-(trifluoromethyl)benzyl]amino } spiro [1,3 -dioxane- 2,3 '-indol] - 2'(I 'H)-one, 5'- { [4-Chloro-3-(trifluoromethyl)benzyl]amino} -1 '-
(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(lΗ)-one, l'-(Cyclopropylmethyl)-5'-[(l- naphthylmethyl)amino]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'- [(2,3-dihydro-l,4-benzodioxin-6- ylmethyl)amino]spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one, r-(Cyclopropylmethyl)-5'-[(4-fluorobenzyl)amino]spiro[l,3-dioxane-2,3'-indol]- 2'(l'H)-one, 5'-[(I -Benzothiophen-2-ylmethyl)amino]-l '-(cyclopropylmethyl)spiro[ 1 ,3-dioxane- 2,3'- indol]-2'(l'H)-one,
5'-[Bis(cyclohexylmethyl)amino]-l'-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]- 2'(l'H)-one, r-(Cyclopropylmethyl)-5'-(dimethylamino)spiro[l,3-dioxane-2,3'-indol]-2'(rH)- one, 1 '-Butyl-5'-(methylamino)spiro[l,3-dioxane-2,3'-indol]-2'(l 'H)-one, 1 '- (Cyclopropylmethy^-S'^methy^pheny^aminoJspirofl^-dioxane^^'-indoll^Xl'^-one, 1'- (Cyclopropylmethyl)-5'-piperidin-l-ylspiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 5'- (Phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 5'-(Phenylsulfmyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, 5'-(Phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 5'- (Phenylthio)spiro[l,3-dioxolane-2,3'-indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'- (phenylthio)spiro[l,3-dioxolane-2,3'-indol]-2'(l'H)-one, 5'-(Phenylsulfonyl)spiro[l,3- dioxolane-2,3 '-indol] -2'( 1 Η)-one, 1 '-(Cyclopropylmethyl)-5 '-(phenylsulfonyl)spiro[ 1 ,3- dioxolane-2,3'-indol]- 2'(l'H)-one, l'-Phenyl-5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'- indol] -2 '( 1 'H)-one, 5 '-(Phenylsulfonyl)- 1 '- [3 -(trifluoromethyl)phenyl] spiro[ 1 ,3 -dioxolane- 2,3'- indol]-2'(l'H)-one, r-(3,4-Difluorophenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxolane-2,3'- indol]-2'(l'H)-one, l'-Plienyl-5'-(phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 1'- Phenyl-5'-(phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, l'-(3,4-Difluorophenyl)-5'- (phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, l'-Phenyl-5'-(phenylsulfonyl)spiro[l,3- dioxane-2,3'-indol]-2'(l'H)-one, 5'-(Phenylsulfonyl)-l'-[3-(trifluoromethyl)phenyl]spiro[l,3- dioxane-2,3'-indol]- 2'(l'H)-one, l'-(3,4-difluorophenyl)-5'-(phenylsulfonyl)spiro[l,3- dioxane-2,3'-indol]-2'(l'H)-one, l'-(2,5-difluorophenyl)-5'-(plienylsulfonyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, r-(3-fluorophenyl)-5T-(phenylsulfonyl)spiro[l,3-dioxane-2,3T-indol]- 2'(l'H)-one, l'-(3,5-dichlorophenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)- one, l'-(3-chloro-4-fluorophenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(rH)- one, r-(4-chlorophenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one, 5'- (phenylsulfonyl)-r-[2-(trifluoromethyl)phenyl]spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one, 1'- (2-methoxyphenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, l'-(4- fluorophenyl)-5'-(phenylsulfonyl)spiro[l,3-dioxane-2,3'-indol]-2'(rH)-one, l'-(2,3- difluorophenyl)-5'-(phenylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l 'H)-one, 1 '- (Cyclopropylmethyl)-5'-(phenylsulfmyl)spiro[l ,3-dioxane-2,3'-indol]-2'(l Η)-one, 5'- (Phenylthio)-r-(2,2,2-trifluoroethyl)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-(phenylthio)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(2-fluorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, r-(Cyclopropylmethyl)-5'-[(2-methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)- one, 5'-[(2-Chlorophenyl)sulfonyl]-l'-(cyclopropylmethyl)spiro[l ,3-dioxane-2,3'- indol]- 2'(l'H)-one, 5'-[(3-Chlorophenyl)sulfonyl]-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2'(l Η)-one, 1 '-(Cyclopropylmethyl)-5'-[(2-methylphenyl)sulfonyl]spiro[l ,3-dioxane- 2,3'- indol]-2'(lΗ)-one, l'^Cyclopropylmethy^-S'-fCS-fluoropheny^sulfonyljspirofl^- dioxane-2,3'- indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(4- fluorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(lΗ)-one, r-(Cyclopropylmethyl)-5'- {[2-(trifluoromethyl)phenyl]sulfmyl}spiro[l,3- dioxane-2,3'-indol]-2'(rH)-one, 1'- (Cyclopropylmethyl)-5'-[(2,5-dichlorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)- one, 5'-[(4-Chlorophenyl)sulfonyl]-l'-(cyclopropylmethyl)spiro[l ,3-dioxane-2,3'- indol]- 2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(3-methoxyphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol] -2'(I Η)-one, 1 '-(Cy clopropylmethyl)-5 '- [(3,4-dichlorophenyl)sulfonyl] spiro [ 1 ,3 - dioxane-2,3'- indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(3- methylphenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'- [(4-methoxyphenyl)sulfonyl]spiro [ 1 ,3 -dioxane-2,3 '- indol]-2'( 1 'H)-one, 5 '-( 1 ,3 -Benzothiazol- 2-ylsulfonyl)-r-(cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(3,4-difluorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(rH)- one, 1 '-(Cyclopropylmethyl)-5'-(pyridin-4-ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]- 2'(I 'H)- one, 1 '-(Cyclopropylmethyl)-5'-(pyridin-2-ylsulfonyl)spiro[l ,3-dioxane-2,3'-indol]- 2'(I 'H)- one, r-(Cyclopropylmethyl)-5'-(pyridin-4-ylthio)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-[(3,4-dichlorophenyl)thio]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(3,4-difluorophenyl)thio]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)- one, l'-(Cyclopropylmethyl)-5'-{[3-(trifluoromethyl)phenyl]sulfanyl}spiro[l,3- dioxane-2,3'- indol]-2'(l'H)-one, r-(Cyclopropylmethyl)-5'-(pyridin-2-ylsulfanyl)spiro[l,3-dioxane-2,3'- indol]- 2'(l'H)-one, l'-(Cyclopropylmetliyl)-5T-(pyridin-4-ylsulfinyl)spiro[l,3-dioxane-2,3T- indol]- 2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-(pyridin-2-ylsulfmyl)spiro[l,3-dioxane-2,3'- indol]- 2'(l'H)-one, r-(Cyclopropylmethyl)-5'-[(3,4-difluorophenyl)sulfmyl]-spiro[l,3- dioxane-2,3'- indol]-2'(l'H)-one, r-(Cyclopropylmethyl)-5'-(pyridin-3-ylsulfanyl)spiro[l,3- dioxane-2,3'-indol]- 2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(4- methylphenyl)sulfanyl]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'- {[4-(trifluoromethyl)phenyl]sulfanyl}spiro[l,3- dioxane-2,3'-indol]-2'(lΗ)-one, 5'-[(3- Chloro-4-fluorophenyl)sulfanyl] - 1 '-(cy clopropylmethyl)spiro [1,3 -dioxane- 2,3 '-indol] - 2'(l'H)-one, 5'-[(6-Chloropyridin-3-yl)sulfanyl]-r-(cyclopropylmethyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, r-(Cyclopropylmethyl)-5'-(naphthalen-l-ylsulfanyl)spiro[l,3- dioxane-2,3'- indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-(thiophen-2-ylsulfanyl)spiro[l,3- dioxane-2,3'-mdol]- 2'(I 'H)-one, l'-(Cyclopropylmethyl)-5'-[(5-methyl-2- thienyl)thio]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 5'-[(5-Acetyl-2-thienyl)thio]-l'- (cyclopropylmethyl)spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 5'-[(2-Chloropyridin-4- yl^hioj-r^cyclopropylmethy^spirofl^-dioxane^^'- indoll^Xr^-one, 1'- (Cyclopropylmethyl)-5'-[(3,5-dichlorophenyl)thio]spiro[l,3-dioxane-2,3'- indol]-2'(lΗ)-one, r-(Cyclopropylmethyl)-5'-[(3,5-dichloropyridin-4-yl)thio]spiro[l,3-dioxane- 2,3'-indol]- 2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(2,4-dichlorophenyl)thio]spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, r-(Cyclopropylmethyl)-5'-[(2,5-dichlorophenyl)thio]spiro[l,3-dioxane- 2,3'- indol]-2'(l'H)-one, 5'-[(4-Chloro-2-fluorophenyl)thio]-l'-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'- indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(2,4- difluorophenyl)thio] spiro [ 1 ,3 -dioxane-2 ,3 '- indol] -2'(I 'H)-one, 1 '-(Cyclopropylmethyl)-5 '- (pyridin-3-ylsulfonyl)spiro[ 1 ,3-dioxane-2,3'-indol]- 2'( 1 'H)-one, 1 '-(Cyclopropylmethyl)-5'- { [3-(trifluoromethyl)phenyl]sulfonyl} spiro [1,3- dioxane-2,3 '-indol]-2'( 1 Η)-one, 1 '- (Cy clopropylmethyl)-5 '- [(4-methylphenyl)sulfony 1] spiro [ 1 ,3 -dioxane-2 ,3 '- indol] -2 '( 1 'H)-one, 1 '-(Cyclopropylmethyl)-5 '- { [4-(trifluoromethyl)phenyl]sulfonyl} spiro [1,3- dioxane-2,3'- indol]-2'(l'H)-one, 5'-[(3-Chloro-4-fluorophenyl)sulfonyl]-r-(cyclopropylmetliyl)spiro[l,3- dioxane- 2,3'-indol]-2'(l'H)-one, 5'-[(6-Chloropyridin-3-yl)sulfbnyl]-r- (cyclopropylmethyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'- (naphthalen-l-ylsulfonyl)spiro[l,3-dioxane-2,3'- indol]-2'(l'H)-one, 1 '-(Cyclopropylmethyl)- 5'-(thiophen-2-ylsulfonyl)spiro[l,3-dioxane-2,3'-indol]- 2'(rH)-one, 1 '-(Cyclopropylmethyl)- 5'-[(5-methyl-2-thienyl)sulfonyl]spiro[l ,3-dioxane-2,3'- indol]-2'(l 'H)-one, 5'-[(5-Acetyl-2- thienyl)sulfonyl]-l'-(cyclopropylmetriyl)spiro[l,3-dioxane-2,3'- indol]-2'(rH)-one, 5'-[(2- Chloropyridin-4-yl)sulfonyl]- 1 '-(cyclopropylmethyl)spiro[ 1 ,3 -dioxane- 2,3 '-indol] -2'( 1 'H)- one, l'-(Cyclopropylmetriyl)-5'-[(3,5-dichlorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]- 2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(3,5-dicliloropyridin-4-yl)sulfonyl]spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'-[(2,4-dichlorophenyl)sulfonyl]spiro[l,3- dioxane-2,3'- indol]-2'(l'H)-one, 5'-[(4-Chloro-2-fluorophenyl)sulfonyl]-l'- (cyclopropylmethyl)spiro[l,3-dioxane- 2,3'-indol]-2'(l'H)-one, l'-(Cyclopropylmethyl)-5'- [(2,4-difluorophenyl)sulfonyl]spiro[l,3-dioxane-2,3'- indol]-2'(lΗ)-one, 1'- (Cyclopropylmethyl)-5'-(4-methoxyphenoxy)spiro[l,3-dioxane-2,3'-indol]-2'(l'H)-one, 1'- (Cyclopropylmethyl)-5'-(4-methoxyphenoxy)spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)-one, 1'- (Cyclopropylmethyl)-5'-[(2,6-difluoropyridin-4-yl)oxy]spiro[l,3-dioxane-2,3'-indol]-2'(lΗ)- one, 1 '-(Cyclopropylmethyl)-5 '-[(2,3,5,6-tetrafluoropyridin-4-yl)oxy] spiro [ 1 ,3 -dioxane-2,3 '- indol]-2'(l 77)-one, 5'-[(3-Chloro-2,5,6-trifluoropyridin-4-yl)oxy]-l '- (cyclopropylmethyl)spiro[l,3-dioxane-2,3'-indol]-2'(r/7)-one, l'-(Cyclopropylmethyl)-5'- [(3,5-difluoro-2,6-dimethoxypyridin-4-yl)oxy]spiro[l,3-dioxane-2,3'-indol]-2'(l'//)-one, 5'- [(3-Chloro-5-fluoro-2,6-dimethoxypyridm-4-yl)oxy]-r-(cyclopropylmethyl)spiro[l,3- dioxane-2,3'-indol]-2'(l'//)-one, r-(Cyclopropylmethyl)-5'-[(2,3,5-trifluoro-6- methoxypyridin-4-yl)oxy]spiro [ 1 ,3 -dioxane-2,3'-indol] -2'( 1 Η)-one and pharmaceutically acceptable salts thereof.
40. A pharmaceutical composition comprising a compound of any one of claims 1 to 39, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
41. A method for treating a CB2-mediated disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.
42. The method of claim 41 , wherein the CB2-mediated disorder is pain, osteoarthritis, atherosclerosis, osteoporosis, or cancer.
43. The method of claim 42, wherein said cancer is glioma.
44. A method for reducing pain in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof.
45. The method of claim 44, wherein the pain is inflammatory pain, post surgical pain, neuropathic pain, or bone pain.
PCT/US2009/067981 2008-12-15 2009-12-15 Substituted oxindole cb2 agonists WO2010090680A1 (en)

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