Quinolines and aza-quinolines as CRTH2 receptor modulators

Patent metadata

Field	Value
Publication number	US-9290453-B2
Application number	US-201113996371-A
Country	US
Kind code	B2
Filing date	Dec 19, 2011
Priority date	Dec 23, 2010
Publication date	Mar 22, 2016
Grant date	Mar 22, 2016

Abstract

The invention provides certain quinolines and aza-quinolines of the Formula (I), and their pharmaceutically acceptable salts, wherein E, J 1 , J a , J b , 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 (IA) or a pharmaceutically acceptable salt thereof,

wherein
J 1 is C(H) or N;
one of J a and J b is N, and the other is C(H);
R 6a and R 6b are independently:
a. H,
b. C 1 -C 10 alkyl,
c. -Q-R AH , wherein R AH is selected from the group consisting of:

and wherein R AH is unsubstituted or substituted with 1 moiety selected from the group consisting of Cl, —CN, —CH 3 , —CF 3 , and —OCF 3 ;
Q is selected from the group consisting of a
(i) bond;
(ii) C 1 -C 3 alkylene, wherein said alkylene is unsubstituted or substituted by one —CH 3 , —CF 3 , or —CH 2 CH 2 OH; and

d. -Q-R HC , wherein
Q is as set forth in c. above;
R HC is selected from the group consisting of:

and wherein R HC is unsubstituted or substituted with 1 to 2 R 12 moieties independently selected from the group consisting of fluoro and chloro, 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)—;

e. 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:

wherein R 6H is unsubstituted or substituted by one R 9 moiety which is —Z—R CY wherein
Z is a bond; and
R CY is selected from the group consisting of:

and
wherein R CY is unsubstituted or substituted by 1 to 2 R 10 moieties, wherein each R 10 moiety is independently selected from the group consisting of fluoro and chloro; and

R 5 is absent or present, and if present, is halo.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (IA) has the formula (IB)

wherein one of J a and J b is N and the other is C(H);
a) R 6a is H and
R 6b is -Q-R AH , wherein R AH is phenyl,
wherein R AH is unsubstituted or substituted with moiety independently selected from the group consisting of fluoro, chloro, C 1 -C 3 alkyl, and —O—(C 1 -C 3 fluoroalkyl);
Q is methylene, wherein said methylene is unsubstituted or substituted by one C 1 -C 3 alkyl or C 1 -C 3 fluoroalkyl;

b) R 6a is H and
R 6b is -Q-R HC , wherein
Q is as set forth in a) above;
R HC is selected from the group consisting of:

and wherein R HC is unsubstituted or substituted with 1 chloro;
c) or R 6a and R 6b together with the N atom to which they are attached form
R 6H , wherein R 6H is

and

R 5 is absent or present, and if present, is fluoro.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein J 1 is C(H), J a is C(H) and J b is N.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein J 1 is C(H), J a is N and J b is C(H).

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein J 1 is N, J a is C(H) and J b is N.

6. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein J a is C(H) and J b is N.

7. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein J a is N and J b is C(H).

8. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(1) 2-phenyl-6-[[[[4-(trifluoromethoxy)phenyl]methyl]amino]carbonyl]-3-quinolinepentanoic acid;
(1D 6-[[[(3-chlorophenyl)methyl]amino]carbonyl]-2-phenyl-3-quinolinepentanoic acid;
(1E) 6-[[[(4-methylphenyl)methyl]amino]carbonyl]-2-phenyl-3-quinolinepentanoic acid;
(1L) 2-phenyl-6-[(3(R)-phenyl-1-piperidinyl)carbonyl]-3-quinolinepentanoic acid;
(1T) 2-phenyl-6-[[(1(S)-phenylethyl)amino]carbonyl]-3-quinolinepentanoic acid;
(1AD) 6-[[[1(R)-(4-chlorophenyl)ethyl]amino]carbonyl]-2-phenyl-3-quinolinepentanoic acid;
(1AE) 6-[[[1(S)-(4-chlorophenyl)ethyl]amino]carbonyl]-2-phenyl-3-quinolinepentanoic acid;
(1AF) 6-[[[1(R)-(4-chlorophenyl)-2,2,2-trifluoroethyl]amino]carbonyl]-2-phenyl-3-quinolinepentanoic acid;
(1AG) 6-[[[1(S)-(4-chlorophenyl)-2,2,2-trifluoroethyl]amino]carbonyl]-3-phenyl-2-quinolinepentanoic acid;
(1M) 6-[[(2,3-dihydro-1H-inden-1(R)-yl)amino]carbonyl]-2-phenyl-3-quinolinepentanoic acid;
(2) 2-phenyl-6-[[(phenylmethyl)amino]carbonyl]-3-quinolinepentanoic acid;
(2C) 6-[[[(4-fluorophenyl)methyl]amino]carbonyl]-2-phenyl-3-quinolinepentanoic acid;
(3E) 3-phenyl-7-[(4-phenyl-1-piperidinyl)carbonyl]-2-quinolinepentanoic acid;
(4) 5-(7-(3-chlorobenzylcarbamoyl)-3-phenylquinolin-2-yl)pentanoic acid;
(4E) (R)-5-(7-(1-(4-fluorophenyl)ethylcarbamoyl)-3-phenylquinolin-2-yl)pentanoic acid;
(5G) 2-(4-fluorophenyl)-6-[[(1,2,3,4-tetrahydro-1(R)-naphthalenyl)amino]carbonyl]-3-quinolinepentanoic acid;
(5o) 6-[[(5-chloro-2,3-dihydro-1H-inden-1(R)-yl)amino]carbonyl]-2-(4-fluorophenyl)-3-quinolinepentanoic acid; and
(6G) 6-[[(6-chloro-1,2,3,4-tetrahydro-1(R)-naphthalenyl)amino]carbonyl]-2-(4-fluorophenyl)-1,8-naphthyridine-3-pentanoic acid.

9. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(1AH) (R)-5-(6-((1-(4-fluorophenyl)ethyl)carbamoyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1Ai) 5-(2-phenyl-6-(4-phenylpiperazine-1-carbonyl)quinolin-3-yl)pentanoic acid;
(1AJ) 5-(6-(3-(3-fluorophenyl)azetidine-1-carbonyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1AK) 5-(6-((4-fluorobenzyl)(methyl)carbamoyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1AL) (S)-5-(6-(chroman-4-ylcarbamoyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1AM) (R)-5-(6-(3-(4-fluorophenyl)pyrrolidine-1-carbonyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1AN) (S)-5-(6-(3-(4-fluorophenyl)pyrrolidine-1-carbonyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1Ao) (R)-5-(6-((2,3-dihydrobenzofuran-3-yl)carbamoyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1AP) 5-(6-((2,2-dimethylchroman-4-yl)carbamoyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1AQ) 5-(6-((4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1AR) 5-(6-(3-cyano-3-phenylpyrrolidine-1-carbonyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1AS) 5-(6-((2-oxo-1,2,3,4-tetrahydroquinolin-4-yl)carbamoyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1AT) 5-(6-((2-(4-fluorophenyl)propan-2-yl)carbamoyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1AU) 5-(6-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carbonyl)-2-phenylquinolin-3-yl)pentanoic acid;
(1AV) 5-(2-phenyl-6-(3H-spiro[isobenzofuran-1,4′-piperid

Assignees

• Boyce Christopher W
• Fevrier Salem
• Mccormick Kevin D
• Palani Anandan
• Aslanian Robert G
• Siliphaivanh Phieng
• Methot Joey L
• Brown William Colby
• Vaccaro Henry
• Merck Sharp & Dohme

Inventors

• Boyce Christopher W
• Fevrier Salem
• Mccormick Kevin D
• Palani Anandan
• Aslanian Robert G
• Siliphaivanh Phieng
• Methot Joey L
• Brown William Colby
• Vaccaro Henry

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12

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

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• C07D405/12

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

• C07D471/04

  Ortho-condensed systems · CPC title