IP Library › Granted Patent US 9,351,965
Granted Patent B2
US 9,351,965 · App. 13/994,224 · Granted May 31, 2016

Indazole derivatives useful as ERK inhibitors

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Quick Facts
Patent No.
US 9,351,965
App. No.
13/994,224
Granted
May 31, 2016
Kind
B2
Abstract

The present invention provides a compound of the Formula I, or a pharmaceutically acceptable salt, solvate or ester thereof, wherein R, R 1 , R 2 , R 3 , m and are as defined herein. The compounds are ERK inhibitors. Also disclosed are pharmaceutical compositions that comprise the above compounds, and methods of treating cancer using the same.

Claims (119)

1. The compound selected from the group consisting of:

N-[3-[(2-fluorophenyl)methyl]-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(hydroxymethyl)-3-phenoxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-amino-3-[(2-fluorophenyl)methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-[(2-fluorophenyl)methyl]-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(2-fluorophenoxy)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(2-fluorophenoxy)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(1H-imidazol-1-ylmethyl)cyclohexyl]-3-(2-methyl-2H-indazol-)-1H-indazole-5-carboxamide;

N-[3-(2-chlorophenoxy)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(2,6-dimethylphenoxy)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(2,6-difluorophenoxy)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(aminocarbonyl)-3-(3-fluorophenoxy)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-(1H-imidazol-1-ylmethyl)cyclohexyl]-3-(2-methyl-2H-indazol-)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-(1H-imidazol-1-ylmethyl)cyclohexyl]-3-(2-methyl-2H-indazol-)-1H-indazole-5-carboxamide;

N-[3-[(2-fluorophenyl)methyl]-3-(formylamino)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-[(2-fluorophenyl)methyl]-3-methoxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-[(2-fluorophenyl)methyl]-3-methoxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(2-fluorophenoxy)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(3-fluorophenoxy)-3-(hydroxymethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(1H-benzimidazol-1-ylmethyl)cyclohexyl]-3-(2-methyl-2H-indazol-)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-(1H-pyrazol-1-ylmethyl)cyclohexyl]-3-(2-methyl-2H-indazol-)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-(1H-pyrazol-1-ylmethyl)cyclohexyl]-3-(2-methyl-2H-indazol-)-1H-indazole-5-carboxamide;

N-[trans-3-(1H-benzimidazol-1-ylmethyl)-3-hydroxycyclohexyl]-3-(2-methyl-2H-indazol-)-1H-indazole-5-carboxamide;

N-[cis-3-(1H-benzimidazol-1-ylmethyl)-3-hydroxycyclohexyl]-3-(2-methyl-2H-indazol-5-yl)-1H-indazole-5-carboxamide;

N-[3-(difluorophenylmethyl)-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-hydroxy-3-(hydroxyphenylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

3-imidazo[1,2-a]pyridin-6-yl-N-[3-(1H-pyrazol-1-ylmethyl)cyclohexyl]-1H-indazole-5-carboxamide;

N-(3-benzoyl-3-hydroxycyclohexyl)-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-[(2,6-difluorophenyl)methyl]-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-(1H-1,2,4-triazol-1-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-(1H-1,2,4-triazol-1-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

3-imidazo[1,2-a]pyridin-6-yl-N-[3-(1H-1,2,4-triazol-1-ylmethyl)cyclohexyl]-1H-indazole-5-carboxamide;

Ethyl-1-[(2-fluorophenyl)methyl]-3-[[[3-(2-methyl-4-pyridinyl)-1H-indazol-5-yl]carbonyl]amino]cyclohexanecarboxylate;

N-[3-[(2-fluorophenyl)methyl]-3-(hydroxymethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(2-chlorophenoxy)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3 (R)-hydroxy-3-(1H-indazol-1-ylmethyl)-1(R)-cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3 (S)-hydroxy-3-(1H-indazol-1-ylmethyl)-1(R)-cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-[(2-fluorophenyl)methyl]-3-hydroxycyclohexyl]-3-imidazo[1,2-a]pyridin-6-yl-1H-indazole-5-carboxamide;

3-(6-benzothiazolyl)-N-[3-[(2-fluorophenyl)methyl]-3-hydroxycyclohexyl]-1H-indazole-5-carboxamide;

1-[(2-fluorophenyl)methyl]-3-[[[3-(2-methyl-4-pyridinyl)-1H-indazol-5-yl]carbonyl]amino]cyclohexanecarboxylic acid;

3-(6-benzothiazolyl)-N-[3-[(2-fluorophenyl)methyl]-3-hydroxycyclohexyl]-1H-indazole-5-carboxamide;

N-[3-[(2-methyl-1H-benzimidazol-1-yl)methyl]cyclohexyl]-3-(2-methyl-6-benzothiazolyl)-1H-indazole-5-carboxamide;

N-[3-[(3-cyano-1H-indol-1-yl)methyl]cyclohexyl]-3-(2-methyl-6-benzothiazolyl)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-[[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-[[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(difluorophenylmethyl)-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-[(2-methyl-1H-benzimidazol-1-yl)methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-[(2-methyl-1H-benzimidazol-1-yl)methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-(1H-imidazo[4,5-b]pyridin-1-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(2-chlorophenoxy)-1-piperidinyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-hydroxy-3-(hydroxyphenylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-hydroxy-3-(hydroxyphenylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(hydroxymethyl)-3-(phenylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-(3-benzoyl-3-hydroxycyclohexyl)-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-(2H-pyrazolo[3,4-b]pyridin-2-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-(1H-pyrazolo[3,4-c]pyridin-1-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-(2H-pyrazolo[3,4-c]pyridin-2-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-[(2-fluorophenyl)methyl]-3-(hydroxymethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(2,4-difluorophenoxy)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(4-fluorophenoxy)-3-(hydroxymethyl)-1-piperidinyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-[(2,4-di fluorophenyl)methyl]-3-(hydroxymethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-[(4-fluorophenyl)methyl]-3-(hydroxymethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

1-[(4-fluorophenyl)methyl]-3-[[[3-(2-methyl-4-pyridinyl)-1H-indazol-5-yl]carbonyl]amino]cyclohexanecarboxylic acid;

N-[3(S)-[(2-fluorophenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-(2-methyl[1,2,4]triazolo[1,5-a]pyridiN-6-yl)-1H-indazole-5-carboxamide;

N-[3(S)-[(2-fluorophenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-(2-methyl-6-benzothiazolyl)-1H-indazole-5-carboxamide;

N-[3(S)-[(2-fluorophenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-imidazo[1,2-a]pyridin-6-yl-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-(2H-pyrazolo[3,4-b]pyridin-2-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-(1H-pyrazolo[3,4-b]pyridin-1-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-(1H-pyrazolo[3,4-c]pyridin-1-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-(1H-imidazo[4,5-b]pyridin-1-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

3-(2-methyl-4-pyridinyl)-N-[3-(2H-pyrazolo[3,4-b]pyridin-2-ylmethyl)cyclohexyl]-1H-indazole-5-carboxamide;

3-(2-methyl-4-pyridinyl)-N-[3-(1H-pyrazolo[3,4-b]pyridin-1-ylmethyl)cyclohexyl]-1H-indazole-5-carboxamide;

3-(2-methyl-4-pyridinyl)-N-[3-(1H-pyrazolo[3,4-c]pyridin-1-ylmethyl)cyclohexyl]-1H-indazole-5-carboxamide;

N-[3-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(1H-imidazo[4,5-b]pyridin-1-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-[(2,6-difluorophenyl)methyl]-3-(hydroxymethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3(S)-[(2,6-difluorophenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-(2-methyl-6-benzothiazolyl)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-[(2,3-dihydro-2-oxo-1H-indol-1-yl)methyl]-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-[(2-oxo-1(2h)-quinolinyl)methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-hydroxy-3-(2H-indazol-2-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-[(2,3-dihydro-2-oxo-1H-indol-1-yl)methyl]-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-[(2-oxo-1(2h)-quinolinyl)methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-(2H-indazol-2-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

3-(2-methyl-4-pyridinyl)-N-[3-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)cyclohexyl]-1H-indazole-5-carboxamide;

N-[3-[(2,3-dihydro-2-oxo-1H-indol-1-yl)methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

3-(2-methyl-4-pyridinyl)-N-[3-[(2-oxo-1(2H)-quinolinyl)methyl]cyclohexyl]-1H-indazole-5-carboxamide;

N-[3-(2H-indazol-2-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(1H-indazol-1-ylmethyl)cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-[(2-fluorophenyl)methyl]-3-(hydroxymethyl)cyclopentyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-[(2-fluorophenyl)methyl]-3-(hydroxymethyl)cyclopentyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-[(4-fluoro-1H-indazol-)methyl]-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-[(6-fluoro-2H-indazol-)methyl]-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-[(7-fluoro-2H-indazol-)methyl]-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-[(4-fluoro-1H-indazol-)methyl]-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[trans-3-[(7-fluoro-1H-indazol-)methyl]-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-hydroxy-3-[[6-(trifluoromethyl)-1H-indazol-1-yl]methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-(2-fluorophenoxy)-1-piperidinyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[-3-[(5-fluoro-2H-indazol-)methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3-[(7-fluoro-1H-indazol-)methyl]cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[cis-3-[(6-fluoro-1H-indazol-)methyl]-3-hydroxycyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3(S)-[(2-fluorophenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-[2-(1-methylethoxy)-4-pyridinyl]-1H-indazole-5-carboxamide;

N-[3(S)-[(2-fluorophenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-[6-(1-methylethoxy)-3-pyridinyl]-1H-indazole-5-carboxamide;

N-[3 (S)-[(2,6-difluorophenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-[6-(1-methylethoxy)-3-pyridinyl]-1H-indazole-5-carboxamide;

N-[3(S)-[(2,6-difluorophenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-(2-methyl-2H-indazol-)-1H-indazole-5-carboxamide;

3-(6-benzothiazolyl)-N-[3 (S)-[(2,6-difluorophenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-1H-indazole-5-carboxamide;

N-[3(S)-[(2,6-difluorophenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indazole-5-carboxamide;

N-[3(S)-[(2-fluoro-6-methoxyphenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-(2-methyl-4-pyridinyl)-1H-indazole-5-carboxamide;

N-[3(S)-[(2-fluoro-6-methoxyphenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-imidazo[1,2-a]pyridin-6-yl-1H-indazole-5-carboxamide;

N-[3(S)-[(2-fluoro-6-methoxyphenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-(2-methyl-6-benzothiazolyl)-1H-indazole-5-carboxamide;

N-[3(S)-[(2-fluoro-6-methoxyphenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-[2-(1-methylethoxy)-4-pyridinyl]-1H-indazole-5-carboxamide; and

N-[3(S)-[(2-fluoro-6-methoxyphenyl)methyl]-3-hydroxy-1(R)-cyclohexyl]-3-[4-(1-methylethoxy)phenyl]-1H-indazole-5-carboxamide;

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Assignments (3)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
CHANGE OF NAME Recorded Jun 17, 2013
From: SCHERING CORPORATION
To: MERCK SHARP & DOHME CORP.
Reel/Frame 030621/0399 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 14, 2013
From: SHIPPS, GERALD W., JR.; HUANG, XIAOHUA; DENG, YONGQI; ZHU, LIANG; COOPER, ALAN B.; SUN, BINYUAN; ACHAB, ABDELGHANI ABE; LO, SIE-MUN
To: SCHERING CORPORATION
Reel/Frame 030613/0158 →