Claims for Patent: 9,682,968

Summary for Patent: 9,682,968

Title:	Piperidinyl-indole derivatives complement factor B inhibitors and uses thereof
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.
Inventor(s):	Christopher Michael ADAMS, Michael Paul Capparelli, Takeru Ehara, Rajeshri Ganesh Karki, Nello Mainolfi, Chun Zhang
Assignee:	Novartis AG
Application Number:	US14/904,694
Patent Claims:	1. A compound, or salt or tautomer thereof, according to Formula (I): Wherein n is 0, 1 or 2; R is hydrogen, C1-C4alkyl, or hydroxyC1-C4alkyl; R1 is halogen, hydroxy, C1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, C1-C6alkoxy, haloC1-C6alkyl, hydroxyC1-C6alkyl, aminoC1-C6alkyl, C1-C6alkoxyC1-C6alkyl, C1-C6alkoxyC1-C6alkoxy, C3-C6cycloalkylC1-C6alkoxy, haloC1-C6alkoxy, —S(O)pC1-C6alkyl, —CH2NHC(O)C1-C4alkyl or —OCH2C(O)R7, p is 0, 1, or 2; R2 is C1-C6alkyl, C1-C6alkoxy, hydroxyC1-C6alkyl or halogen; R3 is hydrogen, halogen, cyano, C1-C4alkyl, haloC1-C4alkyl, —CH2C(O)R7, 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 C1-C4alkyl groups, and wherein alkyl and haloalkyl optionally substituted with 0 or 1 hydroxy; R4 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 R5 and further substituted by 0 or 1 substituents selected from halogen, C1-C4alkyl, C1-C4alkoxy, hydroxy C1-C4alkyl, hydroxy, and cyanomethyl; R5 is —C(O)R8, —CH2C(O)R8, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)m(C1-C4alkyl)2-m, —SO2C1-C4alkyl, cyano, halogen, hydroxyC1-C4alkyl 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(R6)2; R6 is independently selected at each occurrence from the group consisting of hydrogen, hydroxy, amino, mono- and di-C1-C4alkylamino, C1-C4alkyl, hydroxyC1-C4alkyl, cyanoC1-C4alkyl or C1-C4alkoxy; or C(R6)2, taken in combination, form a spirocyclic carbocycle having 3 to 6 ring atoms; R7 is hydroxy, C1-C4alkoxy, amino or mono- and di-C1-C4alkylamino; R8 is hydroxy, C1-C4alkoxy, amino or a 5 to 7 member saturated heterocycle having 1, 2, or 3 ring heteroatoms independently selected from N, O or S; or R8 is mono- and di-C1-C4alkylamino which is unsubstituted or substituted with halogen, hydroxy or C1-C4alkyl; and R9 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 C1-C4alkyl 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 CHR6 or C(CH3)R6. 4. The compound of claim 1, or a salt or tautomer thereof, wherein R1 is C1-C4alkyl, C1-C4alkoxy, or cyclopropyl. 5. The compound of claim 1, or a salt or tautomer thereof, wherein R2 is methyl. 6. The compound of claim 1, or a salt or tautomer thereof, wherein R3 is hydrogen, halogen or C1-C4alkyl. 7. The compound of claim 1, or a salt or tautomer thereof, wherein R3 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 R4 is pyridin-3-yl which is substituted para to the piperidine ring with R5. 11. The compound of claim 1, or a salt or tautomer thereof, wherein R4 is phenyl substituted para to the piperidine ring with R5 and optionally substituted with fluoro, methoxy, hydroxymethyl or hydroxy. 12. The compound of claim 11, or a salt or tautomer thereof, wherein R4 is phenyl substituted para to the piperidine ring with R5. 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 R5 is CO2H, CO2NH2, SO2NH2 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)acetic acid; 5-(1-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-4-methoxypiperidin-2-yl)picolinic acid; 2-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)thiazole-4-carboxylic acid; 2-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-4-methylthiazole-5-carboxylic acid; 3-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid; 4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)azepan-2-yl)benzoic acid; 4-((2-(4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole; 4-((2-(4-(1H-pyrazol-3-yl)phenyl)piperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole; 4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-1-naphthoic acid; 1-(2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)piperidin-2-yl)benzoic acid; 2-methoxy-4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid; 2-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)-2-phenylpiperidin-4-yl)acetonitrile; 4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-methylpiperidin-2-yl)benzoic acid; 4-(4-methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid; 5-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)picolinic acid; 4-(1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4,4-dimethylpiperidin-2-yl)benzoic acid; 4-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzonitrile; 4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid; 4-((4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid; 4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)-4-methoxypiperidin-2-yl)benzoic acid; 4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)-4-ethoxypiperidin-2-yl)benzoic acid; 4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)-4-ethoxypiperidin-2-yl)benzoic acid; 4-(1-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-4-methoxypiperidin-2-yl)benzoic acid; 4-(1-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-4-ethoxypiperidin-2-yl)benzoic acid; 4-(1-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)-4-ethoxypiperidin-2-yl)benzoic acid; 4-(5-methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid; 4-(5-methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzamide; 4-(5-methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid; 4-(5-hydroxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid; 1((5,7-dimethyl-1H-indol-4-yl)methyl)-N-methyl-2-phenylpiperidin-4-amine; (4-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)phenyl)methanamine; (4-(4-methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)phenyl)methanol; 4-((2-(3-(2H-tetrazol-5-yl)phenyl)piperidin-1-yl)methyl)-5,7-dimethyl-1H-indole; 3-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzamide; (3-(1-((5,7-dimethyl-1H-indol-4-yl)methyl)piperidin-2-yl)phenyl)methanol; (4-((2-(4-(1H-tetrazol-5-yl)phenyl)-4-ethoxypiperidin-1-yl)methyl)-5-methoxy-7-methyl-1H-indole; 4-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-N-(methylsulfonyl)benzamide; 4-(4-methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-N-methylbenzamide; 4-(4-methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-N,N-dimethylbenzamide; (4-(4-methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)phenyl)(morpholino)methanone; N-(2-hydroxyethyl)-4-(4-methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzamide; 4-(4-methoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)-N-(2-methoxyethyl)benzamide; N-((4-(1-((5-cyclopropyl-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)phenyl)sulfonyl)acetamide; 4-(6-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-6-azaspiro[2.5]octan-5-yl)benzoic acid; 4-ethyl-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid; ethyl 4-((2S,4R)-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-4-methylpiperidin-2-yl)benzoate; ethyl 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoate and salts, stereoisomers and tautomers thereof. 16. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of claim 1. 17. A compound of claim 1 which is 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid or a pharmaceutically acceptable salt thereof.