Complement factor B inhibitors and uses there of

Patent metadata

Field	Value
Publication number	US-9475806-B2
Application number	US-201414774430-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 14, 2013
Publication date	Oct 25, 2016
Grant date	Oct 25, 2016

Abstract

The present invention provides a compound of formula (I): wherein X is N or CH, Y is NH, O or S, methods for manufacturing these compounds, and their uses as Factor B inhibitors for the treatment of conditions and diseases associated with complement alternative pathway activation such as age-related macular degeneration, diabetic retinopathy and related ophthalmic diseases. The present invention further provides pharmaceutical compositions and combinations of pharmacologically active agents.

First claim

What is claimed is:

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

Wherein
is a single or double bond;
X is N or CH;
Y is N(H), O or S;
R 1 is halogen, 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, hydroxyC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, C 3 -C 6 cycloalkylC 1 -C 5 alkoxy, haloC 1 -C 6 alkoxy, S(O) p C 1 -C 6 alkyl, CH 2 NHC(O)C 1 -C 4 alkyl or OCH 2 C(O)R 7 ,
p is 0, 1, or 2;
R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 6 alkyl or halogen;
R 3 is hydrogen, halogen, cyano, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, CH 2 C(O)R 7 , phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S, wherein the phenyl or heteroaryl is optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups, and wherein alkyl and haloalkyl optionally substituted with 0 or 1 hydroxy;
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, C 3 -C 6 cycloalkyl, phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S;
or R 3 and R 5 taken in combination form a divalent —CH 2 —CH 2 — or —CH 2 —N(H)— group;
R 6 is hydrogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, mono- and di-C 1 -C 4 alkylamino, amino C 1 -C 6 alkylamino, [CR A 2 ] n R 10 , O[CR A 2 ] n R 7 , NHC(O)C 1 -C 6 alkyl, NHS(O 2 )C 1 -C 6 alkyl, CH 2 R 9 , OCH 2 R 9 , O[CR A 2 ] n R 7 , N(H)[CR A 2 ] n R 7 , C(O)R 7 or N(H) [CR A 2 ] n C(O)R 7 ;
or CR 5 R 6 , taken in combination, form a divalent carbonyl group, a divalent ═CH 2 group or cyclopropyl which cyclopropyl is optionally substituted by CO 2 H or CH 2 OH;
or when R 5 is hydrogen, then R 6 may also be selected from [CR A 2 ] n R 7 or [CR A 2 ] n C(O)R 7 ;
n is 1, 2, or 3;
R A is independently selected at each occurrence from hydrogen, halogen or C 1 -C 4 alkyl;
R 7 is hydroxy, C 1 -C 4 alkoxy, amino, or mono- and di-C 1 -C 4 alkylamino;
R 8 is hydrogen or halogen;
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; and
R 10 is amino or mono- and di-C 1 -C 4 alkylamino.

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

3. The compound of claim 1 , or salt or tautomer thereof, wherein R 4 is absent.

4. The compound of claim 1 , or salt or tautomer thereof, wherein R 3 is hydrogen, chloro or phenyl.

5. The compound of claim 1 , or salt or tautomer thereof, wherein R 3 is hydrogen.

6. The compound of claim 1 , or a salt or tautomer thereof, wherein R 2 is methyl.

7. The compound of claim 1 , or a salt or tautomer thereof, wherein R 1 is halogen, C 1 -C 4 alkyl, vinyl, cyclopropyl, C 1 -C 4 alkoxy, hydroxyC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkoxy, cyclopropylC 1 -C 4 alkoxy, haloC 1 -C 4 alkoxy or S(O) 2 C 1 -C 4 alkyl.

8. The compound of claim 1 , or a salt or tautomer thereof, wherein R 1 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyclopropyl, bromo or difluoromethoxy.

9. The compound of claim 1 , or a salt or tautomer thereof, wherein R 5 is hydrogen, methyl, ethyl cyclopropyl or trifluoromethyl.

10. The compound of claim 1 , or a salt or tautomer thereof, wherein R 6 is hydrogen, hydroxy, methoxy, amino, mono- and di-methylamino or CH 2 R 10 ;
or when R 5 is hydrogen, then R 6 may also be selected from CH 2 R 7 or CH 2 C(O)R 7 , [CH 2 ] 2 R 7 or [CH 2 ] 2 C(O)R 7 ;
R 7 is hydroxy, amino, N(H)CH 3 or N(CH 3 ) 2 ; and
R 10 is amino, N(H)CH 3 or N(CH 3 ) 2 .

11. The compound of claim 1 , or a salt or tautomer thereof, wherein R 5 is methyl or trifluoromethyl;
R 6 is hydroxy, methoxy, amino, methylamino or CH 2 R 7 ; and
R 7 is amino, N(H)CH 3 or N(CH 3 ) 2 .

12. The compound of claim 2 , salt or tautomer thereof, wherein
R 1 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or cyclopropyl;
R 2 is methyl;
R 3 and R 4 are hydrogen;
R 5 is hydroxyl, amino, mono- and di-C 1 -C 2 alkylamino, C 1 -C 2 alkyl, or C 1 -C 2 alkoxy; and
R 6 is hydrogen, C 1 -C 2 alkyl, or trifluoromethyl.

13. The compound of claim 1 , or a salt or tautomer thereof, which compound is selected from the group consisting of
(+)-2-(1-amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(−)-2-(1-amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(+)-2-(hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carbonitrile;
(−)-2-(hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carbonitrile;
(+)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(−)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(+)-2-(1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(−)-2-(1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(+)-2-(2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(−)-2-(2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(+)-2-(1-amino-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(−)-2-(1-amino-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(+)-2-(1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(−)-2-(1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
2-(2-(5-methoxy-7-methyl-1H-indol-4-yl)propan-2-yl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(+)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(−)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(±)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(±)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(±)-2-(1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile;
(±)-2-(1-amino-1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoroethyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile; and salts and tautomers thereof.

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

Assignees

• Adams Christopher Michael
• Babu Charles
• Capparelli Michael Paul
• Ding Jian
• Ehara Takeru
• Jendza Keith
• Ji Nan
• Karki Rajeshri Ganesh
• Kawanami Toshio
• Xue Liang
• Mainolfi Nello
• Powers James J
• Serrano-Wu Michael H
• Zhang Chun
• Novartis Ag

Inventors

• Adams Christopher Michael
• Babu Charles
• Capparelli Michael Paul
• Ding Jian
• Ehara Takeru
• Jendza Keith
• Ji Nan
• Karki Rajeshri Ganesh
• Kawanami Toshio
• Xue Liang
• Mainolfi Nello
• Powers James J
• Serrano-Wu Michael H
• Zhang Chun

Classifications

• A61P33/00

  Antiparasitic agents · CPC title

• A61P43/00

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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

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

• A61P3/06

  Antihyperlipidemics · CPC title