Azole amides and amines as alpha v integrin inhibitors

A compound of Formula (I):

• wherein:
• A, E, and G are independently N or CR6;
• L1 and L2 are each independently C1-4 alkylene;
• X is a C1-6 alkylene substituted with 0, 1, or 2 R7b;
• Y is C(O) or CH2;
• Z is a covalent bond, O, S, NH, —O—(C1-3 alkylene)-, —S—(C1-3 alkylene)-, or —NH—(C1-3 alkylene)-, wherein the C1-3 alkylene is each independently substituted with 0, 1, or 2 R7a;
• g is an integer of 1 or 2;
• n is an integer of 1 or 2;
• r is an integer of 0, 1, 2, or 3;
• t is an integer of 0, 1, 2, or 3;
• R1 is an Arginine mimetic moiety selected from the group consisting of
• one of the asterisks in each of the arginine mimetics moiety is an attachment point to X, and the other two asterisks are hydrogen;
• R2 is hydrogen or C1-6 alkyl;
• R3 is hydrogen, 3- to 10-membered carbocyclyl, carbocyclylalkyl, 6- to 10-membered aryl, arylalkyl, 3- to 14-membered heterocyclyl, heterocyclylalkyl, 5- to 14-membered heteroaryl, or heteroarylalkyl, wherein the alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, by themselves or as part of another group, are each independently substituted with 0, 1, 2, or 3 R8;
• R3X is hydrogen;
• or alternatively, R3 and R3X, together with the atom to which they are attached, form a carbocyclyl or a heterocyclyl, and the carbocyclyl and heterocyclyl are each independently substituted with 0, 1, 2, or 3 R12;
• R4 is hydrogen, C1-10 alkyl, 3- to 10-membered carbocyclyl, carbocyclylalkyl, 3- to 10-membered heterocyclyl, heterocyclylalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 14-membered heteroaryl, heteroarylalkyl, NRaRb, OH, ORa, S(O)nR10, C(O)NRaRb, NHC(O)ORa, NHC(O)NRaRb, NHC(O)R10, OC(O)NRaRb, OC(O)R10, NHS(O)nNRaRb, or NHS(O)nR10;
• wherein the alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, by themselves or as part of another group, are each independently substituted with 0, 1, 2, or 3 R15;
• R5 is H, R5a, or a structural moiety selected from
• R5a and R5b are each independently C1-6 alkyl, phenyl, or 5- to 7-membered heterocyclyl;
• wherein the alkyl, phenyl, and heterocyclyl are each independently substituted with 0 to 3 R5d;
• R5c, is C1-6 alkyl or 5- to 7-membered carbocyclyl;
• wherein the alkyl and carbocyclyl are each independently substituted with 0 to 3 R5d;
• R5d, at each occurrence, is independently halo, OH, alkoxy, oxo, or alkyl;
• or alternatively, two adjacent R5d, together with the atoms to which they are attached, forma carbocyclyl moiety;
• R6 is hydrogen, C1-6 alkyl, C3-5 cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, and heteroaryl are each independently substituted with 0, 1, 2, or 3 R9;
• R7a and R7b are each independently halo, cyano, hydroxyl, oxo, NRaRb, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, heteroalkyl, aryl, cycloalkyl, heteroaryl, cycloheteroalkyl, amido, carbamate, or sulfonamide;
• wherein the aryl and heteroaryl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• and the cycloalkyl and cycloheteroalkyl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, oxo, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• R8 at each occurrence is independently halo, cyano, nitro, OH, NRaRb, C1-6 alkyl, alkoxy, alkylamino, haloalkyl, haloalkoxy, haloalkylamino, hydroxyalkyl, aminoalkyl, alkylsulfonyl, sulfonamide, 3 to 6 membered carbocyclyl, 3 to 6 membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl;
• or alternatively, two R8 at adjacent positions, together with the atoms to which they are attached, form a carbocyclyl or heterocyclyl;
• wherein the aryl and heteroaryl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• and the carbocyclyl and heterocyclyl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, oxo, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• R9 at each occurrence is independently halo, cyano, nitro, OH, alkoxy, NRaRb, C1-6 alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl;
• wherein the aryl and heteroaryl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• and the cycloalkyl and cycloheteroalkyl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, oxo, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• R10 is C1-6 alkyl, 3 to 10 membered carbocyclyl, or 3 to 10 membered heterocyclyl, wherein the alkyl, carbocyclyl, and heterocyclyl are each independently substituted with 0, 1, 2, or 3 R11;
• R11 is halo, cyano, nitro, OH, alkoxy, NRaRb, alkyl, aryl, cycloalkyl, heteroaryl, cycloheteroalkyl, or S(O)g(aryl);
• wherein the aryl, alkyl, cycloalkyl, heteroaryl, and cycloheteroalkyl are each independently substituted with 0, 1, 2, or 3 R13;
• R12 at each occurrence is independently halo, cyano, nitro, OH, alkoxy, NRaRb, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl;
• or alternatively, two R12 at adjacent positions, together with the atoms to which they are attached, form a carbocyclyl or heterocyclyl;
• wherein the aryl and heteroaryl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• and the cycloalkyl and cycloheteroalkyl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, oxo, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• R13 and R14, at each occurrence, are independently halo, cyano, nitro, OH, alkoxy, NRaRb, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, or cycloheteroalkyl;
• wherein the aryl and heteroaryl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• and the cycloalkyl and cycloheteroalkyl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, oxo, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• R15 at each occurrence is independently halo, cyano, nitro, OH, NRaRb, C1-6 alkyl, alkoxy, alkylamino, haloalkyl, haloalkoxy, haloalkylamino, hydroxyalkyl, aminoalkyl, alkylsulfonyl, sulfonamide, 3 to 6 membered carbocyclyl, 3 to 6 membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl;
• or alternatively, two R9 at adjacent positions, together with the atoms to which they are attached, form a carbocyclyl or heterocyclyl;
• wherein the aryl and heteroaryl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• and the carbocyclyl and heterocyclyl, by themselves or as part of another group, are each independently substituted with one or more groups independently selected from halo, cyano, hydroxyl, amino, oxo, C1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, haloalkoxy, amido, carbamate, and sulfonamide;
• Ra and Rb, at each occurrence, are independently hydrogen, C1-10 alkyl, 3 to 10 membered carbocyclyl, or 3 to 10 membered heterocyclyl;
• wherein the alkyl, carbocyclyl, and heterocyclyl are each independently substituted with 0, 1, 2, or 3 R14;
• Re is OH, C1-4 alkyl, halo, haloalkyl, or C1-4 cycloalkyl;
• Rf=H, CH3, CH2CH3, or COOCH2CH3;
• and
• Rg=CH3, CH2CH3, CH2CCl3, phenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl,
• or a pharmaceutically acceptable salt thereof.