Process for the preparation of chymase modulators

A process for the preparation of a compound of formula (I)

• wherein
• is independently selected from the group consisting of aryl, heteroaryl, and benzo fused heterocyclyl;
• optionally substituted with R2 and R3;
• R2 is one to three substituents independently selected from the group consisting of C1-4alkyl, methoxy, C2-6alkoxy, NH2, NH(C1-6alkyl), —N(C1-6)dialkyl, aryl, heteroaryl, halogen, hydroxy, and nitro;
• wherein the C1-4alkyl and C2-6 alkoxy 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 substituents independently selected from the group consisting of hydrogen, C1-6 alkyl, and aryl;
• wherein the C1-6alkyl substituent of R11 or R12 is optionally substituted with a substituent selected from the group consisting of hydroxy, aryl, —C(═O)C 1-4alkoxy, and —NR15R16;
• wherein said R15 and R16 are substituents independently selected from the group consisting of hydrogen, C1-6 alkyl, and aryl,
• alternatively, R15 and R16 are 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, C1-6alkoxy, —OCH2(C2-6)alkenyl, NH2, —NH(C1-6alkyl), —N(C1-6)dialkyl, —NHC(═O)Cy, —N(C1-6alkyl)C(═O)Cy, —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(═)NR19R20, halogen, hydroxy, nitro, cyano, aryl, and aryloxy;
• wherein alkyl and alkoxy are optionally substituted with one to three substituents independently selected from the group consisting of —NR21R22, —NHcycloalkyl, —N(C1-6alkyl)cycloalkyl, —NHCy, —N(C1-6alkyl)Cy, aryl, heteroaryl, halogen, —C(═O)NR23R24, —OC(═O)NR25R26, —C(═O)(C1-4)alkoxy, and —C(═O)Cy;
• wherein alkenyl is optionally substituted on a terminal carbon with aryl and —C(═O)NR27R28;
• and, wherein aryl and cycloalkyl are optionally substituted with one to three substituents independently selected from R14;
• each 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;
• wherein 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;
• R17, R 18, R19, R20, R21, R22, R23, R24, R25 and R26 are substituents independently selected from the group consisting of hydrogen, C1-6alkyl and aryl;
• wherein the C1-6alkyl and aryl are each optionally substituted with hydroxy, aryl, aryloxy, —C(═O)-aryl, —C(═O)C1-4alkoxy, NH2, —NH(C1-6alkyl), or —N(C1-6)dialkyl;
• alternatively, R17 and R18, R19 and R20, R21 and R22, R23 and R24 or R25 and R26 are taken together with the atoms to which they are attached to form a ring of five to seven members;
• R27 and R28 are independently hydrogen;
• C1-6alkyl optionally substituted with hydroxy, aryl, —C(═O)C1-4alkoxy, NH2, —NH(C1-6alkyl) or —N(C1-6)dialkyl;
• or aryl;
• alternatively, R27 and R28 are taken together with the atoms to which they are attached to form a ring of five to seven members;
• R29 and R30 are independently hydrogen, C1-6alkyl optionally substituted with hydroxy, aryl, —C(═O)C1-4alkoxy, NH2, —NH(C1-6alkyl), or —N(C1-6)dialkyl;
• or aryl;
• alternatively, R29 and R30 are 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 C1-6 alkyl, C1-6alkyl(═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 aryl and the aryl portion of the C1-6alkylC(═O)aryl, —C(═O)aryl and —SO2aryl are optionally substituted with one to three substituents independently selected from the group consisting of C1-6alkyl, C1-6alkoxy, halogen, hydroxy, NH2, NH(C1-6alkyl), or —N(C1-6)dialkyl;
• and wherein heterocyclyl is optionally substituted with aryl, one to three halogen atoms, or one to three oxo substituents;
• and, wherein heterocyclyl is optionally spiro-fused to said Cy;
• R5 is selected from the group consisting of hydrogen;
• C1-3alkyl optionally substituted with NH2, —NH(C1-6)alkyl, —N(C1-6)dialkyl, 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, C2-6 alkenyl, —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;
• and provided that R5 is other than C1-3alkyl substituted with di(C1-6)alkylamino-carbonyl when ring system A is 3,4-difluoro-phenyl, R6 is OH, and Z—R4 is 5-chloro-benzothiophen-3-yl;
• and provided that R5 is other than C1-3alkyl substituted with C1-6alkylcarbonylthio when ring system A is 3,4-difluoro-phenyl, R6 is CH3, and Z—R4 is 5-chloro-benzothiophen-3-yl;
• R6 is selected from the group consisting of C1-6alkyl, C1-8alkoxy, heteroaryl, aryl, and hydroxy;
• wherein alkyl and C1-8alkoxy are optionally substituted on a terminal carbon atom with a substituent selected from C1-3alkoxy, aryl, or hydroxy;
• and alkoxy is optionally substituted on a terminal carbon with a substituent independently selected from the group consisting of C1-6alkylcarbonyloxy, and di(C1-6)alkylaminocarbonyl;
• and wherein heteroaryl and aryl are optionally substituted with one to three substituents independently selected from the group consisting of aryl, hydroxy, C1-6alkoxy, and halogen;
• Z is a bicyclic aryl or bicyclic heteroaryl;
• R4 is one to three substituents selected from the group consisting of H, C1-6alkyl, C1-6alkenyl, C1-6alkoxy, aryl(C2-6)alkenyl, halogen, —C(═O)Cy, —C(═O)NR31R32, aryl, —CO2H, oxo, and cyano;
• wherein the alkyl and alkoxy are optionally substituted with a substituent independently selected from the group consisting of —NR33R34, aryl, one to three halogen atoms, and hydroxy;
• wherein the aryl is optionally substituted with a substituent independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxy, aryl, halogen, 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;
• or R31 with R32, or R33 with R34 are optionally taken together with the atoms to which they are attached to form a ring of five to seven members;
• or a pharmaceutically acceptable salt thereof;
• comprising the steps of
• (a) reacting a compound of formula (IV), wherein PG1 is an oxygen protecting group;
• with a source of nitrogen;
• in the presence of CO2 gas;
• in an organic solvent;
• to yield the corresponding compound of formula (IX);
• (b) reacting the compound of formula (IX) with a compound of formula (XVI);
• in the presence of CuI;
• in the presence of an inorganic base;
• in the presence of a ligand;
• in an organic solvent or mixture thereof;
• to yield the corresponding compound of formula (XVII);
• (c) de-protecting the compound of formula (XVII);
• to yield the corresponding compound of formula (Ia);
• and
• (d) optionally reacting the compound of formula (Ia) with a compound of formula (XVIII), wherein Q1 is a leaving group and wherein R5 is other than hydrogen;
• in the presence of an organic base;
• in an organic solvent;
• to yield the corresponding compound of formula (Ib), wherein R5 is other than hydrogen.