GB2497806A - Pyridinone and pyrimidinone derivatives as factor XIa inhibitors - Google Patents

Pyridinone and pyrimidinone derivatives as factor XIa inhibitors Download PDF

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GB2497806A
GB2497806A GB1122139.7A GB201122139A GB2497806A GB 2497806 A GB2497806 A GB 2497806A GB 201122139 A GB201122139 A GB 201122139A GB 2497806 A GB2497806 A GB 2497806A
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alkyl
oxo
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nhc
compound
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Takashi Kondo
Akira Imagawa
Shingo Nakatani
Sho Kouyama
Steve Courtney
Chris Yarnold
Stuart Flanagan
John Barker
Osamu Ichihara
Gareth Brace
Elise Gadouleau
Anthony Richardson
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Ono Pharmaceutical Co Ltd
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Ono Pharmaceutical Co Ltd
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Priority to GB1122139.7A priority Critical patent/GB2497806A/en
Publication of GB201122139D0 publication Critical patent/GB201122139D0/en
Priority to EP17193874.9A priority patent/EP3290413B9/en
Priority to NZ626176A priority patent/NZ626176B2/en
Priority to DK12813423.6T priority patent/DK2794597T3/en
Priority to MX2014007269A priority patent/MX351471B/en
Priority to PL12813423T priority patent/PL2794597T3/en
Priority to PT128134236T priority patent/PT2794597T/en
Priority to KR1020147016952A priority patent/KR102011534B1/en
Priority to HUE12813423A priority patent/HUE036010T2/en
Priority to US14/366,396 priority patent/US9732085B2/en
Priority to JP2014548196A priority patent/JP6137193B2/en
Priority to TW101148629A priority patent/TWI613199B/en
Priority to CN201280070352.3A priority patent/CN104136431B/en
Priority to EP12813423.6A priority patent/EP2794597B1/en
Priority to PCT/GB2012/053217 priority patent/WO2013093484A1/en
Priority to IN4676CHN2014 priority patent/IN2014CN04676A/en
Priority to ES12813423.6T priority patent/ES2655669T3/en
Priority to RU2014129797A priority patent/RU2630677C2/en
Priority to ES17193874T priority patent/ES2765891T3/en
Priority to BR112014015669-7A priority patent/BR112014015669B1/en
Priority to NO12813423A priority patent/NO2794597T3/no
Priority to SG11201403402VA priority patent/SG11201403402VA/en
Priority to CA2859604A priority patent/CA2859604C/en
Priority to AU2012356374A priority patent/AU2012356374B2/en
Publication of GB2497806A publication Critical patent/GB2497806A/en
Priority to IL233154A priority patent/IL233154A/en
Priority to PH12014501365A priority patent/PH12014501365B1/en
Priority to HK14111900.0A priority patent/HK1198386A1/en
Priority to JP2017091408A priority patent/JP6447660B2/en
Priority to US15/644,655 priority patent/US10717738B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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Abstract

Compounds of the general formula (I), their salts and N-oxides, and solvates and prodrugs thereof: wherein Y is N or C(R5); Cyc1, Cyc2 and Cyc3 are C3-8cycloalkyl, 5-10-membered heterocycloalkyl, C5-10­aryl or 5-10-membered heteroaryl; R2 and R3 are hydrogen or substituents or R2 and R3 may be taken together to form C2-8alkylene, or R3 and R4 may be taken together to form C2-8alkylene wherein one carbon of the alkylene chain may be replaced by oxygen or sulphur (for example so as to form a dihydropyrrolo[1,2-a]pyrimidin-4(6H)-one or a 5-oxo-1,2,3,5-tetrahydro-3-indolizinyl group together with the adjacent ring); R4 and R5 are hydrogen or substituents; , R6 and R7 are substituents with R6 preferably being a 1H-tetrazol-1-yl group; and m, s and n are all 0-6; may be useful as inhibitors of Factor XIa. These compounds may be useful in the prevention of and/or therapy for thromboembolic diseases including stroke, myocardial infarction, atherosclerosis, deep vein thrombosis, arterial embolism or pulmonary embolism.

Description

COMPOUNDS
TECHNICAL FIELD
The present invention relates to a series of pyridinone and pyrirnidianne derivatives which are useflul as inhibitors of factor Xla.
Thus, the present invention relates to a compound of formula (I): XRYZ fl V7 (I) (wherein all symbols have the same meanings as described hereinafter) or a pharmaceutically acceptable salt thereof, an N-oxide thereof; a solvat.e thereof; or a prodrug thereof, use of such compounds in treatment and/or prevention of a thromboembolic disease and processes for the preparation of said compounds.
BACKGROUND OF THE INVENTION
Thromboembolism is an important cause of morbidity and mortality. It occurs when a blood clot breaks free and is carried by the blood stream to obstruct a blood vessel at another site, Thromboembolie disease includes venous thromboembolism, for example deep vein thrombosis or pulmonary embolism, arterial thrombosis, stroke and myocardial infarction.
Thromboembolic diseases maybe treated using anticoagulants. One approach has been to target the inhibition of factor Xla (FXla). Factor XIa is a plasma serine protcase involved in the regulation of blood coagulation. Factor Xla is an activated form of ctor Xl, which is activated by factor Xlla, thrombin, and it is also autocatalytic. FXla is a member of the °eontact pathway and activates factor IX by selectively cleaving arg-ala and arg-val peptide bonds. Factor IXa, in turn, activates factor X, The safety of this target is supported by the observations that FXI deficiency in humans (hemophilia C) results in a mild bleeding disorder. In addition to this, the efficacy and side effects of this target have been shown using experimental thrombosis and bleeding models in mice lacking FXI, and in baboons and rabbits treated with anti-FXJ neutralizing antibodies. These results suggest that FXIa inhibitors will show a potent anti-thrombotic effect without bleeding. Therefore, factor XIa is an attractive target for anti-thrombotic therapy without any bleeding side effect.
It has been described in Patent literature I that compounds of formula (A): OR1IA H (4)
IA H
wherein A" represents a 5-to 12-membered heterocycle, etc.; LIA represents -CFI=CH-, etc.; RIIA represents benzyl, etc.; MA represents imidazolyl. ete; are useful as selective inhibitors of factor XIa or dual inhibitors of FXIa and plasma kallikrein.
Furthermore, it has been described in Patent literature. 2 that a compound of formula (B-I): / R3 oilS I (B-I)
N
R88 -"R4e wherein A'3 represents a 5-to 12-membered heterocycle, etc.; Li8 represents -CH=C1-I-, etc.; R'1'3 represents benzyl, etc.; R3'3 represents phenyl, etc.; R4 represents chlorine, etc.; RSaB represents hydrogen, etc; or formula (B-Il): AJXtB 18 M R118 wherein M'3 represents pyridyl, etc.; and the other symbols have the same meanings as described above; inhibit factor XIa and/or plasma kailitrein.
Furthermore, it has been described in Patent literature 3 that compounds of formula (C):
H
RIAC wc
04C NTh R9c RIOC G4 (A) (B)) (C) G2t wherein wc represents CO. etc.; oCrepresents a direct bond, etc.; Qc G2C, 03C and G4C each independently represents C or N, etc.; R represents aryl, etc.; represents heteroaryl, etc.; RLAC represents heteroarylalkyl, etc.; are useful as gamma secretase modulators, however, it is not reported that the compound represented by formula (C) has factorXla inhibitory activity.
Furthermore, it has been described in Patent literature 4 that compounds of formula (D): R20 wherein RID represents hydrogen, etc.; R21J represents aryl, etc.; R30 represents hydrogen, etc.; Rt represents hydrogen, etc.; R50 represents heteroarylalkyl, etc.; is useful as p38 MAP kinase modulator.
Furthermore, it has been described in Patent literature S that compounds of fonnula (E): R2E LEXE N' R3EVtK%ZE wherein LE represents a linker providing 0-6 atoms, etc.; XE represents heteroaryl, etc.; Z' represents halogen, etc.; QE represents CO. etc.; R2E and R3E each independently represents hydrogen, aryl, etc.; are useful as dipeptidyl peptidase inhibitors.
[Patent literature 1] W02007070826 [Patent literature 2] W02008076805 [Patent literature 3] W02009076337 [Patent literature 4] W02003068230 [Patent literature 5] EPISO696IA1
DISCLOSURE OF THE INVENTION
It is desirable to Jind new compounds which may be more effective in treating thromboeinbolic diseases. Advantageous compounds desirably have good inhibitory and selectivity for factor XIa (and preferably also for plasma kaHikrein) and/or good oral bioavailability.
The present inventors have made extensive studies to find a compound that can become a therapeutic agent for thromboembolic diseases. As a result, we have found that the object is achieved by a compound represented by formula (1), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof (hereinafter, which may be abbreviated to compounds of the present invention) have good inhibitory and selectivity for factor XIa. and/or good oral bioavailability, and then st have completed the present invent ion.
Namely, the present invention relates to the following aspects: (1) A compound represented by formula (I): iRc,,R2 fl V - R7) (I) wherein Cyc! represents C3-C8 cycloalkyl, 5-to lO-membered heterocycloalkyl, CS-ClO aryl or 5-to lO-membered heteroaryl; Cyc2 represents C3-C8 cycloalkyl, 5 to l0-mernbered heterocycloalkyl, C5-C10 aryl or 5-or 6-membered heteroaryl; Cyc3 represents C3-C8 cycloalkyl. 5-to lO-membered heterocycloalkyl, CS-dO aryl or 5-to IG-membered heteroatyl: S 5 each R' may be the same or different and represents (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) halogen, (5) nitro, (6) cyano, (7) oxo, (8) amidino, (9) -CI-8 alkyl- 0R8,(1O)-0R9, (11)-COOR'°, (12) -C1-4 alkyl-COOR", (13) -NHC(O)-C1-4 alkyl or (14) -NHC(O)O-R'2, wherein R9, R'°. R" and R'2 each independently represents (1) hydrogen, (2) Cl- 8 alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C3-C8 cycloalkyl, (6) 5-to 10-membered beterocycloalkyl, (7) C5-C10 aryl, (8) 5-to lO-niembered heteroaryl or (9) Cl -4 alkyl substituted with I to 5 groups selected from C3-C8 cycloalkyl, 5-to 10-memberS heterocycloalkyl, CS-DO aryl and 5-to lO-membered heteroarvi; s represents an integer of 0 to 6; represents (1) hydrogen, (2) Cl-S alkyl, (3) C2-8 alkenyl, (4) C2-8 alkyny!, (5) Cyc4 or (6) C 1-8 alkyl, C2-S alkenyl or C2-8 alkynyl, which are substituted with I to 5 groups selected from halogen, nitro, trifluoromethyl, cyano, Cyc5, -NR'3R'4, -OR'5, -SR'6, -NHC(O)-Cyc6, -NFIC(O)-CI-8 alkyl, -NHC(O)O-R'7 and Cyc5 substituted with 1 to 3 groups selected from Cl-S alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen. nitro, trifluoromethyl, cyano, oxo, amidino and -OR'8, wherein R'3, R'4, R'5, R'6, R'7 and R'8 each independently represents (1) hydrogen, (2) Cl-K alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C3-C8 cycloalkyl, (6) 5-to 10-membered heterocycloalkyl, (7) C5-ClO aryl, (8) 5-to 10-membered heteroaryl or (9) C1-4 alkyl substituted with Ito 5 groups selected from C3-C8 cycloalkyl, 5-to 10-membered heterocycloalkyl, CS-dO aryl and 5-to lO-membered heteroaiyl, wherein Cyc4, Cyc5 and Cyc6 each independently represents C3-C8 cycloalkyl, 5-to lO-membered heterocycloalkyl, CS-C 10 aryl or 5-to lO-membered heteroaryl; R3 represents (1) hydrogen, (2) Cl-S alkyl, (3) C2-8 alkenyl, (4) C2-S alkynyl, (5) Cyc7 or (6) Cl-S alkyl, C2-8 alkenyl or C2-8 alkynyl, which are substituted with 1105 groups selected from halogen, nitro, trifluoromethyl, cyano, Cyc8, -NR'9R20, -OR21, -SR22, -NHC(O)-Cyc9. -NHC(O)-CI-8 alkyl, -NFIC(O)O-R23 and Cyc3 substituted with I to 3 groups selected from Cl-S alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen, nitro, trifluoromethyl, cyano, oxo, amidino and -OR24, wherein R19, R20, R21, R22, R23 and R24 each independently represents (1) hydrogen.
(2) Cl-S alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C3-C8 cycloalkyl, (6) 5-to 10-inembered heterocycloalkyl, (7) CS-C10 airy!, (8) S-to lO-inembered heteroaryl or (9) C1-4 alkyl substituted with ito 5 groups selected from C3-C8 cycloalkyl, 5-to 10-membered heterocycloalkyl, CS-C 10 aryl and 5-to 10-memberS heteroaxyl, wherein Cve7, Cyc8 and Cyc9 each independently represents C3-C8 cycloalkyl, 5-to lO-membered heterocycloalkyl, C5-C10 aryl or 5-to lO-ruembered heteroaryl; Y represents N or C(R'); R4 and R5 each independently represents (1) hydrogen, (2) halogen, (3) CI-4 alkyl, (4) C3-C8 cycloalky), (5) 5-to lO-membered heterocycloalkyl, (6) CS-C 10 aryl, (7)5 to JO-membered heteroaryl or (8) C1-4 alkyl substituted with Ito 5 groups selected from C3-CS cycloalkyl, 5-to 10-memberS heterocycloalkyl. C5-C10 axyl and 5-to 10-memberS heteroaryl; R2 and R3 may be taken together to form C2-8 alkylene; or It3 and R4 may be taken together to form C2-8 alkylene; wherein one carbon of the alkylene chain may be replaced by oxygen or sulthr, each It6 may be the same or different and represents (1) Cl-S alkyl, (2) C2-8 alkenyl.
(3) C2-8 alkynyl, (4) Cyc°, (5) halogen, (6) nitro, (7) cyano, (8) oxo, (9) amidino, (10)- OR25, (11) -C00R26, (12) -C1-4 alkyl-C00R27, (13) -NHC(O)-C1-4 alkyl, (14)- NHC(O)-H, (15) -NHC(O)O-R25, (16) trifluoroniethyl, (17) -NT-IC(NH)N112, (18) -C(O)-CI-4 alkyl or (19) Cyc'° substituted with Ito 5 groups selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl. halogen, nitro, trifluoromethyl, cyano, oxo, amidino. -OR29, -SR30, -NR31R32, -NHC(O)NR33R4, -NFIC(O)-C1-4 alkyl-COOH, -NH-S(O)-C1-4 alkyl, -NH-S(O)2-Cl-4 alkyl, -C00R35, -NHC(O)-R36, -NHC(O)O-R37, -C(O)NFI-R38 and -OC(O)NH-R'9, wherein Cyc'° represents C3-C8 cyeloalkyl, 5-to lO-membered heterocycloalkyl, CS-ClO aryl or 5-to 10-memberS heteroaryl; wherein R25, R26, it27, R2, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38 and R39 each independently represents (1) hydrogen, (2) Cl-S alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C3-C8 cycloalkyl, (6) 5-to 1 0-membered heterocycloalkyl, (7) CS-C 10 aryl. (8)5-to 10-memberS heteroaryl or (9) CI-4 alkyl substituted with Ito 5 groups selected from C3-CS cycloalkyl, 5-to lO-membered heterocycloalkyl, C5-C10 aryl and 5-to 10-membered heteroaryl; m represents an integer of 0 to 6; each R7 maybe the same or different and represents (I) Cl-K alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) halogen, (5) nitro, (6) trifluorornethyt, (7) cyano, (8) oxo, (9) amidino, (10) -OR40, (11)-SR41. (12) -NR42R43, (13) -NHC(O)NR'4R45, (14) -NHC(O)-C1-4 alkyl-NR46R47, (15) -NHC(O)-C1-4 alkyl-COOl-!, (16) -NH-S(O)-CI-4 alkyl, (17) -NFJ-S(O)2-C1-4 alkyl, (18) -C00R48, (19) -NHC(O)-R49. (20) -NHC(O)-C1-4 alkyl- OR50, (21) -NHC(O)O-R5, (22) -NHC(O)O-C1-4 alkyl-0R52, (23) -C(O)NH-R53, (24)- OC(O)NFI-R54, (25) -OC(O)-R55, (26) -C(O)-R56. (27) -CH(OH)-R57, (28) -C1-4 alkyl- NH2, (29) -Cl -4 alkyl-OH, (30) -Cl -4 alkyl-OC(O)-C 1-4 alkyl, (31) -Cl -4 alkyl- NHC(O)-C 1-4 alkyl, (32) -Cl -4 alky!-NHC(O)O-C 1-4 alkyl, (33) -Cl -4 alkyl-NHC(O)-CF3, (34) -C1-4 alkyl-NHC(O)NH-C1-4 alkyl, or (35) -CnN-OR58, wherein R40, R41, R42, R43, R, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57 and R'8 each independently represents (1) hydrogen, (2) trifluoromethyl, (3) Cl-S alkyl, (4) C2-8 alkenyl, (5) C2-S alkynyl, (6) C3-C8 cycloalkyl, (7) 5-to I 0-membered heterocycloalkyl, (8) CS-C 10 aryl, (9) 5-to 1 0-membered heteroaryl or (10) Cl -4 alkyl substituted with Ito 5 groups selected from C3-C8 cycloalkyl, 5-to lO-membered heterocycloalkyl, C5-C1O aryl and 5-to lO-membered heteroaryl; and n represents an integer of 0 to 6; a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.
(2) The compound according to (1), wherein the compound represented by formula (I) represents a compound represented by formula (I-A):
V
R (I-A) (R6)mj.J wherein U represents S or CH2; and the other symbols have the same meanings as described above.
(3) The compound according to (1), wherein the compound represented by formula (I) represents a compound represented by formula (I-B): * 8 (I-B) wherein Cyc1 represents 5-to 1 0-membered heteroaryl; Cyc3 represents CS-C 10 aryl or 5-to lO-membered heteroaryl; Cyc'° represents (1) 5-to lO-membered heteroaryl or (2) 5-to lO-membered S heteroaryl substituted with I to S groups selected from halogen, cyano, nitro, trifluoromethyl, -COOH, -COO-C1-4 alkyl and -CON1-12; mb represents an integer of 0 to 5; and the other symbols have the same meanings as described above.
(4) The compound according to (1), wherein the compound represented by formula (1) represents a compound represented by formula (I-C): (IC) wherein Cyc represents 5-to lO-membered heteroaryl; cyc3C represents CS-Cl 0 aryl or 5-to lO-membered heteroaryl; CyctOC represents (1) 5-to lO-membered heteroaryl or (2) 5-to lO-membered heteroaryl substituted with I to 5 groups selected from halogen, cyano, nitro, trifluoroinethyl, -COOH, -cOO-C1-4 alkyl and -CONIi2; mc represents an integer of 0 to 5; and the other symbols have the same meanings as described above.
(5) The compound according to (I) or (2), wherein Cyc' represents phenyl, imidazolyl, triazolyl. pyrrolyl, pyrazolyl, furanyl, oxazolyl, thiazolyl, isothiazolyl, 0 9 furazanyl. oxadiazolyl, thiadiazolyl, thienyl, pyridazinyl, indazolyl or benzimidazolyl.
(6) The compound according to (3), wherein Cyc'8 represents imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridazinyl, indazolyl or benzimidazolyl.
(7) The compound according to (4), wherein Cyc represents imidazolyl, triazolyl, tetrazoly, oxazolyl, pyridazinyl, indazolyl or benzimidazolyl.
(8) The compound according to (1) or (2). wherein c?) represents MN AR'}. MN? KN2 UN7 1((R'h. p(RuI;14R7In _4R'J, _(R1')n _.(R'),, J\-e >Rn)" : Q; wherein R59 represents hydrogen, C1-4 alkyl or halogen; the arrow represents a binding position; and the other symbols have the same meanings as described above (9) The compound according to any one of (1) to (8), wherein Cyc2 represents pyridyl or phenyl.
(10) The compound according to any one of(1) 10(9), wherein -Cyc2-R6), Cyc2(- 1(6) mbCyc° or Cyc2(-R6) mcCyc' represents S 10
N-S N-N
II
N NN NN2 R6° R6° R6° wherein R6° represents hydrogen, methyl or halogen; R6' represents (1) hydrogen, (2) halogen, (3) nitro, (4) trifluoromethyl, (5) -COOH, (6) -COO-C 1-4 alkyl, (7) cyano or (8) -CONH2; and the arrow represents a binding position.
(11) The compound according to any one of(I) to (4), wherein Cye2 represents pyridyl or phenyl.
(12) A pharmaceutical composition which comprises the compound according to any one of(1) to (11), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof (13) The pharmaceutical composition according to (12), which is a factor XIa inhibitor or a factor XIa and plasma kallikrein dual inhibitor.
(14) The pharmaceutical composition according to (13), which is an agent for the treatment or prevention of a thromboembolic disease.
(15) The compound according to any one of(1) to (11) for use in the treatment of the human or animal body by therapy.
(16) The compound according to any one of(1) to (11) for use in treating or preventing a thromboembolic disease.
(17) The compound for use according to (16), wherein the thromboembolic disease is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders and thromboembolic disorders in the chambers of the heart or in the peripheral circulation. S 11
(18) The compound for use according to (17), wherein the thromboembolic disease is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient isehemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.
(19) A method for treating a patient suffering from or susceptible to a thromboembolic disease, which method comprises administering to said patient a therapeutically effective amount of a compound accoixling to any one of(l) to (11).
(20) Use of a compound according to any one of (1) to (11), in the manufacture of a medicament for use in treating or preventing a thromboembolic disease.
(21) A method for treating a patient suffering from or susceptible to a thromboembolic disease, which method comprises administering to said patient a therapeutically effective amount of a compound according to (1).
(22) The method according to (21), wherein the thromboembolic disease is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolie disorders and thromboenibolic disorders in the chambers of the heart or in the peripheral circulation.
(23) The method according to (22), wherein the thromboembolic disease is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophiebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.
Definitions: As used herein, a Cl-S alkyl group or moiety is a linear or branched alkyl group or moiety containing from ito 8 carbon atoms. Typically a Cl-8 alkyl group or moiety S 12 is a C1-4 alkyl group or moiety. A C1-4 alkyl group or moiety is a linear or branched alkyl group or moiety containing from Ito 4 carbon atoms. Examples of Cl -8 alkyl groups and moieties include methyl, ethyl, n-propyl. i-propyl, n-butyl, i-butyl, t-butyl, 3-methyl-butyl, pentyl, hexyl, heptyl, octyl, and isomers thereof, Examples of Cl-4 alIcyl groups and moieties include methyl, ethyl, n-propyl, 1-propyl, n-butyl, i-butyl and t-butyl. For the avoidance of doubt, where two ailcyl moieties are present in a group, the alkyl moieties may be the same or different.
In the present specification, the C2-8 alkenyl includes, for example, ethenyl, propenyt, butenyl, pentenyl, hexenyl, heptenyl arid isomers thereof.
In the present specification, the C2-8 alkynyl includes, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and joiners thereof.
1 5 In the present specification, the halogen atom includes, for example, fluorine, chlorine, bromine and iodine, and is preferably fluorine, chlorine or bromine.
Cyc' represents C3-C8 cycloalkyl, 5-to tO-membered heteroeycloalkyl, C5-CIO aryl UT 5-to I 0-membered heteroaryl.
"C3-CS cycloalkyl" refers to a C3-C8 cyclic hydrocarbon. Examples of C3-C8 cycloalkyl include cyclopropane, cyclobutane. cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclobutene, cyclopentene, eyclohexene, cycloheptene, cyelooctene, eyclobutadiene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene rings and the like.
"5-to IG-membered heterocycloalkyl" refers to a "5-to lO-membered mono-or bi-non-aromatic beterocyclic ring having I to 4 nitrogen atom(s), I or 2 oxygen atom(s) andior I or 2 sulfur atom(s) as a hetero atom(s)". Examples of 5-to I 0-membered heterocycloalkyl include pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine.
dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimicline, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine. perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetral-iydrotbran, dihydropyran, tetrahydropyran, dihydroxepine, tetrahydroxepine, perhydroxepine, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepin, tetráhydrothiepin, perhydrothiepin, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thi azohdine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofürazan, tetrahydroftrazan, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine, tetrahydroxadiazine, dihydroxazepine, tetrahydroxazepine, perhydroxazepine, dihydroxadiazepine, tetrahydroxadiazepine, perhydroxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), 0 dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofiiran, dihydroisobenzofuran, perhydraisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobeuzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine. dihydronaphtbyridine, tetrahydronaphthyridine. perhydronaphthyridine, dihydroquirioxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dibydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobeazoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenaimidazole, dioxolane, dioxane, dithiolane, dithiane, dioxaindane, benzodioxane, chroman, benzodithiolane, benzodithiane. 6,7-dihydro-5H-cyclopenta[b]pyrazine, SH-eyclopenta[b]pyrazine, 2,4-dihydro-1H-benzo[d][1,3]oxazine rings and the like.
"C5-C10 aryl" refers to a "CS-b mono-or hi-aromatic carbocyclic ring".
Examples of CS-C 10 aryl include benzene, azulene, naphthalene rings and the like.
Thus the C5-Cb0 aryl may be, for example, a phenyl ring and the like.
"5-to lO-membered heteroaryl" refers to a "5-to lO-membered mono-or bi-aromatic heterocyclic ring having Ito 4 nitrogen atom(s), 1 or 2 oxygen atom(s) and/or I or 2 sulflur atom(s) as a hetero atom(s)". Examples of 5-to lO-membered heteroarl include pyrrole, imidazole. triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene. oxazole, isoxazole, thiazole, isothiazole, furazan., oxadiazole, thiadiazole, indole, isoindole, benzofijran, isobenzofuran, beuzothiophene, isobenzothiophene, indazole, quinoline, isoquinotine, purine, phthalazirie, pteridiiie, S naphihyridine, quinoxahne, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole. benzofirazan, beuzothiadiazole, benzotriazole, isoxazolo(4,5-djpyridazine rings and the like.
In sonic embodiments, Cyc7 also represents Cyc' or Cyc. Cyc' and Cyc independently represent 5-to lO-membered heteroaryl. The "5-to lO-membered heteroaryl" represented by Cyc or Cyc may he selected from aiiy of the examples provided above for "5-to lO-membered heteroaryl".
Cyc2 represents C3-C8 cycloalkyl, 5-to lO-membered heterocycloalkyl, CS-C10 aryl or 5-or 6-membered heteroaryl.
The "C3-C8 cycloalkyl" represented by Cyc2 may be selected from any of the examples provided above for "C3-C8 cycloalkyl".
The "5-to I 0-membered heterocydoalkyl" represented by Cyc2 nay he selected from any of the examples provided above for "5-to lO-membered heterocycloalkyl".
The "C5-ClO aryl" represented by Cyc2 may be selected from any of the examples provided above for "CS-C 10 aryl".
"5-to 6-rnembered heteroaryl" refers to a "5-to 6-membered mono-aromatic heterocyclic ring having I to 4 nitrogen atom(s), I or 2 oxygen atom(s) and/or I or 2 sulfur atom(s) as a hetero atom(s)". Examples of 5-to 6-membered heteroaryl include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyriniidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole. isothiazole, furazan, oxadiazole, thiadiazole, rings and the like.
Cyc3 represents C3-C8 cycloalkyl, 5-to lO-membered heterocycloalkyl, CS-C 10 aryl or 5-to lO-membered heteroaryl.
The "C3-C8 cycloalkyl" represented by Cyc3 may be selected from any of the examples provided above for "C3-C8 cycloalkyl".
The "5-to lO-membered heterocycloalkyl" represented by Cye3 may be selected from any of the examples provided above for "5-to I 0-membered heterocycloalkyl". 0 15
The "CS-C 10 aryl" represented by Cyc3 may be selected from any of the examples provided above for "C5-C1O aryl".
The "5-to I 0-membered heteroaryl" represented by Cyc3 may be selected from any of the examples provided above for "5-to lO-membered heteroaryl".
In some embodiments, Cyc3 also represents Cyc3 or CyC3C. Cyc3 represents CS-C 10 aryl or 5-to I 0-membered heteroaryl. The "CS-C 10 aryl" represented by Cye3 may be selected from any of the examples provided above for "CS-dO aryl". The "5-to I 0-membered heteroaryl" represented by Cyc3 may be selected from any of the examples provided above for "5-to lO-membered heteroaryl".
Cyc3C represents C5-C10 aryl or 5-to lO-membered heteroaryl. The "CS-C 10 aryl" represented by Cye3 maybe selected from any of the examples provided above for "CS-dO aryl". The "5-to lO-membered heteroaryl" represented by Cyc3< may be selected 1mm any of the examples provided above for "5-to lO-membered heteroaryl".
dye4, dye6, dye7 and dye9 each independently represent C3-C8 eyeloalkyl, S-to I 0-membered heterocycloalkyl, CS-C 10 aryl or 5-to I 0-membered heteroaryl.
The "C3-C8 cycloalkyl" represented by Cyc4, Cyc6, Cyc7 or Cye9 may be selected from any of the examples provided above for "C3-CS cycloalkyl".
The "5-to lO-membered heterocycloalkyl" represented by dye4, dye6, dye7 or dye9 may be selected from any of the examples provided above for "5-to lO-membered heterocycloalkyl".
The "CS-Gb aryl" represented by dye4, dye6, Cyc7 or Cyc9 may be selected from any of the examples provided above for "C5-CIO aryl".
The "5-to lO-membered heteroaryl" represented by Cyc4, dye6, dye7 or dye9 may be selected from any of the examples provided above for "5-to LO-membered heteroaryl".
Cyc5 represents C3-C8 cycloalkyl, 5-to lO-menibered heterocycloalkyl, CS-C 10 aryl or 5-to lO-membered heteroaryl, any of which may be optionally substituted with I to 3 groups selected from Cl-S alkyl, C2-S alkenyl, C2-S alkynyl, halogen, nitro, trifluoromethyl, cyano, oxo, aniidino and -OR8.
Cyc8 represents C3-C8 cycloalkyl, 5-to lO-membered heterocycloalkyl, C5-CIO aryl or 5-to 10-membered heteroaryl, any of which may be optionally substituted with I to 3 groups selected from Cl-S alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen, nitro, trifluoromethyl, cyano, oxo, arnidino and -OR24.
The optionally substituted "C3-C8 cycloalkyl" represented by Cyc5 or Cyc8 may be selected from any of the examples provided above for "C3-C8 cyeloalkyl".
The optionally substituted "5-to I 0-membered heterocycloalkyl" represented by Cyc5 or Cyc8 may be selected from any of the examples provided above for "5-to 10-membered heterocycloalkyl".
The optionally substituted "CS-do aryl" represented by dye5 or dye8 may be selected from any of the examples provided above for "CS-Cl 0 aryl" The optionally substituted "5-to lO-membered heteroaryl" represented by Cyc5 or dye8 may be selected from any of the examples provided above for "5-to 10-membered heteroaryl".
dyet° represents C3-C8 cydoalkyl, 5-to lO-membered heterocycloalkyl, C5-dO aryl or 5-to lO-membered heteroaryl, any of which may be optionally substituted with ito 5 groups selected from C1-8 alkyl, C2-8 alkenyl, C2-S alkynyl, halogen, nitro, trifluoromethyl, cyano, oxo, amidino, -OR29, -SR30, -NR31R32, -NHC(O)NR33R34, - NHC(O)-Cl-4 alkyl-COOM, -NH-S(O)-Cl-4 alkyl, -NH-S(O)2-O-4 alkyl. -dOOR35, -NHC(O)-R36, -N1-IC(O)O-R31, -C(O)NJ1-R38 and -OC(O)NH-R39.
The optionally substituted "C3-C8 cycloalkyl" represented by Cyc1° may be selected from any of the examples provided above for "C3-C8 cyeloalkyl".
The optionally substituted "5-to 10-mernbered heterocycloalkyl" represented by dye1° may be selected from any of the examples provided above for "5-to 10-membered heterocycloalkyl".
The optionally substituted "CS-C 10 ary!" represented by Cyc'° may be selected from any of the examples provided above for "CS-diM aryl".
The optionally substituted "5-to I0-mernbered heteroaryl" represented by dye'° may be selected from any of the examples provided above for "5-to lO-membered heteroaryl".
In some embodiments, dye'° also represents Cyc'°5 or Cyc°°. CycB and Cyc'° each independently represents (1) 5-to 1 0-membered heteroaryl or (2) 5-to 10-membered heteroaryl substituted with I to 5 groups selected from halogen, cyano, nitro, trifluoromethyl, -COOH, -COO-C 1-4 alkyl and -CONH2. The optionally substituted c5 to lO-membered heteroaryl" in options (1) or (2) of Cy&oaand Cyc' may be selected from any of the examples provided above for "5-to lO-meinbered heteroaryl".
Preferably, Cyc1 represents a C5-ClO arvi or 5-to 10-memberS heteroaryl, more preferably phenyl, imidazolyl, triazolyl, tetrazolyl. pyrrolyl. pyrazolyl, furanyl, oxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, thienyl, pyridazinyl, indazolyl or benzimidazolyl, more preferably as-to to-memberS heteroaryl such as imidazolyl, ti-iazolyl, oxazolyl. pyridazinyl, indazolyl or benzimidazoly). In one embodiment, Cyc' preferably represents imidazolyl or triazoiyi.
Preferably, Cyc'8 or Cyc represents imidazolyl, triazolyl, tetrazotyl, oxazolyl, pyridazinyl, indazolyl or beuzimidazolyl, more preferably imidazolyl, triazolyl, oxazolyl, pyridazinyl, indazolyl or benzimidazolyl.
Preferably, Cyc2 represents a CS-do aryl, preferably a C5-C6 aryl, more preferably phenyl, or a 5-to 6-rn embered heteroaryl such as pyridyl.
Preferably, Cyc3 represents (i) C5-C6 cycloalkyl, such as cyclohexane, (ii) 5-to 1 0-membered heterocycloalkyl such as indotine, isoindoline, dihydroquinoline, dihydroquinazoline, dihydrobenzoxazine or dihydrobenzoxazole, (iii) C5-Cl0 aryl, for example C5'C7 aryl, such as phenyl, or (iv) 5-to lO-membered heteroaryl, such as pyrazole, pyridine, pyrazine, thiophene, oxazole, thiazole, indazote. quinoline, isoquinotine, quinoxaline or henzimidazole. In particular, the 5-to I 0-membered heterocycloalkyl such as indoline, isoindoline, dihydroquinolinc, dihydroquinazoline, dihydrobeuzoxazine or dihydrobenzoxazole, or 5-to lO-membered heteroaryl such as quinoline or quinoxaline may be substituted with an oxo group to form, for example, indolone, isoindolone, dihydroquinolinone, dihydroquinazolinone, benzoxazinone, benzoxazolone, quinolione or quinoxalinone. In one embodiment, Cyc3 preferably represents phenyl or pyridinyl.
Preferably, Cyc34 or Cyc3C represents CS-Cl 0 aryl, for example C5-C7 aryl such as phenyl, or 5-to I 0-membered heteroaryl, such as pyrazole, pyridine, pyrazine, thiophene, oxazote, thiazole, indazole, quinoline, isoquinoline, quinoxaline or henzimidazole, more preferably pyrazole or pyridine.
Preferably, Cyc4, Cyc6, Cyc7 and Cyc9 each independently represent C5-Cl0 aryl, for example CS-C7 aryl such as phenyl.
Preferably, Cyc5 and Cye8 each independently represent CS-Cl 0 aryl, for example C5-C7 a'l such as phenyl, or a 5-to 6-membered heteroaryl such as pyridyl, any of which may be optionally substituted as set out above. Preferably, Cyc5 and Cy& Preferably, Cyc'° represents aS to 10 membered heteroaryl, preferably imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, pyridazinyl, indazolyl, benzimidazolyl, thiazolyl or thiadiazolyl, more preferably thiadiazolyl, triazolyl or tetrazolyl, any of which may be optionally substituted as set out above.
Preferably, Cyc'° or Cyc'° each independently represents imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridazinyl, indazolyl, benzimidazolyl, thiazolyl or thiadiazolyl, more preferably thiadiazolyl, triazolyl or tetrazolyl, any of which may be optionally substituted with I to 3 groups selected from halogen, nitro, trifluoromethyl, -COOH, -COO-C 1-4 alkyl, cyano and -CONH2.
Preferably, each R1 independently represents Cl-S alkyl or halogen, more preferably C 1-4 alkyl or halogen (preferably chlorine).
Preferably, s represents an integer of 0, 1 or 2.
Preferably, R3, R9, R'°, R1' and R12 each independently represents hydrogen or Cl -8, preferably C 1-4, alkyl.
Preferably, P7 represents (I) hydrogen. (2) Cl-S alkyl, (3) Cyc4 or (4) Cl-S alkyl substituted with 1 to 3 groups selected from Cyc5 and -OR'5, wherein Cyc4 and Cyc5 are preferably as set out above. Mote preferably, B? represents (1) hydrogen, (2) Cl -4 alkyl, (3) Cyc4 or (4) Cl -4 alkyl substituted with 1 or 2 groups selected from Cye5 and -OR'5, wherein Cyc4 and Cyc5 are preferably as set out above and R'5 is selected from hydrogen and Cl -4 alkyl.
Preferably, R13, R'4, R15, R'6, R" and R5 each independently represents hydrogen or C1-8, preferably C 1-4, alkyl.
When not taken together with 14 to form a C2-8 alkylene, it preferably represents (I) hydrogen, (2) Cl-S alkyl, (3) Cyc7 or (4) Cl-S alkyl substituted with ito 3 groups selected from Cyc8 and OR21, wherein Cyc7 and Cyc2 are preferably as set out above. More preferably, R3 represents (I) hydrogen, (2) Cl-4 alkyl, (3) Cyc7 or (4) Cl- 4 alkyl substituted with I or 2 groups selected from Cyc and OR21, wherein Cyc' and Cyc8 are preferably as set out above and R21 is selected from hydrogen and C 1-4 alkyl.
Most preferably, R3 is hydrogen.
Preferably, R19, B?°, R21, RY, R23 and R24 each independently represents hydrogen or C1-S, preferably Cl-4, alkyl.
Preferably, R4 and R5 each independently represents hydrogen or Cl -4 alkyl, more preferably hydrogen, methyl or ethyl.
In another embodiment, R3 and R4 are preferably taken together to form a C2-8 alkylene, preferably a C2-4 alkylene, more preferably ethylene.
Preferably, each R6 independently represents (1) Cy&°. (2) methyl, (3) halogen (preferably chlorine), (4) amidino, or (5) Cyc1° substituted with 1 to 3 groups selected from halogen (preferably chlorine). nitro, trifluoromethyl, cyano, -OR29, -C00R35, -NHC(O)-R36 and -C(O)NH-R3, wherein Cyc'° is preferably as set out above. More preferably, P.6 represents (I) Cyc'°, (2) methyl. (3) halogen (preferably chlorine), or (4) Cy&° substituted with 1 to 3 groups selected from halogen (preferably chlorinc), nitro, trifluoromethyl, -COOl-I, -COO-Ci-4 alkyl, cyano or -CONFI2, wherein Cyc'° is preferably as set out above.
Preferably, R25, R26, R27, R28, R', B.30, R31, B.32. B.33, B.4, R35, R36, B.31, B.38 and R each independently represents hydrogen or Cl-S, preferably C 1-4, alkyl.
Preferably, in represents an integer of 0, 1 or 2.
Preferably, each P2 independently represents (1) cl-s alkyl, (2) halogen, (3) nitro, (4) trifluoromethyl, (5) cyano, (6) oxo, (7) -OR40, (8) -NR42R'3, (9) -NHC(O)NRtR45. (10) -NHC(O)-C1-4alkyl-NR46R47,(11)-NHC(O)-Cl-4 alkyl-COOH,(12y-NH-S(O)2-C1-4 alkyl, (13) -C00R48, (14) -NHC(O)-R49, (15) -NI-IC(O)-CI-4 alkyl-0R50, (16)-NHC(O)O-R51, (17) -NHC(O)O-C1-4 alkyl-0R52, (IS) -C(O)NH-R53, (19) -OC(O)-R55, (20) -C(O)-R56, (21) -CH(OH)-R57,(22) -C1-4 alkyl-N1-12, (23) -C1-4 alkyl-OFL, (24)-C1-4 alkyl-OC(O)-C1-4 alkyl, (25) -0-4 alkyl-NHC(O)-Cl-4 alkyl, (26) -C1-4 alkyl.
NHC(O)O-C1-4 alky-1. (27) -0-4 alkyl-NHC(O)-CF3, (28) -C1-4 alkyl-NHC(O)NIi-C1-4 alkyl, 01(29) -CHN-OR5. More preferably, R7 represents (1) methyl, (2) ethyl, (3) fluorine, (4) chlorine, (5) bromine, (6) nitro. (7) trifluoromethyl, (8) cyano, (9) oxo, (10) -OR40, (11) -NR42R43, (12) -N1JC(O)NRR45, (13) -NHC(O)-C1-4 alkyl-NR45R47, (14) -NHc(O)-C1-4 alkyl-COOH, (15) -NH-s(o)2-cl-4 alkyl, (16) -C00R48, (17)- NFIC(O)-R49, (18) -NHC(O)-C1-4 alkyl-0R50, (19) -NHC(O)O-R51, (20) -NHC(O)O- C1-4 alkyl-0R52, (21) -C(O)NH-R53, (22) -OC(O)-R", (23) -c(O)-R56, (24) -CH(OH)-P?7, (25) -0-4 alkyl-NH2, (26) -0-4 alkyl-OH, (27) -CI-4 alkyl-OC(O)-C1-4 alkyl, (28) -Cl-4 alkyl-NHC(O)-C1-4 alkyl, (29) -0-4 alkyl-NHC(O)O-cl-4 aikyl, (30) -Cl- 4 alkyl-NFIC(O)-CF3, (31) -Ci-4 alkyl-NHC(O)NH-C1-4 alkyl, or(32) -CHN-0R58, wherein R40. R41, R42. R43, R44, R45, R46, R47, R48, R49, K50. R51, R52, R53, R54, R55, R56, R7 and K58 are independently selected from hydrogen, C 1-4 alkyl and trifluoromethyl.
More preferably, K' represents (1) -NH2, (2) -NHC(O)O-C1-4 alkyl, (3) -NHC(O)O- 0-4 alkyl-O-C1-4 alkyl or (4) halogen.
Preferably, R40, R41, K42, K43, R", R45, K46, K47, R48, R49, K50, K51, R32, R53, K54, K55, R56, K5' and R58 each independently represents hydrogen, trifluoromethyl or ci -8, preferably C1-4, alkyl.
Preferably, n represents an integer of 0, 1,2 or 3.
In a preferred embodiment, Cyc3 represents cs-cio aryl or 5-to lO-menibered heteroaryl, more preferabty phenyl, n is I and K' represents (1) -NH2, (2) -NHC(O)O-C1-4 alkyl or (3) -NHC(O)O-Cl-4 alkyl-O-C1-4 alkyl. or it is 2 and one K' represents * 21 (I) NFI2, (2) NHC(O)0-C1-4 alkyl or (3) -NHC(O)O-C1-4 alkyl-0-C14 alkyl and the other t represents halogen.
In a preferred embodiment represents _,e(R', 4R1),, :_4Rr)a 15.Ae H "s "N "N çcAR)s çdRt) 4Rt)fl _(Rt), çIF4RT)n ç__(flT?n )jR N wherein R59 represents hydrogen, Cl -4 alkyl or halogen; the arrow represents a binding position; and the other symbols have the same meanings as described above, preferably wherein a is I and K7 represents (1) -NH2, (2) -NHC(0)0-Cl-4 alkyl or (3) -NHC(0)0-C1-4 alkyl- 0-Cl -4 alkyl. orn is 2 and one R' represents (I) -NH2, (2) -NHC(O)O-C 1-4 alkyl or (3) -NHC(0)0-C1-4 alkyl-0-C1-4 alkyl and the other R7 represents halogen.
iS In a preferred embodiment, -Cyc2-(R6)m represents * 22 R61 N-S N-N N-/ // II\ R6° wherein R6° represents hydrogen, methyl or halogen; represents (1) hydrogen, (2) halogen, (3) nitro, (4) trifluoromethyl, (5) -COOH, (6) -coo-c 1-4 alkyt. (7) cyano or (8) -CONH2; and the arrow represents a binding position.
In one embodiment, preferred compounds of the present invention are pyridinone or pyrimidinone derivatives represented by formula (I-A):
V
R (I-A) (R)m.,JcJ wherein U represents S or CU2; and the other symbols have the same meanings as described above. Thus, preferred C-ye', Cyc2, C-ye3, R', s, R2, R5, R6, m, R7 and n in the formuta (I-A) are the preferred options as described above. * 23
Preferred compounds of formula (1-A) are those in which: Cyc' represents a C5-C 10 aryl or 5 to 10 membered heteroaryl; Cyc2 represents a C5-Cl0 aryl, preferably a C5-C6 aryl; Cyc3 represents cyclohexane, indoline, isoindoline, dihydroquinoline, dihydroquinazoline, dihydrobentoxazine, dihydrobenrzoxazole, phenyl, pyrazole, pyridine, pyrazine, thiophene, oxazole, thiazole, indazole, quinoline, isoquinoline, quinoxaline or benzimidazole; each R' independently represents CI-8 alkyl or halogen; s represents an integer of 0 or 1; R2 represents (1) hydrogen, (2) Cl-S alkyl, (3) Cyc4 or (4) Cl-S alkyl substituted with 1 to 3 groups selected from Cyc5 and -OR'5; Cyc4 represents CS-C 10 aryl; Cyc5 represents CS-C 10 aryl, for example CS-C7 aryl, or a 5-to 6-membered heteroaryl; R'5 is selected from hydrogen and Cl -4 alkyl; Y represents N or CH-; U represents S or CH2; each R6 independently represents (1) methyl, (2) Cyc'°, (3) halogen, (4) amidino, or (5) Cyc'° substituted with 1 to 3 groups selected from halogen, trifluoromethyl, cyano, -OR29, -C00R35, -NHC(O)-R36 and -C(O)NH-R38; R29, R35, R36 and R33 each independently represent hydrogen or Cl -4 alkyl; Cyc1° represents imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, pyridazinyl, indazolyl, benzimidazolyl, thiazolyl or thiadiazolyl; m represents an integer of 0, 1 or 2; each R7 independently represents (1) Cl-8 alkyl, (2) halogen, (3) nitro, (4) trifluoromethyl, (5) cyano. (6) oxo, (7) -OR40, (5) -NR42R43, (9) -NHC(O)NRR45, (10) -NHC(O)-C1-4 alkyl-NR46R47, (11) -NHC(O)-Cl-4 alkyl-COOH, (12) -Nfl-S(O)2--Cl-4 alkyl, (13) -C00R48, (14) -NHC(O)-R49, (15) -NHC(O)-Cl-4 alkyl-0R50, (16) -NI-IC(O)O-R51, (17) -NHC(O)O-C1-4 alkyl-0R52, (18) -C(O)NIH-R53, (19) -OC(O)-R55, (20) -C(O)-R56, (21) -CFI(OIi)-R57, (22) -C1-4 alkyl-Nfl2, (23) -C1-4 alkyl-ON, (24) - C1-4 alkyl-OC(O)-C1-4 alkyl, (25) -Cl-4 alkyl-NHC(O)-C1-4 alkyl, (26) -C1-4 alkyl- NHC(O)O-Cl-4 alkyl, (27) -C1-4 alkyl-NHC(O)-CF3, (28) -C1-4 alkyt-NHC(O)NH-Cl-4 alkyl, or (29) -CHN-0R58; * 24 R40, R41, R42, R43, R4', R45, R46, R47, R48, R49, R50, RSI, R52, R53, R54, R55, R56, R37 and R55 each independently represent hydrogen, Cl -4 alkyl or trifluoromethyl; and n represents an integer of 0, I, 2 or 3.
Preferred compounds of formula (I-A) include those in which: Cyc1 represents phenyl, imidazolyl, thazolyl, tetrazolyl, pyrrolyl, pyrazolyl, furanyl, oxazolyl, thiazolyl, isothiazolyl, fürazanyl, oxadiazolyl, thiadiazolyl, thienyl, pyridazinyl, indazolyl or benzimidazolyl; Cyc2 represents pyridyl or phenyl; Cyc3 represents cyclohexane, iridoline, isoindoline, dihydroquinoline, dihydroquinazoline, dihydrobenzoxaiine, dihydrobenzoxazole, phenyl, pyrazole, pyridine, pyrazine, thiophene, oxazole, thiazole, indazole, quinoline, isoquinoline, quinoxaline or benzimidazole; each Rt independently represents methyl, ethyl or chlorine; s represents an integer of 0 or 1; represents hydrogen; Y represents CH; U represents Cl-I2; each R5 independently repitsents (1) methyl, (2) Cy&°, (3) halogen (preferably chlorine), or () Cy&° substituted with I to 3 groups selected from halogen (preferably chlorine), nitro, trifluoromethyl, -coon, -coo-cl -4 alkyl, cyano or -CONH2; Cyc'° represents pyrazolyi. thiacliazotyl, triazolyl or tetrazolyt; m represents an integer of 0, 1 or 2; each R' independently represents (1) methyl, (2) ethyl, (3) fluorine, (4) chlorine, (5) bromine, (6) nitro, (7) trifluoromethyl, (8) cyano, (9) oxo, (10)-OR40, (11) - NR42R43, (12) -NHC(O)NR44R45. (13) -NHc(o)-c1-4 alkyl-NR46R47, (14) -NHC(O)-Ci -4 alkyl-COOH, (15) -NH-S(O)2-c 1-4 alkyl, (1 6) -COOR4, (17) -NI-IC(O)-R49, (18) -NI-lC(O)-C1-4 alkyl-0R50, (19) -NHC(O)O-R51, (20) -NIIC(O)O-Ct-4 alkyl-0R52, (21) -c(o)NH-R53, (22) -oc(o)-R'5, (23) -C(O)-R56, (24) -CH(OH)-R57, (25) -Cl-4 alkyl-NH2, (26) -C1-4 alkyl-OH, (27) -Cl-4 alkyl-OC(O)-C1-4 alkyl, (28) -0-4 alkyl- NHc(o)-cl-4 alkyl, (29) -C1-4 alkyl-NHC(O)O-C1-4 alkyl, (30) -C1-4 alkyl-NHC(O)-CF3, (31) -Cl -4 alkyl-NHC(O)NH-cl -4 alkyl, or (32) CHNORss * 25 R40, R4L, R42. R43, it'4, it45, R6, R47, R48, it49, it50, R5', it52, it53, it54, R", R56, R5' and R5 are independently seketed from hydrogen, C1-4 aikyl and trifluoromethyl; aiid n represents an integer of 0, 1, 2 or 3.
Further preferred compounds of formula (I-A) indude those in which represents 11S'). ç1__(RY). 1[(R'L 4R'L 1fRT), v_7 41ItF JN.k(R1). çAR7)n ç1jI_RlLI çy4Rh)n cS-$R K" P5' wherein R59 represents hydrogen, Cl -4 alkyl or halogen; the arrow represents a binding position; and the other symbols have the same meanings as described above, preferably wherein n is 1 and DY represents (1) -NH2, (2) -NHC(O)O-Cl-4 alkyl or (3) -NHC(O)O-C1-4 alkyl-O-Cl-4 alkyl, or n is 2 and one It7 represents (I) -NH2, (2) -NHC(O)O-Cl-4 alkyl 01(3) -NIHC(O)O-C1-4 alkyl-O-C1-4 alkyl and the other R7 represents halogen.
Further preferred compounds of formula (I-A) include those in which -Cyc2-(R6) represents N-S N-N N-/ II ll\ II) R6° wherein R6° represents hydrogen, methyl or halogen; represents (1) hydrogen, (2) halogen, (3) nitro, (4) trifluoromethyl, (5) -COOH, (6) -coo-c 1-4 alky], (7) cyano or (8) -cONH2; and the arrow represents a binding position.
Further preferred compounds of formula (I-A) include a compound of (I-A-i): YJNX(RI) (R7) (I-A-I) wherein all symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of(I-A-2):
Y
(I-A-2) wherein all symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of (J-A-3):
Y
(I-A-3) wherein all symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of(1-A-4): Cyc3 7' Y (I-A 4) (R1 wherein s represents an integer of 0 to 1; and the other symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of (I-A-5): (I-A-5) (R6)mcIiCL wherein in represents an integer of 0 to 5; and the other symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of (i-A-6): (I-AM) wherein s represents an integer 0 to 1; m represents an integer 0 to 5; and the other symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), and the Iike In another embodiment, preferred compounds of the present invention are pyridinone derivatives represented by forrntila (I-B): * 29 (I-B) wherein Cyc represents 5-to 1O-mernbered heteroaryl; Cyc3 represents CS-DO aryl or 5-to lO-membered heteroaryl; Cyc° represents (1) 5-to lO-nienibered heteroaryl or (2) 5-to 1O-membered heteroaryl substituted with 1 to 5 groups selected from halogen, cyano, nitro, trifluoromethyl. -COOH, -COO-C!-4 alkyl and -CONH2; mb represents an integer of 0 to 5; and the other symbols have the same meanings as described above. Thus, preferred CyciB, Cye2, Cyc3, R', a, R2, R4, R5, R6, Cy&°°, R7 and a in the formula (I-B) are the preferred options as described above.
Preferred compounds of formula (I-B) are those in which: Cyc1 represents imidazolyl, triazolyl, teirazolyl, oxazolyl, pyridazinyl, indazolyl or benzimidazolyl; Cyc2 represents a CS-Cl 0 my!, preferably a C5-C6 my!; Cyc3B represents CS-C 10 aiyl, for example C5-C7 aryl such as phenyl, or 5-to I 0-membered heteroaryl, such as pyrazole, pyridine, pyra2ine, thiophene, oxazole, thiazole, indazole, quinoline, isoquinoline, quinoxaline or benzimidazole, more preferably pyrazole or pyridine; each R' independently represents halogen or Cl -4 alkyl; s represents an integer of 0 or 1; R2represents (1) hydrogen, (2) Cl-S alkyl, (3) Cyc4 or(4) Cl-8 Sky! substituted with Ito 3 groups selected from Cyc5 and -OR5; Cyc' represents CS-C 10 my!; Cyc5 represents CS-C 10 my!, for example C5-C7 aryl or a 5-to 6-membered heteroaryl; R'5 is selected from hydrogen and 0-4 alkyl; R4 represents hydrogen or Cl-4 alkyl; R5 represents hydrogen; each R6 independently represents methyl, halogen or amidirio; mb represents an integer of 0 or 1; Cyc'°3 represents imidazolyl, triazo]yl, tetrazolyl, oxazolyl, pyridazinyl, indazolyl, benzimidazolyl, thiazolyl or thiadiazolyl, any of which optionally substituted with I to 3 groups selected from halogen, cyano, nitro, trifluoromethyl, -COOl-I, -COO-C1-4 alky[ and -CONH2; each R7 independently represents (I) C1-8 alkyl, (2) halogen, (3) nitro, (4) trifluorotnethyl, (5) eyano, (6) oxo, (7) -OR40, (8) -NR42R43, (9) -NHC(O)NR"R45, (10) -NFIC(O)-C1 -4 a1kyI-NRR47, (11) -NFIC(O)-C1 -4 alkyl-COOFI, (12) -N1-1-S(O)2-C 1-4 alkyl, (13) -COOR, (14) -NHC(O}-R49, (15) -N}IC(O)-C1-4 alkyl-0R50, (16)-NHC(O)O-R51 (17) -NHC(O)O-C 1-4 a1ky1-OR5. (18) -C(O)NH-R53. (19) -OC(O)-R55, (20) -C(O)-R56, (21) -CH(OH)-R57, (22) -C1-4 alkyl-NJ-{2, (23) -C1-4 alkyl-OI-1, (24)- C1-4 alkyl-OC(O)-C1-4 alkyl, (25) -C1-4 alkyl-NHC(O)-C1-4 alkyl, (26) -Ch4 alkyl- NHC(O)O-C1-4 alkyl, (27) -0-4 aikyl-NI-IC(O)-CF3, (28) -C1-4 alkyl-NHC(O)NH-Cl-4 alkyl, or (29) -CFIN-0R58 R40. R41, R42, R43, R, R45, R46, R47, R48, R49, R'°, R51, R52, R53, R54, R55, R56, R57 and R58 each independently represent hydrogen, C1-4 alkyl or trifluoromethyl; and 11 represents an integer of 0, 1,2 or 3.
Preferred compounds of formula (I-B) include those in which: Cyc' represents irnidazolyl, triazolyl, tetrazolyl, oxazolyt, pyridazinyl, indazojyl or benzimidazolyl; Cyc2 represents pyridyl or phenyl; Cyc38 represents CS-Cl 0 aryJ, more preferably pheny]; each R independently represents halogen or 0-4 alkyl; s represents an integer of 0 or 1; R2 represents (1) hydrogen, (2) Cl -4 alkyl, (3) Cye4or (4) Cl -4 alkyl substituted with 1 or 2 groups selected from Cye5 and -OR'5; Cyc4 represents phenyl; Cyc5 represents phenyl or pyridyl; R'5 is selected from hydrogen and Cl -4 alkyl; 3' R4 represents hydrogen, methyl or ethyl; represents hydrogen; each R6 independently represents methyl or halogen (preferably chlorine); mb represents an integer of 0 or 1; Cyc10 represents thiadiazolyl, triazolyl or tetrazolyl, any of which optionally substituted with 1 to 3 groups selected from halogen (preferably chlorine), nitro, trifluoromethyl, -COOH, -COO-Cl -4 alkyl, cyano or -CONE2; each R7 independently represents (1) -NH2, (2) -NHC(O)o-cl-4 alkyl, (3) -NHC(O)O-Cl -4 alkyl-O-C1-4 alkyl or (4) halogen; and nrepresentsanintegerof0, l,2or3.
Further preferred compounds of formula (I-B) include those in which -Cyc'(-R1)-Cyc38(-R7% represents I4N' NN' fr-N ç1__(R')n 5R') 14R') CR')n y( >3RU L< ° wherein R59 represents hydrogen, 0-4 alkyl or halogen; the arrow represents a binding position; and the other symbols have the same meanings as described above, preferably wherein ii is I and R7 represents (1) -NH2, (2) -NHC(O)O-C1-4 alkyl or (3) -NHC(O)O-Cl-4 allcyl-O-Cl-4 alkyl, or n is 2 and one R7 represents (I) -NH2, (2) -NHC(O)O-Cl-4 alkyl or (3) -NFIC(O)O-C 1-4 alkyl-O-C 1-4 alkyl and the other R7 represents halogen.
Further preferred compounds of formula (I-B) include those in which -Cyc2(-R6) mbCyC represents R61 T IXorY R60 R60 R6° wherein R6° represents hydrogen, methyl or halogen; R6' iepresents (1) hydrogen, (2) halogen, (3) nitro, (4) trifluoromethyl, (5) -COOH, (6) -COO-Cl-4 alkyl, (7) cyano or (8) -CONH2; and the arrow represents a binding position.
Further preferred compounds of formula (I-B) include a compound of (I-B-1): (I-B-I) wherein all symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of (I-B-2): R4 (1-8-2) (R6)mb wherein all symbols have the same meanings as deseHbed above and the same preferred definitions as set out above (alone or in combination), a compound of (I-B-3): (1-8-3) Cyc1'8 (R6)mb wherein all symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of (1-BA): H Cyc (R (1-84) (R6)mb wherein s represents an integer of 0 to 1; and the other symbo's have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of (l-B-5): (? (t-B-5) (R6)m wherein nib represents an integer of 0 to 4; and the other symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of(I-B-6): (RT) (I-B -6) (R6)m wherein s represents an integer 0 to 1; mb represents an integer 0 to 4; and the other symbols have the same meanings as described above and The same preferred definitions as set out above (alone or in combination), and the like. I0
In another embodiment, preferred compounds of the present invention axe pyrimidinone derivatives represented by formula (I-C): cyc3C N) (I-C) (R6)mc wherein Cyc represents 5-to lO-membered heteroaryl; Cyc represents C5-C1O aryl or 5-to lO-membered heteroaryl; Cyc10 represents (1) 5-to 10-membered heteroaryl or (2) 5-to 10-membered heteroaryl substituted with I to 5 groups selected from halogen. cyano, nitro, trifluoromethyl, -COOH, -COO-C 1-4 alkyl and -CONH2; mc represents an integer of 0 to 5; and the other symbols have the same meanings as described above. Thus, preferred CycC, Cyc2, Cyc3, It', s. It2, R4, R6, Cyct, R7 and n in the formula (I-C) are the preferred options as described above.
Preferred compounds of formula (I-C) are those in which: Cyc' represents imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridazinyl, indazolyl or benzimidazolyl; Cyc2 represents a CS-dO aryl, preferably a CS-Co aryl such as phenyl; Cyc3 represents CS-dO aryl, for example CS-Cl aryl such as phenyl, or 5-to 1 0-membered heteroaryl, such as pyrazole, pyridine, pyrazine, thiophene, oxazole.
thiazole, indazole, quinoline, isoquinoline, quinoxaline or benzixnidazole, more preferably pyrazole or pyridine; each R' independently represents halogen or Cl -4 alkyl; s represents an integer of 0 or 1; 1(2 represents hydrogen, (I) C 1-8 alkyl, (2) Cyc4 or (3) Cl -8 alkyl substituted with 1 to 3 groups selected from Cyc5 and -OR'5; Cyc4represents C5-C10 aryl; Cyc5 represents C5-ClO aryl, for example CS-Cl aryl, or a S-to 6-membered heteroaryl; R15 is selected from hydrogen and C1-4 alkyl; 1(4 represents hydrogen orCl-4 alkyl; each 1(6 independently represents methyl, halogen or amidino; mc represents an integer of 0 or 1; Cyc' represents imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridazinyl, indazolyl, benzimidazolyl, thiazoiyi or thiadiazolyl, any of which optionally substituted with 1 to 3 groups selected from halogen, eyano. nitro, trifluoromethyl, -COOM, -COO-CI-4 alkyl and -CONH2; * 36 each R' independently represents (1) Cl-S alkyl, (2) halogen, (3) nitro, (4) trifluoroinethyl, (5) cyano, (6) axe, (7) -OR40, (8) NR42R43, (9) -NHC(O)NRR4, (10) -NHC(O)-C1-4 a1kyI-NR4'R47, (11) -NHC(O)-C1-4 alkyl-COOB, (12) -NH-S(O)2-C1-4 alkyl, (13) -C00R48, (14) -NHC(O)-R49, (15) -NHC(O)-C14 alkyl-OR", (16) -S NHC(O)O-R', (17) -N1-IC(O)O-C1 -4 alkyl-0R52, (18) -C(O)NH-R53, (19) -DC(O)-R'5, (20) -C(O)-R56, (21) -CH(OH)-R57, (22) -C1-4 alkyl-NH2, (23) -C1-4 alkyl-OH, (24)- C1-4 alkyl-OC(O)-Cl-4 alkyi (25) -C1-4 alkyl-NHC(O)-Cl-4 alkyl, (26) -C1-4 alkyl- NF{C(O)O-Cl-4 alkyl, (27) -C 1-4 alkyl-NUC(O)-CF3, (28) -C 1-4 alkyl-NHC(O)NH-C1-4 alkyl, or (29) -CHN-OR55; R40, R4, R42, R43, Ru, R45, R46, R47, R48, R49, R50, R', R52, R53, R54, R55, R56, R5' and R58 each independently represent hydrogen, Cl -4 aIlcyl or trifluoromethyl; and n represents an integer of 0, 1, 2 or 3.
Preferred compounds of formula (i-C) include those in which: CycC represents imidazolyl, triazolyl, tetraolyl, oxazolyl. pyridazinyl, indazolyl or benzimidazolyl; Cyc2 represents pyridyl or phenvl; CyC3C represents CS -Cl 0 aryl, more preferably phenyl; each R1 independently represents halogen or 0-4 alky); s represents an integer of 0 or 1; R2 represents (1) hydrogen, (2) 0-4 alkyl, (3) Cyc4 or (4) C1-4 alkyl substituted with I or 2 groups selected from Cyc5 and -OR'5; Cyc4 represents phenyt; Cyc5 represents phenyl or pyridyl; R'5 is selected from hydrogen and Cl -4 alkyl; R4 represents hydrogen, methyl or ethyl; each R6 independently represents methyl or halogen; CycC represents represents thiadiazolyl, triazojyl or tetrazolyl, any of which optionally substituted with 1 to 3 groups selected from halogen (preferably chlorine), nitro, trifitioromethyl, -COOl-I. -COO-Cl -4 alkyl, cyano or -CONH2; each R7 independenfly represents (1) -NFl2, (2) -NHC(O)O-C1-4 alkyl, (3)-NHC(O)O-Cl-4 alkyl-O-Cl-4 alkyl or (4) halogen; and n represents an integer of 0, 1,2 or 3.
Further preferred compounds of formula (I-C) include those in which -Cyc'(-R1)-Cyc3(-R7) represents _f_(M___(}n kN.I H _ __(7n 1,R'L1,,-(RT)0 1__(Rr]n J! $Ri' YRn)N wherein R59 represents hydrogen, Cl -4 alkyl or halogen; the arrow represents a binding position; and the other symbols have the same meanings as described above, preferably wherein n is I and R7 represents (I) -NH2, (2) -NHC(O)O-Cl-4 alkyl or (3) -NHC(O)O-Cl-4 alkyl-O-Cl-4 alkyl, or n is 2 and one R7 represents (1) -N}12, (2) -Nl-IC(O)O-CI -4 to alkyl or (3) -NHC(O)O-C1-4 alkyl-O-Cl-4 alkyl and the other R7 represents halogen.
Further preferred compounds of formula (I-C) include those in which -Cyc2(-R5) mcCYC' represents R61
N-S N-N
II II\\ II\\ N z R6° wherein R6° represents hydrogen, methyl or halogen; R61 represents (1) hydrogen, (2) halogen, (3) nitro, (4) trifluoromethyl, (5) -COOll, (6) -COO-C 1-4 alkyl, (7) cyano or(S) -CONH2; and the arrow represents a binding position.
Further preferred compounds of formula (I-C) include a compound of (I-C-I): (I-C-I) wherein all symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of (I-C-2): (I-C-2) wherein all symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of (I-C-3): N1N (R7 (I-C-3) (R6)me wherein all symbols have the same meanings as descdbed above and the same preferred definitions as set out above (alone or in combination), a compound of(I-C-4):
NV H Cyc
I )n
(R6)mc wherein s represents an integer of 0 to 1; and the other symbols have the sante meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of(J-C-5):
N
(I-C-5) (R)mc wherein mc represents an integer of 0 to 4; and the other symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), a compound of (l-C-6): 0 40 -C-6) wherein s represents an integer 0 to 1; mc represents an integer 0 to 4; and the other symbols have the same meanings as described above and the same preferred definitions as set out above (alone or in combination), and the like.
As used herein, general references to "compounds of formula (I)" include compounds of formula (I-A), (I-B) and (I-C).
Particularly preferred compounds of formula (I) include: 4-(4-cMoro-2-{( 1 S)-1 -[4-(2,54ichlorophenyl)-2-oxo-1 (2H)-pyridthylj-2-phenylethyl) -I H-imida.zol-5-yl)benzoic acid, 4-(2-{(1 S)-l -[4-(2,5-dichlorophenyl)-2-oxo-l (2H)-pyridinyl]-2-phenylethyl} -I H-imidazol-5-yl)benzoic acid, 3-(4-chloro-2-( 1 S)-1 -[4-(2,5-dich1oropheny-2-oxo-l (2H)-pyridinyl]-2-phenylethyl) -1 H-imidazol-5-yl)benzoic acid, 3-{2-[(S)-[4-(2,5-dichlorophenyl)-2-oxo-l(2H)-pyridinyl]henyl)methylj-1 H-imidazol-5-yI}benzoic acid, salts thereof, N-oxides thereof, solvates thereof, and prodrugs thereof.
Particularly preferred compounds of formula (I-A) include: methyl [4-(2-{2-[S-chloro-2-(1 H-tetrazol-I -yl)phenylj-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-ajpyrimidin-6-yl} -1 I1-imidazol-5-ypheny1Jcarbamate, methyl [4-(2-{7-[5-chloro-2-( I H-tetrazol-l -yl)phenylj-S-oxo-1,2,3,5-tetrahydro- 3-indolizinyl) -1 1-1-iniidazol-4-yl)phenyljcarbamate, * 41 methyl 4-(4-ch1oro-2-{ 7-{5-chloro-2-(l 11-tetrazol-J -yl)pheny]J-5-oxo-1,2,3,5-tetrahydro-3 -indolizinyl} -l H-imidazol-5-yl)phenyl]carbamate, 3-(4-chloro-2-{7-[5-chloro-2-( 1 H-tetrawl-1 -yl)phenyl]-5-oxo-) ,2,3,5-tetrahydro-3-indolizinyl} -I I1-imidazol-5-yl)benzoic acid, (3 S)-7-[5-chloro-2-(IH-tetrazol-1-yl)phenyl}-3-(5-phenyl-1}i-imidazol-2-yfl- 2,3-dihydro-5(1 Fl)-indolizinone, formic acid -methyl (4-(2-{7-[5-chloro-2-( lHtetrazol-I -yl)phenyl]-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl J-4-methyl-I H-imidazol-5-yI)phenyl]carbamate (1:1), formic acid -methyl [4-(2-{ 7-[5-chloro-2-(IH-tetrazol-I -yl)phenyl]-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl} -4-ethyl-I I-1-imidazol-5-ypheriyl}carbamatc (1:1), formic acid -methyl (4-{2-(7-(5-chloro-2-formamidophenyl)-5-oxo-1,2,3, 5-tetrahydro-3-indo1izinyl-4-ethyl-1 H-imidazoh5-yl)phenyl)carbamate (1:1), 5-(2-{7-(5-chloro-2-(1H-tetrazol-1 -yI)phenyl}-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-4-yl)-1,3-dihydro-2H-indol-2-one, iS 6-(2-{ 7-[5-chloro-2-(1 H-tetrazol-I -yl)phenyl}-5-oxo-I.2,3,5-tetrahydro-3-indolizinyl} -I H-imidazo-4-yO-3,4-dihydro-2(II1)-quinoiinone.
6-(4-chloro-2-(7-[5-chloro-2-( IFI-tetrazol-1 -yI)pheuyl]-5-oxo-1,2,3,5-tetrahydro-3-indo?iziuyl}-IH-imidazol-5-yl)-3, 4-dihydro-2(1 H)-quinolinone, methyl [4-(2-{7-{5-chloro-2-( I H-tetrazol-I.-yl)phenylj-5-oxo-1,2,3,5-tetrahydro- 3-indolizinyl}-1 H-imidazo1-5-yl)-2-fluorophenyIearbamate, methyl 4-4-ch1oro-2-{7-[5-chloro-2-( 1H-tetrazol-I -yI)phenyl]-5-oxo-1,2,3.5-tetraliydro-3-indolizinyl}-I H-imidazoI-5-yl)-2-fluoropheny]carbamate, methyl [4-(2-{7-[5-chloro-2-(IH-tetrazol-1-yl)phenyl-5-oxo-1,2.3,5-tetrahydro- 3-indolizinyl}-I H-imidazol-5-yI)-3-fmuorophenyl]carbamate, methyl [4-(4-chloro-2-{7-[5-chloro-2-( I H-tetrazol-I -yflpbenyl}-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazot-5-yl)-3-fluorophenyl]carbamate, methyl [4-(2-{7-[5-chloro-2-(IH-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro- 3-indo1izinyl}-1fl-imidazoI-5-yl)-3-inethylphenycarbamate, methyl [44-cWoro-2-{7-[5-ch1oro-2-(1 H-tetrazoI-1-yl)phenyI-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)-3-nwthylphenyl]carbamate, methyl t4-(2-(7-[5-chIoro-2-(IH-telrazol-I -yl)phenyl3-5-oxo-1,2,3,5-tetrahydro- 3-indolizinyl) -I H-imidazol-5-yI)-3-ethylphenyljearbamate, * 42 methyl [4-(4-ehloro-2-{7-[5-chloro-2-(l H-tetrazol-L-yl)phenyl}-5-oxo-1,2,3,5-tetrahydzo-3-indolizinyl} -1 H-iniidazol-5-yl)-3-ethylphenyl]carbamate, methyl [3-chloro-4-(2-{ 7-[5-ehloro-2-(1 1-1-tetrazol-I -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)phenyljcarbaniate, S methyl [4-(2-{(3S)-7-[5-chloro-2-(1 H-teti-azol-1 -yI)phenyl]-5-oxo-1,2,3,5-tetráhydro-3 -indolizinyl} -1 H-imidazol-5-yI)-3 -methoxyphenyl)carbamate, methyl [2-bromo-4-(2-{(3 S)-7--[5-chloro-2-( I 1-1-tetrazol-I -yI)pfienylj-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl}-I H-imidazol-S-yl)-5-methoxyphenyl}carbamate, methyl [4-(2-{(3 S)-7-[5-chloro-2-(1 ll-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1}{-imidazol-5-yI)-3-(trifluoromethyl)phenyljcarbaznate, methyl [4-(4-chloro-2-{(3S)-7-[5-chloro-2-(1 H-tetrazol-I -yt)phenyl]-5-oxo- I,2,3,5-tetrahydro-3-indolizinyl}-1 I-1-imidazol-5-yI)-3- (trffluoromethyl)phenyljcarbamate, 4-(2-{7-[5-chloro-2-( 1 H-tetrazol-I -yI)phenylj-5-oxo-1,2,3,5-tetrahyclro-3-indolizinyl}-IH-imidazol-4-yl) benzoic acid ammoniate, 4-(2-{ 7-[5-chloro-2-( 1 H-tetrazol-1 -yl)phenylJ-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-l H-irnidazol-4-yflbenzamide, 4-(4-chloro-2-( 7-[5-chloro-2-( 1 H-tetrazol-l-yflphenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -I H-imidazol-5-yl)benzamide, 4-(2-{7-[5-cbloro-2-(I H-tetraz&-l -yl)pbenylj-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1 I-1-imidazol-5-yl)-2-fluorol,enzamide, 4-(2-{7-15-chloro-2-UH-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-teti-ahydro-3-indolizinyl}-1 H-imidazol-4-yJ)-N-methylbenzaniide, 4-(5-chloro-2-( 7-[5-chioro-2-(I H-tetrazol-1 -yl)phenyl j-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-4-yl)-N-methylbenzamide, 4-(2-{ 7-[5-ehloro-2-( 1}1-tetrazol-1 -yl)phenyl]-S-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 F1-imidazol-4-yL)-N-ethylbenzamide, 4-(4-chloro-2-{ 7-[5-chloro-2-(1 H-tetrazol-I -yl)phenylj-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1}1-iniidazol-5-yl)-N-ethylbenzamide, 7-[5-ehloro--2-(1 H-tetrazol-l -yl)phenyl}-3-(5-(4-nitrophenyl)-I H-irnidazol-2-yI}- 2,3-dihydro-5(1 H)-indolizinone, 3-[5-(4-aminophenyl)-I H-imidazol-2-yIJ -7-[5-chioro-2-(1 I-1-tetrazol-1 -yl)phenyl}-2,3-dihydro-5( I 11)-indolizinone, ethyl [4-(2-{ 7-[5-chloro-2-(1 H-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1H-imidazol-5-yI) phenyl]carbamate, isopropyl [4-(2-{7-{5-chloro-2-(1 H-tetrazol-1..y1)pheny1-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)phenyl]carban,ate, 2-tnethoxyethyl [4-(2-(7-[5-chloro-2-(1 H-tetrazol-I -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -l H-imidazol-5-yl)phenyl]carbarnate, N-[4-(2-{745-chloro-2-(1 H-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yI)phenyl]acetamide.
N-[4-(2-{7-[5-chloro-2-( 1 H-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-.
indolizinyl}-1H-imidazol-5-yl)phenyl]-2-methoxyacetamide.
N-[4-(2-{ 7-[5-chioro-2-( I H-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-telrahydro-3-indolizinyl}-I H-imidazol-5-yl)phenyl]-3-methoxypropanamide, N-[4-(2-{7-[5-chloro-2-( 1 H-tetrazol-1-yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yI)phenyl]rnethanesulfonamide, ethyl [4-(4-chloro-2-{ 7-[5-chloro-2-(1 H-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-iridolizinyl} -1 H-iniidazol-5 -yl)phenyl}carbamate, isopropyl [4-4-ch1oro-2-{7-[5-chloro-2-(1 Fi-tetrazol-I -yl)phenyl]-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl} -I H-imidazol-S-yl)pheriyflcarbamate, N-[4-(4-chloro-2-{7-[5-chloro-2-( 1 H-tetrazol-1 -yl)phenyl]-5-oxo-I,2,3,5-tetrahydro-3 -indolizinyl} -1 H-imidazol-S-yl)phenyl]acetamide, N44-(4-chloro-2-{7-[5-chloro-2-( 1 H-tetrazol-1 -yl)phenyl]-5-oxo-I,2,3,5-tetrahydro-3 -indolizinyl} -1 F1-iniidazol-5-yl)phenyl}methanesulfonamide, 1 -[4-(2-{7-[5-cbloro-2-( 1 H-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1H-imidazol-S-yI) phenyl]-3-ethylurea, 3-[4-(2-(7-[5-ch1oro2-(1 il-tetrazol-I -yI)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)phenyl]-I,1 -dimethylurea, N-[4-(2-{7-[5-chloro-2-(1 H-tetrazol-I -yI)pheny1-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1 H-inñdazol-5-yl)phenyll-2-(dimethylamino)acetamide, 3-{ [4-(2-( 7-[5-chloro-2-( 1 H-tetrazol-1 -yl)phenylj-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -I H-imidazol-5-yl)phenyl]amirio} -3-oxopropanoic acid, 6-(2-( 7-[5 -chloro-2-(1 H-tetrazol-I -yl)phenyfl-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)-4-hydroxy-2(1 H)-quinolinone, 4-(2-{7-[5-chloro-2-(1 H-tetrazol-1 -yI)phenyl]-5-oxo-1,2,3.5-tetrahyctro-3-indolizinyl}-I H-imidazoI.S-y-2-thiorobenzonitri1e, 3-(5-(3-amino-IH-indazol-6-yl)-IH-imidazol-2-yl]-7-[5-ch]cro-2- (IH-tetrazol- -yflphcnyl]-2,3-dihydro-5(I Ifl-indolizinone, 7-0-(7-[5-chloro-2-( I H-tctrazol-1 -yflphenyfl-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1 F1-imidazol-5-yl)-2H-1,4-bcnzoxazin-3(4H)one, -0-{(3S)-7-[5-chloro-2 -(1 N-tetrazo)-I -yI)phenyl]-5-oxo-1,2,3,5-tetráhydro-3-indolizinyl}-I H-imidazol-5-yl)-4-methyl-21-1-I,4-benzoxazin-3(41-I)-one, 7-(4-chloro-2-{ (3S)-7-{5-chloro-2-(1 H-tetrazol-l -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3--indolizinyl}-IH-imidazol-5-yl) -4-methyl-2H-1,4-benzoxazin-3(4H)-one, 6-(2-(7-[5-ehloro-2-(1 1-1-tetrazol-1 -yI)phenyl]-5-oxo-1,2,3,5-tetrahydro-3 indolizinyl} -1 1-1-imidazol-5-yl)-1,4-dihydro-2H-3, I -benzoxazin-2-one, 6-(4-ehloro-2-{7-[5-ehloco-2-(IH-tetrazol-I -yI)phenyl]-5-oxo-1,2.3,5-tetrahydro-3-indolizinyl}-1 H-itnidazot-5-yl)-1,4-dihydro-2H-3, 1-benzoxazin-2-one, 6-(2-(7-[5-ehloro-2-(l H-tetrazol-1-yI)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indotizinyl}-I J-1-irnidazol-5-yI)-I,3-benzoxazoi-2(3Ffl-one.
6-(4-chloro-2-{7-[5-chloro-2-(1 H-tctrazol-1-yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyi} -1 H-imidazol-5-yl)-I,3-benzoxazol-2(3H)-one.
6-a-{7-[5-.chloro-2-(1 I1-tetrazol--1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1H-imidazol-5-y])-1 -isoindolinone, 6-0-{(3S)-7-[5-chloro-2-(1 H-tetrazoi-1 -yI)phenyl]--5-oxo-1,2.3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-y])-3-methyl-3,4-dihydro-2(1 H)-quinazolinone, 6-(2-{7-[5-chloro-2-(1H-tetrazol-l -yI)phenylj-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-11-I-imidazol-5-yI)-2 (1 H)-quinoxalinone, (3S)-7-1S-chloro-2-( 1 FI-tetrazol-I -yl)phenyl3-3-[5-( I-methyl-i H-benzimidazol- 5-yl)-1 H-imidazol-2-yIj-2,3-dihydro-5(1 1-1)-indolizinone, 3-(4-chloro-5-(1-methyl-1H-benzimidazol-5-yl)-1 H-imidazol-2-yI]-7-[5-chloro- 2-0 H-tctrazol-I -yI)phenyfl-2,3 -dihydro-5(i H)-indotizinone, (3S)-7-[5-chioro-2-(1 H-tetrazol-1 -yl)phenyl]-3-[5-( I H-indazol-5-yl)-1 H-irnidazol-2-yI]-2,3-dihydro-5(1 H)-indolizinone, 7-[5-ehloro-2-( I H-tetrazol-1-yl)phenyl]-3-(5-[4-(hydroxymethyl)phenyl]-1 1-1-irnidazol-2-yl) -2,3-dihydro-5(1 H)-indolizinone, 4-(2-(7-[5-chloro-2-( H-tetrawl-1 -yl)pheny)-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazoi-S-yI)benzyl acetate, 4-(2-(3S}-7-5-ch1oro-2-(1 H-tetrazol-l-y1)pheny1]-5-oxo1l,2.3,5-tetrahydro3 indolizinyl} -1 H-imidaz& -5y1)benza1dehyde oxime, 4-(2-{(3S)7-[5-ch1oro-2-(1F1-tetrazo1-1-yflphenyl]5-oxo-l,2,3, 5-tetrahydro-3-indolizinyl) -1 FI-imidazol-5-yI)benzaldehyde O-rnethyloxime, (3S)-3-[5-(4-acelylphenyJ)-1 H-imidazol-2-yl]-7-[5-ehloro-2-(1 11-tetrazol-1-yl)phenylj-2,3-dihydro-5( 1 11)-indolizinone, (3S)-7-[5-chloro-2-(1 FI-tetrazol-I-yl)pheny}J-3-(5-[4-( t-hydroxyethyl)phenyl]- 1 H-imidazol-2-yfl-2,3-dihydro-5(1H)-indolizinone, 2-methyl-2-propanyl [4-(2-{(3S)-7-[5-chloro-2-(IH-tetrazol-l-yl)phenyl]-5-oxo-I,2,3, 5-tetrahydro-3 -indolizinyl}-I H-imidazol-5-yI)benzyl]carbamate, (3S)-3-{5-[4-(aminomethyl)phenyl}-1 H-iinidazol-2-yI}-7-[5-chloro-2-(1 H-tetrazol-1 -yI)phenyl]-2,3 -dihydro-5( I 11)-indolizinone dihydrochioride, methyl [4-(2-ft3S)-7-[5-chloro-2-(1 il-tetrazol-I -yI)phenyl}-5-oxo-1,2,3,5-terahydro-3-indolizinyt)-I H-imidazol-5-yl)benzyl]carbamate, N-[4-(2-{(3S)-7-[5-chloro-2-(IH-tetrazol-l-yI)phenylj-5-oxo-L2, 35-tetrahydro- 3-indolizinyl}-1 H-imidazol-5-yl)benzyl]acetamide, N.[4-(2-{(3S)-7-[5-ehloro-2-(IH-tetrazol-1-yI)phenylj-5-oxo-1,2,3, 5-tetrahydro- 3-indolizinyl}-I H-imidazol-5-yl)benzylj-2,2,2-trifluoroacetamide.
I -[4-(2-{(3S)-7-[5-chloro-2-(IFI-tetrazol-1-yI)phenyl}-5-oxo-I,2.3, S4etrabydro- 3-indolizinyl}-1 H-imidazol-5-yl)benzytj-3-ethvlurea, (3S)-7-[5-chloro-2-(IH-tetrazol-I -yl)phenyl}-3-[5-(4-pyridinyl)-IH-imidazol-2-yI]-2,3-dihydro-5(I 11)-indolizinone, (3S)-7-[5-ehLoro2-(1H-tetrazoI-1-y})phenyI]-3-{5-(3-pyridiny-I H-imidazol-2-yl]-2,3 -dihydro-5(1 H)-indolizinone, (3S)-7-5-ch1oro-2-(1H-tetrazo1-1-vI)phenyIJ-3-[5-(2-pyridinyl) -1H-imidazo1-2-yI]-2,3-dihydro-5(l H}-indolizinone, (38)-7-[5-chloro-2-(IH-tetrazol-1-vl)phenyl}-3-[5-(1,3-thiazol-2-vl) -IH-imidazol-2-ylJ-2,3-dihydro-5(I [1)-indolizinone.
(3S)-7-[5-chloro-2-(1H-tetrazol-1-yI)phenyl]-3-[5-(2-pyrazinyl)-I FI-imidazo}-2-yI]-2,3-dihydro-5(I H)-indolizinone, * 46 (3S)-7-[5-chloro-2-(IH-tetrazol-1 -yl)phenyl]-3-[5-(2-methoxyphenyl)-IH-imidazol-2-yI] -2,3-dihydro-5(1 H)-indolizitone, (3S)-7-[5-ehloro-2-(1H-tefrazol-1 -yl)phenvl]-3-[5-(3-methoxyphenyl)-1 H-imidazol-2-yI]-2,3-dihydro-5(1 H)-indolizinone, (3S)-7-[S-chloro-2-( 11-1-tetrazol-1 -yl)phenyl]-3-[5-(4-methoxyphenyl)-1 H-imidazol-2-ylj-2,3-dihydro-5(l F1)-indolizinone, (3S)-7-[5-chloro-2-(I H-tetrazof-I -yI)phenyl]-3-[5-(3 -fluorophenyl)-I FL-imidazol-2-yl]-2,3-dihydro-5(1 H)-indolizinone, (3S)-7-[5-chloro-2-( IH-tetrazol--1 -yl)phenyl}-3-{5-(4-fluorophenyl)-1 H-imidazol-2-yl]-2,3-dihydro-5ç11-T)-indolizinone, (3S)-7-[5-chloro-2-( 1 H-tetrazol-I -yl)phenylj-3-[5-(2,4-diinethyl-1,3-oxazol-5-yl)-11-1-imidazol-2-yJJ-2, 3-dihydro-5( I H)-indolizinone, (3S)-7-[5-chloro-2-( 11-I-tetrazol-1 -yl)phenyfl-3-[5-( 1 -methyl-1H-pyrazol-4-yfl- 1 H-imidazol-2-yl]-2,3-dihydro-5( I H)-indolizinone, methyl 5-(2-{ 7-[5-chloro-2-(1H-tetrazol-1 -yl)pheny1-5-oxo-1,2,3,5-tetrahyclro- 3-indolizinyl} -1 H-imidazol-5-yI)-2-thienyljearbamate, 2-methyl-2-propanyl [trans-4-(2-{(3S)-7-{5-chloro-2-( 1 H-tetrazol-1 -yphenyfl- 5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-I H-imidazol-5-yflcyclohexyl]earbamate, (3S)-3-[5-(trans-4-aminocyc1ohexy-I 1J-imidazol-2-yI]-7-{5-chloro-2-Ø H-telrazol-1 -y])phenylj-2,3-dihydro-5(I H)-indolizinone, methyl [trans-4-(2-((3S)-7-[5-ehloro-2-( I H-tetrazol-I -yl)phenylj-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1 H-imidazol-5-yl')eyclohexyl]carbamate, (3S)-3-[5-(trans-4-aminocyclohexyl)-4-ehloro-I H-imidazol-2-yI]-7-[5-chloro-2- (lH-tetrazol-1 -yl)phenylj-2,3-dihydro-5(1H)-indotizinone, (3S)-3-[5-(2-amino-4-pyridiny1)-1I--I-imidazo1-2-y1J-7-[5-ch1oro-2- (1I-I-tetrazo1-I -yl)phenyl]-2,3-dihydro-5(IH)-indolizinone, 3-[4-(6-aniino-3-pyridinyl)-l H-imidazol-2-ylJ-7-[5-chloro-2-(l1-1-tetrazol-1-yl)phenyl]-2,3-dihydro-5(t H)-indotizinone, methyl 5-(2-{(3S)-745-ehloro-2-( I H-tetrazol-I -yl)phenyl]-5-oxo-l,2,3,5-tetrahydro-3-indolizinyl}-1 H-imidazol-5-yI)-2-pyridinyl]carbamate, methyl [5-(4-cliloro-2-{(3S)-7-[5-chloro-2-(1 H-tetrazol-1 -yI)phenyl]-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl}-1 H-imidazol-5-yl)-2-pyridinyl]carbamate, ethyl [5-(2-{(3S)-7-[5-chloro-2-( 1H-tetrazol-I -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -l H-im.idazol-5-yl)-2-pyridinyllcarbamate, (3S)-3-[5-(6-amino-3-pyridinyl)-4-chloro-1H-imidazol-2-ylJ-7-[5-chloro-2- (1H-tetrazol-1 -yl)phenyl]-2,3 -dihydro-5(IH)-indolizinone, (3S)-3-[5-(6-amino-3-pyridinyl)-4-methyl-1H-imida2ol-2-yi]-7-[5-chloro-2- (1H-tetrazol-I -yI)phenylJ-2,3-dihydro-5( I 11)-indolizinone, methyl [5-(2-{(3S)-7-[5-chloro-2-( 1H-tetrazol-1 -yl)phenyfl-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -4-methyl-I H-imidazol-5-yl)-2-pyridinyljcarbaniate, (3S)-3-[5-(6-amino-2-chloro-3-pyridinyl)-1H-imidazol-2-yl]-7-[5-chloro-2- (1H-tetrazol-I -yl)phenyl]-2,3-dihydro-5(1 H)-indolizinone, (3S)-3-[5-(6-amino-2-metbyl-3-pyridinyl)-lf{-ixnidazol-2-yl]-7- [5-ehloro-2-(IH-tetrazol-l-yl)phenylj-2,3-dihydro-5(I H)-indolizinone, methyl [5-(2-{(3S)-7-[5-chloro-2-(1 H-tetrazol-I -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1 H-imidazol-5-yI)-6-methyl-2-pyridinyl]carbamate, (3S)-3-[5-(6-aniino-2-fluoro-3-pyridinyl)-1H-imidazol-2-yl]-7-[5-chloro-2- (1H-tetrazol-l-yI)phenyl]-2,3-dihydro-5(1H)-indoliziiione, (3S)-7-[5-chloro-2-(1 H-tetrazol-1 -yl)phenyfl-3-[5-(6-methyl-3-pyridinyl)-1H-imidazol-2-ylJ-2,3-dihydro-5(J 11)-indolizinone, (3S)-3-[4-chloro-5-(6-methyl-3-pyridinyl)-1 H-imidazol-2-yl]-7-[5-chloro-2- (1 11-tetrazol-1 -yl)phenyl] -2,3-dihydro-5( 1 1-1)-indolizinone, 2-methyl-2-propanyl [6-(2-{7-[5-chloro-2-(1 H-tetrazol-I -yl)phenyl]-S-oxo- 1,2,3,5-tetrahydro-3-indolizinyl} -l H-imidazol-5 -yl)-3 -pyridinyl]carbamate, 3-[5-(5-amino-2-pyridinyl)-I H-irnidazoi-2-yl}-7-[5-chloro-2-(11-I-tetrazol-1-yl)phenyl]-2,3-dihydro-5 (j H)-indolizinone, 3-[5-(5-amino-2-pyridinyl)-4-chloro-1H-imidazol-2-yI]-745-ehloro-2- (1ll-tetrazol-l-yl)phenyl]-2,3-dihydro-5( 1 H)-indolizinone, methyl [6-(2-{7-[5-chloro-2-(1 il-tefrazol-I -yl)phenyl}-5-oxo-1,2,3,5-tetrahydro- 3-indolizinyl} -1 H-imidazol-5-yl)-3-pyridinyl]carbaznate, methyl 16-(4-ehloro-2-{ (3S)-7-[5-chloro-2-( 1 H-tetrazol-I -yl)phenyl]-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl} -l R-imidazol-5-yI)-3-pyridinylJcarbamate, isopropyl 6-(2-{(3 S)-7-5-chloro-2-( 1 FI-tetrazol-1 -yl)phenylj-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yI)-3-pvridinylcarbamate, isobutyl 6-(2-{(3S)-7-[5-ch1oro-2-(1H-tetrazo1-1-yl)pheny1]-5-oxo-1,2,3, 5-tetrahydro-3-indolizinyl}-I H-imidazol-5-yl)-3-pyridinyl]carbamate, N-[6-(2-{(3 S)-7.-[5-chloro-2-(1 H-tetrazol-1 -yl)phenyfl-5-oxo-1,2,3.5-tetrahydro- 3-indolizinyl) -1 H-imidazol-5-yl)-3-pyridinylJacetamide, (3S)-3-[5-(5-amino-2-pvridinyl)-4-methyl-1 H-imidazol-2-ylJ-7-[5-ehloro-2-(1 H-tetrazol-1 -yI)phenyl]-2,3-dihydro-5( 1 H)-indolizinone, N-[6-(2-{(3S)-7-[5-chloro-2-(1 H-tetrazo1-1-y1)phenyl-5-oxo-1,2,3,5-tetrahydro- 3-indolizinyl} -4-methyl-1H-imidazol-5-yl)-3-pyridinyljacetamide, methyl [6-(2-{(3S)-7-[5-ebloro-2-( I ll-tetrazol-I -yJ)phenylj-5-oxo-1,2,3,5 -tetrahydro-3-indolizinyl}-4-methyl-1 H-imidazol-5-yl)-3-pyridinyflcarbamate, (3S)-3-[5-(2-amino-1,3-thiazol-5-yl)-1H-imidazol-2-ylj-7-[5-eliloro-2-(1 H-tetrazol-1 -yl)phenyl}-2,3-dihydro-5(1 H)-indolizinone, (3S)-3-[5-(1-amino-6-isoquinolinyfl-lH-imidazol-2-yl]-7-[5-chloro-2- (IH-tetrazol-I -yl)phenylJ -2,3-dihydro-5 (1 1-1)-indolizinone diacetate, methyl [4-(5-(7-[5-chloro-2-( I H-tetrazol-I -yI)phenyfl-5-oxo-I,2,3,5-tetrahydro- 3-indolizinyl}-1H-imidazol-2-yI)pheny]caEbamaie, methyl [4-(4-chloro-5-{7-5-ch1oro-2-(i H-tetrazol-1 -yl)phenyl3-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -I H-imidazol-2-yl)phenyl]carbamate, 3-[5-(4-aminopheny-4H-1,2,4-triazol-3-yIJ-7-[5.-chloro-2-(1}I-tetrazol-1 -yl)phenylJ-2,3-dihydro-5 (1 1-1)-indolizinone, methyl [4-(5-{ 7-[5-chloro-2-(1 H-tetrazol-I -yphenyIj-5-oxo-1,2,3,5-tetrahydro- 3-indoliziriyl} -41-I-I,2,4-triazo!-3-yl)phenyLcarbamate, methyl [4-(6-{7-[5-chloro-2-(1 H-tetrazol-1 -yI)phenyl]-5-oxo-1,2,3,5-tetrahydro- 3 -indolizinyl} -3-oxo-2,3-dibydro-4-pyridazinyl)phenylJcarbamate, methyl [4-(4-{ 7-f 5-chloro-2-(1 il-tetrazol-I -yl)phenyl]-5-oxo-1,2,3,5-tetrahyclro- 3-indoliziriyl) -I H-i,2,3 -triazol-I -yl)phenyl]carbainate, methyl [4-(5-(745-cliloro-2-(1 H-tetrazol-1 -yl)phenyl-5-oxo-1,2,3,S-tetrahydro- 3-indolizinyl)-1,2-oxazol-3-yflphenyl]carbamate, methyl [4-(2-{(3S)-7-[5-chloro-2-(l 11-tetrazol-1 -yl)phenylj-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl) -1 H-imidazol-4-yt)phenyl]carbamate, methyl [4-(2-{(3R)-7-[5-chloro-2-(i I-l-tetrazol-1 -yl)phenyl]-5-oxo-2,3-dihydro- 51141,3 jtbiazolo[3,2-a]pyridin-3-yI} -1 H-imidazol-5-yl)phenyl]carbamate, methyl [3-chLoro-4-(2-{(3 S)-7-[5-chloro-2-(1 H-tetrazol-I -yl)phenyl]-5-oxo- 1,2,3,5-tetrahydro-3-indoiizinyl} -1 H-imidazo1-4-yl)phenylIcarbamate, 6-(2-((3 S)-7-[5-chloro-2-(1 H-tetrazol-1-yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)-3,4-dihydro-2(1 H)-quinolinone, S ethyl [4-(2-{(3S)-7-[5-chioro-2-( I H-tetrazol-I -yl)phenylj-5-oxo-1,2,3,5-tetrahydro-3 -indolizinyl} -1 H-imidazol-5 -yl)phenyl]carbarnate, 4-(2-{(3 S)-7-[5-ehlore-2-(i H-tetrazol-1 -yl)phenyl]-5-oxo-I,2,3,5-tetrahydro-3-indolizthyl} -1 H-imidazol-5-yl)benzamide, 4-(4-chioro-2-{(3 S)-7-[5-chloro-2-( 1 H-tetrazol-I -yflphenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -l Fl-imidazol-5-yl)benzamide, methyl [4-(2-{(3R)-7-[S-chloro-2-( I H-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1 H-imidazol-5-yl)phenyl]carbamate, methyl [4-(2-{(3S)-7-[5-cliloro-2-(iH-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -5-methyl-i H-imidazol-4-yl)phenyllcarbamate, methyl [4-(2-{(3 S)-7-[5-chloro-2-( 1 H-tetrazol-1 -yl)pheriyl}-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -5-methyl-i,3-oxazol-4-yl)phenyl}carbamate, 2-methyl-2-propanyl 1-{4-chloro-2-[(3 S)-3-(5-{4- ((methoxycarbonyl)amino]phenyl} -1 H-imidazol-2-yl)-5-oxo-I,2,3,5-tctrahydro-7-indolizinyl]phenyl} -1 H-1,2,3 -triazole-4-carboxylate, methyl I -{4-chloro-2-[(3 S)-3-(5-{4-[(methoxycarbony])amino]phenyl} -Ill- imidazol-2-yl)-5-oxo-1,2,3,5-tetrahydro-7-indolizinyl]phenyl} -1 H-i,2,3-triazole-4--carboxylate, 1-{4-cliloro-2-[(3S)-3-(5-{4-{(methoxycarbonyl)amino]phenyl} -1H-imidazol-2-yI)-5-oxo-I,2,3,5-tetrahydro-7-indolizinyl]phenyl} -1 H-i,2,3-triazole-4-carboxylic acid, methyl [4-(2-{(3S)-7-[2-(4-carbamoyl-1 H-i,2,3-triazol-I -yi)-5-chlorophenyl] -5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1 H-imidazol-5-yl)phenyl]carbamate, methyl [4-(2-{(3S)-7-[5-chloro-2-(4-cyano-i H-i,2,3-triazol-1 -yl)phenyl]-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl} -i H-imidazol-5-yl)phenyl}carbarnate, methyl [4-(2-{(3S)-7-[5-chloro-2-(3-hydroxy-1 H-i,2,4-triazol-1 -yflphenyl]-5-oxo-i,2,3,5-letrahydro-3-indolizinyl} -I H-imidazol-5-yl)phenyl]earbamate, methyl [4-(2-{(3S)-7-[5-methyl-2-(l Il-tetrazol-1 -yl)-3-pyridinyl}-5-oxo-1.2,3,5-tetrahydro-3 -indolizinyl} -1 H-imidazol-5-yl)phenyl]carbamate, methyl [4-(2-{(3S)-7-[5-methyl-2-( 1 FI-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3 -indolizinyl} -1 H-imidazoI-5-y1)pheny1carbamate, methyl [4-(2-{(3 S)-7-[5-chloro-2-(4-chloro-I H-I,2,3-triazol-1 -yflphenyl]-5-oxo-I,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)phenyljcarbamate, methyl [4-(2-{(3S)-7-[5-fluoto-2-(IH-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)phenyljcarbamate, methyl [4-(2-{ (3 S)-5-oxo-7-[2-( 1 H-tetrazol-1 -yI)-5-(triuluoroniethyl)phenylj- 11,2,3,5-tetrahydro-3-indoUzinyl} -IH-imidazol-5-yl)phenyl]carbamate, (6S)-6-[5-(6-amino-2-fluoro-3-pyridinyl)-ll-1-imidazol-2-yl]-2- [5-chloro-2-(IH-tetrazol-I -yl)phenyl]-7,8-dihydropyrrolo[ 1,2-aJpyrimidin-4(6H)-one, (6S)-6-[5-(6-amino-3-pyridinyl)-4-ehloro-IH-imidazol-2-yl]-2-[5-chloro-2- (IH-tetrazol-I.-yl)phenylj--7,8-dihydropyrolo[ I,2-a]pyrimidin-4(6ff)-one, (6S)-6-[5-(6-amino-2-chloro-3-pyridinyl)-1H-imidazol-2-yl]-2- [5-chioro-2-fllH-tetrazol-1 -yI)phenyl}-7,8-dihydropyrrolo[ I,2-a}pyrimidin-4(6H)-one, and 2-methoxyethyl [6-(4-cMoro-2-{(6S)-2-[5-chloro-2-(1 H-tetrazol-1 -yl)phenylj-4- oxo-4,6,7,-tetrahydropyrro1o[ 1,2-a]pyrimidin-6-yl}-1 H-imidazol-5-yl)-3-pyridinylcarbaxnate, salts thereof, N-oxides thereof, solvates thereof, and prodrugs thereof.
Particularly preferred compounds of formula (I-B) include: 4-[5-chloro-2-( I H-tetrazol-1-yI)phenyfl-1 -[(5-phenyl-I H-imidazol-2-yl)methyl]- 2(1 H)-pyriciinone, methyl {4-[2-U4-[5-chlorci-2-( 1N-tetrazol-I -yl)phenylj-2-oxo-I (2H)-pyridinyl}methyl)-I H-imidazoF-4-yljphenyl}carbamate, methyl {4-[5-ch1oro-2-4-[5-chIoro-2-(1 H-tetrazol-I -yI)phenyl}-2-oxo-1(2W-pyridiny) }methyl)-I H-imidazol-4-ylJphenyl}carbamate, methyl (4-12-0 -(4-f 5-chloro-2-(1H-tetrazol-11 -yl)phenyl}-2-oxo-1(2K)-pyridinyl}propyl)-IH-imidazol-4..yljphenyl} carbamate, methyl (4-[5-chloro-2-(1 -{4-[5-chloro-2-( I Fl-tetrazol-I -yI)phenylJ-2-oxo- 1(2H)-pyridinyl}propyl)-I H-imidazol-4-yl)phenyl}carbamate, methyl {4-[2-( 1 -{445-chloro-2-(1 H-tetrazol-1 -yl)phenyll..2-oxu-1 (2H)-pyridinyl}ethyO-1H-imidazol-5-yljphenyl}carbamate, methyl (4-[2-( 1-{4-[5-chloro-2-(IH-tetrazol-1 -yl)phenyl}-2-oxo-I (2H)-pyridinyl J cyclopropyl)-I H-imidazol-5-yljphenyl} carbamate, methyl {442-(1 -{4-[5-ch1oro-2(1H-tetrazoI-1 -yl)phenylj-2-oxo-1(211)-pyridinyl} -2-phenylethyl)-IH-imidazol-4-yl]phenyl} carbamate, methyl [4-(2-{ I -[4-(2-carbamimidaniido-5-ch1orophenyl)-2oxo-l (211)-pyridinyl]-2-phenylethyl) -1 H-imidazol-4-yl)phenyl]carbamate acetate, methyl {4-[5-chloro-2-(1 -(4-{5-chloro-2-(1H-tetraaol-1 -yI)phenyl]-2-oxo- 1 (2H)-pyridinyl}-2-phenylethyl)-1 H-imidazol-4-yl]phenyl) carbamate, 4-[5-chIoro-2-( 1 H-tetrazol-1 -yl)phenyl)-1 -{2-phenyl-1 -[5-( 1 H-pyrazol-1 -yl)- 1H-benzimidazol-2-yl]ethyl}-2(Ifl)-pyridinone, I -{ I -[5-(4-aminophenyl)-1 H-imidazol-2-yl]-2-phenylethyl} -4-(2,5-dichlorophenyl)-2( 1 H)-pyridinone, methyl [4-(2-{ I -[4-(2,5-dichlorophenyl)-2-oxo-1 (2H)-pyridinyfl-2-phenylethyl} -1 H-imidazol-4-yl)phenyl]carbamate, methyl 4-(5-ch1oro-2-( 144-(2,S-dichloi-ophenyl)-2-oxo-I (2H)-pyridinyl]-2-phenylethyl} -I FI-imidazol-4-yflphenyl]carbamate, formic acid -methyl (4-12-(j4-15-chloro-2-(1 H-tetrazol-1 -yphenyfl-2-oxo-I (2H)-pyridinyl}methyl)-4-methyl-I H-imidazol-5-yl]phenyl}carbanrnte (1:1), formic acid -methyl (4-[2-4-[5-chloro-2-( 1 H-tetrazol-1 -yI)phenyl]-2-oxo- 1 (2H)-pyridinyl)methyl)-4-ethyl-I H-imidazol-5-yI]phenyl}carbamate (1:1), 6-[2-({4-[5-chloro-2-( I I4-tetrazol-1 -yl)phenyl]-2-oxo-1 (2H)-pyridinyl}methyl)- 1 H-imidazol-5-ylJ-3,4-dihydro-2(IH)-quinolinone, 6-[4-chloro-2-({4-[5-.chloro-2-( I H-tetrazol-I -ypheny1j-2-oxo-I (2H)-pyridinyl} methyl)-1 H-imidazol-5-yl]-3,4-dihydro-2(1 H)-quinolinone, methyl (3-chloro-4-[2-([445-chloro-2-(1ll-tetrazol-i -yl)phenyl]-2-oxo-1(211)-pyridinyl}methyl)-I H-imida2ol-5-yl]phenyl} carbamate.
4-2-({445-ch1oro-2-( I H-tetrazol-1 -yI)phenyl]-2-oxo-1(2H)-pyridinyl}methyl)- 1 H-imidazol-5-yI]benzamide, 4-[4-chloro-2-( { 4-15-chloro-2-( 1H-tetrazol-I -yl)phenyl]-2-oxo-1(211)-pyridinyl}methyl)-1 H-imidazol-5-yljbenzamide, 6-[2-({4-[5-chloro-2-( I H-tetrazol-1-yI)phenylj-2-oxo-1 (2H)-pyridinyl}methyl)-I H-imidazol-5-yl}-3-methyl-3,4-dihydro-2(1H)-quinazolinone, 6-[4-ehloro-24{4[5-ehloro-2-(1H-tetrazol 1 -yI)phenyl]-2-oxo-1(H)-pyridinyl}methyl)-1 H-imidazd-5 -yl-3-methy1-3,4-clihydro-2(lH)-quinazolinone, I -{[5-(6-amino-3 -pyridinyl)-l H-imidazol-2-y]methyl} -4-[5-th1oro2-(I H-tetrazol-1 -yl)phenyl}-2( I H}-pyridinone, methyl { 5-[2-({4-[5-chloro-2-( IH-tetrazol-1-yl)phenylj-2-oxo-1(2H)-pyridinyl)methyl) -IH-imidazol-5-ylJ-2-pyridinyl}carbamate.
1-{[5-(6-amino-2-chloro-3-pyridinyl)-IH-imidazol-2-yl]methyl}-4- [5-ehloro-2- (1 H-tetrazol-1 -yl)phenylj-2( I H)-pyridinone, methyl {6-[2-({4-[5-chloro-2-(1H-tetrazol-I -yI)phenyl}-2-Qxo-I (2H)-pyridinyl}methyl)-l H-imidazol-5-yl}-3-pyridinyl)earbamate, methyl {4-[2-(1 -{4-{5-chloro-2-(1ll-tetrazol-1 -yl)phenylj-2-oxo-1(211)-pyridinyl} -3-methoxypropyl)-I 11-imidazol-5-ytjphenyl} carbamate.
methyl {4-[4-ehloro-2-(I -{4-[5-choro-2-(lH-tetrazo1-1 -yI)phenyl]-2-oxo-I (2H)-pyridinyl} -3-methoxypropyl)-I H-imidazol-5-yl]phenyl}carbaniate, methyl (4-(2-[(l S)-1 -(4-[5-chloro-2-(IH-tetrazol-I -vl)phenyl]-2-oxo--l (2H)-pyridinyl}-2-phenylethylj-1H-imidazol-4-yl}phenyl)carbamate, methyl {4-[2-({4-[5-chloro-2-(1 H-tetrazol-l -yphenyl]-2-oxo-1(2H)-pyridinyl}methyi)-4-methyl-i H-imidazo-5-ylJphenyl}carbamate, methyl (4-{2-[1 -{4-[5-ehloro-2-(I H-tetrazol-l -yl)phenyi]-2-oxo-l (21-1)-pyrithnyl}-2-(3-pyridinyl)ethyl}-IH4midazo1-5-yI}phenyearbarnate, methyl (4-{4-chloro-2-[1-{4-[5-chloro-2-( I H-tetrazo1-1-ypheny1}-2-oxo- 1(2H)-pyridinyt}-2-(3-pyridinyethylj-IH-imidazol-5-y1)phcny1)carbamate.
methyl I -(4-chloro-2-{ 1 -[(1 8)-I -(5-f4-[(methoxyearbony)amino}pheny1}-11-1- imidazol-2-yl)-2-phenylethyl]-2-oxo-l,2-dihydro-4-pyridinyl}phenyl)-IH-I, 2,3-triazol e-4-carboxylate, methyl [4-(2-{(l 8)-I -[4-{5-chloro-2-[4-(tritluoromethyfl-11-i-I,2,3-triazol-1-yljphenyl} -2-oxo-1(2H)-pyridinylj-2-phenylethyl}-1 H-imidazol-4-yt)phenyl]earbamate, methyl (4-(2-[(IS)-1-{4-[5-chloro-2-(4-chloro-1H-1.2,3-triazcil-1-yl)phenyl] -2-oxo-l (2H)-pyridinyl} -2-phenylethyl]-I H-imidazol-5-yf}phenvl)carbamate, methyl (4-(2-[(1 8)-I -(4-[5-chloro-2-(4-liuoro-IH-pyrazol-I -ypheny1-2-oxo-I (2H)-pyridinyl}-2-phenylethy1-I H-imidazot-5-y)phenyearbamate, methyl [n-C-{(1 S)-1-j4-{ 5-chloro-2-{4-(trifluoromethyl)-l H-pyrazol-1-yl]phenyl}-2-oxo-1 (2H)-pyridinyl]-2-phenykthyl}-1H-imidazol-4-yI)phenyl]carbamate, methyl {4-[2-(1-{4-[5-cbloro-2-( 1 H-tetrazol-1-yl)phenyl]-6-methyU2-oxo-l(2H)-pyz-idinyl}ethyl)-I H-imidazoI5y1]phenyI}carbamate, methyl (4-[2-((4-[5-ehloro-2-(1 H-tetrazoi-l y1)phenyl]-6-methy1-2-oxo-1(2H1-pyridinyl}methyl)-l H-imidazol5-yl]phenyl}carbamate, and methyl {4-[2-({4-[5-ekloro-2-(1H-tetrazol-I -yl)phenyl]-6-ethyl-2-oxo-I (214)-pyridinyl}methyl)-1}1-imidazol-5-yI]phenyl} carbamate, salts thereof, N-oxides thereof, solvates thereof, and prodrugs thereof, Particularly preferred compounds of formula (I-C) include: methyl {4-[2-({4-[5-chloro-2-(1 H-tetrazol-1 -yl)phenyl]-2-methyl-6-oxo-I (614)-pyrimidinyl}methyl)-1H-imidazol-5-yl]phenyl}carbamate, 2-methoxyethyl {4-[2-({4-[5-chloro-2-(l1-I-tetrazol-I -yI)phenyl)-2-methyl-6-oxo-l(ÔFI)-pyrimidinyl}methyl)-1 H-imidazol-5-yljphenylJcarbamate, 2-methoxyethyl {4-[4-ehloro-2-( {445-chloro-2-( I H4etrazol-I -yl)phenyl]-2-methyl-&-oxo-1 (611)-pyrimidinyl}methyl)-I H-imidazol-5-yl]phenyl}earbamate, 3-{[5-(6-amino-3-pyridinyD-l H-imidazol-2-yI}methyl}-6-[5-chloro-2-(1H-tetrazol-1 -yl)phenyl]-2-rnethyl-4(31-I)-pyrimidinone, arid 3-{[5-(6-amino-3-pyridinyl)-4-chloro-1H-imidazol-2-yljmcthyl} -645-chloro-2- (1 H-tetrazo1-l-ypheny1]-2-methyl-4(3H)-pyrimidinone, salts thereof, N-oxides thereof, solvates thereof, and prodrugs thereof.
Compounds of the present invention containing one or more chiral centres may be used in enantiomerically or diastereoisomerically pure form, or in the form of a mixture of isomers. For the avoidance of doubt, the compounds of ihe invention may be used in any tautomeric form.
Unless otherwise specifically mentioned, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl, alkoxy and alkylthio may be straight chain or branched. Moreover, all isomers due to double bond, ring and fused ring (E-, Z-, cis-and trans-forms), isomers due to the presence of asymmetric carbon(s) etc. (R-, a-and 3-configuration, enantiomer and diastereomer), optically active substances having optical rotation (I)-, L-, d-and 1-forms), polar compounds by chromatographic * 54 separation (more polar compounds and less polar compounds), equilibrium compounds, rotational isomers, a mixture thereof in any proportion and a racemic mixture are included in the present invention.
According to the present invention, symbol represents cx-configuration, symbol represents n-configuration and symbol represents configuration, f3-configuration or a mixture of them. There is no particular limitation for the ratio of cx-conliguration and p-configuration in the mixture.
SALTS: The salt of the compound of foimula (I) includes all noifloxic salts or pharmaceutically acceptable salts. With regard to the pharmaceutically acceptable salts, those which are low-toxicity and soluble in water are preferred. Examples of appropriate sails of the compound of formula (1) are salt with alkaline metal (such as potassium, sodium and lithium), salt with alkaline earth metal (such as calcium and magnesium), arnmonium salt (such as ammonium salt, tetramethylammonium salt and tetrabutylammonium sail), salt with organic amine (such as triethylamine, methylamine, dimethylamine, cyclopentylamine, beuzylamine, phenethylamine, piperidine, monoethanulamine, diethanulamine, tris(hydroxymethyi) methylamine, lysine, arginine and N-methyl-D-glucamine) and acid addition salt (such as inorganic acid salt (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate) and organic acid salt (e.g., formate, acetate, trifluoroacetate, lactate, tartrate, oxalate. fumarate.
maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isothionate, glucuronate and ghiconate), etc.). The salt of the compound of the present invention also includes sovates and also solvates with the above-mentioned alkaline (earth) metal salt, ammonium salt, organic amine salt and acid addition salt. The solvate is preferably low-toxic and water-soluble. Examples of an appropriate solvate are solvates with water and with alcoholic solvent (such as ethanol).
The compounds of the present inverttion are converted to low-toxicity salts or pharmaceutically acceptable salts by known methods.
Moreover, the salt includes a quatcrnary ammomum salt. The quaternary ammonluin salt of the compound represented by formula (1) is the compound where nitrogen of the compounds represented by formula (I) is quarternalized by R° (R° is Cl- 8 alIcyl or C 1-8 alkyl substituted by phenyl.).
The salt also includes an N-oxide. The compound of the present invention can be converted into an N-oxide by known methods. The N-oxide is the compound where nitrogen of the compound represented by formula (I) is oxidized.
Prodrugs: A prodrug of the compound of formula (I) means a compound which is converted to the compound of formula (I) by reaction with an enzyme, gastric acid or the like in the living body. For example, with regard to a prodrug of the compound of formula (I), when the compound of formula (I) has an amino group, compounds in which the amino group is. for example, acylated, alkylated or phosphorylated (e.g., compounds in which the amino group of the compound of formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-l,3-dioxolen-4 yI)methoxycarbonylated, tetrahydrolliranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, tert-butylated, etc.); when the compound of formula (1) has a hydroxyl group, compounds where the hydroxyl group is, for example.
acylated, alkylated, phosphorylated or borated (e.g., compounds in which the hydroxyl group of the compound of formula (1) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, flimarylated, alanylated or dimethylaminomethylcarbonylated); and when the compound of formula (I) has a carboxyl group, compounds in which the carboxyl group is, for example, esterified or arnidated (e.g., compounds in which the carboxyl group of the compound of formula (1) is made into ethyl ester, phenyl ester, phenylethyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester. ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl -2-oxo-I,3-dioxolen-4-yI)methyl ester, cyclohexyloxycarbonylethyl ester or methylamide). Those compounds may be produced by a kno'wn method per se. The prodrug of the compound of formula (I) maybe either a hydrate or anon-hydrate. A prodrug of the compound of formula (1) may also be a compound which is converted to the compound of formula (I) under physiological conditions as described in "Jyakuhin no kaihatsu, Vol.7 (Bunshi-sekkei), pp. 163-198 (1-lirokawa-Shoten), 1990". Further, the compound of formula (1) may also be labeled S 56 by a radio isotope (such as 211 3F1, c, 13C, 4C, 3N, 5N, IsO 170, 180 3ss, 8p, 36ci, 23i, l25 etc.).
PROCESSES FOR THE PREPARATION OF TI-SE COMPOUND OF THE PRESENT
INVENTION: The compounds of the invention can, for example, be prepared according to the following reaction schemes.
The compound of the present invention represented by the formula (1) may be prepared by known methods, for exan-ipie, a method combining the following methods, the method according to these methods, the methods described in the examples and/or methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons mc, 1999), etc., which are appropriately modified in each following method for the preparation.
Salts of the starting materials may be used.
It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. Protection reactions may be carried out by the methods, for example, described in T. W. Greene, Protective Groups in Organic Synthesis. Wiley, New York, 1999.
The compound of formula (I) can be prepared from a compound represented by formula (II): ycJ N' wherein R21, R3', R41 and R6' have the same meanings as It2, R3, R4 and R6 respectively, with the proviso that carboxyl, hydroxyl, amino or thiol in R21, R3', R4' and R6' may be protected, if necessary, or a compound represented by the forinuja (III): Sl R31 1121 (frl)YtIICf( Pg wherein Pg represents a protective group of carboxyl, such as C1-4 alkyl, and the other symbols have the same meaning described above, by Cyci ring formation reactions described below.
1) The compound of formula (I) wherein Cyci represents an imidazole ring which is attached to Cyc3 at the 4-position and has an R'1, that is, a compound represented by formula (I-I): 1t R1 (t1)J wherein R'1 and R7' have the same meanings as R' and R7 respectively, with the proviso that, carboxyl, hydroxyl, amino or thiol in R' and R7 may be protected, if necessary, and the other symbols have the same meaning described above, can be prepared as outlined in Reaction Scheme 1.
Reaction Scheme I r' (if-'). I' o OH.tIkySatlon (fl_N O%:[jLEE;% (W1) (U) CyC3 -NH OAc imtdnole fonfltiOn H AsJIid&ttofl
IC
U4-' R" I R"t' NN,OAc in,idazole fonnation)e5_-L0N, In Reaction Scheme 1, the reaction from the compound represented by formula (II) to the compound represented by formula lb is an alkylation reaction.
The alkylation reaction is well known. For example, the compound represented by formula (II) with the compound represented by formula la: R1 7Th I (cyc) wherein X represents fluorine, chlorine, bromine or iodine, and the other symbols have the same meaning described above, can be conducted in a solvent such as dimethylformamide, tetrahydrofuran, dichloromethanc, acetone or acetonitrile in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate potassium bicarbonate. N,N-diisopropylethylamine or triethylamine at -20°C to reflux temperature to form a compound represented by formula lb wherein all symbols have the same meaning described above.
The reaction from the compound represented by formula lb to the compound represented by formula (I-I) is an imidazole formation reaction.
The imidazole formation reaction is well known. For example, the compound represented by formula lb and ammonium acetate or ainmonium trifluoroacetate in a suitable solvent such as xylene, toluene or acetic acid, on heating and/or microwave irradiation, can form compounds of formula (I-I).
Alternatively, the compound represented by formula (Id) can be prepared from the compound represented by formula. (II). The reaction from the compound represented by formula (II) to the compound represented by formula Id is an amidation reaction.
The amidation reaction is well known. For example, the reaction of the compound represented by formula ([1) with the compound represented by formula 1 c wherein all symbols have the same meaning described above is exemplified by: (1) A reaction procedure with use of an acid halide, (2) A reaction procedure with use of a mixed acid anhydride, and (3) A reaction procedure with use of a condensing agent.
Referring specifically to these reaction procedures, (1) The rcaction procedure employing an acid halide is conducted in practice, for example, by reacting a carboxylic acid with an acid halogenating agent (e.g., oxalyl chloride, thionyl chloride, etc.) in an organic solvent (e.g., chloroform, dichioromethanc, diethyl ether, tetrahydroibran, dimethoxyethane, etc.) at a temperature from about.-20 °C to the rethucing temperature, followed by reaction of the resultant acid halide with an amine in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofhran, acetonitrile, ethyl acetate, etc.) or solvent-free in the presence of a base (e.g., pyridiac, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) at a temperature of approximately 0 to 40° C. Alternatively, the procedure can be carried out by reacting the resultant acid halide with an amine in an organic solvent (e.g., dioxane, tetrahydroibran, dichioromethane, etc.) in the presence or absence of a phase-transfer catalyst (e.g., tetrabutylammonium chloride, triethylbenzylammoniuni chloride, iri-n-octylmethylammonium chloride, trimethyldecylammonium chloride, tetramethylammonium chloride, trimethyldecylammonium chloride, tetramethylammonium chloride, etc.) at a temperature of about 0 to 40 °C, whilst using an aqueous alkali solution (e.g., an aqueous sodium bicarbonate or sodium hydroxide solution, etc.).
(2) The reaction procedure employing a mixed acid anhydride is conducted iii practicc, for example, by reacting a carboxylic acid with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or an acid derivative (e.g.. ethyl chioroformate, isobutyl ebloroformate, etc.) in an organic solvent (e.g., chloroform, diehioromethane, diethyl ether, tetrahydrofliran, etc.) or solvent free S 60 in the presence dbase (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylarnine, etc.) at a temperature of about 0 to 40 °C, followed by reaction of the resultant mixed acid anhydride with an amine in an organic solvent (e.g., chloroform, dichioroethane, diethyl ether, tetrahydrothran, etc.) at a temperature of about 0 to 40 °C.
(3) The reaction procedure with use of a condensing agent is carried out, for example, by reacting a carboxylic acid with an amine in an organic solvent (e.g., chloroform, dichioromethane, dimethylformamide, diethyl ether, tetrahydroffiran, etc.) or solvent-free in the presence or absence of a base (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.), with use of a condensing agent (e.g., I.3-dicyclohexylcarbodiimide (DCC), l-ethyl-3-[3- (dimethyIamino)propvLcarbodiimide (EDC), 1,1 -earbonyldiimidazole (CDI), 2-chloro-I -methylpyridinium iodide, 1,1 -propylphosphonic ac.id anhydride (1-propanephosphonic acid cyclic anhydride, PPA), etc.) and with or without use of 1-hydroxybenztriazoie (HOBO, at a temperature of about 0 to 40 °C.
The reaction from the compound represented by formula id to the compound represented by formula (I-I) is an imidazole formation reaction. The imidazole formation reaction can be carried out by the same method as described above in Reaction Scheme 1.
In the course of the synthesis of the compound of the present invention represented by the formula (I-I), the deprotection reaction can be carried out at an appropriate synthetic stage, when the protective groups of carboxy. hydroxy. amino or mercapto group exists.
The deprotection reaction of the protective groups of carboxy, hydroxy, amino or mercapto group is well-known and includes, for example, (I) a deproteetion reaction by alkali hydrolysis, (2) a deprotection under acidic conditions, (3) a deprotection reaction by hydrogenolysis, (4) a deprotection reaction of silyl group, (5) a deprotection reaction using a metal, (6) a deprotection reaction using a metal complex, etc. To explain these methods in detail: (I) The deprotection reaction by alkali hydrolysis is carried out, for example, in an organic solvent (methanol, tetrahydrofuran, I,4-dioxane, etc.) using a hydroxide of alkali metals (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxide of alkaline earth metals (barium hydroxide, calcium hydroxide, dc.), carbonate (sodium carbonate, potassium carbonate, etc.) or a solution thereof or a mixture thereof at a temperature of 0 to 40 °C.
(2) The deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (dichioromethane, chloroform, dioxane, ethyl acetate, anisole, etc.), in an organic acid (acetic acid, trifluoroacetic acid, mcthancsulfonic acid, p-toluenesulfonie acid. etc.) or an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrobromic acidlacetic acid, etc.) in the presence or absence of 2,2,2-trifluoroethanol at a temperature of 0 to 100 °C.
(3) The deprotection reaction by hydrogenolysis is, for example, carded out in a solvent (e.g. ethers such as tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethyl ether, etc.; alcohols such as methanol, ethanol. etc.; bentenes such as benzene, toluene, etc.; ketones such as acetone, methyl ethyl ketone, etc.; nitriles such as acetonitrile etc.; amides such as N,N-dimethylfomiamide, N,N-diniethylacetamide etc.; water, ethyl acetate, acetic acid or a mixture of two or more thereof, etc.) in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.) under an atmosphere of hydrogen at normal or increased pressure, or in the presence of ammonium formate at a temperature of 0 to 200 °C.
(4) The deprotection reaction of a silyl group is, for example, carried out in a water-miscible organic solvent (tetrahydrottiran, acetonitrile, etc.) using tetrabutylammonium fluoride at a temperature of 0 to 40 °C.
(5) The deprotection reaction using a metal is carried out, for example, in an acidic solvent (acetic acid, a buffer of pH 4.2 to 7.2 or a mixture of the solution thereof and an organic solvent such as tetrahydrofuran etc.) in the presence of zinc powder at a temperature of 0 to 40 C optionally under sonication.
(6) The deprotection reaction using a metal complex is carried out, for example, in an organic solvent (dichloromethane, N,N-dimethylfonnamide, tetrahydrofluran, ethyl acetate, acetonjtrjle, dioxane, ethanol, etc.), water or a mixture thereof, in the presence of a trapping reagent (tributyltin hydride, tricthylsilanc, dimedonc, morpholine, diethylamine, pyrrolidine. 1,3-dimethylbarbituric acid, etc.), an organic acid (acetic acid, formic acid. 2-ethythexanecarboxylic acid, etc.) andfor a salt of an organic acid (sodium 2-ethylhexanoate, potassium 2-ethylbexanoate, etc.) in the presence or absence of a phosphine reagent (triphenylphosphine etc.) using a metal complex (tetrakis(triphenylphosphine)palladium (0), palladium(H) bis(triphenylphosphosphine) dichloride, palladi um(1T) acetate, rhodium(1) tris(tripherjylphosphine) chloride, etc.) at a temperature of 0 to 40 °C.
In addition to the above, deprotection reactions may be carried out by the methods, for example, described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
A protective group for carboxy includes, for example, methyl, ethyl, allyl, tert-butyl, tricliloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, 2-chiorotrityl or a solid carrier containing these structures, etc. A protective group for hydroxy includes, for example, methyl, trityl, methoxymethyl (MOM), I -ethoxyethyl (EE), methoxyethoxymethyl (IvIEM), 2- tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), ten-butyldimethylsilyl (TBDMS), tert-butyidiphenylsily) (TBDPS). aeetyl (Ac), pivaolyl, beazoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc) or 2,2,2-triehioroethoxycarbonyl (Troc), etc. A protective group for amine includes, for example, benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-I -(4-biphenyl)ethoxycarbonyl (Bpoc), triuluoroacetyl, 9-fluorcnylmethoxycarbonyl (FMoc). benzyl (Bn). p-methoxybenzyl, benzyloxymethyl (BOM), 2-(trimethylsilyl)elhoxymethyl (SEM), etc. A protective group for mereapto includes, for example, benzyl, methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyraiwl (TNP), diphenylmethyl, acetyl (Ac), etc. Protective groups for carboxy, hydroxy, amino or mercapto group are not limited to those described above, but include groups which are easily and selectively deprotected. For example, those groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 1999.
As is easily understood by those skilled in the art, the target compound of the present invention may be prepared easily by selecting these deprotection reactions.
2) The compound of formula (I) wherein Cye I represents an imidazole ring which is attached to Cyc3 at the 4-position and possesses R!.ha!, that is, a compound represented by formula (I-lI-b): R4' R'4 4 (W wherein R' represents fluorine, chlorine, bromine or iodine, and the other symbols have the same meaning described above, can be prepared as outlined in Reaction Scheme 2.
Reaction Scheme 2 r Sf J'-C1c3 halogenation I H (R7)f (I-Il-a) (i-Il-b) wherein all symbols have the same meaning described above.
In Reaction Scheme 2, the reaction from the compound represented by formula (I-lI-a) to the compound represented by formula (I-If-b) is a halogenatiori reaction.
The halogenation reaction is well known. For example, the reaction of the compound represented by formula (I-fl-a) with brominating or chlorinating agent, such as N-bromosuccinimide, N-chlorosuccinimide or 1,3-dichloro-5,5-dimcthyl-hydantoin in a suitable solvent such as acetonitrile, chloroform or tetrahydrofuran from -20 °C to the refluxing temperature provides the compound represented by formula (I-Il-b).
3) The compound of formula (I) ierein Cyci represents imidazole ring which is attached to Cyc3 at the 2-position, that is, a compound represented by formula (1-Ill-a): ir R31R21 j OH) wherein all symbols have the same meaning described above, and a compound represented by formula (1411-b): r1 R3 YJN4Q ob' wherein all symbols have the same meaning described above, can be prepared as outlined in Reaction Scheme 3.
Reaction Scheme 3 fl4t rr.Nt. TMSCH4 YJ5dCOOH CM I. HX 12 (R,I,L a s n fCyc3 I imwnoio
NH
ir' " ir' ir' r i,.I,gcnanoa,røL NJ(skJ3 (K"), -(flit-al (I-Ni-b) wherein all symbols have the same meaning described above.
In Reaction Scheme 3, the reaction from the compound represented by formula (Ii) to the compound represented by formula Bc can be prepared as described below The compound represented by formula 3b can be prepared by treatment of the appropriately furictionalized compound represented by formula (11) with acid halogenating agent (e.g., only! chloride, thionyl chloride, l-chloro-N,N,2-trimethyl-l--propenyla.mine etc.) in an organic solvent (e.g, chlorofonn, dichioromethane, diethyl ether, tetrahydrofliran, dimethoxyethane, etc.) at a temperature from about -20 °C to the refluxing temperature, followed by reaction of the resultant acid halide with diazomethane or (trimethylsi1ydiazomethane in an organic solvent (e.g., chloroform, dichioromethane, hexane, diethyl ether, tetrahydrofuran, acetonitrile, etc.). The compound represented by formula 3c can be prepared by treatment of the compound represented by formula 3b with FIX (e.g., hydrochloric acid, hydrobromic acid etc.) in an organic solvent (e.g., chloroform, dichloromethane, hexane, diethyl ether, S 65 tetrahydrofliran, acetonitrile, etc.).
The reaction from the compound represented by formula 3c to the compound represented by formula (1-111-a) is an imidazole formation reaction. The intidazole formation reaction can be carried out by the same method as described in Reaction Scheme 1 above, The reaction from the compound represented by formula (I-Il-a) to the compound represented by formula (I-TI-b) is a halogenation reaction. The halogenation reaction can be carried out by the same method as described in Reaction Scheme 2.
4) The compound of formula (I) wherein Cyci represents 1,3,4-triazole ring, that is, a compound represented by formula (I-fl'): ar1 1?i
I I
)... CycS (R6)'t wherein all symbols have the same meaning described above, can be prepared as outlined in Reaction Scheme 4.
Reaction Scheme 4 R' ge' R' R" , Y H<OOH NH a,nwauon yj H'<ffØ + S r'L), (R"J, t3,4tnazole Matiflfl fr4-1 gL* Y''.i (Mv, wherein all symbols have the same meaning described above.
In Reaction Scheme 4, the reaction from the compound represented by formula (11) to the compound represented by formula 4b is an amidation reaction. The amidation reaction can be carried out by the same method as described in Reaction Scheme 1.
The reaction from the compound represented by formula 4b to the compound represented by formula (I-[V) is a 1,3,4-triazole formation reaction. The I,3,4-triazole formation reaction is well known. For example, the reaction cart be carried out by heating the compound represented by 4b in a suitable solvent such as acetic acid, xylene or toluene to give the compound represented by formula (LIV).
5) The compound of formula (I) wherein CycI represents pyridazinone ring, that is, a compound represented by formula (LV): 11 R I,2I Cyc3 wherein all symbols have the same meaning described above, can be prepared as outlined in Reaction Scheme 5.
Reaction Scheme 5 11-* -r' n3-' 1) ? )N'C p:-base 2) H,NNHR'1
YIN
(RIJJJ (I-',) wherein all symbols have the same meaning described above.
In Reaction Scheme 5, the reaction from the compound represented by formula (111) to the compound represented by formula 5a can be prepared as described below.
The compound represented by formula 5a can be prepared by treatment of the appropriately functionalized compound represented by formula (III) with dimethylinethyiphosphonate in the presence of base such as n-butyllithium in a solvent such as tetraliydrofuran.
The reaction from the compound represented by formula 5a to the compound represented by formula (LV) is a Horner-Wadsworth-Enimons reaction.
The Horner-Wadsworth-Emmons reaction is well known. For example, the compound represented by fonnula 5a and the compound represented by formula Sb in the presence of base such as potassium carbonate in a solvent such as ethanol or tetrahydrofüran gives an a, 13-unsaturated ketone derivative which can then be condensed with a suitably substituted hydrazine derivative represented by H2NNI-1R1 -t to give the compound represented by formula (t-V).
6) The compound of formula (I) wherein Cyc 1 represents a I,2,3-triazole ring, that is, a compound represented by formula (1-VI): iv-? (l)±N<C\N I'flh4) wherein all symbols have the same meaning described above, can be prepared as outlined in Reaction Scheme 6.
Reaction Scheme 6 na-i ga-I J. it v* NX( OH MeNHOMe reduction ()_ Y - 0 amId: Uoa 0 db base rile, na-' e' gfl Hnlsgea react:: (i-Vt) wherein all symbols have the same meaning described above.
In Reaction Scheme 6, the reaction from the compound represented by formula (II) to the compound represented by formula 6a is an arnidation reaction. The amidation reaction can be carried out by the same method as described in Reaction Scheme 1 using N,O-dirnethylhydroxylamine instead of the compound represented by formula ic.
The reaction from the compound represented by formula 6a to the compound represented by formula 6b can be prepared as described below.
The compound represented by formula 6b can be prepared by treatment of the appropriately thnctionalized compound represented by formula 6a with lithium aluminum hydride or diisobutylaluznithuni hydride in tetrabydrofiiran to give the compound represented by formula 6b.
The reaction from the compound represented by formula 6b to the compound represented by formula 6c can be prepared as described below.
The compound represented by formula 6c can be prepared by treatment of the ID appropriately functionalized compound represented by formula 6b with diinethyl (1-diazo-2-oxopropyl) phosphonate in the presence of base such as potassium carbonate in a solvent such as methanol.
The reaction from the compound represented by formula 6c to the compound represented by formula (I-VT) is a Fluisgen reaction. The Huisgen reaction can be prepared as described below.
The compound represented by formula (I-VT) can be prepared by treatment of tile appropriately functionafized compound represented by formula 6c and a suitably substituted compound represented by formula 6d in the presence of a copper (II) salt such as copper (IT) sulfate, an ascorbate such as sodium ascorbate and a base such as sodium hydroxide which on heating and/or microwave irradiation gives the compound represented by formula (I-VT).
7) The compound of formula (I) wherein Cyci represents 1,2,-oxazole ring, that is, a compound represented by formula (1-Vu): r R1 YN CycS (1)m.. (R't) wherein all symbols have the same meaning described above, can be prepared as outlined in Reaction Scheme 7.
Reaction Scheme? 0H -(W-1) A4' gt' R' )NkCOOH ____ YJNK
C II 7W
r' A'-' _____ (tI) Y*LN7c>c3 Cu powder 0 N Cu (IJ) salt Cyc2 (IV)!) wherein all symbols have the same meaning described above.
In Reaction Scheme 7, the reaction from the compound represented by formula S 7a to the compound represented by formula 7c can be prepared as described below.
The compound represented by formula 7c can be prepared by treatment of an appropriately functionalized compound represented by formula 7a with hydroxylainine hydrochloride in a solvent such as tert-butanol and water to provide the conesponding oxime compound represented by formula 7b, which can be converted to a nitrile oxide compound represented by formula 7c by treatment with an oxidant such as cliloramine-T trihydrate.
The reaction from the compound represented by formula (II) to the compound represented by formula 7d can be prepared by the same method as described in Reaction Scheme 6.
The reaction from the compound represented by formula 7d to the compound represented by formula (I-Vu) can be prepared as described below.
The compound represented by formula (I-Vu) can be prepared by combining the compound represented by formula 7c and the compound represented by formula ld in * 70 the presence of a copper (II) salt such as copper (TI) sulfate and copper powder in a solvent such as tert-butanol and water at a temperature from approximately 20 °C to the refluxing temperature with or without microwave irradiation.
8) The compound of formula (I-A) can be prepared from a compound represented by formula (TI-A) or a compound represented by formula (111-A) by Cyci ring formation reactions by the same methods described in Reaction Schemes I to 7. u
c1 dng katIon N R2; c3 Cyc (H1)* Pg (I-A) wherein all symbols have the same meaning described above.
The compound represented by formula (IT-A) and formula (111-A) wherein Y is C(H) and U is CH2, that is, a compound represented by formula (Il-A-I) and (Ill-A-I) respectively, can be prepared as outlined in Reaction Scheme 8. * 71
Reaction Scheme S 0 0 0 ? r-\, a_ps Pg Rb o (IV) a. Sc C"' OH 9 C\i OH HO decaffi esfer ft -0 sIlo,, I I oxytatlon depsa (action -. _.ç-__t0 Rd a. a, fRSI) Rs / a Q7-;1B....0_2 ON Leaving p1" )*ThK (VI) -rh,/Jo _ formation g)L0 surukl coupling Cyt2 cyc2 (V-I) (lilA-I) (IDA-I) - Pd catalyst
N
0% zukI coupIIg (Vu-I) wherein Lg represents Inflate, tosylate, chlorine or bromine and R8a represents C1-4 alkyl, R1 and Rn.2 represents hydrogen, or Ra and RB.2 may be taken together to form -C(CI-{3)2C(CH3)2-and the other symbols have the same meaning described above.
In Reaction Scheme 8, imidate formation of an appropriately protected compound represented by formula (IV) can be conducted by using alkylating agent such as trimethyloxonium tetrafluoroborate, triethyloxonium tetrafluoroborate or dimethyl sulfate in a solvent such as dichioromethane, acetonitrile or dimethyl carbonate or without a solvent to form an imidate compound represented by formula 8a.
Imidate compounds represented by formula Sa can be condensed with a suitably protected 1,3-acetonedicarboxylic acid represented by formula Sb in an organic base such as tniethylamine, N,N-diisopropylethylamine or N-meth'lmorpho1ine at a temperature from about 20 °C to the refluxing temperature to provide a diester compound represented by formula Sc.
The diester compound represented by formula 8c can be convened to the corresponding dicarboxylic acid represented by formula 8d by the same method as * 72 described above for the deprotection reaction of carboxy).
The decarboxylation of a dicarboxylic acid represented by formula Sd can be carried out by treatment with an acid such as hydrochloric acid or 2,4,6-trichiorophenol at reflux to give the carboxylic add represented by formula 8e.
The esterification of the compound represented by formula 8e can be conducted in a solvent such as methanol or ethanol in the presence of acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid at refluxing temperature to give the ester compound represented by fonnula Sf.
The ester compound represented by formula SI can be converted to the compound represented by formula (V-I) by treatment with trifluoromethanesulfonic anhydride, N-phenyltrifluoromethanesulfonimide, 2-ftJ,N-bis(trifluoromethanesulfonyi)amino]pyridine, p-toluenesulfonyl chloride, phosphorous oxychioride, phosphorous oxybromide at a temperature from about 0 °C to refluxing temperature in a solvent such as dimethylformamide or tetrahydrofuran or solvent-free in the presence of a base such as triethylamine or diisopropylethylamine or without base.
Suzuki coupling between a compound represented by formula (V-I) and an appropriateLy functionalized aryl boronic acid or ester compound represented by formula (VI) in the presence of a base such as anhydrous cesium carbonate, cesium fluoride, sodium carbonate or potassium phosphate in a solvent such as 1,4-dioxane, diniethylformamide or dimethytsulfoxide using a catalyst such as tetrakis(triphenylphosphine)palladium(0), 1,1 -bis(diphenylphosphino)fcrroccnc palladium(1I) chloride, palladiumØ ) acetate or bis(dibenzylidenacetone)pafladium(0), with or without a phosphine ligand such as triphenylphosphine, tri-t-butylphosphine or l,l-bis(diphenylphosphino)ferrocene at a temperature from about 70°C to the refluxing temperature provided the compounds represented by formula (111-A-I).
in cases where suitably substituted boronic acids or esters are not commercially available, the 4,4.5,5-tetramethyl-[1,3,2]dioxaborolane intermediate can be prepared from the corresponding aryl halide or aryl Inflate by a palladium mediated coupling with a diboron species such as bis(pinacolato)diboron using the method of lshiyama, I ci aT (I Org. Chern. 1995, 60(23), 7508). Alternatively, the corresponding boronic acid can be prepared by metal-halogen exchange of the aryl/hetercaryl halide, quenching with a trialkoxyborate reagent and aqueous workup to provide the boronic acids (Miyaura, N.; Suzuki, A. Client Review, 1995, 95. 2457). Alternatively, a compound represented by formula (V-I) can be convened to the corresponding 4,4,5,5-tetraniethyl- [1,3,2}dioxaborolane intermediate compound represented by formula (VII-I) by the same methods described above.
Suzuki coupling between a compound represented by formula (Vu-I) and an appropriately flinctionalized aryl halide or aryl triflate compound represented by formula (VIII) provided the compounds represented by forniula (Ill-A-I).
The compound represented by formula (Ill-A-I) can be converted to the compound represented by formula (lI-A-I) by the deprotection reaction as described above.
9) The compound represented by formula (11-A) and formula (111-A) wherein Y is N and U is CH2, that is, a compound represented by formula (Il-A-Il) and formula (lil-A-Il) respectively, can be prepared as outlined in Reaction Scheme 9.
Reaction Scheme 9 R -,. jmo-pg -H/I Pg I. I_2°0 IC OR, 1 Pg (Cç) OR., )I1TV-Pg -II' N _____. (R') C) (r'J_ 0 S.an.ki coupling y1> ° rion a (llI-A41) (li-AM 0 Suzuki coupling (%JJ4J) wherein X1 represents hydroxyl, chlorine or 0-4 alkoxy and the other symbols have the same meaning described above.
In Reaction Scheme 9, treatment of an irnidate compound represented by formula Sa with an ammonium salt such as ammonium chloride in a solvent such as ethanol at a temperature from about 20 °C to the refluxing temperature provides an amidine compound represented by formula 9a.
The amidine compound represented by formula 9a can be condensed with malonie acid derivatives represented by formula 9b such as mono-ethyl malonate or ethyl malonyl chloride by the same methods as described above for the amidation reaction to give the acylated arnidine intermediates, which then cyclize to provide a pyrimidinone compound represented by formula 9c.
The pyrimidinone compound represented by formula 9e can be converted to the compound represented by formula (Il-A-IJ) or formula (111-A-IT) by the same method described in Reaction Scheme 8.
Alternatively, the amidine compound represented by formula 9a can be condensed with a suitably substituted beta-ketoester cothpound represented by formula 9d in the presence of base such as triethylamine in a solvent such as toluene at a temperature from about 20 °C to the refluxing temperature to give the compound represented by formula (111-A-Il).
The compound represented by formula (111-A-Il) can be converted to the compound represented by formula (Il-A-Il) by the deproteetion reaction as described above.
10) The compound represented by formula (Il-A) and formula (Ill-A) wherein Y is CH and U is 5, that is, a compound represented by formula @1-A-In) and formula (lil-A-Ill) respectively, can be prepared as outlined in Reaction Scheme 10.
Reaction Scheme 10 * bc flu-A-Ill) (tJ-A4lI) wherein all symbols have the same meaning described above.
In Reaction Scheme 10, the compound represented by formula (Ill-A-ITT) can be prepared from acylated Meldrum's acid derivatives represented by formula lob, which are prepared from the compound represented by formWa ba using the method of Hans, E. et cii. (1 Org. CJ-iem. 2001, 66, 6756).
The compound represented by formula (Ill-A-Ill) can be converted to the compound represented by formula (H-A-Ill) by the deprotection reaction as described above.
11) The compound represented by formula (1-A) wheTein Y is CH or N and U is Cit2 or S and at least one of the R6 is CyclO, that is, a compound represented by formula (I-A-TV): (R'4) Cyc3 tyt wherein all symbols have the same meaning described above, can be prepared as outlined in Reaction Scheme 11.
Reaction Scheme 11 Ma_I I-v & OR,, V Pg a (V.4)or(V41) OR_,_______________________________ (WI, Swain coupling Ma-' a a u r' U1 r\,IR) -i (VN4)air (VIM') R WI un, a (VIII) W4j i'-'A jfl19) arpfla4fl) P Pp (PLA-l), fI1Aj!) or [fl_44SI N J Cr10 n,.aSoa I 4'tlO 1 Cyclofannatlo" Cyci u u R' ,, c sown cotrpflng) crc v A,a...nsvon (WU*) (W')_, {RslJ_4 (01.4-4% s Pg (I.A4ll Swuki toapilog Cr')-., win..) wherein R2 represents amine, fluorine, chlorine, bromine or iodine and the other symbols have the same meanings as described above.
In Reaction Scheme 11, CyclO can be constructed at the appropriate synthetic stage by Cyc 10 formation reaction. The Cyc 10 formation reaction can be prepared by the method described in Reaction Schemes 12 to 16 described below.
The reactions such as Suzuki coupling, Cyc I formation, etc. described in Reaction Scheme 11 can be prepared by the same methods as described above.
12) The compound represented by formula (I-A-IV) wherein Cyc2 is awl or hetcroaryl and CyelO is tetrazole ring which is attached to Cyc2 at the 1-position, that is, a compound represented by formula (I-A-IV-l): j3yca N -,>CyLL (W4A (R11) wherein all symbols have the same meaning described above, can be prepared as outlined in Reaction Scheme 12.
Reaction Scheme 12 Nfli j 311 AcOH -- (Wile!) (nil-br) (l-A-IV4) wherein all symbols have the same meaning described above.
In Reaction Scheme 12, an appropriately substituted aryl or heteroaryl amine represented by formula (VIII-a-I) can be converted to tetrazole compound represented by formula (VIII-b-I) by treatment with sodium axide and trimethylorthoformate or triethylorthoformate in acetic acid at a temperature from about 0 °C to 95 °C.
The compound represented by formula (VI1I-b-I) can be converted to the compound reptesented by formula (I-A-IV-I) by the same method as described in Reaction Scheme 11.
Alternatively, the tetrazole ring formation can be conducted at the appropriate synthetic stage using an intermediate having an aryl or heteroaryl amino group as shown in Reaction Scheme 11.
13) The compound represented by formula (I-A-IV) wherein Cyc2 is aryl or heteroaryl and CyclO is a 1,2,3-triazole ring which is attached to Cyc2 at the 1-position, that is, a compound represented by formula (I-A-[V-II): RI, N-N?< 1k tyc (R") (t')mi wherein all symbols have the same meaning described above, can be prepared as outlined in Reaction Scheme 13.
Reaction Scheme 13 a" Nfl N') ffJLo:.
( )_, (Mafl) (V1U-a-F) (VhJ.-U) (VIJI-b-IJJ Ii (l-A.1V41) wherein all symbols have the same meaning described above.
In Reaction Scheme 13, an appropriately substituted aryl or heteroaryl amine compound represented by formula (YIN-a-I) can be treated with sodium nitrite in the presence of acid such as hydrochloric acid in water to produce the corresponding diazonium salt, which can be treated with sodium azide in water to form the corresponding azide compound represented by formula (VIIl-a-II). Alternatively, an appropriately substituted aryl or heteroaryl amine compound represented by formula (VIII -a-I) can be converted to the corresponding azide compound represented by formula (VIIl-a-II) treatment with trimethylsilyl azide and tert-butyl nitrite in acetonitrile at a temperature from about 0 °C to 40 °C.
The azide compound represented by formula (V1II-a-1I) can be treated with the appropriately substituted alkyne in a solvent such as toluene at the refiuxing temperature to give I,2,3-triazole derivatives represented by formula (VllI-b-Jfl.
The compound represented by formula (V1ll-b-II) can be converted to the compound represented by formula (I-A-IV-Il) by the same method as described in Reaction Scheme II.
AlternativeLy, I,2,3-triazole ring formation can be conducted at the appropriate synthetic stage using an intermediate having an aryl or heteroaryl amino group as shown in Reaction Scheme II.
14) The compound represented by formula (I-A-IV) wherein Cyc2 is aryl or heteroaryl and CyclO is 4-ehloro-1,2,3-triazole attached to Cyc2 at the 1-position, that is. a compound represented by formula (I-A-IV-III): N-N OKC (R'1),, Cyc2 (R'4) (Rt-91 wherein all symbois have the same meaning described above, can be prepared as outlined in Reaction Scheme 14.
Reaction Scheme 14 nOb ,, C! "il N Lg Sn(nB.I N} chlorination W 9 (Wit-a-if) fVJIi-b.iIf) (VIlI-b-11f4) C, a Cyc2 (i-A -I V-i/i) wherein all symbols have the same meaning described above.
In Reaction Scheme 14, an appropriately substituted aryl or heteroaryl azide represented by formula (VIIl-a-II) can be treated with ethynyl-tri-n-butyltin in a solvent such as toluene at reflux to give the 4-tributystarmyl-1,2,3-triazole represented by formula (VIII-b-HJ).
The compound represented by formu)a (V1II-b-1I1-1) can be prepared from the precursor compound represented by formula (V1lI-b411) by treatment with N-chiorosuccinimide or 1,3 -dichIoro-5,5-dimethy1hydantoin in a solvent such as acetonitrile at a temperature from approximately 20 °C to reflux.
The compound represented by formula (VIII-b-TIl-I) can be converted to the compound represented by formula (I-A-TV-Ill) by the same method as described in Reaction Scheme 11.
Alternatively, 4-Chloro-l,2,3-triazole ring formation can be conducted at the appropriate synthetic stage using an intermediate having an aryl or heteroaryl amino group as shown in Reaction Scheme II.
15) The compound represented by formula (1-A-IV) wherein Cyc2 is aryl or heteroaryl and CyclO is a 1,2-pyrazole which is attached to Cyc2 at the 1-position, that is, the compound represented by formula (I-A-IV-IV): CYr4 H--_J k-' (R7'),, (ft&l) wherein R4'5 represents hydrogen or C1-4 alkyl and the other symbols have the same meaning described above, can be prepared as outlined iii Reaction Scheme 15.
Reaction Scheme 25 (W'j Cfl2 -(d1%.1 Cyct pa -S V-ft (VMS-a-SW) (VUS-b4W) wherein all symbols have the same meaning described above.
In Reaction Scheme 15, an appropriately substituted aryl or heteroaryl fluoride represented by formula (VI1I-a-1V) can be convened to the I,2-pyrazole compound represented by formula (VIII-b-IV) by treatment with the appropriately substituted 1, 2- pyrazole in the presence of a base such as cesium carbonate in a solvent such as N,N-dimethylacetamide at a temperature from approximately 20 °C to 100 °C.
The compound represented by formula (VIII-b-IV) can be converted to the compound represented by formula (I-A-IV-IV) by the same method as described in Reaction Scheme 11.
16) The compound represented by formula (I-A-IV) wherein CyclO represents 4-fluoro-1,2-pyrazole, that is, a compound represented by formula (I-A-IV-V): NTYJ%J ccy!t wherein all symbols have the same meaning described above, can be prepared as outlined in Reaction Scheme 16.
Reaction Scheme 16 (.9 -Lg --s-H (CYc1-fR'-') Cya Cyc2 Cyc2 (1).
(R), (R (I.A-W-V) 1 5 (WIll-b-lW-I) wherein all symbols have the same meaning described above.
In Reaction Scheme 16, the compound represented by formula (V1I1-b-IV-I) can be converted to the 4-fluoro-1,2-pyrazole compound represented by formula (VIII-b-IV- II) by treatment with a fluorinating agent such as 1-chloromethyl-4-fluoro--1,4-diazoniabicyelo[2.2.2]octane bis(tetrafluoroborate) in a solvent such as acetonitrile at a temperature from about 20 °C to 100 °C.
The compound represented by formula (VIII-b-1V-TI) can be converted to the compound represented by formula (I-A-IV-V) by the same method as described in Reaction Scheme 11.
17) The compound of formula (I-B) can be prepared as outlined in Reaction Scheme 17.
Reaction Scheme 17 R' e1 r' s 1) E,Setfonsatlon I 2) l.nving peap -O atfon 0. 0 0 HOO 19 0 . 0 -. 0 B 0 (V.$.) V-D.f) Sciiitk COMPIIJI9 (VI) r r.
L9 tZJN ° R R' r',k N)t\()
________ I
(J44) -(V111) - ° ________ cyct lan,,aUai, Suzuki cot*DIIatg (tlII.a) p11.0-7) N (11.0.1) 9 N j GvclO.B fonnation cS'clO-B frrmaticn cycoa ibnn.iMn t' R' r' (crcio.o II R cycf8 t iNi0 Susan caupang c1 4111114) (R')_, 1111.0-2) 0 Pg 11.0! (110.2) 0 H OR_, Suzuki Coupling (Wa-b) wherein all symbols have the same meaning described above.
In Reaction Scheme 17, an appropriately substituted 4-hydroxy-2-pyrone derivative 17a can be treated with a suitably substituted amino acid derivative 17b in the presence of alkali such as sodium hydroxide or potassium hydroxide in water at a temperature from about 20 °C to reflux to give the carboxylic acid compound represented by formula 17c.
The carboxylic acid represented by formula I 7c can be converted to the contsponding ester compound represented by formula (V-B-I) by ester formation and leaving group formation as described previously. The ester compound represented by formula (V-B-i) can be converted to the compound represented by the formula (I-B) by the method as described above.
18) The compound of formula (1-C) can be prepared as outlined in Reaction Scheme 1 8.
Reaction Scheme 18 OR., (cvc1o ° OR.a ?c2 A' N as.r,,J tOjFSjfr N N C, I IX Ir' *V N CYCle-Cf fltSWIiltfclO.C N N -in r' d11fl cyt7O.CTOrmaCJofl( uwn jr itb o.
A', ,,.. , r' r' -," Cycle-C (I n.e-f (Io.c.q r'_, S wherein all symbols have the same meaning described above.
In Reaction Scheme iS, appropriately substituted boronic ester derivative srepresented by formula NI-a), which are commercially available or can be prepared by the method described above, can be convened to a 4-aryl-6-chloropyrimidine compound represented by formula iSa using the 2,4-dichloropyrimidine derivative represented by formula IX by a Suzuki coupling reaction as described above.
4-AryI-6-chloropyrimidine compounds represented by formula I Sa can be hydrolyzed to 4-aryl-pyriinidinone compounds represented by forniu1a lSb by treatment with an acid such as hydrochloric acid at a temperature from approximately 20 °C to refiux.
4-Aryl-pyrimidinone compounds represented by formula I 8b can be convened to the ester compounds represented by formula (Ill-C-I) by treatment with alkylating agents represented by the formula I Sc by the same method as described above, The ester compound represented by formula (111-C-I) can be converted to the compound represented by the formula (111-C-Il) by a CyclO-C formation reaction. The Cyc 10-C formation reaction can be carried out by the same method as described previously.
The compound represented by formula (Ill-C-Il) can be converted to the compound represented by formula (I-C) by the same method as described above for the Cyci formation reaction.
The compounds of the present invention can be prepared by the reactions or modified variants of the reactions described above.
Other starting compounds or compounds used as reagents are known compounds which can be prepared easily by a combination of known methods, for example, the methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Willey & Sons mc, 1999) or Elmer J. Rauckman et a!., J. Org. Chem., vol.41, No.3, 1976, p564-565 etc. In each reaction of the specification, the reactions with heating, as will be apparent to those skilled in the art, may be carried out using a water bath, an oil bath, a sand bath, a heating block or by microwave.
In each reaction of the specification, a solid phase reagent may be used which is supported by a polymer (for example, polystyrene, polyacrylamide, polypropylene or polyethyleneglycol etc.).
In each reaction of the specification, the products obtained may be purified by conventional techniques. For example, the purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography with silica gel or magnesium silicate, by thin layer chromatography, by ion-exchange resin, by scavenger resin, by colunm chromatography, by washing, trituration or recrystallization. The purification may be carried out after each reaction stage or after several reaction stages.
In a reaction of the specification where polystyrene resin is used, the obtained products may be purified by conventional techniques. For example, the purification may be carried out by multiple washing with a solvent (for example, dimethylformamide, dichloromethane, methanol, tetrahydroffiran, toluene, acetic acidltoluene, etc.).
TOXICITY: The toxicity of the compound represented by formula (I), the salt thereof, the N-oxide thereof or the solvate thereof, or the prodrug thereof is very low and therefore it may be considered safe for pharmaceutical use.
S APPLICATION TO PHARMACEUTICALS: The compounds of the present invention are therapeutically useful. The present invention therefore provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, for use in the treatment of the human or animal body by therapy.
Also provided is a pharmaceutical composition comprising a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof or a pmdrug thereof, and a pharmaceutically acceptable carrier or diluent.
Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention. Preferred pharmaceutical compositions are sterile and pyrogen free.
Further, the pharmaceutical compositions provided by the invention typically contain a compound of the invention which is a substantially pure optical isomer.
The compounds of the present invention may normally be administered systemically or locally, usually by oral or parenteral administration.
A therapeutically effective amount of a compound of the invention is administered to a patient. The doses to be administered are determined depending upon, for example. age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment. In the human adult, the doses per person are generally from 2 tug to 1000 rug, by oral administration, up to several times per day, and from I mg to 100 mg, by parenteral administration (preferably intravenous administration), up to several times per day, or continuous administration from 1 to 24 hours per day from vein.
As mentioned above, the doses to be used depend upon various conditions.
Therefore, there are eases in which doses lower than or greater than the ranges specified above may be used.
The compounds or pharmaceutical compositions of the present invention may be administered for example, in the form of a solid for oral administration, liquid forms for oral administration, injections, liniments or suppositories for parenteral administration.
Preferably, the compounds or pharmaceutical compositions of the present invention are administered orally.
Solid forms for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules. Capsules include hard capsules and soft capsules.
In such solid forms, one or more of the active compound(s) may be admixed with vehicles (such as lactose, mannitol, glucose, microcrystalline cellulose or starch), binders (such as hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate). disintegrants (such as cellulose calcium glycolate), lubricants (such as magnesium stcarate), stabilizing agents, solution adjuvants (such as glutamic acid or aspartic acid, disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures, dyeswffs, sweeteners, wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical fonnulations, and prepared according to methods well known in normal pharmaceutical practice, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes. The solid forms may, if desired, be coated with coating agents (such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. Furthermore, coating may include containment within capsules of absorbable materials such as gelatin.
Liquid forms for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs. In such forms, one or more of the active compound(s) may be dissolved, suspended or emulsified into diluent(s) commonly used in the art (such as purified water, ethanol or a mixture thereof). Besides such liquid forms may also comprise some additives, such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, aroma, preservative or buffering agent. The syrups may contain as caniers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methyiccllulose, carboxymethylcellulose, or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
Solutions for injection or infusion may contain as carder, for example. sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
Injections for parenteral administration include sterile aqueous, suspensions, emulsions and solid forms which are dissolved or suspended into solvent(s) for injection immediately before use. In injections, one or more of the active compound(s) may be dissolved, suspended or emulsified into solvent(s). The solvents may include distilled water for injection, saline, vegetable oil, propylene glycol, polyethylene glycol, alcohol such as ethanol, or a mixture thereof. Injections may comprise some additives, such as stabilizing agents, solution adjuvants (such as gluta.mic acid, aspartic acid or POLYSURBATE8O (registered trade mark)), suspending agents, emuLsifying agents, soothing agent, buffering agents, preservative. They may be sterilized at a final step, or may be prepared according to sterile methods. They may also be manufactured in the form of sterile solid forms such as freeze-dried products, which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before use.
Other forms for parenteral administration include liquids for external use, ointments and endermic liniments, inhalations, sprays, suppositories and vaginal suppositories which comprise one or more of the active compound(s) and may be prepared by methods known per se.
Sprays may comprise additional substances other than diluents, used commonly, stabilizers such as sodium hydrogensulfite and buffers capable of imparting isotonicity, for example, isotonic buffers such as sodium chloride, sodium citrate or citric acid.
EFFECT OF THE INVENTION: The compounds of the present invention represented by formula (I) act as potent and selective inhibitors of Factor XIa, with good oral availability. In particular, the compounds of the present invention act as a Factor XIa inhibitor or a Factor XIa and plasma kallikrein dual inhibitor. Thus the compounds of the present invention are * 87 useflul in preventing andlor treating thromboembolic diseases. One advantage of the compounds of the present invention is that they can provide high inhibitory activity against FXIa and high plasma exposure level after oral administration.
The present invention therefore provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, for use in treating or preventing a thromboembolic disease.
Also provided is a method for treating a patient suffering from or susceptible to a thromboembolic disease, which method comprises administering to said patient an effective amount of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt (hereof, an N-oxide thereof, a solvate thereof or a prodrug thereof Further provided is the use of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, in the manufacture of a medicament for use in treating or preventing a thromboembolic disease.
The thromboembolic disease may be, for example, selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolie disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders and thromboembolic disorders in the chambers of the heart or in the peripheral circulation.
More specifically, arterial cardiovascular thromboembolic disorders may be exemplified by coronary artery disease, isehemic cardiomyopathy, acute coronary syndrome, coronary arterial thrombosis, ischemic complications of unstable angina and non-Q-wave myocardial infarction, acute ST-segment elevation myocardiai infarction managed medically or with subsequent percutaneous coronary intervention, angina pectoris such as stable effort angina pectoris, variant angina pectoris, unstable angina pectoris, myocardial infarction (e.g. first myocardial infarction or recurrent myocardial infarction), acute myocardial infarction, reocclusion and restenosis after coronary artery bypass surgery, reocciusion and restenosis after percutaneous transluminal cardiac angioplastyl transluminal coronary artery stent placement surgery or after thrombolytic therapy for coronary artery, ischemic sudden death. Venous cardiovascular thromboembohc disorders may be exemplified by deep vein thrombosis (DVT) and/or S 88 pulmonary embolism (PB) in rnaj or general surgery, abdominal surgery, hip replacement surgery, knee replacement surgery, hip fracture surgery, multiple fracture, multiple injury, trauma, spinal cord injury, bums, critical care unit, DYT andlor PB in medical patients with severely restricted mobility during acute illness, DVT and/or PB in patients with cancer chemotherapy, DVT and/or PE in patients with stroke, symptomatic or asymptomatic DVT with or without PB, pulmonary embolism. Arterial cerebrovascular thromboembolic disorders may be exemplified by stroke, ischemic stroke, acute stroke, stroke in patients with non-valuvelar or valuvelar atrial fibrillation, cerebral arterial thrombosis, cerebral infarction, transient ischemic attack (TIA), lacuna infraction, atherosclerotic thrombotic cerebral infarction, cerebral artery embolism, cerebral thrombosis, cerebrovascular disorder, asymptomatic cerebral infarction.
Venous cerebrovascular thromboembolic disorders may be exemplified by intracranial venous thrombosis, cerebral embolism, cerevral thrombosis, sinus thrombosis, intracranial venous sinus thrombosis, cavernous sinus thrombosis. Thromboembolic disorders in the chambers of the heart or in the peripheral circulation may be exemplified by venous thrombosis, systemic venous thromboembolism, thrombophiebitis, non-valuvelar or valuvelar atriat fibrillation, disseminaed intravascular coagulopathy (DIC), kidney embolism, atherosclerosis, atherothrombosis, peripheral artery occlusive disease (PAOD), peripheral arterial disease, arterial embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface (such as catheters, starts, artificial heart valves, or hemodialyzer) that promotes thrombosis.
Preferably, the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction (e.g. first myocardial infarction or recurrent myocardial infarction), ischeniic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial discase, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface (such as catheters, starts or artificial heart valves) that promotes thrombosis.
The compounds of the present invention may also be administered in combination with one or more further therapeutic agents. Thus, in another embodiment, the present invention provides a method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount S of a first and second therapeutic agent, wherein the first therapeutic agent is a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, and the second therapeutic agent is at least one agent selected from a second factor XIa inhibitor, an anti-coagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, and a fibrinolytic agent. Preferably, the second therapeutic agent is at least one agent selected from warfarin, unfraetionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, disulfatohirudin, lepirudin, bivalirudin, desirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, prasugrel, ticagrelor, elinogrel, cilostazol, sarpogrelate, iroprost, beraprost, limaprost, tirofiban, eptifibatide, abciximab, melagatran, ximelagatran, dabigatran, rivaroxaban, apixaban, edoxaban, darexaban, betrixaban, TAK-442, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase. Preferably, the second therapeutic agent is at least one anti-platelet agent. Preferably, the anti-platelet agent(s) are clopidogrel, prasugrel ticagrelor, elinogrel, cilostazol, sarpogrelate, iroprost, beraprost, limaprost and/or aspirin, or a combination thereof. The present invention also provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereoL an N-oxide thereof, a solvate thereof or a prodrug thereof, in combination with a second therapeutic agent selected from those listed above, for use in treating or preventing a thromboembolic disease. The present invention also provides the use of a compound of formula (1), as defined above, or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for use in treating or preventing a thromboembolic disease.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof an N-oxide thereof, a solvate thereof or a prodrug thereof and an additional therapeutic agent. Preferably, the further additional therapeutic agent(s) are selected from potassium channel openers, potassium channel blockers, calcium channel blockers, sodium hydrogen exchanger inhibitors, antiarrhytbmic agents, antiatheroscierotie agents, anticoagulants, antiplatelets, antithrombotic agents, prothrombolytic agents, fibrinogen antagonists. diuretics, antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor antagonists, phospodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis modulators, antiosteoporosis agents, hormone replacement therapies, hormone receptor modulators, oral contraceptives, antiobesity agents, antidepressants, antianxiety agents, antipsychotic agents, antiproliferative agents, antitumor agents, antiutcer and gastroesophageal refiux disease agents, growth hormone agents andfor growth hormone secretagogues, thyroid mimetics, anti-infective agents, antiviral agents, antibacterial agents, antifungal agents, cholesterol/lipid lowering agents and lipid profile therapies, and agents that mimic ischcmic preconditioning andlor myocardial stunning, or a combination thereof.
Tn another embodiment, the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s) selected from an anti-arrhythniic agent, an anti-hypertensive agent, an anti-coagulant agent, an anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, a fibrinolytic agent, a calcium channel blocker, a potassium channel blocker, a cholesterol/lipid lowering agent, or a combination thereof.
In another embodiment, the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s) selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaceharide, hirudin, disulfatohirudin, lepirudin, bivalirudin, desirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, prasugrel, ticagretor, elinogrel, cilostazol, sarpogrelate, iroprost, beraprost, limaprost, tirofiban, eptifibatide, abciximab, melagatran. ximelagatran, dabigatran, rivaroxaban, apixaban, edoxaban, darexaban, betrixaban, TAK-442, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase, or a combination thereof.
In a preferred embodiment, the present invention provides a pharmaceutical composition wherein the additional therapeutic agent is an antihypertensive agent 9' selected from ACE inhibitors, AT-I receptor antagonists, beta-adrenergic receptor antagonists, ETA receptor antagonists, dual ETAIAT-l receptor antagonists, and vasopepsidase inhibitors, an antiarrythmic agent selected from IKur inhibitors, an anticoagulant selected from thrombin inhibitors, antithrombin-Hl activators, heparin co-factor II activators, other factor XIa inhibitors, other kallikrein inhibitors, plasminogen activator inhibitor (PAl-i) inhibitors, thrombin activatable fibrinolysis inhibitor (TAFT) inhibitors, factor Vila inhibitors, factor IXa inhibitors, factor XIIa inhibitors and factor Xa inhibitors, or an anti-platelet agent selected from GPIIIIIIa blockers, protease activated receptor (PAR-1) antagonists, PAR-4 antagonists, phosphodiesterase-IJI inhibitors, P2Y1 receptor antagonists, P2Y12 antagonists, thromboxane receptor antagonists, cyclooxygcnse-1 inhibitors, glycoprotein VI (GPVI) antagonists, glycoprotein lb (GPIb) antagonists, Growth antst-specific gene 6 product (Gasó) antagonists and aspirin, or a combination thereof.
In a preferred embodiment, the present invention provides a pharmaceutical composition, wherein the additional therapeutic agent(s) are an anti-platelet agent or a combination thereof
BEST MODE FOR CARRYING OUT THE NVENTION
The present invention is illustrated by the following Examples and biological Examples, but it is not limited thereto.
The run time, solvents and column conditions used in the LC/MS analysis of the following Examples is reported using a superscript a, b, c or d appended to the analytical results which corresponds to the following conditions: a. 3 minute run time; 0.1% formic acid in water and 0.1% formic acid in acetotiitrile as mobile phascs, Waters Atlantis® dC 18, 2.1 nun x 50 mm, 3 pm column b. 7 minute run time; 0.1% formic acid in water and 0.1% formic acid in acetonitrile as mobile phases, Waters Atlantis® dC 18, 2.1 mm x 100 mm, 3 pm column c. 4.5 minute run time; 0.1% formic acid in water and 0.1% formic acid in acetonitrile as mobile phases, Waters Atlantis® dClS, 3 nun x 50 mm, 3 pm column S 92 d. 6 minute mn time; 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile as mobile phases, Waters Xterra® MS C18, 3 mm x 50 mn', S tm column The solvents in the parentheses described in chromatographic separation and TLC show the eluting or developing solvents, and the ratios of the solvents used are given as percentage mixtures in chromatographic separations or TLC. Where a compound is described as dried either anhydrous magnesium or sodium sulphate was used. The solvents in the parentheses in NMR show the solvents used in measurement.
DMSO represents dhnethylsnlfoxide; CDCI3 represents deuterated chloroform. The following abbreviations are used in reporting the H NMR spectra: s (singlet), d (doublet), t (triplet), q (quartet), br. (broad), app. (apparent), ohs. (obscured).
Including compounds in the following Examples, compounds used in the present specification were commonly named using a computer program capable of naming in accordance with IUPAC rules; ACDfNaxne® manufactured by Advanced Chemistry Development Inc., Jchem for Excel or MarvinSketch manufactured by ChemAxon Ltd., or EUPAC nomenclature. In each of the following Examples, the name of the objective compound of the Example is described subsequently to the number of the Example, and the compound is sometimes referred to as the "title compound".
Example 1: ethyl ($5-rnethoxy-3,4-dihydro-2H-pyrrole-2-carboxylate C02E* To a dicifloromethanc (500 mL) solution of ethyl 5-oxo-L-prolinate (51.2 g) was added trimethyloxonium tetrafluoroborate (50.5 g) and the mixture was stirred at room temperature for 3 hours. To the cookd (0 °C) reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate (350 mL) and water (50 mL) was added sequentially followed by extraction with dichioromethane. The combined organic layers were dried and concentrated giving the title compound having the following physical properties (42.2 g).
TLC: Rf 0.50 (ethyl acetate) Example 2: 3-ethyl 8-methyl (3S)-7-hydmxy5-oxo-l,2,3,5-tetrahydroindolizine-3.8-dicarboxylate 0.-CO2Et The compound prepared in Example 1(42.2 g) was combined with ditnethyl 3-oxopentanedioate (42.9 g) and thethylamine (2.40 mL) and the mixture was stirred at °C for 3 hours. On cooling, this gave the crude title compound having the following physical properties (85.6 g).
LC/MS tR 1.55 minutes; MS (ES) ,n/z282(M.fH)a Example 3: (38)-7-hydroxy-5-oxo-I,2,3,5-tetrahydroindolizine-3,8-dicarboxylic acid HO2C
N no N
To the compound prepared in Example 2 (150.9 g), 2 M sodium hydroxide (1130 mL) was added and the mixture was stirred overnight at room temperature. To the reaction mixture, an aqueous solution of 6 M hydrochloric acid was added and the solid removed by filtration. The filter cake was washed sequentially with water and dichioromethane then dried under vacuum. The filtrate was concentrated to 850 mL and iS the solid removed by filtration. Washing and drying of the filter cake as detailed above gave the title compound in two batches having the following physical properties (31.7 g).
LCIMS t 0.50 minutes; MS (ES) in/z 240 (M+H) a Example 4: (3S)-7-hydroxy-5-oxo-1,2.3,5-tetrahydroindolizine-3-carboxylic acid CO2H To the compound prepared in Example 3 (31.7 g), 6 M hydrochloric acid (1140 inL) and 12 M hydrochloric acid (200 mL) were added sequentially and the mixture stined at 140 °C for 20 hours. The reaction mixture was concentrated and the solid azeotroped with toluene to dryness giving the title compound having the following physical properties (29.1 g).
LC/MS tR 0.63 minutes; MS (ES) rn'z 196 (M+H) a Example 5jcthyj (3S)-7-hvdroxy5-oxo-1,2.3.5tetrjyçftpjndoie-3-carboxylate -. cop To an ethanol (115 mL) suspension of the compound prepared in Example 4 (29 g), concentrated sulfUric acid (0.96 mL) was added and the mixture was stirred at 100 °C for 4 hours. The reaction mixture was concentrated to give the title compound having the following physical properties (29.4 g).
LCIMS tR 1.21 minutes; MS (ES) ,nk 224 cM4H)a Example 6: ethyl (3S)-5-oxo7-ftthfluoromethy1)sulpyfloxy}-1.2,3. 5-tetrzjyQjndoIizine-3-carboxylate ff N CO2Et Fts o'_L0 To an N.N-dimethylformamide (190 niL) solution of the compound prepared in Example 5 (29.4 g), triethylamine (21.2 mL) and 1,1.lifluoroN-phenyl-N [(trifluoromethyi)sulfonylmethanesWfonaniide (49.4 g) were added sequentially and the mixture stirred at room temperature for 1 hour. To the reaction mixture, water (400 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (20 to 50% ethyl acetate in heptanes) to give the title compound having the following physical properties (31.3 g).
LC/MS 1R 1.89 minutes; MS (ES) m/ 356 (M+H)a Exanjple 7: ethyl (38 742amino-5-chlojphenyIE5-oxo-I,2trthydroindoIizine- 3-carboxylate irH2
CI
To a 1,4-dioxane (625 nit) solution of the compound prepared in Example 6 (31.3 g) were added 4-chloro-2-(4,4,S,5-tetramethyl-I,3,2-dioxaborolan-2-yl)aniline (22.4 g) and caesium fluoride (33.5 g) under an atmosphere of nitrogen. The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium(0) (2.6 g) added and the reaction mixture stirred at 105 °C for 30 minutes. To the reaction mixture, water (700 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (25% to 100% ethyl acetate in heptanes, then ito 5% methanol in ethyl acetate) to give the title compound having the following physical properties (24.3 g).
LC/MS tR 1.87 minutes; MS (ES) m/z 333 (M+I-1)3 Example 8: (3S)-7-(2-amino-5-chlorophenyl)-5-oxo-1,2,3, 5-tetrahydroindolizine-3-carboxylic acid NH2 IJ1I?_CO2H Cl To a methanol (120 xnL) solution of the compound prepared in Example 7(12 g), 2 M sodium hydroxide (72 mL) was added and the mixture stirred at room temperature for 4 hours. The methanol was removed under reduced pressure and 2 M hydrochloric acid added until the solution was pH 4. The solution was extracted with ethyl acetate followed by a 1:1 mixture of 2-propanol and chloroform and the combined organic layers were dried and concentrated to give the title compound having the following physical properties (10.1 g.
LC/MS 1R 1.58 minutes; MS (ES4) m, 305 (M-i-H) a S Exampk 9: (35)-7-[5-chloro-2-(1 H-I,2,3,4-tetrazol-I -yflphenyl]-5-oQj23,5-tetrahydroindolizine-3 -carboxylic acid CO2H C' To a glacial acetic acid (150 niL) solution of the compound prepared in Example 8(9.3 g) was added trimethyl orthoformate (10 mL) followed after 30 minutes by sodium azide (5.93 g). The mixture was stirred at room temperature for 16 hours.
Further tdmethyl orthoformate (1.7 mL) and sodium azide (1.0 g) was added and the mixture was stirred at room temperature for a further 16 hours. To the cooled (0 °C) reaction mixture, a solution of sodium nitrite (5.32 g) in water (50 mL) was added dropwise over 30 minutes and the mixtire stined at 0 °C for a further hour followed by extraction into ethyl acetate. The combined organic Sayers were washed with water and brine, dried and concentrated. The residue was azeotroped with toluene to give the title compound having the following physical pmperties (10.9 g).
LCIMS tR 1.54 minutes; MS (ES) rn/z 358 (M+H)a
Example
I,2,3.5-tetrahydroindoliiine-3-carboxylate To a tetrahydrofuran (220 niL) solution of the compound prepared in Example 7 (10 g) was sequentially added di-ren-butyl dicarbonate (14.7 g), triethylamine (8.2 niL) and 4-dimethylaminopyridine (073 g) and the mixture was stirred at 61) °C for 2 hours. To the reaction mixture, saturated aqueous potassium hydrogen sulfate solution (400 niL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to obtain the tide compound having the following physical properties (16.8 g).
1JCIMS fg 2.29 minutes; MS (ES) nil: 555 (M+Na), 533 (M+H), 433 (M-CO2C(CH3)3+H)8 Example 11: (38)-7-(2-{ [(tert-butaxy)cy1lamino}-5-ch1oropheny1)-5-oxo-1,2,3, 5-tetrahydroindolizine-3-carboxylic acid To a methanol (80 mL) solution of the crude compound prepared in Example tO (17.6 g) was added 2 M sodium hydroxide (66 mL) and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated and the residue dissolved in water (200 niL) followed by extraction with dichioromethane. To the aqueous layer, 2 M hydrochloric acid (66 mL) was added followed by extraction into ethyl acetate. The combined ethyl acetate layers were washed with brine, dried and concentrated to obtain the title compound having the following physical properties (12.1 g).
LcIMS z I £5 minutes; MS ES) tn/z 405 M+}l) a Example 12: 7-hydroxy-5-oxo-1,2,3,5-tetrahydroindolizine-3-carboxylic acid To a stirred melt of 2,4,6-thch(orophenol (98.2 g) at IOU °C was added the compound prepared in Example 3(29.7 g). The mixture was heated slowly to 180°C whilst gas evolution occurred. The reaction mixture was maintained at 180 OC for 48 hours before cooling to room temperature and suspending the residue in dichloromethane (200 mL). The solid was collected by filtration and added to a second melt of 2,4,6-trichlorophenol (98.2 g) at 100 "C. The reaction mixture was stirred at 180 "C for a further 24 hours before cooling to room temperature and suspending the residue in dichloromethane (200 mL). The solid was collected by filtration to afford the title compound having the following physical properties (24.3 g).
1H NMR (500 MHz, DMSO-d6) ö 10.53 (br. s, 1 H), 5.82 (s, 1 H), 5.43 (d, I H), 4.78 (dd, I H), 2.98 (dd, 2 1-1), 2.46-2.37 (in, I H), 2.16-2.05 (m, I I-fl.
Example 13; etbyl-7-hydroxy-5-oxo-1,2.3,5-tetrahydroindolizine-3-carboxylate The compound prepared in Example 12(18.9 g) was treated as detailed in Example S to give the title compound having the following physical properties (21.5 g).
LCIMS R 1.19 minutes; MS (Est) m/z 224 (M+H) A Example 14: ethyl-5-oxo-7-{J(gjftuoromethyOsulfonv11oxy}-1.2,3,5-tetraydroindo1izine-3 -carboxylate The compound prepared in Example 13 (20 g) was treated as detailed in Example 6 to give the title compound having the following physical properties (31.8 g).
LC/MS R 1.29 minutes; MS (ESt) rn/z 356 (M+H) a Example 15: ethyl-7-(2-amino-5-chlorophenyfl-5-oxo-l,2,3,5-tctrahydroindolizine-3-late The compound prepared in Example 14(25.1 g) was treated as detailed in Example 7 to give the title compound having the following physical properties (23.8 g).
LCIMS R 1.81 minutes; MS (ES) rn/i 333 (M+H)8 nipie16:7-2-amino-5-cMorohenl-S-oxo-1,Z3, 5-tetrahydroindoiizine-3-carboxylic acid The compound prepared in Example 15 (2.0 g) was treated as detailed in Example 8 to give the title compound having the following physical properties (1.83 g).
LC/MS 1R 1.56 minutes; MS (13St) in': 305 (M+H) a Example 17: 7-[5ch1oro-24lH-1,2,3,4-tetrazol-1-y1)pheny11-5-Qj2.3, 5-tetrahvdroindolizine-3-carboxylic acid The compound prepared in Example 16 (1.28 g) was treated as detailed in Example 9 to give the title compound having the following physical properties (1.17 g).
LC/MS (g 1.54 minutes; MS (ES) in,': 358 (M+H) a Exampj&eth17-(2-Jis{(tert-butoxy)carbony11amino} -5-chlorophenyl)-5-oxo-I,2,3,5-tetrahydroindolizine-3-carboxylate The compound prepared in Example 15 (21.8 g) was treated as detailed in Example 10 to give the crude title compound having the following physical properties (32.9 g).
LC/MS i 2.30 minutes; MS ES) rn/i 535 (M+Na). 533 (M+H), 433 (M-CO2C(CH3)3+H) a Example 19: 7-(2-( f(tert-butoxycarbonylJ4jgJ-5-cWompheuvfl-5-oxo-1.2,3, 5-tetrahydroindolizine-3 -carboxylic acid The compound prepared in Example 18 (32.9 g) was treated as detailed in S Example Ill to give the title compound having the following physical properties (20.5 g.
LC/MS R 1.84 minutes; MS (ES4) rn/i 405 (M+Na) a Example 20: tert-butyl 2-{4-(benzy1oxy)2-oxo-I,2dihydropyridin-l -vilacetate To atetrahydrofuran (lOt) mL) solution of 4-benzyloxypyridone (25 g), potassium tert-butoxide (15 g), tetrabutylanmonium bromide (2 g) and tert-butyl bromoacetate (18 niL) was sequentially added and the mixture was stirred at room temperature for 48 hours. To the reaction mixture, water (500 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to give the title compound having the following physical properties (35 g).
LCiMS 1.96 minutes; MS (ES4) m/z 316 (MI-H) a amp1e21jtert-buty1 2-[4-hydroxy-2-oxo-1,2-dihydropyridin-1 -yllacetate To an ethanol (300 mL) solution of the compound prepared in Example 20 (20 g) was added 5% palladium-carbon (4.05 g) and the mixture was stirred under an atmosphere of hydrogen for 4 hours. The reaction mixture was then filtered through Celite® and the filtrate was concentrated to give the title compound having the following physical properties (14.3 g).
LC/MS ta 1.42 minutes; MS (ES4) rn/i 226 (M+H) a Example 22: tert-y-2-oxo4jflromethane)suIfonyloy]-I,2-dihydropyridin-kyl}acetate The compound prepared in Example 21(14.3 g) was treated as detailed in Example 6 to give the title compound having the following physical properties (16.2 g).
LCIMS ta 1.97 minutes; MS (ES4) rn/i 301 (M-C(CH3)3+H)° Example 23: tert-butyl 2-[4-(2-amino-5-chlorophenyl)-2-oxo-1jh dropyridin-1-ate The compound prepared in Example 22 (6.4 g) was treated as detailed in Example 7 to give the title compound having the following physical properties (7.0 g).
LC/MS tR 1.95 minutes; MS (ES) m/r335 (M+H)1 Example 24: tert-butyl 2-4-l5-chloro-2fl234-teto1-fljphejfl2-oxo-l,2-dihydropyridin-l -yl} acetate To a glacial acetic acid (100 mL) solution of the compound prepared in Example 23 (7.0 g) was added trimethyl orthoformate (6.9 niL) followed after 30 minutes by sodium azide (4.1 g) and the mixture stirred at room temperature for 16 hours. To the reaction mixture, water (100 mL) was added followed by extraction into ethyl acetate.
The combined organic layers were washed with water and saturated brine, dried and concentrated. The residue was purified by column chromatography (50 to 100% ethyl acetate in heptanes) to give the title compound having the following physical properties (6.5 g).
LCtMS ig 1.90 minutes; MS (ES) m/z 410 (M+Na) a Examule 25: 2-{4-(5-chloro-2-(1 H-I.2,3.4-tetrazol-lyflphenyl}-2-oxo-1,2- çjjjy4ropyridin-1-yl} acetic acid To a 1,4-dioxane solution (100 mL) of the compound prepared in Example 24 (6.5) was added I M hydrochloric acid (84 mL) and the mixture was heated at 90 °C for 3 hours. The reaction mixture was concentrated to appmxiinately half the original volume and the resultant precipitate collected by filtration to give the title compound having the following physical properties (4.1 g).
LCIMS 1R 1.48 minutes; MS (ES) m1z 332 (M+1-1) a Example 26: tert-butyl 2-[4-(benzy1oy)-2-oxo-l,2-dihydroyyridin-l -yl13-phenylpropanoate To a cooled (-78 °C) tetrahydrofuran (150 mL) solution of the compound prepared itt Example 20(15.3 g) was added benzyl bromide (7.76 niL) followed by a 1 M solution of lithium hexamethyldisila2ide in tetrahydrofuran (52.2 mL) and the mixture was stirred at -78 °C for 90 minutes. To the cooled (-78 °C) reaction mixture, a saturated aqueous solution of ammonium chloride (150 mL) was added followed by water (150 mL) and the mixture was allowed to warm to room temperature, then extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (10 to 30% ethyl acetate in heptanes) to give the title compound having the following physical properties (11.8 g).
LC/MS g 2.39 minutes; MS (ESt) jn/z 406 (M-{-H) Example 27: 2-(4-[5chIoro-24JH-l,2.3,4-tetrazoh.l -yl)phenyfl-2-oxo-l,2-The same operation as in Example 21 -+ Example 22 -. Example 23 Example 24 -t Example 25 was conducted from the compound prepared in Example 26 to give the title compound having the following physical properties.
LC/MS tR 1.84 minutes; MS (ESt) rn/z 422 (M+H) a Example 28: methyl (2S)-2-144benzy1oxy)-2-oxopyridin-lyijeny1propanoate To a tetrahydrofuran (70 mL) solution of 4-benzyloxypyridone (10.8 g), potassium tert-butoxide (6.64 g) and tetrabutylammonium bromide (0.87 g) were added sequentially and the mixture was stirred at room temperature for 30 minutes. To the cooled (0 °C) reaction mixture, a tetrahydrofliran (70 mL) solution of methyl (2R)-3-phenyl-2-{ [(trifluoromethyl)-sulfonyl]oxy}propanoate [Tetrahedron 51(38), 10513 (1995)] (16.8 g) was added over 30 minutes, then the mixture was stirred at 0 °c for I hour. To the reaction mixture, water (150 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (50% to 75% ethyl acetate in heptanes) to give the title compound having the following physical properties (12.7 g).
TLC: Rf 0.60(50% ethyl acetate in heptanes) Example 29: methyl (2S)-24442.5-dichlorophenyl)-2-oxopyridin-1 (2H)yl1-3-phenylpropanoate The same operation as in Example 21 -i Example 22 -Example 23 was conducted from the compound prepared in Example 28 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 23 in the operation, 2,5-dichiorophenylboronic acid was used).
LCIMS R 2.33 minutes; MS (ES4) m/z 402 (M4-1-1) a
S
To a 1: 1 methanol and tetrahydrofuran (18 mL) solution of the compound prepared in Example 29 (0.71 g) was added I M sodium hydroxide (4.4 niL) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and the residue dissolved in water (50 mL) followed by extraction with tcfl-butyl methyl ether. The aqueous layer was acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried and concentrated to give the title compound having the following physical properties (0.64 g).
LCJMS i 4.33 minutes; MS (ES4) m/z 388 (M+H) b Example 31: tert-butyl 2-f4-(2-4bis[(tert-butoxy)carbonyl]amino}-5-chlorophenyl)-2-oxo-1,2 -dihydropvridin-1 yflacetate The compound prepared in Example 23 (4.53 g) was treated as detailed in Example 10 to give the tide compound having the following physical properties (4.13 g).
LC/MS tg 2.47 minutes; MS (ES1) ith 557 (M-4-Na) a Example 32: -5-chlorophenyl)-2-oxo-1,2- 4jyppyridin-l-yljacetic acid The compound prepared in Example 31(0.96 g) was treated as detailed in Example 30 to give the title compound having the following physical properties (0.76 g).
L'JMS! 1.79 minutes; MS ES1) in/z 379 (M+F1) a Example 33: ethyl 3-(5-chlonifrophenyl)-3-oxoprpMe To a toluene (100 mL) solution of 5-chloro-2-nifrobenzoic acid (12 g) was added thionyl chloride (10 mL) and the mixture was stirred at reulux for 4 hours. The reaction mixture was concentrated and residual thionyl chloride removed by azeotroping with toluene. To a cooled (0 °C) dichioromethane (550 mL) solution of the residue was sequentially added 2,2-dimethyl-1,3-dioxane-4, 6-diane (7.5 g) and 4-dimethylaminopyridine (23 g) and the mixture was stirred at 0 °C for 2 hours. To the reaction mixture, 1 M hydrochloric acid (100 mL) was added and the diehloromethane layer isolated. The dichloromethane layer was washed, I M hydrochloric acid (100 mL x 2), water (100 mL x 2) and brine (100 mL), dried and concentrated. To a toluene (100 mL) solution of the residue was added ethanol (25 tnL) and the mixture was stirred in a sealed system at KS °C for 12 hours. The reaction mixture was concentrated and the residue purified by column chromatography (0 to 30% ethyl acetate in hexanes) to give the title compound having the following physical properties (2.5 g).
LCI'MS R 2.83 minutes; MS (ES) ,n/z 270 (MM) C Example 34: ethyl 2 -(5-chloro-2-nitTophenyfl-4-oxo-4,6,7,8-tetrahydropyrrolo[ 1,2-alpyrimidine-6-carboxylate To an o-xylene (20 mL) solution of the compound prepared in Example 33(2 g) was sequentially added 1,8-diazabicyclo[5.4.0undec-7-ene (4.1 mL) and ethyl (2S)-5-aminopyrrolidine-2-carboxylate [J. Org. Chem. 52(26), 5717 (1987)] (1.2 g) and the mixture was stirred at 130 °C for 1 hour. The reaction mixture was concentrated and the residue purified by column chromatography (0 to 30% ethyl acetate in hexanes) to give the title compound having the following physical properties (0.35 g).
LCIMS R 2.71 minutes; MS (ES) ,n/z 364 (M+H) Example 35: ey1 2-(2-amino-5-chlorophenyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1, 2-alnyrimidine-6-carboxylate NH C02E1 To an ethyl acetate (15 niL) solution of the compound prepared in Example 34 (0.35 g) was sequentially added tin(ll) chloride dihydrate (0.73 g) and 6 M HO (1 mL) and the mixture was stirred at reflux for 2 hours. To the reaction mixture, a saturated S 104 aqueous solution of sodium hydrogen carbonate (25 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with water and brine, dried and concentrated. The residue was triturated with pentane and the solid collected by filtration to give the title compound having the following physical properties (026 g).
LC!MS Ig 2.53 minutes; MS (ES) in/z 334 (M+H)' Example 36: tert-butvj,,--f4-chloro-2-(6-methyl-4oxo4H,6ft7H,3H-pyrrolofl.2- &pyriinidin-2-yl} phcnyflcarbamate To a tert-butanol (10 mL) solution of the compound prepared in Example 35 (0.45 g) was added di-tert-butyl dicarbonate (1.17 g) and the mixture was stirred at go 0. for 8 hours. The reaction mixture was concentrated and the residue obtained purified by column chromatography (0 to 30% ethyl acetate in hexanes) to give the title compound having the following physical properties (0.40 g).
LC/MS 1R 3,35 minutes; MS (ES) m/r 434 (M4-1-I)t Exainnle 37: 2-(2-4[(tert-butoxy)carbonyllamino} -5-chlorophenyfl-4-ox 4H,6H,7H8H-pyrrolo[1,2-alpythnidine-6-carboxylie acid To a tetrahydrofuran (5 mL) solution of the compound prepared in Example 36 (0.19 g) was added 2 NI sodium hydroxide (1 mL) and the mixture was stirred at room temperature for 12 hours. The reaction mixture Was concentrated and the residue obtained dissolved in water (5 mL). To the aqueous solution, potassium hydrogen sulfate was added to pH of 5 -6. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to give the title compound having the following physical properties (0.13 g).
LC/MS ig 2J8 minutes; MS (Est) rn/z 406 (M-f-H)° ErnpkM: 1 2-aJpyrimidine-6-carbcxs'lat late To an acetonitrile (15 mE) solution of the compound prepared in Example 37 (0.62 g) and methyl [4-(brornoacctyl)-phenyl}carbamate [1. Am. (Them. Soc. 119(10), 2453 (1997)) (0.46 g) was added potassium carbonate (0.53 g) and the mixture was stirred at 50 °C for S hours. The reaction mixture was filtered and the filtrate concentrated. The residue was purified by column chromatography (0 -2% methanol in dichlommethane) to give the title compound having the following physical properties (0.60 g).
LCA4S ig 3.40 minutes; MS (ES) m/z 597 (M+H) Example 39: tert-butyl N-{4-chloro-2-[645.-{4-ftmethoxycarbonyl)aminojphenyi -ijj imidazol-2-yfl-4oxo-4H,6H,7H,8H-yrroIo[l,2-alpyrimidin-2-yl}phenyl} carbamate To a toluene (10 mL) solution of the compound prepared in Example 38 (0.60 g) was added ammonium acetate (0.78 g) and the mixture was heated at retlux for 12 hours. The reaction mixture was concentrated and the residue suspended in water and extracted into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (0 -45% ethyl acetate in heptanes) to give the title compound having the following physical properties IS (0.41g) LCIMS 1R 2.59 minutes; MS (EW) m/z 577 (M+H) Examnie 40: methyl N-14-2-[2-(2-amino-5-chlorophenyl)-4-oxo-4H.6ft7H.SH-pyrrolof I,2-ajpyrimidin-6-ylJ-1 H-imidazol-5-yl}phenyl)carbamatc To a dichloromethane (5 mL) solution of the compound prepared in Example 39 (100mg) was added trifluoroacetic acid (1 mL) and the mixture stirred at room temperature for 2 hours. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate (15 mL) was added followed by extraction into dichioromethane.
The combined organic layers were washed with brine, dried and concentrated to give the title compound having the following physical properties (65 mg).
LCIMS tR 2.05 minutes; MS (ES) ,ná 477 (M+H) C amDle 41: methyl 14-(2-fl-[5-cliloro-2-( lH1etrazol-1 -yflphenyll-4-oxo-4,6.7,8-yoolo12-arimidin-6-yl I -IH-imidazol-5-yl)phenyl]carbaniate -U OMe NYO1 I ro a glacial acetic acid (1 niL) solution of the compound prepared in Example (60 mg) was added triethyl orthoformate (60 ML) followed after 30 minutes by sodium azide (25 mg) and the mixture stined in a sealed tube at 65 "C for 1 hour. The reaction mixture was then concentrated and the residue purified by column chromatography (0 -5% methanol in dichioromethane) to give the title compound having the following physical properties (20 mg) LC/MS tR 3.07 minutes; MS (ESt) nj/z 530 (M4-H) b 1H NMR (500 MHz, methanol-d4) ô 9.45 (a, I H), 7.92 (d, I H), 7.78 (dd, I H), 7.71 (ci, 1 H), 7.57 (d, 2 H), 7.44 (d. 2 H), 7.25 (br. s. 1 H), 6.34 (s, I 11). 5.72 (dd, 1 H), 3.73 (a, 3 11), 3.37-3.24 (obs. m. 1 H), 2.97-2.87 (m, I 11), 2.73 -2.62 (in, 1 H), 2.43 -2.33 (m,lH).
42:methl4-2-7-5-coro-2-1H-ol-l-lhcnl-5-oxo-l.235-jydro-3-itidolizinvl} -1H-jjdazol-4-1henylcarbamate OMe The same operation as in Example 38 -. Example 39-. Example 40 -.
Example 41 was conducted from the compound prepared in Example 1910 give the dUe compound having the following physical properties.
LC/MS ts 3.04 minutes; MS (ESt) ink 529 (M+H)" H NMR (500 MHz, methanol-&) ö 9.37 (s, 1 H), 7,78 -7.73 (in, 211), 7.70 (d, 1 H), 7.58 (d, 2 H), 7.46 (ci, 211), 7.24 (br. a, I H), 6.15 (s, I H), 6.10 (s, I H), 5.83-5.72 (m, 1 1-1), 3.76 (a, 3 H), 3.52 -3.41 (m, I H), 3.17-3.08 (in, I H), 2.71 -2.59 (in, I H), 2.54 -2.44 (m, 1 H).
Example 43: tert-butyl N-{4-ehloro-2-{3-(5-{4-ftmethoxycarbonyl)aminolphenyl}-1 H imidazol-2-yl)-5-oxo-1,2,3,5-tetrahydroindolizin-7-yllphenyl} carbamate The same operation as in Example 38 -* Example 39 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties.
LC/MS 1R 1.75 minutes; MS (ES) tn/z 576 (M+HV' Example 44: tert-butyl N-{4-chloro-2-13-(4-chloro-5-M- [(methoxycarbonyl)amino]phenyl}-1 H-imidazol-2-vjj-5-oxo-1,2,3,5-tetrahydroindolizin-7yflj,henyl} carbamate A tetrahydrofuran (20 inL) solution of the compound prepared in Example 43 (0.20 g) was cooled to 0 °C and N-chlorosuccinimide (70 mg) was added. The mixture was stirred at room temperature for 16 hours, cooled to 0 °C and further N-chiorosuccinimide (35 mg) added. The mixture was stirred for a further 24 hours, water (20 mL) was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (40 to 50% ethyl acetate in heptanes) to give the title compound having the following physical properties (0.16 g).
TLC: Rf 0.27 (ethyl acetate) Examuç 45: methyl [4-(4-chloro-2-{7-[5-chloro-2-( I H-tetrazol-I -yl)phenyll-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl}-I H-imidazol-5-yl)phenyIcarbainate The same operation as in Example 40 -* Example 41 was conducted from the compound prepared in Example 44 to give the title compound having the following physical properties.
LC/MS R 2.75 minutes; MS (ES) m'z 563 (M+H) C H NMR (300 MHz, CDCI3) 8 11.23 (br. s, 1 H), 8.53 (s, I H), 7.68 -7.28 (m, 5 H), 7.23 (d, 2 H), 6.77 (s, I H), 6.32 (s, I H), 5.80 (dcl, I H), 5.71 (s, I H), 3.80 (s, 3 Fl), 3.52 -3.35 (m, 1 H), 3.28-3.18 (m, 1 H), 3.06-2.92 (m, I H), 2.53 -2.35 (m, 1 H).
Example 46:
12. ,5-tetrcthydroindolizin-3-yll-l H-imidazol-5-yl}benzoate The same operation as in Example 38 -* Example 39 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 38 in the operation, methyl 3-(bromoacetyl)benzoaie was used in place of methyl [4-(bromoacetyl)-phenyl]carbamate).
LCJMS i 287 minutes; MS (ES) tn/i 559 (M-H)t pie17:methj2-f7-(2-([(tert-butoxy)carbonylJamino}-5-ch1oropyJ)-ox I,2,3,5-tetrahydroindolizin-3-yll-4-chloro-1 H-imidazol-5y1Ibenzoate A dichloromethane (25 mL) solution of the compound prepared in Example 46 (0.25 g) was cooled to 0 °C and N-chlorosuccinimide (72 mg) was added. The mixture was stirred at room temperature for 2 hours. [he reaction mixture was then filtered and the filtrate concentrated. The residue was purified by column chromatography (30 to 35% ethyl acetate in heptanes) to give the title compound having the following physical properties (0.10 g).
LC/MS 1R 3.44 minutes; MS (ES") m/z 595 (M+H)C p48:methyl 3-t2-[7-L2-amino-5ch]orophenyi)-5-QxQ-L-icdroindoIizin-3-yfl-4-chloro-l H-imidaw-5-y!}x The compound prepared in Exampk 47 (0.25 g) was treated as detailed in Example 40 to give the title compound having the following physical properties (0.20 g).
LCJMS 1R 3.05 minutes; MS (ES") in/z 495 (M+H)° Example 49: 3-{247-(2-amirio-5-chlorophenyfl-5-oxo-1,2,3,5-tefrahvdroindolizin-3: y114-chloro-l H-imidazol-5-yl}beioic acid To a solution of the compound prepared in Example 48(0.14 g) in a 1: I mixture of tetrahydrofuran and water (4 mL) was added lithium hydroxide monohydrate (24 mg) and the mixture stirred at room temperature for 16 hours. The reaction mixture was concentrated to approximately half its original volume and the aqueous residue acidified to pH 2-3 by portion-wise addition of potassium hydrogen S 109 sulfate followed by extraction into dichiorometharie. The combined organic layers were washed with brine, dried and concentrated to give the title compound having the following physical properties (0.12 g).
LCIMS 1R 2.71 minutes; MS (ES4) m/z 481 (M1-H) Example 50: 3-(4-chloro-2-?-[5-chloro-2-(lH-tetmo1-1-yflphenyfl-5-oxo-1,23 tctrahydro-3-indolizinyl} -1 H-imidazol-5-yL)benzoic acid The compound prepared in Example 49 (75 mg) was treated as detailed in Example 41 to give the title compound having the following physical properties (60 mg).
LC/MS R 2.65 minutes; MS (ES4) m/z 534 (M+H), 506 (M-N2+H) C H NMR (300 MHz, DMSO-d6) ö 13.20 (hr. s, 1 H), 9.71 (s, 1 H), 8.33 (s, I H), 7.97 (d, I Fl). 7.88 (d, 1 H), 7.89-7.77 (in, 3 H), 7.60 (t, I Fl), 5.99 (s, I H), 5.95 (s, I H), 5.59 (dd. I H), 3.34 -3.23 (obs. m, 1 H), 3.07 -2.90 (in, I H), 2.56-240 (in, 1 H), 2.30 - 2.20(m,1H).
Example 51: 7-i5-chIoro-241.2,3,4-letzol-lryflphenyll-5-oxo-3-ft2-oxoethoxylcarbonyll indolizin-8-yl To an N,N-dimethylformamide (3 mL) solution of the compound prepared in Example 9(100mg) was added potassium carbonate (151 mg) and the mixture stin ed at room temperature for 30 minutes. To the reaction mixture, a solution of 2-bromo-l-phenylethan-I-one (72 mg) in N,N-dimetbylformamide (3 mL) was added and the mixture stined at room temperature for 2 hours. The reaction mixture was then diluted with ethyl acetate (30 niL), filtered and the filtrate concentrated to give the crude title compound having the following physical properties (193 mg).
LC'MS 1R 3.97 minutes; MS (ES4) mlz 476 M±H) a Example 52: (3S)-7-[5-cHoro-2-UH4etrj-lhenI-3-5-phenyHH-imida2ol-2-yl)-2,3-dihydro-5(l H)-indolizinone To a toluene (5 mL) suspension of the compound prepared in Example 51(193 mg) was sequentially added glacial acetic acid (0.50 niL) and ammonium acetate (231 mg) and the mixture stined at reflux for 2 hours. The reaction mixture was concentrated and the residue suspended in a saturated aqueous solution of sodium hydrogen carbonate (10 mL) followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (5% methanol in ethyl acetate) followed by high performance liquid chromatography (5 to 100% acetonitrile in 2 mM aqueous ammonium hydrogen carbonate) to give the title compound having the following physical properties (54.5 mg).
LC/MS tR 3.20 minutes; MS (ES) ,nz 456 (M+H)' NMR analysis showed a 2: 1 ratio of tautomers.
H NMIR (500 M}lz, CDCI3) 6 11.19 and 10.77 (br. s, I H), 8.54 (s, 1 H), 7.78-7.73 (ci, I H), 7.61 (dd, 1 H), 7.57-7.52 (ci, 1 H), 7.52-7.43 (m, 2 H), 7.42 -7.31 (m, 2 H), 7.27-7.15 (m, 2 H), 6.32 (s, 1 H), 5.92-5.79 (m. 1 H), 5.70 (s, 1 H), 3.54-3.25 (m, 2 H), 3.01 (dd, 1 H), 2.53 -2.39 (ci, I H).
Example 53: 4-[5-chloro-2-( 1 H-tetrazol-1 -yl)yhenyl]-1 -[(5-phenyl-1H-imidazol-2- 1 5 y1)mejyfl-2(1H)-pvridinone The same operation as in Example 38 -÷ Example 39 was conducted from the compound prepared in Example 25 to give the title compound having the following physical properties.
LC/MS tR 3.16 minutes; MS (ES) rn/i 430 (Mi-F1 H NMR (250 MHz, DMSO-dg) 6 9.69 (s, I H), 7.80 (app. br. s, 3 H), 7.75 -7.62 (m, 3 H), 7.50 (br. s, 1 H), 7.32 (t, 2 H), 7.17 (t, I H), 6.27 (d, 1 H), 5.86 (dd, I H), 5.09 (s, 2 H).
Example 54: tert-butyl N-(4-cbloro-2-{ 1 -[(5-{4-[(methoxycarbonyl)aminolphenyl} -l H-imiclazol-2-yl)methyll-2-oxo-1,2-dihydropyridin-4yflphenyl)carbamate The same operation as in Example 38 -. Example 39 was conducted from the compound prepared in Example 32 to give the title compound having the following physical properties.
LC/MS tR 1.69 minutes; MS (ES) rn/a-550 (M+H)a Example 55: methyl N-[4-(2-{ [4-(2-amino-5-ch1orophenyfl-2-oxo-1.2-dihydropyjçIin-I -yl1çthyl} -1 H-imidazol-5-yflyhenyl}carbarnate To a 1, 4-dioxane (0.75 mL) solution of the compound prepared in Example 54 (109 rug) was added 4 M hydrochloric acid in dioxane (0.75 mL) and the mixture was stirred at room temperature for 16 hours. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford the title compound having the following physical properties (78 mg).
LC/MS 1R 1.54 minutes; MS (ES1) tn/z 450 (M+H)a Example 56: methyl {4-[2-( .14-[5-chloro-2-( I H-tetrazol-I -yflphenyll-2-oxo-1 (211)-pyridinyl tmethyl) I H-imidazo1-4-ylphenyI}carbamate The compound prepared in Example 55 (78 mg) was treated as detailed in Example 41 to give the title compound having the following physical properties (40 mg).
LC/MS R 3.04 minutes; MS (ES4) In/z 503 (M+H) b 1fl NMR (500 M}h, DMSO-d6) a 9.70 (s, 1 H), 9.68 (s, 1 H), 7.83 -7.78 (m, 3 H), 7.70 (d, 1 H), 7.62 (d, 2 H), 7.57 -7.35 (m, 4 H), 6.29 (s, I H), 5.89 (d, I H), 5.13 (s, 2 H), 3.66 (s, 3 H).
Example 57: methyl 445-chloro-2-({4-[5 -chloro-2-( 1 H-tetra2ol-1 -yl)phenyl]-2--oxo-I (2H)-pyridinyl}methvl)-1 H-imidazol-4-v j]phenyl} carbamate 0' The compound prepared in Example 56 (72 mg) was treated as detailed in Example 47 to give the title compound having the following physical properties (16.2 mg).
LC/MS tR 3.96 minutes; MS (ES4) in/z 537 (M+H) b 3H NMR (500 MHz, DM80-do) 8 9.76 (s, I H), 9.71 (s, I H), 7.84 -7.79 (m, 3 H), 7.68 (d, 1 II), 7.63 (br. s, 1 Fl), 7.62 (d, 2 H), 7.52 (d, 2 H), 6.26 (d, 1 H), 5.88 (dd, 1 H), 5.04 S 112 (s, 2 H), 3.69 (s, 3 1-1).
Example 58: tert-butyl 2-[4-(2-{bis[Uert-butoxy)carbonyl1amjno}jjorophenvfl2-oxo-I.2-d ihvdropyjijn-I -ylibutanoate To a cooled (-78°C) tetrahydrofliran (25 mL) solution of the compound prepared in Example 31 (2.5 g) was added 1 M lithium hexamethyldisilazide in tetrahydrofliran (5.61 mL) and the mixture was stirred at -78°C for 30 minutes. To the cooled (-78°C) reaction mixture, iodoethane (0.45 mL) was added awl the mixture was stirred at 78°C for 2 hours. To the cooled (-78°C) reaction mixture, a saturated aqueous solution of ammonium chloride was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography (10% to 20% ethyl acetate in heptanes) to give the title compound having the following physical properties (2.37 g).
LCIMS R 2.62 minutes; MS (ES) mz 585 (M+Na) a
Example 59: methyl
py4jjyl1propyl)-1 H-imidazol-4-yl]phenyl} carbamate The same operation as in Example 25 -a Example 9 -Example 38 -* Example 39 was conducted from the compound prepared in Example 58 to give the title compound having the following physical properties.
LC/tvlS i, 3.54 minutes; MS (ES4) nz' 531 (M+H) b ii NMR (500 MHz, DMSO-d6) 8 12.32 (s, I 11), 9.68 (s, 1 H), 9.62 (s, 1 H), 7.84 -7.77 (m, 31-1), 7.71 (d, I H), 7.68 -7.39 (m, 5 H), 6.24 (s, I H), 5.96 (s, I H), 5.92 (dd, I H), 3.68 (s, 3 Fl), 2.28 -1.83 (m. 2 H), 0.79 (t, 3 H).
xamp1e 60: methyl {4-[5-chloro-2-(1-jj[-chloro-24lH-tetrazol-l -yflphenyl]-2-oxo-i(if)pyridinvlthrovvfl-1H-imidazol-4-yllphenyl}carbamate The compound prepared in Example 59 (200 mg) was treated as detailed in Example 47 to give the title compound having the following physical properties (42.5 mg).
LC1MS tR 4.22 minutes; MS (ES) m/ 565 (M+H) b H NMR (500 MHz, DMSO-d) 12.69 (s, I H), 9.79 (s, I H), 9.69 (s, 1 H), 7.85 -7.78 (m, 3 H), 7.67 (ci, 1 1-1), 7.62 (ci, 2 H), 7.54 (d, 2 H), 6.24 (d, I H), 6.04-5.86 (in, 2 H), 3.69 (s, 3 11), 2.23 -1.83 (m, 211), 0.79 (t, 3 H).
Example 61: methyl {4-[2-(l -4-15-chloro-2-(1 H-tetrazol-1 -yl)phenyll-2-oxo-1(211)-pyridinyl}ethyl)-I H-imidazol-5-yflphenyl} carbamate The same operation as in Example 58 -Example 25 -÷ Example 9 -Example 38 -Example 39 was conducted from the compound prepared in Example 31 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 58 in the operation, iodomethane was used).
LC/MS tR 3.16 minutes; MS (ES) n/ 517 (M+H)L io H NMR (500 MHz, DMSO-d6) 12.29 (br. s, 1 11), 9.68 (s, 1 H), 9.60 (br. s, 1 11), 7.87 -7.76 (m, 3 H), 7.67 (d, 2 H). 7.60-7.38 (m, 4 H). 6.25 (s, I 1-1), 6.12 (q, I H), 5.90 (d, I H), 3.66 (s, 3 H), 1.64 (d, 3 H).
Example 62: ethyl 2-14-(benzyloxy).-2-oxo-I.2-dihydropyridin-I -yflproy-2-enoate To a dichloromethane (25 niL) solution of ethyl prop-2-ynoate (0.61 niL), 4- (benzyloxy)pyridin-2(1H)-one (1.0 g) and triphenylphosphine (0.20 g) were sequentially added at 0 °C and the mixture was stirred at room temperature for 16 hours.
The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography to give the title compound having the following physical properties (1.0 g).
LCIMS R 1.87 minutes; MS (ES) mi 300 (M+H) a Example 63: ethyl 1 -[4-(heniyloxy)-2-oxo-1,2-dibydropyridin-1 -yfleyclopropane-I -1ate To a dimethylsulfoxide (8 mL) solution of trimethylsulphoxonium iodide (0.91 g), sodium hydride (0.16 g, 60% dispersion in mineral oil) was added and the mixture was stined at room temperature for 15 minutes. A dimethylsulfoxide (6 mL) solution of the compound prepared in Example 62 (1.0 g) was added and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, water (50 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography to give the title compound having the following physical properties (0.39 g).
LCJMS tR 1.88 minutes; MS (ES) m/z 314 (M+H)a Example 64: 1 -[44bery1oxy)-2-oxo-1,2-dihydro.pyridin-I -ylleyclopropane-1 -lic acid The eompoutd prepared in Example 63 (0.39 g) was treated as detailed in Example 8 to give the title compound having the following physical properties (0.27 g).
LC/MS 1R 1.64 minutes; MS (ES) nilz 284 (M-H) a gp65: methyl (44241 -{445-chlom-2-( 1 H-tetrazol-I -y1)pheny1]2-oxo-1 (2H)-pyridinyt}cyclopropyl)-1 H-imidazol-5-yl]phenyl}carbamate The same operation as in Example 51 -* Example 52--* Example 21 -.
Example 6 -÷ Example 7 -Example 41 was conducted from the compound prepared in Example 64 to give the title compound having the following physical properties.
(Note: in the step corresponding to Example 51 in the operation, methyl [4- (bromoacetyl)-phenyl]earbamate [J. Am. Chem. Soc. 119(10), 2453 (1997)] was used).
LC/MS Fg 3.10 minutes; MS (ES) yn/z 529 (M+H)a 1H NMR (500 MHz, DMSO-d6) 6 11.72 (br. s, I H), 9.69 (s, 1 II), 9.59 (hr. s, I H), 7.84 -7.80 (m, 2 H), 7.79 (d, 1 H), 7.71 (d, 1 H), 7.58 (d, 2 H), 7.40 (br. d, 2 H), 7.35 (d, I H), 6.29 (d, I H), 5.79 (dd. I H), 3.64 (s, 3 H), 1.63 (hr. s, 2 H), 1.38 (1w. s, 2 H).
Examples 66(1) and 66(2): methyl (4-[2-(l -(4-15-chloro-2-(1 H-tetrazol-I -yl)phenvl-2-and njçy1 [4-(2-{ I -{442-carbamimidamido-5-chlorophenvi)-2-oxo-1 (2H)-pyridinyl-2-phenylethyl 1-1 H-imidazol-4-yflpbenyllcarbamate acetate The same operation as in Example 38 -Example 39 was conducted from the compound prepared in Example 27 to obtain the title products in a 5: 2 ratio having the following physical properties.
Example 66(l)
LCIMS i 3.63 minutes; MS (ES') ,n/z 593 (M+H) b LH NMR (500 MHz, DMSO-d5) 6 12.25 (s, 1 H), 9.64 (s, I H), 9.61 (s, I H), 7.85 -7.78 (m, 3 H), 7.76 (d, 1 H), 7.69 (d, 2 H). 7.48 -7.38 (m, 3 H), 7.25 (t, 2 H), 7.17 (t, I H), 7.11 (d, 2 H), 6.33-6.21 (m, 1 H), 6.20 (s, I H), 5.90 (d, 1 H), 3.67 (s. 3 H), 3.56-3.46 (m,2H).
(5 115 le662 LCIMS R 3.50 minutes; MS (ES) rnz 582 (MW) b H NMR (500 MHz. DMSO&) 6 12.24 (s, I}1), 9.61 (s, 1 II), 9.49 (s, I 11). 7.99 (d, I H). 7.71 (d, 2 H), 7.52 (d, 211), 7.48-7.42 (m, 5 H), 7.37 (s, I H), 7.30-7.17 (in, 51171.
7.19 -7.13 (in, 1 H), 6.40 (s, 1 11), 6.35 (s, 11-1). 6.30 (d, 1 11), 3.66 (s, 3 11), 3.79 3.53 (in, 2 1-1), 1.88 (s, 3 II).
Exampkó'7j methyl {4-[5-chloro-241-{4-[5-chloro-24111-tetrazpjl-yl)phenyfl-2-oxo-The compound prepared in Example 66(1) (38 mg) was treated as detailed in Example 47 to give the title compound having the following physical properties (16.8 mg).
LC/MS tR 4.51 minutes; MS (ESt) rnz 627 1$+H)1' ?H NMR (500 MHz, DMSO-d6) 6 12,77 (s, I H), 9.78 (s, I H), 9.64 (s, I H), 7.84 -7.78 (m, 3 H), 7.77 (d, 1 H). 7.60, 2 H), 7.53 (d, 2 H), 7.27 (t, 2 H), 7.20 (t. 1 H), 7.09 (d, 2 H), 6.25 (t, I II), 6.18 (d, I H), 5.93 (dd, I H), 3.68 (s, 3 H), 3.56 -3.35 (m, 2 H).
Example 68: 2-rjitro-5-( I H-pyrazol-1 -vl)aniline To an N,N-dimethylformaniide (4 mL) solution of 5-chloro-2-nitroaniline (200 mg) was added 1H-pyrazole (316 mg) and potassium hydroxide (98 mg) and the mixture stirred at 100 °C for 20 hours. To the reaction mixture at room temperature, water (10 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified 23 by column chromatography (0 to 50% ethyl acetate in heptanes) to obtain the title compound having the following physical properties (52 mg).
LCftvIS r 1.71 minutes; MS (Est) in/z 205 (M+H)a Example 69: 4-Cl H-pyrazol-1-y 1)benzene-I,2-diamine To a 4: 1 ethanol: water (2 mL) solution of the compound prepared in Example 68 (52 mg) was added a saturated aqueous solution of anunonium chloride solution (0.5 niL) and iron powder (113 ing) and the mixture stirred at room temperature for 1.5 -hours. The reaction mixture was filtered through Celite® and the filtrate concentrated, (1-116 The residue was triturated with dichioromethane and the precipitate formed was isolated by filtration giving the title compound with the following physical properties (49 mg).
LC/MS 1R 0.70 minutes; MS (ES4) tn/z 175 (M+H)a Example 70: N42-amino-4-(1H-pyrazoI-1-yl)yhenyll-2-M-[5-ch1oro-2-(1H-l,2, 34-tetrazol-1-yl)phenyl]-2-oxo-1,2-diy4pyridin-1-l-3-hen1ropnjde To an NJ'T-dimethylformamide (1 mL) solution of the compound prepared in Example 69 (49 mg) and the compound prepared in Example 27 (55 mg) was added 0- (7-azabenzotriazol-I -yl)-N,N,N' ,N' -tetramethyluronium bexafluorophosphate (59.67 rug) and diisopropylethylamine (40 1.iL) and the mixture stired at room temperature for 16 hours. To the reaction mixture, water (5 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and then concentrated. The residue was purified by column chromatography (0 to 50% ethyl acetate in heptanes) to obtain the title compound having the following physical IS properties (29 mg).
LC/MS 1R 1.98 minutes; MS (ES4) m/z 578 (M+H) a Example 71: 4-[5ch1oro-2-(1 H-tetrazol-I -yl}yhenyl]-1-2-phenyl-1-15-C lH-pWQid yj)-1 1i-benzimidazoj2-\'lJçfly1H-dne A glacial acetic acid (1 mL) solution of the compound prepared in Example 70 (29 mg) was stirred at 60 °C for 1 hour. To the cooled (0 °C) reaction mixture, 2 M sodium hydroxide (2 mL) and Water (2 mL) was sequentially added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by high performance liquid chromatography (5 to 100% acetonitrile in 2 mM aqueous ammoniunl hydrogen carbonate) to give the title compound having the following physical properties (5 rug).
LC/MS tR 4.07 minutes; MS (ES') in/i 560 (M+H) b H NMR (500 MHz, DMSO-d6) 8 9.20 (s, I H), 8.48 (d, 1 H), 7.96 (br. s, I H), 7.86 (d, 1 H), 7.84-7.68 (m, 5 H), 7.65 (lx. s, I H), 7.31 (t, 2 H), 7.23 (t, 1 H), 7.12 (d, 2111), 6.53 (t, 1 H), 6.47-6.36 (m, 1 H), 6.22 (d, 1 H), 5.90 (dd, I H), 3.68 (dd, I III), 3.46 (dd, IH).
(1 117 Example 72: 2-r4-(2,5-dichlorophenvfl-2-oxo-1,2-dihydropyridin-1 -yl]-N-[2-(4-nitrophenvfl-2-oxoethvll-3 -phenyipropanamide To a pyridine (8 niL) solution of the compound prepared in Example 30(0.63 g) and 2-amino-l-(4-nitrophenyflethanone hydrochloride hydrate (0.46 g) was added N-[3 S (dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (0.40 g) and the mixture stirred at room temperature for 20 hours. To the reaction mixture, 0.5 M hydrochloric acid (50 itt) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (5% to 50% ethyl acetate in heptanes) to obtain the title compound having the following physical properties (0.64 g).
TLC: Rf 0.13 (50% ethyl acetate in heptanes) Example 73: 44,5-dichlorophenyfl-1 -{ 1 4444-nitrophenyfl-IH-imidazol-2-yl]-2-phenylethyfij2-dihdropyridin-2-one To an o-xylene (50 mL) solution of the compound prepared in Example 72 (0.62 g) was added animonium acetate (0.87 g) and the mixture stirred at 150°C for 1 hour.
The reaction mixture was concentrated and the residue suspended in a saturated aqueous solution of sodium hydrogen carbonate (100 mL) followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated.
The residue was purified by column chromatography (10% to 50% ethyl acetate in heptanes) to obtain the title compound having the following physical properties (0.61 g).
TLC: RI 0.11(50% ethyl acetate in heptanes) Example 74: l-{ 1-[5-(4-aminotthenvl)-IH-imidazol-2-yll-2-phenylethyU-4-(. 5-dichlorophenyfl-2(l Ffl-pyridinoue To a solution of the compound prepared in Example 73 (0.30 g) in an 8:1:1 mixture of ethanol, saturated aqueous ammonium chloride solution and water (7.5 mL) was added iron powder (0.25 g) and the mixture stirred at 50 °C for 3 hours. The reaction mixture was filtered through Celite® and the filtrate concentrated. The residue obtained was suspended in water and extracted into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (50% ethyl acetate in heptanes) to obtain the title compound having the following physical properties (0.27 g).
LCIMS tR 3.63 minutes; MS (Est) In/i 501 (M+H)b H NMR (500 MHz, mcthanol-d4) 7.89 (d, 1 H), 7.48 (d, I 1-1), 7.40 (dd, 1 II), 7.37 (d, 1 Fl), 7.31 (app. br. s, 2 H), 7.25 -7.19 (m, 4 H), 7.18 (s. I H). 7.18-7.13 (in, I H). 6.73 (d, 2 H), 6.48 (d, 1 H), 6.43 (d, 1 Fl), 6.42 (br. s, I H), 3.78 -3.59 (in, 1 H), 3.59-3.37 (m,11-1).
Example 75: methyl [4-(2-I -[4-(2,5-dicheny1)-2-oxo-1(2B)-pyridiny1]-2-phertylethyl}-1 H-imidazoJ-4-yIphenyl]carbamate To a dichloromethane (2.5 mL) solution of the compound prepared in Example 74 (0.26 g) was sequentially added methyl chloroformate (50.tl) and N,N-diisopropylethylamine (135 jiL) and the mixture stirred at room temperature for 1 hour.
To the reaction mixture, water (20 mL) was added followed by extraction with dichioromethane. The combined organic layers were washed with brine, dried and concentrated. To a methanol (2.5 mL) solution of the residue, 1 M sodium hydroxide (0.51 mL) was added and the mixthre was stirred at room temperature for 30 minutes.
To the reaction mixture, water (30 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated.
The residue was purified by column chromatography (10% to 50% ethyl acetate in heptanes) to obtain the title compound having the following physical properties (0.22 g).
LCIMS ig 4.18 minutes; MS (ESt) nz1z 559 (M+H) b H NMR (500 MI-k, methanol-cl4) ö 7.93 (hr. s, 1 H), 7.70 (hr. s, I H), 7.49 (d, 211), 7.46 (d,2 H), 7.41 (dd, I H), 7.38 (1, 1 H), 7.33 (s, I H), 7.27-7.19 (rn, 4 H), 7.19 - 7.12 (m, I H). 6-49 (d, I H), &45 (d, I H), 655 -6.30 (ni, 1 H), 3.74 (s, 3 H), 3.80- 3.62 (m, I H), 3.53 (app. br. s, 1 H).
pçnylethyl}-1 H-imidazo1-4-ypheny1]ckgte To an acetonitrile (3.5 mL) solution of the compound prepared in Example 75 (0.195 g) was added I -chloropyrrolidine-2,5-dione (50 trig) and the mixture stirred at 60 °C for 5.5 hours. The reaction mixture was concentrated and the residue purified by column chromatography (5% to 50% ethyl acetate in heptanes) to obtain the title compound having the following physical properties (52 nig).
LCIMS 1R 5.09 minutes; MS (ES') nil: 593 (M-)-H) b "9 1-1 NMR (500 MHz, methanol-d4) 5 7.94 (d, I 1-1), 7.57 (d, 2 H), 7.50 (d, 2 H), 7.49 (d, 1 H), 7.41 (dd, 1 H), 7.38 (d, I H), 7.26 -. 7.21 (m, 4 H), 7.21 -7.15 (m, 1 H), 6.48 (s, H), 6.47 (dd, I H), 6.42 (t, I H), 3.74 (s, 3 H), 3.65 (dd, I H), 3.45 (dd, 1 II).
Example 77: methyl N-(4-propanoylphenyflcarbamate To a dichloromethane (10 mL) solution of l-(4-arninophenyl)propan-l -one (0.25 g), pyridine (0.27 mL) and methyl chloroforniate (0.15 mL) were added sequentially and the mixture stirred overnight at room temperature. To the reaction mixture, water (25 mL) was added followed by extraction with dichioromethane. The combined organic layers were washed sequentially with I M hydrochloric acid, water and brine, dried and concentrated to obtain the title compound having the following physical properties (0.23 g).
If/MS tR t.68 minutes; MS (ES) mhz 208 (M+1-I) a Example 78: methyl N44-(2-bromoyropanoyl)phenyl]carbamate To a glacial acetic acid (10 niL) solution of the compound prepared in Example 77(0.23 g) was added pyridinium tribromide (0.35 g) followed by a solution of 33 wt.
% hydrogen bromide in acetic acid (0.15 niL) and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and a saturated aqueous solution of sodium hydrogen carbonate (25 mL) was added to the residue followed by extraction with ethyl acetate. The combined organic layers were washed with water, brine, dried and concentrated to obtain the title compound having the following physical properties (0.29 g).
LCMS tR 1.87 minutes; MS (ES') mhz 286 and 288 (M-FH) a Example 79: formic acid -methyl I4-(2-{7-r5-chloro-2-(1H-tetrj-yl)pheny1I-5-oxo-1,2,3, 5-tetrahydro-3-indolizinyl}-4-niethyl-1 H-imidazol-5-yflphenyljcarbamate (1:1) HOyO The same operation as in Example 38 -. Example 39 -Example 40 -÷ Example 41 was conducted from the compound prepared in Example 19 to obtain thç title compound having the following physical properties. (Note: in the step corresponding to Example 38 in the operation, the compound prepared in Example 78 was used in the step corresponding to Example 41 in the operation, high performance liquid chromatography [5 to 100% mobile phase 8 (0.1% formic acid in acetonithie) in mobile phase A (0.1% aqueous formic acid)] was used to give the title product as the formic acid salt).
LC/MS tR 3.00 minutes; MS (ES) rn/i 543 (M+H) 1ll NMR (500 MHz, DMSO-d6) 3 11.92 (s, 1 H), 9.69 (s, 1 Fl), 9.59 (s. 1 H), 8.51 (br. s, 114), 7.80-7.79 (in, 31-1). 7.52-7.39 (m, 414), 5.97 (s, I H), 5.94 (s, 1 11). 5.57-5.55 (m, I H), 3.66 (s, 3 H), 3.36-3.34 (obs. m, I H), 3.00-2.96 (m, 11-1), 2.51 -2.49 (obs.
m, 1 H). 2.33 (s, 3 H), 2.19 (app. lx. s, I H).
Example 80: methyl N44-(2-bromobutanoyl)phenyllcarbamate The same operation as in Example 77 -* Example 78 was conducted from l-(4-arninophenyl)butan-1-one to obtain the title compound having the following physical properties.
LCIMS fl 2.00 minutes; MS (ES) m/z 300 and 302 (M+H)3 81(lIand 81(2): formic acid -methyl [4-({J5-cMoro-22{jH-tefrazoI-1- yJ)phenyl]-5-oxo-l,2,3,5-tetrahydro-3-indolizinyi}-4-ethvl-I H-irnidazol-5- yflphcnlcarbamate(l:l) and formic açjç4meth14-2-7-5-cWoro-- formamidophenyl)-5-oxo-1,2,3, 5-tetrahydro-3-indoliziny-4-ethyl-1H-imidazol-5-yl}phenyflpate (1:1)
UI
The same operation as in Example 38 -. Example 39 -. Example 40 -* Example 41 was conducted from the compound prepared in Example 19 to obtain the title compounds having the following physical properties. (Note: in the step corresponding to Example 38 in the operation, the compound prepared in Example 80 was used. In the step corresponding to Example 41 in the operation, high performance liquid chromatography [5 to 100% mobile, phase B (0.1% formic acid in acetonitrile) in mobile phase A (0.1% aqueous formic acid)1 was used to give the title products in a 4: I ratio as their formic acid salts).
Example 81(1)
LCIMS 1R 3.10 minutes; MS (ES') in/z 557 (MI-H) S H NMR (500 M}Tz, DMSO-d6) ö 11.93 (s, 1 H), 9.69 (s, 1 H), 9.60 (s, 1 H), 8.51 (hr. s, I H), 7.80 -7.78 (m, 3 H), 7.50-7.37 (m, 4 H), 5.97 (s, I H), 5.94 (s, 1 H), 5.S7 (d, 1 H), 3.66 (s, 3 H), 3.36-3.34 (obs. m, 2 H), 3.00-2.95 (m, 1 H), 2.73 -2.71 (m, I H), 2.51 -2.49 (ohs. m, 1 H), 2.31 -2.27 (m, 1 1-1), 1.19 (t, 3 H).
Example 8 1(2)
LC/MS R 3.04 minutes; MS (ES) m/2 532 (MI-H) b H NMR (500 MHz. DMSO-d6) 8 11.93 (s, I H), 9.73 (s, 1 H), 9.63 (s, 1 11), 8.21 (d, I H), 8.33 (s, 1 H), 7.99 (d, I H), 7.49 -7.43 (m, 611), 6.27 (s, I H). 6.19 (s, 11-1), 5.65 (d, I H), 3.67 (s, 3 1-1), 3.36-3.34 (cbs. in, 311), 3.17-3.12 (m, I H), 2.72-2.70(m, 2 1-1), 1.18 (t, 3 H).
Example 82: formic acid -methyl 442-({4-[5-chloro-2-(lH-tetrazol-1-yl)yhenyl1-2- çpjj2H-ridinlmethl-4-methy1-1 H-iniidazol-ylJpheny1}carbarnatejjJ) L HOtO The same operation as in Example 38 -. Example 39 was conducted from the compound prepared in Example 25 to obtain the title compound having the following physical properties. (Note: in the step corresponding to Example 38 in the operation, the compound prepared in Example 78 was used. In the step corresponding to Example 39 in the operation, high performance liquid chromatography [5 to 100% mobile phase B (0.1% formic acid in acetonitrile) in mobile phase A (0.1% aqueous formic acid)] was used to give the title product as the formic acid salt).
LCIMS Ig 3.03 minutes; MS (ES) in/z 517 (M+H)' 1-I NIvIR (500 MHz, DMSO-d6) S 11.98 (hr. s), 9.70 (s, I H), 9.63 (br. s, I H), 8.25 (s, I H), 7.86 -7.73 (m, 3 H), 7.68 (U, 1 H), 7.46 (app. hr. s, 4 H), 6.27 (U. I H), 5.88 (dd, I H), 5.03 (s, 2 H), 3.67 (s, 3 1-i), 2.30 (s, 3 1-1).
Example 83: formic acid -methyl 4-124 44S-chloro-2-( 1H-tetrawl-l -yl)phenylj-2-oxo-1 (2F1)-pyridinyl}methy-4-ethyl-1 H-imidazol-5-vlphenyflearbamate (1:1) -0.,, The same operation as in ExampSe 38 -÷ Example 52 was conducted from the compound prepared in Example 25 to obtain the title compound having the following physical properties. (Note: in the step corresponding to Example 38 in the operation, the compound prepared in Example 80 was used. In the step corresponding to Example 39 in the operation, high performance liquid chromatography [5 to 100% mobile phase B (0.1% formic acid in acetonitrile) in mobile phase A (0.1% aqueous formic acid)] was used to give the title product as the formic acid salt).
LC/MS tR 3.11 minutes; MS (ES) m/z 531 (M+H' H NMR (500 MHz, DMSO-d6) 8 11.99 (br. s, 1 H), 9.70 (s. I H), 9.63 (br. s, 1 H), 8.26 (br. s, I H), 7.88-7.76 (m, 3 H), 7.68 (d, I H), 7.45 (app. br. d, 4 H), 6.28 (d, I H). 5.87 (dd, 1 H), 5.04 (s, 2 H), 3.67 (s, 3 H), 2.69 (app. br. s,2 H), 1.17 (t, 3 H).
S
Example 84: 2-oxo-2-(2-oxo-2,3-djhydro-I H-indol-5-yl)ethyl 7-(2-{ [(tert butoxy)carbonyllarnino} -5-clilorophenyfl-5-oxo-1,2.3,5-tetrahydroindolizine-3-carboxylate To an acetonitrile (4 mL) solution of the compound prepared in Example 19 (0.35 g) was added 5-(bromoacetyl)-1,3-dihydro-2H-indol-2-one (0.25 g) and N.N-diisopropylethylamine (0.22 mL) and the mixture was stirred at 50 °C for 16 hours. To the reaction mixture, water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to give the crude title compound having the following physical properties (0.67 g).
LCIMS tn 1.99 minutes; MS (ES4) ,n/z 578 (MI-H) a Example 85: 5-(2-(7-15-chloro-2-(l H-tetrazol-l-yflphenyl]-5-oxo-l,2,3, 5-tetriyrg-3-indo1izinv1J-1H-imidazo1-4-yQ-I3-dihydro-2H-indol-2-one The same operation as in Example 39 -* Example 55 -i Example 41 was conducted from the compound prepared in Example 84 to give the title compound having the following physical properties.
LCIMS (i 2.80 minutes; MS (ES) ,n/z 511 (M-fH) b H NMR (500 MHz, DMSO-d6) 6 12.05 (s, 1 H), 10.36 (s, I H), 9.70 (s, 1 H), 8.48 (br.
s, 1 H). 7.95 -7.63 (m, 3 1-1), 7.55 (s, I 1-1), 7.50 (br. s, 1 1-1), 7.35 (s, I II), 6.78 (d, 1 H), 5.97 (s, 1 H), 5.95 (s, I H), 5.62 (dcl, 1 H), 3.50 (s, 2 H), 3.45-3.30 (abs. it, I EQ. 2.99 (ddd, 1 H), 2.54 -2.43 (obs. m, I H), 2.33 (app. hr. s, 1 H).
Example 86: 642-(7-[5-chloro-2-(1 H-tetrazol-I -yl)phenyll-5-oxo-1 2,3,5-tetrahydro-3-indolizinyl} -1 H-iniidazol-4-yl)-3,4-djhydro-2(11-fl-gujnoljnorie The same operation as in Example 84 -Example 52 -p Example 40 -* Example 41 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. ote: in the step corresponding to Example 84 in the operation, 6-(bromoacetyl)-3,4-dihydroquinolin-2(IH)-one was used).
LCIMS tg 2.88 minutes; MS (ES) m/z 525 (M+H) b TH NMR (500 MHz, DMSO-d5) 8 12.09 (br. s, 1 H), 10.08 (br. s, 1 H), 9.69 (s, 1 II), 7.84-7.75 (m, 3 H), 7.51 (s, I H), 7.46 (d, I II), 7.38 (br. s, 1 H), 6.83 (d, 1 H), 5.98 (s, 1 II), 5.96 (s, 1 H), 5.63 (d, 1 H), 3.42 -3.34 (obs. m, 1 H), 3.01 (ddd, 1 H), 2.91 (t, 2 H), 2.56-2.49 (cbs. iii. 1 H), 2.46 (t, 2 H), 2.35 -2.26 (in, 1 H).
Exampç87:_6-(4-cbloro-2-{7-[5-chloro-2-(1H-tetrazo1-1-yl)pgy11-5-oxo-1, 2,3,5-tetrahydro-3-indolizinyl 1-1 H-iniidazol-5-yl)-3,4-dihydro-2( 1 H)-guinolinone The compound prepared in Example 86 (0.10 g) was treated as detailed in Example 44 to give the title compound having the following physical properties (0.11 g).
LC/MS tR 3.84 minutes; MS (ES) n/a 559 (M*H)b HNMR (500 MHz, DMSO-d5) 5 12.78 (br. s, I H), 10.20 (s, 1 H), 9.71 (s, 1 II), 7.90- 7.76 (in, 3 H), 7.50 (s, I H), 7.48 (d, I 11), 6.93 (d, 1 H), 5.99 (s, I H), 5.94 (s, 1 H), 5.56 (dd I H), 3.35 -3.23 (obs. m, I H), 2.99 (dd, 1 H), 2.93 (t, 2 H), 2.62-2.42 (ohs.
m, 3 1-1), 2.23-2.14 (m, I H).
Example 88: 6-1 2-( (445-chloro-2-(1l-1-tetrazol-I -yl)yhenyl]-2-oxo-I (2H)-pyridinyl nethyI)-l H-imidazol-5-vll-3,4-dihydro-2(IH)-guinojinone The same operation as in example Example Si -Example 52 was conducted from the compound prepared in Example 25 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, 6-(bromoacetyl)-3,4-dihydroquinolin-2( 1 H)-one was used).
LC/MS tft 2.89 minutes; MS (ES) ,n/z 499 (M+H) b ii NMR (500 MHz, methanol-d4 9.38 (s, 1 1-1), 7.78-7.74 (ni, 2 H), 7.70 (ci, I H), 7.68 (d, H), 7.54 (br. s, 1 H), 7.50 (hr. d, 1 H), 7.33 (br. s, 1 H), 6.90 (d, 1 II), 6.42 (d, 1 H), 6.05 (dd, I H), 5.20 (s, 2 H), 3.01 (t, 2 H), 2.61 (t, 2 H).
Example 89: 644-chloro-2-U4-f5-chloro-24JH-tetrazol-1 -yflphenyflqxo-1(21fr yyridinyl}methyl')-1 H-imidazol-5-yI]-3,4-dihydro-2(1H)-guinolinone The compound prepared in Example 88 (100mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (38 rug), LC/MS 1R 3.69 minutes; MS (ES4) m/ 533 (M+H) b H NMR (500 MHz, DMSO-d6) 5 12.86 (s, 1 11), 10.22 (s, I H), 9.72 (s, 1 H), 7.87 - 7.77 (m, 3 H), 7.69 (d, I H), 7.49 (s 1 H), 7.47 (d, 1 13), 6.92 (d, I H), 6.28 (s, 1 H), 5.88 (dd, I H), 5.05 (s, 2 H), 2.96 -2.87 (m. 2 H), 2.57 2.47 (ohs. in, 2 H).
anjp1ç 90: mjçthy1 N-(4-acetyl-2-fluorophenyj)carbamate To an N,N-dimethylformamide (9 mL) solution of methyl N-(2-fluoro-4-iodophenyDcarbamate [J. Med. Chem. 48(18), 5823 (2005)1 (1.20 g) was added propane-1,3-diylbis(diphenylphosphane) (0.IQ g), palladium(II) diacetate (28 rug) arid 3 M aqueous potassium carbonate solution (2.28 mL). The mixture was partitioned equally across four microwavable vessels and all were degassed with nitrogen for 5 minutes. To each reaction mixture, n-butyl vinyl ether (0.66 mL) was added and the reaction mixtures were irradiated under microwave conditions (100 N) at 100°C for 30 minutes. The reaction mixtures were combined and concentrated. The residue was suspended in tetrahydrofuran (12 mL) and 1 M hydrochloric acid (12 mL), stirred for 2 hours at room temperature and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (2% to 100% ethyl acetate in heptanes) to afford the title compound having the following physical properties (0.49 g).
LC/MS tR 1.57 minutes; MS (ES4) ink 212 (M+H Example 91: methyl N-14-(2-bromoacetyl)-2-fluorophenyl]carbamate To a cooled (5 °C) glacial acetic acid (16 mL) solution of the compound prepared in Example 90 (0.49 g) was added a solution of33 wt. % hydrogen bromide in acetic acid (0.32 rnL) followed by pyridinium tribroinide (0.73 g) and the mixture stirred at room temperature for 5 hours. To the reaction mixture, a saturated solution of aqueous sodium bicarbonate (100 niL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and then concentrated. The residue was triturated with a 1: 1 mixture of ethyl acetate and heptane and the precipitate isolated by filtration to give the title compound having the following physical properties (0.44 g).
LC!MS JR 1.79 minutes; MS (ES1) mlz 290 and 292 (M+H)8 Example 92: methyl (4-(247-[5-chloro-2-fl-tetrazo1d-yflpheny1]-12.35- çjdro-3-indo1izinyfl -1 H-irnidazol-5-yfl-2-fluorophenyl]carbamate The same operation as in Example 84 -* Example 39 -. Example 40 Example 41 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to 1 5 Example 84 in the operation, the compound prepared in Example 91 was used).
LCIMS 1R 3.31 minutes; MS (ES) m'z 547 (M+H) b H NMR (500 MHz, methanol-&) 89.37 (s, 1 H), 7.81 (br. s, I H), 7.77 -7.73 (in, 2 H), 732 -7.68 (m, I H). 7.53 -7.43 (in, 2K), 7.42-7.34 (in. 1H), 6.15 (s, I H), 6.10 (s, I Fl), 5.79 (dU, I H), 3.78 (s, 3 H), 3.52-3.41 (in, I H), 3.12 (ddd, 1 H), 2.65 (qd, 1H), 2.52 (app. br. s, 1 H).
Exan, j,leS3: methyl_14-(4-cq2-7-5-chloro-2-(1 H-tetrazol-1-ypeny(1-5-oxo-j,3,5-tetrahvdrcEjnpliziny1}-1FI-fr idazol-5-yfl-2-Ouorophçpyflcarbamate The compound prepared in Example 92 (160 rug) was treated as detailed in Example 47 to give the title compound having the following physical properties (40 mg).
LC/MS tg 4.19 minutes; MS (ES) m/z 581 (M+H)1' 1H NMR (500 MHz, DMSO-d) 8 13.03 (br. s, 1 H), 9.71 (s, 1 H), 9.48 (hr. s, 1 H), 7.86 -7.80 (in, 2 H), 7.80-7.72 (in, 2 Fl), 7.59-7.48 (in, 2 H), 5.99 (s, I 1-1), 5.94 (a, I H), 5.57 (dd, 1 H), 369 (s, 311), 3.31 -3.24 (obs. in, I 1-1), 3.00 (ddcl, 11-1), 2.58 -2.54 (ohs.
m, I 1-1),2.24-2.17(m, 111).
ppje 94: methyl N-[4-(2-brornoacctyl)-3 -fluoroyhenyilcarbamate S 127 The same operation as in Example 77 -÷ Example 90 -. Example 91 was conducted from 4-bromo-3 -fluoroani line to give the title compouud having the following physicat properties.
1F1 NMR (500 MHz, CDCI3) 67-86 (t, 1 H), 7.50 (dd, 1 H), 6.97 çdd, 1 14), 6.80 (hr. s, 1 H), 4.42 (d, 2 1-1), 3.75 (s, 3 H).
Example 95: methyj j4-(2-7-f5-chloro-24) H-tetrazol-1 -yl)phenylI5-oxo-1,2,3,5-tetxahydro-3-indolizinyl}-1 H-imidazol-5-y1)-3-f1uorppçpyllcarbamate The same operation as in Example 84 -÷ Example 52 -p Example 40 -* Example 41 was conducted from the compared prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 84 in the operation, the compound prepared in Example 94 was used).
LC/MS 1R 3.36 minutes; MS (ES) m1z 547 (M+H)" THNMR(500 MHz, methanol-d4) 89.25 (s, 1 H), 7.72 (app. br. s, I H), 7.65 -7.61 (m, 2 H), 7.60-7.56 (in, 1 H), 7.34 (1i, I II), 7.19 (hr. s, I H), 7.06 (app. hr. s, I 14), 6.04 (a, I H), 5.98 (a, I H), 5.70 (dd, I H), 3.65 (a, 3 H), 3.39-3.30 (in, I 1-1), 3.01 (ddd, I H), 2.53 (qd, I Fl), 2.41 (hr. a, I H).
Example 96: methyl 14-(4-e 2-7-F5-chloflH-tetrazol-1 -yl)phenyll-5-oxo- 1,23,5-teIrahydro-3-indolizinyl-lfl-imidazo1-5-y)-3-fluqwnlieiui41çgbaje The compound prepared in Example 95 (125 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (25 mg).
LCIMS Ig 4.19 minutes; MS (ES') m/z 581 (M+H) b H NMR (500 MHz, DMSO-d5)& 12.81 (hr. a, I H), 10.09(br. s. 111), 9.72 (s, I H), 7.88 -738 (m, 3 H), 7.60-7.41 (m, 214), 7.31 (d, 11-1), 5.99 (s, 114), 5.95 (a, 1 H), 5.59 (dd, I H), 3.71 (a, 3 H), 3.30-3.23 (in, I H), 2.98 (ddd, I H), 2.55-2.44 (abs. m, I H), 2.24-2.16 (in,) H).
Example 97: methyl N-[4-(2-bromoacctyfl-3-methylphenyllcarbamate The same operation as in Example 77 -Example 90 -* Example 91 was conducted from 4-bromo-3-methylaniline to give the title compound having the following physical properties.
LC/MS ii 1.83 minutes; MS (ES) ,n/z 286 and 288 (M+HY mp1e 98: methyl [442-{7-[5-chloro-2-( 1 1-1-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1 H-imidazol-5-yl)-3-methylphenyllcarbaniate The same operation as in Example 84 -÷ Example 52 -* Example 40 Example 41 was conducted from the compared prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 84 in the operation, the compound prepared in Example 97 was used).
LC/MS tR 3.07 minutes; MS (ES) m/z 543 (M+H)b 1H NMR (500 MHz, methanol-d4) 8 9.25 (s, I H), 7.67-7.61 (m, 211), 7.58 (d, 1 H), 7.22 (m, 3 H), 6.91 (br. s, 1 H), 6.02 (s, 1 H), 5.99 (s, 1 H), 5.70 (dd, I H), 3.64 (s. 3 11), 3.39-3.29 (m, 1 H), 3.00 (ddd, 1 H), 2.58 -2.48 (m, I H), 2.38 (app. br. s, I H), 2.25 (s, 3H &mple 99: methyl [4-(4-chloro-2-{ 7-15-chloro-2-(1 H-tetrazol-1 -ylThhny11-5-oxo-I,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)-3-methylphenyi]carbamate The compound prepared in Example 98 (90 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (48 mg).
LC/MS tR 3.18 minutes; MS (ES) ?n/z 577 (M+H)b 1H NMR (500 MHz, methanol-d4) 8 9.26 (s, I H), 7.66 -7.62 (m, 2 H), 7.58 (d, 1 H), 7.30 (app. s, 1 H), 7.26 (d, 1 H), 7.12 (d, I H), 6.03 (s, 1 H), 5.99 (s, I H), 5.60 (dd, I 1-fl, 3.65 (s, 3 11), 3.40-3.31 (m, 111), 3.01 (ddd, I H), 2.54 (qd, 1 10,2.37-2.30 (m, 1 H). 2.15 (s, 3 H).
kMmple 100: myl N-(3-ethvlnhenyl)carbamate 3-Ethylaniline (4.0 g) was treated as detailed in Example 77 to give the title compound having the following physical properties (5.9 g).
LC/MS k 1.90 minutes; MS (ES) ,n/z 180 (M-l-H)" Example 101: methyl N-(4-acetyl-3-ethylphenyl)carbamate To a dichloroethane (7 mL) solution of the compound prepared in Example 100 (0.50 g) was added acetyl chloride (0.21 mL) and aluminium trichloride (0.93 g) and the mixture stirred at room temperature overnight. To the reaction mixture, ice-water (5 mL) was cautiously added followed by extraction into dichloromethane. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (7% to 60% ethyl acetate in heptanes) to afford the tide compound having the following physical properties (0.43 g).
LC/MS R 2.13 minutes; MS (ES4) n/z 222 (M+H)a Example 102: methyl N-[4-(2-bromoacetyl)-3-ethylpbenyllcarbamate The compound prepared in Example 101 (0.41 g) was treated as detailed in Example 91 to give the title compound having the following physical properties (0.41 g).
LCIMS R 1.96 minutes; MS (ES) in/z 300 and 302 (M+H)a Example 103: methyl [4-12-7-[5-ch1oro-2-(1 1-1-tetrazol-I -yI)phenyll-5-oxo-1,2,3,5-tetrahydro-3 -indoliz.inyl -1 H-imidazol-5-yl)-3-ethylphenyllcarbamate The same operation as in Example 84 -* Example 52 -f Example 40 -Example 41 was conducted from the compared prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 84 in the operation, the compound prepared in Example 102 was used).
LCJMS R 3.18 minutes; MS (ES1) ,nlz 557 (M+H)" H NMR (500 MHz, methanol-cl4) 3 9.36 (s, I H), 7.77 -7.72 (m, 2 H), 7.69 (d, 1 H), 7.45-7.26 (m, 3 H), 7.11 -6.84 (m, 1 H), 6.14 (s, I H), 6.10 (s, I H), 5.82 (dd. 1 H), 3.76(s,3 H), 3.51 -3.40 (m, 1 H), 3.12 (dcl. 1 II). 2.72 (q, 2 H), 2.69-2.59 (m, 1 H), 2.51 (app. br. s, 1 H), 1.15 (app. br. s,3 H).
Example 104: methyl 14-(4-chloro-2-{ 7-[5-chloro-2-(1H-tetrazol-1 -yl)phenyl]-5-oxo-I,2,3,5-tetrahydro-3-indolizinyl} -1 F1-imidazol-5-yl)-3-ethylphenyllcarbamate The compound prepared in Example 103 (40 mg) was treated as detailed in Example 44 to give the tide compound having the following physical properties (26.7 mg).
LC/MS R42' minutes; MS (ES4) ,n/z 591 (M+H)t II NMR (500 MHz, methanol-cL4) 8 9.38 (s, 1 H), 7.78 -7.74 (m, 2 H), 7.70 (d, 1 H), 7.45 (app. s, I H), 7.39 (dd, 1 H), 7.19 (d, 1 H), 6.14 (s, 1 H), 6.11 (s, I H), 5.70 (dd, 1 H), 3.77 (s, 3 H), 3.51 -3.42 (m, 1 11), 3.12 (ddd, I H), 2.71 -2.62 (m, 1 H), 2.59 (q, 2 H), 2.47-2.40 (m, 1 11), 1.10 (t, 3 H).
Example 105: methyl N-[4-(2-bromoacetyl)-3-ch1orophenylcarbanate The same operation as in Example 77 -Example 90 -÷ Example 91 was conducted from 4-bromo-3-chloroaniline to give the title compound having the following physical properties.
LC/MS tyR 1.89 minutes; MS (ES) m/z 306 (M+H) a Example 106: methyl [3-chloro-4-(2-{ 7-[5-chloro-2-( I H-tetrazol-I -yl)phenyll-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)phenyllcarbainate The same operation as in Example 84 -Example 39 -* Example 40 -÷ Example 41 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 84 in the operation, the compound prepared in Example 105 was used).
LCIMS R 3.38 minutes; MS (ES4)nilz 563 (M+H)" H NMR (500 MHz, methanol-d4) 8 9.37 (s, 1 11), 7.77 -7.73 (m, 3 H), 7.73 -7.66 (m, 2 11), 7.53 (app. hr. s, 1 H), 7.36 (app. hr. s, I H), 6.16 (s, 1 H), 6.10 (s, 1 H), 5.83 (dd, 1 1-1), 3.77 (s, 3 H), 3.53 -3.42 (at 1 H), 3.12 (ddd, 1 H), 2.70-2.60 (m, 1 11), 2.54 (app.
br. s, I H).
Example 107: methyl {3-chloro-4-[2-((4-[5-chjoro-2-( 1H-tetrazol-1 -y1)phenyll-2-oxo- 1 (2Hjpyridinyl} methyl)-1 H-imidazol-5-yllphenyl} carbamç The same operation as in Example 38 -t Example 39 was conducted from the compound prepared in Example 25 to obtain the title compound having the following physical properties. (Note: in the step corresponding to Example 38 in the operation, the compound prepared in Example 105 was used).
LC/MS ig 3.03 minutes; MS (ES) ?n/z 537 (M+H) b H NMR (500 MHz, DMSO-do) 8 12.28 (hr. s, 1 H), 9.85 (br. s, 1 H), 9.71 (s, 1 11), 7.91 (d, I H), 7.86-7.77 (m, 3 H), 7.73 (d, 1 H), 7.63 (app. hr. s, I H), 7.58 (s, 1 H), 7.41 (dcl, 1 H), 6.30 (app. hr. s, 1 H), 5.87 (dcl. 1 H), 5.11 (s, 2 H), 3.68 (s, 311). S 131
Example IOSU) and Example 108(2): methyl N-[4-(2-bromoacetyl)-3- methoxyphenylicarbamate and methyl N-[2-bromo-4j2-brornoacetyfl-5 -methoxyphenv11carbamai The same operation as in Example 77 -b Example 90 -* Example 91 was conducted from 4-bromo-3-methoxyaniline to give a 3: 5 mixture of the title compounds having the following physical properties.
Example lOSfl)j
tX/MS tR 1.82 minutes; MS (ES4) rn/i 302 and 304 (M+H) a
Example 10812):
LC/MS tR 2.10 minutes; MS (ES) rn/i 379. 381, 383 (M+H) a QjlO9(l) and Example 109(2): methyl [442-U3S)-7-[5-chloro-2-( I H-tetraiol-I - yl)phenvI}-5-oxo-1,2,3,5-tetrahydro-3-indoliñnyl}-IH-imidgç-5-l-3- xhen'Ic&bnatejdethyl [2-brorno-4-(2{{3S}7-[5-chloro-211 H-tetrazol- I -yflphenyl]-5-oxo-1,2,3,5-tetrahydro-3indolizinyfl-l H-imidazo1-5-yI}-.-inethoxyphenylicarbarnate The same operation as in Example 84 -. Example 39 was conducted from the compound prepared in Example 17 to give die tide compounds in a 2: 1 ratio having the following physical properties. (Note: in the step corresponding to Example 84 in the operation, the 3: 5 mixture of the compounds prepared in Example 108 was used).
Example 109(1):
L/MS Ig 312 minutes; MS (ES) ith 559 (M+H)" H NMR (500 MHz, DMSO-&) 8 11.97 (s, 1 H), 9.70 (s, I H), 9.69 (s, 1 H), 7.88-7.78 (m, 4 H), 7.31 (d, I H), 7.27 (s, I H), 7.04 (dd, I H), 5.99 (s, 111), 5.96 (s, I II), 5.63 (dd, I II), 3.83 (s, 3 H), 3.66 (s, 3 H), 3.30-3.21 (in. 1 H), 3.00 (dd, I H), 2.48-2.41 (m, 1 H), 2.39-2.32 (m, 1 H). n
Example 109(2):
LC/MS (R 3.59 minutes; MS (ES) ,n/z 637 and 639 (M+H) HNMR (500 MHz, DMSO-d6) a 12.15 (s, I H), 9.70 (s, I H), 8.89 (s. 1 H), 8.06 (s, 1 H), 7.85 -7.77 (in, 3 H), 7.45 (d, I H), 7.25 (s, I H), 5.99 (s, I H), 5.95 (s, 1 H), 5.64 (dd, I H), 3.87 (s, 3 H), 3.66 (s, 3 H), 3.45 -3.38 (m, 1 H). 3.02 (dd, I H), 2.54-2.46 (ohs. m, 1 H), 2.43 -2.35 (m, I H).
jjje 110: methyl N-f4-(2-bromoacetyl)-3-(trit1uoromethyi)phenytcarbamate The same operation as in Example 77 -Example 90 -. Example 91 was conducted from 4-bromo-3-trifluoromethylanilinc to give the title compound having the following physical propertics.
LCiMS tR 1.38 minutes; MS (ES) ,Wg 340 and 342 (M±H) a Example Ill: methyl f4-(2-(3S)-7-(5-chloro-2-(l1l-tetrazol-l-vflphetjjjoxo- I,2,3j-tctrahydro-3-indotizinyl-jjjjmidol-5-l-3- &illuQromethyl)phdnxllcarbamate The same operation as in Example 51 -p Example 52 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties.(Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 110 was used).
LC/MS tR 3.59 minutes; MS (ES') :n'z 597 (M+lflb H NMR (500 MHz, methanol-d4) 6 9.36 (s, 1 H), 7.95 br. s, 1 H), 7.78 -7.72 (in, 2 1-1), 7.73 -7.66 (m, 2 H), 7.62-7.50 (tin, I H), 7.13 (br. s, 1 H), 6.15 (s, I H), 6.10 (s, I H), 5.82 (Ud, I H), 3.78 (s, 3 H), 3.53 -3.40 (in, 1 1-fl, 3.16-3.07 (in, 1 H), 2.70-2.59 (in, I H), 2.53 (app. br. s, I H).
Example 1 1 2jhJ [4-(4-chloro-2-(3S)-7-[5-ch1oro-2-( I H-tetrazol-t-yflpheny1-5- oxo-1,2,3,5-tetmhj-indoIizin1-fflimido1-5j'1) -3-rifluoromftyflhenvl1carbamate The compound prepared in Example 111(50 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (25 rag).
LCIMS tR 4.29 minutes; MS (ES4) m/ 631 (M+H), 1H NMR (500 MHz, methanol-d4) ö 9.38 (s, I H), 8.03 (s, I H), 7.78 -7.74 (in, 3 Fl), 7.70 (d, 1 II), 7.43 (d, 1 H), 6.16 (s, I H), 6.11 (s, I H), 5.12 (dd, I H), 3.80 (s, 3 H), 3.48-3.39 (m, I H), 3.12 (ddd, 1 H), 2.72-2.60 (m, 1 H), 2.45 -2.36 (m, I H).
Example 113: 4-a-{ 7-[5-chloro-2-fl H-tetrazol-1 -yl)phenyll-5-oxo-I,23,5-tetryp- 3-indohzinyl}-l H-imidazol-4-yDbenzoic acid ammoniate The same operation as in Example 84 -÷ Example 39 -÷ Example 37 -Exarnpie 55 -. Example 41 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 84 in the operation, methyl 4-(2-bromoacetyl)benzoate [J.
Am. Chem. Soc. 122(39), 9361 (2000)] was used. In the step corresponding to Example 41 in the operation, high performance liquid chromatography (5 to 100% acetonitrile in 2 mM aqueous ammonium hydrogen carbonate) was used to give the title product as the ammonium salt.
LCJMS R 3.13 minutes; MS (ES4) ,th 500 (M+H) b H NMR (500 MHz, DMSO-d6) 59.70 (s, I H), 7.89 (d, 2 H), 7.85 -7.72 (m, S H), 7.64 (s, I H), 5.98 (s, 1 H), 5.96 (s, 1 H), 5.64 (dd, 1 H), 3.45 -3.30 (obs. m. 1 H), 3.00 (dd, 1 II), 2.58 -2.45 (ohs. m, 1 H), 2.34 (app. hr. s, I H).
Example 114: 4-(2-{7-[5jQro-2-1H-tetrazol-l-yflphenyl1-5-oxo-l.2.3,54etrahydro- 3-indsjjzinvl}-I H-imidazol-4-yl)benzainide To an N,N-dimethylformamide (2 mL) solution of the compound prepared in Example 113 (88 mg) was added O-(7-azabcnzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (87 mg), ammonium chloride (47 mg) and N,N-diisopropylethylamine (145 1iL) and the mixture stirred at room temperature for 2 hours. To the reaction mixture, water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated.
The residue obtained on concentration was purified by high performance liquid chromatography (5 to 100% acetonitrile in water) to give the title compound having the following physical properties (33.2 mg).
LCIMS tR 2.89 minutes; MS (ES) rn/i 499 (Mi-f-I) b H NMR (500 MI-Iz, DMSO-d6) 8 12.22 (s, I H), 9.68 (s, 1 H), 7.90 (lx. s, 1 H), 7.84 (d, 2 H), 7.81 -7.77 (m, 3 H), 7.76 (d, 2 H), 7.63 (s, 1 H), 7.24 (hr. s, I II), 5.96 (s, 1 H), 5.95 (s, 1 H), 5.64 (d, I H), 3.48 -3.33 (in, I H), 3.00 (dcl, 1 H), 2.56 -2.47 (ol,s, m, 1 H), 2.39 -2.30 (in, I H).
Example 115: 4-(4-cb1oro-2-(7-15-ehloro-2-fllicirazo1-1-y1Thhenvl1-5-oxo-1.2,3, S-tetrahydro-3-indolizinyl} -1 J-l-imida2ol-5-yl)benz]jge The compound prepared in Example 114 (88 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (99 mg).
LC/MS 1R 3.55 minutes; MS (ES) nz1z 533 (M+H) S ii NMR (500 MHz, DMSO-d5) 3 13.12 (s, I H), 9.71 (s. I H), 8.01 (s, 1 H), 7.97 (d, 2 11), 7.83 -7.78 (m, 511), 7.41 (s, 1 Fl), 6.00 (s, 1 H), 5.95 (s, I 1-1), 5.59 (dd, 1 11), 3.35 - 3.22 (in, 1 H), 3.00 (dcl, 1 H), 2.60-2.48 (obs. m, I H), 2.21 (t, 111).
Example Ij Aert-buWI N-(4-cMoro-2-3-(4-(4-eyano-3-fluoroDhenyfl-1H-imidazol-2-yl1-5c_-I,2,3, 5-tetrahydroindolizin-7-vl}phenyflcarbamate The same operation as in Example 38 -. Example 39 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 38 in the operation. 4- (2-bromoacetyl)-2-fluorobenzonitrile [W02007/070826, page 121] was used).
LCIMS tR 2.27 minutes; MS (ES) n1z 546 (M4-H) a Example 117: tert-butyl N-(2-3-{4-(4-carbamoylphenyl)-I H-imidazol-2-yll-5-oxo- 1,2,3,5-tetrahydroindolizin-7-vl}-4-chlorophenyl)carbamate To a diniethylsulfoxide (6 mL) solution of the compound prepared in Example 116 (0.106 g) was sequentially added potassium carbonate (13 ing) and 30% aqueous hydrogen peroxide solution (0.13 mL) and the mixture stirred at 50 °C for 16 hours. To the reaction mixture, a 10% aqueous solution of lithium chloride (3 mL) was added and the mixture stirred at room temperature for 15 minutes followed by extraction into ethyl acetate. The combined organic layers were sequentially washed with a saturated aqueous solulion of sodium hydrogen carbonate and brine, dried and concentrated to obtain the crude title compound having the following physical properties (0.156 g).
LC/MS tk 183 minutes; MS (ES) in/z 564 (M+H) £&w1e 118: 4-1247-F5-chloro-2-f1H-tetrl-1-yflpheny1i-5-oxo-1,2,3.5-tetrahydro- 3-indolizinyfl-1 H-imidazol-5-yfl-2-fluorobenzamide The same operation as in Example 40 -* Example 41 was conducted from the compound prepared in Example 117 to give, the title compound having the following physical properties.
LCIMS 3.30 minutes; MS (ES4) n/z 517 (M+H) b H NMR (500 MHz, methanol-d4) 6 9.37 (s, 1 H)> 7.85 (t, I H), 7.78 -7.73 (m, 2 H), 7.70 (d, 1 H), 7.66-7.52 (m, 3 H). 6.15 (s, I H), 6.11 (s, 1 H), 5.80 (dd, I H), 3.56- 3.42 (m, I H), 3.14 (ddd, I H), 2.73-2.61 (m, I H),2.58 -2.44 (m, I H).
Example 119: 442-bromoacetyflbeuzamide 4-Acetylbenzamide. Org. Chem.. 65(26), 9103 (2000)] (0.25 g) was treated as detailed in Example 91 to give the title compound having the following physical properties (0.37 g).
LC/MS 1R 1.33 minutes; MS (ES) m/z 242 and 244 (M-3-Fl) a Example 120: 4-j 24 T4-[5.chloro-241 li-tetrazol-I -yl)phenvll-2-oxo-1 (211)-pyridinyl} methy1)-1H-imidazo1-5-vlbenzamide The same operation as in Example 51 -* Example 52 was conducted from the compound prepared in Example 25 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 119 was used).
LC!MS 2.88 minutes; MS (ES) m/z 473 (M±H)'° H NMR (500 MHz, methanol-cta) 89.37 (s. I H). 7.90 (d, 2 H), 7.80 (d. 2 11), 7.77- 7,72 (in, 2 H), 7.70 (d, 1 H), 7.68 (d, 1 H). 7.55 (s, 1 H), 6.41 (d, 1 H), 6.04 (dd, 1 H), 5.22 (s, 2 H).
Example 121: 4-[4-chloro-2-4-[5-ch[oro-2-( IH-tetrazol-I -yllphenvll-2-oxo-I (2H)-rvridinyl methyI)-.1H-imidazol-5-yljbenzamide The compound prepared in Example 120 (50 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (16 tug).
LC/MS tR 3.52 minutes; MS (ES) mhz 507 (M+H) b H NMR (500 MHz, DMSO-d6) t 13-13 (hr. s, I H), 9.72 (s, I H), 7.99 (br. s. I H), 7.93 (ci, 2 H), 7.85 -7.76 (m, 5 H), 7.69 (d, I Fl), 7.38 (br. s, I Fl), 6.26 (app. s, I 1-1), 5.88 (dd, 1 H), 5.05 (s, 2 H) Example 122: 4(j7-5-chloro-2-(IH-tetrazo1-1-yl)phenyl-5-oxo-1,23,5-tetrthvdro- 3-indolizinyli-I H-imidazol-4-yl)-N-methyfbenzamide The compound prepared in Example 113 (88 mg) was treated as detailed in Example 114 using methylamine hydrochloride instead of ammonium chloride to give the title compound having the following physical properties (46,8 mg).
LC/MS ER 2.97 minutes; MS (ES) ln/z 513 (M+H) b H NMR (500 MT-li, DMSO-d6) 8 12.23 (s. I H). 9.69 (s, I Fl), 8.36 (q, I H). 7.91 -7.68 (m, 7 H). 7.63 (s, I H), 5.98 (s, I H), 5.97 (s, 1 H), 5.64 (dcl, I H), 144 -3.33 (in, 1 H), 3.02 (dd, I H), 2-78 (ci, 3 H), 2.57 -2.48 (ohs. m, I H), 238 -2,31 (m, 1 H).
Example 123: 4-(5-chloro-2-{7-[5-chloro2-(l H-tetrazol-1 -yI)phenyfl-5-oxo-l.2,3,5-trahygro-3-indoliziuyn-1H-imnidazoi-4-yl) jethlbeamide The compound prepared in Example 122 (90 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (11.1 mg).
LC/MS Eg 372 minutes; MS (ES) ni/a 547 (M4-H) b 1H NMR (500 MHz, DMSO-d6) 8 13.10 (s, I Fl), 9.71 (s, I H), 8.48 (q, 1 11), 7.93 (d, 2 11), 7.87 -7.72 (m, 5 H), 6.00 (s, I Fl), 5.95 (s, 1 II), 5.59 (dd. 1 Fl), 3.36-3.22 (ohs. m, I H), 2.80 (d, 3 H), 2.59-2.50 (ohs. tu, I H), 2.39-2.12 (in, 211).
Example U4j4-7-[5-ch1oro-2-(1 H-tetrazol-1 -yI)phenyll-5-oxo-I,2,3,5-te.Iyt 3-indolizinyfl-1H-iniidazol-4-yfl-N-ethylbenzamide The compound prepared in Example 113 (88 mg) was treated as detailed in Example 114 using ethylamine hydrochloride instead of ammonium chloride to give the title compound having the following physical properties (48.6 mg).
LCIMS tR 3.11 minutes; MS (ES) rn/z 521 (MFH)b H NMR (500 MHz, DM50-cl6) 6 12.23 (s, I H), 9.70 (s, I H), 8.40 (t, 1 H), 7.90 -7.69 (m, 7 H), 7.64 (s, 1 H), 5.98 (s, I H), 5.97 (s, I H), 5.64 (dd, I H), 3.45 -3.33 (m, 1 H), 3.32-3.23 (m, 2 H), 3.01 (dd, I H), 2.56-2.48 (ohs. m, 1 H), 2.38-2.30 (m, 1 11), 1.13 (t, 3 H).
Example 125: 4-(4-chloro-2-7-[5-ch1oro-2-(1 H-tetrazo1-1-yflphenyl-5-oxo-I,2,3, tetrahydro-3-indolizinyl}-1 H-imidazo1-5-y1)-N-ethylbenzani The compound prepared in Example 124 (93 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (24.9 mg).
LC/MS 1R 3.96 minutes; MS (ES) mhz 561 (M+11) b 1fl NMR (500 MHz, DMSO-d6) 8 13.11 (s, I H), 9.71 (s, 1 H), 8.51 (t, I H), 7.94 (d, 2 H), 7.87 -7.68 (m, 5 11), 6.00 (s, I H), 5.95 (s, 1 H), 5.59 (dd, I H), 3.40-3.23 (obs. m, 3 H), 3.00 (dd, I H), 2.58 -2.46 (obs. m, I H), 2.20 (t, 1 H), 1.14 (t, 3 H).
Example 126: 7-[5-cfflo-2-(1 H-tetrazol-1 -y1Thhenyl]-3-[5-(4*nitrophiyfl-1 H-imidazdl-2-yIl-2,3-dihydro-5( I 1-fl-indolizinone The same operational sequence as in Example 38 -* Example 39 -Example 40 Example 41 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 38 in the operation, 2-bromo-1-(4-nitrophenyl)-ethanone was used).
LCIMS t 4.03 minutes; MS (ES4) in/z 501 (M-FH) b NMR (500 MHz, DMS0-d) 8 12.49 (br. s, I H), 9.70 (s, I H), 8.21 (d, 211), 7.95 (d, 2 H), 7.89-7.77 (m, 4 H), 5.99 (s, 1 H), 5.97 (s, 1 H), 5.65 (dd, I H), 3.44-3.25 (obs. in, 1 Fl), 3.02 (dd, I H), 2.58 -2.42 (obs. in, 111), 2.36 -2.25 (in, 1 H).
Example 127: 3-15-(4-aminophenyfl-lH-imidazol-2-yll-7-[5-chloro-2- (IH-tetrazol-1-ylhenyfl-2.3-dihydro-5( 1 H)-indolizinone The compound prepared in Example 126(1.10 g) was treated as detailed in S 138 Example 74 to give the title compound having the following physical properties (0.86 g).
LCIMS ig 2.74 minutes; MS (ES) m'z 471 (M+}4)' H NMR (500 MHz. methanol-d4 6 9.37 (s, I H), 7.78 -7.73 (m, 2 H). 7.70 (d, I H), 7.39 (app. hr. s, 2 H), 7.06 (hr. s, I H), 6.75 (d, 2 H), 6.14 (s, I H), 6.10 (s. 1 H), 5.79 (dd, I Fl), 3.52-3.39 (m, 1 Fl), 3.11 (ddd, 1 H), 2.69-2.58 (m, I H), 247 (app. hr. s, I H).
Example 128: ethyl [4-(2-17-[5-chlorn-2-flH-tetrazol-1-yI)phenylj-5-oxo-l,2,3, 5-tetrahydrqjndolizinyfl -1H-imidazol-5-yl)phenyflcarbamate To a cooled (0 °C) dichoromethane (5 mL) solution of the compound prepared in Example 127 (130 mg), pyridine (45 RL) and ethyl chioroformate (26 12L) were added sequentially and the mixture stirred overnight at room temperature. The reaction mixture was concentrated and dissolved in methanol (5 mL), concentrated aqueous ammonia solution (0.21 mL) was added and the mixture stirred 3 hours at room temperature. The reaction mixture was concentrated, the residue suspended in water (3 niL) and extracted into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (25% to 100% ethyl acetate in heptanes followed by 1% to 3% methanol in ethyl acetate) to afford the title compound having the following physical properties (76 mg).
LCIMS R 3.21 minutes; MS (EW) nih 543 (M+H) b H NMR (500 MHz, methanol-d4) 69.37 (s, I II), 7.78 -7.72 (iii, 2 H), 7.70 (d, I H), 7.65-7.40 (iii, 4 H), 7.36-7.10 (m, I H), 6.15 (s, 1 H), 6.10 (s, I H), 5.80 (dU, I H), 4.20 (q, 2 H), 3.52 -3.41 (m. I H), 3.12 (ddd, I Fl), 2.65 (qd, 1 H), 2.50 (app. br. s, I H), 1.33 (t, 3M).
Example 129(1) to Example 129(6) The compounds of the present invention having the following physical data were synthesised from the compound prepared in Example 127 and the corresponding acid chlorides, chlorofonnates, sulfonyl chlorides or acetic anhydride using the method as detailed in Example 128.
Example 129(1): isopropyl [4-(j75-chloro-2-( 1 H-tetrazol-1 jflpjnyl}-5-oxo- 1,2,3,5-tetraliydro-3-indolizinyl} -1H-imidazol-5-yl)phenyllcarbaniate LCIMS tR 3.36 minutes; MS (ES) m/z 557 (M+H) b H NMR (500 MHz, methanol-&) ö 9.37 (s, 1 H), 7.78 -7.73 (m, 2 H), 7.70 (d, 1 H), 7.65 -7.38 (m, 4 H), 7.30-7.10 (m, 1 H), 6.15 (s, 1 H), 6.10 (s, 1 H), 5.80 (dd, 1 II), 5.02-4.94 (m, 1 H), 3.51 -3.41 (m, I H), 3.12 (ddd, 1 H), 2.71 -2.61 (m, 1 H), 2.52 (hr. s, 1 H), 1.32 (d, 6 H).
Example 129(2): 2-methoxyethyl 14-(2-(7-[5-ehloro-2-(1 H-tetrazol-1 -yl)phenyl]-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl 1-1 H-imidazol-5-yl)phenyllearbamate LCJMS tR 3.11 minutes; MS (ES) m/z 573 (M+H), 545 (M-N2+H)" H NMR (500 MHz, methanol-cL4) 6 9.38 (s, 1 H), 7.79 -7.72 (m, 2 1-1), 7.72 -7.67 (m, 1 H), 7.59 (app. hr. s, 2 H), 7.46 (app. br. s, 2 H), 7.37-7.07 (m, I H), 6.14 (s, 1 H), 6.10 (s, 1 H), 5.80 (d, 1 H), 4.36-4.19 (m, 2 H), 3.72-3.61 (m, 2 H), 3.52 -3.43 (m, I H), 3.41 (s, 3 H), 3.17-3.05 (m, 1 H), 2.71 -2.59 (m, 1 H), 2.49 (app. br. s, 1 H).
Example 129(3): N-14-(2-7-[5-eh1oro-2-( 1 H-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imida.zol-5-yl)phenyllacetamide LCIMS tR 2.89 minutes; MS (ES) ,n/z 513 (M+H)" H NMR (500 MHz, methanol-th) 6 9.37 (s, 1 H), 7.77-7.73 (m, 2 H), 7.70 (d, 1 H), 7.64-7.55 (m, 4 H), 7.27 (br. s, 1 H), 6.15 (s, I H), 6.11 (s, 1 H), 5.80 (dd, 1 H), 3.52- 3.43 (m, 1 H), 3.12 (ddd, I H), 2.71 -2.59 (m, 1 H), 2.53 -2.44 (m, 1 Fl), 2.14 (s, 3 H).
Example 129(4): N-[4-(2-{7-[5-ehloro-2-(IH-tetrazol-1-yflphenyll-5-oxo-1,2,3, 5-tetrahydro-3 -indolizinyl} -1 H-imidazo]-5-yflphenylJ-2-methoxyaeetamide LC/MS tg 3.01 minutes; MS (ESt) in/z 543 (M+H)" H NMR (500 MHz, DMSO-d6) 6 12.04 (s, 1 H), 9.72 (s, 1 H), 9.68 (s, 1 H), 7.84 -7.77 (m, 3 H), 7.68 (d, 2 H), 7.58 (ci, 2 H), 7.43 (s, 1 H), 5.99 (s, I H), 5.96 (s, I H), 5.62 (dd, 1 H), 3.99 (s, 2 H), 3.38 (s, 3 Ii), 3.38-3.30 (obs. in, 1 H), 3.00 (dd, 1 H), 2.55 -2.44 (obs. in, 1 H), 229-2.39 (in, 1 H).
Example 129(5): N-[4-(2-1 7-[5-chloro-2-( 1 H-tetrazol-1 -yI)yhenvl]-5-oxo-1,2.3,5-tetrahydro-3-indolizinyl} -1H-imidazol-5-yl)phenyfl-3-methoxyproyanamide LC/MS 1R 3.03 minutes; MS (ESt) m/z 579 (M+Na), 557 (M+H), 529 (M-N2-i-H) H NMLR (500 MHz, methanol-d4) ö 9.36 (s, I H), 7.78 -7.72 (in, 2 H), 7.71 -7.66 (m, 1 H). 7.59 (app. br. s, 4 H), 7.27 (br. s, I 1-1), 6.14 (s, I 1-I), 6.09 (s, I 11), 5.79 (dd, 1 H), 3.74 (t, 2 H), 3.53 -3.40 (in, 1 H), 3.37 (s, 3 Fl), 3.11 (ddd, 1 H), 2.69-2.59 (in, 3 H), 2.49 (app. br. s, 1 II).
Example 129(6): N-[4-(2-I 7-15-chloro-2-( 1 H-tetrazol-1 -yl)phenyl]-5-oxo-1,2,3,5-tetrahydro-3 -indolizinyl -1 H-imidazol-5-yI)phenyljmethanesulfonamide LCIMS R 2.98 minutes; MS (ES4) m/z 549 (M+H) b 1H NMR (500 MHz, methanol-cl4) 6 9.25 (s, 1 H), 7.66-7.61 (m, 2 H), 7.60-7.44 (in, 3 H), 7.22 (br. s, 1 H), 7.15 (d, 211), 6.03 (s, 1 H), 5.99 (s, 1 1-1), 5.68 (dd, 1 H), 3.40- 3.29 (m, I H), 3.01 (add, I H), 2.86 (s, 31-11), 2.59-2.49 (in, 1 H), 2.38 (app. br. s, I H).
Example 130(1) to Example 130(4) The compounds of the present invention having the following physical data were synthesised from the compounds prepared in Examples 128, 129(1), 129(3) or 129(6) using the method as detailed in Example 44.
Example 130(1): ethyl [4-(4-chloro-2-{ 7-[5-ehloro-2-( 1 H-tetrazol-1 -y])phenyll-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)phenyljcarbamate LC/MS 1R 4.28 minutes; MS (ESt) pn/z 577 (M+H)" H NMR (500 MHz, DMSO-d5) a 12.86 (br. s, 1 1-1), 9.76 (s, 1 II), 9.71 (s, 1 H), 7.85 - 7.80 (m, 3 Fl), 7.60 (d, 2 H), 7.55 (d, 2 H), 5.99 (s, 1 H), 5.94 (s, 1 H), 5.57 (dd, 1 II), 4.15 (q, 2 H), 3.30 -3.24 (obs. m, 1 H), 3.03 -2.95 (m, 1 U), 2.58 -2.54 (obs. m, 1 H), 2.23 -2.17 (m, 1 H), 1.26 (t, 3 H).
Example 130(2): isopropyl [4-(4-chloro-2-{7-[5-chloro-2-(1 H-tetrazol-1 -yI)phenyll-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1 H-imidazol-5-yl')phenyll carbamate LC/MS R 4.46 minutes; MS (ES) m/z 591 (M+H)b H NMR (500 MHz, DMSO-d6) a 12.86 (br. s, 1 H), 9.71 (app. s, 2 H), 7.86 -7.78 (m, 3 H), 7.64 -7.52 (m, 4 H), 5.99 (s, 1 H), 5.94 (s, 1 H), 5.57 (dd, 1 H), 4.91 (quintet, 1 H), 3.30-3.25 (m, 1 H), 2.99 (ddd, 1 H), 2.58-2.54 (obs. m, 1 H), 2.20 (t, 1 H), 1.27 (d, 6 Fl).
Example 130(3): N-[4-(4-chloro-2-{7-15-chloro-2-( 1 H-tetrazol-1 -yl)phenyll-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl}-1 H-iniidazol-5-yI)phenyllacetamide LC/MS R 3.85 minutes; MS (ES) ,n/,z 547 (M+H)' 1HNMR (500 MHz, DMSO-d6) ö 12.88 (br. s, 1 H), 10.06 (s, 1 H), 9.71 (s, 1 H), 7.89- 7.75 (m, 3 H), 7.72-7.58 (m, 4 H), 5.99 (s, 1 H), 5.94 (s, 1 H), 5.57 (dd, 1 H), 3.30- 3.24 (m, 1 H), 2.99 (dd, 1 H), 2.59 -2.55 (obs. m, I H), 2.25 -2.16 (m, 1 H), 2.06 (s, 3 H).
Example 130(4): N-14-(4-chloro-2-{7-[5-chloro-2-( 1 H-tetrazol-1 -yl)phenyll-5-oxo- 12,5-tetrahydro-3 -indolizinyfl -1 H-imidazol-5-yl)phenyl]methanesulfonamide LC/MS tR 3.93 minutes; MS (ES) m/z 583 (M+H)' H NMR (500 MHz, DMSO-d6) 8 12.92 (br. s, 1 H), 9.91 (br. s, 1 H), 9.71 (s, 1 H), 7.88 -7.77 (m, 3 H), 7.70 -7.62 (m, 2 H), 7.29 (d, 2 H), 5.99 (s, I H), 5.94 (s, 1 H), 5.58 (dd, 1 H), 3.30 3.25 (m, I H), 3.04 (s, 3 H), 3.03 2.96 (m, 1 1-1), 2.57 2.54 (cbs. m, 1 H), 2.21 (dcl, 1 H).
Example 131: 1 44-(2-fl45-chloro-2-( I H-tetrazol-1 -yl)phenyll-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl I -IH-imidazol-5-yl')phenyl]-3-ethylurea To a dichloromethane (7 mL) solution of the compound prepared in Example 127 (130 mg) was added ethyl isocyanate (20 j.iL) and the mixture stirred at room temperature for 3 hours. To the reaction mixture, further ethyl isocyanate (20.tL) was added and the mixture stirred at room temperature for 72 hours. One fhrther treatment with ethyl isocyanate (20 isL) was required, and the mixture stirred at room temperature for 4 hours. The precipitate was collected by filtration and purified by high performance liquid chromatography (5 to 100% acetonitrile in water) to give the title compound having the following physical properties (28 mg).
LC/MS tR 2.95 minutes; MS (ES) m/z 542 (M+H) b H NMR (500 MHz, methanol-d.4) 69.37 (s, 1 H), 7.77 -7.73 (m, 2 H), 7.70 (d, 1 H), 7.55 (app. br. s, 2 H), 7.39 (d, 2 H), 7.21 (br. s, 1 H), 6.14 (s, 11-1), 6.10 (s, I H), 5.79 (dd, 1 H). 3.52 -3.41 (m. 1 1-1), 3.25 (q, 2 H), 3.12 (Odd, 1 H), 2.72 -2.59 (m, 1 H), 2.52 -2.45 (m, 1 1-1), 1.17 (t, 3 H).
Example 132: 3-[4-(2-f7-15-chloro-2-(1 H-tetrazol-1 -yI)phenyl]-5-oxo-1,2,3.5-tetrahydro-3 -indolizinyl i-I F1-imidazo1-5-y1)phenyjjjdimethyJurea To a cooled (0 °C) dichloromethane (7 mL) solution of the compound prepared in Example 127 (130 mg) was sequentially added pyridine (45 jiL) and dimethylcarbamic chloride (21 iL) and the mixture stirred at room temperature for 3 hours. To the reaction mixture, further dimethylcarbamic chloride (21 RL) was added and the mixture stirred at room temperature for 72 hours. One further treatment with dimethylcarbamic chloride (21 j.tL) was required, and the mixture stirred at room temperature for 4 hours.
The reaction mixture was concentrated and purified by high performance liquid chromatography (5 to 100% acetonitrile in water) to give the title compound having the following physical properties (32 mg).
LC/MS ig 2.93 minutes; MS (ES4) m/z 542 (M+IHI)" H NMR (500 MHz, methanol-&) S 9.35 (s, 1 H), 7.75 -7.79 (m, 2 H), 7.69 -7.65 (m, I H), 7.54 (d, 2 H), 7.38 (d, 2 II), 7.20 (hr. s, 1 H), 6.13 (s, I 1-1), 6.08 (s, I II), 5.78 (d, I 1-1), 3.49-3.39 (m, 1 H), 3.14-3.05 (m, 1 H), 3.02 (s, 6 H), 2.68-2.57 (m, 1 I-fl, 2.5! - 2.42 (m, lii).
Example 133: N-[4-(2-{ 7-15-chloro-2-(1 FI-tetrazol-1 -yflphenyl]-5-oxo-1,2,3,5-tetrahydro-3 -indolizinyl} -I H-imidazol-5 -ylkihenyll -2-(dimethylarnino)acetamide To anN,N-dimethylformamide (6 mL) and pyridine (2 mL) solution of the compound prepared in Example 127 (100mg) and N,N-dimethylglycine (26 mg) was added 1-{3-(dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride (49 mg) and the mixture stirred at room temperature for 16 hours. The reaction was concentrated and the residue suspended in water (15 mL) followed by extraction into a 3: 1 mixture of ethyl acetate and propan-2-ol. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by high performance liquid chromatography (5 to 100% acetonitrile in 2 mM aqueous ammonium hydrogen carbonate) to give the title compound having the following physical properties (21 mg).
LC/MS Ig 2.52 minutes; MS (ES) ink 279 [(M+2H)/23 b H NMR (500 MHz, methanol-d4) ö 9.37 (s, I H), 7.77 -7.72 (in, 2 H), 7.71 -7.67 (m, I H), 7.63 (app. br. s,4 H), 7.29 (br. s, I H), 6.14 (s, I H), 6.10 (s, I H), 5.80 (dd, I H), 3.53 -3.38 (m, I H), 3.16 (s, 2 H), 3.14-3.08 (m, 1 H), 2.70-2.59 (m, I H), 2.55 -2.43 (in, I H),2.39(s,6H).
Example 134: 3-([4-12-{7-[5-chloro-2-(I H-tetrazol-l-yjjphenyfl-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -lH-imidazol-5-yl)phenyl1anilno}-3-oxoropanoje acid methyl ester -To a cooled (0°C) dichloromethane (1 mL) solution of the compound prepared in Example 127 (54 mg) was sequentially added pyridine (11 p1) and methyl-3-chloro- 3-oxopropanote (20 p1) arid the mixture stirred for 3 hours at room temperature. To the reaction mixture, water (5 mL) was added followed by extraction into dichioromethane.
The combined organic layers were sequentially washed with 1 M hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and brine, dried and concentrated. The residue thus obtained was triturated with a 1: 4 mixture of ethyl acetate in heptanes, the resultant precipitate being isolated by filtration to give the title compound having the following physical properties (56 mg).
LC/MS tg 1.2! minutes; MS (Est) m/z 571 (M+HY Example 135: 3-( [4-(2-(7-[5-chloro-2-(l H-tetrazol-I -yl)phcnyll-5-oxo-1,2,3,5- çydro-3-indolizinvl1 -1 H-imidazol-5 -yflphenyllamino} -3 -oxopropanoic acid To a methanol (0.5 mL) solution of the compound prepared in Example 134 (56 rng) was added a solution of sodium carbonate (10.4 ing) in water (0.5 mL) and the mixture stirred at room temperature for 16 hours. Further sodium carbonate (10.4 mg) was then added and the mixture stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue suspended in 1 M hydrochloric acid (0.4 niL) [0 followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue thus obtained was triturated with a 1: 4 mixture of ethyl acetate in heptanes, the resultant precipitate being isolated by filtration to give the title compound having the following physical properties (53 mg).
LCIMS Ia 2.84 minutes; MS (ESt) an/z 557 (M+H) 1H NMR (500 MHz, DMSO-&) ö 12.59 (s, 1 II), 12.05 (s, I H), 9.69 (a 1 H), 7.80 (app. s, 3 14). 7.59 (d, 2 H), 7.50 (d, 2 H), 7.40 (a, I H), 5.99 (s, I H), 5.94 (s, 1 14), 5.62 (d, I H), 3.44-3.30 (obs. m, 1 H), 3.05 -2.92 (m, I H), 2.83 (s, 2 H), 2.49-2.42 (obs.
m, I ii), 2.38 -2.32 (m, 1 H).
Example 136: 6-(2-{7-[5-chloro-2-ffljftggoI-I -y1)phenyl-5-oxo-I.2,3,5-tetrahydro- 3-indolizinyflJflJjdazol-5-yD-4-hydroxy-2( l}fl-guinolinone The compound prepared in Example 135 (31 nig), was suspended in Eaton's reagent (0.21 mL) and the mixture stirred at 100 °C for 2 hours. To the cooled (0 °C) reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate (5 mL) was carefully added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated and the residue purified by high performance liquid chromatography (5 to 100% acetonitrile in water). The residue was purified further by trituration from a boiling 9: 1 solution of dichioromethane and methanol, The resultant precipitate was isolated by filtration to give the title compound having the following physical properties (2.8 mg).
LCIMS i 2.88 minutes; MS (ES) m/z 539 (M+H) b H NMR (500 MHz, DMSO-d6) 8 11.30 (hr. s, I H), 11.14 (br. s, I H), 9.70 (s, 1 H), 8.08 (s, I H). 7.87-7.76 (in, 4 H), 7.51 (br. s, 1 H), 7.24 (hr. s, 11-1), 6.53 (hr. s, I H), 5.99 (s, 1 H), 5.96 (s, 1 H), 5.74 (hr. s, 1 H), 5.64 (d, I H), 3.36 -3.27 (ohs. in, 1 H), 3.02 (dd, I H), 2.54-2.45 (obs, m, 1 I-I), 2.40 -2.32 (m. I H).
Example 137: 4-a-7-[5-ch1oro-2-UH-tetrazol-yflpheny1]-5-oxo-1,2.3,5-tetrahydro- 3-indolizinyl}-I H-imidazol-5-yI)-2-fiuorobenzonitrile The same operation as in Example 40 -+ Example 41 was conducted from the compound prepared in Example 116 to give the title compound having the following physical properties.
LC/MS R 4.12 minutes; MS (ES4) ink 499 (M+H)t' H NMP. (500 M1I-Jz, CDCI3) 6 8.43 (s, 1 II), 7.60 -7.38 (m, 6 H), 7.29 (s, I H), 6.21 (s, 1 H), 5.72 (d, 1 H), 5.65 (s, 1 H). 3.41 -3.24 (in, 2 H), 3.02-2.91 (m, I H), 2.49-2.31 (m, I H).
Example 138: 3-[5-(3-amino-1H-indazol-6-yl)-1H-imidazol-2-yl)-7-[5-chloro-2- (1H-tetrazol-1yflpeny1]-2.jhdrçQ.jfl-indo1izinone To a methanol (1 mL) solution of the compound prepared in Example 137 (125 mg) was added hydrazine hydrate (105 pL) and the mixture stirred at 80 °C for 20 hours. To the reaction mixture. further hydrazine hydrate (105 1.zL) was added and the mixture stirred at 80 °C for 24 hours. To the reaction mixture, water (5 mL) was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by high performance liquid chromatography (5 to 100% acetonitrile in 2mM aqueous ammonium hydrogen carbonate) to give the title compound having the following physical properties (6.5 mg).
LC/MS tg 2.29 minutes; MS (ES4) ink 511 (M+H) b H NMR (500 MHz, methanol-&) 6 9.39 (s, 1 H), 7.79-7.56 (m, 5 H), 7.38 (br. s, I H), 7.32 (d, I H), 6.16 (s, 1 H), 6.12 (s, 1 H), 5.81 (dd, I H), 3.55 -3.42 (m, 1 H), 3.14 (ddd, 1 Fl), 2.74 -2.59 (in, 1 H), 2.52-2.49 (m, 1 H).
3gple 139: 7-acetyl-3,4-dihydro-2H-1,4-benzoxazin-3-one To an N,N-dimethylformarnide (5 mL) solution of 7-bromo-2H-1,4-benzoxazin- 3(4H)-one (0.50 g) was added tributyl(1-ethoxyethenyl)stannane (0.81 mL). The mixture was degassed with nitrogen for 5 minutes and tetrakis(triphenylphosphine)palladium(0) (51 mg) was added. The mixture was stirred * 146 at 120°C in a pressure tube for 3 hours. To the reaction mixture. I M hydrochloric acid was added and the mixture was stirred for 2 hours then extracted into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was triturated with hot cyclohexane and the precipitate isolated by filtration to give the title compound having the following physical properties (0.35 g).
LCIMS ta 1.30 minutes; MS (ES) m/2 192 (M+H) a Example 140: 742-c7-[5-chloro-2-( H-tetzQi-l henyll-5-oxo-1,2,3,5-tetrahydro- 3-indolizinyl} -1H-imidazol-5-yfl-2H-1,4-benzoxazin-3(4F1)-one The same operation as in Example 91 -, Example 84 -÷ Example 39 was conducted from the compound prepared in Example 139 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 84 in the operation, the compound prepared in Example 17 was used).
LCIMS tR 2.90 minutes; MS (ES) n/z 527 (MI-H) , H NMR (500 MHz, DMSO-&) ö 12.07 (s, I H), 10.66 (s, I II), 9.68 (s, I II), 7.85- 7.75 (m, 3 H), 7.44 (br. s, I H). 7.29 (d, I H), 7.25 (s, 1 1-fl, 6.85 (d, I H), 597 (s, 1 H), 5.94 (s, I H), 5.60 (dd, I H), 4.55 (s, 2 H), 3.45 -3.34 (obs. m, I H), 2.99 (dd, I H), 2.53-2.43 (obs. m, lii), 2.37-2.29 (in, I U).
Example 141: 7-bromo-4-methyl-3,4-dihydro-2H-I,4-benzoxazin-3-one To an N,N-dimethy(formamide (15 mL) solution of 7-bromo-2H-l,4-benzoxazin-3(4H)-one (1.0 g) was sequentially added potassium carbonate (1.21 g) and iodomethane (1.0 mL) and the mixture stirred under nitrogen for 3 hours. To the reaction mixture, water (25 mL) was added followed by extraction into ethyl acetate.
The combined organic layers were washed with brine, dried and concentrated to afford the title compound having the following physical properties (1.1 g).
LC/MS R 1.93 minutes; MS (ES) ,n/z 242 and 244 (M+H) a Example 142: 7-(2-U3S)-7jIsh1oro-2-(1 H-tetrazol-1 -yflphenyll-5-oxo-1,2jj tetrahydro-3-indolizinyl%jH-imidazol-S-yfl-4-methyl-2H-S,4-benzoxazJn-3 (434H)-one The same operation as in Example 139 -Example 91 -Example 84 -.
Example 52 was conducted from the compound prepared in Example 141 to give the title compound having the Ibliowiug physical properties. (Note: in the step corresponding to Example 84 in the operation, the compound prepared in Example 9 was used).
LCIMS R 3.15 minutes; MS (ES) nilz 54! (M+H)" H NMR (500 MHz, DMSO-d6) 6 12.12 (br. s, 1 H), 9.69 (s, I H), 7.83 -7.77 (m, 3 H), 7.50 (hr. s, I II), 7.40 (d, I H), 7.31 (4 1 H), 7.11 (br. s, 1 H), 5.97 (s, I H), 5.93 (s, I H), 5.60 (dd, 1 H), 4.64 (s, 2 H), 3.27 (s, 3 H), 3.48 -3.36 (ohs. m, 1 H), 2.99 (dd, I H), 2.58-2.46 (obs. m, I H), 2.38 -2.25 (m, I H).
Example 143: 7-(4-chloro-2-U3S)-7-F5-chloro-2-(1 H-tetrarzol-I -yl)phenyfl-5-oxo- j-tetiahydro-3-indoIizinyl}-l H-imidazol-5-yl)-4-methyl-2H-iepoxazin-ne The compound prepared in Example 142 (100mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (28 mg).
LCIMS 4.09 minutes; MS (ES) m/z 575 (M+H) b 1H NMR (500 MHz, DMSO-d6) 8 12.99 (s, 1 H), 9.71 (s. 1 1-fl, 7.88-7.73 (m. 3 H), 7.43 (del, 1 H), 7.34 (d, 1 II), 7.27 (d, 1 H), 5.99 (s, 1 H), 5.93 (s, I H), 5.56 (dcl, I H), 4.70 (s, 2 H), 3.35 -3.21 (m, I H), 3.30 (s, 3 H), 2.99 (del, I H). 2.58-2.48 (m, I H), 2.20 (t, I H).
Example 144: 6-12-t7-[5-chioro-2-(l H-tetrazol-l -yflphenyll-5-oxo-I,2,3,5-tetmhydro- 3indoIizinIHH-imidzo1-5Y1-14-dih'dro-2H-3l-benzoxin-2-one The same operation as in Example 139 -÷ Example 91 -Example 51 -.
Example 39 was conducted from 6-bromo-1,4-dihydro-211-3j-benzoxazin-2-one to give the title compound having the following physical properties. (Note: in the step corresponding to Example 5! in the operation, the compound prepared in Example 17 was used).
LC/MS t 2.91 minutes; MS (Est) in/z 527 (M+H) b H NMR (500 MHz, DM50-cl6) 8 12.09 (s, I H), 10.12 (s. I H), 9.70 (s, S H), 7.82 - 7.77 (m, 3 H), 7.57 (d, 1 H), 7.54 (s, I H). 7.41 (d, 1 H), 6.84 (U, 1 H). 5.95 (app. s, 2 H), 5.61(4 1 H), 5.31 (s, 211), 3.38-3.26 (obs. m, 1 H), 3,00 (dd, I H), 2.54-2.46 (Ohs. in, I II), 2.20 (t, I H).
Example 145: 6-(4chloro-2-{ 7-[5-c}floro-2-( 1 H-tetraol-1 -yI)pherjylj-S-oxo-1,2,3,5-tetrahydro-3-indolizinyjjjjJrnidazo1-5-y1)-I, 4-clihydro-2H-3, 1 -benzoxazin-2-one The compound prepared in Example 144 (40 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (10.6 mg).
LCIMS tp. 3.79 minutes; MS (ES) m/z 561 (M+H)" H NMR (500 MHz, DMSO-d5) 6 12.75 (s, I 11), 10.30 (s, 1 H), 9.71 (s, I H), 7.90 - 7.74 (m, 3 H), 7.57 (d, I H), 7.52 (app. s, 1 H), 6.97 (d, I H), 6.00 (s, 1 H), 5.94 (s, 1 H), 5.54 (dd, 1 H), 5.35 (s, 2Ff), 3.38 -3.28 (obs. in, 1 F[), 2.99 (dd, I H), 2.59-2.48 (ohs. m, I H), 2.21 (t, 1 H).
Example 146: 6-(2-I 7-15-chloro-2-(l}l-tetrazol-1 -yl)yhenyll-S-oxo-1,2.3,S-tetrahydro- 3-indolizinyl} -1 1-1-imidazol-5-yI)-1,3-benzoxazol-2(3H)-one The same operation as in Example 84 -÷ Example 52 -t Example 40 -.
Example 41 was conducted from the compound prepared in Example 19 to give the title compound having the fo]lowing physical properties. (Note: in the step corresponding to Example 84 in the operation, 6-(2-bromoacetyl)benzoxazol-2(3H)-one [J. Med. Cherm, 34(6), 1860 (1991)] was used).
LCJMS tg 2.96 minutes; MS (ES) nilz 513 (M-i-H) b H NMR (500 MHz. DMSO-d6) 6 12.10 (s, I H), 11.58 (hr. s, 1 H), 9.68 (s, 1 H), 7.87 - 7.74 (in, 3 H), 7.57 (s, I H), 7.52 (d, I H), 7.48 (s, I H), 7.02 (d, I H), 5.98 (s, I H), 5.96 (s, I Fl), 5.62 (dd, 111), 3.45-3.36 (abs. m, I H), 3.11 -2.88 (m, 1 H), 2.50 (ohs.
I H), 2.40 -2.09 (m, I H).
pjçj47:6-(4-cb1oro-2-{7-[5-ch1oro-2-ffl{-tWazo1-1-yphenyI1-5-oxo-I,2,3. 5-telrahydro-3-indolizinyl}-IH-imidazol-5-yfl-l,3-benzoxazol-2(3H)-one The compound prepared in Example 146 (105 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (4 ing).
LC/MS tv 3.85 minutes; MS (ES) m/z 547 (M+H) b H NMR (500 MHz, methanol-d.) 6 9.36 (s, I 1-1), 7.74 (s, 1 1-fl, 7.73 (dd, I H), 7.68 (d, 1 H), 7.55 (4, 1 H), 7.52 (dd, 1 H), 7.16 (d, I H), 6.13 (s, 1 H), 6.10 (s, I H), 5.71 (dd, I Fl), 3.49-3.40 (m, I H), 3.11 (ddd, 1 II), 2.65 (ddd, 110, 2.40 (dcli, I H). 0 149
crnpie 148: 6-(2-{745-chloro-2-(JH-tetrazol-1-yflphenyl]-5-oxo-l.2,3,5-tetrahydro- 3-indolizinyl -l H-imidazol-5-yl'}-I -isoindolinone The same operation as in Example 84 -Example 52 -b Example 40 -÷ Example 41 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. (Note; in the step corresponding to Example 84 in the operation, 6-(bromoacetyl)isoindolin-1-one [Bioorg. Med. Chem., 16(6), 3091 (2008)] was used).
[f/MS 1R 2.98 minutes; MS (ES4) rn/z 511 (Mi-Fl) b H NMR (500 MHz, methanol-d4) 59.36 (s, I H), 7.93 (br. s, I H), 7.83 (br. s, I H), 7.75 (hr. s, I H), 7.75-7.70 (in, 2 H). 7.68 (d, I H), 7.54 (br. s, I H), 6.14 (s, I H). 6.10 (s, I H), 5.80 (d, I H), 4.49 (s, 2 H), 3.56-3.39 (in, 1 H), 3.36-3.26 (obs. in, 1 H), 3.12 (ddd, I H), 2.71 -2.58 (in, 1 H).
Example 149: 6-(2-bromoacety1)3-mehy1-l 4tetry4gojjjjn-2-one To a cooled (0°C) suspension of aluminium trichloride (2.06 g) in 1,2-dichloroethane (5 niL) was added bromoacetyl bromide (1.1 niL) and the mixture stirred at 0 °C for 30 minutes. To the reaction mixWre, a solution of 3-methyl-3,4-dihydroquinazolin-2Ø 11)-one (1.0 g) in I,2-dichloroethane (5 mL) was added and the mixture stirred at 50 °C for 3 hours. The reaction mixture was concentrated and the residue suspended in iced water (20 rnL). The resultant precipitate was isolated by filtration to give the title compound having the following physical properties (1.51 g).
LC/MS 1R 1.53 minutes; MS (ES) ,n/z 283 and 285 (M+H) a Example 150: 642-j(3S)-7-[5-chloro-2-(I H-tetrazol-1 -yflphenvll-5-oxoJj- tetrahyindoIizin1-1F{-imidazot-5-yfl-3-methy1-3.44ihvdro-2(lH)-olinone The same operation as in Example 51 -Example 52 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 149 was used).
LCIMS e 2.94 minutes; MS (ES4) rn/z 540 M+H) b 11 NMR (500 MHz, CDCI3) 5 11.16 (s, I H), 8.25 (s, 1 H), 8.23 (s, I H), 8.03 (d, I H), 7.98 -7.89 (m, 2 H), 7.47 (d, 1 H), 7.33 (dd. I II), 7.14 (d, 1 H), 6.47 (s, 1 Fl), 6.40 (br.
s, 1 H), 622 (s, 1 H), 5.95 (d, 1 H), 3.65-3.46 (m, 2 H), 3.24 (dd, 1 H), 2.65-2.50 (m, 1 H), 2.05 (s, 2 H), 1.57 (s, 3 H).
Example 151: 6-[2-(4-[5-chJoro-2-( I H-tetrazol-1-yl)phenyll-2-oxo-I (21-fl-S pyridinyl}methyl)-lH-imidazol-5 yI]-3-methvl-3,4-dihy 21 Hi-guinazolinone The same operation as in Example 38 -p Example 39 was conducted from the compound prepared in Example 25 to obtain the title compound having the following physical properties. (Note: in the step corresponding to Example 38 in the operation, the compound prepared in Example 149 was used).
LCIMS 1R 2.90 minutes; MS (ES4) m/z 514 (M+H) b lj NMIR (500 MHz, DMSO-d6) 3 12.08 (br. s, I 11). 9.70 (s, 1 11), 9.17 (br. s. 1 H), 7.88 -7.76 (m, 3 11), 7.69 (d, I 1-fl, 7.53 -7.44 (m, 2 11), 7.39 (s, 1 H), 6.72 (d, 1 H), 6.29 (s, I II), 5.87 (dd, 1 1-1), 5.07 (s, 2 H), 4.43 (s, 211), 2.87 (s. 3 11).
Example 152: 6-[4-chloro-2-H4-15-chloro-2-(1H-tetrazol-1 -yI)phcnyll-2-oxo-1(21-fl-pyñdinymethyfl-I H-imidazol-5-yl]-3-methj dzdih dro-2( lFfl-guinazolinone The compound prepared in Example 151 (70 rug) was treated as detailed in Example 44 to give the title compound having the following physical properties (6.0 rug).
LC/MS 1R 3.68 minutes; MS (ES) n/z 548 (M+H) b H NMR (500 MHz. DMSO-4) 8 12.82 (hr. s, I H), 9.71 (s, 1 H), 9.36 (s, 1 H), 7.88 - 7.77 (in, 3 H), 7.69 (d, 1 H), 7.45 (d, l U), 7.41 (s, 1 H), 6.84 (d, I H), 6.28 (d, I H), 5.89 (ad. 1 H), 5.06 (s, 2 H), 4.46 (s, 2 H), 2.88 (s, 3 H).
Example 153: 2-hromo-l -(2-chloroguinoxalin-6-yflj1-one To an acetonitrile (10 mL) suspension of 2-oxo-1,2-dihydroquinoxaline-6-carboxylic acid [patent W02006/040568, page 75, 82) (0.38 g) was sequentially added pyridine (8 p1), N,N-dimethylformamide (7.5 pL) and thionyl chloride (2.2 mL) and the mixture stuffed at 90 °C for 1 hour. The reaction mixture was concentrated and the residue dissolved in acetonitrile (10 mL). To the cooled (0 °C) acetonitrile solution, a 2 M solution of (trirnethylsiiyl)diazomethane in diethyl ether (2.5 mL) was added and the mixture stirred at 0 C for 2 hours. To the reaction mixture, a solution of 33 wt. % hydrogen bromide in acetic acid (0.86 mL) was added and the mixture stined at 0 °C for a further 30 minutes. A saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to obtain the title compound having the following physical properties (0.35 g).
LC/MS 1.96 minutes; MS (ES4) m/z 285 and 287 (M+H) a Example 154: 6-(2-L7-[5-chloro-2-(1 H-tetrazol-1 -yl)phenyl]-5-oxo-1.2,3.5-tetrahydro- 3-indolizinyl}-1 H-imidazol-5-yl)-2(1 I-fl-guinoxalinone The same operation as in Example 51 -. Example 52 -Example 40 -÷ Example 41 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 1153 was used).
LC/MS tp 2.95 minutes; MS (ES) ith 524 (M+H) b H NMR (500 MHz, DMSO-d6) 8 12.17 (br. s, 1 H), 9.69 (s, 1 H), 8.15 (s, 1 H), 8.06 (d, 1 H), 7.92 (dU, I H), 7.82-7.76 (m, 3 H), 7.61 (s, I H), 7.28 (d, I H), 5.98 (s, I H), 5.95 (s, I H), 5.63 (dd, 1 H), 3.45 -3.37 (ni, 2 H), 3.02 (dd, I H), 2.41 -2.31 (m, 1 H).
Example 155: (3S)-7-[S-ch1oro-fj H-tetrazol-1 -yl)phenyll-3-[5-( 1-methyl-i H benzimidazol-5-yl)-1 H-imidazol-2-ylJ-2,3-dihydro-5(1 T{li-indolizinone The same operation as in Example 5i-÷ Example 39 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, 2-bromo-1 -(1 -methyl-I H-benzimidazol-5-yl)ethanone hydrobromide was used).
LC/MS tR 2.75 minutes; MS (ES) nv'z 510 (M+H)b H NMR (500 MHz. methanol-d4) 89.37 (s, J H), 8.13 (s, I H), 7.96 (s, 11-1), 7.76- 7.74 (m, 2 H), 7.71 -7.69 (in, 211), 7.58 -7.56 (m, 1 H), 7.32 (s, I H), 6.15 (s, I H), 6.12 (s, I H), 5.84-5.82 (m, 1 11), 3.92 (s, 311), 3.53-3.46 (m, 1 H), 3.16-3.11 (in, 1 H), 2.69-2.63 (m, 1 1-1), 2.55 -2.50 (m, I H).
Example 156: 3-[4-chloro-5-(l-methy1-1H-benzimidazol-5-yl)-1H-imidazo1-2-y1]-7-[ chloro-2-( 1 H-tetrazol-1 -yl)phenylj-2,3-dihydro-5( 1 1-1)-indolizinone The same operation as in Example 84 -* Example 39 -Example 47 -Example 40 -* Example 41 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 84 in the operation, 2-bromo-1-( 1-methyl-I H-benzimidazol- 5-yethanone hydrobromide was used).
LC/MS t 3.16 minutes; MS (ES) ,n/z 544 (M+H)1, H NMR (500 MHz, DMSO-d6) 6 12.90 (br. s, 1 H), 9.71 (s, I H), 8.24 (s, I H), 7.97 (s, I H), 7.84-7.78 (m, 3 H), 7.68 (d, I H), 7.63 (d, I H), 6.00 (s, I H), 5.94 (s. I H), 5.59 (dd, 1 H), 3.86 (s, 3 H), 3.32 -3.25 (m, I H), 3.00 (dd, I H), 2.60-2.52 (m, 11-1), 2.29- 2.16(m, 1 H).
Example 157: (3S)-7-15-chloro-24111-tetrazol-1-yflyhenyll-3-15-(1fl-indazol-5-ylirjjj imidazol-2-yll-2,3-dihydro-5( 1 H)-indolizinone The same operation as in Example 51 -* Example 39 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, 2-bromo-I -( I H-indazol-5-yl)ethan-l -one [Bioorg. Med. Chem. Lett. 21(5), 1480 (2011)1 was used).
LCIMS 1R 192 minutes; MS (ES4) m/z 496 (M+H) b 1HNMR (500 MHz, DMSO-d6) & 12.96 (s, I H), 12.04 (s, 1 H), 9.69 (s, 1 H), 8.07 (d, I H), 8.01 (d, I H), 7.84 -7.77 (m, 3 H), 7.73 (d, I II), 7.50 -7.43 (m. 2 H), 5.99 (s, 1 H), 5.96 (s, I 1-fl, 5.64 (d, I H), 3.38 -3.27 (ohs. m, I H). 3.02 (dd, I H), 2.56-2.44 (ohs.
m, I H), 2.40 -2.32 (m, 1 H).
çpj58: ethyl 4-{2-[7-(2-{ fttert-buxoxy)carbonvllaminoI-5-chloroyhenyl)-5-oxo- 1...2,3,5-trahygroindolizin-3-yl}-1 H-imidazol-4-yl} benzoate The same operation as in Example 84 -* Example 39 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 84 in the operation, ethyl 4-acetylbenzoate [Bioorg. Med. Chew. Left. 18, 2886 (2008)] was used).
LC/MS tR 2.16 minutes; MS (ES) rn/z 575 (M4-H) a Example 1 59: tert-butyl 2-yfl-5-oxo-1,2,3.5-tetrahydroindolizin-7-yflphenyllcarbamate To a cooled (0 °C) tetrahydrofuran (20 mL) solution of the compound prepared 153 in Example 158 (0,50 g) was added a I M solution of lithium aluminium hydride in tetrahydrofuran (1.39 mL) and the mixture stirred at 0 °C for 1 hour. To the cooled (0 °C) reaction mixture, a saturated aqueous solution of ammonium chloride (10 mL) was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to give the title compound having the following physical properties (0.30 g).
LC!MS 1R 1.71 minutes; MS (ES) m/2 533 (M+H) a Example 160(1) and Example 160(2): 7-[5-chloro-2-( I H-tetrazol-I -yI)phenyl]-3-{5-f4- (hydroxymethyl)phenyll-IH-imidazol-2-yl}-2,3-dihydro-5(1H)-indolizinone and 442- {7-[5-chloro-2-( 1 H-tetrazol-1 -yI)phenyfl-S-oxo-1,2,3,5-tetrahydro-3-indoliziny1 -l H imidazol-5-yl)benzyl acetate The same operation as in Example 40 -* Example 41 was conducted from Example 159 to give the title compounds in a 2: 1 ratio having the following physical properties.
Example lóOuj.jj
LC/MS R 2.89 minutes; MS (ES1 mh 486 (M+H)" H NMR (250 MHz, methanol-d4) 8 9.36 (s, 1 H), 7.78 -7.58 (m, 5 H), 7.42 -7.25 (m, 3 H), 6.12 (s, 1 Fl), 6.09 (s, 1 1-1), 5.78 (dd, I H), 4.59 (s, 2 H), 3.43 (dd, I H), 3.13 (dd, 1 H), 2.74 -2.36 (m, 2 1-1').
Example 160(2):
LCIMS t 3.31 minutes; MS (ES') ,niz 528 (M+H) b H NMR (500 MHz, methanol-d4) 3 9.37 (s, 1 H), 7.78 -7.64 (m, 5 II), 7.38 (d, 2 1-1), 7.37 (br. s, I H), 6.15 (s, I H), 6.11 (s, I H), 5.80 (dd, I H), 5.12 (s, 2 H), 3.53 -3.41 (m, I H), 3.22-3.07 (m, 1 H), 2.73 -2.61 (m, I H), 2.55 -2.40 (m, I H), 2.10 (s, 3 H).
Example 161: tert-butyl N-(4-ch1oro-2-{3-[4- (4-formylphçgyi-1H-imidazo1-2-ylj-5-pj235-tetrahydroindolizin-7y1}yhenyI) carbaniate To a dichloromethane (5 mL) solution of the compound prepared in Example 159 (0.39 g) was added Dess-Martin periodinane (1,1,1 -Triacetoxy-1,1 -dihydro-! ,2 benziodoxol-3(1H)-one) (0.33 g) and the mixture stined at room temperature for 16 0 154 hours. To the reaction mixture, a 1:1 mixture of a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium sulfite was added (10 mL) and the mixture stirred at room temperature for 15 minutes followed by extractioti into dichioromethane. The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate, brine, dried and concentrated to obtain the title compound having the following physical properties (0.30 g).
LCIMS 1R 2.04 minutes; MS (ES) nilz 531 (M+H) Example! 62: tert-bjN-4-ch1oro-2-{3-(4-f 4-ffhythoxyimino)methvflphenyl -! lj imidazol-2-yfl-5-oxo-I.2,3.5-tetrahydroindolizin-7-yflphenvli carbamate To an ethanol (2 mL) solution of the compound prepared in Example 16! (0.15 g) was added hydroxylaniine hydrochloride (15.1 mg) and 2 M sodium hydroxide (124 pL) and the mixture stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue suspended in water (5 niL) and extracted into dichloromethane. The combined organic layers were washed with brine, dried and concentrated to obtain the title compound having the following physical properties (0.15 g).
LC(MS tR 1.84 minutes; MS (ES) m'z 546 M+H) a pjl63: 4-0-113S)-7-15-chloro-2-(l H-te zolyj)phenyfl-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -l}-I-imidazol-5 -yflbenzaldehvde oxime The same operation as in Example 40 -. Example 41 was conducted from the compound prepared in Example 162 to give the title compound having the following physical properties.
LCIMS ig 3.10 minutes; MS (ES3) nv'z 499 (M+H) H NMR (500 MFIz, methanol-&) 8 9.38 (s, I II), 8.09 (s, I H), 7.78 -7.67 (m, 5 H), 7.60 (d, 2 Fl), 7.40 (br. s, I Ii), 6.15 (s, 1 H), 6.11 (s, I H), 5.80 (dd, I H), 3.47 (td, I H), 3.13 (ddd, 1 H), 2.71 -2.62 (m, 1 H). 2.49 (by. s, I H).
Example 164: 4-(2-{(3S)745-ch1oro--2-(IH-tetrazol-I-y1)phenyl1-5-oxo-l,2,3, 5-tetrahydro-3 -indolizinvI}-1H-imidazo1-5-y1)benza1deyç 0-methyloxime The same operation as in Example 162 -Example 40 -* Example 41 was conducted from the compound prepared in Example 161 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 162 in the operation, melhoxyamine hydrochloride was used).
LCIMS r 361 minutes; MS (ES4) rn/i 513 (MR-H) b 1H NMR (500 MHz, methanol-cl4) 6 9.38 (s, 1 H), 8.09 (s, I H), 7.78 -7.68 (rn, 5 H), 7.61 (d, 2 1-1), 7.42 (s, I H), 6.15 (s, I II), 6.12 (s, 1 H), 5.81 (ad, I H), 3.95 (s, 31-1), 3.52-3.43 (m, 1 H), 3.20-3.07 (m, 1 H), 271 -2.62 (m, 1 11), 2.53 -2.46 (m, 1 11).
Example 165: (3S)-34544-acerylphenyfl-1}1-imidazol-2-vll-7-[5-chloro-2-(1 H-tetrazol I -yl')phenylj-2,3-dihydro-5(IH)-indolizjnone The same operation as in Example 84 -.--Example 39 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 84 in the operation, 1- (4-acetylphenyl)-2-bromoethan-1-one [Chem. Pharm. Bull. 40 (5), 1170(1992)] was used).
LC/MS tR 3.48 minutes; MS (ES4) in/i 498 (M±H) b HNMR (500 MHz, methanol-d4) 69.38 (s, 1 H), 8.01 (d, 211), 7.85 (app. hr. s,2 H), 7.77-7.68 (m, 3 H), 7.55 (hr. s, 1 H), 6.15 (s, 1 II), 6.12 (s, 1 H), 5.81 (dd, 1 H), 3.53- 3.43 (m. 1 H), 121 -3.08 (m, 1 11), 2.72 -2.65 (m, I H), 2.62 (s, 3 H), 2.57-2.46 (m, I H) Exj6:3S-7-5-chloro-241}jetrajjyj)phenyfl-3-{ 54441-bYrQxethnlheny11 1 H-imidaQ-'l -23-dihydro-5(1 H)-indolizinone To a cooled (0 °C) tetrahydrofuran (2 mL) solution of the compound prepared in Example 165 (30 mg) was added sodium borohydride (1.1 mg) and the mixture stirred at room temperature for 25 minutes. To the cooled (0 °C) reaction mixture, water (10 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (0 to 15% methanol in dichloromethane) to obtain the title compound having the following physical properties (5.5 mg) LC/MS tg 2.97 minutes; MS (ES4) rn/i 500 (M+1-T) b 11 NMR (500 MHz, methanoi-d4) 6 9.26 (s, 1 11), 7.68 7.60 (m, 2 H), 7.58 (d, 1 H), 7.50 (app. br. s,2 11), 7.28 (d, 2 1-1), 7.17 (hr. s, 1 1-1), 6.04 (s, 1 11), 6.00 (s, 1 H), 5.68 (dd, I H), 4.70 (q, 1 Fl), 3.41 -3.30 (m. 1 H), 3.07 -2.96 (m, 1 H), 2.59-2.45 (m, I 1-I). * 156
2.41 -2.25 (m, 1 H), 1.34 (d, 3 H).
Example 167: 2-methyl-2-propanyl [4-(2-{(3S)-7-[5-chloro-2-(1 H-tetrazol-1-yflpbenyll-5-oxo-1,2,3,5-tetrahvdro-3-indolizinvl 1-1 H-imiclazol-5-ylThenzyllcarbamate The same operation as in Example 51 -* Example 39 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, tert-butyl N-{[4-(2-bromoacetyl)phenyflmethyl} carbamate [Bioorg. Med. Chem. Left.
13(20), 3557 (2003)J was used).
LC/MS R 3.51 minutes; MS (ES4) ,n/z 585 (M+H)b H NMR (500 MHz, CDCI3) ö 8.58 (s, 11-1), 7.62 (dd, I H), 7.54 (d, 1 H), 7.52 (d, 1 H), 7.28 (s, 1 H), 7.27 (app. a, 4 H), 7.22 (s, 1 H), 6.31 (s, I H), 5.86 (d, I H), 5.75 (a, 1 H), 4.88 (br. a, I H), 4.31 (Iiw. d, 211), 3.53-3.42 (m, 1 H), 3.42-3.31 (m, I H), 3.03 (dd, I H), 2.49 (quintet, 1 Fl), 1.47 (s, 911).
Example 168: (3 S)-3-{ 5-[4-(aminomethyl)phenyll-1H-imidazol-2-yl} -7-15-chloro-2- (1 H-tetrazol-l -yl)phenyl]-2,3-dihydro-5(l H)-indolizinone dihydrochioride The compound prepared in Example 167 (0.19 g) was treated in accordance with Example 55 to give the title compound having the following physical properties (0.13 g).
LC/MS tR 2.46 minutes; MS (ES) ink' 485 (M+H) b H NMR (500 M}Iz, DMSO-d6) 89.71 (s, 1 11), 8.39 (br. a, 3 H), 8.10 (hr. a, 1 H), 7.88 (d, 2 1-1), 7.84 (dd, 1 H), 7.82 (d, 1 H), 7.72 (d, 1 H), 7.62 (d, 2 H), 6.10 (s, I H), 6.00 (s, 1 H), 5.84 (dd, 1 H), 4.14-4.02 (q, 2 H), 3.34-3.24 (m, 1 H), 3.15 -3.05 (m, I H), 2.75 -2.67 (in, 1 H), 2.41 -2.30 (m, I H).
Example 169: methyl [4-(2-{(3S)-7-[5-chloro-2-[1 H-tetrazol-I -yl)phenyl1-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl} -1 H-imidazol-5-yl)benzyllcarbamate The compound prepared in Example 168 (100 mg) was treated in accordance with Example 77 to give the title compound having the following physical properties (30 mg).
LC/MS z, 3.07 minutes; MS (ES) m/z 543 (M+H) b H NMR (500 MHz, methanol-d4 9.37 (s, 1 11), 7.80 -7.59 (in, 5 H), 7.31 -7.26 (m, 3 H), 6.13 (s. 1 H). 6.09 (s, I H), 5.80 (dd, I H), 4.29 (a. 2 H), 3.68 (s, 3 H), 3.51 -3.41 (m, 1 H), 3.18-3.07 (in, 1 H), 2.65 -2.60 (m. I H), 2.52-2.41 (in, I H).
Example 170: N-[4-(2-ft3S)-7-L5-chloro-2-UH-tetrazol-I-vl)phenvl]-5-oxo-1,2,3, 5-jdro-3-indolizinvl3-IH-iinidazol-5-yl)benrvljacetamide To a dichloromethane (3 mL) solution of the compound prepared in Example 168 (100 mg was sequentially added pyridine (29 j.tL) and acetic anhydride (13.6 tL) and the mixture stirred at room temperature for 4 hours. To the cooled (C) °C) reaction mixture, 1 M hydrochloric acid (6.60 mL) was added followed by extraction into dichloroinethane. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (0 to 15% methanol in dichloromethane) to obtain the title compound having the following physical properties (27.4 trig).
LCJMS 1R 2.89 minutes; MS (ES4) nlz 527 (M+1-l) b II NMR (500 MHz, methanol-cL) S 9.39 (s, 11!), 7.77-7.68 (m, 3 Fl), 7.63 (d, 2 H), 7.31 -7.27 (m, 3 H), 6.15 (s. I H), 6.14 (s, I H), 5.8! (dd, I H), 4.37 (s, 2 H), 3.54- 3.37 (m, 1 H), 3.22-3.07 (m, I H), 2.74-2.59 (m, 1 II), 2.55 -2.38 (m, 1 H), 2.02 (s, 3 H).
Example 171: N44-(2-{(3S)-745-chloro-2-(1H-tetrazo1-l-y1) phenyfl-5-oxo-j235-tetrahydro-3-indolizinyl} -1 FI-imidazol-5-yI)benzy)]-2,2,2-trifluoroacetamide To a cooled (0 °C) dichloromethane (3 mL) solution of the compound prepared in Example 168 (100 mg) was sequentially added triethylamine (57 pL) and trifluoroacetic anhydride (59 zL) and the mixture stirred at 0 °C for 3 hours. To the reaction mixture water (5 mL) was added followed by extraction with dichioromethane.
The combined organic layers were washed with brine, dried and concentrated. The residue was purified by high performance liquid chromatography (5 to 100% acetonitrile in 2 raM aqueous ammonium hydrogen carbonate), then triturated with a 1:1 mixture of dichioromethane and heptanes. The precipitate was collected by filtration to give the title compound having the following physical properties (2 mg.
LC(MS ta 3.35 minutes; MS (ES4) m/z 581 (Mi-H) , I-I NMR (500 MHz. methanol-cL) 69.38 (s, 1 H), 7.78 -7.73 (m, 2 H), 7.69 (d. I H), 7.67 (app. br. s, 2 H), 7.36 (hr. s, I H), 7.33 (d, 2 H), 6.15 (s, 1 H), 6.12 (s, 1 H), 5.80 * 158 (dd, 1 Fl), 4.47 (s, 2 H), 3.55 -3.39 (in, 1 H), 3.14 (dd, I H), 2.66 (dd, I H), 2.52 -2.36 (rn, 1 H).
Example 172: j4j2-3S)-7-[5-ch1oro-2-(1H4etrazol-1-yflpheny11-5-oxo-l.2.3.5-tetrahydro-3 -indolizinyl} -1 Fl-imidazol-5-yl)benzyll-3-ethylurea To a dichioromethane (3 mL) solution of the compound prepared in Example 168 (100mg) was added ethyl isocyanate (29 pL) and the mixture stirred at room temperature for 3 hours. To the reaction mixture water (5 mL) was added followed by extraction with dichioromethane. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by high performance liquid chromatography (5 to 100% acetonitrile in 2 mM aqueous arnmonium hydrogen carbonate) to give the title compound having the following physical properties (8.9 mg).
LC/MS tg 2.99 minutes; MS (ES) ln/z 556 (M+H) b 1H NMR (500 MHz, methanol-&) 6 9.27 (s, I H), 7.68-7.62 (in, 2 H), 7.58 (d, 1 H), 7.57-7.44 (in, 2 H), 7.28-7.11 (in, 3 H), 6.04 (s, I H), 6.01 (s, 1 H), 5.69 (d, I H), 4.22 (s, 2 H), 3.40-3.29 (in, I H), 3.07(q, 2 I-I), 3.05-2.97 (in, 1 H), 2.61 -2.42 (m, 1 H). 2.34-2.19 (in, 1 H), 1.02 (t, 3 II).
Example 173(1) to Example 1730 U The compounds of the present invention having the following physical data were prepared using the corresponding alpha-bromoketones from the compound prepared in Example 9 in the process of Example 51 -* Example 52.
Example 173(1): (3 S)-7-[5-chloro-2-( 1H-tetrazol-1-yl)phenyll-3 -[5-(4-pyridinyl)-1 H-imidazol-2-yll-2,3-dihydro-5(1 H)-indolizinone LC/MS g 2.81 minutes; MS (ES4) mlz 457 (M+H) b H NMR (500 MHz, DMSO-d6) a 12.39 (br. s, 1 H), 9.70 (s, I H), 8.47 (d, 2 1-1). 7.94- 7.73 (in, 4 H), 7.64 (d, 2 H), 5.98 (s, 1 H), 5.96 (s, 1 H), 5.63 (dd, 1 H), 3.44 -3.37 (in, 1 H), 3.01 (dd, 1 H), 2.55 -2.52 (m, I H), 2.38 -2.26 (m, 1 H).
Example 173(2): (3 S)-7-[5-chloro-2-(1 H-tetrazol-1-vl)phenvl]-3 -[5-(3-pyridinyl)-I H imidazol-2-yIl-2,3-dihydro-5(1 11)-indolizinone LC/MS tR 2.85 minutes; MS (ES4) m/z 457 (M-i-1-l)1, 1H NMR (500 MHz. DMSO-d5) $ ii.94 (hr. s, I 11), 9.70 (s, 1 H), 8.93 (s, I H), 8.37 (d, I H). 8.03 d, 1 H), 7.84 -717 (in. 3 H), 7.67 (hr. s, 1 11), 7,34 (s, I H), 5.99 (s. 1 FE), 5.97 (s, 1 H), 5.62 (d, 1 H). 3.45 -3.36 (ohs. m, I H), 3.00 (dd, 1 H), 2.58 -2.45 (obs.
in, 1H),2.38-2.25(m,1H) Mnipk 173(3): (3S1-745-chloro-2-(IH-tetrazol-1-yl)phenyl]-3-[5-(2-pyridinyl)-I H imidazol-2-yI]-2.3-dihvdro-5( I HI-indolizinone LC/MS t 2.91 minutes; MS (ES) in/z 457 (M+H)" NMR analysis showed a 2: 1 ratio of lautomers, Major tautomer: 1 NMR (500 MHz, DMSO-d6) 5 12.28 (hr. s, I Fl), 9.70 (s, 1 H), 8.46 (d, 1 H), 7.84-7.70 (m. SF1), 7.59 (s, I H), 7.16 (td, I H), 5.97 (app. s, 2 H), 5.65 (d, 1 H), 3.41 -3.34 (in, I H), 3.01 (dd. 1 H), 2.57-2.44 (ohs. in, 1 H), 2.38 -2.31 (in, I El).
Minor tautomer: 111 NMR (500 MHz, DM504) 8 12.60 (hr. s, I H), 9.71 (s, 1 H), 8.55 I H), 7.84 -7.70 (in, 5 H), 7.46 (s, 1 H), 7.23 dd, 114), 5.97 (s, 2 H), 5.95 (s, I H).
iS 5.73 (d, I H), 3.31 -3.21 (in, I H), 2.98 (dci, 1 H), 2.57 -2.44 (ohs. in. 1 11), 2.28 -2.21 (in, 1 H).
Example 173(4): (3S)-745-çgç-2-1H-tetrzo1-1-yflphenyfl-345-ft3-tjgI-2-1-I H-imidazol-2-yfl-2,3-dihydro-5( I FO-indolizinone LCIMS R 3.62 minutes; MS (ES") m'z 463 (M÷H?' HNMR (500 MHz, DMS0-d6 a 12.47 (hr. s, 1 H). 9.69 (s. I H). 7.84-7.77 (in, 311), 7.69 (s, I H). 7.65 (s, 1 H). 5.99 (s. 1 11), 5.97 (s, I 1-1), 5.62 (dd, I H), 3.32-3.24 (ohs.
in, 1 11). 3.0! (dd, I H), 2.59-2.52 (obs. In. 1 11), 2.37-2.25 (in, I H).
25]ppe173(J:3S).7-[5-chloro-2-fl H-tetrazol-1 -yflpheny1]-345-pyrazinyfl-111- 1H-indohzinone In the step corresponding to Example 51 in the process, 2-bromo-1-(pyrazin-2-yl)ethan-1.one [J. Med. Chem. 41(13), 2436 (1998)] was used.
LC/MS tR 3.29 minutes; MS (ES') m/z 458 (M+Ftf I-i NMR (500 MFJz, DMSO-) 8 12.47 (hr. s, 1 11), 9.69 (s, 1 H), 8.98 (app. hr. s, 1 H), 8.52 (app. hr. s. I H), 8.42 (app. br. s, I H). 7.82 -7.78 (in, 3 H), 7.73 (hr. s, 1 H), 5.97 (s, I H), 5.96 (s, I H), 5.66 (d, I H), 3.45-3.34 (ohs. in, I H), 3.01 dd, I H), 2.59- 2.45 cobs. in, I H), 2.38 -2.32 cm, I H). /
Example 173(6): (35)-745-chloro-2-(1 H-tetrazol-1 -yl)phenyl]-3-[5-(2-methoxvphenyfl-I H-imidazol-2-yll-2.3-dihydro-5(1 1-[)-indolizinone LCIMS 1R 3.23 minutes; MS (ES4) pn/z 486 (M+H) b H NMR (500 MHz, CDCI,) 611.71 (hr. s, 1 H), 8.53 (s, 1 £1), 760 (dd, 1 H), 7.59 (app. hr. s, I H), 7.54 (d, 1 H), 7.50 (d, 1 H), 7.30 (br. s, 1 1-1), 7.26-7.18 (m, 1 H), 7.05 -6.90 (m, 211), 6.31 (s, 1 11), 5.88 (d, 1 H), 5.68 (s, 1 H), 4.02 (s, 3 11), 3.54 -3.26 (m, 2 H), 3.00 (dd, 1 H), 2.45 (quintet, 1 H).
Example 173(7): (3 S)-7-[5-chloro-2-( 1 1-1-tetrazol-1 -yI)phenyll-3-[5-(3-methoxyphenyl)- 1 H-imidazo1-2-y1-2.3-dihydro-5(1 H)-indolizinone LCIMS R 3.31 minutes; MS (ES4) ,n/z 486 (M+11)" NMR analysis showed a 2: 1 ratio of tautomers.
Major tautomer: H NMR (500 MHz, CDCI3) 6 10.77 (br. s. 1 H), 8.54 (s, I H), 7,61 (d, I H), 7.54 (d, 1 H), 7.51 (br. s, 1 H), 7.37-6.96 (m, 4 H), 6.79 (ci, 1 1-1), 6.32 (s, I H), 5.83 (d, 1 H), 5.70 (s, 1 H), 3.86 (s, 3 H), 3.53 -3.25 (m, 2 H), 3.06 -2.95 (m, 1 H), 2.53 -2.40 (rn, I H).
Minor tautomer: H NMR (500 MHz, CDCI3) 6 11.16 (br. s, 1 11), 8.54 (s, 1 H), 7.61 (d, 1 H), 7.54 (d, I H), 7.51 (br. s, 1 H), 7.37 -6.96 (m, 4Ff), 6.82 (d, 1 H), 6.36 (s, 1 H), 5.87 (ci, 1 11), 5.70 (s, 1 H), 3.84 (s, 3 H), 3.53 -3.25 (m, 2 H), 3.06 -2.95 (m, 1 H), 2.53 -2.40 (m, 1 H).
Example 173(8): (3 S)-7-15-chloro-2-(1 H-tetrazol-1 -yl)phenyll-3-[5-(4-methoxyphenyl)- 1 H-imidazol-2-yll-2,3-dihydro-5( 1 H)-indolizinone LCIMS 1R 3.17 minutes; MS (ES4) mit 486 (M+H) h NMR analysis showed a 3: 2 ratio of tautomers.
Major tautomer: H NMR (500 MHz, CDC13) 6 10.68 (br. s, I H), 8.53 (s, 1 H), 7.68 (ci, 2 H), 7.62 (d, 1 H), 7.54 (ci, 1 H), 7.51 (s, 1 H), 7.17 (s, 1 H), 6.96-6.86 (m, 2 H), 6.32 (s, I H), 5.90-5.80 (m, 1 H), 5.69 (s, 1 H), 3.83 (s, 3 H), 3.54-3.27 (m, 211), 3.07- 2.96 (m, 1 H), 2.46 (quintet, 1 H).
Minor tautomer: H NMR (500 MHz, CDCI3) 6 11.02 (br. s. 1 H), 8.53 (s, 1 H), 7.62 (ci, I H), 7.54 (d, 1 H), 7.51 (s, 1 H), 7.42 (ci, I H), 7.11 (s, 1 H), 6.96 -6.86 (m, 2 H), 6.36 (s, 1 H), 5.90-5.80 (in, 1 H), 5.69 (s, I H), 3.83 (s, 3 H), 3.54-3.27 (m, 2 H), 3.07- 2.96 (m, 1 Fl), 2.46 (quintet, ill).
jwigj73(9): (37-[5-ch1oro-2-UH4etrazo1-1 -yi)pheny11-3j5-(3-fluqppjeny1)-IH-imidazol-2-yIl-2,3-dihydro-5( I H)-indolizinone LU/MS (g 3.59 minutes; MS (ES) m/z 474 (M+Hf' 1H NMR (500 MI-fr. DMSO-d6) 12.21 (hr. s, I H), 9.68 (s, 1 H), 7.84-7.74 (m, 3 H), 7.60 (s, I H), 7.54 (d, I H), 7.48 (dd, 1 H), 7.35 (dd, I H), 6.96 (td, 11-1), 5.97 (s, I H), 5.96 (s, 1 H), 5.62 (dd, 1 Fl). 3.44-3.36 (m, I H). 3.00 (dd. 1 1-1), 2.60-2.45 (obs. m, I H), 2.38 -2.30 (m, 1 H).
Example 173(10): (3S)-7-[5-chloro-2-(1 H-tetrazol-I -vI')phenyll-3-15-(4-fluorophenyU-IH-imidazol-2-yI]-2,3-dihvdro-5( 1Ff)-indohzinone LU/MS tR 3.38 minutes; MS (ES) ,n/z 474 (Mi-Fl) h jfl NMR (500 MHz. DMSO-d6) 6 12.11 (hr. s, I H), 9.69 (s, 1 H), 7.82 -7.76 (m, 3 H), 7.72 (dd, 2 H), 7.49 (s, 1 H), 7.14 (t, 2 1-1), 5.97 (s, 1 H), 5.96 (s, I Fl), 5.63 (dd, I H), 3.47-3.35 (ohs. m, I H), 3.01 (dd, I H), 2.57-2.44 (obs. m, I H), 2.40-2.28 (m, 1 H).
Example 173(11: (3S)-7-[5-chloro-2-( 1 H-tetrazol-1 -yl')phenyll-3-[5-(2,4-dimethyl-1,3- 1-5-l-1 U-nid?zgj2-yU2,32dihdro-51H-indo)ijnone LU/MS R 3.36 minutes; MS (ES) m/z 475 (M+H) b f-I NMR (500 MHz. CDCI3) 6 10.97 (br. s, I H), 8.57 (s, 1 H), 7.60 (dd, I H), 7.53 (s, I H), 7.49 (d, I Fl), 7.09 (d, 1 H), 6.29 (s, I H), 5.81 (d, 1 H), 5,72 (s, I Fl), 3.50-3.37 (m, H), 3.34 (dd, I H), 3.00 (dcl, 1 H), 2.51 -2.44 (in, I H), 2.43 (s, 3 H), 2.33 (s, 3 1-1) Example 174: 2-bromo-I -(1 -methyl-i 1-I-pyrazol-4-yflethan-1 -one A suspension of 1-methyl-1H-pyrazole-4-carboxylic acid (0.25 g) in thiony chloride (4 niL) was stirred at reflux for 30 minutes. The reaction was concentrated, the residue azeotroped with toluene and dissolved in acetonitrile (5 niL). To the cooled (0 °C) solution, a 2 M solution of (trimethylsilyl)diazomethane in hexanes (1.5 mL) was added and the mixture stirred at 0 °C for 1 hour. A solution of 33 wt. % hydrogen bromide in acetic acid (1.0 mL) was added and the mixture stirred at room temperature for a further 80 minutes. To the reaction mixture, tert-butyt methy( ether (20 mL) was added and the resultant precipitate isolated by filtration to give the title product having the following physical properties (0.22 g).
LC/MS 1R 1.23 minutes; MS (ES) ,n/z 203 and 205 (M+H) Example 175: (35)-7-[5-chloro-2-(1lI-tetrazol-1 -yl)phenyl]-3-[5-(1-methyl-1 H-pyrazol 4yfl-IH-imidazol-2-vj]-2,3-dihydro-5(1 H)-indolizinone The same operation as in Example 51 -k Example 52 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example SI in the operation, the compound prepared in Example 174 was used).
LCIMS 1R 2.79 minutes; MS (ES) rn/z 460 (M+H) b H NMR (500 MHz, DMSO-d6) 8 11.94 (br. s, 1 H), 9.74 (s, I H), 7.89 -7.82 (m, 4 H), 7.62 (s, 1 H), 7.17 (s, 1 H), 5.98 (s, 1 H), 5.96 (s, 1 H), 5.58 (dd, 1 H), 3.87 (s. 3 H), 3.40 -3.27 (obs. in, I H). 3.04 (dd, 1 H), 2.64 -2.46 (obs. m, 1 H), 2.45 -2.34 (m. 1 H).
Example 176: methyl N-13-bromo-5-(2-bromoacetyl)thiophen-2-yl]carbamate To a dichloromethane (15 nTh) suspension of 5-acetylthiophene-2-carboxylic acid (1.0 g) was added sequentially oxatyl chloride (0.32 mL) and N,N-dimethylformamide (15 RL) and the mixture stirred at room temperature for 2 hours.
The reaction mixture was concentrated and the residue dissolved in acetone (6 mL). To the mixture a solution of sodium azide (0.50 g) in water (2 mL) was added and the reaction stirred at room temperature for 30 minutes. The resultant precipitate was isolated by filtration, dissolved in toluene (80 niL) and the mixture refluxed for 1 hour.
Methanol (10 mL) was added at room temperature and the mixture stirred at room temperature for a further hour, then concentrated to approximately 30 mL. The resultant precipitate was collected by filtration to give the title compound having the following physical properties (0.56 g).
LC/MS tp 1.38 minutes; MS (ES) m/z 200 (M+H)a Example 177: methyl N-[3-bromo-5-(2-bromoacetyl)thiophen-2-yflcarbamate The compound prepared in Example 176 (0.46 g) was treated as detailed in Example 91 to give the title compound having the following physical properties (0.68 g).
LC/MS R 1.84 minutes; MS (ES) m/z 356, 358, 360 (M+H) a Example 178: methyl N-F5-(2-azidoacetyfl-3-bromothiophen-2-yl1caprnte To an N,N-dimethylformamide (15 mL) solution of the compound prepared in Example 177 (0.68 g) was added sodium azide (0.25 g) and the mixture stirred at room temperature for 1 hour. To the reaction mixture, water (100 mL) was added followed by extraction with ethyl acetate. The combined organic layers were dried and concentrated to give the title compound having the following physical properties (0.51 g).
LCIMS 1R 1.81 minutes; MS (ES) nv'z 319 and 321 (M+H) a Example 179: methyl N-[5-(2-aminoaeetyl)thiophen-2-yllcarbainate hydrochloride To an ethanol (25 inL) solution of the compound prepared in Example 178 (0.51 g) was sequentially added 2 M hydrochloric acid (1.60 mL) and 5% palladium-carbon (0.10 g) and the mixture was stirred under an atmosphere of hydrogen for 16 hours. The reaction mixture was filtered through Celite® and the filtrate concentrated. The residue was dissolved in water (15 mL) and washed with ethyl acetate. The aqueous layer was concentrated to give the title compound as the hydrochloride salt having the following physical properties (0.28 g).
H NMR (500 MHz, DMSO-d6) 6 11.52 (hr. s, 1 H), 7.88 (d, 1 H), 6.69 (d, 1 H), 4.39 (s, 211), 3.77 (s, 3 H).
Example 180: methyl N-{ 5-[2-({ 74-ch1oro-2-(1H-1.2,3 4-tetrazo1-1 -yl')phenyll-5-oxo- 1.2,3,5-tetrabydroindolizin-3-yj} forinarnido)acetyl}thiophen-2-yl} carbamate To an N,N-dimethylformamide (1 mL) solution of the compound prepared in Example 179 (0.15 g) and the compound prepared in Example 17 (0.20 g) was sequentially added O-(7-azabenzotriazol-1 -y])-N,N,N' ,N' -tetramethyluronium hexafluorophosphate (0.23 g) and diisopropylethylamine (0.29 mL) and the mixture stirred at room temperature for 3 hours. To the reaction mixture, water (15 mL) was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was triturated in ethyl acetate and the precipitate collected by filtration to give the title compound having the following physical properties (0.095 g).
LC/MS R 1.70 minutes; MS (ES) rn/z 554 (M+H) a Example 181: methyl [5-a-I 7-[5-chloro-2-( I H-tetrazol-1-yI)phenyl]-5-oxo-I,23,j, tetrahydro-3 -indolizinyt} -. H-imidazol-5-yl)-2-thienyllcarbamate To a toluene (3 mL) suspension of the compound prepared in Example 180 (95 mg) was sequentially added glacial acetic acid (0.30 mL) and anunonium acetate (93 mg) and the mixture stirred at reflux for 40 minutes. Further ammonium acetate (62 mg) was added and the mixture stirred at reflux for 50 minutes. To the cooled (room temperature) reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate (15 mL) was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by high pcrfonTnance liquid chromatography (5 to 100% acetonitrile in water) to give the title compound having the following physical properties (14 mg).
LCJMS tR 3.18 minutes; MS (ES) nilz 535 (M+H)" H NMR (500 MHz, rnethanol-d4) S 9.38 (s, 1 IT), 7.78 -7.73 (m, 2 H), 7.70 (d, I H), 7.09 (hr. s, I H), 6.95 (d, I I-I), 5.50 (d, 1 H), 6.14 (s, I H), 6.10 (a, I II), 5.76 (dd, 1 H), 3.78 (s, 3 H), 3.50-3.41 (m. I H), 3.11 (ddd, 1 H), 2.67-2.59 (m, I H). 2.48 (app. hr. s, 111).
Example 182(1) and 182(2): 2-({[4-(bromoaeetyl)cyclohexvl]carbamoyl}oxy)-2- 1ohexlcarbamo'1ox-2-methyipropylidyne To a dich)oromethane (100 mL) solution of 4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylic acid [Eur. J. Med. Chem. 36(3), 265 (2001)] (2.80 g) was added 1-ehloro-N,N,2-trimethyl-1-propenylamine (3.05 mL) and the mixture stirred at room temperature for 1 hour. To the cooled (0 C) reaction mixture, a 2 M solution of (trimethylsilyl)diazomethane in hexanes (11.5 mL) was added and the mixture stirred at room temperature for 16 hours. The reaction was cooled (0 °C) and a solution of 48 wt. % hydrogen bromide in water (0,86 rnL) was added and the mixture stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogen carbonate (50 mL) was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was triturated vith a 1: 2 mixture of ethyl acetate and heptanes and the resultant solid isolated via filtration to give the title compounds in a 1: 1 ratio having the following physical properties (2.13 g).
ExampjJ2( 1): LCIIvIS tR 1.99 minutes; MS (ES4) n1z 264 and 266 [M-C(C1-13)3+H) a
Example 18l):
[IC/MS tR 1.95 minutes; MS (ES4) m/z 220 [M-C(CH3)3+H) a Exampie 183: 2-methyl-2-propanyl ftrans-4-(2-((3S)-7-[5-chloro-2-( 1 H-tetrazol-1 - yl)phenyll-5-oxo-I,2,3,5-tetrahydro-3-indolizinyl} -1 H-iinidazol-5-yl)cyclohexyl]carbamate The same operation as in Example 178 -* Example 179 -* Example 180 -.
Example 181 was conducted from the 1: 1 mixture of compounds prepared in Example 182 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 180 in the operation, the compound prepared in
Example 9 was used).
[IC/MS i 3.27 minutes; MS (ES) m/z 577 (M-i-F1) b NMR analysis showed a 2: 1 ratio of tautomers.
Major tautomer: H NMR (500 MI-lz, methanol-d4) 9.36 (s, 1 11), 7.78 -7.70 (m, 2 H), 7.68 (d, I H), 6.65 (s, 1 H), 6.58 (hr. s, I H), 6.10 (s, 1 H), 6.07 (s, 1 H), 5.71 (app. d, 1 H), 3.59 (hr. s, 1 H). 3.43 -3.31 (obs. m, I H), 3.12-3.02 (m, I 11), 2.64-2.53 (m, I H), 2.49 (t, 1 H), 2.44-2.33 (m, 1 H), 2.07-1.92 (m, 411), 1.82-1.62 (m, 2 H), 1.44 (s, 9 H), 1.36-1.25 (m, 2 H).
Minor tautomer: H NMR (500 MHz, methanol-d4) 9.36 (s, I FE), 7.78 -7.70 (m, 2 H), 7.68 (d, I H), 6.71 (s, I H), 6.58 (br. s, I H), 6.10 (s, I H), 6.09 (s, 1 H), 5.71 (app. d, I Fl), 3.65 (br. s, 1 H), 3.43 -3.31 (ohs. in, I 11), 3.12-3.02 (m, 1 H), 2.75-2.64 (m, 1 H), 2.64-2.53 (m, I H), 2.44-2.33 (m, 1 H), 2.07-1.92 (in, 411), 1.82-1.62 (m. 211), I.44(s, 911), 1.36-1.25 (in, 2 H).
Exampç 184: (3S-3-[5-(traus-4-aminocyc1ohexyfl-l H-imidazol-2-y)]-7-[5-chloro-2- (1 H-tetrazol-I -yQpy[-2,3-dihydro-5(1 th-indolizinone The compound prepared iii Example 183 (0.32 g) was treated as detailed in Example 40 to give the title compound having the following physical properties (0.15 g).
LCIMS i 2.28 minutes; MS (ES') #n/z 477 (M+H), 239 [(M+2H)/2] b H NMIR (500 MHz, methanol-cLi) 5 9.35 (s, I H), 7.77 -7.70 (m, 2 H), 7.67 (d, 1 H), 6.64 (br. s, I H), 6.10 (s, 1 H), 6.08 (s, I H), 5.70 (dd, I H), 3.42-3.32 (m, 1 H), 3.08 (dd, 1 H), 2.70 (ft. 1 14), 2.62 -2.54 (m, 11-f), 2.54-2.45 (in. 1 H), 2.43 -2.34 (in, 1 H), 2.09-1.91 (m, 4 H), 1.43 (ddt, 2 H), 1.28 @dd, 2 H).
Example 185: methyl ftrans-4-(2-ff3S)-7-[5-chloro-241 FI-retrazol-I -yflphçpyfl-5-oxo- 12,3,5-tetrahvdro-3-indolizinyfl-1 H-imidazol-5-yI)cyclohexyl]carbamate The compound prepared in Example 184 (78 mg) was treated as detailed in Example 128 to give the title compound having the following physical properties (19 mg). (Note: in the step corresponding to Example 128 in the operation, methyl chioroformate was used).
LC/MS R 2.92 minutes; MS (ES') nilz 535 (M+H) b H NMR (500 MHz, methanol-cL) 6 9.38 (s, 1 1-1), 7.79 -7.72 (in, 2 H), 7.70(4, 1 H), 6.68 (br. s, I H), 6.12 (s, 1 H), 6.10 (s, 1 H), 5.72 (dt, I H), 3.71 (br. s, I H), 3.63 (s, 3 II), 3.45-3.35 (in, 2 H), 3.13 -3.04 (m, 1 H), 2.64-2.54 (in, 1 H), 2.41 (hr. s, 1 H), 2.10-1.97 (m, 2 H), 1.80 (hr. s, 2 H), 1.71 (br. s, 2 H), 1.40-1.29 (m, 2 H).
rnple 186: (3S-3-f5-(trans-4-aminocyelohexy1)-4-ch1oro-1H-imidazol-2-y11-7- [5-chloro-2-(l H-tetrazo1-1-ylThhenyfl.3-dihydro-5(lH)-indoIizinone The same operation as in Example 44 -* Example 40 was conducted from the compound prepared in Example 183 to give the title compound having the following physical properties.
LC/MS tg 2.94 minutes; MS (ES') m/z 5711 (M-4-H). 255.5 [(M+2H)/2] H NMR (500 MHz, methanol-d4) 6 9.38 (s, I H), 7.78 -732 (in, 2 H), 7.70 (4, 1 14), 6.11 (s, I H), 6.10 (s, I H), 5.65 (dd, I H), 3.48 -3.35 (in, I H), 3.08 (ddd, I H), 2.75 (U, 1 H), 2.68 (U, 1 H), 2.64 2.54 (m, I IhI), 2.33 (ddt, I H), 2.01 (hr. d, 2 H), 1.93 I.84(m,2H), 1.68-1.56(m,2H), 1.37-J.24(m,2H).
Example 187: 2-j[(4jjffioxyphenyflmethy1lamino pyridine-4-carbonitrile A mixture of 4-cyano-2-fluoropyridine (LO g) and 4methoxyber1amine (2.25 g) was stirred at 100°C for 1 hour and purified by column chromatography (0 to 50% ethyl acetate in heptanes) to give the title compound having the following physical properties (1.69 g).
LCIMS tR 1,81 minutes; MS (ESD m/z 240 (M+H) a Example 188: 1-12-{ [(4-methoxyphenyl)methyljamino} pyridin-4-yflethan-1-one To a diethyl ether (25 mL) solution of the compound prepared in Example 187 (0.8 g) was added a 1.4 M solution of methyl magnesium bromide in 3: 1 toluene / tetrahydrofuran (7.2 niL) and the mixture stirred at room temperature for 16 hours;To the reaction mixture, a saturated aqueous solution of ainmoniwn chloride (10 mL) was added followed by 6 M hydrochloric acid (5 mL) and the mixture stirred at room temperature for 1 hour. The mixture was then basified top11 12 by addition of 2 M sodium hydroxide and extracted into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to give the title compound having the following physical properties (0.47 g).
LC/MS lp. 1.35 minutes; MS (ES4) nv'2257(M+HY Example 189: 1 dihydrobromide To a glacial acetic acid (7 mL) solution of the compound prepared in Example 188 (0.38 g) was sequentially added 33 wt. % hydrogen bromide in acetic acid (1.28 mL) and bromine (76 j.iL) and the mixture stined at 70 °C for 2 hours. The reaction mixture was concentrated and the residue triturated with dichloromethane (10 mE). The precipitate formed was isolated by filtration to give the title compound having the following physical properties (0.38 g).
H NMR (500 MIHz, methanol-cLj) 67.88 -7.83 (m, 1 H), 7.24 (d, 1 H), 7.01 (dd, I H), 3.71 (d, IH), 3.64 (d, 1H).
Example 190: (3S)-3-[5-(2-amino-4-pyidinyl)-1H-imidazol-2-yl1-7j}joro-2-(lH-tetrazol.-I -yflphenyl]-2,3-dihydro-5( 1H)-indolizinone The same operation as in Example 51 -* Example 52 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 189 was used).
LC/MS tR 2.85 minutes; MS (ES) /n/z 472 (M+H) b H NMR (500 MHz, methanol-th) 6 9.39 (s, 1 H), 7.85 (d, 1 1-1), 7.78 -7.74 (m, 2 II), 7.73-7.69 (m, 1 H), 7.52 (hr. s, 1 H), 6.96-6.88 (m, 2 H), 6.17 (s, 1 H), 6.11 (s, 1 H), 5.80 (dd, 1 H), 3.50-3.41 (m, 1 H), 3.13 (ddd, 1 H), 2.70-2.61 (m, 1 H). 2.51 -2.43 (in, 1 H).
Example 191: 2-bromo-1 -(6-nitroyyridin-3-yl)ethanone To a stirred solution of 1-(6-nitropyridin-3-yl)ethan-1-one [patent W02010/089292, page 7fl (0.83 g) in tetrahydrofuran (10 mL) was added N-bromosuccinirnide (1.78 g) and the mixture stirred at 50 "C for 16 hours. The reaction mixture was concentrated and the residue purified by column chromatography (20 to 100% ethyl acetate in dichloromethane) giving the title compound having the following physical properties.
LC/MS tR 1.53 minutes; MS (ES) m/z 245 and 247 (M+l1)a Example 192: 3-[4-(6-amino-3-pyridinyl)-IH-imidazol-2-yll-7-[5-chloro-2-(1H-tetrazol-1 -yl)phenyll-2,3-dihydro-5(1H)-indolizinone The same operation as in Example 84 -* Example 39 -* Example 40 -.
Example 41 -÷ Example 74 was conducted from the compound prepared in Example 19 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 191 was used).
LC/MS R 2.66 minutes; MS (ES) ,n/z 472 (M+H) b H NMR (500 Mhz, DMSO-d6) 6 11.97 (br. s, 1 H), 9.68 (s, 1 H), 8.25 (d, 1 H), 7.83 - 7.75 (m, 3 H), 7.66 (dd, lii), 7.28 (s, 1 II), 6.43 (d, I H), 5.96 (s, 1 H), 5.95 (s, 1 H), 5.81 (hr. a, 2 H), 5.60 (d, 1 II), 3.43 -3.31 (ohs. rn, I H). 3.05-2.92 (m. I H), 2.52- 2.43 (m, 1 H), 2.39-2.29 (m. I H).
Example 193: 1 -(6-aminopyrid3 -yl)-2-bromoethan-1-one dihydrobromide l-(6-aminopyridin-3-yl)ethan-l-onc [patent US2007/027184, page 17] (0.46 g) was treated as detailed in Example 91 to give the title compound having the following physical properties (0.70 g).
H NMR (500 MHz, methanol-cU) ö 8.65 (d, 1 11), 8.01 (dd, 4 H), 6.60 (d, 1 H), 4.51 (s, 2H el94:3S-3-46-amino-3-ñdin'I-1H-idol-2-'1-7-5Moro-2-lH-tetrazol-I -vflpheny1L2jdihvdjffl-indolizinone The same operalion as in Example 51 -Example 52 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 193 was used).
LC/MS tR 1.38 minutes; MS (ES) ink 472 (M+Hf jj95:methl5-2-'3S-7-5-ch1oro-2-llj-tetrol-l-yl)pheny1J-5-oxo- 1.2,3jtrahydro-3-indolizjnyl}-l H-imidazol-5-yl)-2-pyridinyllcarbarnate The compound prepared in Example 194 (80 mg) was treated as detailed in Example 128 using methyl ehlorofonnate in place of ethyl ebloroformate to give the title compound having the following physical properties (66 mg).
LCJMS tg 3.11 minutes; MS (ES') nv'z 530 (M+H) b 1H NMR (500 MHz, methanol-cU) 69.35 (a, I H), 8.56 (app. hr. a, I H). 8.02 (app. hr. a, H), 7.88 (app. hr. s, 1 H), 7.76-7.70 (it, 211). 7.69 (d. 1 H), 7.41 (hr. s, I 11). 6.13 (a, I H), 6.09 (s, 1 H), 5.78 (dcl, 1 H), 3.77 (a, 3 H), 3.52-3.40 (m, 1 H), 3.16-3.06 (it, 1 H), 2.71 -2.59 (in, I H), 2.52 (app. hr. s, 1 H).
Example 196: methyl I5-(4-chipo-2-U3S)-7-F5-ch1oro-2-(1H-tetrazol-l -yflphenyl]-5-oxo-l,2,3,54etrahydro-3-indo1iziiyfl. Jjjjmidazo1-5-yfl-2-pyridiny11carbamate The compound prepared in Example 195 (46 ing) was treated as detailed in Example 44 to give the title compound having the following physical properties (20 rug).
LC/MS 1R 3.92 minutes: MS (ES) m/z 564 (M-1-H) b H NMR (500 MHz, methanol-cL) & 9.38 (s, I H), 8.59 (d, I H), 8.07 (d, 1 H), 8.00 (d, 1 H), 7.78 -7.73 (m, 2 H), 7.20 (d, I H), 6.15 (s. 1 H), 6.10 (s, 1 H), 5.73 (cM, 1 H), 3.52 3.41 (m, I H), 3.12 (ddd, I H), 2.72-2.61 (in, 1 H), 2.46-2.36 (m, 1 H).
Example 197: ethyl 15-(ZdI3S)-7-15-chloro-2-(1 H-tetrazol-1-yl)phenyfl-5-oxo-1,2,3,5-tetrahydxo-3-indolizinyfl-1 H-imidazol-5-yfl-2-pyridinyllcmtajnate The compound prepared in Example 194 (50 rug) was treated as detailed in Example 128 to give the tide compound having the following physical properties (21 rug).
LC/MS tR 3.29 minutes; MS (ES1) tn/z 544 (Mi-H) b H NMR (500 MHz. methanol-cl4) 3 9.36 (s, 1 11), 8.56 (br. s, 1 11), 8.07 -8.00 (in. 1 H), 7.91 -7.84 (m, ii-!), 7.75 -7.71 (m, 2 H), 7.70-7.66 (m, I H), 7.42 (br. s, I H), 6.13 (s, 1 H). 6.09 (s, I 11), 5.78 (dd, 1 H), 4.22 (q, 2 H), 3.50-3.41 (m, I H), 3.15 -3.06 (m, I H), 2.69-2.60 (in, I H), 2.55 -2.46 (in, 1 H), 1.32 (t, 314).
Example 198: (3S-3j5-(6-amino-pyñin1.4-cMoro-lH-imidazol-2-yfl-7-[5-eh1oro- 241 H-te.trazol-I -yflpheny11-2,3-dihvdro-5(1m-in4jzinone The compound prepared in Example 194 (50 rug) was treated as detailed in Exampk 44 to give the title compound having the following physical properties (13 mg).
LC/MS tR 2.97 minutes; MS (ES) m/z 506 (M+H)t) H NMR (500 M1-lz, methanol-cl4) 9.36 (s, 1 H), 8.21 (s, 1 H), 7.78 -7.71 (in, 3 1-1), 7.70-7.66 (m, I H), 6.65 (d, I H). 6.13 (s. I 1-1), 6.08 (s, 1 H), 5.69 (d, 1 11). 3.49-3.39 * 171 (m, I 11), 3.10 (dd, I 11), 2.69-2.58 (m, I H), 2.42 -2.34 (m, 1 11).
Examviej.9: 14[46-arnino-3-pyridinvfl-1 H-imidazol-2-yllmethyl3-4-[5-chloro-2- (1 H-tetrazol-I -yl)phenyll-2( 1 th-pvridinoi The same operation as in Example 51 -Example 52 was conducted from the compound prepared in Example 25 to give the title compound having the following physical properties. (Mote: in the step corresponding to Example 51 in the operation, the compound prepared in Example 193 was used).
LCAI S t, 2.61 minutes MS (ES) m"z 446 (M+H) b H MAR (500 MHz, methanol-th) 59.37 (s. I H), 8.21 (br. s, 1 H). 7.81 -1.72 (m. 3 H).
7.70-7.63 (in, 2 H), 7.26 (br. s, 1 11), 6.66 -6.62 (m, I H), 6.42 -6.38 (in, I H), 6.05 - 6.00 (m, I H), 5.17 (s, 211).
Example 200: methyl ( 5-f2-(44-[5-chloro-2-( 1 H-retrazol-1-yZ)phenyl]-2-oxo-I (2H)-pyridinyl}methyl)-1H-imidazol-5-yfl-2-pyridinyl}carbamate The compound prepared in Example 199 (200 mg) was treated as detailed in Example 128 using methyl chioroformate in place of ethyl chioroformate to give the title compound having the following physical properties (9 mg).
[C/MS 1R 3.06 minutes; MS (Est) mz 504 (M+H) b 1-1 NMR (500 MHz, DMSO-&) 6 12.27 (br. s. I H), 10.22 (br. s, 1 H), 9.72 (s, I H), 8.63 (s, 1 II), 8.01 (d, I H), 7.92-7.75 (m, 4 H), 7.68 (d, 1 H), 7.55 (br. s, 1 11), 6.26 (s, I H), 5.85 (dd, 1 H), 5.09 (s, 2 H), 3.64 (s, 3 H).
Example 201: 6-amino-N-methoxy-N-mcthylpyridine-3-carboxamide To an N,N-dimethylfonnamide (50 mL) solution of 6-aminopyridine-3 -carboxylic acid (2.0 g) was added N,O-dimethylhydroxylamine hydrochloride (1.69 g), O-(7-azabenzotriazol-1 -yl)-N,N,N,N'-tetramethyluronium hexatluorophosphate (6.06 g) and diisopropy]ethylamine (7.6 mL) and the mixture stirred at room temperature for 16 hours. To the reaction mixture, water (250 mL) was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated and the residue purified by column chromatography (0 to 15% methanol in dichioromethane) to give the title compound having the following physical properties (0.61 g).
H NMR (500 MHZ, DMSO-d6) S 8.31 (d. 1 H), 7.69 (dd, 1 H), 6.42 (d, 1 H), 3.57 (s, 3 H). 3.21 (s. 3 H).
Example 202: -te-butoxy)carbonyfl-N-{5- [methoxy(methyl)carbamoyl}pyridin-2-yJ} carbamate The compound prepared in Example 201 (0.61 g) was treated as detailed in Example 10 to give the title compound having the following physical properties (0.58 g).
LC/MS tR 1.99 minutes; MS (ES) m/z 382 (M-I-I-1) a mple 203: tert-butyl N-IS -proyanoylpyHdin-2-yflcarbamate To a cooled (0 "C) tetrahydrofiiran (10 mL) solution of the compound prepared in Example 202 (0.53 g) was added a 1 M solution of ethylmagnesium bromide in tetrahydrofitran (1.73 mL) and the mixture stirred at room temperature for 16 hours. To the cooled (0 °C) reaction mixture, a saturated aqueous solution of animonium chloride (1.5 mL) and water (30 mL) was sequentially added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to give the title compound having the following physical properties (0.43 g).
LC/MS tR 2.03 minutes; MS (ES) ink 251 (M+H) a Example 204: tert-butyl N45-(2-bromoiropanoyl')pyridin-2-yflcarbamate To a glacial acetic acid (5 rnL) solution of the compound prepared in Example 203 (0.20 g) was added a solution of 33 wt. % hydrogen bromide in acetic acid (0.28 mL) followed by bromine (41 gL) and the mixture stirred at room temperature for I hour. To the reaction mixture, a saturated solution of aqueous sodium bicarbonate was added (20 mL) followed by extraction into ethyl acetate. The combined organic layers were dried, filtered and concentrated and the residue purified by column chromatography (0 to 50% ethyl acetate in heptane) to give the title compound having the following physical properties (0.20 g).
LCIMS 4 2.23 minutes; MS (ES) .n/z 329 and 331 (M+1l) a Example 205: tert-butyl N-(5-{2-[(3 S)-7-15-chlorpZ-(1 1-1-1,2,3,4-tetrazol-1 -yDpheny p-l,3,5-tetrahydroindojj4n-3-l4-meth'1-1H-jrnidazol-5-yflpynidjp-2-atc The sante operation as in Example 51 -* Example 52 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 204 was used).
LtD/MS 1R 1.66 minutes; MS (ES) m/z.586 (M+H) a Examp206:_(3S)-3-J5fgjno-3-pyridinyl)-4-methyl-1H-imidazo1-2.jj7-5-pro-24 I 1-ktetragpjj-yflphenyl] 2,3 -dihvtflHindo1izinone To a 1,4-dioxane (0.5 mL) solution of the compound prepared in Example 205 (42 mg) was added I M hydrochloric acid (0.4 mL) and the mixture heated at 90 °C for 3 hours. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate (40 mL) was added followed by extraction into ethyl acetate. The combined organic layers were dried, filtered and concentrated to give the title compound having the following physical properties (25 nig).
LtD/MS tR 2.53 minutes; MS (ES) m/z 486 (M+H) b 1H NMR (500 MHz, methanol-&) 59.25 (s, 1 H), 7.91 (br. s, 1 Fl). 7.65 -7.61 (m, 2 H), 7.60-7.55 (m, I H), 7.51 (d, I H), 6,54 (d, I H), 6.02 (s, 1 H). 5.98 (s, I H), 5.60 (dd, I H), 3.39-3.29 (iii, I H), 2.98 (ddd, 1 H), 2.5! (qd, 1 H), 2.37-2.28 (m, I H). 2.18 (br.
s, 3 H).
Example 207: methjjj5424(3S)-745-chloro-2-(IH-tetrazol-1-yflpjjyl-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl}-4-petlJH-imidazo1-5-yfl-2-pyridinyl] carbamate The compound prepared in Example 206 (100 mg) was treated as detailed in Example 128 using methyl chloroformate in place of ethyl chioToformate to give the title compound having the following physical properties (28 mg).
LtD/MS 3.00 minutes; MS (ES) m1z 544 (M+H) b 14 NMR (500 MHz, methanol-&) S 9.37 (s, I H), 8.41 (s, I 14), 7.96 -7.88 (m, 2 H), 7.77 -7.73 (m. 2 I-fl, 7.71 -7.68 (m, I I-fl, 6.14 (s, 1 H), 6.10 (s, I H), 5.74 (dcl, I H), 3.79 (s, 3 H), 3.51 -3.42 (m, 1 H), 3.16-3.07 (m, 1 H), 2.69-2.60 (m, 1 H), 2.51 -2.42 (m, 1 H), 2.36 (s, 3 H).
Example 208: 6-chIoro-5-iodopyridin-2-amine To an N,N-dimethylformamide (30 mL) solution of 2-amino-6-chloropyridine (1.0 g) was added N-iodosuccinirnide (1.75 g) and the mixture stirred at room temperature for 16 hours. To the reaction mixture, water (200 mL) was added followed by extraction into ethyl acetate. The combined organic layers were dried, filtered and concentrated. The residue was triturated with dichioromethane and the resultant precipitate collected by filtration to give the title compound having the following physical properties (0.49 g).
LC/MS R 1.72 minutes; MS (ES) m/z 254 (M+H) a Example 209: 1 -(6-amino-2-chlorop'yridin-3 -yl)-2-bronioethan-1 -one dihydrobromide The same operation as in Example 90 -. Example 91 was conducted from the compound prepared in Example 208 to give the title compound having the following physical properties.
LC/MS tR 1.52 minutes; MS (ES) m/z 249 and 251 (M+H) a Example 210: (3S)-3-[5-(6-amino-2-chloro-3-pyridinyl)-ll-I-imidazol-2-yll-7-[5-chloro- 2-(1 I-I-tetrazol-1 -yI)phenyll-2,3 -dihydro-5( 1 fl)-indolizinone The same operation as in Example 51 -* Example 52 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 209 was used).
LC/MS tR 2.98 minutes; MS (ES) in/z 506 (M+H)1' H NMR (500 MHz, methanol-d4) 5 9.35 (s, I H), 7.81 (app. br. a, I H), 7.76 -7.71 (m, 2 H), 7.70-7.66 (m, 1 1-1), 7.32 (app. br. s, 1 H), 6.56 (d, I H), 6.14 (a, 1 1-1), 6.08 (s, 1 H'), 5.79 (dd, 1 H), 3.50-3.38 (m, I H), 3.10 (ddd, 1 H), 2.68-2.57 (m, I H), 2,50 (Md, lii).
Example 211: l-{[5-.(6-amino-2-chloro-3-pyridinvl)-1 H-jmjdazolyj]methyl}-4-[5-ch1oro-2-(1H-tejl-l')pheny11-2( 1HI-pyridinone The same operation as in Example 51 -* Example 52 was conducted from the compound prepared in Example 25 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 209 was used).
LC/MS 1R 2.92 minutes; MS (ES') ,n4r 481 (M-fH) b H NMIR (500 MI-k, methano1-d.) S 9.36 (a, I H), 7.86 (br. a, I H), 7.76 -7.7] (m, 2 II), 7.70-7.64 (m, 2 H), 7.39 (hr. a, 1 H), 6.56 (d, 1 Fl), 6.40 (s, 1 H), 6.02 (dd, 1 I{), 5.18 (s,2H).
Example 212: 1 -(6-amino-2-methylpyridin-3-yfl-2-bromoethan-1-one dihydrobromide The same operation as in Example 90 -+ Example 189 was conducted from 5-bromo-6-methyipyridin-2-amine to give the title compound having the following physical properties.
H NMR (50Q MHz, methanol-d4) 5 8.39 (d, 1 H), 6.96 (d, 1 H), 4.57 (a, 2 H), 2.75 (a, 3 H).
Example 213: (3S)-3-F5-(6-amino-2-rnethyi-3-pyridinyl) -1H-imidazol-2-yll-7-F5-chloro-241 H-tetrazol-I -yI)phenytl-2,3-dihydro-5fl 1-[)-indohzinone The same operation as in Example 51 -* Example 52 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 212 was used).
LC/IvlS tft 2.62 minutes; MS (ESt) ith 486 (M+H) b H NMR (500 MHz, methanol-th) S 9.38 (a, I II), 7.77 -7.73 (m, 2 H), 7.72 -7.68 (m, I H), 754 (d, I H), 6.99 (a, 1 H), 6.48 (d, I H), 6.14 (a, I H), 6.12 (a, I H), 5.80 (dd, I H), 3.51 -3.39 (in, I Fl), 3.16-3.08 (m, I Fl). 2.69-2.59 (m, I U), 2.52 -2.46 (m, I 1-1), 2.41 (s, 3 H).
Example 214: methyl [5-(2-{ (3 S)-7-[5-chloro-2-( I H-tetrazol-1 -yl')phenyl]-5-oxo-I,2,3,5-tetrahydro-3-indoljzinyl}-IH-imidazol-5-yI) -6-methyl-2-pyridinvflcarbamate The compound prepared in Example 213 (33 mg) was treated as detailed in Example 128 using methyl chloroformate in place of ethyl chioroformate to give the title compound having the following physical properties (21 mg).
LC/MS tg 3.07 minutes; MS (ES) m/z 544 (M+H) b II NMR (500 MHz, methanol-d4) S 9.35 (s, 1 H), 7.89 (hr. d, 1 H), 7.77-7.70 (m, 3 H), 7.68 (d, 1 H), 7.19 (br. s, I H), 6.13 (s, I H), 6.09 (s, I H), 5.80 (dcl, I H), 3.51 -3.41 (m, I H), 3.15 -3.07 (m, I H), 2.68 -2.60 (m, 1 II), 2.56-2.40 (ohs. in, 1 H), 2.50 (s, 3 H).
Example 215: 1 46-aniino-2-fluoropyridin-3-yl)-2-bromoethan-1 -one dihydrobromide The same operation as in Example 90-. Example 189 was conducted from 2-amino-6-fluoro-S-iodopyridine [J. Org. Diem. 71(8), 2922 (2006)] to give the title compound having the following physical properties.
LC'MS 1R 1.50 minutes; MS (ESU) m/z 233 and 235 (M+H)'t Example 216: (3S)-3-f5-(6-aniino-2-fluoro-3-pyridinyl-I H-imidazol-2-yfl-7-[5-chloro- 2-(IH-tetrazol-I -y1)pçpy11-2.3-dihydro-5 1-[)-indolizinone The same operation as in Example 51 -* Example 52 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 215 was used).
LC/MS R 2.94 minutes; MS (ES') m/.z 490 (M±H) b H NMR (500 MI-li, methanol-d4 89.35 (s, I H), 7.97 (app. hr. s, 1 H), 7.75 -7.70 (m, 2 H), 7.68 (d, 1 Fl), 7.15 (hr. s, 1 II), 6.45 (dd, 1 H), 6.14 (s, 1 Fl), 6.07 (s, I II). 5.79 (d, 1 1-1), 3.50-3.38 (iii, I Fl), 3.14-3.05 (m, I H), 2.67-2.56 (m, I H). 2.52 -2.44 (m, I II).
Examnle 217: (3S)-7-[5-chloro-2-(1 H-tetrazol-1.y1)penyl1-3-[5(jpethyl-3-pyridinyl)-1 H-imidazol-2-yll-dihydçglH)-indolizinon The same operation as in Example 204 -* Example 51 -Example 52 was conducted from 2-methyl-5-acetyl-pyridine to give the title compound having the following physical properties. (Note: in the step corresponding to Example St in the operation, the compound prepared in Example 9 was used).
LC/MS R 2.83 minutes; MS (ES4) ith 471 (M+H) b H NMR (500 MHz, methanol-d4) 6 9.35 (s, I H), 8.73 (app. s, 1 II), 8.01 (d, I H), 7.75 -7.71 (m, 2 H), 7.68 (ii, 1 H), 7.46 (hr. s, I Fl), 7.30 (d, I H), 613 (s, 1 H), 6.09 (s, 1 H), 5.78 (dd, 1 H), 3.51 -3.41 (m, 1 II), 3.12 (ddd, I H), 2.70-2.59 (m, 2 H), 2.52 (s, 3 H).
Examp1j:3S-3-(4-chloro-5-(6-methy1-3-pyridinvfl-l H-imidazol-2-yfl-7-[5-chloro-2-( I H-tetrazol-l -yl)phenyll-2,3-dihydro-5(1 J-r)-indolizinone The compound prepared in Example 217 (45 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (19 mg).
LC/MS 3.18 minutes; MS (ES*) in/z 505 (M+H)" H NMR (500 MHz, methanol-d4) 6 9.36 (a, I H), 8.75 (d, I H), 8.05 (dd, I H), 7.76 - 7.72 (in, 2 H), 7.68 (d, 1 H), 7.40 (d, 1 H), 6.13 (s. 1 H), 6.10 (d, I H), 5.72 (dd, 1 H), 3.45 (td, 1 H). 3.12 (ddd. I H), 2.66 (qd, 1 H), 2.57 (s, 3 H), 2.44-2.36 (m, I H).
Exarnpjjjjtert-buty!_N-t6-(2-bromoacetyl)pyridin-3j]carbaniate The same operation as in Example 10-' Example 188-1 Example 91 was conducted from 5-amino-2-cyanopyridine to give the title compound having the following physical properties.
LC/MS tR 2.07 minutes; MS (ES-t-) nl/z 315 and 317 (M+H) a Example 220: 2-methyl-2-propanyl 16-(2-{7-[5-chloro-2-(l H-tetrazol-I-yflphenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -lH-imidazol-5-yI)-3-pyridinyIcarbamate The same operation as in Example 84 -+ Example 39 was conducted from the compound prepared in Example 17 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 84 in the operation, the compound prepared in Example 219 was used).
LC/MS tR 3.37 minutes; MS (ES) m/z 572 (M+H)" H NMR (500 MHz, methanol-cLs) 8 9.36 (s, 1 H), 8.54 (d, 1 Fl), 7.92 (dd, 1 II), 7.79 - 7.64 (m, 4 1-1), 7.48 (s, 1 H), 6.14 (s, 1 II), 6.08 (s, 1 H), 5.80 (dd, I H), 3.54-3.37 (m, 1 H), 3.18 -3.03 (m, 1 H), 2.72-2.43 (m, 2 H), 1.53 (s, 9 H).
Example 221: 3-[5-(5-amino-2-pyridjnvl)-1H-imidazol-2-yll-7-15-chloro-2-(1H-tetrazol-l -y1)pheny11-2,3-dihydro-5(1H-indo1izinone The compound prepared in Example 220 (130 mg) was treated as detailed in Example 206 to give the title compound having the following physical properties (104 mg).
LC/MS R 2.79 minutes; MS (ES') m/z 472 (M±H)1, H NMR (500 MHz, methanol-d4 6 9.35 (s, 1 H), 7.95 (br. s, 1 H), 7.75 -7.71 (m, 2 H), 7.67 (d, 1 H), 7.53 (hr. s, 1 H), 7.32 (br. s, I H), 7.10 (dd, 1 H), 6.14 (s, I H), 6.07 (s, 1 H), 5.79 (d, 1 H), 3.51 -3.39 (in, 1 H), 3.09 (dd, 1 H), 2.65 -2.56 (in, I H), 2.54 -2.45 (m, 11-1).
Example 222: 3-[5-(5-amino-2-pyridinyl)-4-cbIoro-1H-imidazol-2-y11-7-[5çKloro-2- (1 H-tetrazol-1 -yflphcj&1-2,3-dihydro-5( 1 fl)-indolizinone The same operation as in Example 44 -* Example 206 was conducted from the compound prepared in Example 220 to give the title compound having the following physical properties.
LC/MS I 3.38 minutes; MS (ES') rn/z 506 (MiH)t, H NMR (500 MHz, methanol-&) 69.35 (a, 1 H), 8.04 (a, 1 H), 7.75 -7.70 (m, 3 H), 7.69-7.66 (m, 1 H), 7.09 (dd, 1 H), 6.15 (s, I H), 6.07 (s, 1 H), 5.77 (dd, 1 H), 3.43 - 3.35 (in, I H), 3.12-3.05 (m, I H), 2.60 (qd, I H), 2.50-2.41 (m, I H).
Example 223: methyl [642-7-[5-chloro-2-flH-tetrazol-I -yflphenyl]-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl}-1H-imidazol-5-yI)-3-i, yridinylicarbaxnate The compound prepared in Example 221 (60 mg) was treated as detailed in Example 128 using methyl chioroformate in place of ethyl ehioroformate to give the title compound having the following physical properties (30.2 mg).
LC(MS tR 3.00 minutes; MS (ES4) miz 530 (M+H) b NMR analysis showed a 2: 1 ratio of tautomers.
Major tautomer: H NMR (500 MHz, DMSO-d6) ö 1218 (s, I H), 9.79 (br. s, 1 H), 9.69 (s, I H), 8.53 (d, I H), 7.91 -7.81 (m, 1 H), 7.81 -7.74 (m, 3 H), 7.69 (d, 1 H), 7.48 (U, 1 H), 5.97 (app. s,2 H), 5.64 (dd, I H), 3.68 (s, 3 1-1), 3.40-3.30 (obs. m, 1 H), 3.07- 2.90 (m. 1 H), 2.53 -2.44 (obs. in, 1 H), 2.38-2.30 (m, 1 H).
Minor tautomer: H NMR (500 MHz, DMSO-d) 3 12.49 (s, I II), 9.89 (br. s, I 1-1), 9.70 (s, I H), 8.63 (d. 1 Fl), 7.91 -7.81 (in, 1 H). 7.81 -7.74 (m, 3 H), 7.68 (d, 1 H), 7.33 (d, I H), 5.96 (s, 1 H), 5.95 (s, 1 H), 5.71 (dd, I H), 3.70 (s, 3 H), 3.29-3.21 (m, 1 H), 3.07 -2.90 (m, I H), 2.53 -2.44 (ohs. m, I H), 2.29-2.21 (in, I H).
Exanjple 224: 2-(5-amigop4jn-2-l-2-oxoeth12-E-t5-ch1oro2-t1,2334-tetrazol-yl)phenvl] -2-oxopyridin-I -yft acetate The compound prepared in Example 25 (0.55 g) was treated as detailed in Exampk 51 using the compound prepared in Example 219 in place of 2-bromo-1-pheuylethan-1-one to give the title compound having the following physical properties (0.26 g).
LC/MS ta 1.66 minutes; MS (ES) tn/z 466 (M+H) Example 225: 2-4 5-[(methoxycarbonyllaminolpvridin-2-yl} -2-oxoethyl 2-(4-15-chloro- è4-tetrol-l;yl)phenyiJ2-oxqpyricin-I -yU acetate To a dichioromethane (25 niL) solution of the compound prepared in Example 224 (0.24 g) was added diisopropylethylamine (0.10 g) and methyl chloroformate (44 iL) and the mixture stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue purified by column chromatography (0 to 80% ethyl acetate in heptanes) to give the title compound having the following physical properties (0.lOg).
LCIMS tR 3.06 minutes; MS (ES4) nilz 524 (M+H) a Example 226: methyl 6-[2-fl4-[5-chloro-2-(1H-tetrazol-1 -yflphenyll-2-oxo-1(2H)-pyridpyl)rnethyl)-1 H-imidazo1-5-y11-3-pydinyl} carbamate The compound prepared in Example 225 (102 mg) was treated as detailed in Example 52 to give the title compound having the following physical properties (17 mg).
LC/MS R 2.99 minutes; MS (ES4) m/z 504 (M+H) b H NMR (500 MI-Iz, methanol-d4) a 9.38 (s, 1 Fl), 8.59 (br. s, 1 H), 7.97 (br. d, 1 H), 7.77 (app. br. s, 1 H), 7.77 -7.7J (in, 2 H), 7.71 -7.63 (in, 2 H), 7.55 (app. br. s, I H), 6.42 (s, 1 H), 6.03 (d, I H), 5.22 (s, 2 Fl), 3.80 (s, 3 Fl).
irnp1e 227: 245-aminopyridin-2-yl)-2-oxoethyl (3S)-7-[5-chloro-2-(1H-1,2,3,4-tetrazol-1-yl)phenyll-5-oxo-l,2,3. 5-tetrahydroindolizine-3-carboxylate The compound prepared in Example 9(0.39 g) was treated as detailed in Example 51 using the compound prepared in Example 219 in place of 2-bromo-1-phenylethan-l -one to obtain the title compound having the following physical properties (0.54 g).
LC/MS R 1.73 minutes; MS (ES4) m!z 492 (M+H) a Examples 228(1) and 228(2): 2-(5-{ fttert-butoxy)carbonyl]amino} pyridin-2-yl)-2- oxoethyl (3 S)-7-[5-chloro-2-(IH-I,2.3,4-tetrazol-I -yl)phenyll-5-oxo-1,2,3,5-tetrahydroindolizine-3 -carboxylate and 2-(5-bis[(tert-butoxy)carbony11amino} pyridin 2-yl)-2-oxoethyl (3S)-7-[5-chloro-2-UH-l,2,3,4-tetrazol-i -yl)phenyl-S-oxo-1,2,3,5-tetraliydroindolizine-3-carboxylate To a dichloromethanc (50 mL) solution of the compound prepared in Example 227 (0.54 g) was added di-tert-butyl dicarbonate (1.19 g) and 4-dimethylaminopyridine (0.27 g) and die mixture stirred at room temperature for 16 hours. The reaction mixture was concentrated and the residue purified by colunm chromatography (0 to 20% methanol in dichioromethane) to obtain the title compounds in a 2: I ratio having the following physical properties (0.65 g).
Example 228(1):
LC/MS R 2.09 minutes; MS (ES4) m/z 592 (M+H) a
Example 228(2):
LCIMS tR 2.27 minutes; MS (ES4) m'z 692 (M+H) a Example 229: (3S)-3-[4-(5-aminopyridin-2-yl)-l H-imidazol-2-yl]-7-[5-ehloro-2-( 111-j,.3,4-tetrazo1-1-yiyl}-1.2,3,5-tetraliydroindolizin-5-one The same operation as in Example 52 -Example 55 was conducted from the 2:1 ratio of compounds prepared in Example 228 (0.65 g) to obtain the title compound having the following physical properties (0.27 g).
LC/MS tR 1.54 minutes; MS (ES4) m/z 472 (M+H) a Example 230: methyl 16-14-ch1oro-2-(3S)-7-[5-chloro-2-Q j-tetrazol-1 -y1)phenyl1-oxo-1,2,3,5-ty4ro-3-indo1izinyl}-1 H-imidazoI-5-yfl-3-pyridiny1carbamate The same operation as in Example 128 -÷ Example 44 was conducted from the compound prepared in Example 229 to obtain the title compound having the following physical properties. (Note: in the step corresponding to Example 128 in the operation, methyl chioroformate was used).
LCJMS tg 3.99 minutes; MS (ES4) mhz 564 (M+H) b H NMR (500 MHz, DMSO-d6) 8 12.97 (br. s, 1 Fl), 1000 (br. s, 1 H), 9.70 (s, I 11), 8.73 (s, 1 H), 7.96 (dd, I H), 7.90 (d, 1 H), 7.85 -7.77 (m, 3 H), 5.98 (s, 1 H), 5.93 (s, I H), 5.67 (dd, 1 11), 3.70 (s, 311), 3.23 (td, 1 H), 3.02 -2.92 (m, 1 H), 2.55 -2.44 (obs.
in, I H), 2.18 (t, 1 H).
Examp1ejfjflo Example 231(3) The compounds of the present invention having the following physical data were synthesised from the compound prepared in Example 229 and the corresponding chlorofonnates or acetic anhydride using the method as detailed in Example 128.
Example 231(1): isopropyl F6-(2-U3S)-7-[5-chloro-2-flfljtrazol-1 -yl)phenyll-5-oxo-I,2,3,5-tetrahydro-3-indolizinl}-l g-imidol-syl}3-pdthyljcarbate LC/MS tR 3.32 minutes; MS (ES4) m/z 558 (M+H)t, NMR analysis showed a 2: 1 ratio of tautomers.
Major tautomer: H NMR (500 MI-h, DMSO-d5) 6 12.19 (hr. s, I H), 9.72 (br. s, I H), 9.69 (s, I H), 8.52 (d, I H), 7.91 -7.83 (m, 1 Fl), 7.82-7.77 (in, 3 H), 7.67 (d, 1 H), 7.48 (s, I Fl). 5.99-5.93 (in, 2 H), 5.63 (dd, I H), 4.90 (septuplet, 1 H), 3.30-3.21 (in, 1 H), 3.04 -2.93 (m, I H), 2.56 -2.42 (ohs. m, 11-1), 2.38 -2.29 (m, I H), 1.25 (d, 6 H).
Minor tautomer: 111 NMR (500 MHz, DMSO-d6) 8 12.50 (br. s, 1 H). 9.82 (br. s, 1 H), 9.70 (s, 1 H), 8,64 (d. 11-1), 7.91 -7.83 (m, I H), 7.82-7.77 (in, 3 H), 7.66 (ci, I H'), 7.32 (s, 1 H), 5.99-5.93 (m, 2 H), 5.70 (dd. 1 H), 4.90 (septuplet, 1 H), 3.30-3.21 (in, 1 H), 3.04-2.93 (m, I H), 2.56-2.42 (ohs. m, 1 H), 2.28 -2.20 (m, 1 H), 1.27 (d, 6 H) Examp'e 231(2): isobutyl F6-(2-{L S)7jchIoro-2-(1 H-tetrazol-I -yl)phenyll-5-oxo-I,2,3,5-tetrahydro-3-indolizinyl}-I H-imidazol-5-yfl-3-pvridinyl]carbamate LCIMS 1R 3.52 minutes; MS (ES4) rn/z 572 (M+H)' NIVIR analysis showed a 1: 1 ratio of tautomers.
H NMR (500 MHz, CDCI3) 6 11.40 and 10.88 (br. s, 1 H), 8.55 (s, 1 H), 8.41 (br. s, I Il), 8.13 -7.92 (in, 1 11), 7.87 (d, 0.5 Il), 7.61 (dd. 1 II), 7.58 -7.43 (m, 3 I-i), 7.32 (br. s.
0.5 H), 7.14-7.02 and 6.77 (m and br. s, 1 H), 6.40 and 6.34 (hr. s, I H), 5.86 (t, 1 H), 5.68 and 5.64 (br. s, I H), 3.97 (d, 2 H), 3.52-3.17 (m, 211), 3.00 (dci, 1 H), 2.53 -2.39 (m, I Fl), 1.98 (dquintet, I H), 0.97 (ci, 6 H).
1(3): N-16-f'2-ff3S)-7-15-chloro-2-(IH-tetrazol-1-yl)phenyl]-5-oxo-I,2,3, 5-tetrahvdro-3-indolizinyl I I Wiinidazol-5-yI)-3-yyridinyflaeethmide LC/MS tR 2.94 minutes; MS (ES4) m/z 514 (M+H) b NMR analysis showed a 2: 1 ratio of tautomers.
Major Tautomet: HNMR (500 MHz, DM50-cl6) 8 12.21 (hr. s, I H), 10.12 (s, 1 H), 9.69 (s, I H), 8.61 (d, I H), 8.00 (dd, 1 H), 7.82-7.77 (m, 3 H), 7.69 (d, 1 H), 7.50 (s, 1 H), 5.99-5.93 (in, 2 H), 5.63 (dci. 1 H), 3.33 -3.21 (in, 1 H), 3.05 -2.92 (m, I H), 2.56 -2.42 (obs. m, I H), 2.38 -2.29 (m, I H), 2.06 (s, 3 11).
Minor Tautomer: H NMR (500 MHz, DMSO-d5) 8 12.52 (br. s, 1 H), 10.20 (s, 1 H), 9.70 (s, I H), 8.70 (d, I H), 8.03 (dci, 1 H), 7.82-7.77 (m, 3 H), 7.68 (ci, 1 H), 7.34 (s, 1 H), 5.99-5.93 (m, 211), 5.70 (d, I H), 3.33 -3.21 (in, 1 H), 3.05-2.92 (in, 1 H), 2.56- 2.42 (ohs. m, I H), 2.28 -2.20 (in, 1 H), 2.07 (s, 3 H).
Examples 23Z0 mc1232(2): (3S)-3-J5j-amino-2-Dyridinvfl-4-methy1-1 H-imidazol-2- yfl-7-[5-cbloro-2-(1H-tetcazol-1-yflphenyl]-2,3-dihvdro-5(1FO-indolizinone and N-[6- (2-((3S)-7-[5-chloro-2-(IH-tetrazol-I-yflphenyl]-5-oxo-1,2,3, 5-tetrahydro-3-indolizinyl -4-methyL-1 H-huidazol-5-y1)-3-pyjjny11acetamide The same operation as in Example 188 -. Example 189 -* Example 51 -f Example 52 was conducted from 5-amino-2-cyanopyridine to obtain the title compounds in a 4: 1 ratio having the following physical properties. (Note: in the step corresponding to Example 188 in the operation, a 3 M solution of ethyl magnesium bromide in tetrahydroffiran was used. In the step corresponding to Example Si in the operation, the compound prepared in Example 9 was used).
232 1: liD/MS t 2.88 minutes; MS (ES) m/z 508 (M+Na), 486 (M+H), 243 E(M+2H)/2] b H NMR (500 MHz, methanol-d.) 6 9.36 (s, I H), 8.00 (hr. s, I II), 7.75 -7.70 (m, 2 F, 7.70-7.66 (m, I H), 7.35 (app. hr. s, I H), 7.11 (dd, I Fl), 6.13 (s, 1 H), 6.07 (s, I H), 5.74 (app. hr. s, 1 H), 3.08 (±1. 1 H), 2.65-2.55 (m, 11-1), 2.50-2.43 (m, 2 Fl), 2.36 (hr. s,3H
Example 232(2):
LCIMS tR 2.92 minutes; MS (ES) n/z 528 (M+H) b H NMR (500 MHz, methanol-d4) 6 9.36 (s. 1 11), 8.71 (d, 1 H), 8.05 (br. s, 1 H), 7.73 (app. 5,211), 7.71 -7.56 (in. 2 H), 6.14 (s, I H), 6.08 (s, 1 H), 5.75 (d. 1 H), 3.50-3.40 (m, I H), 3.14 -3.05 (m, 1 H), 2.67-2.58 (m, I H), 2.52-2.43 (ohs, m, I Fl), 2.46 (br.
s. 3 H),2.16(s,3 H).
Exaniple 233: methyl [6-(2-((3 S)-7-[5-chloro-2-( I il-tetrazol-1 -yl)phenyll-5-oxo-j-tetrahydro-3-indolizinyl}-4-rnethyl-1 H-imidazol-5-vfl-3-pyridigyllcarbamate The compound prepared in Example 232(1, 80 mg) was treated as detailed in Example 128 using methyl chioroformate in place of ethyl chioroformate to give the title compound having the following physical properties (22.9 mg).
LCIMS ig 3.04 minutes; MS (ES) m12 544 (M+H)' H NMR (500 MHz, methanol-cl4) 6 9.36 (s, 1 1-1), 8.60 (hr. s, I H). 7.95 (app. hr. s, I H), 7.72 (app. s. 2 H), 7.70-7.67 (m, I H), 7.62 (app. hr. s. I H), 6.14 (s, I H), 6.08 (s, I H), 5.75 (d, 1 H), 3.77 (s, 3 H), 3.51 -3.39 (m, I H), 3.13 -3.05 (m, I Fl), 2.67-2.57 (m. I H), 2.52 -2.41 (obs. m, I H), 2.47 (s, 3 H).
5-13ol-2-1c&bamate To an cooled (0°C) dichloromethane (4 niL) solution of 2-[(tert-butoxycarbonyl)amino]-l,3-thiazole-5-carboxylic acid (0.30 g) was added a solution of oxalyl chloride (0.13 ruL) in dichloromethane (1 mL). One drop of N,N-dimethylformamide was added and the mixture stirred at room temperature for 1 hour.
The reaction mixture was concentrated and the residue dissolved in acetonitri Ic (5 niL).
To the cooled (0 °C) acetonitrile solution, a 2 M solution of (trimethylsilyl)diazomethane in hexanes (1.23 mE) was added and the mixture stirred at 0 °C for 1 hour. To the reaction mixture, a solution of 33 wt. % hydrogen bromide in acetic acid (0.20 mL) was added and the mixture stirred at 0 °C for a further 20 minutes.
A saturated aqueous solution of sodium hydrogen carbonate (50 mE) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated to give the crude title compound having the following physical properties (0.37 g).
LCiMS R 1.92 minutes; MS (ES) m/z 265 and 267 (M-C(CH3)3+H) a Example 235: (3S)-3-f5fjino-1, 3-thiazo1-5-vfl-1H-imidazol-2-y11-745-cMoro-2-flj-l-teflzol-I -v1)phenyI1ihydm-5( 1 Fl)-indolizinone The same operation as in Example 51 -. Example 52 -* Example 40 was conducted from the compound prepared in Example 9 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 234 was used).
[C/MS R 2.79 minutes; MS (ES) rn/z 478 (M+11), 239 [(M+2H)/2] h li-I NMR (500 MHz. methanol-d4) a 9.35 (s, 1 H), 7.76-7.70 (m, 2 H), 7.68 (d. 1 H), 7.10 (s, I H), 7.09 (hr. s, I H), 6.13 (s, I H), 6.07 (s. 1 H), 5.72 (dd, 1 H), 3.46 -3.36 (m, I H), 3.09 (ddd, I H), 2.66 -2.56 (m, I H), 2.46 (app. hr. s, I H).
Example 236: (3S)-3-[5-(l -amino-5-isoguinoljnyl).I H-imidazol-2-yll-7-[5-chloro-2- (I H-tetrazol-I-yflphenvll-2.3-dihvdro-5(1H)-indolizinone diacetate * 185 The same operation as in Example 90 -Example 189 -+ Example 51 -, Example 52 was conducted from 6-bromoisoquinolin-1-amine to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 9 was used).
S LC/MS tR 2.94 minutes; MS (ES) ,n/z 522 (M+H) b H NMR (500 MHz, methanol-&) 6 9.38 (s, 1 I-I), 8.24 (d, 1 II), 8.11 (br. 8, 1 H), 7.99 (d, 1 Fl), 7.77-7.73 (m, 2 H), 7.70 (d, I H), 7.66 (br. s, 1 II), 7.58 (d, 1 H), 7.15 (d, 1 H), 6.16 (s, 1 H), 6.12 (s. I H), 5.82 (dd, 1 H), 3.53 -3.43 (m, 1 H), 3.14 (ddd, 1 H), 2.67 (ddd, I II), 2.54 -2.44 (m, 1 H), 1.98 (s, 6 H).
Example 237: methyl N-(4-carbamimidoylphenyl)carbamate To a cooled (0°C) ethanol (10 mL) suspension of methyl N-(4-cyanophenyl)carbamate [J. Chem. Soc., Perkin Trans. 1, 2587 (1984)] was added acetyl chloride (4 mL) and the mixture stirred at room temperature for 16 hours. Further acetyl chloride (1 mL) was added and the mixture stirred at 50°C for 3 hours. The reaction mixture was concentrated and the residue dissolved in ethanol (10 mL). To the solution, ammonium carbonate (2.73 g) was added and the mixture stirred at room temperature for 6 hours. The solids were removed by filtration and the filtrate concentrated. The residue was triturated with dichloromethane (10 mL) and the precipitate isolated by filtration to give the title compound having the following physical properties.
LC/MS tR 0.66 minutes; MS (ESt) m/z 194 (M+ll) a Examples 238(1) and 238(2): tert-butyl N-{2-3-(2-bromoacetyl)-5-oxo-2,3-dihydro- I H-indolizin-7-yll-4-chlorophenyl}carbamate and tert-butyl N-{4-chloro-2-[3-(2-chloroacetyl)-5-oxo-2,3-dihydro-1 H-indolizin-7-yl]phenyll carbamate The compound prepared in Example 19 (0.50 g) was treated as detailed in Example 182 to give a 2: 7 mixture of the title compounds having the following physical properties (22.9 mg).
Example 23 8(1):
LC/MS tg 2.10 minutes; MS (ESt) m/z 503 and 505 (M+Na), 481 and 483 (M+1-l) a
Example 238(2):
LC/MS tR 2.07 minutes; MS (ES) rn/z 459 (M-ENa), 437 (M+1-J) a Example 239: tert-butyl N-{4-ch1oro-2-[3-(j4-[(methoxvcarbony1')amino Iyhenvfl - 3H-imidazol-4-yfl-5-oxo-2,3-dihydro-1 H-indolizin-7-yl]yhenyllcarbamate To an acetonitrile (tO mL) suspension of the compound prepared in Example 237(0.125 g) and the 2: 7 ratio of compounds prepared in Examples 238(1) and 238(2) (0.26 g) was added potassium carbonate (0.16 g) and the mixture stirred at retlux for 4 hours. Water (50 mL) was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated and the residue purified by column chromatography (0 to 5% methanol in dichioromethane) to give the title compound having the following physical properties (0.21 g).
LC/MS 1R 1.78 minutes; MS (ES4) m/z 576 (M+H) a Example 240: methyl [4-(5-I 7-{5-chloro-2-( I Il-tetrazol-I -yl)phenyl}-5-oxo-1.2,3,5-tetrahydro-3-indolizinvl} -IH-imidazol-2-yflphenyljcarbamate The same operation as in Example 40 -. Example 41 was conducted from the compound prepared in Example 239 to give thetitle compound having the following physical properties.
LC/MS ig 2.99 minutes; MS (ES4) m/z 529 (M+H) b H NMR (500 MHz, methanol-cl4) ö 9.40 (s, I H), 7.80 -7.74 (m, 4 H), 7.71 (d, I H), 7.54 (d. 2 H), 6.77 (s, 1 H), 6.18 (s, I H), 6.09 (s, I H), 5.82 (d, I H), 3.77 (s. 3 Fl), 3.40 -3.36 (m, 1 H), 3.06 (dd, 1 H), 2.64-2.54 (m. I Fl), 2.42 (dd, I H).
Exathple 241: methylj4j4-chloro-5-17-[5-chloro-2-(1 H-tetrazol-1-yflphejyjoQ- 2-lhen1carbate The compound prepared in Example 240 (80 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (21 tug).
LC/MS 1R 3.79 minutes; MS (ES) m/z 563 (M+H) b H NMR (500 MHz, methanol-cl4) 89.36 (s, I H), 7.78 -7.72 (m, 411), 7.72-769 (m, I H), 7.55 (d, 2 II), 6.21 (s, I H), 6.05 (s, I H), 5.81 (dd. I H), 3.77 (s, 3 H), 3.40-3.34 (m, I H), 3.14 (ddd. 111), 2.75-2.65 (m. 1 H), 2.33 (tdd, 1 H).
Example 242: tert-butyl N-[4-chloro-2-(3-(N'-1(4- nitrophenyl)carboximidoyllhydrazineearbonyl -5-oxo-1,2,3.5-tetrahydroindolizin-7-yflplienyllcarbamate To a cooled (0 °C) tetrahydrofuran (5 mL) solution of the compound prepared in Example 19 (0.40 g) was added ethyl chloroformate (0.11 mL) and 4-methylmorpholine (0.16 mL) and the mixture stirred at 0°C for 25 minutes. A solution of N-amino-4-nitrobenzenecarboximidamide [Justus Liebigs Ann, Cheni. 298, 51(1897)1 in tetrahydroftiran (5 mL) was added and the mixture stirred at room temperature for 16 hours. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate (25 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (0 to 10% ethyl acetate in heptanes) to obtain the title compound having the following physical properties (0.23 g).
LC/MS tg 1.79 minutes; MS (ES4) tn/z 567 (M+H) a Exam,le 243: 7-(2-amino-5-clilorophenyl)-3-[5-(4-nitrophcnylI-4H-l,2, 4-triazol-3-yll-LL3,5-tetrahydroindolizin-5-one A glacial acetic acid (2.1 mL) solution of the compound prepared in Example 242 (0.23 g) was stirred at 110 °C for 3 hours. To the mixture, a saturated aqueous solution of sodium hydrogen carbonate (30 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (0 to 20% methanol in ethyl acetate) to obtain the title compound having the following physical properties (0.086 g).
LCIMS t 1.97 minutes; MS (ES4) m/z 449 (M+H) a Example 244: 3-[5-(4-aminoyhenyl)-4H-1,2,4-triazol-3-yll-7-[5-chloro-2-( 1H-tetrazol- 1-yl)phenyl]-2,3-dihydro-5(1 H)-indolizinone The same operation as in Example 41 -* Example 74 was conducted from the compound prepared in Example 243 (110mg) to obtain the title compound having the following physical properties (77 mg).
LC/MS 1R 3.31 minutes; MS (ES') m/z 472 (M+F1)b 1HNMR(500 MHz, DMSO-d6) 8 13.68 (hr. 5, 1 H), 9.68 (s, I 1-1), 7.80 (app. s,3 H), 7.58 (d, 2 H), 6.61 (d, 2 H), 5.95 (s, H), 5.93 (s, 1 H), 5.62 (d, 1 H), 5.57 (br. s, 2 H), 3.27-3.08 (in, I 11), 2.95 (dd, I HI). 2.58 -2.44 (cbs. in, I Fl), 2.15 -2.00 (m, I H).
Example 245: methyl [4-(5-f7-15-chloro-2-ITH-tetrazol-1-yflphenyfl-5-oxo-I.2,3. 5-tetrahydro-3-indolizinyl -4H-l,2,4-triazol-3-yI)phenyllcarba.mate The compound prepared in Example 244 (65 ing) was treated as detailed in Example 128 using methyl chloroformate in place of ethyl chloroformate to give the title compound having the following physical properties (29.6 mg).
LC/MS i 3.67 minutes; MS (ES) mlz 530 (M+H) b II NMR (500 MHz, CDCI3) 6 12.89 (br. s, I Fe, 8.71 (hr. s, I H), 7.77 (app. br. s, 2 H), 7.65 -7.53 (m, 2 H), 7.53 -7.45 (in, I H), 7.34 (app. hr. s, 2 H), 6.31 (hr. s, 1 H), 5.91 (hr. s, I H), 5.76 (app. br. s, I Fl), 3.75 (hr. s, 3 H), 3.46-3.28 (in, I 1-1), 3.07 -2.91 (m, I H), 2.79 -2.46 (m, 2 H).
Example 246: methyl 7-(2-{ftert-butoxycarbony1laminoI-5-chloronhenvl-5-o I,2,3,5-tetrahydroindolizine-3-carboxvlate To a dichloromethane (7.5 mL) and methanol (2.5 niL) solution of the compound prepared in Example 19 (1.0 g) was added a 2 M solution of (trimethylsilyfldiazomethane in diethyl ether (2.2 mL) at 0 °C and the mixture stirred at room temperature for 16 hours. To the reaction mixture, acetic acid (0.5 mL) and a saturated aqueous solution of sodium hydrogen carbonate (30 mL) were sequentially added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (10% to 100% ethyl acetate in heptanes) to obtain the title compound having the following physical properties (0.83 g).
LC/MS 1R 2.01 minutes; MS (ES) ,n/z 419 (M+F1)8 rnpi.24?: tert-butyl N-(4-chloro-2-{3-[2-(djgioxhosholace1-S-oxo-I, 23j-tetrahydroindolizin-7-vlIphenyflcarbamate To a cooled (-78 °C) tetrahydrofuran (20 mL) solution of dimethyl methyiphosphonate (1.1 mL) was added a 2.5 M solution of n-butyllithium in hexanes (4.0 mL) and the mixture stirred at -78 92. for 30 minutes. A solution of the compound prepared in Example 246 (0.83 g) in tetrahydrofuran (10 mL) was added and the mixture stirred at -78 °C for 1 hour. To the cooled (-78 °C) reaction mixture, a saturated aqueous solution of am.monium chloride (5 niL) was added followed by water (30 mL) arid the mixture was allowed to Warm to room temperature then extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated.
The residue was purified by colunm chromatography (20% to 100% ethyl acetate in heptanes, then 0 to 20% methanol in ethyl acetate) to obtain the title compound having the following physical properties (0.67 g).
LCIMS tR 1.92 minutes; MS (Est) m/z 511 (M+H) a Example 248: tert-bujfN-(4-chJoro-2-(3-[5-(4-nitrophenyl)-6-oxo-1, 6-dihydropyridazjn-3-yl]-5-oxo-1.2,3,5-tetrahydroindolizin-7-yl} phenyflcarbainate To a cooled (0 °C) ethanol (7 mL) suspension of the compound prepared in Example 247 (0.67 g) and potassium carbonate (0.27 g) was added ethyl (4-nitrophenyl)(oxo)acetate (0.31 g) and the mixture stirred at 0 °C for 90 minutes then at 1 5 room temperature for 2 hours. Hydrazine hydrate (0.6 mL) was added and the mixture stirred at room temperature for 3 hours. To the reaction mixture, 0.5 M hydrochloric acid (25 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (0 to 100% ethyl acetate in heptanes). The product was triturated with a 1: 2 mixture of dichioromethane and heptanes and the solid collected by filtration to give the title compound having the following physical properties (0.24 g) LC/MS tR 2.08 minutes; MS (ES) m/z 576 (M+H)a Example 249: methyl [4-(6-I 745-chloro-2-(1H-tetrazol-1 -yl)phenyll-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl} -3-oxo-2.3-dihydro-4-pyridazinyl)phenyllcarbamate The same operation as in Example 74-. Example 128 -. Example 40 -.
Example 41 was conducted from the compound prepared in Example 248 (0.24 g) to obtain the title compound having the following physical properties (0.075 g). (Note: in the step corresponding to Example 128 in the operation, methyl chloroformate was used).
LC/MS tR 3.69 minutes; MS (ES4)m/z 557 (M+H)" 1HNMR(500 M1-Jz, DMSO-cLs) 5 12.98 (hr. s, 1 H), 9.89 (s, I H), 9.71 (s, I H), 7.88 (d, 2 H), 7.82-7.78 (m, 3 H), 7.61 (s, 1 H), 7.56 (d, 2 H), 5.96 (s, 1 H), 5.94 (s, 1 H), 5.55 (dd, I I-i), 3.68 (s, 3 H), 3.16-3.05 (m, I H), 2.97 (ddd, I H), 2.59 -2.46 (abs. m, I H), 2.25 -2.15 (m, I H).
Example 250: tert-butyl N44-chloro-2-{ 3-[metl,oxv(methyl)carbamoyl]-S-oxo-1,2,3,5-tetralvqdroindolizin-7-yI phenyflearbarnate To an N,N-dimethylformamide (12.5 mL) solution of the compound prepared in Example 19 (1.0 g) was added N,O-dimethythydroxytamine hydrochloride (0.36 g), 0- (7-azabenzotriazol-I -yl)-N,N,N' ,N' -tetrametbyluronium hexafluorophosphate (1.0 g) and diisopropylethylamine (1.2 mL) and the mixture stined at room temperature for 16 hours. The reaction mixture was concentrated and the residue suspended in a saturated aqueous solution of sodium hydrogen carbonate (30 mL) followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (0% to 20% methanol in ethyl acetate) to obtain the title compound having the following physical properties (0.73 g).
LCJMS ig 1.99 minutes; MS (ES) m/z 448 (M+H) a Example 251: tert-butyl N44-chloro-2-(3-formyl-5-oxo-l,2,3,5-tetrahydroindolizin-7-yflphenyl] carbamate To a cooled (-45 °C) tetrahydrofuran (6.5 mE) solution of the compound prepared in Example 250 (0.60 g) was added a I M solution of lithium aluminium hydride in tetrahydrofuran (1.6 mE) over 10 minutes. The reaction mixture was stined at -45 °C for 30 minutes, 0 °C for 90 minutes then cooled to -45 °C and a solution of potassium hydrogen sulfate (0.36 g) in water (1.0 mE) added. The mixture was warmed to room temperature and extracted into ethyl acetate. The combined organic!ayers were washed sequentially with 1 M hydrochloric acid (25 mL). a saturated aqueous solution of sodium hydrogen carbonate (30 niL) and brine (25 mE), dried and concentrated to give the title compound having the following physical properties (0.45 g).
LCIMS tR 1.84 minutes; MS (ESiin/z 389 (M+H' Example 252: tert-butyl N-[4-chIoro-2-(3-etny1-5-oxo-I,2,3,5-tetrahydroindolizin-7-y)pheny1] carbamaç To a methanol (15 mE) suspension of the compound prepared in Example 251 (0.45 g) and potassium carbonate (0.32 g) was added dimethyl (1-diazo-2-oxopropyl)phosphonate (0.2 mL) and the mixture stirred at room temperature for 4 hours. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate (25 mL) was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (0 to 100% ethyl acetate in heptanes) to obtain the title compound having the following physical properties (0.29 g).
LCIMS tp. 2.02 minutes; MS (ES4) m/z 385 (M+H) a ExampIe2jteP-butyl N-(2-{3-[1-(4-aminophenyfl-IH-l,2,3-triazob4zyjj5-oxo-j, tetrahydroindo1izin-7-yl 1 -4-chlorophenyl)carbamate To an acetonitrile (1.2 mL) solution of the compound prepared in Example 252 (0.14 g) was added 4-azidoaniline hydrochloride (59 mg), copper(II) sulfate pentahydrate (8 mg), a solution of sodium ascorbate (31 mg) in water (0.60 mL) and I 1 5 M sodium hydroxide (0.35 mL). The reaction mixture was irradiated under microwave conditions (120 W) at 80°C for 1 hour and a saturated aqueous solution of sodium hydrogen carbonate (30 mL) was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography ((0 to 100% ethyl acetate in heptanes) to obtain the titLe compound having the following physical properties (0.16 g).
LC/MS ER 2.01 minutes; MS (ES4) rn/z 519 (M+H) a Example 254: methyl [4-(4-7-[5-chloro-2-il ll-tetrazoj-I -yl)phenylj-5-oxo-1,2.3,5-tetrahydro-3-indolizinyjj -111-1,2,3-triazol-l -yI)phenyllcarbamate The same operation as in Example 128 -. Example 40 ---p Example 41 was conducted from the compound prepared in Example 253 (0.16 g) to obtain the tide compound having the following physical properties (0.11 g). (Note: in the step corresponding to Example 128 in the operation, methyl chloroformate was used).
LC/MS R 3.88 minutes; MS (ES4) m/z 530 (M+H)" H NMR (500 MHz, DM5046) 59.94 (s, I H), 9.69 (s, I H). 8.55 (s. 1 H), 7.83 -7.74 (m, 51-1), 7.64 (d, 2 H), 5.96 (s, 1 H), 5.95 (s, I H), 5.79 (d, 1 H), 3.69 (s, 3 H), 3.39- 3.33 (m, 1 H), 3.04 (dd, 1 H), 2.61 -2.52 (m, 1 11), 2.32 (dd, 1 H).
Example 255: tert-butyl N-(4-chloro-2-{ 3-13-(4-nitrophenyfl-l,2-oxazol-5-yll-5-oxo- 1,2.3.5-tetrahydroindolizin-7-yl}phenyl)carbamate To a tert-butanol (1.0 mL) and water (1.0 mL) suspension of 4-nitrobenzaldehyde (63 mg) was added hydroxylamine hydrochloride (29 mg) and the mixture stirred at room temperature for 1 hour. Chloramine-T trihydrate (117 mg) was added and the mixture stirred at room temperature for 5 minutes to afford the intermediate nitrile oxide.
To the suspension, copper powder (2.4 mg), copper(I1) sulfate pentahydrate (9.4 mg) and a solution of the compound prepared in Example 252 (145 mg) in tert-butanol (1.0 mL) was sequentially added and the mixture stirred at room temperature for 16 hours.
The nitrile oxide was re-prepared as detailed above, added to the reaction and the mixture stirred at room temperature for 16 hours then at 80 °C for 20 hours. To the reaction mixture, a 10% aqueous solution of ammonia (20 mL) was added followed by extraction into ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue obtained on concentration was purified by column chromatography (12% to 80% ethyl acetate in heptanes) to obtain the title compound having the following physical properties (49.5 mg).
LC/MS tR 2.33 minutes; MS (ES) mhz 549 (M+H) a Example 256: methyl f4-(5- 7-[5-chloro-2-(l H-tetrazol-I -yflphenyll-5-oxo-1,2,3,5-tetrahvdro-3-indolizinyj1,2-oxazol-3-yl) phenyllcarbamate The same operation as in Example 40 -# Example 41 -* Example 74 -÷ Example 128 was conducted from the compound prepared in Example 255 (49.5 mg) to obtain the title compound having the following physical properties (8.4 mg). (Note: in the step corresponding to Example 128 in the operation, methyl chioroformate was used).
LCIMS tR 4.12 minutes; MS (ES) mhz 530 (M+H) b 1H NMR (500 M}Iz, DMSO-d6) S 9.91 (s, I II), 9.71 (s, 1 II), 7.83 -7.79 (m, 3 H), 7.77 (d, 2 H), 7.58 (d, 2 H), 6.75 (s, 1 H), 6.02 (s, 1 H), 6.00 (s. 1 H), 5.86 (dcl, 1 H), 3.69 (s, 3 H), 3.18 (td, 1 H), 3.09-2.99 (m, I H), 2.61 -2.53 (m, I H), 2.27-2.19 (m, 1 H).
Examole 257: 2-niethyl-2-propanyl (2S)-2-[2-oxo-4-{ [(trifluoromethy1)sulfonyl1oxy I (2H)-pyridiny1-3-phenyIyropanoate The same operation as in Example 20 -* Example 21 -* Example 22 was conducted from 2-methyl-2-propanyl (2R)-3 -phenyl-2- {Rtrifluoromethyl)sulfonylloxy}propanoate (W02006/57961) to give the title compound having the following physical properties.
TLC: RI 0.33 (20% ethyl acetate in hexane) Example 258: (2S)-2-[4-(2,5-dichjorophenyfl-2-oxo-1 (2H}-pyridinyi]-3-phenyipropanoic acid The same operation as in Example 23 -. Example 25 was conducted from the compound prepared in Example 257 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 23 in the operation, 2,5 -dichlorophenylboronic acid was used).
TLC: RI 0.18 (10% methanol in dichioromethane) Example 259: 4-(4-chloro-2-{(1 S)-1-I442,5-dich1oropbenyfl-2-oxoJ(2}-jjnylJ -penyIethy -1 H-imLdazo1-5-yQbnzpjc acjd The same operation as in Example 72 -* Example 73 -. Example 76 -.
Example 49 was conducted from the compound prepared in Example 258 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 72 in the operation, methyl 4-(bromoacetyl)benzoate was used).
TLC: RI 0.41(10% methanol in dichioromethane) H NMR (300 MHz, DMSO-&) d 13.21 (br. s, I H), 8.10-7.92 (m, 3 H), 7.85 (s, 2 H), 7.66-7.44 (m, 3 H), 7.34-7.11 (m, 511), 6.51 -6.31 (in, 311), 3.60 (dd, I H), 3.39 (dd, 11-1).
Example 260: 442-1(1 S)-1 -1442.5-dichlorophenyl)-2-oxo-1 (211)-pvridinylj-2-phenylethyU-1 H-imidazol-5-iflhcnzoic acid The same operation as in Example 72 -* Example 73 -÷ Example 49 was conducted from the compound prepared in Example 258 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 72 in the operation, methyl 4-(bromoacetyl)benzoate was used).
TLC: Rf 0.47 (10% methanol in dichloromethane) H NMR (300 MHz, DMSO-do) 6 12.98 (br. s, 1 H), 8.08 -7.91 (m, 5 H), 7.86 (d, 1 H), 7.68 -7.40 (m, 3 H), 7.36 -7.03 (m, 5 H), 6.45 (s, 111), 6.38 -6.32 (m, 1 11), 6.32 -623 (m, I H), 3.86-3.72 (m, 1 H), 3.65 -3.48 (m, 1 H).
Exampj 261: 3-(4-chloro-2-{ (IS)-1 -[4-(2,5-dich1orophey1)-2-oxo-I (2I-{)-yyridinyl-2-phenylethyl}-1 H-itnidazol-5-yl)benzoic acid The same operation as in Example 72 -Example 73 -Example 76 -* Example 49 was conducted from the compound prepared in Example 258 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 72 in the operation, methyl 3-(bromoacetyl)benzoate was used).
TLC: Rf 0.45 (10% methanol in dichloromethane) H NMR (300 MHz, DMSO-&) 3 13.29 (br. s, 1 H), 12.98 (hr. s, I 11), 8.31 (s, I I-i), 8.03-7.94 (m, 2 H), 7.89 (d, 1 H), 7.66-7.45 (m, 4 H), 7.31 -7.11 (m, 5 H), 6.50- 6.32 (m, 3 H), 3.60 (dd, 1 H), 3.47 -3.36 (m, 1 H).
Example 262: 3-{2-{(S)-[4-(2.5-dichlorophenyl)-2-oxo-1 (2H)-pyridinyll(phenyl)methyl]-I FJ-imidazol-5-yl}benzoic acid The same operation as in Example 20 -Example 21 -. Example 22 -.
Example 23 -p Example 30 -.Example 72 -. Example 73 -÷ Example 49 was conducted from methyl (2R)-ch1orohenyl)acetate [Justus Liebigs Annalen der Chemie, 501, 208, (1933)] to give the title compound having the following physical properties.
(Note: in the step corresponding to Example 23 in the operation, 2,5-dichlorophenylboronic acid was used. In the step corresponding to Example 72 in the operation, methyl 3-(bromoacetyl)benzoate was used).
TLC: Rf 0.57 (10% methanol in dichloromethane) H NMR (300 MHz. DMSO-&) 5 13.21 (br. s, 1 H), 12.71 (br. s, 1 1-1), 8.32 (br. s, 1 H), 7.97 (d. 211), 7.77 (d, 2 H), 7.65-7.23 (m, 1011), 6.54 (d, 1 1-1), 6.42 (ci, 1 H).
Example 263: methyl {4-[2-(l -{4-[5-chloro-2-( I H-tetrazol-1 -yflyhenyl]-2-oxo-1 (21-fl-pyridir,yI}-3-methoxypropyflJ1-imidazol-5-yl1phenyl}carbamate The same operation as in Example 26 -* Example 21 -Example 22 Example 23 -Example 24 -.Example 25 -*Example 38 -Example 39 was conducted from the compound prepared in Example 20 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 26 in the operation, 2<hioroethyl methyl ether was used).
TLC: Rf 0.26 (ethyl acetate) H NMR (300 MHz, CDCI3) 811.17 (br. s, I H), 8.67-8.51 (m, 1 H), 7.82 7.33 (m. 8 14), 7.20 (br. s, 1 H), 6.53.-5.99 (m, 211), 5.84-5.64 (in, I H), 3.89 -3.62 (m, 3 H), 3.50-3.30 (in, 2 H), 3.28-3.08 (m, 3 H), 2.71 -2.33 (in, 2 H).
Example 264: methyl {4-f4-chloro-2-flf445eh1oro-2-UH-teazol-1 -yl)phenyl]-2- -I(2H)-pwidinyl I-3-methoxypropyl)-1 H-imidazol-5-yI]phenyflcarbamate The compound prepared in Example 263 (40mg) was treated as detailed in Example 47 to dYe the title compound having the following physical properties (18 mg).
TLC: RI' 0.57 (5% methanol in ethyl acetate) H NMR (300 MHz, COO3) 8 11.78 (br. s, I H), 8.59 (s. 1 H), 7.79-7.39 (in, 8 H), 6.77 (s. I H), 6.40 (s, I H), 6.19 br. s, I H), 5.79 (d, 1 H). 3,79(s, 3 H), 3.53 -3.32 (in.
2 H), 3.32-3.06 (in, 3 H), 2.59 d, I H), 2.45 br. s, 1 H).
&le 265: methyl (4-{2-[( I SI-i -4-[5-chloro-2-U H-tetrazol-l -yflphenyl]-2-oxo-l(2H)-pyridinvll -2-phenylethy11flj-imidazol-4-vl}phenvflcarbarnate The same operation as in Example 23 -. Example 24 -. Example 25 -Example 38 -. Example 39 was conducted from the compound prepared in Example 257 to give the title compound having the following physical properties.
TLC: Rf 0.57(80% ethyl acetate in hexane) I-I NMR (300 MHz, DMSO-d6) 5 12.30 (s, I H). 9.76-9.49 (m, 2 H), 731 -7.61 (m, 5 H), 7.61 -7.35 (in, 4 H), 7.34-6.99 (m, 511). 6.40-6.10 (in, 2 H), 5.89 (dd, I H), 3.66 (s, 3 H), 3.58-3.43 (in, 1 11), 3.27 (br. s, I H).
Example 266: methyl [4-(2-ff3S)-7-15-ehloro-2-(1 H-tetrazol-l -yflphenyll-5-oxo-I,2,3,5-tetrahydro-3-indolizinyl} -I H-imidazol-4-yl)phenyllcarbamate The same operation as in Example 38 -* Example 39 -Example 40 -* Example 41 was conducted from the compound prepared in Example 11 to give the title compound having the following physical properties.
TLC.: Rf 0.29 (ethyl acetate) H NMJt (300 MHz, DMSO-d) 8 12.03 (s, lI-f), 9.75 -9.63 (m, I H), 9.58 (s, 1 H), 7.87 -7.72 (m, 311), 7.66 -7.31 (at 5 H), 6.01 -5.88 (in, 2 H), 5.68 -5.53. (m, 1 H), 3.72-3.59 (in, 3 H), 3.48-3.34 (at 1 H), 2.99 (dd, 1 H), 2.46-2.10 (in, 2 H).
Example 267: 5-[(5-chloro-2-nitrophenyl)(hydroxy)methylenel-2, 2-dimethyl-L3-dioxane-46-dione: A mixture of 5-chloro-2-nitrobenzoic acid (11.0 g) and thionyl chloride (11.8 niL) was stirred at 90 °C for 2 hours then concentrated. The resulting residue was dissolved in dichioromethane (50 niL) and added to a stirred solution of 2,2-dimethyl- 1,3-dioxane-4,6-dione (7.86 g) and 4-(dimethylamino)pyridine (13.3 g)in dichloromethane (200 mL) at -12 °C. After being stirred for 2 hours, the reaction mixture was washed with I M hydrochloric acid (100 mL x 3) and water, dried and concentrated. The residue thus obtained was triturated with acetonitrile followed by acetone to afford the tide compound having the following physical properties (6.0 g).
TLC: Rf 0.43 (ethyl acetate) Example 268: methyl (3R)-7-(5-chloro-2-nitrophenyfl-5-oxo-2.3 -dihydro5H-LL3lthiazolo[3,2-aJpvridine-3 -carboxylate To a dichloromethane (80 niL) solution of the compound prepared in Example 267 (7.67 g) was added (4S)-methyl 2-methyl-4,5-dihydro-l,3-thiazole-4-carboxylate [Journal of Organic Chernistiy, 66(20), 6756, (2001)] (1.57 g) and the stirred mixture treated with gaseous hydrogen chioride at 0 °C for 1 5 minutes. The reaction mixture was then heated for 24 hours at 64 °C for before allowing to cool to room temperature.
To the reaction mixture, water was added followed by extraction with dichioromethane.
The combined organic layers were washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried and concentrated. The residue was purified by column chromatography (30 -55% ethyl acetate in hexanes) to give the title compound having the following physical properties (310 mg).
TLC: Rf 0.35 (50% ethyl acetate in hexane) Example 269: methyl (3R)-7-[2-(bist [(2-methyl-2-yropanyl)oxylcarbonyl} amino)-5-chlorophenyll-5-oxo-2,3-dihydro-SH-[ 1,3]thiazolo[3,2-alpyridine-3-carboxylate To a mixture of ammonium chloride (250 mg) and zinc powder (341 mg) in water (2.5 mL) was added a solution of the compound prepared in Example 268 (234 mg) in ethyl acetate (12.5 mL) and the mixture stirred for 3 hours at room temperature.
The reaction mixture was filtered through Celite® and the filtrate was washed with brine, dried and concentrated. The residue thus obtained was dissolved in tetrahydrofuran (5 mL) and to this solution triethylamine (0.16 mL), 4- (dimethylamino)pyridine (13 mg) and di-tert-butyl diearbonate (247 mg) were sequentially added. The reaction mixture was warmed to 60 °C for 1 hour before allowing to cool to room temperature. To the reaction mixture, a saturated aqueous solution of potassium bisulfate was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (70% ethyl acetate in hexanes) to give the title compound having the following physical properties (189 ing).
TLC: P10.63 (80% ethyl acetate in hexane) Example 270: methyl [4-a-{(3R)-7-F5-chloro-2-( I H-tetrazol-I -yl)yhenyll-5-oxo-2.3-dihydro-5H-[ 1,3lthiazolo[3,2-a}pyridin-3-yl}-1 H-imidazol-5-yl)yhenyllcarbamate The same operation as in Example 11 -* Example 38 -* Example 39 -.
Example 40 -* Example 41 was conducted from the compound prepared in Example 269 to give the title compound having the following physical properties.
TLC: P10.49(5% methanol in ethyl acetate, NH Silica) H NMR (300 MHz, CHLOROFORM-cl) S ppm 10.58 (br. s., 1 II), 8.58 (s, 1 H), 7.72 (d, 2 H), 7.67-7.28 (m, 4 H), 7.26 -7.06 (m, 2 H), 6.80 -6.45 (m, 1 II), 6.23 (d, I H), 6.17-5.97 (in, 1 H), 5.80 (s, I H), 4.71 (d, 1 H), 4.00-3.65 (in, 4 H) Example 271(1) to Example 271(4) The compounds of the present invention having the following physical data were S prepared using the corresponding aipha-bromoketones from the compound prepared in Example 11 in the process of Example 38 -* Example 39 -* Exampk 40 -Example Example 2711): methyff çhloro-4-2-(3S)-7-FS-ehloro-2-fl H4etrazol-S -yl)nhenvll 5-oxo-1,2,3,5-tetrahydro-3-indolizinyl 1-1 H-imidazol-4-yl)phenyllcarbamate TLC 0.55 (5% methanol in ethyl acetate, NH Silica) H NMR (300 MHz, DMSO-d) 12.20 (s, I H), 9.82 (s, 1 H), 9.74-9.58 (m, I H), 7.93 -7.84 (m, I H), 7.84 -7.72 (m, 3 11), 7.62 (d, 1 H), 7.58 -7.36 (in, 2 11), 5.96 (s, 2 H), 5.73 -5.55 (in, I H), 3.73 -3.61 (m, 3 H), 3.46-3.33 (in, 1 H), 3.10-2.87 (in, I H), 2.47-2.19 (in, 2 H).
rnp1e 27jQ)j,Q-(2-l(3S)-7-F5-chloro-2-UH-tetrazol-l-yI)phenyll-5-oxo-l,2.3. 5-tetrahydro-3 -indolizinyl) -1 H-imidazol-5-vl')-3,4-dihydro-211 H)-guinolinone TLC: RI 0.28 (10% methanol in ethyl acetate, NIT! Silica) LH NMR (300 Mhz, DMSO-d) ö 12,01 (s, I H), 10.03 (s. I H), 9.79 -9.50 (m, I H), 7.85 -7.70 (in, 3 H), 7.60 -7.28 (m, 3 H), 6.98 -6.61 (in, I H), 6.13 -5.84 (in, 2 H), 5.60 (d, I 1-1), 3.54-3.19 (m, 3 H), 3.10-2.77 (m, 3 H), 2.45 -2.07 (m, 211).
Example 271(3): ethyl 14-(2-U3S)-7-15-chloro-2-( lH-tetrazol-1yflpl-S-oxo-TLC: RI 0.52 (10% methanol in ethyl acetate) LHNMR (300 MHz, DMSO-&) 3 12.02 (s, I 11), 9.79-9.60 (in, 1 H), 9.54 (s, 1 H), 7,95 -7.68 (in, 3 11), 7.68 -7.34 (in, 511), 6.09-5.80 (m, 211), 5.73 -5.48 (in, 1 H), 4.19-4.06 (in, 21-1), 3.46 -3.35 (in, 1 11), 2.99 (dd, 1 1-1), 2.61 -2.53 (in, I H), 2.40 - 2.24 (in, 11-1), 1.24 (t, 3 H).
Examsle 271 (4): 4-(2-{(3S)-7-[5-chloro-2-(1 1-1-tetrazol-I -yI)phenvil-5-oxo-1,2.3,5-tetrahydro-3-inde1idnyi -1 H-imidazol-5-yl)benzamide TLC: Rf 0.55 (10% methanol in dichioromethane) F! NMR (300 MHz, DMSO-d6) 5 12.22 (s, 1 H), 9.72 -9.66 (m, 1 H), 7.99 -7.60 (m, 9 H), 7.25 (br. s, I H), 6.07-5.82 (m, 2 Fl), 5.67-5.53 (m, I H), 3.52-3.35 (Ui, 1 H), 3.01 (dd, I H), 2.46 -2.24 (in, 2 Fl').
Example 272: 444-chloro-{(3S)-7-[5-ch1oro-2-UH-tefrazol-1-yllyhenyll-5-oxo- 1,2,3,5-tetraho-3-indo1iziny1} -1 H-ixnidazol-5-yl)benzamide The compound prepared in Example 271(4) (250 rag) was treated as detailed in Example 44 to give the title compound having the following physical properties (152 mg).
TLC: RI 0.64 (6% methanol in ethyl acetate) HNMR(300MT-Iz,1)MSO-d6)S 13.11 (s, I H),9.70(s 1 H),8.12-7.74(m,8H), 7.40 (hr. s, I H), 6.06-5.82 (m, 2 H), 5.58 (dd, I H), 3.28 -3.15 (m, I H), 3.00 (ad, I Fl), 2.65-2.54 (m, I H), 2.33 -2.11 (m, 111).
Example 273: methyl [442-I (3R)-7-[5-cMom-241 H-tetrazol-I -ylIphenyll-5-oxo-j3.5-tetrahvdro-3-indolizinyl 1-1 H-imidazol-5-yl')phenyflcarbamate The compound prepared in example 42 was separated by preparative chira] HPLC (CH1R.ALPAK 113 50 mm x 250 mm, hexane!tetrahydrofuranldiethylarnine = 20(80/0.1) to give the title compound having the following physical properties.
TLC: 1(10.50 (ethyl acetate) H NMR (300 MHz, DMSO-d.3) & 12.03 (s, 1 11), 9.81 -9.63 (m, 1 Fl), 9.58 (s, 1 H), 7.87-7.73 (in, 3 H), 7.68-7.29 (m, 511), 6.04-5.89 (m, 2 Fl), 5.68-5.54 (in. I H), 3.71 -3.59 (m, 3 H), 3.47-3.35 (iii, 1 H), 2.99 (dd, 1 H), 2.43-2.14 (in, 211).
Example 274(1) and Example 274(2): 2-methyl-2-propanyl {4-chloro-2-[(3S)-3-j5-14-I (rnethoxycarbonvl)aminolphenyl}-4-methyl-IH-imidawl-25yfl-5-oxo-I tetrahydro-7-indo1izinylphenyl} carbamate and 2-methyjropany1 14-cho-2-[(3S)- (jj4-methox'c&bon1)aminoJphenyI}-5-methyi-I.3-oxazol-2-yt5-oxo-2, 3j-jjjdm-7-indolizinlhen1l}%c at ate The same operation as in Example 38 -÷ Example 39 was conducted from the compound prepared in Example 11 to obtain the title products in a 1: 1 ratio having the following physical properties. (Note: in the step corresponding to Example 38 in the S 200 operation, the compound prepared in Example 78 was used)
Example 274(1)
LC/MS tR 4.13 minutes; MS (ES) m/z 589 (M+H) d
Example 274(2)
LC/MS tR 4.59 minutes; MS (ES) m/z 590 (M+H)d Example 275 methyl [4-(2-ft3 S)-7-[5-chloro-2-(I H-tetrazol-1 -yl)phenyl]-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl}-5-niethyl-l H-imidazol-4-yl)phenyllcarbamate The same operation as in Example 40 -. Example 41 was conducted from the compound prepared in Example 274(1) to give the title compound having the following physical properties.
TLC: Rf 0.54 (5% methanol in ethyl acetate, NH Silica) H NMIR (300 MHz, DMSO-d6) 6 11.87 (s, 1 H), 9.81 -9.62 (m, 1 H), 9.58 (s, 1 H), 7.92 -7.68 (m, 3 H), 7.54 -7.36 (m, 4 H), 6.06 -5.84 (in, 2 H), 5.63 -5.40 (m, 1 H), 3.72-3.60 (m, 3 H), 3.47-3.35 (m, 1 H), 3.10-2.86 (m, 1 H), 2.47-2.39 (m, 2 H), 2.32 (s, 3 H).
Example 276 methyl [4-g-{(3S)-7-[5-chloro-2-( I H-tetrazol-1 -yl)yhenyfl-5-oxo- 1,2,3,5-tetrahydro-3 -indolizinyl}-5-methyl-1,3-oxazol-4-yl)phenyl]carbamate The same operation as in Example 40 -. Example 41 was conducted from the compound prepared in Example 274(2) to give the title compound having the following physical properties.
TLC: Rf 0.45 (5% methanol in ethyl acetate, NH Silica) H NMR (300 MHz, DMSO-d6) 69.86 -9.51 (m, 2 H), 7.81 (app. s, 3 H), 7.52 (app. s, 4 H), 6.00-5.97 (m, 2 H), 5.66 (dd, 1 H), 3.67 (s, 3 I-I), 3.25 -3.09 (m, 1 H), 3.08 -2.94 (m, 1 H), 2,48 (s, 3H), 2.31 -2.10 (m, 2 H).
Example 277: methyl (4-[2-({4-[5-chloro-2-(1 1-1-tetrazol-1 -yl)phenyli-2-oxo-1(21-fl-pyridinyl}methyl)-4-methyl-I H-imidazol-5-yllphenyl} carban-iate The same operation as in Example 38 -* Example 39 -÷ Example 40 -Example 41 was conducted from the compound prepared in Example 32 to obtain the title compound having the following physical properties. (Note: in the step corresponding to Example 38 in the operation, the compound prepared in Example 78 was used) TLC: RI 0.32 (5% methanol in ethyl acetate, NFl Silica) 1H NMR (300 MHz. CDCI3) 8 10.01 (br. s, I H), 8.53 (s, I If). 7.68 -7.59 (a,, 1 I-f), 7.59-7.32 (ni, 7 H), 6.63 (br. s, 1 H), 6.54 (ci, 1 H), 5.73 (d, I H), 5,08 (s, 2 H), 3.80 (s, 3 H), 2.40 (br. s, 3 H).
Example 278: mejiuyij4-CMIB-5-chioro-2-(1 fl-tetrazol-1 -yl)phenjfl-2-oxo-i 1211k pyridinyl} -2-(3-pyridinyl)ethvl]-1 H-imidazol-5-ylIphenvl)carbamate The same operation as in Example 26 -i Example 21 -Example 22 -.
Example 23 -* Example 24 -*Example 25 -*Example 38 -Example 39 was conducted from the compound prepared in Example 20 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 26 in the operation, 3 -(ch!oromethyl)pyridine hydrochloride was used).
1 5 TLC: RI 030 (5% methanol in ethyl acetate, NH Silica) H NMR (300 MHz, DM504) 6 12.32 (s. 1 II), 9.80-9.59 (m, 2 H), 8.47 -8.29 (m, 2 i-fl, 7.87-7.61 (m, 6 H), 7.61 -7.35 (m, 4 H), 7.34-7.19 (in, I H), 6.44-6.07 (m, 2 H), 5.92 (d, I H). 3.66 (s, 3 H), 3.62-3.40 (m, I H), 3.33-3.16 (m, 1 H).
Example 279: methyl (4-j4--chloro-2-[j -j445-chloro-2-(1 H-tetrazol-1 -yl)phenyll-2-oxo-I (2H-pyridiny1}-2-(3-pyridinyl')ethyll-lH-imidazol-S-yl I uhenyflcarbarnate The compound prepared in Example 278 (126 mg) was treated as detailed in Example 47 to give the title compound having the following physical properties (60 mg).
TLC: Rf 0.21 (5% methanol in ethyl acetate) II NMR (300 MHz, DMSO-d6) 6 ppm 12.94 (s, I II), 9.80 (s, 1 H), 9.64 (s, I H), 8.56 - 8.24 (m, 2 H), 7.95 -7.68 (m, 4 H), 7.56 (q, 4 Fl), 7.45 -7.12 (in, 2 H), 6.34-6.20 (in, 1 H), 6.16 (ci, I H), 5.95 (dci, I 1-f), 3.74-3.62 (m, 3 H), 3.54 (dd, I 1-1), 3.28 (br. s., I H).
Example 280: 1 -azido-2-bromo-4-chlorobenzene To a solution of concentrated hydrochloric acid (100 niL) in water (300 mL) was added 2-bromo-4-chloroaniline (10.0 g).). To this stirred suspension, a solution of sodium nitrite (3.68 g) in water (150 mL) was added dropwise at -5 °C. After being stirred at-S °C for 1 hour, a solution of sodium azide (3.46 g) in water (IS mL) was * 202 added dropwise and the resulting suspension stirred at -5 °C for a further hour. The reaction mixture was then extracted with ethyl acetate and the organic layer washed with brine, dried and concentrated to obtain the title compound having the following physical properties (10.7 g).
H NMR (300 MHz, CDCI3) ö 7.56 (d, 1 H), 7.32 (dd, I H), 7.09 (d, 1 II).
Example 281:2-methyi-2-proj,anyl 1 -C -bromo-4-ehlorophenylj-1 11J2,3-triazole-4-carboxylate To a toluene (50 mL) solution of the compound prepared in Example 280 (2.4 g), tert-butyl propiolate (3 mL) was added and the mixture stirred at reflux for 6 hours. The reaction mixture was concentrated and the residue purified by column chromatography (7 to 20% ethyl acetate in hexane) to give the title compound having the following physical properties (2.3 g).
LCIMS R 4.51 minutes; MS (ES4) m/z 358 and 360 (M+Fl) ci Example 282: ethyl C3S)5-oxo-7-(4,4,5,5-tetrmethyl-1 3,2-dioxabQ[o1yij-12.
tetrahydro-3-indolizinecarboxylate To a 1,4-dioxane (7 mL) solution of the compound prepared in Example 6 (500 mg) was sequentially added bis(pinacolate)diboron (393 mg) and potassium acetate (415 mg). The mixture was degassed with argon then 1,1'-bis(diphenylphosphino)ferrocene palladium (H) dichloride dichloromethane complex (115 mg) was added and the reaction mixture stirred at 100 °C for 3 hours. To the reaction mixture, ethyl acetate was added followed by filtration with Celite. The filtrate was washed with water and brine, dried and concentrated to obtain the title compound having the following physical properties (412 mg).
IX NMR (300 MHz, CDCI3) ö 6.86 (br s, 1 H), 6.40 (br s, 1 H), 5.11 (dd, I H), 4.39 - 4.17 (m, 211), 3.25-3.10 (in, I H), 3.09 -2.96 (m, I H), 2.55 -2.39 (m, 1 H), 2.32- 2.20 (m, 1 H), 1.39-1.21 (in, 15 H).
Examole83: ethyl (3 S)-7-15cWo-2zQtJ [fZ-meyjpropanyl)oxy1carbony1}-lH-I,2,3-triazol-1 -yflyhenyll-5-oxo-I,2,3,5-tetrahydro-3-indolizinecarboxylate To a 1,4-dioxane (30 mL) solution of the compound prepared in Example 281 (1.01 g) was added the compound prepared in Example 282(1.10 g) and a solution of sodium carbonate (1.20 g) in water (6.0 mL). To the reaction mixture, tetrakis(triphenylphosphine)palladium(0) (487 mg) was added then the mixture degassed with argon and stirred for 16 hat 100 °C. The reaction mixture was concentrated and the residue thus obtained suspended in ethyl acetate and washed with water and brine. The organic layer was dried and concentrated and the residue purified by column chromatography (15% methanol in ethyl acetate) to give the title compound having the following physical properties (613 mg).
LC/MS tg 4.30 minutes; MS (ES) in/z 485 (M+H) d Example 284: 2-methyl-2-propanyl 1-f4-chloro-2-[(3S)-3-(5-{4- [(methoxycarbonyl)aminolphenyl} -I Fl-imidazol-2-yl)-5-oxo-I,2,3,5-tetrahydro-7-indolizinyllphenyfl-l H-i,2,3-triazole-4-carboxylate The same operation as in Example 8 -Example 38 -*Example 39 was conducted from the compound prepared in Example 283 to give the title compound having the following physical properties.
TLC: Rf 0.72 (6% methanol in ethyl acetate) H NMR (300 Mhz, DMSO-d6) 6 12.02 (s, I H), 9.57 (s, 1 H), 8.99 (s, I H), 7.80 -7.70 (m, 3 H), 7.62-7.37 (m, 5 H), 6.07 (s, 1 H), 5.93 -5.89 (m, I H), 5.60 (d, 1 H), 3.70- 3.63 (m, 3 H), 3.52-3.36 (m, 1 H), 3.03 (dd, 1 H), 2.47-2.33 (m, 2 H), 1.59-1.47 (m, 9H).
Example 285: methyl 1-{4-chloro-2-[(3S1-3 -(5-{4-[(methoxycarbonyl)aminolphenyl} - lll-imidazol-2-yl)-5-oxo-1,2,3,5-tetrahydro-7-indolizinyl]yhenyl}-l H-I,2,3-tria.zole-4-carboxylate To a methanol (1 mL) solution of the compound prepared in Example 284 (91 mg) was added a 20% solution of sodium rnethoxide in methanol (50 pL) and the mixture stirred for 2 hours at 40 °C. To the cooled (0 °C) reaction mixture, a saturated aqueous solution of sodium bisulfate was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated and the residue purified by column chromatography (20% ethyl acetate in methanol) to give the title compound having the following physical properties (52 mg).
TLC: RfO.55 (6% methanol in ethyl acetate) 1H NMR (300 MHz, DMSO-d6) 5 12.02 (s, 1 H), 9.57 (s, I H), 9.11 (s, I H), 7.79-7.70 * 204 (in, 3 H), 7.61 -7.36 (m, 5 H), 6.01 (s, 1 11), 5,92 (s, I 1-1), 5.59 (d, 1 Fl), 3.87-3.80 (m, 3 1-1), 3.65 (s, 3 Fl), 3.51 -3.35 (in, 1 H), 3.06-2.95 (in, 1 H), 2.47-2.25 (m, 211).
Example 286: I -{4-chioro-2-U3S)-3-(5-{4-Ifmethoxycarbonvflamino]phenyl} -1 H S imidazol-2-yfl-5-oxo-1,2,3,5-tetrahydro-7-indolizinyllphenyl}-1 H-1,2,3-triazole-4-carboxylic acid To a dichloromethane (1.5 mL) solution of the compound prepared in Example 284 (51 mg) was added trifluoroacetic acid (0.5 mL). After stirring for 5 hours at 45 °C, the reaction mixture was concentrated and the resulting residue triturated with ethyl acetate to give the title compound having the following physical properties (27 mg).
TLC: Rf 0.41 (ethyl acetate/methanol/acetic acid, 10/5/2) 1H NMR (300 MHz, DMSO-d6) 3 9.84 (s, 1 11), 9.03 (s, I H), 7.94 -7.60 (m, 7 H), 7.60 -7.45 (m, 2 H), 6.12 (s, I H), 5.98 (d, I I-f), 5.75 (dd, 1 11), 3.68 (s. 3 H), 3.30 (di, I H), 3.20-2.94 (m, I H), 2.76 -2.56 (m, I H), 2.40-2.16 (in, I H).
287: 1 -(2-bromo-4-chlorophenyl)-I H-I,2,3-triazole-4-carboxylic acid To a dichloromethane (10 mL) solution of the compound prepared in Example 281 (2.3 g), was added trifluoroacetic acid (10 niL). After being stirred at room temperature for 1 hour, the reaction mixture was concentrated and the resulting residue triturated with dichioromethane to give the title compound having the following physical properties (1.5 g).
LCIMS 1R 4.07 minutes; MS (ES) nih 302, 304 (M+H) Example 288: 1 -(-bromo-4-chlorophenylFjjjj,2,3-triazole-4-carboxamide To an N,N-dimethylfonnamide (3 mL) solution of the compound prepared in Example 287 (500 mg) was sequentially added triethylamine (0.69 niL) and O-Q-azabenzotriazol-I -yI)-N,N>N' ,IV' -tetramethyluronium hexafluorophosphate (753 mg).
After being stirred at room temperature for 15 minutes, a 28% aqueous solution of ammonia (0.7 mL) was added and the mixture stirred at room temperature for a further 15 minutes. To the reaction mixture, water was added and the resulting precipitate collected by filtration. The precipitate was washed with water and dried to give the title compound having the following physical properties (463 mg).
LC/MS t 4.02 minutes; MS (ES9) ,n/z 301, 303 (M+H) d S 205 Example 289: methyl [4-(2-3S)-7-f2-(4-carbamoy1-1H-I,2,3-triazol-1-yfl-5- chlomphcnyjji5-oxo-1,2,3, 5-tetrahydro-3-indoliziny1-IH-imidazol-5-yflphçpyl}carbaniatc The same operation as in Example 283 -Example 8 Example 38 -Examp1e 39 was conducted from the compound prepared in Example 288 to give the title compound having the following physical properties.
TLC: P10.34(10% methanol in ethyl acetate, NIH Silica) H NMR (300 MHz, DMSO.4) S 12.10-11.89 (m, 1 H), 9.57 (s, 1 H), 8.94-8.69 (in, 1 H), 7.97 (s, I H), 7.83 -7.64 (in, 3 H), 7.64 -7.26 (m, 6 H), 6.08-5.99 (in, 1 H), 5.93 (s, I II), 5.61 (d, I H), 3.73-3.59 (iii, 3 H), 3.50-3.40 (in. 1 H), 3.09-2.93 (in, 1 H), 2.43-2.27 (in, 2 H).
pple 290: methyl [4-(2-{(3S)-7-(5-chloro-2-(-cyano-IH-l.2,3-triazol-1-yflpnyfl-5-oxo-I,2,3, 5-tetrahydro-3-inclolizinyL}-1Fl-imidazol-5-vflphenyl1carbai To a dichloromethane (50 mL) solution of the compound prepared in Example 289 (70 rug) was added triethylamine (0.17 mL) and trifluoroacetie anltydridc (0.17 mL) and the reaction stined at room temperature for 1 hour. The reaction mixture was concentrated and the resulting residue purified by colunm chromatography (5% ethyl acetate in methanol, NH silica) to give the title compound having the following physical properties (55 mg).
TLC: RI 0.53 (10% methanol in ethyl acetate, NH Silica) H NMR (300 MHz, DMSO-d,j) 5 12.04 (s, 1 H), 9.57 (s, I H), 9.37 (ci, I H), 7.84-136 (in, 3 H), 7.62 -7.51 (in, 2 H). 7.49 -7.37 (in, 3 H), 5.97 (s, I H), 5.94 (s, 1 H), 5.65- 5.57 (in, 1 H), 3.68-3.63 (in, 3 H), 3.47-3.36 (m, I H), 3.01 (dd, I H), 2.41 -2.08 (in, 2H).
pje 291: methyl I -(2-bromo-4-chlorophenyl)-lH-jdazo1e-4-carboxyLate To a methanol (5 niL) solution of the compound prepared in Eicample 287 was added concentrated sulfuric acid (0.2 mL) and the mixture heated at reflux for 6 hours before allowing to cool to room temperature. The reaction mixture was concentrated, diluted with water (5 mL) and neutralized with a saturated aqueous solution of sodium hydrogen carbonate followed by extraction with ethyl acetate. The combined organic I 206 layers were washed with brine, dried and concentrated to give the title compound having the following physical properties (132 mg).
TLC: Rf 0.50 (50% ethyl acetate in hexane) Example 292: 2-methvl-2-proyanyl (2S)r42-oxo-4-(4,4,5,5-tetramethy1-13,2-dioxaborolan-2-yl)-1 (2F1)-pyridinyll-3-phenylpropanoate The compound prepared in Example 257 (1.88 g) was treated as detailed in Example 282 to give the title compound having the following physical properties (1.35 g).
11 NMR (300 MHz, CDCI3) 5 7.30-7.05 (in, 6 H), 6.93 (hr s, I H), 6.27 (dd, 1 H), 5.47 (dd, I H), 3.43 (dd, 1 Fl), 3.25 (dd, 1 H), 1.40 (s, 91-1), 1.30 (s, 1211).
Example 293: methyl I -(4-chloro-2-{ 1-1(1 S)-1 -(5-{4- 1(methoxycarbonvl)aminoJphenyl}-l H-irnidazol-2-yl)-2-phenylethyl]-2-oxo-l, dihydro-4-pyridinyl}phenyl)-l H-I,2.3-triazole-4-carboxylate The same operation as in Example 283 -* Example 25 -. Example 38 -* Example 39 was conducted from the compound prepared in Example 292 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 283 in the operation, the compound prepared in Example 291 was used) H NMR (300 MHz, DMSO-d6) 5 12.29 (s, 1 H), 9.61 (s, 1 H), 9.20 -8.90 (m, 1 H), 7.92-7.60 (m, 6 H), 7.57.-7.35 (m, 3 1-1), 7.30-7.06 (m, 5 H), 6.39 -6.08 (m, 211), 6.03 -5.84 (m, 1 H), 3.85 (s, 3 H), 3.73 -3.61 (in, 3 H), 3.59-3.40 (in, 1 H), 3.31 -3.09 (in, 1 H).
Example 294: 1 -(2-bromo-4-chlorophenvl}-4-(trifluoromethyl)-1 H-I,2,3-triazole The compound prepared in Example 280 (2.0 g) was treated as detailed in Example 281 using 3,3,3-trifluoropropyne in place of tert-butyl propiolate to give the title compound having the following physical properties (100 mg) H NMR (300 MHz, CDC13) 5 8.25 (in, 1 H), 7.81 (in, I H), 7.50-7.55 (in, 2 H).
Example 295: methyl [4-(2j (1 S)-jj4-{ 5-ehloro-2-[4-(trifluoromethyflj Fl-I 2,3 - triazol-1 -yliphenyll -2-oxo-1 (2ffl-pyridinyl1-pjnylethy1}-tH-imidazol-4-vllphenvllcarbamate The same operation as in Example 283 -p Example 25 -k Example 38 -k Example 39 was conducted from the compound prepared in Exampk 292 to give the title compound having the following physical pwperties. (Note: in the step corresponding to Example 283 in the operation, the compound prepared in Example 294 * was used) TLC: 1110.53 (66% ethyl acetate in hexane) H NMR (300 MHz. DMSO-d6) 5 12.00 (br. s, I H), 9.19 (s, I H), 8.99 (s, I H), 7.87- 7.60 (m, 5 H), 7.58-7.38 (m, 3 H), 7.38-7.31 (tn, 1 11). 7.30-. 6.98 (m, 5 H), 6.43 - 6.12 (m, 2 H). 5.88 (Ud, 1 H), 3.69 (s, 3 H), 3.57 (dd. I H), 3.27 (dcl, I H).
Example 296: 1 42-bromo-4-ch1oropheny4jñbpylstannvl)-I H-I,2,3-triazole The compound prepared in Example 280 (1.86 g) was treated as detailed in Example 281 using ethynyltri-n-butyltin in place of tert-butyl propiolate to give the title compound having the following physical properties (5.03 g) H NMR (300 MHz. CDCI3) 5 7.83 (m, I H), 7.75 (dd, I H). 7.50 (dd, I H), 7.45 (dd, 1 11), 1.64-1.50 (m, 611), 1.42-1.24 (m, 611), 1.22-1.12 (in, 611), 0.89 (t, 911).
le297:l-2-bromo-4-chlorohenI-4-ch1oro-lH-lole To an acetonitrile (72 mL) solution of the compound prepared in Example 296 (2.42 g) was added N-chlorosuccinimide (885 mg) and the mixture stirred fortS hours at 60 °C before cooling to room temperature. The reaction mixture was concentrated and the resulting residue purified by column chromatography (20% ethyl acetate in hexane) to give the title compound having the following physical properties (1.0 g).
H NMR (300 MHz, CDCI3) 57.91 (s, 1 H), 7.79 t. I H), 7.48 -7.51 (m, 2 1-1).
Example 298: methyl (4-{2-ftl 8)-I -{4-[5-chloro-2-(4-chloro-1 H-I.2,3-triazol-l -nlcarbamate The same operation as in Example 283 -. Example 25 -Example 38 -* Example 39 was conducted from the compound prepared in Example 292 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 283 in the operation, the compound prepared in Example 297 was used) TLC: Rf 0.62 (66% ethyl acetate in hexane) H NMR (300 MHz, DMSO-d6) 8 12.30 (br. s, I H), 9.61 (s, 1 H), 8.65 (s, I H), 7.96 - 7.63 (m, S H). 7.63 -7.35 (m, 4 H). 7.35 -7.05 (m, 5 H), 6.47 -6.09 (m, 2 H), 5.89 (d. I H), 3.77 -3.62 (m, 3 Fl). 3.52 (dd, I H), 3.26 (d, I H).
Example 299: I-(2-bromo-4-chlorophenyl)-1 Ifpyrazole To aN,N-dimethylacetamide (20 mL) solution of 2-bromo-4-chloro-1-uluorobenzene (2.0 g) was added cesium carbonate (5.39 g) and pyrazole (780 mg) and the reaction mixture stirred for 3 hours at 100 °C before allowing to cool to room temperature, The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated to give the title compound having the following physical properties (1.52 g).
H NMR (300 MHz, CDC13) 87.81 (d, I H), 7.73 (d, I H), 7.71 (d, I H), 7.46 (d, Ill), 7.40 (dd, I H), 6.47 (t, 1 H).
Example 300:l-(2-hromo-4-cffloronhenvl)-4-fluoro-1H-rvrazole To an acetonitrile (4.5 mL) solution of the compound prepared in Example 299 (300 mg) was added I -chloromethyl-4-fluoro-I,4-diazoniabicyelo[2.2.2]octane bis(tctrafluoroborate) (619 mg) and the reaction mixture stined for 18 hours at 70°C before allowing to cool to room temperature. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried and concentrated. The residue thus obtained was purified by column chromatography [20% ethyl acetate in hexane) to obtained the title compound having the following physical properties (131 mg).
H NMR (300 MHz, CDC13) 8 7.75-7.69 (m, 2 H), 2.60 (ad, I II), 7.44 (dd, I H), 7.40 (dd, 111).
Examyle 301: methyl (4-2-[( I S)-1 -{4-[5-chloro-2-(4-fluoroH-pyrazol-I -vllphenyfl 2-oxoJjH)-pjridinvl -2-phenylethyl-1H-imidazol-5-yl}phenyl)carbamate The same operation as in Example 283 -t Example 25 Example 38 -* Example 39 was conducted from the compound prepared in Example 292 to give the title compound having the following physical properties. (Note: in the step concsponding to Example 283 in the operation, the compound prepared in Example 300 was used) TLC: RI 0.40 (50% ethyl acetate in hexane) H NMR (300 MHz, DMSO-d5) 8 12.30 (s. I H), 9.61 (s, I H), 8.05-7.92 (in, 1 H), 7.81 (d, I H), 7.76-7.38 (m, 9 H), 7.38-7.03 (m, 5 H), 6.47-6.10 (rn, 2 1-1), 5.99- 5.64 (in, 1 II), 3.69-3.61 (m, 3 H), 3.61 -3.43 (m, 1 H), 3.30-3.16 (m, I H).
Example 302: 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyfl-1 H-pyrazole 2-bromo-4-chloro-1-fluorobenzene (40 mg) was treated with 4-(trifluoromethyl) -IH-pyrazole as detailed in Example 299 to give the title compound having the following physical properties (18 mg).
H NMR (300 MHz, Cud3) 6 8.07 (t, I H), 7.93 (s, 1 H), 7.74 (cM, 1 Fl), 7.47 (dcl, ill), 7.44 (dd, I H).
Example 303: methyl [4-(2-{(1 SI-144flçhloro-2-[4-(trifluoromethyfl-1 H-pyrazol-I yllphenyl}-2-oxo-1 (2Iifl-pyridiny1J-2-pylethl-1H-intidazol-4-yI)phenyl1carbainate The same operation as in Example 283 -. Example 25 -* Example 38 -* Example 39 was conducted from the compound prepared in Example 292 to give the title compound having the following physical properties. (Mote: in the step corresponding to Example 283 in the operation, the compound prepared in Example 302 was used) TLC: RI 0.72 (66% ethyl acetate in hexane) H NMR (300 MHz, DMSO-d6) 6 12.29 (s, I H), 9.61 (s, I K), 8.70-8.42 (m, I H), 8.t4 -7.95 (m, I H), 7.90-7.59 (rn, 6 H), 7.59-7.37 (m, 3 H), 7.33 -6.98 (m, 5 H), 6.43 -6.06 (in, 2 H), 5.96 -5.68 (m, 1 H), 3.66 (s, 3 H), 3.56-3.42 (m, I II), 3.29-3.06 (m, I H).
Example 304: 1..(2-bromo-4-chlorophenyl)-I H-I,2,4-triazol-3-ol 2-Bromo-4-chloro-phenylhydrazine [Journal of the American Chemical Society, 79, 934, (1957)) (800 mg) and urea (317 mg) were suspended in xylene(12 mL) and the suspension treated with concentrated sulifiric acid (266 mg) with vigorous stirring. The reaction mixture was heated for 6 hours at 135 °C then allowed to cool to 90 °C, whereupon formic acid (420 mg) and concentrated suiffiric acid (46 mg) was added sequentially. The mixture was heated for 15 hours at 90°C at which juncture additional formic acid (1.26 g) and concentrated sulfuric acid (549 mg) were added. The mixture was stirred for a further 3 hours at 90 °C then allowed to cool to room temperature. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound having the following physical properties (520 mg).
1H NMR (300 MHz, DMSO-d6) & 10.4 (br, s, 1 H), 8.48 (s, 1 Fl), 8.01 (d, 1 H), 7.66- 7.58(m.2H).
Example 305: fbromo-4-ch1orophenyfl-3-ft4-methoxybenzyfloxyl-SW! .2,4-triazole To a N,N-dimethylformamide (5 mL) solution of the compound prepared in Example 304 was sequentially added potassium carbonate (452 mg) and 4-methoxybenzylchloride (256 mg) and the mixture stirred for 3 days at room temperature.
To the reaction mixture, water was added followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated and the residue purified by column chromatography (30% ethyl acetate in hexane) to obtain the title compound having the following physical properties (120 mg).
TLC: Rf 0.87(66% ethyl acetate in hexane) Example 306: methyl r4-a-{(3s)-7-Fs-ch1oro-243-hydrqx1Il-H-1.2.4-triazo1-l-The same operation as in Example 283 -v Example 8 -Example 38 -* Example 39 -. Example 40 was conducted from the compound prepared in Example 305 to give the title compound having the following physical properties.
TLC: 1ff 0.43 (10% methanol in dichioromethanc) H NMR. (300 MHz, methanol-d4) 5 8.12 (s, I H), 7.73 -7.50 (m, 5 H), 7.43 (d. 211), 7.23 (s, 1 11), 6.26 (s. 1 H), 6.17 (s, 1 H), 5.80 (dd, I H), 3,82-3.69 (in, 3 H), 3.59- 3.39 (in, I H), 3.24-3.03 (m, 1 H), 2.73 -2.58 (m, 1 Fl), 2.56-2.45 (m, I H).
Example 307: ethyl (3S)-742-aininojethyl-3-pvridinyfl-5-oxo-1,2,3, 5-tetrahv&1ro-3-indolizinecarboxylate To a 1,4-dioxane (20 mL) solution of 2-amino-3-bronio-5-methylpyridine (1.0 g) was added bis(pinacolate)diboron (1.63 g) and potassium acetate (788 mg) and the mixture degassed with argon. l,V-Bis(diphenylphosphino)ferrocene palladium (IJ) dichioride dichioromethane complex (218 ing) was then added and the reaction mixture stirred for 3 hours at 110 °C before allowing to cool to room temperature. The reaction mixture was diluted with ethyl acetate, filtered and the filtrate washed with brine, dried and concentrated. The resulting residue was treated with the compound prepared in Example 282 as detailed in Example 283 to give the title compound having the following physical properties (290 mg).
LCIMS 1R 3.32 minutes; MS (ES) nilz 314 (M+H) Example 308: methyl F442-((3S)-7-[5-methvl-2-(1H-tetrazol-1 -yl)-3-pvridinyl)-5-oxo- 1,2,3,5-tetrahydro-3-indolizthyfl4H-imidazol-5-yl)phenylcarbamate The same operation as in Example 8 -* Example 38 -÷ Example 39 -, Example 41 was conducted from the compound prepared in Example 307 to give the title compound having the following physical properties.
TLC: Rf 0.38 (5% methanol in ethyl acetate, NH Silica) H NMR (300 MHz, DMSO-d6) ö 12.11 -11.96 (ni, I H), 9.95 9.80 (m, I H), 9.58 (s, I H), 8.58 (d, I II), 8.07 (d, I 11), 7.63-7.51 (m, 2 H), 7.49-7.37 (m, 3 H), 6.18-5.93 (m. 2 H), 5.63 (d. I H), 3.76-3.56 (m, 3 Fl), 3.49-3.30 (in, I H). 3.20-2.90 (in, I H).
2.65.. 2.54 (in, 1 H), 2.47 (br. s, 3 H), 2.40 -2.27 (in, 1 H).
jfflpj309:methyl [442-{(3S)-7-[5-methvl-2-( IH-tetrazol-1-yflphenyll-5-oxo- 1,2,3,5-tetrahydro-3-indolizinyl}JH-iniidazol-5-yl)phenyllcarbamate The same operation as in Example 7 -t Example 8 -. Example 38 -. Example 39 -. Example 41 was conducted from the compound prepared in Example 6 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 7 in the operation, 2-amino-5-methylphenylboronic acid pinacol ester was used) H NMR (300 MHz, DMSO-d6) 6 12.03 (s, 1 H), 9.65 (a, 1 H), 9.58 (a, 1 14), 7.62-7.54 (m, 31-fl, 7.50 (d, 3 H), 7.45-7.37 (m, 2 Fl), 5.93 (s, 1 1-1), 5.86 (s. I H), 5.60 (d, 1 H).
3.65 (s, 3 H), 3.45 -3.35 (in, 1 H), 3.07-2.89 (in, I H), 2.46 (s, 3 11), 2.40-2.23 (in, 2 H).
Example j.Q.meth'l4-2-l(3S)-7- [5-ehloro-2-M-ch1oro-1H-I23-triazoI-l-yflphenyll-5-oxo-l,2, 3j-tetrahydro-3-indolizinyl} -I H-imidazol-5jj)henyl}carbamate Thc same operation as in Example 283 -Example S -. Example 38 -.
Example 39 was conducted from the compound prepared in Example 282 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 283 in the operation, the compound prepared in Example 297 was used) H NMR (300 MHz, DMSO-d6) 12.03 (s, 1 11), 9.57 (s, I 11), 8.79-8.58 (in, I H), 7.83 -7.65 (m. 3 11), 7.65 -7.30 (in, 5 H), 6.04-5.81 (in, 2 H), 5.61 (dd, I 11), 3.74- 3.59 (m, 3 H), 3.49-3.36 (in, I 11), 3.01 (dd, I H), 2.55 (hr. s, 1 H), 2.43 -2.13 (m, I H).
Example 311: 1 42-broino-4-fluoroyheny[)-I H-tetrazole To a glacial acetic acid (10 mL) solution of 2-bromo-4-tluoroaniline (570 mg) was added trimethyl orthoformate (1 mL) followed after 30 minutes by sodium azide (5.93 g) and the mixture stirred for 7 hours at 90 CC. The reaction mixture was concentrated and the resulting residue suspended in ethyl acetate. The suspension thus formed was washed sequentially with water, a saturated aqueous solution of sodium hydrogen carbonate and brine, dried and concentrated. The residue thus obtained was purified by column chromatography (60% ethyl acetate in hexane) to obtained the title compound having the following physical properties (700 mg).
TLC Rf 0.26(25% ethyl acetate in hexane) 1,2,3,5-tetrahydro-3-indolizinylkl H-irnj]-5-lhepyl]carbaniate The same operation as in Example 283 -Example 8 -* Example 38 -.
Example 39 was conducted from the compound prepared in Example 282 to give the title compound having the following physical properties. (Note: in the step corresponding to Exampte 283 in the operation, the compound prepared in Example 311 was used) TLC RfO.33 (5% methanol in ethyl acetate, NH Silica) H NMR (300 MHz. DMSO-d5) 512.04 (s. 1 11), 9.68 (s, 1 H), 9.58 (a, I H), 7.87-7.78 (in, I H), 7.63 7.51 (in, 4 H), 7.49-7.37 (in, 3 H), 5.94 (app. s,2 H), 5.60 (d, I H), 3.68 -3.63 (in, 311), 3.30-3.23 (m, I H). 3,05-2.92 (in, 1 Fl), 2.46-2.23 (m, 2 H).
Exp(e3l3:1-Uiodo-4-(mfluoromethvlnhenvl1-1H-tetrazole 2-iodo-4-trifluoromethylaniline (861 rug) was treated as detailed in Example 311 to give the title compound having the following physical properties (873 mg).
TLC Rf 0.24 (25% ethyl acetate in hexane) Example 314: methy} [4-j2.{1351-5-oxo-7-[24lH-tetrazol-1-yD-5- (trifluoromethyllphenyll-1,2.3,5-tetrahydro-3-indolizinyl} .. 1H-imidazol-5-yDphenyllcarbamate The same operation as in Example 283 -Example 8 -÷ Example 38 -÷ Example 39 was conducted from the compound prepared in Example 282 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 283 in the operation, the compound prepared in Example 313 was used) TLC Rf 0.55 (5% methanol in ethylacetate) H NMR (300 MHz. DMSO-d6) S 12.03 (s, I H), 9.75 -9.73 (in, I H), 9.58 (s, 1 H), 8.15 8.10 (ni, I H), 8.04-8.01 (m. 211), 7.66-7.35 (in, S H), 6-04-5.96 (m, 2 H).
5.62 (d, I H), 3.67 -3.64 (m, 3 H), 3.46-3,35 (m, I H), 3.12 -2.90 (m, I H), 2.46- 2.28 (m, 2 H).
Example 315: 244-hydroxy-6gy3-2-oxo-l 211)-pyridinyl)propanoic acid A suspension of 4-hydroxy-6-methyl-2-pyrone (2.52 g) and DL-alanine (1.78 g) in I M sodium hydroxide (20 mL) was heated at reflux for 15 hours. To (he reaction mixture, an aqueous solution of I M hydrochloric acid (22 mL) was added and the resulting precipitate collected by filtration. The filter cake was washed with I M hydrochloric acid and dried in vacua to obtain the title compouad having the following physical properties (2.3 g).
LC/M S t 2.90 minutes; MS (ES) ,n/z 198 (M+H)'1 Example 316: ethyl 2-(4-hydroxv-6-methyl-2.exe-1 (2H)-pyridinyflpropanoate An ethanol (15 mL) suspension of the compound prepared in Example 315 (2.3 g) was treated with concentrated sulphuric acid (43 pL) and the mixture stirred for 15 hours at 90 °C. The forthcoming precipitate was collected by filtration, washed with ethanol and dried to obtain the title compound having the following physical properties (0.78 g).
LC/MS ig 3.47 minutes; MS (ES) ,n/z 226 (M+H) cl Example 3 17: methyl (412-p -(445-chloro-2-( 1 H-tetrazol-1 -yflphenyll-6-methyl-2-oxo-I (2H)-pyridjyftethyfl-1 lfimidazol-5-yllphenyl}carbam
CH CII
CH
The same operation as in Example 6 -Example 7 -p Example 9 -÷ Example Example 38 -. Example 39 was conducted from the compound prepared in Example 316 to give the title compound having the following physical properties.
TLC RI 0.58 (5% methanol in ethyl acetate) H NMR (300 MHz, CDCI3) 5 11.01 (hr. s, 1 H), 8.69 -8.37 (m, I H), 7.76-7.45 (m, 5 H), 7.39 (d. 2 H), 7.18 (s, I H), 6.69 (hr. , I H), 6.36 (s, 1 H), 5.73 (hr. s, I H), 5,62 - 5.46 (in, I H), 3.85-3.70 (m, 3 H), 2.50 (hr. s,3 H), 1.99 (d, 3 Fl).
Example 318: methyl f4-[2-4-1joro-2-1H-tetro1-l-y1)phenyfl-6-methyl-2-oxo-I (2H)-pyridinyl} methyl)-! H-imidazol-5-yllphenyflcarbamate The same operation as in Example 315 -. Example 316 -Example 6 -Example 7 -* Example 9 -. Example 11 -. Example 38 -Example 39 was conducted to give the title compound having the following physical properties. (Note: in the step corresponding to Example 315 in the operation, glycine was used in place of DL-alanine.) TLC flO.42 (5% methanol in ethyl acetate, NH Silica) H NMR (300 MHz, DMSO-de) & 11.97 (s, I Fl), 9.75 -9.64 (m, 11-1), 9.58 (s, I Fl), 7.86-7.73 (in, 3 H), 7.63-7.50 (in, 2 H), 7.49-7.36 (m, 311), 6.12-5.95 (m, 1 11), 591 (d. 11-1), 5.25 -5.08 (m, 2 H), 3.70 -3.60 (ni, 3 H), 2.55 2.53 (m, 3 H).
Exampje 319: methyl {4jjjJ4-5-chloro-241 H-tettazol-l -ylThhenyil-6-ethvl-2-oxo-JÜU)-rvri dinyflmethyfl-1 H-imidazol-5-yllphenyl}carbamate The same operation as in Example 315 -* Example 316 -÷ Example 6 -p Example 7 -Example 9 -Example 11 -* Example 38 -. Example 39 was conducted from 6-ethyl-4-hydroxy-2-pyrorie to give the title compound having the following physical properties. (Note: in the step corresponding to Example 315 in the operation, glycine was used in place of DL-alanine.) TEC Rf 0.50 (ethyl acetate) HNMR (300 MI1iz, DMSO-d6) 6 11.93 (s, 1 H), 9.77-9.63 (m, I H). 9.58 (s, 1 H), 7.85 -7.80 (m, 3 H), 7.65 -7.36 (m, 5 H), 6.33 -6.04 (m, I H), 5.72 -5.49 (m, I H), 5.17 (s, 2 H), 3.74-3.61 (m, 3 H), 3.00-2.75 (m, 2 H), 1.10-0.91 (m, 3 H).
Example 320: 4-chloro-2-(6-ehloro-2-methyl-4-pyrimidinyl)aniline To a 1,4-dioxane (150 niL) solution of 4,6-dichloro-2-methylpyrimidine (2.0 g) stirring under an atmosphere of argon was added 4-chloro-2-(4,4,5,5-tetraniethyl-1,3,2-dioxaborolan-2-yl)aniline (3.11 g) and 2 M aqueous sodium carbonate solution (18.5 mL). The mixture was degassed with argon then tetrakis(triphenylphosphine) palladium(0) (0.71 g) added and the mixture stirred for 2 hours at 100 °C. To the reaction mixture, ethyl acetate was added and the organic layer washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried and concentrated. The residue thus obtained was thturated with dichloromethane to give the title compound having the following physical properties (1.6 g).
Fl NMR (300 MHz, CDCb) 67.54 (d, I H), 7.48 (s, 1 H), 7.18 (dd, II H), 6.69 (d, 1 H), 6.13 (hr. s, 2 HI), 2.75 (s, 3 1K).
Example 321: 6-(2-amino-5-chlorophenyl)-2-methv(-4(3 H)-pyjmidinone A suspension of the compound prepared in Example 320 (1.2 g) in S M hydrochloric acid (30 rnL) was reflwced for 2 hours. The reaction mixture was concentrated and the residue azeotroped with ethanol and toluene to obtain the title compound having the following physical properties (1.7 g).
H NMIR (300 MHz, DMSO-&) 6 7.38 (d, 1 H), 7.17 (dd, I H), 6.80 (d, I Fl), 6.46 (s. I H), 2.37 (s, 3 H), 4.50-3.50 (obs. m, 3 H).
Example 322: 2-methyl-2-propanyl 14-(2-amino-5-chIorophenyiethyl-6-oxo- 1 (F1J-pyrimidinyll.cetate To an N,N-dimethylformamide (30 mL) solution of the compound prepared in Example 321 (0.69 g) was added tert-butyl bromoacetate (0.45 mL) and potassium * 216 carbonate (1.06 g) and the mixture stirred at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue thus obtained was purified by column chromatography (15 to 50% ethyl acetate in hexane) to give the title compound having the following physical properties (370 mg).
H NMR (300 MHz, CDCI3) 37.37 (d, I 11), 7.12 (dd, I H), 6.62 (d, 1 H), 6.60 (s, I H), 5.38 (hr. s,2 H), 4.74 (s, 2 H), 2.51 (s, 311), 1.50 (s, 9 H).
Example 323: methyl 44-[2-({4-[5-chloro-2-(1 H-tetrazol-1 -yl)pbenyll-2-rnethyl-6-oxo- 1 (6H)-pyrimidinyl}methyl)-1H-imidazol-5-yllphenyl}carbamate
N-N CH
The same operation as in Example 24 -p Example 25 -* Example 38 -÷ Example 39 was conducted from the compound prepared in Example 322 to give the title compound having the following physical properties.
TLC RI 0.58 (5% methanol in ethyl acetate) H NMR (300 MI-h, DMSO-d6) S 12.10 (br. s, 1 1-1), 9.73 (s, 1 11). 9.57 (s, 1 H), 7.98 (s, I H), 7.92 -7.70 (m, 211), 7.60 (d, 2 H), 7.55 -7.26 (m, 3 H), 6.53 (s, I H), 5.18 (s, 2 H), 3.65 (s, 3 H), 2.55 -2.44 (obs. in, 3 H).
Example 324: 2-methoxyethyl [4-(bromoacetyl)phenyl]carbamate The same operation as in Example 77 -i Example 78 was conducted from 4-aminoacetophenone to give the title compound having the following physical properties.
(Note: in the step corresponding to Example 77 in the operation, 2-methoxyethyl chloroformate was used) TLC Rf 0.40 (50% ethyl acetate in hexane) Example 325: 2-methoxyethyl {4-[2-( {4-[5-chloro-2-11H-tetrazol-1 -yl)phenyll-2-methyl-6-oxo-1 (6Ffl-pyrimidinyl}methyl)-1H-imidazol-5-flphenyl} carbam The same operation as in Example 24 -. Example 25 -. Exarnçñe 38 -.
Example 39 was conducted from the compound prepared in Example 322 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 38 in the operation, the compound prepared in Example 324 S was used) TLC RI 0.52 (5% methanol in ethyl acetate) lff NMR (300 MHz, DMSO-d6) 6 12.10 (s, I H), 9.75 -9.63 (m, 2 H), 8.04 -7.92 (in. I H), 7.92-7.69 (in, 2 H), 7.62-7.34 (in, 5 H), 6.70-6.33 (in, 1 11), 5.18 (s, 211), 4.23 - 4.13 (in, 211), 3.71 -3.46 (in, 211), 3.28 -3.26 (in,] Fl), 2.55 -2.44 (obs. m, 31-i).
S5-cffloro-2-1H-tetro1-1- yflphenyl l-2-methvi-6-oxo-I (6H)-pyrimidinvl}methyl)-1 H-imidazol-5-1c&ate The compound prepared in Example 325 (39 mg) was treated as detailed in Example 4410 give the title compound having the following physical properties (II mg).
TLC RI 0.83 (5% methanol in ethyl acetate) H NMR (300 MHz, DMSO-d6) 6 12.84 (s, 1 H), 9.88 (s, 1 H), 9.74 (s, 1 H), 8.01 (d, I H), 7.91 -7.71 (in, 2 H). 7.69-7.34 (in, 4 H), 6.51 (s, 1 H), 5.17 (s, 2 H), 4.28 -4.13 (in, 211), 3.6? -3.49 (in, 2 H), 3.29 (s, 3 11), 2.39 (s, 3 H).
Example 327: 3-4 1 5-(6-amino-3pyridinyF)-l Fl-imidazol-2-yllmethyl}-645-chloro-2-fldinone The same operation as in Example 24 -. Example 25 -. Example 38 -.
Example 39 was conducted from the compound prepared in Example 322 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 38 in the operation, the compound prepared in Example 193 was used) TLC RI 0.20 (5% methanol in ethyl acetate) 1-1 NMR (300 MHz. DMSO-d6) 8 12.07 (s, I H), 9.73 (s. I Fl), 8.29-8.17 (in, 1 H), 7,98 (s, I 11), 7.92-7.73 (in, 2 H), 7.65 (d, 2 H), 7.31 (s, 1 11), 6.52 (s, 1 1-1), 6.42 (d, I H), 5.78 (d, 1 H), 5.17 (s, 2 H), 2.55-2.44 (obs. in, 3 H).
xample 328: 3-{[S-(6-antho-3-pyjjpy1)-4-chioro-lH-imidazol-2-ylImethyl}-6-15-ehloro-2- ( 1 H-tetrazol-1 -yflphenyl-2-methy1-4(3H)-pyrimidinone The compound prepared in Example 327 (30 mg) was treated as detailed in Example 44 to give the title compound having the following physical properties (7 mg).
TLC Rf 062(5% methanol in ethyl acetate) H NMR (300 MHz, methanol-cl4) 6 9.44 (s, I H), 8.18 (d, 1 H), 8.03 -7.85 (m, 1 H), 7.84 -7.56 (m, 3 H), 6.64 (dd, I H), 6.50 (s, I H), 5.25 (s, 2 H), 2.46 (s, 3 H).
Example 329: (6S)-64546-aino-2-fluom3-pvddinyfl-1H-imidazqjy]j-2-[5-chloro- 2-( 1 H-tetrazol-1 -yl)phenyll-7,8-dihydropyrrolo[ 1,2-apyrimidin-4(6H)-one JNIJTJI1T NH2 The same operation as in Example 8 -. Example 9 -f Example Si -Example 52 was conducted from the compound prepared in Example 35 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 215 was used).
LCIMS tR 2.86 minutes; MS (ES) In/z 491 (M+il)' H NMR (300 MH2, DMSO-d) 5 12.22 (hr. s, I H), 9.73 (s, 1 II), 7.99 (dd, I 10, 7.96 (ci, I H), 7.S5 (dcl, 1 H), 7.82 (d, I H), 7.11 (d, I H). 6.36 (dcl, I H), 6.35 (s, 1 H), 6.26 (br. s, 2 H), 5.62 (dd, I H), 3.18 (ddd, 1 H), 2.76 (ddd, 1 H), 2.59-2.52 (ohs. m, 1 H), 2.24-2.16(rn, 1 H).
Example 330: (6S)-6-f5-(6-aino-3-pyiidinyfl-4-chlorojmidazol-2-yll-2-f5-ehloro- 24 IH-tetrazol-1 -yF)phenyi]-7,8-dihydropyrrolofl,2-alpyrimidin-4(6H)-one The same operation as in Example 8 -Example 9 -Example 51 -Example 52 -. Example 44 was conducted from the compound prepared in Example 35 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 193 was used).
LCIMS r 2.78 minutes; MS (IES) m/z 507 (M+H)" H NMR (300 MHz, methanol-d4) 3 9.45 (s, I H), 8.20 (d, I Fl), 7.92 (d, I Fl), 7.80 - 7.73 (m, 2 H), 7.70 (d, 1 H), 6.65 (d, 1 H), 6.36 (s. 1 H), 5.65 (ild, I H). 3.30 -3.22 (in, tO 1 H), 2.91 ddd, 1 H), 2.67 (dq, I H), 2.34 (ddt, 1 H).
Example 331: (6S)-6-[5-(6-amino-2-chloro3-pyridinyfl-1H-imidazol-2-ylI-2-[5-ch1oro 2-(IIH-tetrazol-I -yl)phenyI-7,8-dihydropyrrolo I,2-alpyrimidin-4(6Ffl-one The same operation in Example 8 Example 9 Example 51 Example 52 was conducted from the compound prepared in Example 35 to give the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 209 was used).
TLC Rf 0.40(10% methanol in ethyl acetate) H NMR (300 MHz, DMSO-d) 3 ppm 12.23 (s, 1 H), 9.71 (s, I H), 8.02 -7.91 (m, 2 1-1), 7.88 -7.72 (m, 2 II), 7.42 (d, I H), 6.55 -6.24 (m, 4 H), 5.62 (dd, I H), 3.25 -3.07 (m, 1 H), 2.83 -2.66 (in, I H), 2.59-2.52 (ohs. in, LII), 2.31 -2.13 (in, 1 H).
Example 332: 2-methoxyethyl [6-(4-ehloro-2-{(6S)-2-15-chloro-2-(l H-tetrazol-1- yl)phenyll-4-oxo-4,6,7.8-tetrahvdropyrrolo[ 1,2-a]pyrimidin-6-yl} -1 fl-imidazol-5-yl)-3-pvridinyllcarbamate -CH3 The same operation as Example 8 -. Example 9 -. Example 51 -Example 52 Example 55 -. Example 128 -÷ Example 44 was conducted from the compound prepared in Example 35 to obtain the title compound having the following physical properties. (Note: in the step corresponding to Example 51 in the operation, the compound prepared in Example 219 was used. In the step corresponding to Example 128 in the operation, 2-methoxyethyl chlorofonnate was used).
LC/MS tR 3.87 minutes; MS (ES) ,n/z 609 (M+H) b H NMR (500 MHz, DMSO-d6) 5 13.09 (br. s, 1 1-1), 10.12 (hr. s, 1 H), 9.73 (s, 1 1-1), 8.76 (d, 1 H), 8.00 (d, J H), 7.96 (dd, 1 H), 7.91 (d, 1 H), 7.86 (dd, 1 H), 7.82 (d, 1 H), 6.33 (s, I H), 5.65 (ad, I H), 4.25 (dd, 2 H), 3.61 -3.57 (m, 2 H), 3.30 (s, 3 H), 3.08 (td, I H), 2.77 (ddd, I H), 2.60-2.53 (m, I H), 2.18-2.08 (m, I H).
PHARMACOLOGICAL ACTIVITIES
The compounds of the present invention possess Factor XIa inhibitory activity and oral bioavailability, for example, such an effect of the compounds of the present invention was confirmed by the following tests.
All the procedures were conducted by conventionally used techniques on the basis of basic biological methods. Furthermore, the measuring method of the present invention was modified to improve the accuracy andlor sensitivity of measurement for evaluating the compound of the present invention. The detailed experimental method was as follows.
EXPERIMENTAL METHOD S 221
troAssa Inhibitory activities of compounds of the present invention against factor Xla, Xa, XlIa, IXa, VIla, plasma kallikrein or thrornbin were evaluated using appropriate purified proteases and synthetic substrates. The rate of hydrolysis of the chromogenic substrate by the relevant protease was continuously measured at 405 nm.
Irthibitory activity against each enzyme was calculated as % inhibition using the equation described below.
% Inhibition = [(rate without compound)-(ratc with compotmd)]/(rate without compound)] 100%.
Each half maximal inhibitory concentration (1C50) value was determined by plotting the concentration of compound of the invention against the % inhibition.
QJ) Factor Xla enzyme activity Human Factor Xla (l-Iaematologic Technologies Inc.) activity was measured at an enzyme concentration of 0.1 UIrnL in 150mM NaCI, 5 mM KC1, I mglmL PEG6000, 50 mM HEPES-NaOH (p147.4) with 300 1.tM 5-2366 (pyroolu-Pro-Arg-pNA, Chromogenix), (1-2)P1asmaka1liheineeactivi Human plasma kallikrein (Enzyme Research Laboratories Lid) activity was measured at an enzyme concentration of 0605 mU!mL in 200mM NaCI, 5 mglmL PEG6000, 100 imM Phosphate-NaOH (p147.4) with 150 1tM 5-2302 (H-D-Pro-Phe-Arg-pNA, Chromogenix).
(1-3) Factor Xa and thrombin enzyme activity Human Factor Xa (American Diagnostica Inc.) and human thrombin (Sigma) activities were measured at the enzyme concentrations of 0.18 U(mL and 0.12 U/niL, respectively in the same buffer containing 150mM NaCI, 2 mg/niL PEG6000, 50mM Tris-HCI (pH7.4), except that the reactions were started with 300 1sM 3-2222 (phenyl-IIe-Glu-Cfly-Arg-pNA, Chromogenix) and 300 jsM 3-2366, respectively.
fl4) Factor XIIa enzyme4jyiSy Hunrnn Factor cz-XIla (Enzyme Research Laboratories Ltd) activity was measured at an enzyme concentration of 0.17 LJ/mL in 150 mMNaCI, 50mM Tris-HCI (pH7.4) with 300 flM S-2302 (Pro-Phe-Arg-pNA, Chronogenix).
(1-5) Factor IXa enzyme activity Human Factor IXa (American Diagnostica Inc.) activity was measured at an enzyme concentration of 13 U/mL in 100 mM NaCI, 5 mM CaCI2, 30% ethy(ene glycol.
50mM Tris-HCI (pJ-ll.4) with 3 mM Pefachrome IXa 3960 (Leu-Ph'Gly-Arg-pNA, Pee tapharm). to
(1-6) Factor VITa enzyme activity Human Factor ViTa activity was measured using recombinant human Factor VITa (American Diagnostica Inc.) in the presence of recombinant human tissue factor which was produced according to the method described in the literature (Protein expression and purification, 3,453-460 (1992) in a buffer containing 150 mM NaCI, 5 mM CaCI2, 0.5 mg/mL FF06000, 50 mM FIEPES-NaC1 (pH7.4) with 3 mM 5-2288 (lIe-Pro-Arg-pNA, hromogenix).
(1-7) APTT. PT mesurement Activated partial thromboplastin time (APTT) and prothrombin time (PT) were measured using automatic coagulation analyzer (CA-1500, Sysmex Corporation). For the APTT or PT measurement, standard human plasma (Siemens Healthcare Diagnostics Ombil) were mixed with each compound dilutions followed by the automatic addition of APU reagent (Siemens Healiheare Diagnostics OmbU) and 0.02 M calcium chloride or PT reagent (Siemens Healthcare Diagnostics GmbH) to start clot formation. The anticoagulant activities (APTT2 or PT2) of the compounds of the invention were expressed as the concentrations necessary to double the clotting time in vehicle (1% DMSO) group. APTT2 or PT2 was determined by plotting the concentration of compound of the invention against the fold increase of clotting time.
( Rat oral administration test Each compound of the present invention in a solution of 20% wellsolve @eles(e) was given to fasted male Crj:CD(SD)ICIS rats as a single 3 mg/kg, p.o. dose by gavage.
Blood samples were drawn from jugular vein into syringes containing 3.2% sodium citrate (the volume ratio of blood to anticoagulant = 9:1) after oral administration at 0.5, 1. 2, 4 and 6 hours. Plasma was harvested by centrifugation and stored at -20°C until measurement of plasma concentration.
To measure plasma concentrations of the compounds of the present invention, plasma samples were deproteinized with acetonitrile, followed by evaporation of the acetonitrile to dryness. The residual was then re-dissolved with DMSO and its FXTa inhibitory activity was measured by enzyme assay described above. Plasma concentrations of each compound of the present invention were quantitated by generating a standard curve of known compound concentration in rat plasma.
The compounds of the present invention were tested in the Factor XIa assay and the rat oral administration test described above, and found to have a good Factor XIa inhibitory activity and good oral bioavailability. Table 1 described below lists Factor 1 5 XIa 1C50 values measured for the following examples.
Table 1
In vitro FXIa inhibitory activity
Example No
1C50 (jiM) 41 0.0065 0.015 57 0.0024 0.0072 61 0.014 86 0.0039 129(2) 0.0046 181 0.047 198 0.0015 210 0.0028 216 0.0038 230 0.011 241 0.0048 245 0.017 264 0.0061 270 OO1l 278 0.0057 290 0.0025 -309 0.0083 310 0.0049 Comparative experiments CompEx 1, Ex2, Ex3 and Ex4 as comparative compounds are prepared according to the reported preparation in W020071070826 (Ex.64 and Ex254), W02008/076805 S (Ex. 1) and W020091076337 (Ex. 1). The comparative compounds were also tested in the Factor XIa assay and the rat oral administration test described above. Table 2 described below lists Factor XIa IC 50 values and plasma concentrations measured for the comparative compounds and the typical compound of the present invention.
Table2
In vitro FXIa rat plasma concentration
Example inhibitory
Structure after po administration No activity Cmax (pM) at 3mpk ICSO QtM) 0.015 1.25
CL -0
o hx0 I 41 0.0065 2.28 Comp a, H 00036 0.015 ExI ° ti-3 01, Comp 0.040 0.025 /1 Comp 0.130 o.ogg Ex 3 Comp. H Ex >10 Not tested As a result, the compounds of the present invention showed good oral bioavailability compared with the comparative compounds described above.
Therefore, the results indicated that the compounds of the present invention possess Factor XIa inhibitory activity, with good oral bioavailability.
Formulation example I The following components were admixed in conventional method and punched out to obtain 10,000 tablets each containing 10 mg of active ingredient.
methyl [4-(2-{(3 S)-7-15-chloro-2-(1 H-tetrazol-1 -yl)phenyfl-5-oxo-1,2,3,5-tetrahydro-3-indolizinyl) -5-methyl-I H-iinidazol-4-yl)phenyl]carbamate 100 g Carboxymethylcellulose calcium (disintegrating agent) 20 g Magnesium stearate (lubricating agent) 10 g Microcrystalline cellulose 870 g Foimulation example 2 * 226 The following components were admixed in conventional method. The solution was sterilized in conventional manner, filtered through dust removal equipment, placed mL portions into ampouks and sterilized by autoclave to obtain 10,000 anipoules each containing 20 mg of the active ingredient.
methyl [4-(2-{(3S)-7-[5-cMoro-2-(IFJ-tetrazol-l-yl)phenyl]-5-oxo-l,2,3, 5-tetrahydro-3-indolizinyl}-5-methyl-I H-imidazol-4-yl)phenyl]carbamate 200 g mannitot 20 g distilled water 50 L
INDUSTRIAL APPLICABILITY
The compounds of the present invention represented by formula (I) act as potent and selective inhibitors of Factor Xla, with good oral availability. In particular, the compounds of' the present invention act as a Factor XIa inhibitor or a Factor Xla and plasma kallikrein dual inhibitor. Thus the compounds of the present invention are usef\il in preventing and/or treating thromboembolic diseases, for exanple arterial cardiovascular thromboembolie disorders, venous cardiovascular thromboembolie disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders and thromboembolie disorders in the chambers of the heart or in the peripheral circulation. The compound of the present invention is therefore useful as a medicament.

Claims (1)

  1. <claim-text>CLAIMS1. A compound represented by formula (I): V N > ( R cLlRl) wherein Cyc' represents C3-C8 cycloalkyl, S-to lO-membered heterocycloalkyl, CS-ClO aryl or 5-to lO-membered heteroaryl; Cyc2 represents C3-C8 cycloalkyl, 5-to lO-membered heterocycloalkyl, C5-C1O aryl or 5-or 6-membered heteroaryl; Cyc3 represents C3-C8 cycloa)kyl, 5-to I 0-membered heterocycloalkyl, C5-C1O aryl or 5-to JO-membered heteroarvi; each R' may be the same or different and represents (1) Cl-S alkyl, (2) C2-S alkenyl, (3) C2-S alkynyl, (4) halogen. (5) nitro, (6) cyano, (7) oxo. (8) amidino, (9) -C 1-8 alkyl-OR8, (10) -OR9, (11) -COOR°, (12) -0-4 alkyl-COOR11, (13) -NHC(O)-C1-4 alkyl or (14) -NHC(O)O-R'2, wherein R8, R9, R°, R" and R12 each independently represents (1) hydrogen, (2) Cl- S alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C3-CS cycloalkyl, (6) 5-to 10-membered heterocycloalkyl, (7) CS-CIa aryl, (8) 5-to IO-rnenthered heteroaryl or (9) C1-4 alkyl substituted with Ito 5 groups selected from C3-CS cycloalkyl, 5-to 10-memberS heterocycloalkyl, CS-dO aryl and 5-to 1O-rnembered heteroaryl; s represents an integer of 0 to 6; R2 represents (1) hydrogen, (2) Cl-S alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) dye4 or (6) Cl-S alkyl, C2-8 alkenyl or C2-8 alkyny), which are substituted with Ito 5 groups selected from halogen, niiro, trifluoromethyl, cyano. Cyc5, -NR'3R'4, ORls, -SR16, -NI-LC(O)-Cyc6, -NHC(O)-CI-8 alkyl, -NUC(O)O-R17 and Cyc5 substituted with 1 to 3 groups selected from 0-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, halogen, nitro, trifluoromethyt, cyano, oxo, amidino and -OR, wherein R'3, R'4, R15, R!6, R'7 and R'8 each independently represents (1) hydrogen, (2) Cl-S alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C3-C8 cycloalkyl, (6) 5-to 10-membered heterocycloalkyl, (7) CS-C 10 aryl, (8) 5-to lO-membered heteroaryl or (9) CIA alkyl substituted with Ito 5 groups selected from C3-C8 eycloalkyl, 5-to 10-membered heterocycloalkyl, CS-dO aryl and 5-to lO-membered heteroaryl, wherein Cyc4, Cyc5 and dye6 each independently represents C3-C8 cycloalkyl. 5-to IG-membered heterocyeloalkyl, C5-Cl0 aryl or 5-to lO-membered heteroaryl; R3 represents (1) hydrogen, (2) Cl-S alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) dye7 or (6) Cl-S alkyl, C2-8 alkenyl or C2-8 alkynyl, which are substituted with 1 to 5 groups selected from halogen, nitro, tritluoromethyl, cyano, dye8. -NR'9R20. -OR21, -SR22. -NHC(O)-Cyc9, -NHC(O)-C1-8 alkyl, -NHC(O)O-R23 and Cyc8 substituted with 1 to 3 groups selected from Cl-S alkyl, C2-S ailcenyl, C2-8 alkynyl, halogen, thtro, trifluoromethyl, cyano, oxo, aniidino and -OR24, wherein R19, R20, R21, R, R23 and R24 each independently represents (1) hydrogen, (2) Cl-S alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C3-C8 cycloalkyl, (6) 5-to 10-inembered heterocycloalkyl, (7) CS-C 10 aryl, (8) 5-to lO-membered heteroaryl or (9) Cl-4 alkyl substituted with ito 5 groups selected from C3-C8 cycloalkyl, 5-to 10-membered heterocycloalkyl, CS-C 10 aryl and 5-to lO-membered heteroaryl, wherein Cyc', Cyc8 and dye9 each independently represents C3-CS cycloalkyl, 5-to 10-membered heterocycloalkyl, CS-C 10 aryl or 5-to lO-membered heteroaryl; 1' represents N or C(R5); R4 and R5 each independently represents (1) hydrogen, (2) halogen, (3) C1-4 alkyl, (4) C3-C8 cycloalkyl, (5) 5-to lO-membered heterocycloalkyl, (6) C5-C1O aryl, (7) 5-to lO-meinbered heteroaryl or (5) Cl-4 alkyl substituted with ito 5 groups selected from C3-C8 cycloalkyl, 5-to lO-membered heterocycloalkyl, C5-C10 my! and 5-to 10-membered heteroary]; R2 and R3 may be taken together to form C2-S alkylene; or R3 and R4 may be taken together to form C2-8 alkylene; wherein one carbon of the alkylerie chain may be replaced by oxygen or sulfur; each R6 may be the same or different and represents (I) Cl-S alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) dye10, (5) halogen, (6) nitro, (7) cyano, (8) oxo. (9) amidino, (10) - OR25, (11) -C00R26, (12) -C1-4 alkyl-C00R27, (13) -NHC(O)-Ci-4 alkyl, (14)- NHC(O)-H, (1 5) -N1-IC(O)O-R28, (16) tthluoromethyl, (17) -NRCINH)NH2, (18) -C(O)-C1-4 alkyl or (19) Cyc'° substituted with ito 5 groups selected from Cl-S aikyl, C2-8 alkenyl, C2-8 alkynyl, halogen, nitro, trifluoromethyl, cyano, oxo, amidino, -OR29, -SR30. -NR31R32, -NHC(O)NR33R4, -NHC(O)-Cl-4 alkyl-COOH, -NH-S(O)-C1-4 alkyl, -NH-S(O)2-C 1-4 alkyl, -C00R35, -NHC(O)-R36, -NHC(O)O-R37, -C(O)NH-R38 S and -OC(O)NH-R39, wherein Cy&° represents C3-C8 cycloalkyl, 5-to lO-membered heterocycloalkyl, CS-Ci 0 aryl or 5-to I 0-membered heteroaryl; wherein R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38 and R39 each independently represents (1) hydrogen, (2) Cl-S alkyl, (3) C2-8 alkenyl, (4) C2-8 alkynyl, (5) C3 -C8 cycloalkyl, (6) 5-to 1 0-membered heterocycloalkyl, (7) CS-C 10 aryl, (8)5-to lO-membered heteroaryl or (9) 0-4 alkyl substituted with ito 5 groups selected from C3-c8 cycloalkyl. 5-to lO-membered heterocycloalkyl, C5-C1O aryl and 5-to I 0-membereci heteroaryl; in represents an integer of 0 to 6; each R' may be the same or different and represents (1) C1-8 alkyi, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) halogen, (5) nitro, (6) trifluoromethyl, (7) cyano, (8) oxo, (9) amidino, (10) -OR40, (11)-SR41. (12) -NR42R43, (13) -NHC(O)NRR45, (14) -NHC(O)-CI -4 alkyl-NR46R47, (15) -NHC(O)-C1 -4 alkyl-COOH, (16) -NH-S(O)-C1 -4 alkyl, (17) -NH-S(O)2-C1-4 alkyl, (18) -C00R48, (19) -NHC(O)-R49, (20) -NHC(O)-C1-4 alkyl- OR50, (21) -NHC(O)O-R51, (22) -NHC(O)O-C1-4 alkyl-0R52, (23) -C(O)NH-R53, (24) - OC(O)NH-R54, (25) -OC(O)-R55, (26) -C(O)-R56, (27) -CH(OI-I)-R57, (28) -C1-4 alkyl- NH2, (29) -C 1-4 alkyl-OH, (30) -C 1-4 alkyl-OC(O)-C 1-4 alkyl, (31) -C 1-4 alkyl- NHC(O)-C1-4 alkyl, (32) -Cl-4 alkyl-NHC(O)O-C1-4 alkyl, (33) -C1-4 alkyl-NHC(O)-CF3. (34) -C1-4 alkyl-NHC(O)NH-C1-4 alkyl, or (35) -CHN-0R58, wherein R40. R41, R42, R43, R44, R45, R46, R47, R48. R49, R50, R51, R52, R53, R54, R55, R56, R57 and R58 each independently represents (1) hydrogen, (2) trifluoromethyl, (3) C1-8 alkyl, (4) C2-8 alkenyl, (5) C2-8 alkynyl, (6) C3-C8 cycloalkyl, (7)5-to lO-membered heterocycloalkyl, (8) CS-C 10 aryl, (9) 5-to I 0-membered heteroaryl or (10) C 1-4 alkyl substituted with I to 5 groups selected from C3-C8 cycloalkyl, 5-to lO-meinbered heterocycloalkyl, C5-C10 aryl and 5-to lO-membered heteroaryl; and n represents an integer of 0 to 6; a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.</claim-text> <claim-text>2. The compound according to claim 1, wherein the compound represented by formula (I) represents a compound represented by formula (I-A): (I-A) (R6)mJJ wherein U represents S or CH2; and the other symbols have the same meanings as described in claim 1.</claim-text> <claim-text>3. The compound according to claim 1, wherein the compound represented by formula (I) represents a compound represented by formula (I-B): (I-B) wherein Cyc' represents 5-to I O-membered heteroaryl; Cyc3a represents cs-Cm aryl or 5-to 10-membered heteroaryl; Cye'° represents (1) 5-to lO-membered heteroaryl or (2) 5-to lO-membered heteroaryl substituted with I to 5 groups selected from halogen, cyano, nitro, trifluoromethyl, -COOH, -COO-C 1-4 alkyl and -CONH2; mb represents an integer of 0 to 5; and the other symbols have the same meanings as described in claim I. 4. The compound according to claim 1, wherein the compound represented by formula (I) represents a compound represented by formula (1-C): wherein Cyc represents 5-to lO-membered heteroaryl; Cyc3 represents CS-C 10 aryl or 5-to lO-membered heteroaryl; Cyc10 represents (1) 5-to lO-membered heteroaryl or (2) 5-to lO-membered heteroaryl substituted with 1 to 5 groups selected from halogen, cyano, nitro, trifluoromethyl, -COOH, -COO-C 1-4 alkyl and -CONH2; mc represents an integer of 0 to 5; and the other symbols have the same meanings as described in claim 1.5. The compound according to claim I or 2, wherein Cyc1 represents phenyl, iniidazolyl, triazolyl, pyrrolyl, pyrazolyl, furanyl. oxazolyl, thiazolyl, isothiazoly!, thrazanyl, oxadiazolyl, thiadiazolyl, thienyl, pyridazinyl, indazolyl or benzimidazolyl.6. The compound according to claim 3, wherein Cyc represents imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridazinyl, indazolyl or benzirnidazolyl.7. The compound according to claim 4, wherein Cyc represents iniiclazolyl, triazolyl, tetrazolyt, oxazolyl, pyridazinyl. indazolyl or benzimidazolyl.8. The compound according to claim 1 or claim 2, wherein represents MN7 MN HN MN7 MN7 HN 51R') cR7) ç[(Wh. ç1AW)n L)R' 4)4N wherein R59 represents hydrogen, C1-4 alkyl or halogen; the arrow represents a binding position; and the other symbols have the same meanings as described in claim 1.9. The compound according to any one of claims 1 to 8, wherein Cyc2 represents pyridyl or phenyl.10. The compound according to any one of claims ito 9, wherein -Cyc2-(R6), Cyc2(-R6) nibCYC' or Cyc2(-R6) mcCyc° represents R61N-S N-NII Ii\\ N NN,,) NN/ wherein R6° represents hydrogen, methyl or halogen; R61 represents (1) hydrogen, (2) halogen, (3) nitro, (4) trifluoromethyl, (5) -COOFI, (6) -COO-C 1-4 alkyl, (7) cyano or (8) -CONH2; and the arrow represents a binding position.11. A pharmaceutical composition which comprises the compound according to any one of claims Ito 10, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof 12. The pharmaceutical composition according to claim 11, which is a factor XIa inhibitor or a factor XIa and plasma kallikrein dual inhibitor.13. The pharmaceutical composition according to claim 12, which is an agent for the treatment or prevention of a thromboembolic disease.14. The compound according to any one of claims I to 10 for use in the treatment of the human or animal body by therapy.15. The compound according to any one of claims I to 10 for use in treating or preventing a thromboembolic disease.] 6. The compound for use according to claim 15, wherein the thromboembolic disease is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular tljromboembolic disorders, arterial cerebrovascular thromboembolic disorders, venous cerebrovascular thromboembolic disorders and thromboembolic disorders in the chambers of the heart or in the peripheral circulation.17. The compound for use according to claim 16, wherein the thromboembolic disease is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophiebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting frommedical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.18. A method for treating a patient suffering from or susceptible to a thromboernbolic disease, which method comprises administering to said patient a therapeutically effective amount of a compound according to any one of claims I to 10.19. Use of a compound according to any one of claims I to 10, in the manufacture of a medicament for use in treating or preventing a thromboembolic disease.</claim-text>
GB1122139.7A 2011-12-21 2011-12-21 Pyridinone and pyrimidinone derivatives as factor XIa inhibitors Withdrawn GB2497806A (en)

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GB1122139.7A GB2497806A (en) 2011-12-21 2011-12-21 Pyridinone and pyrimidinone derivatives as factor XIa inhibitors
AU2012356374A AU2012356374B2 (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor XIa inhibitors
PCT/GB2012/053217 WO2013093484A1 (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor xia inhibitors
ES12813423.6T ES2655669T3 (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as inhibitors of factor XIa
NZ626176A NZ626176B2 (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor xia inhibitors
MX2014007269A MX351471B (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor xia inhibitors.
PL12813423T PL2794597T3 (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor xia inhibitors
PT128134236T PT2794597T (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor xia inhibitors
KR1020147016952A KR102011534B1 (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor xia inhibitors
HUE12813423A HUE036010T2 (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor xia inhibitors
US14/366,396 US9732085B2 (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor Xia
JP2014548196A JP6137193B2 (en) 2011-12-21 2012-12-20 Novel pyridinone and pyrimidinone derivatives as factor XIa inhibitors
TW101148629A TWI613199B (en) 2011-12-21 2012-12-20 Compounds
CN201280070352.3A CN104136431B (en) 2011-12-21 2012-12-20 Pyridone and pyrimidone derivatives as plasma thromboplastin antecedent a inhibitor
EP12813423.6A EP2794597B1 (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor xia inhibitors
EP17193874.9A EP3290413B9 (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor xia inhibitors
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DK12813423.6T DK2794597T3 (en) 2011-12-21 2012-12-20 PYRIDINON AND PYRIMIDINON DERIVATIVES AS FACTOR XIA INHIBITORS
RU2014129797A RU2630677C2 (en) 2011-12-21 2012-12-20 Compounds
ES17193874T ES2765891T3 (en) 2011-12-21 2012-12-20 Pyridinone and pyrimidinone derivatives as factor XIa inhibitors
BR112014015669-7A BR112014015669B1 (en) 2011-12-21 2012-12-20 COMPOUNDS DERIVED FROM PYRIDINONE AND PYRIMIDINONE, PHARMACEUTICAL COMPOSITION INCLUDING THE SAID COMPOUNDS AND THEIR USE FOR THE TREATMENT OR PREVENTION OF A THROMBOEMBOLIC DISEASE
NO12813423A NO2794597T3 (en) 2011-12-21 2012-12-20
SG11201403402VA SG11201403402VA (en) 2011-12-21 2012-12-20 Compounds
CA2859604A CA2859604C (en) 2011-12-21 2012-12-20 Compounds
PH12014501365A PH12014501365B1 (en) 2011-12-21 2014-06-16 Compounds
IL233154A IL233154A (en) 2011-12-21 2014-06-16 Compounds, pharmaceutical compositions comprising the same and uses thereof
HK14111900.0A HK1198386A1 (en) 2011-12-21 2014-11-25 Pyridinone and pyrimidinone derivatives as factor xia inhibitors xia
JP2017091408A JP6447660B2 (en) 2011-12-21 2017-05-01 Novel pyridinone and pyrimidinone derivatives as factor XIa inhibitors
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