Substituted Fused Imidazole Derivatives, Pharmaceutical Compositions, and Methods of Use Thereof

A method of treating a disease or condition of the eye comprising administering to a human subject a compound,

• wherein the disease or condition of the eye is glaucoma, uveitis, wound healing, eye trauma, corneal graft, macular degeneration, cataracts, light retinopathy, and retinopathy of prematurity or diabetes;
• wherein the compound is a compound of Formula (I) or a pharmaceutically acceptable salt thereof
• wherein
• one of X1, X2, X3, and X4 is
• and the remaining members of X1, X2, X3, and X4 are independently N or
• G is hydrogen, —C1-8 alkyl, —C3-10 cycloalkyl, —C1-6 alkylene-C3-10 cycloaklyl, heterocyclyl, —C1-6 alkylene-C3-10 heterocyclyl, phenyl, heteroaryl, or NRhRk, where the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rc;
• L is —CH2—C(O)N(R6)—, —C(O)N(R6)—, —C(O)—O—, —SO2—, —C(O)—, heteroarylene optionally substituted one or more times with substituents independently selected from Rx, or heterocyclylene optionally substituted one or more times with substituents independently selected from Rx;
• or the group -L-G is -cyano;
• R1 is hydrogen, Ra, phenyl, or heteroaryl, where the phenyl and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;
• R2 is Rb;
• R3 is hydrogen, —C1-6 alkyl, or —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rz;
• R4 is —C1-6 alkyl or —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry;
• R6 is hydrogen, —C1-6 alkyl, —C1-6 alkylene-C3-10 cycloaklyl, where the alkyl, alkylene, and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Rx;
• Ra is
• a) -halogen,
• b) —C1-6 alkyl,
• c) —C3-10 cycloalkyl,
• d) -heterocyclyl,
• e) -cyano,
• f) —CF3,
• g) —OCF3,
• h) —O—Rd,
• i) —S(O)w—Rd,
• j) —S(O)2O—Rd,
• k) —NRdRe,
• l) —C(O)—Rd,
• m) —C(O)—O—Rd,
• n) —OC(O)—Rd,
• o) —C(O)NRdRe,
• p) —C(O)-heterocyclyl,
• q) —NRdC(O)Re,
• r) —OC(O)NRdRe,
• s) —NRdC(O)ORd, or
• t) —NRdC(O)NRdRe,
• where the alkyl, cycloalkyl, and heterocyclyl groups are optionally substituted one or more times with substituents independently selected from Ry;
• Rb is
• a) -halogen,
• b) —C1-6 alkyl,
• c) —C3-10 cycloalkyl,
• d) -heterocyclyl,
• e) -phenyl,
• f) -heteroaryl,
• g) -cyano,
• h) —CF3,
• i) —OCF3,
• j) —O—Rf,
• k) —S(O)w—Rf,
• l) —S(O)2O—Rf,
• m) —NRfRg,
• n) —C(O)—Rf,
• o) —C(O)—O—Rf,
• p) —OC(O)—Rf,
• q) —C(O)NRfRg,
• r) —C(O)-heterocyclyl,
• s) —NRfC(O)Rg,
• t) —OC(O)NRfRg,
• u) —NRfC(O)ORf, or
• v) —NRfC(O)NRfRg,
• where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz;
• Rc is
• a) -halogen,
• b) —C1-6 alkyl,
• c) —C3-10 cycloalkyl,
• d) -heterocyclyl,
• e) -cyano,
• f) —CF3,
• g) —OCF3,
• h) —O—Rh,
• i) —S(O)w—Rh,
• j) —S(O)2O—Rh,
• k) —NRhRk,
• l) —C(O)—Rh,
• m) —C(O)—O—Rh,
• n) —OC(O)—Rh,
• o) —C(O)NRhRk,
• p) —C(O)-heterocyclyl,
• q) —NRhC(O)Rk,
• r) —OC(O)NRhRk,
• s) —NRhC(O)ORk,
• t) —NRhC(O)NRhRk,
• u) —NRhS(O)wRk,
• v) -phenyl,
• w) -heteroaryl, or
• x) —O—(C1-4 alkylene)-O—(C1-4 alkylene)-N(Rh)C(O)—ORk,
• where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;
• Rd and Re are independently hydrogen, C1-6 alkyl, or C3-10 cycloalkyl, where the alkyl and cycloalkyl groups are optionally substituted one or more times with substituents independently selected from Ry;
• or, if Rd and Re are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Ry;
• Rf and Rg are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rz;
• or, if Rf and Rg are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rz;
• Rh and Rk are independently hydrogen, C1-6 alkyl, C3-10 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are optionally substituted one or more times with substituents independently selected from Rx;
• or, if Rh and Rk are both attached to the same nitrogen atom, together with that nitrogen atom may optionally form a heterocyclic ring selected from the group consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino, piperazino, morpholino, thiomorpholino, and azepano, where each ring is optionally substituted one or more times with substituents independently selected from Rx;
• Ry is
• a) -halogen,
• b) —NH2,
• c) -cyano,
• d) -carboxy,
• e) -hydroxy,
• f) -thiol,
• g) —CF3,
• h) —OCF3,
• i) —C(O)—NH2,
• j) —S(O)2—NH2,
• k) oxo,
• l) —C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• m) -heterocyclyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• n) —C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• o) —O—C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• p) —O—C3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• q) —NH—C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• r) —N(C1-6 alkyl)2 optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• s) —C(O)—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• t) —C(O)—O—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• u) —S—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• v) —S(O)2—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• w) —C(O)—NH—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• x) —C(O)—N(C1-6 alkyl)2, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• y) —S(O)2—NH—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• z) —S(O)2—N(C1-6 alkyl)2, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• aa) —NH—C(O)—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2, or
• bb) —NH—S(O)2—C1-6 alkyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2;
• Rx is
• a) —Ry
• b) -phenyl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• c) -heteroaryl, optionally substituted one or more times with substituents selected independently from the group consisting of halogen, —OH, —O—C1-6 alkyl, —NH2, —NH—C1-6 alkyl, and —N(C1-6 alkyl)2,
• d) —O-phenyl,
• e) —O-heteroaryl,
• f) —C(O)-phenyl,
• g) —C(O)-heteroaryl,
• h) —C(O)—O-phenyl, or
• i) —C(O)—O-heteroaryl;
• Rz is
• a) —Ry
• b) -phenyl,
• c) -heteroaryl;
• d) —O-phenyl,
• e) —O-heteroaryl,
• f) —C(O)-phenyl,
• g) —C(O)-heteroaryl,
• h) —C(O)—O-phenyl, or
• i) —C(O)—O-heteroaryl;
• v is an integer from 0 to 4, and
• w is an integer from 0 to 2.