IP Library › Granted Patent US 9,487,504

Granted Patent B2

US 9,487,504 · App. 14/409,147 · Granted Nov 8, 2016

Imidazolyl analogs as syk inhibitors

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Quick Facts

Patent No.: US 9,487,504
App. No.: 14/409,147
Granted: Nov 8, 2016
Kind: B2

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Abstract

The present invention provides novel imidazole analogs of Formula I which are potent inhibitors of spleen tyrosine kinase, and are useful in the treatment and prevention of diseases mediated by said enzyme, such as asthma, COPD, rheumatoid arthritis, and cancer.

Claims (94)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Y a1 is CH or N;

Y b1 is CH or N, such that Y b1 and Y a1 cannot both simultaneously be C or N;

R 1a and R 1b are independently H or C 1 -C 3 -alkyl;

R 1 is:

(CR a R b ) n -cyclohexyl, wherein said cyclohexyl may optionally be substituted with one to four substituents selected from hydroxyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxyl, (CR a R b ) n CO 2 R c , (CR a R b ) n CONR d R e , and a spiro-linked —OCH 2 CH 2 O—;

R a and R b are independently: H, OH, or C 1 -C 3 -alkyl optionally substituted with 1-3 hydroxyl;

R c is: H or C 1-4 alkyl;

R d and R e are independently: H, C 1 -C 3 -alkoxyl or C 1 -C 6 -alkyl, optionally substituted with 1-4 substituents selected from: CN, OH, oxo; NH 2 , halogen, CO 2 R c , CONH 2 , C 1 -C 3 -alkoxyl, CO 2 R c ; aryl, carbocyclyl, and heterocyclyl, as defined below;

or alternatively, R d and R e taken together with the nitrogen to which they are attached form a heterocyclic 5- to 6-membered monocyclic ring containing 0-2 additional heteroatoms selected from O, N, or S, the ring may be saturated, unsaturated or aromatic; the heterocyclic ring is optionally substituted with 1-2 substituents selected from CN; OH; oxo; NH 2 ; halogen; COCH 3 , CO 2 R c ; CONH 2 ; C 1 -C 3 -alkyl; C 1 -C 3 -haloalkyl; C 1 -C 3 -alkoxyl optionally substituted with OH; aryl optionally substituted with C 1 -C 3 -alkoxyl; CH 2 aryl; Oaryl optionally substituted with halogen; and heterocyclyl, wherein aryl and heterocyclyl are as defined below;

wherein said heterocyclyl, carbocyclyl and aryl of R d and R e are as follows:

heterocyclyl is a 4-, 5-, 6-, or 7-membered monocyclic ring or 8-, 9-, 10-membered bicyclic ring, or 13- or 14-membered tricyclic ring; the monocyclic, bicyclic or tricyclic ring can be saturated, unsaturated or aromatic, containing 1, 2, 3 or 4 heteroatoms selected from O, N, or S, the heterocyclyl may optionally be substituted with one to four substituents selected from oxo, halo, hydroxyl, C 1 -C 3 -alkyl, C 2 -C 6 -alkenyl, C 1 -C 3 -alkoxyl, (CR a R b ) n CO 2 R c , (CR a R b ) n CONR d R e ; (CHR a ) n NHCONR d R e ; and (CHR a ) p —C(O)-heterocyclyl;

carbocyclyl is a 4-, 5-, 6-, 7- or 8-membered monocyclic ring or 8-, 9-, 10-membered bicyclic ring, or 13- or 14-membered tricyclic ring, in which all ring atoms are carbon, at least one ring is saturated or partially unsaturated and that ring being isolated or fused to one or two such rings or to a benzene ring; the carbocyclyl may optionally be substituted with one to four substituents selected from hydroxyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxyl, (CR a R b ) n CO 2 R c , (CR a R b ) n CONR d R e , and a spiro-linked —OCH 2 CH 2 O—;

aryl is a 6-membered monocyclic or 10-membered bicyclic aromatic carbon ring, the aryl may optionally be substituted with one to four substituents selected from hydroxyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxyl, (CR a R b ) n CO 2 R c , and (CR a R b ) n CONR d R e ;

n is 0, 1, 2, 3 or 4;

p is 0 or 1;

R 2 is H or CH 3 ;

R 3 is H, CF 3 , CH 3 , or CF 2 H; and

R 4 is H, Cl or F.

2. The compound of claim 1 , wherein the compound of Formula I has the Formula Ia

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound of Formula I has the Formula Ib

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is CF 3 and R 2 is methyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof selected from:

Cis-4-hydroxy-N-methyl-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxamide;

Trans-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxylic acid;

Cis-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxylic acid;

Rac-(1R,3S,4S)-3,4-dihydroxy-1-methyl-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxylic acid;

Rac-(1R,3R,4R)-3,4-dihydroxy-1-methyl-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxylic acid;

2-{Cis-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexyl}acetamide;

Trans-4-{1-hydroxy-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]ethyl}cyclohexanecarboxamide;

Trans-4-[1-hydroxy-1-(1-{3-methyl-5-[(4-methyl-pyrimidin-2-yl)amino]-phenyl}-1H-imidazol-4-yl)ethyl]cyclohexane-carboxylic acid;

Trans-4-{1-hydroxy-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]ethyl}-cyclohexanecarboxylic acid;

Butyl Trans-4-[1-hydroxy-1-(1-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1H-imidazol-4-yl)ethyl]-cyclohexanecarboxylate;

Butyl Trans-4-{1-hydroxy-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]ethyl}cyclohexanecarboxylate;

{Trans-4-hydroxy-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexyl}acetic acid;

{Cis-4-hydroxy-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexyl}acetic acid;

{Trans-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexyl}acetic acid;

{Cis-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexyl}acetic acid;

Methyl {Trans-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexyl}acetate;

Methyl {Cis-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexyl}acetate;

Trans-4-hydroxy-1-methyl-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxylic acid;

Ethyl Trans-4-hydroxy-1-methyl-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxylate;

Ethyl 2-{Cis-4-hydroxy-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexyl}-2-methylpropanoate;

Ethyl 2-{Trans-4-hydroxy-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexyl}-2-methylpropanoate;

4-Hydroxy-2,2-dimethyl-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxylic acid;

Trans-4-hydroxy-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexanecarboxylic acid;

Cis-4-hydroxy-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexanecarboxylic acid;

Ethyl Trans-4-hydroxy-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexanecarboxylate;

Ethyl Cis-4-hydroxy-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexanecarboxylate;

Cis-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]-4-(morpholin-4-ylcarbonyl)cyclohexanol;

Cis-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]-4-(pyrrolidin-1-ylcarbonyl)cyclohexanol;

Cis-4-hydroxy-N,N-dimethyl-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxamide;

Trans-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxamide;

Cis-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxamide;

Trans-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxylic acid;

Ethyl Trans-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxylate;

Cis-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexane-1,4-diol;

Cis-1-(1-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1H-imidazol-4-yl)cyclohexane-1,4-diol;

Cis-1-(1-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1H-imidazol-4-yl)cyclohexane-1,4-diol;

Cis-1-(1-{6-[(5-chloro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1H-imidazol-4-yl)cyclohexane-1,4-diol;

Cis-1-(1-{4-methyl-6-[(4-methylpyridin-2-yl)amino]pyridin-2-yl}-1H-imidazol-4-yl)cyclohexane-1,4-diol;

Cis-4-(1-{6-[(5-fluoro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1H-imidazol-4-yl)-4-hydroxycyclohexyl benzoate;

Cis-4-(1-{6-[(5-chloro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1H-imidazol-4-yl)-4-hydroxycyclohexyl benzoate;

Cis-4-hydroxy-4-(1-{4-methyl-6-[(4-methylpyridin-2-yl)amino]pyridin-2-yl}-1H-imidazol-4-yl)cyclohexyl benzoate;

4-Hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanone;

(1S,3S,4S)-3-Methyl-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexane-1,4-diol;

(1R,3S,4S)-3-Methyl-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexane-1,4-diol;

(1S,3S,4R)-3-Methyl-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexane-1,4-diol;

Cis-1-(1-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1H-imidazol-4-yl)cyclohexane-1,4-diol;

Cis-4-(1-{3-[(5-fluoro-4-methylpyrimidin-2-yl)amino]-5-methylphenyl}-1H-imidazol-4-yl)-4-hydroxycyclohexyl benzoate;

Trans-1-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexane-1,4-diol;

Cis-1-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexane-1,4-diol;

Trans-4-hydroxy-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexyl benzoate;

Cis-4-hydroxy-4-[1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-imidazol-4-yl]cyclohexyl benzoate;

Trans-1-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexane-1,4-diol;

Trans-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexyl benzoate;

Ethyl cis-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxylate; and

Cis-4-hydroxy-4-[1-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-imidazol-4-yl]cyclohexanecarboxylic acid.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof selected from: