Novel phosphonic acid compounds as inhibitors of serine proteases

A compound of Formula (Ia):

• 25
• wherein
• R7 is selected from the group consisting of hydrogen, C1-8 alkyl and C2-8 alkenyl;
• and,
• R8 is selected from the group consisting of:
• aa). C1-8 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, amino (with two substituents independently selected from the group consisting of hydrogen and C1-8 alkyl), (halo)1-3 and hydroxy;
• ab). cycloalkyl;
• ac). cycloalkenyl;
• and,
• ad). heterocyclyl (wherein the point of attachment at R8 is a carbon ring atom);
• wherein the ab). cycloalkyl, ac). cycloalkenyl and ad). heterocyclyl (wherein the ad). heterocyclyl contains at least one nitrogen ring atom) substituents and the cycloalkyl, heterocyclyl, aryl and heteroaryl portions of the aa). substituent are optionally substituted with one to four substituents independently selected from the group consisting of:
• ba). C1-8 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (with two substituents independently selected from the group consisting of hydrogen and C1-8 alkyl), (halo)1-3 and hydroxy;
• bb). C1-8 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of carboxyl, (halo)1-3 and hydroxy;
• bc). carbonyl substituted with a substituent selected from the group consisting of C1-8 alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-8)alkenyl, heteroaryl, heteroaryl(C1-8)alkyl and heteroaryl(C2-8)alkenyl;
• bd). aryl;
• be). heteroaryl;
• bf). amino substituted with two substituents independently selected from the group consisting of hydrogen and C1-8 alkyl;
• bg). cyano;
• bh). halogen;
• bi). hydroxy;
• bj). nitro;
• bk). heterocyclyl optionally substituted with one to two oxo substituents;
• and,
• bl). sulfonyl substituted with a substituent selected from the group consisting of C1-8 alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-8)alkenyl, heteroaryl, heteroaryl(C1-8)alkyl and heteroaryl(C2-8)alkenyl;
• wherein the bd). aryl, be). heteroaryl and bk). heterocyclyl substituents and the aryl and heteroaryl portions of the bc). substituent are optionally substituted with one to four substituents independently selected from the group consisting of C1-4 alkyl (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8 alkyl), (halo)1-3 and hydroxy), C1-4 alkoxy (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of (halo)1-3), amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), halogen, hydroxy and nitro;
• and, provided that the optional substituent attached to the ad). heterocyclyl nitrogen ring atom is not selected from the group consisting of bf). amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8 alkyl), bh). halogen, bi). hydroxy and bj). nitro;
• and isomers, racemates, enantiomers, diastereomers and salts thereof.

A compound of Formula (Ib):

• 26
• wherein
• R1 is a heterocyclyl ring (wherein the point of attachment for the heterocyclyl ring at R1 is a nitrogen ring atom);
• wherein the heterocyclyl ring is optionally substituted with one to two substituents independently selected from the group consisting of:
• a). C1-8 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of aryl, heteroaryl, (halo)1-3 and hydroxy;
• b). C1-8 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of carboxyl, (halo)1-3 and hydroxy;
• c). aryl;
• d). heteroaryl;
• e). cyano;
• f). halogen;
• g). hydroxy;
• h). nitro;
• and,
• i). heterocyclyl optionally substituted with one to two substituents independently selected from the group consisting of oxo and aryl;
• and, optionally fused with the carbon of attachment to form a spiro heterocyclyl moiety;
• and, wherein the aryl portion of the a). and i). substituent, the heteroaryl portion of the a). substituent and the c). aryl and d). heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C1-4 alkoxy, cycloalkyl, heterocyclyl, aryl, aryl(C1-4)alkyl, aryloxy, heteroaryl, heteroaryl(C1-4)alkyl, halogen, hydroxy, nitro, (halo)1-3(C1-4)alkyl and (halo)1-3(C1-4)alkoxy;
• and isomers, racemates, enantiomers, diastereomers and salts thereof.

A compound of Formula (Ic):

• 27
• wherein
• R2 and R3 are attached to a benzene ring and independently selected from the group consisting of
• ca). hydrogen;
• cb). C1-4 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy;
• cc). C1-4 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of (halo)1-3 and hydroxy;
• cd). C2-4 alkenyl;
• ce). amino substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl;
• cf). halogen;
• and,
• cg). hydroxy;
• optionally, R2 and R3 together form at least one ring fused to the benzene ring;
• thereby providing a multiple ring system;
• wherein the multiple ring system is selected from the group consisting of C9-C14 benzo fused cycloalkyl, C9-C14 benzo fused cycloalkenyl, C9-C14 benzo fused aryl, benzo fused heterocyclyl and benzo fused heteroaryl;
• and, wherein the multiple ring system can optionally be substituted with one to four substituents independently selected from the group consisting of
• da). C1-4 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy;
• db). C1-4 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of (halo)1-3 and hydroxy;
• dc). amino substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl;
• dd). halogen;
• de). hydroxy;
• and,
• df). nitro;
• R4 is selected from the group consisting of C1-4 alkyl (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of aryl and heteroaryl), aryl and heteroaryl;
• wherein aryl and heteroaryl and the aryl and heteroaryl portions of the substituted alkyl are optionally substituted with one to four substituents independently selected from the group consisting of C1-4 alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), cyano, halogen, hydroxy and (halo)1-3(C1-8)alkyl;
• R5 is selected from the group consisting of hydrogen and C1-8 alkyl (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy) and aryl (optionally substituted with one to four substituents independently selected from the group consisting of C1-8 alkyl and halogen);
• and,
• R6 is selected from the group consisting of C1-8 alkyl, aryl(C1-8)alkyl, C1-8 alkoxy, aryl(C1-8)alkoxy, C2-8 alkenyl, C2-8 alkenyloxy, aryl(C2-8)alkenyl, aryl(C2-8)alkenyloxy, aryl, aryloxy and hydroxy;
• and isomers, racemates, enantiomers, diastereomers and salts thereof.

A process for preparing a compound of Formula (I) comprising coupling under suitable conditions a first compound of Formula (A):

• 28
• with a second compound selected from the group consisting of Formula (B) and Formula (C):
• 29
• to produce a third compound selected from the group consisting of Formula (D) and Formula (E):
• 30
• wherein
• R7 is selected from the group consisting of hydrogen, C1-8 alkyl and C2-8 alkenyl;
• R8 is selected from the group consisting of:
• aa). C1-8 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8 alkyl), (halo)1-3 and hydroxy;
• ab). cycloalkyl;
• ac). cycloalkenyl;
• and,
• ad). heterocyclyl (wherein the point of attachment at R8 is a carbon ring atom);
• wherein the ab). cycloalkyl, ac). cycloalkenyl and ad). heterocyclyl (wherein the ad). heterocyclyl contains at least one nitrogen ring atom) substituents and the cycloalkyl, heterocyclyl, aryl and heteroaryl portions of the aa). substituent are optionally substituted with one to four substituents independently selected from the group consisting of:
• ba). C1-8 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (with two substituents independently selected from the group consisting of hydrogen and C1-8 alkyl), (halo)1-3 and hydroxy;
• bb). C1-8 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of carboxyl, (halo)1-3 and hydroxy;
• bc). carbonyl substituted with a substituent selected from the group consisting of C1-8 alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-8)alkenyl, heteroaryl, heteroaryl(C1-8)alkyl and heteroaryl(C2-8)alkenyl;
• bd). aryl;
• be). heteroaryl;
• bf). amino substituted with two substituents independently selected from the group consisting of hydrogen and C1-8 alkyl;
• bg). cyano;
• bh). halogen;
• bi). hydroxy;
• bj). nitro;
• bk). heterocyclyl optionally substituted with one to two oxo substituents;
• and,
• bl). sulfonyl substituted with a substituent selected from the group consisting of C1-8 alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-8)alkenyl, heteroaryl, heteroaryl(C1-8)alkyl and heteroaryl(C2-8)alkenyl;
• wherein the bd). aryl, be). heteroaryl and bk). heterocyclyl substituents and the aryl and heteroaryl portions of the bc). substituent are optionally substituted with one to four substituents independently selected from the group consisting of C1-4 alkyl (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8 alkyl), (halo)1-3 and hydroxy), C1-4 alkoxy (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of (halo)1-3), amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), halogen, hydroxy and nitro;
• and, provided that the optional substituent attached to the ad). heterocyclyl nitrogen ring atom is not selected from the group consisting of bf). amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-8 alkyl), bh). halogen, bi). hydroxy and bj). nitro;
• R4 is selected from the group consisting of C1-4 alkyl (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of aryl and heteroaryl), aryl and heteroaryl;
• wherein aryl and heteroaryl and the aryl and heteroaryl portions of the substituted alkyl are optionally substituted with one to four substituents independently selected from the group consisting of C1-4 alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), cyano, halogen, hydroxy and (halo)1-3(C1-8)alkyl;
• R2 and R3 are attached to a benzene ring and independently selected from the group consisting of
• ca). hydrogen;
• cb). C1-4 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy;
• cc). C1-4 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of (halo)1-3 and hydroxy;
• cd). C2-4 alkenyl;
• ce). amino substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl;
• cf). halogen;
• and,
• cg). hydroxy;
• optionally, R2 and R3 together form at least one ring fused to the benzene ring;
• thereby providing a multiple ring system;
• wherein the multiple ring system is selected from the group consisting of C9-C14 benzo fused cycloalkyl, C9-C14 benzo fused cycloalkenyl, C9-C14 benzo fused aryl, benzo fused heterocyclyl and benzo fused heteroaryl;
• and, wherein the multiple ring system can optionally be substituted with one to four substituents independently selected from the group consisting of:
• da). C1-4 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy;
• db). C1-4 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of (halo)1-3 and hydroxy;
• dc). amino substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl;
• dd). halogen;
• de). hydroxy;
• and,
• df). nitro;
• R5 is selected from the group consisting of hydrogen and C1-8 alkyl (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy) and aryl (optionally substituted with one to four substituents independently selected from the group consisting of C1-8 alkyl and halogen);
• R6 is selected from the group consisting of C1-8 alkyl, aryl(C1-8)alkyl, C1-8 alkoxy, aryl(C1-8)alkoxy, C2-8 alkenyl, C2-8 alkenyloxy, aryl(C2-8)alkenyl, aryl(C2-8)alkenyloxy, aryl, aryloxy and hydroxy;
• X is selected from the group consisting of O, S, imino, (C1-4)alkylimino and hydroxyimino;
• and,
• Z is selected from the group consisting of a bond, hydrogen and C1-8 alkyl;
• if Z is a bond (wherein Z forms a double bond with the carbon of attachment for X), then X is selected from the group consisting of hydrogen, C1-8 alkoxy, C2-8 alkenyloxy, aryloxy, aryl(Cl4)alkoxy and hydroxy,
• and isomers, racemates, enantiomers, diastereomers and salts thereof.

A compound of Formula (C):

• 33
• wherein
• R2 and R3 are attached to a benzene ring and independently selected from the group consisting of
• ca). hydrogen;
• cb). C1-4 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy;
• cc). C1-4 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of (halo)1-3 and hydroxy;
• cd). C2-4 alkenyl;
• ce). amino substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl;
• cf). halogen;
• and,
• cg). hydroxy;
• optionally, R2 and R3 together form at least one ring fused to the benzene ring;
• thereby providing a multiple ring system;
• wherein the multiple ring system is selected from the group consisting of C9-C14 benzo fused cycloalkyl, C9-C14 benzo fused cycloalkenyl, C9-C14 benzo fused aryl, benzo fused heterocyclyl and benzo fused heteroaryl;
• and, wherein the multiple ring system can optionally be substituted with one to four substituents independently selected from the group consisting of
• da). C1-4 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy;
• db). C1-4 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of (halo)1-3 and hydroxy;
• dc). amino substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl;
• dd). halogen;
• de). hydroxy;
• and,
• df). nitro;
• R4 is selected from the group consisting of C1-4 alkyl (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of aryl and heteroaryl), aryl and heteroaryl;
• wherein aryl and heteroaryl and the aryl and heteroaryl portions of the substituted alkyl are optionally substituted with one to four substituents independently selected from the group consisting of C1-4 alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), cyano, halogen, hydroxy and (halo)1-3(C1-8)alkyl;
• R5 is selected from the group consisting of hydrogen and C1-8 alkyl (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy) and aryl (optionally substituted with one to four substituents independently selected from the group consisting of C1-8 alkyl and halogen);
• and,
• R6 is selected from the group consisting of C1-8 alkyl, aryl(C1-8)alkyl, C1-8 alkoxy, aryl(C1-8)alkoxy, C2-8 alkenyl, C2-8 alkenyloxy, aryl(C2-8)alkenyl, aryl(C2-8)alkenyloxy, aryl, aryloxy and hydroxy.

A process for making a benzolactone of Formula (C) comprising

• a) reacting an anhydride of Formula (F):
• 34
• with a compound of Formula (G):
• 35
• under suitable conditions in the presence of an alkali metal (M) to provide a compound of Formula (H):
• 36
• b) and, reacting the compound of Formula (H) under conditions suitable to form the benzolactone of Formula (C):
• 37
• wherein
• R2 and R3 are attached to a benzene ring and independently selected from the group consisting of
• ca). hydrogen;
• cb). C1-4 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy;
• cc). C1-4 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of (halo)1-3 and hydroxy;
• cd). C2-4 alkenyl;
• ce). amino substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl;
• cf). halogen;
• and,
• cg). hydroxy;
• optionally, R2 and R3 together form at least one ring fused to the benzene ring;
• thereby providing a multiple ring system;
• wherein the multiple ring system is selected from the group consisting of C9-C14 benzo fused cycloalkyl, C9-C14 benzo fused cycloalkenyl, C9-C14 benzo fused aryl, benzo fused heterocyclyl and benzo fused heteroaryl;
• and, wherein the multiple ring system can optionally be substituted with one to four substituents independently selected from the group consisting of
• da). C1-4 alkyl optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy;
• db). C1-4 alkoxy optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of (halo)1-3 and hydroxy;
• dc). amino substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl;
• dd). halogen;
• de). hydroxy;
• and,
• df). nitro;
• R4 is selected from the group consisting of C1-4 alkyl (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of aryl and heteroaryl), aryl and heteroaryl;
• wherein aryl and heteroaryl and the aryl and heteroaryl portions of the substituted alkyl are optionally substituted with one to four substituents independently selected from the group consisting of C1-4 alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), cyano, halogen, hydroxy and (halo)1-3(C1-8)alkyl;
• R5 is selected from the group consisting of hydrogen and C1-8 alkyl (optionally substituted on a terminal carbon atom with a substituent selected from the group consisting of amino (substituted with two substituents independently selected from the group consisting of hydrogen and C1-4 alkyl), (halo)1-3 and hydroxy) and aryl (optionally substituted with one to four substituents independently selected from the group consisting of C1-8 alkyl and halogen);
• and
• R6 is selected from the group consisting of C1-8 alkyl, aryl(C1-8)alkyl, C1-8 alkoxy, aryl(C1-8)alkoxy, C2-8 alkenyl, C2-8 alkenyloxy, aryl(C2-8)alkenyl, aryl(C2-8)alkenyloxy, aryl, aryloxy and hydroxy.