2-benzyl-benzimidazole complement factor B inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9676728-B2
Application number	US-201415032872-A
Country	US
Kind code	B2
Filing date	Oct 29, 2014
Priority date	Oct 30, 2013
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

The present invention provides a compound of formula (I) a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

What is claimed is:

1. A compound, or salt or tautomer thereof, according to Formula (I):

Wherein
X is N or CH;
Y is N(H) or O;
one occurrence of R is cyano and the other occurrence of R is hydrogen or R 4 ;
R 1 is hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, haloC 1 -C 6 alkoxy, or S(O) p C 1 -C 6 alkyl;
R 2 is halogen, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, or S(O) p C 1 -C 6 alkyl;
p is 0, 1, or 2;
q is 0, 1, or 2;
R 3 is hydrogen, halogen, cyano, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl C 1 -C 4 alkoxy, or haloC 1 -C 4 alkoxy;
R 4 is 0, 1, or 2 substitutents independently selected at each occurrence from halogen and C 1 -C 6 alkyl;
R 5 is hydrogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl;
R 6 is hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, mono- and di-C 1 -C 4 alkylamino, amino C 1 -C 6 alkylamino, [CR 8 2 ] n R 7 , [CR 8 2 ] n C(O)R 7 , O[CR 8 2 ] n R 7 , NHC(O)C 1 -C 6 alkyl, NHS(O 2 )C 1 -C 6 alkyl, (CH 2 ) n R 9 , O(CH 2 ) n R 9 , C(O)R 7 , N(H)[CR A 2 ] n R 7 , O[CR A 2 ] n C(O)R 7 , N(H)[CR 8 2 ] n C(O)R 7 or tetrazolyl;
n is 1, 2, 3 or 4;
R 7 is hydroxy, C 1 -C 4 alkoxy, amino or mono- and di-C 1 -C 4 alkylamino;
R 8 is independently selected at each occurrence from hydrogen, halogen or C 1 -C 4 alkyl;
R 9 is a 5 member heteroaryl having 1 to 4 ring heteroatoms selected from N, O or S and optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups.

2. The compound of claim 1 , wherein X is N and Y is N(H) or O.

3. The compound of claim 1 wherein X is N and Y is N(H).

4. The compound of claim 1 , wherein R 4 is absent.

5. The compound of claim 1 , wherein R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy.

6. The compound of claim 1 , wherein R 2 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy.

7. The compound of claim 1 , or salt or tautomer thereof, according to Formula (II):

Wherein one occurrence of R is cyano and the other occurrence of R is hydrogen;
R 1 is hydrogen, methyl, methoxy, ethyl or ethyoxy;
R 2 is methyl, methoxy, ethyl or ethyoxy;
R 3 is hydrogen, methyl, methoxy, ethyl or ethyoxy; and
R 10 is hydrogen or halogen.

8. The compound of claim 1 , wherein R 5 is hydrogen, C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl.

9. The compound of claim 1 , wherein R 6 is hydroxyl, amino, C 1 -C 4 alkyl, methoxy, trifluoromethoxy, mono- and di-C 1 -C 4 alkyl amino, or CH 2 C(O)NH 2 .

10. The compound of claim 7 , wherein
One occurrence of R is cyano and the other occurrence of R is hydrogen;
R 1 is hydrogen, methyl, methoxy, ethyl or ethyoxy;
R 2 is methyl, methoxy, ethyl or ethyoxy;
R 3 is hydrogen or methyl;
R 5 is hydrogen, methyl, cyclopropyl or trifluoromethyl;
R 6 is hydroxyl, amino, methoxy, trifluoromethoxy, methylamino or CH 2 C(O) NH 2 ; and
R 10 is hydrogen, chloro or bromo.

11. The compound of claim 1 , or a salt, stereoisomer or tautomer thereof, which compound is selected from the group consisting of (±)-2-(Hydroxy(2-methoxy-4,6-dimethylphenyl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(1-Hydroxy-1-(2-methoxy-4,6-dimethylphenyhethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(2,2,2-Trifluoro-1-hydroxy-1-(2-methoxy-4,6-dimethylphenyhethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(1-(3-bromo-6-methoxy-2,4-dimethylphenyl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(+) or (−)-2-(2,2,2-Trifluoro-1-(2-methoxy-4,6-dimethylphenyl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(−) or (+)-2-(2,2,2-Trifluoro-1-(2-methoxy-4,6-dimethylphenyl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(2,2,2-Trifluoro-1-(2-methoxy-4-methylphenyl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(1-(3-Chloro-6-methoxy-2,4-dimethylphenyl)-2,2,2-trifluoro-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(2,2,2-Trifluoro-1-(2-methoxy-6-methylphenyl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(1-Amino-2,2,2-trifluoro-1-(2-methoxy-4,6-dimethylphenyl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(1-(3-Bromo-6-methoxy-2,4-dimethylphenyl)-2,2,2-trifluoro-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(Amino(2-methoxy-4,6-dimethylphenyl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(1-Amino-1-(2-methoxy-4,6-dimethylphenyl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(Amino(cyclopropyl)(2-methoxy-4,6-dimethylphenyl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;
(±)-2-(1-(5-Cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(2-methoxy-4,6-dimethylphenyl)ethoxy)acetamide;
(+) or (−)-2-(2,2,2-trifluoro-1-methoxy-1-(2-methoxy-4,6-dimethylphenyl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;
(−) or (+)-2-(2,2,2-trifluoro-1-methoxy-1-(2-methoxy-4,6-dimethylphenyl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile; and
(±)-2((2,6-Dimethoxy-4-methylphenyl)(methylamino)methyl)-1H-benzo[d]imidazole-5-carbonitrile; (±)-2-(1-(2,6-dimethoxy-4-methylphenyl)-2,2,2-trifluoro-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile.

12. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of claim 1 .

Assignees

• Adams Christopher
• Ehara Takeru
• Jendza Keith
• Ji Nan
• Karki Rajeshri Ganesh
• Kawanami Toshio
• Mainolfi Nello
• Powers James
• Serrano-Wu Michael
• Zhang Chun
• Novartis Ag

Inventors

• Adams Christopher
• Ehara Takeru
• Jendza Keith
• Ji Nan
• Karki Rajeshri Ganesh
• Kawanami Toshio
• Mainolfi Nello
• Powers James
• Serrano-Wu Michael
• Zhang Chun

Classifications

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title