US 9,212,178 B2Granted

Substituted pyrimidine compounds and their use as SYK inhibitors

AssigneesGenosco, Oscotec Inc.

InventorsJaekyoo Lee, Jang-Sik Choi, Hae-Jun Hwang, Ho-Juhn Song, Jung-Ho Kim, Se-Won Kim, Jong Sung Koh, Jaesang Lee, Tae-Im Lee, Yung-Geun Choi, Sung-Ho Park, In Yong Lee, Byung-Chul Suh, Paresh Devidas Salgaonkar, Dong-Sik Jung

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Abstract

Compounds of Formula (I) and methods for inhibiting kinases, including spleen tyrosine kinases, are disclosed. Also disclosed are methods for treating a kinase-mediated disease or condition by administering to a subject a therapeutically effective amount of the compound of Formula (I).

Claims19

Dependent claims

A compound of Formula (I):

Wherein:
R1, R2, R3, R4, R5, R6a, R6b, X and Y are as described herein:
X is CH or N;
Y is C, CH or N;
n is 1 or 2;
is a single or a double bond, provided that if Y is C, then represents a double bond;
When Y is N or CH and represents a double bond, R2 is absent;
R1 is selected from H, C1-C6alkyl, C3-C7cycloalkyl, C5-C8heterocycloalkyl, aryl, arylalkyl, heteroaryl, C(O)OR7, and S(O)2R7, wherein C1-C6 alkyl, C5-C8heterocycloalkyl, aryl, arylalkyl, or heteroaryl is optionally substituted with one or more halo, hydroxy, or OR7;
When Y is C and represents a double bond, or when Y is CH or N and represents a single bond, then,
R2 is selected from H, halo, CF3, C1-C4alkyl and aryl, wherein the C1-C4alkyl or aryl is optionally substituted with one or more halo, amino, hydroxy, alkoxy, or haloalkyl;
R3 is selected from H, halo, C(O)NR7R7, C(O)R7, S(O)mR7, and S(O)mNR7R7, wherein each m is 1 or 2;
R4 is selected from H, halo, C1-C6alkyl, and C3-C7cycloalkyl, wherein the C1-C6alkyl, or C3-C7cycloalkyl is optionally substituted with one or more halo, amino, hydroxy, alkoxy, or haloalkyl;
R5 is selected from H, halo, C1-C6alkyl, and C3-C7cycloalkyl, wherein C1-C6alkyl or C3-C7cycloalkyl is optionally and independently substituted with one or more halo, alkoxy, or haloalkyl;
R6a is selected from H, halo, hydroxy, CN, CH2OH, NH2, C1-C6alkyl, C3-C7cycloalkyl, C6-C10aryl, heteroaryl, OR7, NR7R7, NHR7, and NHC(O)R7;
R6b is selected from H, CH2OH, CH2NH2, and C1-C6alkyl;
R7 is independently selected from C1-C6 alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C7cycloalkyl, aryl, aryl(C1-C4)alkyl, haloalkyl, heteroaryl, and heterocycloalkyl, wherein the C1-C6alkyl, C3-C6alkenyl, C3-C6alkynyl, C3-C7cycloalkyl, aryl, aryl(C1-C4)alkyl, haloalkyl, heteroaryl, or heterocycloalkyl is optionally and independently substituted with one or more substituents selected from aryl, cycloalkyl, heteroaryl, heterocycloalkyl, alkyl, halo, amino, and hydroxy;
or a pharmaceutically acceptable salt thereof.

14 more elements

A compound selected from the group consisting of

(S)-cyclopropyl(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)methanone;
(S)-1-(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)-2-methylpropan-1-one;
(S)-2,2,2-trifluoro-1-(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)ethanone;
(S)-2,2-difluoro-1-(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)ethanone;
(S)-ethyl 3-acetyl-5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1H-indole-1-carboxylate;
(S)-cyclopropyl(1-ethyl-5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1H-indol-3-yl)methanone;
(S)-2,2,2-trifluoro-1-(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1H-indol-3-yl)ethanone;
(S)-cyclopropyl(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-isopropyl-1H-indol-3-yl)methanone;
(S)-1-(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)ethanone;
(R)-2,2-difluoro-1-(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)ethanone;
(R)-cyclopropyl(1-ethyl-5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1H-indol-3-yl)methanone;
(S)-cyclopropyl(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1H-indol-3-yl)methanone;
cyclopropyl(1-ethyl-5-(4-(4-((4-hydroxy-4-methylisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1H-indol-3-yl)methanone;
cyclopropyl(5-(4-(4-((4-hydroxy-4-methylisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)methanone;
(S)-cyclopropyl(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)methanone;
cyclopropyl(5-(4-(4-((4-hydroxy-4-methylisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)methanone;
(S)-1-(5-(5-chloro-4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)-2,2,2-trifluoroethanone;
(S)-2,2,2-trifluoro-1-(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-methylpyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)ethanone;
(S)-cyclopropyl(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-methylpyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)methanone;
(S)-cyclopropyl(1-ethyl-5-(5-fluoro-4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1H-indol-3-yl)methanone;
(S)-cyclopropyl(1-ethyl-5-(5-fluoro-4-(3-((4-hydroxyisoxazolidin-2-yl)methyl)-4-methyl-1H-pyrrol-1-yl)pyrimidin-2-ylamino)-1H-indol-3-yl)methanone;
(S)-cyclopropyl(1-ethyl-5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-5-methylpyrimidin-2-ylamino)-1H-indol-3-yl)methanone;
(S)-cyclopropyl(1-(2-fluoroethyl)-5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1H-indol-3-yl)methanone;
cyclopropyl(1-(2-fluoroethyl)-5-(4-(4-(((S)-4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)indolin-3-yl)methanone;
(S)-cyclopropyl(5-(4-(3-cyclopropyl-4-((4-hydroxyisoxazolidin-2-yl)methyl)-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-ethyl-1H-indol-3-yl)methanone;
(S)-2-((3-methyl-1-(2-(1-methyl-3-(methylsulfonyl)-1H-indazol-5-ylamino)pyrimidin-4-yl)-1H-pyrazol-4-yl)methyl)isoxazolidin-4-ol;
(S)-cyclopropyl(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-3-methyl-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-(methylsulfonyl)-1H-indol-3-yl)methanone;
(S)-cyclopropyl(1-ethyl-5-(4-(3-((4-hydroxyisoxazolidin-2-yl)methyl)-4-methyl-1H-pyrrol-1-yl)pyrimidin-2-ylamino)-1H-indol-3-yl)methanone;
(S)-cyclopropyl(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-methyl-1H-indol-3-yl)methanone;
(S)-2-((1-(2-(3-chloro-1,2-dimethyl-1H-indol-5-ylamino)pyrimidin-4-yl)-3-methyl-1H-pyrazol-4-yl)methyl)isoxazolidin-4-ol;
(S)-cyclopropyl(1-(2-fluoroethyl)-5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1H-indol-3-yl)methanone;
(S)-cyclopropyl(1-(2,2-difluoroethyl)-5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1H-indol-3-yl)methanone;
and
(S)-cyclopropyl(5-(4-(4-((4-hydroxyisoxazolidin-2-yl)methyl)-1H-pyrazol-1-yl)pyrimidin-2-ylamino)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)methanone;
or a pharmaceutically acceptable salt thereof.

32 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/520,279Filed 21 Oct 2014 · us provisional application
Priority: 21 Oct 2013
Published: US 2015/0111883 A123 Apr 2015
Granted: 15 Dec 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification28 codes

C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61K 31/5355
Having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines: non-condensed oxazines and…
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…