Quinoxalines and AZA-quinoxalines as CRTH2 receptor modulators

Patent metadata

Field	Value
Publication number	US-9469615-B2
Application number	US-201113996361-A
Country	US
Kind code	B2
Filing date	Dec 19, 2011
Priority date	Dec 23, 2010
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

Abstract

The invention provides certain quinoxalines and aza-quinoxalines of the Formula (I), and their pharmaceutically acceptable salts, wherein J 1 , J 2 , R 1 , R 2 , R 3 , R 22 , R a , R b , R c , R d , X, Y, b, n, and q are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions associated with uncontrolled or inappropriate stimulation of CRTH 2 function.

First claim

What is claimed is:

1. A compound of the formula (I)

or a pharmaceutically acceptable salt thereof, wherein
J 1 and J 2 are independently C(H), C(R 1 ), C(R 22 ), or N wherein the following provisos apply
(i) no more than one of J 1 and J 2 is N,
(ii) no more than one of J 1 and J 2 is C(R 22 ); and
(iii) only one R 1 is substituted on the illustrated ring containing J 1 and J 2 ;

R 1 is selected from the group consisting of
(i) —C(O)—N(R 6a )(R 6b ),
(ii) —S(O) 2 —N(R 6a )(R 6b ),
(iii) —C(O)—C(R 7a )(R 7b )(R 7c ),
(iv) —N(H)—C(O)—C(R 7a )(R 7b )(R 7c ),
(v) —C(O)—O—C(R 7a )(R 7b )(R c ), and
(vi) —N(H)—S(O) 2 —C(R 7a )(R 7b )(R 7c );

R 6a and R 6b are independently
a. H,
b. C 1 -C 6 alkyl,
c. C 3 -C 6 alkenyl,
d. C 3 -C 6 alkynyl,
e. —O—(C 1 -C 3 alkyl),
f. -Q-R AH , wherein R AH is phenyl or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S,
and wherein R AH is unsubstituted or substituted with 1 to 5 R 8 moieties independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkyl, —O—(C 1 -C 3 fluoroalkyl), hydroxyl, phenyl, and —CN;

Q is selected from the group consisting of
(a) a bond;
(b) C 1 -C 6 alkylene, wherein said C 1 -C 6 alkylene is unsubstituted or substituted by 1 to 2 fluoro, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, or C 1 -C 3 fluoroalkyl; and
(c)

 wherein t is 1, 2, 3, or 4;

g. -Q-R Hc , wherein R HC is
(i) 5- to 7-membered heterocyclyl containing 1 heteroatom selected from the group consisting of N, O, S, S(O), and S(O) 2 , wherein said heterocyclyl of R HC is optionally fused to a benzene, pyridyl ring; or
(ii) C 3 -C 7 cycloalkyl, wherein said cycloalkyl of R HC is optionally fused to a benzene or pyridyl ring;
and wherein R HC is unsubstituted or substituted with 1 to 5 R 12 moieties independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkyl,
—O—(C 1 -C 3 fluoroalkyl), hydroxyl, —CN, and —S(O) 2 —(C 1 -C 3 alkyl), or wherein when two R 12 moieties are geminally substituted on the same carbon atom, the two geminally substituted R 12 moieties, together with the carbon atom on which they are attached form —C(O)—;

Q is selected from the group consisting of
(a) a bond;
(b) C 1 -C 6 alkylene, wherein said C 1 -C 6 alkylene is unsubstituted or substituted by 1 to 2 fluoro, C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, or C 1 -C 3 fluoroalkyl; and

 wherein t is 1, 2, 3, or 4;

h. or R 6a and R 6b together with the N atom to which they are attached form R 6H , wherein R 6H is independently selected from the group consisting of
(i) a 4- to 9-membered heterocyclyl, optionally containing one additional nitrogen atom, wherein said heterocyclyl of R 6H is optionally fused to phenyl, C 3 -C 6 cycloalkyl, or a 5-membered heteroaryl containing 1 to 3 N atoms;
(ii) a 4- to 7-membered heterocyclenyl, optionally containing one additional nitrogen atom, wherein said heterocyclenyl of R 6H is optionally fused to phenyl; and
(iii) a 6- to 8-membered aza- or a diazabicycloheterocycloalkyl ring;
wherein R 6H is unsubstituted or substituted by 1 to 5 R 9 moieties wherein each R 9 moiety is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 3 fluoroalkyl, fluoro, hydroxyl, —CN,
—(C 1 -C 3 alkylene)-(C 1 -C 3 alkoxy), or
R 9 is —Z—R CY wherein
 Z is
 (i) a bond,
 (ii) —C(O)—,
(iii) —C(═N—OH)—,
 (iv) —S(O) 2 —,
 (v) C 1 -C 3 alkylene, wherein said C 1 -C 3 alkylene of Z is optionally substituted by 1 to 2 fluoro or C 1 -C 3 alkyl;
 (vi) —O—;
 (vii) —O—(C 1 -C 3 alkylene)-; or
 (viii) —C(O)—O—CH 2 —
 R CY is selected from the group consisting of
 (i) phenyl
 (ii) 5- to 10-membered mono or bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S; or
 (iii) 5- to 6-membered heterocyclyl containing 1 to 2 N atoms or 1 O atom, wherein said heterocyclyl of R CY is optionally fused to phenyl;
 wherein R CY is unsubstituted or substituted by 1 to 4 R H ) moieties;
 each R 10 moiety is independently C 1 -C 3 alkyl, halo, hydroxyl, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkyl, —(C 1 -C 3 alkylene)-(C 1 -C 3 alkoxy), —S(O) 2 —(C 1 -C 3 alkyl), —C(O)—(C 1 -C 3 alkyl), —CN, pyridyl, or cyclopropyl or, wherein when two R 10 moieties are geminally substituted on a common carbon atom, together with the carbon atom on which they are substituted, form —C(O)—;
or, optionally, where two R 9 moieties are geminally substituted on a common ring carbon of R 6H , the two R 9 moieties, together with the ring carbon on which they are substituted, form R YC , wherein R YC is
 (i) a 4- to 7-membered cycloalkyl, wherein said cycloalkyl of R YC is optionally fused to phenyl or pyridyl; or
 (ii) a 4- to 7-membered heterocyclyl containing 1 to 2 N atoms or 1 O atom, wherein said heterocyclyl of R YC is optionally fused to phenyl;
 wherein R YC is unsubstituted or substituted by 1 to 4 R 11 moieties;
 each R 11 moiety is independently C 1 -C 3 alkyl, halo, hydroxyl, C 1 -C 3 alkoxy, —(C 1 -C 3 alkylene)-(C 1 -C 3 alkoxy), —S(O) 2 —(C 1 -C 3 alkyl), —C(O)—(C 1 -C 3 alkyl), phenyl, or pyridyl, or, wherein when two R 11 moieties are geminally substituted on a common carbon atom, together with the carbon atom on which they are substituted, form —C(O)—;

R 7a and R 7b are independently
a) H,
b) C 1 -C 6 alkyl,
c) R 7a and R 7b together with the carbon atom on which they are substituted, form R PC , wherein R PC is
(i) C 3 -C 7 cycloalkyl, or
(ii) phenyl, wherein said phenyl of R PC is unsubstituted or substituted by 1 to 5 moieties independently selected from the group consisting of halo, trifluoromethyl, and trifluoromethoxy;

R 7c is
a) H, or
b) absent, when R 7a and R 7b together with the carbon atom on which they are substituted form phenyl;

R 22 is halo, C 1 -C 3 alkyl, or C 1 -C 3 fluoroalkyl;
b is 0 or 1;
X is a bond, —O—, —S—, —S(O)—, —S(O) 2 —, or N(H);
Y is selected from the group consisting of
(i) a bond,

 (iv) —O—, (v) —S—, (vi) —S(O)—, and
(vii) —S(O) 2 —;
wherein
a is 0, 1, 2, or 3;
r is 0, 1, or 2;
s is 0, 1, or 2;

each occurrence of R 4 is independently halo, C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;

R a , R b , R c , and R d are independently H, fluoro, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, or C 1 -C 6 alkoxy;
R 2 is selected from the group consisting of
(i) phenyl; and
(ii) 5- to 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O, and S;
wherein R 2 is unsubstituted or substituted by 1 to 5 R 5 groups independently selected from the group consisting of halo, C 1 -C 3 fluoroalkyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, —CN, —OCF 3 , —C(O)—(C 1 -C 3 alkyl), and —S(O) 2 —(C 1 -C 3 alkyl);

R 3 is —C(O)OH,

 or —N(H)—SO 2 —R e ,
wherein R e is C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 1 -C 6

Assignees

• Boyce Christopher W
• Degrado Sylvia Joanna
• Chen Xiao
• Qin Jun
• Mazzola Jr Robert D
• Yu Younong
• Mccormick Kevin D
• Palani Anandan
• Xiao Dong
• Aslanian Robert George
• Wu Jie
• Rao Ashwin Umesh
• Siliphaivanh Phieng
• Methot Joey L
• Zhang Hongjun
• Kelley Elizabeth Helen
• Brown William Colby
• Jiang Qin
• Gauuan Jolicia Polivina
• Leyhane Andrew J
• Biju Purakkattle Johny
• Dhondi Pawan K
• Dong Li
• Fevrier Salem
• Huang Xianhai
• Vaccaro Henry M
• Merck Sharp & Dohme

Inventors

• Boyce Christopher W
• Degrado Sylvia Joanna
• Chen Xiao
• Qin Jun
• Mazzola Jr Robert D
• Yu Younong
• Mccormick Kevin D
• Palani Anandan
• Xiao Dong
• Aslanian Robert George
• Wu Jie
• Rao Ashwin Umesh
• Siliphaivanh Phieng
• Methot Joey L
• Zhang Hongjun
• Kelley Elizabeth Helen
• Brown William Colby
• Jiang Qin
• Gauuan Jolicia Polivina
• Leyhane Andrew J
• Biju Purakkattle Johny
• Dhondi Pawan K
• Dong Li
• Fevrier Salem
• Huang Xianhai
• Vaccaro Henry M

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P11/14

  Antitussive agents · CPC title