Inhibitors of chymase

A compound of Formula (I)

• wherein
• R1 is selected from the group consisting of hydrogen and C1-4alkyl;
• is selected from the group consisting of aryl, heteroaryl, benzo fused heterocyclyl, cyclopropyl when n is 0 and one of R2 or R3 is phenyl, and benzo fused cycloalkyl, and ring A is optionally substituted with R2 and R3;
• R2 is one to two substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, methoxy, C2-6alkoxy, C1-6alkylthio, —OCF3, —NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro;
• furthermore, R2 is optionally oxo when ring A is heteroaryl or benzo fused heterocyclyl;
• and, wherein any aryl-containing substituent of R2 is optionally substituted with a substituent independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6 alkenyl, C1-6alkylthio, —NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro;
• and, wherein any of the foregoing C1-6alkyl or C2-6alkoxy containing substituents of R2 are optionally substituted with a substituent independently selected from the group consisting of —NR11R12, aryl, heteroaryl, one to three halogens and hydroxy;
• wherein R11 and R12 are independently hydrogen;
• C1-6 alkyl optionally substituted with hydroxy, aryl, —C(═O)C1-4alkoxy, or —NR15R16;
• or aryl;
• R15 and R16 are substituents independently selected from the group consisting of hydrogen, C1-6 alkyl, and aryl, and said R15 and R16 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
• R3 is one to three substituents independently selected from the group consisting of C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkylthio, —OCF3, —OCH2(C2-6)alkenyl, —NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, —NHC(═O)Cy, —N(C1-6alkyl)C(═O)Cy, —(NC(═O))2NH2, —C(═O)C1-4alkoxy, —C(═O)NR17R18, —C(═O)NHcycloalkyl, —C(═O)N(C1-6alkyl)cycloalkyl, —C(═O)NHCy, —C(═O)N(C1-6alkyl)Cy, —C(═O)Cy, —OC(═O)C1-6alkyl, —OC(═O)NR19R20, —C(═O)Oaryl, —C(═O)Oheteroaryl, —CO2H, ureido, halogen, hydroxy, nitro, cyano, aryl, heteroaryl, heteroaryloxy, and aryloxy;
• wherein any of the foregoing C1-6alkyl or C1-6 alkoxy containing substituents of of R3 are optionally substituted with one to three substituents independently selected from the group consisting of —NR21R22, —NH(cycloalkyl), —N(C1-6alkyl)(cycloalkyl), —NHCy, —N(C1-6alkyl)Cy, aryl, heteroaryl, hydroxy, halogen, —C(═O)NR23R24, —OC(═O)NR25R26, —C(═O)C1-4alkoxy, and —C(═O)Cy;
• wherein said R17, R18, R19, R20, R21, R22, R23, R24, R25, R26 are substituents independently selected from the group consisting of hydrogen, C1-6 alkyl, and aryl, wherein C1-6 alkyl is optionally substituted with hydroxy, aryl, —C(═O)C1-4alkoxy, NH2, NH(C1-6alkyl), or —N(C1-6)dialkyl;
• and R17 and R18, R19 and R20, R21 and R22, R23 and R24, and R25 and R26 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
• Cy is a heterocyclyl optionally substituted with a substituent selected from the group consisting of C1-6alkyl, C1-6alkylC(═O)C1-6alkyl, —C1-6alkylC(═O)C1-6alkoxy, C1-6alkylC(═O)aryl, —C(═O)(C1-6)alkyl, —C(═O)(C1-6)alkoxy, —C(═O)aryl, —SO2aryl, aryl, heteroaryl, and heterocyclyl;
• wherein the aryl portion of any aryl-containing substituent of Cy is optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C1-6alkylthio, halogen, hydroxy, NH2, NH(C1-6alkyl), and —N(C1-6)dialkyl;
• and wherein heterocyclyl is optionally substituted with aryl, one to three halogen atoms, or one to three oxo substituents;
• and heterocyclyl is optionally spiro-fused to said Cy;
• and wherein the C1-6alkenyl and C1-6alkynyl substituents of R3 are optionally substituted with aryl or —C(═O)NR27R28;
• wherein said R27 and R28 are independently hydrogen;
• C1-6 alkyl optionally substituted with hydroxy, aryl, —C(═O)C1-4alkoxy, NH2, NH(C1-6alkyl), or —N(C1-6)dialkyl;
• or aryl;
• and R27 and R28 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
• wherein the aryl, heteroaryl, and cycloalkyl substituents of R3 are optionally substituted with one to three substituents independently selected from R14;
• wherein R14 is independently hydrogen, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C1-6alkylthio, —NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro;
• and any one of the foregoing C1-6alkyl- or C1-6alkoxy-containing substituents of R14 is optionally substituted on a terminal carbon atom with a substituent selected from —NR29R30, aryl, heteroaryl, one to three halogen atoms, or hydroxy;
• wherein R29 and R30 are independently hydrogen;
• C1-6 alkyl optionally substituted with hydroxy, aryl, —C(═O)C1-4alkoxy, NH2, NH(C1-6alkyl), or —N(C1-6)dialkyl;
• or aryl;
• and R29 and R30 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
• n is 0 or 1;
• W is O or S;
• X is hydrogen or C1-3alkyl;
• Y is independently selected from SO3H and P(═O)OR5R6;
• R5 is selected from the group consisting of hydrogen;
• C1-6alkyl optionally substituted with NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, 1,3-dioxolan-2-yl, C1-6alkylcarbonyloxy, C1-6alkoxycarbonyloxy, C1-6alkylcarbonylthio, (C1-6)alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, one to three halogens, or hydroxy;
• and aryl optionally substituted with C1-6alkyl, C1-6alkoxy, C1-6alkylthio, C2-6alkenyl, —NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, or nitro;
• alternatively, when R6 is C1-8alkoxy, R5 and R6 are taken together with the atoms to which they are attached to form a 5-8 membered monocyclic ring;
• provided that R5 is other than C1-6alkyl substituted with di(C1-6)alkylamino-carbonyl when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is OH, and Z-R4 is 5-chloro-benzothiophen-3-yl;
• and provided that R5 is other than C1-6alkyl substituted with C1-6alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, n is 1, R6 is CH3, and Z-R4 is 5-chloro-benzothiophen-3-yl;
• R6 is selected from the group consisting of C1-8alkyl, C1-8alkoxy, C2-8alkenyl, heteroaryl, aryl, and hydroxy;
• wherein C1-8alkyl, C1-8alkoxy, and C2-8alkenyl are optionally substituted with a substituent selected from the group consisting of C1-6alkoxy, aryl, heterocyclyl, heteroaryl, NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, C1-6alkyl-carbonyloxy, C1-6alkylcarbonylthio, C1-6alkoxycarbonyloxy, (C1-6)alkylamino-carbonyl, di(C1-6)alkylaminocarbonyl, one to three halogen atoms, and hydroxy;
• and when R6 is C1-8alkyl, said C1-8alkyl is optionally substituted with one to four additional halogen atoms such that one to three halogen atoms are optionally chlorine and one to seven of the halogen atoms are optionally fluorine;
• wherein the heteroaryl and aryl substituents of R6 are optionally substituted with a substituent independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C1-6alkylthio, —NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, halogen, hydroxy, and nitro;
• Z is a seven to fifteen membered monocyclic or polycyclic ring system selected from the group consisting aryl, heteroaryl, benzo fused heterocyclyl, or benzo fused cycloalkyl;
• R4 is one to three substituents selected from the group consisting of:
• H, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, C1-6alkylthio, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, halogen, —C(═O)Cy, —C(═O)NR31R32, aryl, —CO2H, oxo, and cyano;
• wherein C1-6alkyl, C1-6alkenyl and C1-6alkoxy are optionally substituted with —NR33R34, aryl, heteroaryl, cycloalkyl, one to three halogen atoms, or hydroxy;
• and aryl and heteroaryl are each optionally substituted with a substituent independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, C2-6 alkenyl, C1-6alkylthio, —NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, one to three halogen atoms, hydroxy, and nitro;
• wherein said R31, R32, R33, and R34 are substituents independently selected from the group consisting of hydrogen, C1-6 alkyl, and aryl, wherein alkyl is optionally substituted with hydroxy, aryl, —C(═O)C1-4alkoxy, NH2, NH(C1-6alkyl), or —N(C1-6)dialkyl;
• and R31 with R32, and R33 with R34 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
• and pharmaceutically acceptable salts thereof.