Substituted pyridine spleen tyrosine kinase (SYK) inhibitors

Patent metadata

Field	Value
Publication number	US-9376418-B2
Application number	US-201314409151-A
Country	US
Kind code	B2
Filing date	Jun 17, 2013
Priority date	Jun 22, 2012
Publication date	Jun 28, 2016
Grant date	Jun 28, 2016

Abstract

The invention provides certain substituted pyridines of the Formula (I) or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R cy , C y , and t are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk) kinase.

First claim

What is claimed is:

1. A compound of the Formula (I) or a pharmaceutically acceptable salt thereof,

wherein
R 1 is selected from the group consisting of C 1 -C 3 fluoroalkyl;
R 2 is H;
R 3 is H;
R 4 is selected from the group consisting of C 1 -C 3 alkyl and —N(H)C(O)R 4b ;
R 4b is C 1 -C 3 alkyl;

C y is

t is 1;
R cy is a group of the formula

 wherein
Y 1 is a bond;
D 1 is a 4- to 8-membered mono- or bicyclic heterocyclic ring optionally containing one additional heteroatom selected from the group consisting of N and S;
each R 10 is independently selected from the group consisting of C 1 -C 3 alkyl, hydroxyl, —CO 2 H, —CH 2 CO 2 R g , —C(O)N(H)—(CH 2 CO 2 H), or wherein when two R 10 moieties are geminally substituted on a common ring carbon atom of D 1 , the two geminally substituted R 10 moieties together with the carbon atom on which they are attached form —C(O)—;
R g is H or C 1 -C 3 alkyl; and

q is 1.

2. A compound of the Formula (I) or a pharmaceutically acceptable salt thereof,

wherein
R 1 is selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkoxy, and cyclopropyl;
R 2 is H or halo;
R 3 is H;
R 4 is selected from the group consisting of H, C 1 -C 3 alkyl, and halo;
C y is a 6-membered heteroaryl selected from the group consisting of:

t is 1;
R cy is a group of the formula

 wherein
Y 2 is a bond or —N(H)—;
s is 0, 1 or 2;
R i is H, methyl, hydroxyl, or —CO 2 H;
R j is H or methyl;
D 2 is selected from the group consisting of:
(i) cyclohexyl;
(ii) a 5- to 6-membered heterocyclyl containing one to two N atoms;
(iii) a 5-membered heteroaryl containing two to three N atoms; and
(iv) phenyl;

each R 10 is independently selected from the group consisting of C 1 -C 3 alkyl, hydroxyl, —CO 2 R g , —C(O)NH 2 , —C(O)CH 2 CN, and —C(O)CH 2 OH;
R g is H or C 1 -C 3 alkyl; and

q is 0, 1, 2, 3, or 4.

3. A compound of the Formula (I) or a pharmaceutically acceptable salt thereof

wherein
R 1 is selected from the group consisting of C 1 -C 3 fluoroalkyl and cyclopropyl;
R 2 is H or halo;
R 3 is H;
R 4 is selected from the group consisting of H, C 1 -C 3 alkyl, and —N(H)C(O)R 4b ;
R 4b is C 1 -C 3 alkyl;

C y is a 6-membered heteroaryl selected from the group consisting of:

t is 1;
R cy is a group of the formula

 wherein
Y 3 is a bond,

R e is H, C 1 -C 3 alkyl, or —(CH 2 ) n3 CN;
wherein n3 is 2 or 3;

each R a is independently selected from the group consisting of H, C 1 -C 6 alkyl, hydroxy(C 1 -C 3 )alkyl, —(CH 2 ) n4 —O—(C 1 -C 3 )alkyl, —(CH 2 ) n4 C(O)NH 2 , —(CH 2 ) n4 S—(C 1 -C 3 )alkyl, and —(CH 2 ) n4 S(O) 2 —(C 1 -C 3 )alkyl;
wherein each n4 is independently 1, 2, or 3;

each R b is independently selected from the group consisting of H, hydroxyl, C 1 -C 6 alkyl, fluoro, C 1 -C 3 fluoroalkyl, hydroxy(C 1 -C 3 )alkyl, —(CH 2 ) n4 —O—(C 1 -C 3 )alkyl,
—(CH 2 ) n4 C(O)NH 2 , —(CH 2 ) n4 S—(C 1 -C 3 )alkyl, and —(CH 2 ) n4 S(O) 2 —(C 1 -C 3 )alkyl;

each R c and R d is independently selected from the group consisting of H or C 1 -C 3 alkyl;
R f is —CO 2 R g , hydroxyl, or —C(O)N(R h ) 2 ;
R g is H or C 1 -C 3 alkyl;
wherein each R h is independently H, C 1 -C 3 alkyl, or —CH 2 CO 2 H;

n1 is 0, 1 or 2; and
n2 is 0 or 1.

4. A compound of the Formula (IB) or a pharmaceutically acceptable salt thereof,

wherein
R 1 is selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl, and C 3 -C 6 cycloalkyl;
R 4 is selected from the group consisting of H, C 1 -C 3 alkyl and C 1 -C 3 fluoroalkyl;
one of X 1 and X 2 is N and the other is C;
R i is H or hydroxyl;
R j is H or C 1 -C 3 alkyl;
s is 0, 1, 2, or 3;
R 10 is C 1 -C 3 alkyl or hydroxyl;
q1 is 0, 1, 2, or 3;
u is 1 or 2; and
R g is H or C 1 -C 3 alkyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof,
wherein
R 1 is selected from the group consisting of methyl, —CF 3 , and cyclopropyl;
R 4 is selected from the group consisting of H, methyl, and —CF 3 ; and
R i is H or hydroxyl;
R j is H or methyl;
s is 0 or 1; and
R 10 is methyl or hydroxyl.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof,
wherein the group

 is a group of the formula

and
q1 is 0, 1, or 2.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R g is H.

8. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
trans-4-[1-hydroxy-1-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}pyridin-2-yl)ethyl]cyclohexanecarboxylic acid;
trans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyridin-2-yl]-1-hydroxyethyl}cyclohexanecarboxylic acid;
trans-4-{1-hydroxy-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]ethyl}cyclohexanecarboxylic acid;
trans-4-[1-hydroxy-1-(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}pyridin-2-yl)ethyl]cyclohexanecarboxylic acid;
2-methyl-N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]alanine;
trans-4-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}pyridin-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid;
cis-4-hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]cyclohexanecarboxylic acid;
trans-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]cyclohexanecarboxylic acid;
1-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]amino}cyclobutanecarboxylic acid;
3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoic acid;
1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-proline;
N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]serine;
N-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phen

Assignees

• Merck Sharp & Dohme
• Merck Canada Inc

Inventors

• Haidle Andrew M
• Knowles Sandra Lee
• Kattar Solomon D
• Deschenes Denis
• Burch Jason
• Robichaud Joel
• Christopher Matthew
• Altman Michael D
• Jewell James P
• Northrup Alan B
• Blouin Marc
• Ellis John Michael
• Zhou Hua
• Fischer Christian
• Schell Adam J
• Reutershan Michael H
• Taoka Brandon M
• Donofrio Anthony

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• 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

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61P11/06

  Antiasthmatics · CPC title