Aryl aniline beta2 adrenergic receptor agonists

Abstract

The invention provides novel β 2 adrenergic receptor agonist compounds of formula (I): wherein R 1 -R 13 and w have any of the values described in the specification. The invention also provides combinations of such compounds and other therapeutic agents, pharmaceutical compositions comprising such compounds and combinations, methods of using such compounds to treat diseases associated with β 2 adrenergic receptor activity, and processes and intermediates useful for preparing such compounds.

What is claimed is:  
     
         1 . A combination comprising a compound of formula (I):  
       
         
           
           
               
               
           
         
         wherein: 
 each of R 1 -R 5  is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and R a ;  
 or R 1  and R 2 , R 2  and R 3 , R 3  and R 4 , or R 4  and R 5  are joined together to form a group selected from the group consisting of —C(R d )═C(R d )C(═O)NR d —, —CR d R d —CR d R d —C(═O)NR d —, —NR d C(═O)C(R d )═C(R d )—, —NR d C(═O)CR d R d —CR d R d —, —NR d C(═O)S—, —SC(═O)NR d —, —(CR d R d ) p —, —S(CR d R d ) q —, —(CR d R d ) q S—, —S(CR d R d ) r O—, —O(CR d R d ) r S—, and —NHC(R j )═C(R k )—;  
 R 6  is hydrogen, alkyl, or alkoxy;  
 R 7  is hydrogen or alkyl;  
 R 8  is hydrogen or alkyl; or R 8  together with R 9  is —CH 2 — or —CH 2 CH 2 —;  
 R 9  is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and R a , or R 9  together with R 8  is —CH 2 — or —CH 2 CH 2 —;  
 R 10  is hydrogen or alkyl;  
 each R 11 , R 12 , and R 13  is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —NO 2 , halo, —NR d R e , —C(═O)R d , —CO 2 R d , —OC(═O)R d , —CN, —C(═O)NR d R e , —NR d C(═O)R e , —OC(═O)NR d R e , —NR d C(═O)OR e , —NR d C(═O)NR d R e , —OR d , —S(O) m R d , —NR d —NR d —C(═O)R d , —NR d N═CR d R d , —N(NR d R e )R d , and —S(O) 2 NR d R e ;  
 or R 11  and R 12  together with the atoms to which they are attached form a fused benzo ring, which benzo ring can optionally be substituted with 1, 2, 3, or 4 R e ;  
 or R 11  and R 12  together with the atoms to which they are attached form a heterocyclic ring;  
 wherein for R 1 -R 6 , R 9 , and R 11 -R 13 , each alkyl, alkenyl, and alkynyl is optionally substituted with R m , or with 1, 2, 3, or 4 substituents independently selected from R b ; for R 1 -R 6 , R 9 , and R 11 -R 13 , each aryl and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R c , and for R 1 -R 6 , R 9 , and R 11 -R 13  each cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R b  and R e ;  
 each R a  is independently —OR d , —NO 2 , halo, —S(O) m R d , —S(O) 2 OR d , —S(O) m NR d R e , —NR d R e , —O(CR f R g ) n NR d R e , —C(═O)R d , CO 2 R d , —CO 2 (CR f R g ) n CONR d R e , —OC(═O)R d , —CN, —C(═O)NR d R e , —NR d C(═O)R c , —OC(═O)NR d R e , —NR d C(═O)OR e , —NR d C(═O)NR d R e , —CR d (═N—OR c ), —CF 3 , or —OCF 3 ;  
 each R b  is independently R a , oxo, or ═N—OR e ;  
 each R c  is independently R a , alkyl, alkenyl, or alkynyl; wherein each alkyl, alkenyl and alkynyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R b ;  
 each R d  and R e  is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R b ; or R d  and R e  together with the atoms to which they are attached form a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or nitrogen;  
 each R f  and R g  is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R b ; or R f  and R g  together with the carbon atom to which they are attached form a ring having from 5 to 7 ring atoms, wherein the ring optionally contains 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen;  
 each R h  is independently halo, C 1-8 alkyl, C 1-8 alkoxy, —S—C 1-8 alkyl, aryl, (aryl)-C 1-6 alkyl, (aryl)-C 1-8 alkoxy, heteroaryl, (heteroaryl)-C 1-6 alkyl, (heteroaryl)-C 1-8 alkoxy, hydroxy, amino, —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —OC(═O)C 1-6 alkyl, —C(═O)C 1-6 alkyl, —C(═O)OC 1-6 alkyl, —NHC(═O)C 1-6 alkyl, —C(═O)NHC 1-6 alkyl, carboxy, nitro, —CN, or —CF 3 ;  
 R j  and R k  together with the carbon atoms to which they are attached form a phenyl ring that is optionally substituted with 1, 2, 3, or 4 R c ;  
 each R m  is independently aryl, heteroaryl, cycloalkyl or heterocyclyl; wherein each aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of RC, and wherein each cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents selected from R b ;  
 m is 0, 1, or 2;  
 n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;  
 p is 3, 4, or 5;  
 q is 2, 3, or 4;  
 r is 1, 2, or 3; and  
 w is 0, 1, 2, 3, or 4;  
 
         or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof;  
         and a corticosteroid selected from the group consisting of 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester and 6α,9 α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester.  
       
     
     
         2 . The combination of  claim 1  wherein 
 R 6 , R 8 , and R 10  are each hydrogen; and  
 w is 0, 1, or 2.  
 
     
     
         3 . The combination of  claim 1  wherein 
 each of R 1 -R 4  is independently selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxy, N,N-dimethylaminocarbonyloxy, —CH 2 OH, and —NHCHO, and R 5  is hydrogen; or  
 R 1  is hydrogen, R 2  is hydrogen, R 3  is hydroxy, and R 4  and R 5  together are —NHC(═O)CH═CH— or —SC(═O)NH—.  
 
     
     
         4 . The combination of  claim 1  wherein each of R 1 -R 5  is independently selected from the group consisting of hydrogen, alkyl, and R a ; wherein each R a  is independently —OR d , halo, —NR d R e , —NR d C(═O)RC, or —OC(═O)NR d R e ; 
 or R 1  and R 2 , or R 4  and R 5 , are joined together to form a group selected from the group consisting of —C(R d )═C(R d )C(═O)NR d —, —CR d R d —CR d R d —C(═O)NR d —, —NR d C(═O)C(R d )═C(R d )—, —NR d C(═O)CR d R d —CR d R d —, —NR d C(═O)S—, and —SC(═O)NR d —;  
 R 6 , R 8 , and R 10  are each hydrogen;  
 each of R 11  and R 12  is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —NO 2 , halo, —NR d R e , —CO 2 R d , —OC(═O)R d , —CN, —C(═O)NR d R e , —NR d C(═O)R e , —OR d , —S(O) m R d , —NR d —NR d —C(═O)R d , —NR d —N═CR d R d , N(NR d R e )R d , and —S(O) 2 NR d R e ;  
 wherein for R 1 -R 5 , R 11 , and R 12 , each alkyl is optionally substituted with R m , or with 1, 2, 3, or 4 substituents independently selected from R b ; for R 11  and R 12 , each aryl and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R c , and for R 11  and R 12 , each cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R b  and R c ;  
 R 13  is hydrogen;  
 the group comprising —NR 10  is meta or para to the group comprising R 7 ; and  
 w is 0, 1, or 2.  
 
     
     
         5 . The combination of  claim 4  wherein each of R 11  and R 12  is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, —OR d , —S(O) m R d , and —S(O) 2 NR d R e ; wherein each alkyl is optionally substituted with 1 or 2 substituents independently selected from R b , each aryl is optionally substituted with 1 or 2 substituents independently selected from R c , and each heterocyclyl is optionally substituted with 1 or 2 substituents independently selected from R b  and R c ; and m is 0 or 2.  
     
     
         6 . A combination of a compound of formula (IIa):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 4  is —CH 2 OH or —NHCHO and R 5  is hydrogen; or R 4  and R 5  taken together are —NHC(═O)CH═CH—;  
 R 11  is phenyl or heteroaryl, wherein each phenyl is optionally substituted with 1 or 2 substituents selected from halo, —OR d , —CN, —NO 2 , —SO 2 R d , —C(═O)R d , —C(═O)NR d R e , and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and each R d  and R e  is independently hydrogen or C 1-3 alkyl; and wherein each heteroaryl is optionally substituted with 1 or 2 C 1-3 alkyl substituents; and  
 R 12  is hydrogen or —OC 1-6 alkyl;  
 or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof;  
 and a corticosteroid selected from the group consisting of 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester and 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester.  
 
     
     
         7 . The combination of  claim 6  wherein R 11  is phenyl, optionally substituted with 1 substituent selected from halo, —OR d , —CN, —NO 2 , —SO 2 R d , C(═O)R d , and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and R d  is hydrogen or C 1-3 alkyl.  
     
     
         8 . The combination of  claim 6  wherein R 11  is pyridyl, thiophenyl, furanyl, pyrrolyl, isoxazolyl, or indolyl, each of which is optionally substituted with 1 or 2 C 1-3 alkyl substituents.  
     
     
         9 . The combination of  claim 6  wherein R 11  is phenyl, pyridyl, or thiophenyl, wherein each phenyl is optionally substituted with 1 substituent selected from the group consisting of chloro, —OCH 3 , —CN, and —CH 2 NH 2 ; and R 12  is hydrogen, —OCH 3 , or —OC 2 H 5 .  
     
     
         10 . The combination of  claim 9  wherein R 4  and R 5  taken together are —NHC(═O)CH═CH—; R 11  is phenyl or pyridyl, wherein each phenyl is optionally substituted with 1 substituent selected from the group consisting of chloro, —OCH 3 , —CN, and —CH 2 NH 2 ; and R 12  is —OCH 3 .  
     
     
         11 . The combination of  claim 6  wherein the compound of formula (IIa) is a mixture of stereosiomers wherein the amount of the stereoisomer having the (R) orientation at the chiral center to which the hydroxy group is attached is greater than the amount of the stereoisomer having the (S) orientation at the chiral center to which the hydroxy group is attached.  
     
     
         12 . The combination of  claim 6  wherein the compound of formula (IIa) is the stereoisomer having the (R) orientation at the chiral center to which the hydroxy group is attached.  
     
     
         13 . The combination of  claim 6  wherein the compound of formula (IIa) is selected from the group consisting of: 
 N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;  
 N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;  
 N-{2-[4-(3-phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;  
 N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;  
 N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;  
 N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;  
 N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;  
 N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;  
 N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;  
 N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;  
 N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(2-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(2-methoxyphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(3-cyanophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(4-aminomethylphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(3-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(4-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(4-hydroxyphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(3-pyridyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(4-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(thiophen-3-yl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine; and  
 N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(3-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 and pharmaceutically-acceptable salts or solvates thereof.  
 
     
     
         14 . The combination of  claim 6  wherein the compound of formula (1Ha) is selected from the group consisting of: 
 N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(4-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 N-{2-[4-(3-(3-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;  
 and pharmaceutically-acceptable salts or solvates thereof.  
 
     
     
         15 . The combination of  claim 14  wherein the corticosteroid is 6(x,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid S-fluoromethyl ester.  
     
     
         16 . A pharmaceutical composition comprising a therapeutically effective amount of a combination of  claim 1  and a pharmaceutically-acceptable carrier.  
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the composition is formulated for administration by inhalation.  
     
     
         18 . A pharmaceutical composition comprising a therapeutically effective amount of a combination of  claim 6  and a pharmaceutically-acceptable carrier.  
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the composition is formulated for administration by inhalation.  
     
     
         20 . A method of treating a disease or condition in a mammal associated with β 2  adrenergic receptor activity, the method comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition comprising a combination of  claim 1  and a pharmaceutically-acceptable carrier.  
     
     
         21 . The method of  claim 20  wherein the disease or condition is a pulmonary disease.  
     
     
         22 . The method of  claim 21  wherein the pulmonary disease is asthma or chronic obstructive pulmonary disease.  
     
     
         23 . A method of treating a disease or condition in a mammal associated with β 2  adrenergic receptor activity, the method comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition comprising a combination of  claim 6  and a pharmaceutically-acceptable carrier.  
     
     
         24 . The method of  claim 23  wherein the disease or condition is a pulmonary disease.  
     
     
         25 . The method of  claim 24  wherein the pulmonary disease is asthma or chronic obstructive pulmonary disease.