US 8,569,522 B2Granted

6-substituted phenoxychroman carboxylic acid derivatives

AssigneeArray BioPharma Inc.

InventorsLaurence E. Burgess, Christopher T. Clark, Adam Cook, Christopher P. Corrette, Robert Kirk DeLisle, George A. Doherty, Kevin W. Hunt, Todd T. Romoff

Life of this patent

Estimating the term…

Abstract

Compounds of Formula (I): in which A1, A2, W, L, G, R7a, R7b, R8, R9 and R10 have the meanings given in the specification, are DP2 receptor modulators useful in the treatment of immunologic diseases.

Claims37

Dependent claims

A compound of formula I:

or a salt thereof, wherein:
A1 is hydrogen, CN, Cl, F, Br, OMe, (1-4C alkyl) or cyclopropyl;
A2 is hydrogen, Cl, Br, F, (1-4C alkyl) or cyclopropyl;
W is —C(═O)NR1— or —NR2C(═O)—;
R1 and R2 are each hydrogen or methyl;
L is a bond, —(CR3R4)n—(CRaRb)m—(CR5R6)—*, (2-4C)alkenylene, —O(1-4C alkyl)-*, -(1-4C alkyl)-O—*, -(1-4C alkyl)-S—*, (3-6C)cycloalkylene, or hetCyc1, wherein the * indicates the point of attachment to G, provided that when W is —NR2C(═O)— then L is not —(CH═CH)—;
m=0, 1 or 2;
n=0 or 1;
Ra and Rb are independently selected from hydrogen and (1-4C alkyl);
R3 is hydrogen, (1-4C alkyl) or CH2OH;
R4 is hydrogen or methyl;
R5 is hydrogen, (1-4C alkyl), OH, —O(1-4C alkyl) or F;
R6 is hydrogen, F or methyl,
or R5 and R6 together with the carbon to which they are attached form a cyclopropyl ring;
hetCyc1 is a group having the formula
where t is 1 or 2 and p is 0 or 1, and the * indicates the point of attachment to G;
G is Ar1, Ar2, naphthyl, a benzo-fused (5-6C)cycloalkyl ring optionally substituted with one or more substituents independently selected from Cl and OMe, a benzo-fused 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O and N, a (3-6C)cycloalkyl ring optionally substituted with one or more substituents independently selected from (1-4C)alkyl, an oxaspirononanyl ring, or t-butyl;
Ar1 is phenyl optionally substituted with one or more substituents independently selected from F, Cl, Br, CF3, (1-4C)alkyl, OH, —O(1-4C alkyl), —S(1-3C alkyl), —SCF3, cyclopropyl, —CH2N(1-3C alkyl)2, —O-(2-3C)fluoroalkyl, —O-(1-3C)difluoroalkyl —O-(1-3C)trifluoroalkyl, —OCH2(cyclopropyl), and (3-4C)alkynyl;
Ar2 is phenyl which is substituted with Ar3, —O—Ar4, hetAr1 or —O-hetAr2, wherein Ar2 is optionally further substituted with one or more substituents independently selected from F, Cl and CF3;
Ar3 is phenyl optionally substituted with one or more substituents independently selected from F, Cl, Br and (1-4C alkyl);
Ar4 is phenyl optionally substituted with one or more substituents independently selected from F, Cl, Br and (1-4C alkyl);
hetAr1 is a 6-membered heteroaryl having 1-2 nitrogen atoms and optionally substituted with one or more substituents independently selected from (1-4C alkyl);
hetAr2 is a 6-membered heteroaryl having 1-2 nitrogen atoms and optionally substituted with one or more substituents independently selected from (1-4C alkyl) and CF3;
R7a, R7b and R8 are each independently hydrogen or methyl;
R9 is hydrogen, methyl, fluoro or NO2;
and
R10 is hydrogen, methyl or fluoro.

24 more elements

A compound of formula Ie:

or a salt thereof, wherein:
Pg is a carboxyl protecting group;
A1 is hydrogen, CN, Cl, F, Br, OMe, (1-4C alkyl) or cyclopropyl;
A2 is hydrogen, Cl, Br, F, (1-4C alkyl) or cyclopropyl;
W is —C(═O)NR1— or —NR2C(═O)—;
R1 and R2 are each hydrogen or methyl;
L is a bond, —(CR3R4)n—(CRaRb)m—(CR5R6)—*, (2-4C)alkenylene, —O(1-4C alkyl)-*, -(1-4C alkyl)-O—*, -(1-4C alkyl)-S—*, (3-6C)cycloalkylene, or hetCyc1, wherein the * indicates the point of attachment to G, provided that when W is —NR2C(═O)— then L is not —(CH═CH)—;
m=0, 1 or 2;
n=0 or 1;
Ra and Rb are independently selected from hydrogen and (1-4C alkyl);
R3 is hydrogen, (1-4C alkyl) or CH2OH;
R4 is hydrogen or methyl;
R5 is hydrogen, (1-4C alkyl), OH, —O(1-4C alkyl) or F;
R6 is hydrogen, F or methyl,
or R5 and R6 together with the carbon to which they are attached form a cyclopropyl ring;
hetCyc1 is a group having the formula
where t is 1 or 2 and p is 0 or 1, and the * indicates the point of attachment to G;
G is Ar1, Ar2, naphthyl, a benzo-fused (5-6C)cycloalkyl ring optionally substituted with one or more substituents independently selected from Cl and OMe, a benzo-fused 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O and N, a (3-6C)cycloalkyl ring optionally substituted with one or more substituents independently selected from (1-4C)alkyl, an oxaspirononanyl ring, or t-butyl;
Ar1 is phenyl optionally substituted with one or more substituents independently selected from F, Cl, Br, CF3, (1-4C)alkyl, OH, —O(1-4C alkyl), —S(1-3C alkyl), —SCF3, cyclopropyl, —CH2N(1-3C alkyl)2, —O-(2-3C)fluoroalkyl, —O-(1-3C)difluoroalkyl —O-(1-3C)trifluoroalkyl, —OCH2(cyclopropyl), and (3-4C)alkynyl;
Ar2 is phenyl which is substituted with Ar3, —O—Ar4, hetAr1 or —O-hetAr2, wherein Ar2 is optionally further substituted with one or more substituents independently selected from F, Cl and CF3;
Ar3 is phenyl optionally substituted with one or more substituents independently selected from F, Cl, Br and (1-4C alkyl);
Ar4 is phenyl optionally substituted with one or more substituents independently selected from F, Cl, Br and (1-4C alkyl);
hetAr1 is a 6-membered heteroaryl having 1-2 nitrogen atoms and optionally substituted with one or more substituents independently selected from (1-4C alkyl);
hetAr2 is a 6-membered heteroaryl having 1-2 nitrogen atoms and optionally substituted with one or more substituents independently selected from (1-4C alkyl) and CF3;
R7a, R7b and R8 are each independently hydrogen or methyl;
R9 is hydrogen, methyl, fluoro or NO2;
and
R10 is hydrogen, methyl or fluoro.

25 more elements

A compound of Formula I selected from

6-Cyano-7-(4-(4-chlorophenylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(4-chlorophenylcarbamoyl)phenoxy)-6-cyano-4-methylchroman-4-carboxylic acid;
7-(4-(4-Chlorophenylcarbamoyl)phenoxy)-6-cyano-2,2-dimethylchroman-4-carboxylic acid;
6-Cyano-7-(4-(2,4-dichlorophenylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(2,3-dihydro-1H-inden-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(4-Chlorobenzyloxycarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
6-Cyano-7-(4-(3,4-dichlorophenylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-nitrophenoxy)chroman-4-carboxylic acid;
6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-phenylbutylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-(3-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-(4-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
(Z)-6-chloro-7-(4-(4-(2-chlorophenyl)but-3-enylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-(2-chlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
(Z)-6-chloro-7-(4-(4-(2,4-dichlorophenyl)but-3-enylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(4-(2,4-dichlorophenyl)butylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,4-dimethylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(4-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-(4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-cyclopropylethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(2′-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-(2-(2′,3-dichlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2-chloro-4-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(3-chlorobiphenyl-4-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(2-bromo-4-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-(2-(2′,5-dichlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(4-bromo-2-methoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
8-bromo-6-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(4-chlorophenethylcarbamoyl)phenoxy)-6,8-dicyclopropylchroman-4-carboxylic acid;
6,8-dicyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(4-chlorophenethylcarbamoyl)phenoxy)-6-cyclopropylchroman-4-carboxylic acid;
6-cyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-8-cyclopropyl-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-Cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid
6-Cyano-7-(4-(1,2,3,4-tetrahydroisoquinolin-7-ylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6,8-dichloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-((2-Phenylcyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylic acid;
7-(4-((3-Methoxyphenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylic acid;
7-(4-((4-Fluorophenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylic acid;
7-(4-((4-(Trifluoromethyl)phenethyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylic acid;
7-(4-((2-(4-Chlorophenyl)cyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylic acid;
7-(4-(chroman-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid
6-Cyano-7-(4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(naphthalen-1-ylmethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(2-(naphthalen-1-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(2-(naphthalen-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(4-tert-Butylphenethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
7-(4-(2-(Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
7-(4-(2-Biphenyl-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-((R)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-((S)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(trifluoromethoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(3′,4′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(Biphenyl-3-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
7-(4-(Biphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
7-(4-(4′-Chlorobiphenyl-4-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
6-Cyano-7-(4-(3-(2-methylpyrimidin-4-yl)phenylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-Chloro-7-(4-(4′-chloro-6-fluorobiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(1,2,3,4-tetrahydronaphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(5-Chloro-2,3-dihydro-1H-inden-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
7-(4-(4-Chlorophenylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
6-Cyano-7-(4-(4-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(naphthalen-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,6-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,4-difluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-chloro-6-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(naphthalen-1-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(naphthalen-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,5-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,3-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(5-bromo-2-methoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
7-(4-(2-bromophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
7-(4-(2-(biphenyl-2-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-(2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(4′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(3′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(2′-chlorobiphenyl-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-chloro-4-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-chloro-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-chloro-4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-fluoro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(5-chloro-2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylic acid;
Enantiomer 2 of 6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(4′-methylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(3′-methylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(2′,3′-dimethylbiphenyl-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-((2,3-dihydro-1H-inden-2-yl)methylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(p-tolylthio)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(4-chlorophenylthio)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-ethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(2-chlorophenoxy)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(2-tert-butoxyphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-(2-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(1-(3-chlorophenyl)pyrrolidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(1-(3-chlorophenyl)piperidin-4-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)azetidin-3-ylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)pyrrolidin-3-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(1-(3-(trifluoromethyl)phenyl)piperidin-4-ylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(1-(2,4-dichlorophenyl)piperidin-4-ylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-((S)-1-(3-chlorophenyl)piperidin-3-ylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-Cyano-7-(4-((2,3-dihydro-1H-inden-2-yl)methylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
7-(4-(4-tert-Butylcyclohexylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
7-(4-(4-Chlorophenylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(4-Chlorophenethylcarbamoyl)-2-methylphenoxy)-6-cyanochroman-4-carboxylic acid;
6-Cyano-7-(4-((R)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-((S)-2-phenylpropylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(1-(4-Chlorophenyl)propan-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
7-(4-(4-Chloro-3-methoxyphenethylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
7-(4-(3-tert-Butylphenylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
6-Cyano-7-(4-(3-isopropoxyphenylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3,4-dichlorobenzylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,3-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(4-tert-butylphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-(3-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-methylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-(trifluoromethylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3,5-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-phenoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-chlorophenethylcarbamoyephenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Cyano-7-(4-(3-(trifluoromethyl)phenylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
Cis-6-Chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
Trans-6-Chloro-7-(4-(4-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(4-tert-butylcyclohexylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-Chloro-7-(4-(4,4-dimethylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Chloro-7-(4-(3-phenylcyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Chloro-7-(4-(3-(3-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Chloro-7-(4-(3-(4-methylphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Chloro-7-(4-(3-(4-methoxyphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Chloro-7-(4-(3-(4-(methylthio)phenyl)cyclohexylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-Chloro-7-(4-(3-(3-methoxyphenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-phenylcyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Chloro-7-(4-(3-p-tolylcyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Chloro-7-(4-(3-(3-chlorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-(4-chlorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-(3-methylphenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-(3-(trifluoromethyl)phenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxyli c acid;
6-chloro-7-(4-(3-(3-fluorophenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-(3-(methylthio)phenyl)cyclopentylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(3-(3,4-dichlorophenyl)cyclopentylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(3-(4-methoxyphenyl)cyclopentylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-(4-(methylthio)phenyl)cyclopentylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(4-(4-chlorophenyl)cyclohexylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-phenylcyclobutylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(3,3-dimethylbutylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-cyclohexylethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-2-methylphenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-3-methylphenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(2-chlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2-cyclopentylethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(1-oxaspiro[4.4]nonan-3-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(4-chlorophenyl)-2-fluoroethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3,5-dimethoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(3-chloro-2-methoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-(trifluoro-methyl)phenethyl-carbamoyl)phenoxy) chroman-4-carboxylic acid;
7-(4-(2-(benzo[d][1,3]dioxol-4-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-(2-(1-(4-(trifluoromethyl)phenyl)-1H-pyrrol-2-yl)ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(4-chlorophenyl)-2,2-difluoroethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2-ethylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(2,4-dichlorophenyl)-2-hydroxyethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-ethoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-(cyclopropyl-methoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-(2-methoxyethoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4,5-dichloro-2-ethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-isopropoxy-phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-(trifluoromethoxy)phenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(3,5-dichlorophen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)methylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(4-chlorophenoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-phenoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-(4-chlorophenoxy)phenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(3-chlorophenoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(2-chlorophenoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-(3-chlorophenoxy)phenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(3,4-dichlorophenoxy)-5-fluorophenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2-(2,4-dichlorophenoxy)-5-fluorophenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-(2-fluoroethoxy)phenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-(3-fluoropropoxy)phenethylcarbamoyl)phenoxy) chroman-4-carboxylic acid;
6-chloro-7-(4-(2-chloro-6-methoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,6-dimethoxyphen-ethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
5-chloro-7-(4-(4-chlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-((1-(4-chlorophenyl)cyclopropyl)methylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylic acid;
6-chloro-7-(4-(2-phenoxyethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
7-(4-(2,4-bis(trifluoromethyl)phenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid;
6-chloro-7-(4-(2,4,6-trimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-(difluoromethoxy)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,6-dichloro-4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2,4-diethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-chloro-4,6-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-ethoxy-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-ethoxy-4-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-(methylthio)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(4-chloro-2-fluorophenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-((5-chloro-2,3-dihydro-1H-inden-1-yl)methylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-cyclopropyl-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-Chloro-7-(4-(4-chloro-2-hydroxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
Enantiomer 2 of 6-chloro-7-(4-(4-chloro-2-cyclopropylphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
Enantiomer 2 of 6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
Enantiomer 2 of 6-chloro-7-(4-(2,4-dichloro-6-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
Enantiomer 2 of 6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
Enantiomer 2 of 6-chloro-7-(4-(2-methoxy-4-(trifluoromethyl)phenethyl-carbamoyl)phenoxy)chroman-4-carboxylic acid;
Enantiomer 2 of 6-chloro-7-(4-(2,4-dimethoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid;
and pharmaceutically acceptable salts thereof.

240 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/001,201Filed 24 Jun 2009 · us provisional application
Priority: 25 Jun 2008
Published: US 2011/0105463 A15 May 2011
Granted: 29 Oct 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 311/58
Benzo[b]pyrans, not hydrogenated in the carbocyclic ring: other than with oxygen or sulphur atoms in position 2 or 4
A61P 11/02
Drugs for disorders of the respiratory system: nasal agents, e.g. decongestants
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 17/00
Drugs for dermatological disorders

Family

Application61/075,615Us provisional application · filed 25 Jun 2008
US 2011/0105463 A1Pre-grant publication · published 5 May 2011
US 8,569,522 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

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Abstract

Compounds of Formula (I): in which A1, A2, W, L, G, R7a, R7b, R8, R9 and R10 have the meanings given in the specification, are DP2 receptor modulators useful in the treatment of immunologic diseases.

A compound of formula I:

or a salt thereof, wherein:
A1 is hydrogen, CN, Cl, F, Br, OMe, (1-4C alkyl) or cyclopropyl;
A2 is hydrogen, Cl, Br, F, (1-4C alkyl) or cyclopropyl;
W is —C(═O)NR1— or —NR2C(═O)—;
R1 and R2 are each hydrogen or methyl;
L is a bond, —(CR3R4)n—(CRaRb)m—(CR5R6)—*, (2-4C)alkenylene, —O(1-4C alkyl)-*, -(1-4C alkyl)-O—*, -(1-4C alkyl)-S—*, (3-6C)cycloalkylene, or hetCyc1, wherein the * indicates the point of attachment to G, provided that when W is —NR2C(═O)— then L is not —(CH═CH)—;
m=0, 1 or 2;
n=0 or 1;
Ra and Rb are independently selected from hydrogen and (1-4C alkyl);
R3 is hydrogen, (1-4C alkyl) or CH2OH;
R4 is hydrogen or methyl;
R5 is hydrogen, (1-4C alkyl), OH, —O(1-4C alkyl) or F;
R6 is hydrogen, F or methyl,
or R5 and R6 together with the carbon to which they are attached form a cyclopropyl ring;
hetCyc1 is a group having the formula
where t is 1 or 2 and p is 0 or 1, and the * indicates the point of attachment to G;
G is Ar1, Ar2, naphthyl, a benzo-fused (5-6C)cycloalkyl ring optionally substituted with one or more substituents independently selected from Cl and OMe, a benzo-fused 5-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from O and N, a (3-6C)cycloalkyl ring optionally substituted with one or more substituents independently selected from (1-4C)alkyl, an oxaspirononanyl ring, or t-butyl;
Ar1 is phenyl optionally substituted with one or more substituents independently selected from F, Cl, Br, CF3, (1-4C)alkyl, OH, —O(1-4C alkyl), —S(1-3C alkyl), —SCF3, cyclopropyl, —CH2N(1-3C alkyl)2, —O-(2-3C)fluoroalkyl, —O-(1-3C)difluoroalkyl —O-(1-3C)trifluoroalkyl, —OCH2(cyclopropyl), and (3-4C)alkynyl;
Ar2 is phenyl which is substituted with Ar3, —O—Ar4, hetAr1 or —O-hetAr2, wherein Ar2 is optionally further substituted with one or more substituents independently selected from F, Cl and CF3;
Ar3 is phenyl optionally substituted with one or more substituents independently selected from F, Cl, Br and (1-4C alkyl);
Ar4 is phenyl optionally substituted with one or more substituents independently selected from F, Cl, Br and (1-4C alkyl);
hetAr1 is a 6-membered heteroaryl having 1-2 nitrogen atoms and optionally substituted with one or more substituents independently selected from (1-4C alkyl);
hetAr2 is a 6-membered heteroaryl having 1-2 nitrogen atoms and optionally substituted with one or more substituents independently selected from (1-4C alkyl) and CF3;
R7a, R7b and R8 are each independently hydrogen or methyl;
R9 is hydrogen, methyl, fluoro or NO2;
and
R10 is hydrogen, methyl or fluoro.

24 more elements

Facts

Application

13/001,201Filed 24 Jun 2009 · us provisional application

Priority

25 Jun 2008

Published

US 2011/0105463 A15 May 2011

Granted

29 Oct 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification12 codes

C07D 311/58
Benzo[b]pyrans, not hydrogenated in the carbocyclic ring: other than with oxygen or sulphur atoms in position 2 or 4
A61P 11/02
Drugs for disorders of the respiratory system: nasal agents, e.g. decongestants
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 17/00
Drugs for dermatological disorders