Therapeutic compounds

Abstract

and pharmaceutically acceptable salts thereof, wherein the variables A, R6, R7, R8, R9, Rx, L, X, Y, and Z have the meaning as described herein. The compounds are useful for reducing endoplasmic reticulum stress and for producing analgesia in an animal.

What is claimed is: 
     
         1 . A compound of formula Ia′, Ib′ Ic′, or Id′: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 i) wherein the compound of formula Ia′: 
 ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR a , —SR a , —N(R a ) 2 , —NO 2  and —CN; 
 L is selected from the group consisting of: 
 —CH 2 CH 2 —, —CH 2 NH—, —CH 2 C(═O)—, —CH(OH)CH 2 —, 
 
       
         
           
           
               
               
           
         
         R L  is hydrogen, C 1-4  alkyl, C 1-4  haloalkyl or C 3-8  cycloalkyl; 
         ring Y is heteroaryl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR y , —SR y , —N(R y ) 2 , —NO 2  or —CN; 
         R 6  is hydrogen, or C 1-6  alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR f , —SR f , —N(R f ) 2 , oxo, —NO 2  or —CN; or R 6  and R 8  taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR i , —SR i , —N(R i ) 2 , —NO 2  or —CN; 
         R 7  is hydrogen, or C 1-6  alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR g , —SR g , —N(R g ) 2 , oxo, —NO 2  or —CN; 
         R 8  is hydrogen, or C 1-6  alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR h , —SR h , —N(R h ) 2 , oxo, —NO 2  or —CN; or R 6  and R 8  taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR i , —SR i , —N(R i ) 2 , —NO 2  or —CN; 
         X is ═O, ═S or ═N—Rx; wherein R x  is hydrogen, or C 1-6  alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR i , —SR i , —N(R i ) 2 , —NO 2  or —CN; or R x  and R 8  taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR i , —SR i , —N(R i )2, —NO 2  or —CN; 
         each R a  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R a  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R b  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R b  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R c  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R c  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R d  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R d  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R e  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R e  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R f  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; or two R f  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R g is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; or two R g  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R h  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; or two R h  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R i  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; or two R i  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and 
         each R y  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; or two R y  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         ii) wherein the compound of formula Ib′: 
         ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR a , —SR a , —N(R a ) 2 , —NO 2  and —CN; 
         Y is S or —NR 6 —; 
         R 6  is hydrogen, or C 1-6  alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR f , —SR f , —N(R a ) 2 , oxo, —NO 2  or —CN; 
         R 7  is hydrogen, or C 1-6  alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR g , —SR g , —N(R g ) 2 , oxo, —NO 2  or —CN; 
         R 8  is hydrogen, phenyl, or C 1-6  alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR h , —SR h , —N(R h ) 2 , oxo, —NO 2  or —CN; 
         R x  is hydrogen, or C 1-6  alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR i , —SR i , —N(R i ) 2 , —NO 2  or —CN; or R x  and R 8  taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR i , —SR i , —N(R i ) 2 , —NO 2  or —CN; 
         each R a  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R a  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R b  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R b  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R c  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R c  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R d  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R d  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R e  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R e  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R f  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; or two R f  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R g  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; or two R g  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R h  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; or two R h  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and 
         each R i  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; or two R i  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         iii) wherein the compound of formula Ic′: 
         ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR a , —SR a , —N(R a ) 2 , —NO 2  and —CN; 
         L is —CH═N—, or C 1-4  alkylene that is optionally substituted with one or more groups selected from halo, hydroxy or C 3-8  cycloalkyl; 
         R 7  is hydrogen, or C 1-6  alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR g , —SR g , —N(R g ) 2 , oxo, —NO 2  or —CN; 
         ring Z is heteroaryl or unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from oxo (═O), C 1-4  alkyl, —F, —Cl, —Br, —I, —OR i , —SR i , —N(R i ) 2 , —NO 2  or —CN; 
         each R a  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R a  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R e  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl, wherein the C 1-4  alkyl and C 1-4  haloalkyl are optionally substituted with aryl or heteroaryl; or two R e  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         each R g  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; or two R g  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and 
         each R i  is independently hydrogen, C 1-4  alkyl or C 1-4  haloalkyl; or two R i  groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; 
         iv) wherein the compound of formula Id′: 
         ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR a , —SR a , —N(R a ) 2 , —NO 2  and —CN; and 
         R 9  is hydrogen or C(═NH)—NH 2 . 
         provided that the compound is not: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1  that is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . A pharmaceutical composition comprising a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof as described in  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         4 . A method for producing analgesia in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′ or a pharmaceutically acceptable salt thereof as described in  claim 1 . 
     
     
         5 . The method of  claim 4  further comprising administering morphine to the animal. 
     
     
         6 . The method of  claim 4 , wherein the compound is a compound of formula Ia: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 ring A is phenyl; 
 R 1  is C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR a , —SR a , —N(R a ) 2 , —NO 2  or —CN; 
 R 2  is hydrogen, C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR b , —SR b , —N(R b ) 2 , —NO 2  or —CN; 
 R 3  is hydrogen, C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR c , —SR c , —N(R c ) 2 , —NO 2  or —CN; 
 R 4  is hydrogen, C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR d , —SR d , —N(R d ) 2 , —NO 2  or —CN; 
 R 5  is C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR e , —SR e , —N(R e ) 2 , —NO 2  or —CN; 
 and the group 
 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 4 , wherein the compound is a compound of the following formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR a , —SR a , —N(R a ) 2 , —NO 2  or —CN; 
 R 2  is hydrogen, C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR b , —SR b , —N(R b ) 2 , —NO 2  or —CN; 
 R 3  is hydrogen, C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR c , —N(R c ) 2 , —NO 2  or —CN; 
 R 4  is hydrogen, C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR d , —SR d , —N(R d ) 2 , —NO 2  or —CN; 
 R 5  is C 1-4  alkyl, C 1-4  haloalkyl, C 3-8  cycloalkyl, —F, —Cl, —Br, —I, —OR e , —SR e , —N(R e ) 2 , —NO 2  or —CN; and 
 L is selected from the group consisting of —NH—, —CH 2 NH—, —CH 2 C(═O)—, 
 
       
         
           
           
               
               
           
         
       
       and C 1-4  alkylene that is optionally substituted with one or more groups selected from halo, hydroxy and C 3-8  cycloalkyl. 
     
     
         8 . The method of  claim 4 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 5 , wherein the analgesia is produced for synergy in antinociception with reduced sedation or cardiovascular effects. 
     
     
         10 . The composition of  claim 3  further comprising acetaminophen. 
     
     
         11 . The composition of  claim 10  wherein the compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof is E-guanabenz or Z-guanabenz, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of  claim 4  further comprising administering acetaminophen to the animal. 
     
     
         13 . The method of  claim 12  wherein the compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof is E-guanabenz or Z-guanabenz, or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A pharmaceutical composition comprising: 1) a drug that is associated with unwanted endoplasmic reticulum stress, 2) a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof as described in  claims 1 , and 3) a pharmaceutically acceptable carrier;
 provided the compound of formula Ia′, Ib′ Ic′, or Id′ is not 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A method for reducing endoplasmic reticulum stress in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof as described in  claim 1 ;
 provided the compound of formula Ia′, Ib′ Ic′, or Id′ is not 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . A method for reducing drug-induced toxicity in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof as described in  claim 1 . 
     
     
         15 . The method of  claim 14  wherein the drug is acetaminophen. 
     
     
         16 . A method for treating a disease selected from the group consisting of diabetes, viral infection, and cancer in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof as described in  claim 1 ;
 provided the compound of formula Ia′, Ib′ Ic′, or Id′ is not 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.