Bicyclic carboxamides and methods of use thereof

A compound having the Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, isotopic variant or prodrug thereof:

• wherein:
• X1 is N or CH;
• X3 is N or CR3;
• X4 is N or CR4;
• X5 is N or CR5;
• wherein no more than two of X3, X4 and X5 are N;
• L1 is —(CRb2)t—;
• Ring A is aryl;
• each R1 is independently C2-C9alkyl, C2-C9alkenyl, C2-C9alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or —OR8′, wherein C2-C9alkyl, C2-C9alkenyl, C2-C9alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three Ry;
• or two R1 substituents on adjacent atoms of Ring A are taken together with the atom to which they are attached to form an aromatic or non-aromatic ring containing 0-2 heteroatoms selected from the group consisting of —O—, ═N—, —NR10—, —S—, and —S(O)2—, wherein the aromatic or non-aromatic ring is optionally deuterated and optionally substituted with one, two, or three Ry;
• each R8′ is independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl;
• each Ry is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, —OR8, —NR8R9, —CN, —C(O)R11, —C(O)NR8R9, —NR8C(O)R11, —NR8C(O)OR9, —NR10C(O)NR8R9, —OC(O)NR8R9, —S(O)2R11, —S(O)R11, —SR8, —S(O)2NR8R9, —S(O)NR8R9, —NR8S(O)R11, —NR8S(O)2R11, or —NR10S(O)2NR8R9;
• wherein the alkyl is optionally substituted with —OR8 or —NR8R9 and wherein the cycloalkyl and heterocyclyl are optionally substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl;
• each Rx is independently halogen, methyl, C1haloalkyl, or —CN;
• R2, R3, R4, and R5 are each independently hydrogen, alkyl, halogen, —OR8, —NR8R9, —SR8, —S(O)R11, —S(O)2R11, —CN, cycloalkyl, or haloalkyl;
• R6 is hydrogen, alkyl, or haloalkyl;
• R7 is hydrogen, halogen, alkyl, alkoxy, haloalkoxy, hydroxyl, or haloalkyl;
• each R8 and each R9 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl;
• or
• R8 and R9, together with the atom or atoms to which they are attached, form a heterocyclyl optionally substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl;
• each R10 is independently hydrogen or alkyl;
• each R11 is independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl;
• Y1 and Y2 are each independently a bond or —(CRa2)n—, provided that Y1 and Y2 are not both a bond;
• Z1 and Z2 are each —CRa2—;
• L2 is —(CRc2)m—;
• G is —C(O)OR2, —C(O)NHOH, —SO3H, —SO2NH2, —SO2NHRd, —SO2NHC(O)Rd, —NHC(O)NHSO2Rd, -1H-tetrazolyl, —P(OX)(OH)2, -1,2,4-oxadiazol-5(4H)-one, -tetrazol-5(4H)-one, or —C(O)NHSO2Rd;
• R12 is selected from H, C1-C6 alkyl, aryl, aralkyl, CH(R13)OC(O)R4, CH(R13)OC(═O)OR4 and a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group having the following formula:
• wherein Re is C1-C6alkyl;
• R13 is hydrogen or C1-C6 alkyl;
• R14 is C1-C6 alkyl or C3-C6-cycloalkyl;
• each Ra is independently hydrogen, alkyl, halogen, or haloalkyl;
• each Rb is independently hydrogen, alkyl or haloalkyl, or two Rbs, together with the carbon atom to which they are attached, form cycloalkyl or heterocyclyl;
• each Rc is independently hydrogen or halogen;
• Rd is alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl;
• m is 0, 1, or 2;
• each n is independently 1, 2, or 3;
• p is 1 or 2;
• q is 0, 1, or 2;
• and
• t is 1, 2 or 3.