US 8,299,123 B2Granted

CCR10 antagonists

AssigneeBoehringer Ingelheim International GmbH

InventorsKaka Dey, Donghong Amy Gao, Daniel R. Goldberg, Alexander Heim-Riether, John Edward Mangette, Ingo Andreas Mugge, Roger John Snow, Alan David Swinamer, Jiang-Ping Wu, Zhaoming Xiong, Yu Yang

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Abstract

The invention relates to a compound of formula (I): or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R1 to R11, W, X, Y, Z, and n are as defined herein. The invention also relates to methods of using the compounds of formula (I) and compositions thereof to treat various diseases and disorders in a patient. The invention also relates to processes for preparing the compounds of formula (I) and intermediates useful in these processes.

Claims8

Dependent claims

A compound of formula (I):

wherein:
W, X, and Z are C;
Y is O, NH, or S;
n is 1;
R1 is
(a) H;
(b) C1-8alkyl, branched or unbranched, optionally partially or fully halogenated, and optionally substituted with one to two groups selected from —OH, CN, C1-6alkoxy, —CO2C1-6alkyl, and —CON(C1-3alkyl)(C1-3alkyl),
(c) —(CH2)0-1C3-8cycloalkyl,
(d) —CH2Ar, wherein Ar is phenyl or heteroaryl selected from pyridinyl, triazolyl, pyrimidinyl, furanyl, thiazolyl, thienyl, pyrrolyl, imidazolyl, and benzofuranyl, each optionally substituted with one to two groups selected from halogen, —CN, —OH, C1-6alkyl, C1-6alkoxy, —CF3, —CO2C1-6alkyl, and —CONH2, or
(e) —(CH2)2OCH2Ar, wherein Ar is phenyl or heteroaryl selected from pyridinyl, triazolyl, pyrimidinyl, furanyl, thiazolyl, thienyl, pyrrolyl, imidazolyl, and benzofuranyl, each optionally substituted with one to two groups selected from halogen, —CN, —OH, C1-6alkyl, C1-6alkoxy, —CO2C1-6alkyl, —C(O)NH2;
or
if X is C, and Y is O, R1 may form a fused dihydropyran ring with the O it is bound to and X, said dihydropyran ring optionally substituted with one or two methyl groups;
R2 is
(a) H, C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, halogen, —CN, —CO2C1-6alkyl, —S(O)0-2C1-6alkyl, —NO2, —OH, —CF3, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)(C1-6alkyl), —NHC(O)NHC1-6alkyl, —C(O)NH2, —CONH(C1-6alkyl), —CON(C1-6alkyl)(C1-6alkyl), or
b) phenyl, pyridinyl, triazolyl, or pyrimidinyl, each optionally substituted with one or two groups selected from halogen, C1-6alkyl, —CN or C1-6alkoxy;
R3 is in the 4-position and is —CO2H, —(CH2)1-2CO2H, —(CH2)0-1C(CH3)(CH3)CO2H, —C(CH3)(CH3)CO2H, —O(CH2)1-4CO2H, —O(CH2)0-1C(C1-6alkyl)(C1-6alkyl)CO2H, —OC(C1-6alkyl)(C1-6alkyl)CO2H, —(CH2)0-1tetrazol-5-yl, or —C(CH3)(CH3)tetrazol-5-yl;
R4, R5, R6, and R7 are independently selected from H and C1-6alkyl, or R4 and R6 may be joined, together with the carbons they are bonded to, to form a cyclopropane ring;
R8, R9, R10, and R11 are independently H, halogen, C1-6alkyl, C1-6alkoxy, —CN, —CO2C1-6alkyl, —C(O)NH2, —SO2NH2, —NO2, —OH, —NH2, —CF3, or —CH2OH;
or a tautomer thereof or a salt thereof.

16 more elements

A compound selected from the group consisting of:

(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}biphenyl-4-yl)acetic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-2,5-difluorobiphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-3-chlorobiphenyl-4-carboxylic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-3-fluorobiphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-[(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}-2,3-dimethylbiphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}biphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-2-nitrobiphenyl-4-carboxylic acid;
2-{[4′-(2-{[2-(benzyloxy)-5-chlorobenzoyl]amino}ethyl)biphenyl-4-yl]oxy}-2-methylpropanoic acid;
2-(benzyloxy)-5-chloro-N-{2-[4′-(1H-tetrazol-5-yl)biphenyl-4-yl]ethyl}benzamide;
2-[(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}-2,5-difluorobiphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-2-chlorobiphenyl-4-carboxylic acid;
2-[(4′-{2-[(5-chloro-2-propoxybenzoyl)amino]ethyl}biphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-[2-({5-chloro-2-[(3-fluorobenzyl)oxy]benzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
4′-[2-({5-chloro-2-[(3-methoxybenzyl)oxy]benzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-2-fluorobiphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-butoxy-5-chloro-N-(2-{4′-[1-methyl-1-(1H-tetrazol-5-yl)ethyl]biphenyl-4-yl}ethyl)benzamide;
4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-3-fluorobiphenyl-4-carboxylic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-3-methoxybiphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-(2-{[5-chloro-2-(hexyloxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}biphenyl-3-yl)oxy]-2-methylpropanoic acid;
2-{[4′-(2-{[5-chloro-2-(4,4,4-trifluorobutoxy)benzoyl]amino}ethyl)biphenyl-4-yl]oxy}-2-methylpropanoic acid;
4′-(2-{[5-chloro-2-(pentyloxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
4′-(2-{[5-chloro-2-(heptyloxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
4′-[2-({5-chloro-2-[(4-methylpentyl)oxy]benzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
2-[(2,3-dichloro-4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}biphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-butoxy-5-chloro-N-{2-[4′-(1H-tetrazol-5-ylmethyl)biphenyl-4-yl]ethyl}benzamide;
4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-2-methylbiphenyl-4-carboxylic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-3-methylbiphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-2-methylbiphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-[(2-chloro-4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}biphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-[2-({5-chloro-2-[(3-methylbenzyl)oxy]benzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
2-[(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}-2-methylbiphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-2,3-dimethylbiphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-[(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}-3-methylbiphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-[2-({5-chloro-2-[(4-methylbenzyl)oxy]benzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
4′-[2-({5-chloro-2-[(6-hydroxyhexyl)oxy]benzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
2-[(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}-2-fluorobiphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-2-chlorobiphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-[(4′-{2-[(5-chloro-2-isopropoxybenzoyl)amino]ethyl}biphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-3-methoxybiphenyl-4-carboxylic acid;
2-{[4′-(2-{[5-chloro-2-(3,3,4,4,4-pentafluorobutoxy)benzoyl]amino}ethyl)biphenyl-4-yl]oxy}-2-methylpropanoic acid;
2-[(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}-2,5-dimethylbiphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-[2-({2-[2-(benzyloxy)ethoxy]-5-chlorobenzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
2-{[4′-(2-{[5-chloro-2-(4-fluorobutoxy)benzoyl]amino}ethyl)biphenyl-4-yl]oxy}-2-methylpropanoic acid;
2-[(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}-3-fluorobiphenyl-4-yl)oxy]-2-methylpropanoic acid;
3-(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}biphenyl-4-yl)-2,2-dimethylpropanoic acid;
4′-{2-[(5-bromo-2-butoxybenzoyl)amino]ethyl}biphenyl-4-carboxylic acid;
2-[(4′-{2-[(5-chloro-2-ethoxybenzoyl)amino]ethyl}biphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-(2-{[5-chloro-2-(4,4,4-trifluorobutoxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
3-(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}biphenyl-4-yl)propanoic acid;
2-(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}biphenyl-4-yl)-2-methylpropanoic acid;
2-[(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}-3′-fluorobiphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-[2-({5-chloro-2-[(4-fluorobenzyl)oxy]benzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
4′-[2-({5-chloro-2-[(3,4-difluorobenzyl)oxy]benzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-3-nitrobiphenyl-4-yl)acetic acid;
4′-(2-{[5-chloro-2-(3-methylbutoxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
4′-[2-({5-chloro-2-[(2-fluorobenzyl)oxy]benzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
4′-{2-[(5-chloro-2-{[3-(trifluoromethyl)benzyl]oxy}benzoyl)amino]ethyl}biphenyl-4-carboxylic acid;
4′-(2-{[5-chloro-2-(cyclobutylmethoxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
4′-(2-{[(5-bromo-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)carbonyl]amino}ethyl)-biphenyl-4-carboxylic acid;
3-(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}biphenyl-4-yl)-2,2-dimethylpropanoic acid;
2-chloro-4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}biphenyl-4-carboxylic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-3-cyanobiphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-[2-({5-chloro-2-[(3-cyanobenzyl)oxy]benzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
4′-(2-{[5-chloro-2-(cyclohexylmethoxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]-1-methylethyl}biphenyl-4-carboxylic acid;
4′-(2-{[5-chloro-2-(3,3,4,4,4-pentafluorobutoxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
4′-(2-{[(2-butoxy-5-chloropyridin-3-yl)carbonyl]amino}ethyl)biphenyl-4-carboxylic acid;
2-[(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}biphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-butoxy-5-chloro-N-(2-{4-[6-(1H-tetrazol-5-yl)pyridin-3-yl]phenyl}ethyl)benzamide;
4′-(2-{[5-chloro-2-(pyridin-2-ylmethoxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
4′-{2-[(5-chloro-2-{[2-(trifluoromethyl)benzyl]oxy}benzoyl)amino]ethyl}biphenyl-4-carboxylic acid;
2-[(3-chloro-4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}biphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-2-cyanobiphenyl-4-carboxylic acid;
4′-{2-[(5-chloro-2-ethoxybenzoyl)amino]ethyl}biphenyl-4-carboxylic acid;
4′-(2-{[5-chloro-2-(1-methylbutoxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
3-chloro-4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}biphenyl-4-carboxylic acid;
2-[(2′,6′-dichloro-4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}biphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-{2-[(5-chloro-2-isobutoxybenzoyl)amino]ethyl}biphenyl-4-carboxylic acid;
4′-{2-[(5-chloro-2-propoxybenzoyl)amino]ethyl}biphenyl-4-carboxylic acid;
4′-[2-({5-chloro-2-[(4-methyl-1,3-thiazol-2-yl)methoxy]benzoyl}amino)ethyl]biphenyl-4-carboxylic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-2,5-dimethylbiphenyl-4-yl)oxy]-2-methylpropanoic acid;
4′-(2-{[5-chloro-2-(4-fluorobutoxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-3-chlorobiphenyl-4-yl)oxy]-2-methylpropanoic acid;
(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}biphenyl-4-yl)acetic acid;
4′-(2-{[5-chloro-2-(cyclopropylmethoxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
4′-(2-{[5-chloro-2-(pyridin-3-ylmethoxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]-1,1-dimethylethyl}biphenyl-4-carboxylic acid;
4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]propyl}biphenyl-4-carboxylic acid;
4′-(2-{[(5-bromo-2,3-dihydro-1-benzofuran-7-yl)carbonyl]amino}ethyl)biphenyl-4-carboxylic acid;
2-{[4′-(2-{[5-chloro-2-(3,3,3-trifluoropropoxy)benzoyl]amino}ethyl)biphenyl-4-yl]oxy}-2-methylpropanoic acid;
2-amino-4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}biphenyl-4-carboxylic acid;
2-[(4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}-2,6-dimethylbiphenyl-4-yl)oxy]-2-methylpropanoic acid;
2-(4′-{2-[(5-chloro-2-methoxybenzoyl)amino]ethyl}biphenyl-4-yl)-2-methylpropanoic acid;
4′-{2-[(2-butoxy-5-pyridin-3-ylbenzoyl)amino]ethyl}biphenyl-4-carboxylic acid;
4′-(2-{[5-chloro-2-(cyclobutyloxy)benzoyl]amino}ethyl)biphenyl-4-carboxylic acid;
4′-{2-[(2-butoxy-5-chlorobenzoyl)amino]ethyl}biphenyl-4-carboxylic acid;
2-(4-{5-[2-(2-butoxy-5-chloro-benzoylamino)-ethyl]-pyridin-2-yl}-phenoxy)-2-methyl-propionic acid;
2-{4′-[2-(2-butoxy-5-chloro-benzoylamino)-ethyl]-3′-ethyl-biphenyl-4-yloxy}-2-methyl-propionic acid;
2-{3′,5′-Dichloro-4′-[2-(5-chloro-2-methoxy-benzoylamino)-ethyl]-biphenyl-4-yloxy}-2-methyl-propionic acid;
and
a tautomer thereof or a salt thereof.

99 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/738,087Filed 14 Oct 2008 · us provisional application
Priority: 19 Oct 2007
Published: US 2011/0039851 A117 Feb 2011
Granted: 30 Oct 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 249/06
1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles: with aryl radicals directly attached to ring atoms
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 17/00
Drugs for dermatological disorders
A61P 17/04
Drugs for dermatological disorders: antipruritics