OXOPYRIDINE DERIVATIVES USEFUL AS AMINOCARBOXYMUCONATE SEMIALDEHYDE DECARBOXYLASE (ACMSD) INHIBITORS
The present invention is related to a compound represented by the following structural formula: The present invention is also related a method of treating a subject with a disease which can be ameliorated by inhibition of aminocarboxymuconate semialdehyde decarboxylase (ACMSD).
1 . A compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —H, —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN;
R 2 is -halo, (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, monocyclic heteroaryl, —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R b , wherein:
the (C 1 -C 5 )alkyl group represented by R 2 is optionally substituted with —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , —C(═O)R a , (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl and phenyl, wherein the (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl and phenyl substituents on the (C 1 -C 5 )alkyl group represented by R 2 are optionally and independently substituted with —CH 3 , halomethyl, halo, methoxy or halomethoxy;
the (C 3 -C 6 )cycloalkyl, phenyl and monocyclic heteroaryl groups represented by R 2 are optionally and independently substituted with (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, halo, —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R a ;
each R a and each R b are independently selected from —H and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R a or R b is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;
R c is —H, halo(C 1 -C 5 )alkyl or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R c is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;
i is 0, 1, or 2;
each R 3 is independently —H, —CH 3 , or F;
A is absent, —CH 2 —, a phenylene group or a pyridylene group, wherein the phenylene group and the pyridylene group represented by A are optionally and independently substituted with 1 or 2 groups represented by R 4 ;
each R 4 is independently —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN; and
B is —COOH or tetrazolyl,
provided that the compound is other than
or a pharmaceutically acceptable salt of any of the foregoing.
2 - 3 . (canceled)
4 . The compound of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.
7 . The compound of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.
8 . (canceled)
9 . The compound of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
10 . (canceled)
11 . The compound of claim 1 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, furanyl, pyrimidyl, pyridyl, benzyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 - or pyrimidyl-CH 2 —, wherein i) the (C 1 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy or (C 3 -C 6 )cycloalkyl; ii) the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 , halomethyl, —OCH 3 , halomethoxy and —CN; and iii) the thienyl, furanyl, pyridyl, pyrimidyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 — or pyrimidyl-CH 2 — group represented by R 2 is optionally and independently substituted with —CH 3 .
13 . (canceled)
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —H, —CH 3 , —OCH 3 , F, Cl, or —CN;
R 2 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, pyridyl or benzyl, wherein the (C 1 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy or (C 3 -C 6 )cycloalkyl; the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 ;
R 3 is —H, F, or —CH 3 ;
R 4 is F, Cl, —CH 3 , or methoxy; and
n is 0 or 1.
15 . (canceled)
16 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —H, —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN;
R 2 is -halo, (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, monocyclic heteroaryl, —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R b , wherein:
the (C 1 -C 5 )alkyl group represented by R 2 is optionally substituted with —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , —C(═O)R a , (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl and phenyl, wherein the (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl and phenyl substituents on the (C 1 -C 5 )alkyl group represented by R 2 are optionally and independently substituted with —CH 3 , halomethyl, halo, methoxy or halomethoxy;
the (C 3 -C 6 )cycloalkyl, phenyl and monocyclic heteroaryl groups represented by R 2 are optionally and independently substituted with (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, halo, —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R a ;
each R a and each R b are independently selected from —H and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R a or R b is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;
R c is —H, halo(C 1 -C 5 )alkyl or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R c is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;
i is 0, 1, or 2;
each R 3 is independently —H, —CH 3 , or F;
A is absent, —CH 2 —, a phenylene group or a pyridylene group, wherein the phenylene group and the pyridylene group represented by A are optionally and independently substituted with 1 or 2 groups represented by R 4 ;
each R 4 is independently —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN; and
B is —COOH or tetrazolyl.
17 - 18 . (canceled)
19 . The pharmaceutical composition of claim 16 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
20 . The pharmaceutical composition of claim 16 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof.
21 . The pharmaceutical composition of claim 16 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.
22 . The pharmaceutical composition of claim 16 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.
23 . (canceled)
24 . The pharmaceutical composition of claim 16 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
25 . (canceled)
26 . The pharmaceutical composition of claim 16 , wherein the compound is represented by the following structural formula:
or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
27 . The pharmaceutical composition of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 2 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, furanyl, pyrimidyl, pyridyl, benzyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 - or pyrimidyl-CH 2 —, wherein i) the (C 1 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy or (C 3 -C 6 )cycloalkyl; ii) the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 , halomethyl, —OCH 3 , halomethoxy and —CN; and iii) the thienyl, furanyl, pyridyl, pyrimidyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 — or pyrimidyl-CH 2 — group represented by R 2 is optionally and independently substituted with —CH 3 .
28 . (canceled)
29 . The pharmaceutical composition of claim 16 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —H, —CH 3 , —OCH 3 , F, Cl, or —CN;
R 2 is (C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, pyridyl or benzyl, wherein the (C 1 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy or (C 3 -C 6 )cycloalkyl; the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 ;
R 3 is —H, F, or —CH 3 ;
R 4 is F, Cl, —CH 3 , or methoxy; and
n is 0 or 1.
30 . (canceled)
31 . A method of treating a subject with a disease which can be ameliorated by inhibition of aminocarboxymuconate semialdehyde decarboxylase (ACMSD), comprising administering to the subject an effective amount of the pharmaceutical composition of claim 16 , wherein the disease is a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a beta oxidation disease, a metabolic disease, a cancer, a vascular disease, an ocular vascular disease, a muscular eye disease, a renal disease, genetic lipodystrophy, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), renal ischemia/reperfusion injury (IRI), Duchenne & Becker muscular dystrophy, diabetes (type I or type II), obesity, sarcopenia, Alpers's Disease, CPEO-Chronic progressive external ophthalmoplegia, Kearns-Sayra Syndrome (KSS), Leber Hereditary Optic Neuropathy (LHON), MELAS-Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes, MERRF-Myoclonic epilepsy and ragged-red fiber disease, NARP-neurogenic muscle weakness, ataxia, and retinitis pigmentosa, Pearson Syndrome, platinum-based chemotherapy induced ototoxicity, Cockayne syndrome, xeroderma pigmentosum A, Wallerian degeneration, or HIV-induced lipodystrophy.
32 . A method of treating a subject with acute kidney injury, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 16 .
33 . A method of treating a subject with cancer, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 16 .
34 - 38 . (canceled)