US 2013/0296300 A1 · QUINOLINES AND AZA-QUINOLINES AS CRTH2 RECEPTOR MODULATORS

Abstract

The invention provides certain quinolines and aza-quinolines of the Formula (I), and their pharmaceutically acceptable salts, wherein E, J1, Ja, Jb, R2, R3, R22, Ra, Rb, Rc, Rd, 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 CRTH2 function.

A compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein
one of Ja and Jb is N, and the other is C(H);
J1 is C(H), C(R22), or N;
E is selected from the group consisting of:
(i) —N(R6a)(R6b), and
(ii) —O—C(R7a)(R7b)(R7c),
R6a and R6b are independently:
a. H,
b. C1-C10 alkyl,
c. C3-C6 alkenyl,
d. C3-C6 alkynyl,
e. —O—(C1-C3 alkyl),
f. -Q-RAH, wherein RAH is phenyl or 5- to 9-membered mono- or bicyclic heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S,
and wherein RAH is unsubstituted or substituted with 1 to 5 moieties independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 fluoroalkyl, —O—(C1-C3 fluoroalkyl), hydroxyl, phenyl, and —CN;
Q is selected from the group consisting of a
(i) bond;
(ii) C1-C6 alkylene, wherein said C1-C6 alkylene is unsubstituted or substituted by 1 to 2 fluoro, C1-C3 alkyl, C1-C3 hydroxyalkyl, or C1-C3 fluoroalkyl;
and
(iii)
wherein t is 1, 2, 3, or 4;
g. -Q-RHC, wherein RHC is
(i) 5- to 6-membered heterocyclyl containing 1 heteroatom selected from the group consisting of N and O, wherein said heterocyclyl of RHC is optionally fused to a benzene ring;
or
(ii) C5-C7 cycloalkyl, wherein said cycloalkyl of RHC is optionally fused to a benzene ring;
and wherein RHC is unsubstituted or substituted with 1 to 5 R12 moieties independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 fluoroalkyl, —O—(C1-C3 fluoroalkyl), hydroxyl, and —CN, or wherein when two R12 moieties are geminally substituted on the same carbon atom, the two geminally substituted R12 moieties, together with the carbon atom on which they are attached form —C(O)—;
h. or R6a and R6b together with the N atom to which they are attached form R6H, wherein R6H is independently selected from the group consisting of:
(i) a 4- to 7-membered heterocyclyl, optionally containing one additional nitrogen atom, wherein said heterocyclyl of R6H is optionally fused to phenyl;
and
(ii) a 4- to 7-membered heterocyclenyl, optionally containing one additional nitrogen atom, wherein said heterocyclenyl of R6H is optionally fused to phenyl;
wherein R6H is unsubstituted or substituted by 1 to 5 R9 moieties wherein each R9 moiety is independently C1-C6 alkyl, C1-C6 alkoxy, fluoro, hydroxyl, —CN, —(C1-C3 alkylene)-(C1-C3 alkoxy), or
R9 is —Z—RCY wherein
Z is
(i) a bond,
(ii) —C(O)—,
(iii) —C(═N—OH)—,
(iv) —S(O)2—, or
(v) C1-C3 alkylene, wherein said C1-C3 alkylene of Z is optionally substituted by 1 to 2 fluoro or C1-C3 alkyl;
RCY 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 10 atom, wherein said heterocyclyl of RCY is optionally fused to phenyl;
wherein RCY is unsubstituted or substituted by 1 to 4 R10 moieties;
each R10 moiety is independently C1-C3 alkyl, halo, hydroxyl, C1-C3 alkoxy, —(C1-C3 alkylene)-(C1-C3 alkoxy), —S(O)2—(C1-C3 alkyl), —C(O)—(C1-C3 alkyl), —CN, or pyridyl, or, wherein when two R10 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 R9 moieties are geminally substituted on a common ring carbon of R6H, the two R9 moieties, together with the ring carbon on which they are substituted, form RYC, wherein RYC is
(i) a 4- to 7-membered cycloalkyl, wherein said cycloalkyl of RYC is optionally fused to phenyl;
or
(ii) a 4- to 7-membered heterocyclyl containing 1 to 2 N atoms or 10 atom, wherein said heterocyclyl of RYC is optionally fused to phenyl;
wherein RYC is unsubstituted or substituted by 1 to 4 R11 moieties;
each R11 moiety is independently C1-C3 alkyl, halo, hydroxyl, C1-C3 alkoxy, —(C1-C3 alkylene)-(C1-C3 alkoxy), —S(O)2—(C1-C3 alkyl), —C(O)—(C1-C3 alkyl), phenyl, or pyridyl, or, wherein when two R11 moieties are geminally substituted on a common carbon atom, together with the carbon atom on which they are substituted, form —C(O)—;
R7a and R7b are independently
a) H,
b) C1-C6 alkyl,
c) phenyl wherein said phenyl is unsubstituted or substituted by 1 to 3 moieties independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 alkoxy, and CN;
or
d) R7a and R7b together with the carbon atom on which they are substituted, form RPC, wherein RPC is
(i) C3-C2 cycloalkyl, or
(ii) phenyl, wherein said phenyl of RPC is unsubstituted or substituted by 1 to 5 moieties independently selected from the group consisting of halo, trifluoromethyl, and trifluoromethoxy;
R7c e is
a) H, or
b) absent when R7a and R7b together with the carbon atom on which they are substituted form phenyl;
R22 is halo, C1-C3 alkyl, or C1-C3 fluoroalkyl;
b is 0 or 1;
X is a bond, —O—, —S—, —S(O)—, or —S(O)2—;
Y is selected from the group consisting of
(i) a bond,
(iv) —O—, (v) —S—, (v) —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 R4 is independently halo, C1-C6 alkyl, or C1-C6 fluoroalkyl;
Ra, Rb, Rc, and Rd are independently H, fluoro, hydroxyl, C1-C6 alkyl, C1-C6 fluoroalkyl, or C1-C6 alkoxy;
R2 is selected from the group consisting of:
(i) phenyl;
(ii) 5- to 6-membered heteroaryl containing from 1 to 3 heteroatoms selected from the group consisting of N, O, and S;
(iii) 5- to 6-membered heterocyclenyl, containing from 1 to 2 heteroatoms selected from the group consisting of N, O, and S;
and
(iv) 5- to 6-membered heterocyclyl containing from 1 to 2 heteroatoms selected from the group consisting of N, O, and S;
wherein R2 is unsubstituted or substituted by 1 to 5 R5 groups independently selected from the group consisting of halo, C1-C3 fluoroalkyl, C1-C3 alkyl, C1-C3 alkoxy, —CN, —OCF3, —C(O)—(C1-C3 alkyl), and —S(O)2—(C1-C3);
R3 is —C(O)OH,
or —N(H)—SO2—Re,
wherein Re is C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 alkoxy, and phenyl;
n is 1, 2, 3, 4, or 5;
and
q is 0, 1, or 2.

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Quinolines and aza-quinolines as crth2 receptor modulators

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Quinolines and aza-quinolines as crth2 receptor modulators

Life of this patent

Abstract

Claims18