Triazolyl derivatives as Syk inhibitors

Patent metadata

Field	Value
Publication number	US-9586931-B2
Application number	US-201314431895-A
Country	US
Kind code	B2
Filing date	Sep 24, 2013
Priority date	Sep 28, 2012
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

Provided are triazole derivatives of Formula I which are potent inhibitors of spleen tyrosine kinase and pharmaceutical composition. The triazole derivatives are useful in the treatment and prevention of diseases mediated by said enzyme, such as asthma, COPD, rheumatoid arthritis, and cancer.

First claim

The invention claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

is:

ring a is

ring b is

Y a1 is CH;
Y b1 is N;
Y b2 is CH;
R 1a is independently: H, halogen, or C 1 -C 3 -alkyl;
R 1 is
halogen;
Si(CH 3 ) 3 ; or
C 1 -C 6 -alkyl or C 2 -C 6 -alkenyl, optionally substituted with one to four substituents selected from the group consisting of: CN; OH; oxo; NH 2 ; halogen; 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 or fluoro; aryl; Oaryl optionally substituted with halogen; or heterocyclyl;

Heterocyclyl is a 4-, 5-, 6-, or 7-membered monocyclic ring or 8-, 9-, 10-, 11-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 point of attachment of the heterocyclyl can be on the carbon or nitrogen and the heterocyclyl may optionally be substituted with one to four substituents selected from CN; OH; oxo; NH 2 ; halogen; CO(CH 2 ) m CH 3 , optionally substituted with one or two substituents selected from OH and CO 2 R c ; C 1 -C 3 -alkyl; C 2 -C 4 -alkenyl; C 1 -C 3 -haloalkyl; C 1 -C 3 -alkoxyl optionally substituted with OH; aryl optionally substituted with one or two substituents selected from C 1 -C 3 -alkoxyl, halogen, or Oaryl; CH 2 aryl; OCH 2 aryl; Oaryl optionally substituted with one or two substituents selected from halogen; (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 ; (CHR a ) p —C(O)-heterocyclyl; and furyl; or alternatively, 2 substituents which are geminally substituted on a common ring carbon atom of said heterocyclyl may together with the common ring carbon atom form a C 3 -C 6 spirocyclic ring;
Aryl is a phenyl or napthyl ring, the aryl may optionally be substituted with one to four substituents selected from halogen, hydroxyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxyl, Oaryl, (CR a R b ) n CO 2 R c ; and (CR a R b ) n CONR d R e ;
R 2 is halogen, C 1 -C 3 -alkyl, or C 1 -C 3 -haloalkyl;
R 3 is halogen or C 1 -C 3 -fluoroalkyl;
R 4 is H, halogen, or C 1 -C 3 -alkyl;
R a and R b are independently: H, OH, CN, CO 2 R c , CONH 2 , NH 2 , cyclopropyl, C 1 -C 3 -haloalkyl, or C 1 -C 3 -alkyl optionally substituted with hydroxyl;
R c is: H; C 1-4 alkyl; -M-R CH ; —(CH 2 ) 1-2 —R f ; —(CH 2 ) 2 —O—(CH 2 ) 2 —R f ; —(CH 2 ) 2 —R g , —CHR h OCO 2 R i , —CHR i R h , or —(CHR h ) s OC(O)R i ;
R d and R e are independently: H, C 1 -C 3 -alkoxyl or C 1 -C 6 -alkyl, optionally substituted with one, two or three substituents CN; OH; oxo; NH 2 ; halogen; CO 2 R c ; CONH 2 ; C 1 -C 3 -alkoxyl, CO 2 R c ; aryl, carbocyclyl, or heterocyclyl; or cyclopropyl optionally substituted with phenyl;
R f is —OC(O)R f1 ;
R f1 is C 1-4 alkyl; and
R g is OH, C 1-4 alkoxyl, NH 2 , NH(C 1-4 alkyl) or N(C 1-4 alkyl) 2 ;
R h is H or C 1-4 alkyl; and
R i is C 1-4 alkyl, C 3-6 cycloalkyl, or phenyl; and,
M is a bond or —(CH 2 ) 1-3 —;
R CH is (a) aryl or carbocycle optionally substituted with 1-3 groups independently selected from halo, C 1-4 alkyl, or C 1-4 alkoxy; or (b) a 5- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, wherein said heterocycle of R CH is optionally substituted with 1 or 2 groups independently selected from the group consisting of oxo and C 1-3 alkyl;
m is 0, 1, or 2;
n is 0, 1, 2, 3 or 4;
p is 0 or 1; and
s is 1 or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having the Formula Ia:

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having the Formula Ib:

4. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Formula Ia is:

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein Formula Ia is:

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 1 is Si(CH) 3 or C 1 -C 6 -alkyl, optionally substituted with one to four substituents selected from the group consisting of: CN, OH, oxo, NH 2 , halogen, CF 3 , C 1 -C 3 -alkyl, and C 1 -C 3 -alkoxyl.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 -alkyl, optionally substituted with one to four substituents selected from the group consisting of: CN, OH, oxo, NH 2 , halogen, CF 3 , CH 3 and OCH 3 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
2-methyl-3-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propane-1,2-diol;
(3R)-3-hydroxy-4-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]butanenitrile;
3-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propane-1,2-diol;
1-fluoro-3-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propan-2-ol;
3-hydroxy-4-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]pentanenitrile;
(2S)-3-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propane-1,2-diol;
1-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]butane-2,3-diol;
(3R)-3-hydroxy-4-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]butanamide;
2-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethanol;
2-methyl-1-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propan-2-ol;
(2R)-2-[4-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propanamide.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
(R)-1-[4-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2,3-dimethylbutane-2,3-diol;
(S)-1-[4-(6-{[4-(difluoromethyl)pyridin-2-yl]amino}-4-methylpyridin-2-yl)-1H-1,2,3-triazol-1-yl]-2,3-dimethylbutane-2,3-diol;
(R)-1-(4-{6-[(5-chloro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-1H-1,2,3-triazol-1-yl)-2,3-dimethylbutane-2,3-diol;
(S)-1-(4-{6-[(5-chloro-4-methylpyridin-2-yl)amino]-4-methylpyridin-2-yl}-triazol-1-yl)-2,3-dimethylbutane-2,3-diol;
(R)-1-[4-(6-{[4-(1-fluoroethyl)pyridin-2-yl]amino}-4-methylpyridin

Assignees

• Machacek Michelle R
• Romeo Eric T
• Kattar Solomon D
• Christopher Matthew
• Altman Michael D
• Northrup Alan B
• Ellis John Michael
• O'Boyle Brendan
• Donofrio Anthony
• Grimm Jonathan
• Reutershan Michael H
• Childers Kaleen Konrad
• Otte Ryan D
• Cash Brandon
• Ducharme Yves
• Haidle Andrew M
• Spencer Kerrie
• Vitharana Dilrukshi
• Wu Lingyun
• Zhang Li
• Zhang Peng
• Beaulieu Christian
• Guay Daniel
• Merck Sharp & Dohme
• Merck Canada Inc

Inventors

• Machacek Michelle R
• Romeo Eric T
• Kattar Solomon D
• Christopher Matthew
• Altman Michael D
• Northrup Alan B
• Ellis John Michael
• O'Boyle Brendan
• Donofrio Anthony
• Grimm Jonathan
• Reutershan Michael H
• Childers Kaleen Konrad
• Otte Ryan D
• Cash Brandon
• Ducharme Yves
• Haidle Andrew M
• Spencer Kerrie
• Vitharana Dilrukshi
• Wu Lingyun
• Zhang Li
• Zhang Peng
• Beaulieu Christian
• Guay Daniel

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61K9/10

  Dispersions; Emulsions · CPC title

• A61K9/2027

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title