US 2011/0034470 A1Published application

Inhibitors of JNK

AssigneeRoche Palo Alto LLC

InventorsLeyi Gong, Xiaochun Han, Ferenc Makra, Wylie Solang Palmer, Lubica Raptova

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Abstract

The invention relates to JNK inhibitors and corresponding methods, formulations, and compositions for inhibiting JNK and treating JNK-mediated disorders. The application discloses JNK inhibitors, as described below in Formula I: wherein p, q, Y′, r, R1, R2, X, X1, X2, X3, and X4 are as defined herein. The compounds and compositions disclosed herein are useful to modulate the activity of JNK and treat diseases associated with JNK activity. Disclosed are methods and formulations for inhibiting JNK and treating JNK-mediated disorders, and the like, with the compounds, and processes for making said compounds, and corresponding compositions, disclosed herein.

Claims23

Dependent claims

A compound of formula I

or a pharmaceutically acceptable salt thereof,
wherein:
Y′ is CH or N;
X is CH or N;
each X1 is independently halogen, lower alkyl, lower alkoxy, lower haloalkyl, or hydroxy;
m is 0, 1, or 2;
X2 is H, lower alkyl, lower alkoxy, amido, lower haloalkyl, or lower haloalkoxy;
X3 is lower alkyl, lower alkoxy, or lower haloalkyl;
p is 0 or 1;
each X4 is independently lower alkyl, lower alkoxy, lower haloalkyl, hydroxy, lower hydroxylalkyl, OC(═O)Z2, or halogen;
X5 is lower alkyl;
s is 0, 1, or 2;
q is 0, 1, or 2;
r is 0 or 1;
Y is H, OH, C(═O)Z2, C(═O)OZ2, OZ2, OC(═O)Z2, N(Z1)C(═O)(Z2), C(Z1)2S(O)2Z2, N(Z1)S(O)2Z2, N(Z1)S(O)2N(Z1)(Z2), C(Z1)2(Z2), or (C═O)N(Z1)(Z2);
Z1 is H or Z1′;
Z1′ is lower alkyl, optionally substituted with one or more Z1″;
each Z1′ is independently halogen, hydroxy, lower haloalkyl, dialkylamino or amino;
Z2 is H or Z2′;
Z2′ is hydroxy, lower alkyl, lower alkoxy, lower hydroxyalkyl, lower haloalkyl, cycloalkyl, cycloalkyl lower alkyl, heterocycloalkyl, heterocycloalkyl lower alkyl, optionally substituted with one or more Z2″;
each Z2″ is independently halogen, hydroxy, lower alkyl, cycloalkyl, cyano, lower haloalkyl, amino, carboxylic acid, ester, or lower alkoxy;
R1 is a bond, C(═O), C(═O)O, C(═O)CH2C(═O), C(═O)CH2NHC(═O)O, or S(═O)2;
R2 is H or R2′;
R2′ is hydroxy, lower alkyl, N(R3)2, lower hydroxyalkyl, or lower haloalkyl, optionally substituted with one or more R2″;
each R2″ is independently cyano, amino, dialkylamino, hydroxy, lower hydroxyalkyl, or lower alkoxy;
and
each R3 is independently H, lower alkyl, lower cycloalkyl, phenyl, lower heterocycloalkyl, or both R3 together form a heterocyclic ring;
with the proviso that when X is N, X2 is H, Y′ is CH, R1 is C(═O), R2 is methyl, r is 1, m is 0, p is 0, q is 0, Y is N(Z1)S(O)2Z2, and Z2 is methyl, then Z1 is not H or hydroxyethyl.

25 more elements

A compound selected from the group consisting of:

N-{4-[4-(4-piperazin-1-yl-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexyl}-methanesulfonamide;
4-[4-(4-Piperidin-1-yl-indol-1-yl)-pyrimidin-2-ylamino]-cyclohexanol;
N-(4-{4-[4-(4-Methanesulfonyl-piperazin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanesulfonamide;
N-(4-{4-[4-(4-Hydroxy-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanesulfonamide;
N-(4-{4-[4-(4-Acetyl-piperazin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-N-methyl-methanesulfonamide;
N-(4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanesulfonamide;
4-{1-[2-(4-Methanesulfonylamino-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazine-1-carboxylic acid amide;
4-{1-[2-(4-Methanesulfonylamino-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazine-1-sulfonic acid amide;
N-[4-(4-{4-[4-(2-Cyano-acetyl)-piperazin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide;
Acetic acid 2-(4-{1-[2-(4-methanesulfonylamino-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-2-oxo-ethyl ester;
N-[4-(4-{4-[4-(2-Hydroxy-acetyl)-piperazin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide;
4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanol;
N-(4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-acetamide;
2-(4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-propan-2-ol;
[4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl]aminodimethylsulfonamide;
4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-1-methyl-cyclohexanol;
4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-1-methyl-cyclohexanol;
(4-Hydroxy-piperidin-1-yl)-(4-{4-[4-(4-methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone;
4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethylamide;
4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester;
1-[(R)-4-(1-{2-[4-(4-Hydroxy-piperidine-1-carbonyl)-cyclohexylamino]-pyrimidin-4-yl}-1H-indol-4-yl)-3-methyl-piperazin-1-yl]-ethanone;
[2-(4-{1-[2-(4-Methanesulfonylamino-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester;
N-[4-(4-{4-[4-(2-Dimethylamino-acetyl)-piperazin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide;
N-[4-(4-{4-[4-(2-Amino-acetyl)-piperazin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl]-methanesulfonamide;
3-[4-(1-{2-[4-((R)-3-Hydroxy-pyrrolidin-1-ylmethyl)-cyclohexylamino]-pyrimidin-4-yl}-1H-indol-4-yl)-piperazin-1-yl]-3-oxo-propionitrile;
N-[4-(4-{4-[4-(2-Cyano-acetyl)-piperazin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl]-N-(2-dimethylamino-ethyl)-methanesulfonamide;
3-(4-{1-[2-(4-Hydroxymethyl-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-3-oxo-propionitrile;
3-[4-(1-{2-[4-((S)-3-Hydroxy-pyrrolidin-1-ylmethyl)-cyclohexylamino]-pyrimidin-4-yl}-1H-indol-4-yl)-piperazin-1-yl]-3-oxo-propionitrile;
1-[4-(1-{2-[4-((R)-3-Hydroxy-pyrrolidin-1-ylmethyl)-cyclohexylamino]-pyrimidin-4-yl}-1H-indol-4-yl)-piperazin-1-yl]-ethanone;
(4-Ethoxy-piperidin-1-yl)-(4-{4-[4-(4-methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone;
((R)-3-Ethoxy-pyrrolidin-1-yl)-(4-{4-[4-(4-methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone;
((S)-3-Ethoxy-pyrrolidin-1-yl)-(4-{4-[4-(4-methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone;
Cyano-acetic acid (1R,3S)-3-(4-{4-[4-(2-cyano-acetyl)-piperazin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl ester;
3-(4-{1-[2-((1S,3S)-3-Hydroxy-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-3-oxo-propionitrile;
3-(4-{1-[2-((1S,3R)-3-Hydroxy-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-3-oxo-propionitrile;
Cyano-acetic acid (1S,3S)-3-(4-{4-[4-(2-cyano-acetyl)-piperazin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl ester;
1-{4-[1-(2-Cyclohexylamino-pyrimidin-4-yl)-1H-indol-4-yl]-piperazin-1-yl}-ethanone;
3-{4-[1-(2-Cyclohexylamino-pyrimidin-4-yl)-1H-indol-4-yl]-piperazin-1-yl}-3-oxo-propionitrile;
1-[4-(1-{2-[4-(2-Methoxy-ethoxy)-cyclohexylamino]-pyrimidin-4-yl}-1H-indol-4-yl)-piperazin-1-yl]-ethanone;
3-[4-(1-{2-[4-(2-Methoxy-ethoxy)-cyclohexylamino]-pyrimidin-4-yl}-1H-indol-4-yl)-piperazin-1-yl]-3-oxo-propionitrile;
1-(4-{1-[2-(4-Methanesulfonylmethyl-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-ethanone;
3-(4-{1-[2-(4-Methanesulfonylmethyl-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-3-oxo-propionitrile;
1-[4-(1-{2-[4-(1-Hydroxy-1-methyl-ethyl)-cyclohexylamino]-pyrimidin-4-yl}-1H-indol-4-yl)-piperazin-1-yl]-ethanone;
N-[4-(4-{4-[4-(2-Cyano-acetyl)-piperazin-1-yl]-indol-1-yl}-pyrimidin-2-ylamino)-cyclohexyl]-N-(2-hydroxy-ethyl)-methanesulfonamide;
3-[4-(1-{2-[4-(1-Hydroxy-1-methyl-ethyl)-cyclohexylamino]-pyrimidin-4-yl}-1H-indol-4-yl)-piperazin-1-yl]-3-oxo-propionitrile;
(4-Ethyl-piperazin-1-yl)-(4-{4-[4-(4-methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-(4-{4-[4-(4-methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone;
(4-tert-Butyl-piperazin-1-yl)-(4-{4-[4-(4-methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone;
(4-Cyclobutyl-piperazin-1-yl)-(4-{4-[4-(4-methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone;
(4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-(octahydro-pyrido[1,2-α]pyrazin-2-yl)-methanone;
(4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-α]pyrazin-7-yl)-methanone;
(Hexahydro-pyrrolo[1,2-α]pyrazin-2-yl)-(4-{4-[4-(4-methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone;
(5,6-Dihydro-8H-[1,2,4]triazolo[4,3-α]pyrazin-7-yl)-(4-{4-[4-(4-methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone;
(5,6-Dihydro-8H-imidazo[1,2-α]pyrazin-7-yl)-(4-{4-[4-(4-methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone;
3-(4-{1-[2-(4-Hydroxy-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-3-oxo-propionitrile;
3-[4-(1-{2-[4-(4-Ethyl-piperazine-1-carbonyl)-cyclohexylamino]-pyrimidin-4-yl}-1H-indol-4-yl)-piperazin-1-yl]-3-oxo-propionitrile;
3-(4-{1-[2-(4-Hydroxy-cyclohexylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-3-oxo-propionitrile;
3-(4-{1-[2-((1S,3R)-3-Hydroxy-cyclopentylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-3-oxo-propionitrile;
3-(4-{1-[2-((1R,3S)-3-Hydroxy-cyclopentylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-3-oxo-propionitrile;
3-(4-{1-[2-((1S,3S)-3-Hydroxy-cyclopentylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-3-oxo-propionitrile;
3-(4-{1-[2-((1R,3R)-3-Hydroxy-cyclopentylamino)-pyrimidin-4-yl]-1H-indol-4-yl}-piperazin-1-yl)-3-oxo-propionitrile;
4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanol;
4-(4-Acetyl-piperazin-1-yl)-1-[2-(4-hydroxy-cyclohexylamino)-pyrimidin-4-yl]-1H-indole-3-carboxylic acid amide;
4-(4-Acetyl-piperazin-1-yl)-1-[2-(4-methanesulfonylmethyl-cyclohexylamino)-pyrimidin-4-yl]-1H-indole-3-carboxylic acid amide;
4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indazol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester;
and
4-{4-[4-(4-Methanesulfonyl-piperidin-1-yl)-indazol-1-yl]-pyrimidin-2-ylamino}-cyclohexanol.

64 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/852,540Filed 9 Aug 2010
Priority: 10 Aug 2009
Published: 10 Feb 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 403/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
A61P 3/00
Drugs for disorders of the metabolism
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…