Substituted Arylpyrazines

Abstract

Arylpyrazine compounds are provided, including arylpyrazines that can bind with high affinity and high selectivity to CRF 1 receptors, including human CRF 1 receptors. The invention thus includes methods for treatment of disorders and diseases associated with CRF 1 receptors, including CNS-related disorders and diseases, particularly affective disorders and diseases, and acute and chronic neurological disorders and diseases.

1 - 146 . (canceled)  
   
   
       147 . A method according to  claim 152  comprising administering to a patient in need of such treatment between 0.1 to 140 mg per kg body weight per day of the compound or pharmaceutically acceptable salt thereof.  
   
   
       148 - 150 . (canceled)  
   
   
       151 . A method for modulating CRF receptor function, comprising administering to a patient in need of such modulation an effective amount of a compound of the formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein, 
 R 1  is selected from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, halogen, CN, C 1-4  haloalkyl, trifluoromethyl, trifluoromethoxy, —NH(C 1-4  alkyl), —N(C 1-4  alkyl)(C 1-4  alkyl), —O(C 1-4  alkyl), and S(O) n (C 1-4  alkyl);  
 R 2  is selected from the group consisting of —XR A  and Y, wherein —X, R A , and Y are as defined below;  
 R 3  is selected from the group consisting of hydrogen, halogen, C 1-4  alkyl, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), —N(C 1-4  alkyl)(C 1-4  alkyl), —S(O) n (C 1-4  alkyl), haloalkyl, trifluoromethyl, trifluoromethoxy, —XR A  and Y;  
 R 4  is absent or an oxygen atom;  
 Ar is selected from the group consisting of: pyridyl, pyridonyl, pyrimidinyl, and thienyl, each of which is unsubstituted or mono-, di-, or tri-substituted with R C ;  
 R A  and R B , which may be the same or different, are independently selected at each occurrence from the group consisting of: hydrogen and straight, branched, or cyclic alkyl groups consisting of 1 to 8 carbon atoms, which alkyl groups may contain one or more double or triple bonds, and each of which alkyl groups may be further substituted with one or more substitutent(s) selected from oxo, hydroxy, halogen, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), —N(C 1-4  alkyl)(C 1-4  alkyl), —NHC(O)(C 1-4  alkyl), —N(C 1-4  alkyl)C(═O)(C 1-4  alkyl), —NHS(O) n (C 1-4  alkyl), —S(O) n (C 1-4  alkyl), —S(O) n NH(C 1-4  alkyl), —S(O)N(C 1-4  alkyl)(C 1-4  alkyl), and Z;  
 R C  is independently selected at each occurrence from the group consisting of halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C 1-6  alkyl substituted with 0-2 R D , C 2-6  alkenyl substituted with 0-2 R D , C 1-4  alkynyl substituted with 0-2 R D , C 3-7  cycloalkyl substituted with 0-2 R D , (C 3-7  cycloalkyl)C 1-4  alkyl substituted with 0-2 R D , —O(C 1-4  alkyl) substituted with 0-2 R D , —NH(C 1-4  alkyl) substituted, with 0-2 R D , —N(C 1-4 alkyl)(C 1-4  alkyl) each independently substituted with 0-2 R D , —XR A , and Y;  
 R D  is independently selected at each occurrence from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, —O(C 1-4 alkyl), —NH(C 1-4 alkyl), —N(C 1-4 alkyl)(C 1-4 alkyl), morpholino, pyrrolidino, piperidino, thiomorpholino, piperazino, 4-hydroxypiperidino, —S(O) n (C 1-4  alkyl), trifluoromethyl, trifluoromethoxy, CO(C 1-4 alkyl), CONH(C 1-4 alkyl), CON(C 1-4 alkyl)(C 1-4 alkyl), —XR A , and Y;  
 X is independently selected at each occurrence from the group consisting of —CH 2 —, —CHR B —, —O—, —C(═O)—, —C(═O)O—, —S(O) n —, —NH—, —NR B —, —C(═O)NH—, —C(═O)NR B —, —S(O) n NH—, —S(O) n NR B —, —OC(═S)S—, —NHC(═O)—, —NR B C(═O)—, —NHS(O) n —, —OSiH n (C 1-4 alkyl) 2-n -, and —NR B S(O) n —;  
 Y and Z are independently selected at each occurrence from the group consisting of: 3- to 7-membered carbocyclic and heterocyclic groups, which are saturated, unsaturated, or aromatic, which may be substituted with one or more substitutents selected from halogen, haloalkyl, oxo, hydroxy, amino, C 1-4  alkyl, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), —N(C 1-4  alkyl)(C 1-4  alkyl), and —S(O) n (C 1-4  alkyl), and said 3- to 7-membered heterocyclic groups contain heteroatom(s) selected from N, O, and S, with the point of attachment to the pyrazine ring being either carbon or nitrogen; and 
 n is independently selected at each occurrence from 0, 1, and 2.  
 
 
   
   
       152 . A method for treating a CNS disorder or disease selected from an affective disorder, an anxiety disorder, an eating disorder, a stress-related disorder, a sleep disorder, a cardiovascular disease, fibromyalgia, substance abuse, and arthritis, comprising modulating CRF receptor function by administering to a patient in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to  claim 151 .  
   
   
       153 - 155 . (canceled)  
   
   
       156 . A method of  claim 152  wherein the patient is a human patient and the disease or disorder is depression, bipolar disorder, hypertension, tachycardia, post-traumatic stress disorder, fibromyalgia, arthritis, or obesity.  
   
   
       157 . (canceled)  
   
   
       158 . A method according to  claim 152  wherein in a standard in vitro CRF receptor binding assay the compound exhibits an IC 50  value less than or equal to 100 nanomolar.  
   
   
       159 . A method according to  claim 152  wherein in a standard in vitro CRF receptor binding assay the compound exhibits an IC 50  value less than or equal to 10 nanomolar.  
   
   
       160 - 162 . (canceled)  
   
   
       163 . The method of  claim 152 , wherein the compound is a compound in which is absent and Ar is 2-, 3-, or 4-pyridyl, mono-, di-, or tri-substituted with R C .  
   
   
       164 . The method of  claim 152 , wherein the compound is a compound in which R 2  is selected from the group consisting of dipropylamino, 3-pentylamino, 4-heptylamino, 3-pentoxy, 4-heptoxy, piperidin-1-yl, and morpholin-1-yl.  
   
   
       165 . The method of  claim 152 , wherein the compound is a compound in which R 1  and R 3  are selected from the group consisting of methyl, ethyl, methoxy, ethoxy, and methylamino.  
   
   
       166 . The method of  claim 152 , wherein the compound is a compound in which Ar is selected from 2-pyridyl, 3-pyridyl, 2-pyrimidinyl, and 4-pyrimidinyl, each of which is mono- or di-substituted with R C , wherein at least one R C  is ortho or para to the point of attachment of Ar to the pyrazine ring.  
   
   
       167 . The method of  claim 166 , wherein the compound is a compound in which R C  is selected from the group consisting of halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C 1-6  alkyl, C 1-4 alkoxy, C 1-4 alkoxy(C 1-4 alkoxy), mono- or di(C 1-4 )amino(C 1-4 alkoxy), and mono- or di(C 1-4  alkyl)amino.  
   
   
       168 . The method of  claim 152 , wherein the compound is a compound in which R 2  is selected from the group consisting of dipropylamino, 3-pentylamino, 4-heptylamino, 3-pentoxy, 4-heptoxy, piperidin-1-yl, and morpholin-1-yl; 
 R 1  and R 3  are selected from the group consisting of methyl, ethyl, methoxy, ethoxy, and methylamino;    Ar is selected from 2-pyridyl, 3-pyridyl, 2-pyrimidinyl, and 4-pyrimidinyl, each of is mono-substituted or di-substituted with R C , wherein at least one R C  is ortho or para to the point of attachment of Ar to the pyrazine ring; and    R C  is selected from the group consisting of halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C 1-6  alkyl, C 1-4 alkoxy, C 1-4 alkoxy(C 1-4 alkoxy), mono- or di(C 1-4 )amino(C 1-4 alkoxy), and mono- or di(C 1-4  alkyl)amino.    
   
   
       169 . The method of  claim 168 , wherein the compound is a compound in which 
 R 2  is selected from the group consisting of 3-pentylamino, 3-pentoxy, piperidin-1-yl, and morpholin-1-yl;    R 1  and R 3  are selected from the group consisting of methyl, ethyl, and methoxy; and    Ar is selected from 3-pyridyl and 2-pyrimidinyl, each of is mono-substituted or di-substituted with R C , wherein at least one R C  is ortho or para to the point of attachment of Ar to the pyrazine ring.    
   
   
       170 . The method of  claim 152 , wherein the compound is a compound in which Ar is selected from: pyridyl, pyridonyl, pyrimidinyl, and thienyl, each of which substituted with 0-3 R C .  
   
   
       171 . The method of  claim 152  wherein the compound is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein: 
 R X  and R Y  are independently selected from the group consisting of hydrogen and straight, branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, which alkyl groups may contain one or more double or triple bonds, each of which alkyl groups may be further substituted with one or more substitutent(s) independently selected from hydroxy, halogen, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), —N(C 1-4  alkyl)(C 1-4  alkyl), and optionally substituted phenyl.  
 
   
   
       172 . The method of  claim 171 , wherein the compound is a compound in which Ar is 2- or 3-pyridyl, mono-, di-, or tri-substituted with R C ; and R 1  and R 3  are independently selected from the group consisting of hydrogen, halogen, methyl, ethyl, ethoxy and methoxy.  
   
   
       173 . The method of  claim 171 , wherein the compound is a compound in which 
 R X  is hydrogen;    R Y  is chosen from the group consisting of:    straight, branched, or cyclic alkyl groups having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds;    R 1  and R 3  are independently chosen from halogen, C 1-4  alkyl, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), —N(C 1-4  alkyl)(C 1-4  alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and    Ar is 2- or 3-pyridyl, which is mono- or di-substituted with substitutent(s) independently selected from: halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C 1-6  alkyl, C 1-4 alkoxy, C 1-4 alkoxy(C 1-4 alkoxy), mono- or di(C 1-4 )amino(C 1-4 alkoxy), and mono- or di(C 1-4  alkyl)amino.    
   
   
       174 . The method of  claim 171 , wherein the compound is a compound in which R X  is hydrogen and R Y  is 3-pentyl.  
   
   
       175 . The method of  claim 152 , wherein the compound is a compound of the formula:  
     
       
         
         
             
             
         
       
     
     wherein; 
 R X  is chosen from the group consisting of:  
 straight, branched, or cyclic alkyl groups, including (cycloalkyl)alkyl groups, having from 1 to 8 carbon atoms, which may contain one or more double or triple bonds, each of which may be further substituted with one or more substitutent(s) independently selected from  
 (a) hydroxy, halogen, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), —N(C 1-4  alkyl)(C 1-4  alkyl), and  
 (b) 3- to 7-membered carbocyclic and heterocyclic groups, which are saturated, unsaturated, or aromatic, which may be substituted with one or more substitutents selected from halogen, haloalkyl, oxo, hydroxy, amino, C 1-4  alkyl, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), and —N(C 1-4  alkyl)(C 1-4  alkyl) and wherein said 3- to 7-membered heterocyclic groups contain one or more heteroatom(s) selected from N, O, and S, with the point of attachment to the pyrazine ring being either carbon or nitrogen.  
 
   
   
       176 . The method of  claim 175 , wherein the compound is a compound in which 
 R X  is selected from straight, branched, or cyclic alkyl groups containing of 1 to 8 carbon atoms, which may contain one or more double or triple bonds;    R] and R 3  are independently chosen from halogen, C 1-4  alkyl, —O(C 1-4  alkyl), —NH(C 1-4  alkyl), —N(C 1-4  alkyl)(C 1-4  alkyl), haloalkyl, trifluoromethyl, and trifluoromethoxy; and    Ar is 2-, 3-, or 4-pyridyl, which is mono-, di-, or trisubstituted with one or more substitutent(s) independently selected from: 
 halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C 1-6  alkyl, C 1-4 alkoxy, C 1-4 alkoxy(C 1-4 alkoxy), mono- or di(C 1-4 )amino(C 1-4 alkoxy), and mono- or di(C 1-4  alkyl)amino.  
   
   
   
       177 . The method of  claim 152 , wherein, wherein the compound is a compound of the formula:  
     
       
         
         
             
             
         
       
       wherein A is CH 2 , NR A  or O.  
     
   
   
       178 . The method of  claim 152 , wherein the compound is a compound in which 
 R 2  is selected from the group consisting of dipropylamino, 3-pentylamino, 4-heptylamino, 3-pentoxy, 4-heptoxy, piperidin-1-yl, and morpholin-1-yl;    R 1  and R 3  are independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, and methylamino;    R 4  is absent;    Ar is selected from 2-pyridyl, 3-pyridyl, 2-pyrimidinyl, and 4-pyrimidinyl, each of is mono-substituted or di-substituted with R C , wherein at least one of the R C  substitutents is ortho- or para to the point of attachment of Ar to the pyrazine ring; and    R C  is selected halogen, cyano, haloalkyl, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C 1-6  alkyl, C 1-4 alkoxy, C 1-4 alkoxy(C 1-4 alkoxy), mono- or di(C 1-4 )amino(C 1-4 alkoxy), and mono- or di(C 1-4  alkyl)amino.    
   
   
       179 . The method of  claim 178 , wherein the compound is a compound in which 
 R 2  is selected from the group consisting of 3-pentylamino, 3-pentoxy, piperidin-1-yl, and morpholin-1-yl;    R 1  and R 3  are independently selected from the group consisting of methyl, ethyl, and methoxy; and    Ar is selected from 3-pyridyl and 2-pyrimidinyl, each of is mono- or di-substituted with R C , wherein at least one R C  is ortho or para to the point of attachment of Ar to the pyrazine ring.