Piperidinyl-indole derivatives complement factor B inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9682968-B2
Application number	US-201414904694-A
Country	US
Kind code	B2
Filing date	Jul 14, 2014
Priority date	Jul 15, 2013
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

The present invention provides a compound of formula I: (I) a method for manufacturing the compounds of the invention, and its therapeutic uses as inhibitors of the complement alternative pathway, in particular of Factor B. 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
n is 0, 1 or 2;
R is hydrogen, C 1 -C 4 alkyl, or hydroxyC 1 -C 4 alkyl;
R 1 is halogen, hydroxy, 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 6 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 phenyl, naphthyl or heteroaryl, where the heteroaryl is a five or six member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S, and where the phenyl or heteroaryl is optionally substituted by R 5 and further substituted by 0 or 1 substituents selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy C 1 -C 4 alkyl, hydroxy, and cyanomethyl;
R 5 is —C(O)R 8 , —CH 2 C(O)R 8 , R 9 , —C(O)NHSO 2 C 1 -C 4 alkyl, —SO 2 NHC(O)C 1 -C 4 alkyl, —SO 2 N(H) m (C 1 -C 4 alkyl) 2-m , —SO 2 C 1 -C 4 alkyl, cyano, halogen, hydroxyC 1 -C 4 alkyl and 5 member heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring sulfur or oxygen atoms;
m is 0, 1, or 2;
W is O or C(R 6 ) 2 ;
R 6 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, amino, mono- and di-C 1 -C 4 alkylamino, C 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, cyanoC 1 -C 4 alkyl or C 1 -C 4 alkoxy; or
C(R 6 ) 2 , taken in combination, form a spirocyclic carbocycle having 3 to 6 ring atoms;
R 7 is hydroxy, C 1 -C 4 alkoxy, amino or mono- and di-C 1 -C 4 alkylamino;
R 8 is hydroxy, C 1 -C 4 alkoxy, amino or a 5 to 7 member saturated heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O or S; or
R 8 is mono- and di-C 1 -C 4 alkylamino which is unsubstituted or substituted with halogen, hydroxy or C 1 -C 4 alkyl; and
R 9 is a 5 membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atoms, which heterocycle is optionally substituted by 0 to 2 C 1 -C 4 alkyl groups.

2. A compound of claim 1 , or salt or tautomer thereof, wherein n is 1.

3. The compound of claim 1 , or a salt or tautomer thereof, wherein W is CHR 6 or C(CH 3 )R 6 .

4. 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, or cyclopropyl.

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

6. The compound of claim 1 , or a salt or tautomer thereof, wherein R 3 is hydrogen, halogen or C 1 -C 4 alkyl.

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

8. The compound of claim 1 , or salt or tautomer thereof, according to Formula (IIa) or (IIb):

9. The compound of claim 1 , or salt or tautomer thereof, according to Formula (IIIa) or (IIIb):

Wherein X is N or CH.

10. The compound of claim 1 , or a salt or tautomer thereof, wherein R 4 is pyridin-3-yl which is substituted para to the piperidine ring with R 5 .

11. The compound of claim 1 , or a salt or tautomer thereof, wherein R 4 is phenyl substituted para to the piperidine ring with R 5 and optionally substituted with fluoro, methoxy, hydroxymethyl or hydroxy.

12. The compound of claim 11 , or a salt or tautomer thereof, wherein R 4 is phenyl substituted para to the piperidine ring with R 5 .

13. The compound of claim 1 , or salt or tautomer thereof, according to Formula (IVa) or (IVb):

14. The compound of claim 1 , or a salt or tautomer thereof, wherein R 5 is CO 2 H, CO 2 NH 2 , SO 2 NH 2 or tetrazolyl.

15. The compound of claim 1 , or a salt or tautomer thereof, which compound is selected from the group consisting of
1-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-phenylpiperidin-4-ol;
4-((4-methoxy-2-phenylpiperidin-1-yl)methyl)-5,7-dimethyl-1H-indole;
5,7-dimethyl-4-((2-phenylpiperidin-1-yl)methyl)-1H-indole;
1-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-phenyl-piperidin-4-yl)methanol;
4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzenesulfonamide;
3-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzenesulfonamide;
4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)-N-methylbenzenesulfonamide;
3-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)-N-methylbenzenesulfonamide;
4-((2-(4-fluorophenyl)-4-methoxypiperidin-1-yl)methyl)-5,7-dimethyl-1H-indole;
(1-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-phenylpiperidin-2-yl)methanol;
(4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)phenyl)methanol;
5,7-dimethyl-4-((2-(4-(methylsulfonyl)phenyl)piperidin-1-yl)methyl)-1H-indole;
4-((2-(4-(2H-tetrazol-5-yl)phenyl)piperidin-1-yl)methyl)-5,7-dimethyl-1H-indole;
1-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-phenylpiperidin-4-amine;
4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzamide;
4-(1-((5-chloro-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzamide;
4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)-4-methoxypiperidin-2-yl)benzamide;
4-(4-methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-methylpiperidin-2-yl)benzamide;
4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)-4-hydroxypiperidin-2-yl)benzoic acid;
4-(1-((5-chloro-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid;
methyl 4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)-4-methoxypiperidin-2-yl)benzoate;
4-(1-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-2-fluorobenzoic acid;
4-(1-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)pyrrolidin-2-yl)benzoic acid;
5-(1-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)picolinic acid;
4-(1-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-methoxybenzoic acid;
4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid;
5-methoxy-7-methyl-4-((2-(pyridin-4-yl)piperidin-1-yl)methyl)-1H-indole;
5-methoxy-7-methyl-4-((2-(pyridin-3-yl)piperidin-1-yl)methyl)-1H-indole;
3-fluoro-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid;
4-(4-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)morpholin-3-yl)benzoic acid;
6-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)nicotinic acid;
4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-propoxypiperidin-2-yl)benzoic acid;
4-(4-hydroxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid;
4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-3-methylbenzoic acid;
4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-5-methylpiperidin-2-yl)benzoic acid;
4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-ethylpiperidin-2-yl)benzoic acid;
2-(4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)phenyl)acetic acid;
2-(3-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)phenyl)a

Assignees

• Adams Christopher Michael
• Capparelli Michael Paul
• Ehara Takeru
• Karki Rajeshri Ganesh
• Mainolfi Nello
• Zhang Chun
• Novartis Ag

Inventors

• Adams Christopher Michael
• Capparelli Michael Paul
• Ehara Takeru
• Karki Rajeshri Ganesh
• Mainolfi Nello
• Zhang Chun

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/08

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

• A61P7/06

  Antianaemics · CPC title