Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2016251318-A1
Application number	US-201214241374-A
Country	US
Kind code	A1
Filing date	Aug 28, 2012
Priority date	Aug 30, 2011
Publication date	Sep 1, 2016
Grant date	—

Abstract

Certain chemical entities are provided herein. Also provided are pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of KMO activity are described, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one chemical entity as a single active agent or administering at least one chemical entity in combination with one or more other therapeutic agents. Also provided are methods for screening compounds capable of inhibiting KMO activity.

First claim

1 . At least one chemical entity chosen from compounds of Formula I

and pharmaceutically acceptable salts and prodrugs thereof wherein:
X and Y are independently chosen from —N— and —CH—, provided that at least one of X and Y is —N—;
R 1 is aryl or monocyclic heteroaryl, each of which is substituted with
a first group of the formula —Z—R 6 wherein
Z is chosen from —O—, —S—, —S(O)—, —S(O) 2 —, —CR 11 R 12 —, —OCR 11 R 12 —, —NR 13 —, —NR 13 CR 11 R 12 —, —CR 11 R 12 NR 13 —, and —C(O)— where R 11 , R 12 , and R 13 are independently chosen from hydrogen, lower alkyl, hydroxyl, and lower alkoxy,
R 6 is chosen from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, provided that if Z is —O—, then R 6 is not optionally substituted benzyl or optionally substituted pyridylmethyl, or
R 6 and R 13 , taken together with the nitrogen to which they are bound form an optionally substituted 5- to 7-membered heterocycloalkyl ring, and

a second group chosen from halo and lower alkyl optionally substituted with halo, or

R 1 is chosen from: 2,3-dihydrobenzofuran-5-yl, chroman-6-yl, 1,3-benzodioxol-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl, benzothiophen-5-yl, benzothiazol-5-yl, benzoimidazol-5-yl, benzofuran-5-yl, 1H-indol-5-yl, 1H-indazol-5-yl, isoindolin-5-yl, benzo[c][1,2,5]oxadiazol-5-yl, 1,2,3,4-tetrahydroquinolin-6-yl, imidazo[1,2-a]pyridin-6-yl, pyrazolo[1,5-a]pyridine-5-yl, quinolin-6-yl, quinazolin-6-yl, quinazolin-7-yl, and quinoxalin-6-yl, each of which is optionally substituted, or
R 1 and R 3 , taken together with intervening atoms form a bicyclic ring of the formula

which is optionally substituted where m is 0 or 1 and n is 0 or 1, provided that at least one of m and n is 1 and W is —O—, or —N(R 8 )— where R 8 is hydrogen or lower alkyl;

R 2 is chosen from hydrogen and optionally substituted lower alkyl;
R 3 is chosen from hydrogen, halo, optionally substituted lower alkyl, hydroxyl, optionally substituted lower alkoxy, and optionally substituted amino;
L is chosen from —C(O)—, —C(O)O—, —C(O)N(R 4 )—, —C(O)N(OR 7 )—, —N(R 4 )S(O) 2 —, —S(O) 2 N(R 4 )—, and —C(O)N(R 4 )—S(O) 2 —;
R 4 is chosen from hydrogen and lower alkyl;
R 5 is chosen from hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; provided that when L is —N(R 4 )S(O) 2 —, then R 5 is not hydrogen, or
R 4 and R 5 taken together with the nitrogen to which they are bound form an optionally substituted 4- to 7-membered heterocycloalkyl ring, which is optionally fused to an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl ring; or
R 3 and R 5 , taken together with the intervening atoms, form an optionally substituted 5- to 7-membered ring; and
R 7 is chosen from hydrogen and lower alkyl;
provided that the compound of Formula I is not chosen from
6-(3-chloro-4-methyl-phenyl)-pyrimidine-4-carboxylic acid methyl ester;
6-(3-chloro-4-methyl-phenyl)-pyrimidine-4-carboxylic acid;
6-(3-chloro-4-methoxy-phenyl)-pyrimidine-4-carboxylic acid methyl ester; and
6-(3-chloro-4-methoxy-phenyl)-pyrimidine-4-carboxylic acid.

2 . At least one chemical entity of claim 1 wherein R 1 is phenyl substituted with
a first group of the formula —Z—R 6 wherein Z is chosen from —O—, —S—, —S(O)—, —S(O) 2 —, and —CR 11 R 12 —; and R 6 is chosen from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, and
a second group chosen from halo and lower alkyl optionally substituted with halo.

3 . At least one chemical entity of claim 1 wherein Z is —O—.

4 . At least one chemical entity of claim 1 wherein Z is —S—.

5 . At least one chemical entity of claim 1 wherein Z is —S(O) 2 —.

6 . At least one chemical entity of claim 1 wherein Z is —CR 11 R 12 .

7 . At least one chemical entity of claim 1 wherein R 6 is chosen from hydrogen, methyl, difluoromethyl, trifluoromethyl, ethyl, 2,2,2-trifluoro-1-methyl-ethyl, isopropyl, (S)-sec-butyl, (R)-sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, 2-morpholin-4-yl-ethyl, 2-piperidin-1-yl-ethyl, pyrrolidin-3-yl, and tetrahydro-furan-3-yl.

8 . At least one chemical entity of claim 1 wherein R 1 is chosen from 3-chloro-4-cyclobutoxy-phenyl, 3-chloro-4-cyclopentyloxy-phenyl, 3-chloro-4-cyclopropoxy-phenyl, 3-chloro-4-isopropoxy-phenyl, 3-chloro-4-methoxy-phenyl, [4-chloro-3-(2-morpholin-4-yl-ethoxy)-phenyl, 3-chloro-4-(2-piperidin-1-yl-ethoxy)-phenyl, 3-chloro-4-(pyrrolidin-3-yloxy)-phenyl, 4-(S)-sec-butoxy-3-chloro-phenyl, 4-(R)-sec-butoxy-3-chloro-phenyl, 4-chloro-3-(tetrahydro-furan-3-yloxy)-phenyl, 3-chloro-4-trifluoromethoxy-phenyl, 3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,4-dimethoxyphenyl, 3-chloro-4-isopropylphenyl, 3-fluoro-4-methylphenyl, and 3-fluoro-4-isopropylphenyl, 3,4-bis(methylsulfanyl)phenyl, 3,4-bis(methylsulfonyl)phenyl, 3,4-bis(trifluoromethoxy)phenyl, 3-chloro-4-(difluoromethoxy)phenyl, 3-chloro-4-(methylsulfanyl)phenyl, 3-chloro-4-(methylsulfonyl)phenyl, 3-chloro-4-(trifluoromethoxy)phenyl, 3-chloro-4-(cyclopropoxymethyl)phenyl, 3-chloro-4-(cyclopropylmethyl)phenyl, 3-chloro-4-(cyclopropanesulfinyl)phenyl, 3-chloro-4-(cyclopropanesulfonyl)phenyl, 3-chloro-4-[cyclopropyl(hydroxy)methyl]phenyl, 3-chloro-4-(1-cyclopropoxyethyl)phenyl, 3-chloro-4-cyclopropanecarbonylphenyl, 3-chloro-4-cyclopropylphenyl, 4-(aziridin-1-ylmethyl)-3-chlorophenyl, 3-chloro-4-[(dimethylamino)methyl]phenyl, 3-chloro-4-(cyclopropylamino)phenyl, 3-chloro-4-[cyclopropyl(methyl)amino]phenyl, 3-chloro-4-[(cyclopropylamino)methyl]phenyl, 3-chloro-4-{[cyclopropyl(methyl)amino]methyl}phenyl, 3-chloro-4-(1-methoxycyclopropyl)phenyl, 4-chloro-3-[(1,1,1-trifluoropropan-2-yl)oxy]phenyl, 4-chloro-3-(trifluoromethoxy)phenyl, 4-chloro-3-(2-methylpropoxy)phenyl, 4-chloro-3-(propan-2-yloxy)phenyl, 4-chloro-3-(propan-2-yloxy)phenyl, 4-chloro-3-methoxyphenyl, 4-chloro-3-cyclopropoxyphenyl, and 3-chloro-4-{[1-(morpholin-4-yl)propan-2-yl]oxy}phenyl.

9 . At least one chemical entity of claim 8 wherein R 1 is chosen from 3-chloro-4-methoxy-phenyl, 3-chloro-4-(trifluoromethoxy)phenyl, 3-chloro-4-cyclobutoxy-phenyl, 3-chloro-4-cyclopropoxy-phenyl, 3-chloro-4-isopropoxy-phenyl, 3-chloro-4-methoxy-phenyl, 3-chloro-4-(pyrrolidin-3-yloxy)-phenyl, 4-(S)-sec-butoxy-3-chloro-phenyl, 4-(R)-sec-butoxy-3-chloro-phenyl, 4-chloro-3-(tetrahydro-furan-3-yloxy)-phenyl, 3-chloro-4-trifluoromethoxy-phenyl, 3-chloro-4-(2,2,2-trifluoro-1-methyl-ethoxy, 3-methoxy-phenyl, 4-methoxy-phenyl, 3,4-dimethoxyphenyl, 3-chloro-4-isopropylphenyl, 3-fluoro-4-methylphenyl, and 3-fluoro-4-isopropylphenyl, 3,4-bis(trifluoromethoxy)phenyl, 3-chloro-4-(difluoromethoxy)phenyl, 3-chloro-4-(trifluoromethoxy)phenyl, 3-chloro-4-(cyclopropoxymethyl)phenyl, 3-chloro-4-(cyclopropylmethyl)phenyl, 3-chloro-4-(cyclopropanesulfinyl)phenyl, 3-chloro-4-(cyclopropanesulfonyl)phenyl, 3-chloro-4-[cyclopropyl(hydroxy)methyl]phenyl, 3-chloro-4-(1-cyclopropoxyethyl)phenyl, 3-chloro-4-cyclopropanecarbonylphenyl, 3-ch

Assignees

• Courtney Stephen Martin
• Prime Michael
• Mitchell William
• Brown Christopher John
• De Aguiar Pena Paula C
• Johnson Peter
• Dominguez Celia
• Toledo-Sherman Leticia M
• Munoz Ignacio
• Chdi Foundation Inc

Inventors

• Courtney Stephen Martin
• Prime Michael
• Mitchell William
• Brown Christopher John
• De Aguiar Pena Paula C
• Johnson Peter
• Dominguez Celia
• Toledo-Sherman Leticia M
• Munoz Ignacio

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title