Quinazolinone-type compounds as CRTH2 antagonists

Patent metadata

Field	Value
Publication number	US-8927559-B2
Application number	US-201113878654-A
Country	US
Kind code	B2
Filing date	Oct 6, 2011
Priority date	Oct 11, 2010
Publication date	Jan 6, 2015
Grant date	Jan 6, 2015

Abstract

This application provides for compounds of the formula Formula I or a pharmaceutically acceptable salt thereof, wherein the individual variables are defined herein, as well as processes to prepare these compounds, pharmaceutical compositions comprising the same and their use in treating disease state associated with the CRTH 2 receptor.

First claim

We claim:

1. A compound for the formula:

or a pharmaceutically acceptable salt thereof
wherein:
X is a bond or —S(O) m —;
Y is selected from the group consisting of:
a) a bond, —O—, —NH—, —N(R 9 )— or —N(COR 9 )—;

where
A is —O—, —S— or N(R)—;
B is —C— or —N—;
a is 0, 1, 2, or 3;
r is 0, 1 or 2;
s is 0, 1 or 2;

R is H, alkyl or haloalkyl;
R a is independently H, halo, alkyl or haloalkyl;
R b is independently H, halo, alkyl or haloalkyl;
R 1 is heteroaryl, heterocyclyl or heterocyclenyl;
R 2 is aryl, heteroaryl, alkyl or heterocyclyl;
R 3 is —C(O)OH or —N(H)—SO 2 —R c ;
where:
R c is alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl;

R 4 is independently selected from the group consisting of alkyl, —OH, halo, alkoxy, haloalkoxy, —CN and haloalkyl;
R 8 is independently selected from the group consisting of —CN, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl;
R 9 is alkyl, haloalkyl, alkoxy, haloalkoxy or cycloalkyl;

and wherein:
i) the heteroaryl, heterocyclyl or heterocyclenyl group in R 1 ; and
ii) each of the aryl, heteroaryl, alkyl or heterocyclyl groups of R 2 ; are independently unsubstituted or substituted by 1 to 5 R 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, halo, —CN, —SF 5 , —OSF 5 , —NO 2 , —CH 2 OSi(R 14 )(R 15 )(R 16 , —OR 14 , —C(O)R 14 , —C(O)OR 14 , —O—C(O)—R 14 , —O—C(O)N(R 14 )(R 15 ), —C(O)N(R 14 )(R 15 ), —S(O) m R 14 , —S(O) p N(R 14 )(R 15 ), —C(═NOR 14 )R 15 , —N(R 14 )(R 15 ), —N(R 14 )C(O)R 15 , —N(R 14 )S(O) p R 15 , —N(R 14 )S(O) p N(R 15 )(R 16 ), —N(R 14 )C(O)N(R 15 )(R 16 ) and —N(R 14 )C(O)OR 16 ;
or when a position is disubstituted by two R 5 groups, the two R 5 groups can form a cycloalkyl or heterocyclyl ring that is unsubstituted or is substituted by 1 to 5 R 6 groups;

and wherein:
each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl groups in R 5 are independently unsubstituted or substituted by 1 to 5 R 6 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, halo, —CN, —SF 5 , —OSF 5 , —NO 2 , —CH 2 OSi(R 14 )(R 15 )(R 16 ), —OR 14 , —C(O)R 14 , —C(O)OR 14 , —O—C(O)—R 14 , —O—C(O)—N(R 14 )(R 15 ), —C(O)N(R 14 )(R 15 ), —S(O) m R 14 , —S(O) p N(R 14 )(R 15 ), —C(═NOR 14 )R 15 , —N(R 14 )(R 15 ), —N(R 14 )C(O)R 15 ; —N(R 14 )S(O) p R 15 , —N(R 14 )S(O) p N(R 15 )(R 16 ), —N(R 14 )C(O)N(R 15 )(R 16 ); —N(R 14 )C(O)OR 16 and —N(R 14 )C(O)R 16 ; and
wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl groups in R 6 are independently unsubstituted or substituted by 1 to 5 R 7 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, halo, —CN, —SF 5 , —OSF 5 , —NO 2 , —CH 2 OSi(R 14 )(R 15 )(R 16 ), —OR 14 , —C(O)R 14 , —C(O)OR 14 , —O—C(O)—R 14 , —O—C(O)—N(R 14 )(R 15 ), —C(O)N(R 14 )(R 15 ), —S(O) m R 14 , —S(O) p N(R 14 )(R 15 ), —C(═NOR 14 )R 15 , —N(R 14 )(R 15 ), —N(R 14 )C(O)R 15 , —N(R 14 )S(O) p R 15 , —N(R 14 )S(O) p N(R 15 )(R 16 ), —N(R 14 )C(O)N(R 15 )(R 16 ); —N(R 14 )C(O)OR 16 and —N(R 14 )C(O)R 16 ;

wherein:
R 14 , R 15 and R 16 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, R 17 -alkyl, R 17 -alkenyl, R 17 -alkynyl, R 17 -cycloalkyl, R 17 -cycloalkenyl, R 17 -heterocyclyl, R 17 -heterocyclenyl, R 17 -aryl, and R 17 -heteroaryl;
R 17 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, halo-substituted aryl, nitrile-substituted aryl, phenyl-substituted aryl, heteroaryl, halo, —CN, —SF 5 , —OSF 5 , —NO 2 , heteroaryl, haloalkyl, —C(O)R 18 , —C(O)OH, —C(O)OR 18 , —C(O)NHR 19 , —C(O)NH 2 , —C(O)N(R 18 )(R 19 ), —S(O) m R 18 , —S(O) p NH 2 , —S(O)NH p (alkyl), —S(O) p N(alkyl)(alkyl), —S(O) p NH(aryl), —S(O) 2 NHR 19 , —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl)(aryl), haloalkoxy, —OH, —OR 19 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocyclylalkyl, —NH 2 , —NHR 19 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R 19 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 21 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);
R 18 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;
R 19 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;
R 21 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;
b is 0, 1 or 2;
n is an integer from 1 to 5;
m is independently an integer from 0 to 2;
p is an integer from 1 to 2;
q is an integer from 0 to 5;

wherein
each heteroaryl is independently an aromatic monocyclic or bicyclic ring system comprising 5 to 14 ring atoms, wherein one or more of the ring atoms is nitrogen, oxygen, or sulfur,
each heterocyclyl is independently a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 12 ring atoms, wherein one or more of the ring atoms is nitrogen, oxygen, or sulfur; and
each heterocyclenyl is independently a non-aromatic monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, wherein one or more of the ring atoms is nitrogen, oxygen, or sulfur; and wherein the heterocyclenyl contains at least one carbon-carbon double bond or carbon-nitrogen double bond.

2. The compound according to claim 1 which has the formula:

or a pharmaceutically acceptable salt thereof
wherein:
Y is selected from the group consisting of:
a) a bond;

where
A is —O—, —S— or N(R)—;
B is —C— or —N—;
a is 0, 1, 2, or 3;
r is 0, 1 or 2;
s is 0, 1 or 2;

R is H, alkyl or haloalkyl;
R a is independently H, halo, alkyl or haloalkyl
R b is independently H, halo, alkyl or haloalkyl;
R 1 is heteroaryl, heterocyclyl or heterocyclenyl;
R 2 is aryl, heteroaryl, alkyl or heterocyclyl;
R 3 is —C(O)OH or —N(H)—SO 2 —R c ;
where:
R c is alkyl, haloalkyl, cycloalkyl, aryl or heteroaryl;

R 4 is independently selected from the group consisting of alkyl, —OH, halo, alkoxy, haloalkoxy, —CN and haloalkyl;
R 8 is independently selected from the group consisting of —CN, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl;

and wherein:
i) the heteroaryl heterocyclyl or heterocyclenyl group in R 1 ; and
ii) each of the aryl, heteroaryl, alkyl or heterocyclyl groups of R 2 ; are independently unsubstituted or substituted by 1 to 5 R 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, heteroaryl, halo, —CN, —SF 5 , —OSF 5 , —NO 2 , —CH 2 OSi(R 14 )(R 15 )(R 16 ), —OR 14 , —C(O)R 14

Assignees

• Aslanian Robert G
• Boyce Christopher W
• Mazzola Jr Robert D
• Mckittrick Brian A
• Mccormick Kevin D
• Palani Anandan
• Qin Jun
• Tang Haiqun
• Xiao Dong
• Yu Younong
• Caldwell John P
• Kelley Elizabeth Helen
• Zhang Hongjun
• Siliphaivanh Phieng
• Maccoss Rachel N
• Methot Joey L
• Gauuan Jolicia Polivina
• Jiang Qin
• Leyhane Andrew J
• Biju Purakkattle Johny
• Dong Li
• Huang Xianhai
• Shao Ning
• Zhou Wei
• Dhondi Pawan K
• Rao Ashwin U
• Merck Sharp & Dohme

Inventors

• Aslanian Robert G
• Boyce Christopher W
• Mazzola Jr Robert D
• Mckittrick Brian A
• Mccormick Kevin D
• Palani Anandan
• Qin Jun
• Tang Haiqun
• Xiao Dong
• Yu Younong
• Caldwell John P
• Kelley Elizabeth Helen
• Zhang Hongjun
• Siliphaivanh Phieng
• Maccoss Rachel N
• Methot Joey L
• Gauuan Jolicia Polivina
• Jiang Qin
• Leyhane Andrew J
• Biju Purakkattle Johny
• Dong Li
• Huang Xianhai
• Shao Ning
• Zhou Wei
• Dhondi Pawan K
• Rao Ashwin U

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P11/02

  Nasal agents, e.g. decongestants · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title