2-Pyridyl carboxamide-containing spleen tyrosine kinase (SYK) inhibitors

Patent metadata

Field	Value
Publication number	US-9216173-B2
Application number	US-201214349551-A
Country	US
Kind code	B2
Filing date	Oct 1, 2012
Priority date	Oct 5, 2011
Publication date	Dec 22, 2015
Grant date	Dec 22, 2015

Abstract

The invention provides certain 2-pyridyl carboxamide-containing compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein A and B 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
B is pyridyl;
wherein B is unsubstituted or substituted by 1 to 3 R 3 moieties, wherein each R 3 moiety is independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkyl, C 1 -C 3 hydroxyalkyl, halo, hydroxy, amino, (C 1 -C 3 alkyl)amino, di(C 1 -C 3 alkyl)amino, —N(H)SO 2 —(C 1 -C 3 alkyl), —CO 2 H, —C(O)NH 2 , —C(O)N(H)(C 1 -C 3 alkyl), —C(O)N(H)(C 1 -C 3 alkyl) 2 , —CH 2 O—(C 1 -C 4 alkylene)-OH, and E;
E is
(a) -E′,
(b) —CH 2 -E 1 or
(c) —O—CH 2 -E 1 ;
wherein E 1 is:
(i) phenyl; or
(ii) C 3 -C 6 cycloalkyl;
wherein E 1 is unsubstituted or substituted by 1 to 2 moieties independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo, hydroxy, nitro, carboxy, C 1 -C 3 hydroxyalkyl, —O—(C 1 -C 3 fluoroalkyl), —C(H)(OH)—(C 1 -C 3 fluoroalkyl), —N(CH 3 )SO 2 —(C 1 -C 3 alkyl), and R E1 ;
wherein R E1 is
(a) —(CH 2 ) x —R E1a , wherein x is 1, 2, or 3; or
(b) —R E1a ;
wherein R E1a is
 phenyl;
 wherein R E1a is unsubstituted or substituted by 1 to 2 moieties independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy and halo;

A is selected from the group consisting of
(a)

 wherein
Y is —CH—;
R 11 and R 12 are independently H or F; and
n is 1 or 2;
n′ is 0 or 1; or

(b)

 wherein
R a and R b are independently H, C 1 -C 6 alkyl, or phenyl;
or R a and R b together with the carbon atom to which they are attached form —C(O)—;

Q is

 —C(O)—, or —CH 2 CH 2 —;
wherein R c is H, C 1 -C 6 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, —(CH 2 ) r OR 13 , —C(O)NH 2 , —C(O)N(H)(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , —(CH 2 ) r S(O) t R 14 , —(CH 2 ) r -phenyl, or —(CH 2 ) r N(H)C(O)—(C 1 -C 3 alkyl);
R 13 is H or C 1 -C 3 alkyl; and
R 14 is C 1 -C 3 alkyl;
r is 1 or 2;
t is 0, 1, or 2;

R d is H or C 1 -C 6 alkyl, or
R c and R d together with the carbon atom to which they are attached form a group of the formula

 wherein q is 1, 2, 3, or 4; or

(c)

 wherein m is 1 or 2 and m′ is 0 or 1;
(e) H;
(f) —C(O)N(H)—(C 1 -C 3 alkyl); and
(g) —S(O) 2 CH 2 CH 2 NH 2 .

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of:

wherein said B is unsubstituted or substituted by 1 to 2 R 3 moieties.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein B is substituted by no more than 2 R 3 moieties, and no more than 1 of said R 3 moieties is E.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof,
A is

Y is —CH 2 —;
R 11 and R 12 are independently H or F; and
n is 1 or 2;
n′ is 0 or 1.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is

wherein R a and R b are independently H, C 1 -C 6 alkyl, or phenyl;
or R a and R b together with the carbon atom to which they are attached form —C(O)—;

Q

 is —C(O)—, or —CH 2 CH 2 —;
wherein R c is H, C 1 -C 6 alkyl, C 1 -C 3 fluoroalkyl, C 3 -C 6 cycloalkyl, —(CH 2 ) r OR 13 , —C(O)NH 2 , —C(O)N(H)(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , —(CH 2 ) r S(O) t R 14 , —(CH 2 ) r -phenyl, or —(CH 2 ) r N(H)C(O)—(C 1 -C 3 alkyl);
R 13 is H or C 1 -C 3 alkyl; and
R 14 is C 1 -C 3 alkyl;
r is 1 or 2;
t is 0, 1, or 2;

R d is H or C 1 -C 6 alkyl; or
R c and R d together with the carbon atom to which they are attached form a group of the formula

 wherein q is 1, 2, 3, or 4.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein
R a and R b are independently H or C 1 -C 4 alkyl;
Q is —C(O)— or

R c is H, C 1 -C 4 alkyl, cyclopropyl, —CH 2 OR 13 , or —CH 2 SR 14 ;
R 13 is H or C 1 -C 3 alkyl; and
R 14 is C 1 -C 3 alkyl.

8. The compound of claim 1 having the Formula (IA)

or a pharmaceutically acceptable salt thereof, wherein
R 3a is halo, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 3 fluoroalkyl;
R 3b is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo, C 3 -C 6 cycloalkyl, or C 1 -C 3 fluoroalkyl;
R 3c is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo, C 3 -C 6 cycloalkyl, or C 1 -C 3 fluoroalkyl;
A is selected from the group consisting of
(a)

 wherein
Y is —CH 2 —;
R 11 and R 12 are independently H or F; and
n is 1 or 2;
n′ is 0 or 1; or

(b)

 wherein
R a and R b are independently H or C 1 -C 4 alkyl; and
Q is —C(O)— or

R c is H, C 1 -C 3 alkyl, cyclopropyl, —CH 2 OR 13 , or —CH 2 SR 14 ;
 R 13 is H or C 1 -C 3 alkyl; and
 R 14 is C 1 -C 3 alkyl.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein no more than one of R 3a , R 3b , and R 3c is C 3 -C 6 cycloalkyl.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3c are both methyl, and R 3b is H.

11. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

12. The compound of claim 8 or a pharma

Assignees

• Altman Michael D
• Bienstock Corey E
• Butcher John W
• Childers Kaleen Konrad
• Di Francesco Maria Emilia
• Donofrio Anthony
• Ellis John Michael
• Fischer Christian
• Haidle Andrew M
• Jewell James P
• Knowles Sandra Lee
• Northrup Alan B
• Otte Ryan D
• Peterson Scott L
• Smith Graham Frank
• Merck Sharp & Dohme

Inventors

• Altman Michael D
• Bienstock Corey E
• Butcher John W
• Childers Kaleen Konrad
• Di Francesco Maria Emilia
• Donofrio Anthony
• Ellis John Michael
• Fischer Christian
• Haidle Andrew M
• Jewell James P
• Knowles Sandra Lee
• Northrup Alan B
• Otte Ryan D
• Peterson Scott L
• Smith Graham Frank

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D401/12

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

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title