Matrix metalloproteinase (MMP) inhibitors and methods of use thereof
AssigneeForesee Pharmaceuticals USA, Inc.
InventorsWenjin Yang, Kai-Wei Chang, Suying Liu, Cheng-Han Tsai
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Abstract
Hydantoin based compounds useful as inhibitors of matrix metalloproteinases (MMPs), particularly macrophage elastase (MMP-12) are described. Also described are related compositions and methods of using the compounds to inhibit MMP-12 and treat diseases mediated by MMP-12, such as asthma, chronic obstructive pulmonary disease (COPD), emphysema, acute lung injury, idiopathic pulmonary fibrosis (IPF), sarcoidosis, systemic sclerosis, liver fibrosis, nonalcoholic steatohepatitis (NASH), arthritis, cancer, heart disease, inflammatory bowel disease (IBD), acute kidney injury (AKI), chronic kidney disease (CKD), Alport syndrome, and nephritis.
Claims21
A compound of formula (II):
- or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof,
- wherein:
- ring B is optionally substituted furanyl;
- ring C is aryl or heteroaryl;
- ring D is phenyl, pyridinyl, or pyridinyl N-oxide;
- each of X, Y, and Z is independently selected from the group consisting of O, CH2, NRx and S(O)q, wherein Rx is hydrogen or alkyl;
- R1 is hydrogen or alkyl;
- each R2 is independently selected from the group consisting of hydrogen, alkyl, halo, hydroxyl, haloalkyl, alkoxy, alkylthio, amino, amide, alkylamine, aminoalkyl, cyano, hydroxyalkyl, —(CH2)pC(O)OR6, and —(CH2)pOC(O)R6;
- each R3 is independently selected from the group consisting of hydrogen, alkyl and halo;
- R4 is hydrogen or alkyl;
- R5 is hydrogen;
- each R6 is independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of amino, hydroxyl, halo, and alkoxy;
- m is 1, 2, 3, or 4;
- n is 1, 2, 3, 4, or 5;
- p is 0, 1, 2, 3, 4, or 5;
- and
- q is 0, 1, or 2;
- provided that when ring D is phenyl, at least two of the following are true:
- (i) R1 is alkyl;
- (ii) R2 is not methoxy, chloro, or trifluoromethyl;
- and
- (iii) ring C is not unsubstituted phenyl.
A compound of formula (V):
- or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein:
- R1 is alkyl;
- R2 is selected from the group consisting of alkyl, amide, alkoxy, hydroxyl, and hydroxyalkyl;
- each of R4 and R5 is hydrogen;
- and
- R7 is methyl or hydrogen.
A compound selected from the group consisting of:
- or a tautomer, stereoisomer, pharmaceutically acceptable salt, or solvate thereof.
Dependencies are inferred from the claim text.