2,5-Diarylpyrazines, 2,5-diarylpyridines and 2,5-diarylprimidines

Abstract

Diarylpyrazine, diarylpyridine, and diarylpyrimidine compounds that act as selective modulators of CRF 1 receptors are provided. These compounds are useful in the treatment of a number of CNS and periphereal disorders, particularly stress, anxiety, depression, cardiovascular disorders, and eating disorders. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided. Compounds of Formula I are also useful as probes for the localization of CRF receptors and as standards in assays for CRF receptor binding. Methods of using the compounds in receptor localization studies are given.

1 . A compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 Ar 1  and Ar 2  are independently chosen from: 
 phenyl which is mono-, di-, or tri-substituted,  
 1-naphthyl and 2-naphthyl, each of which is optionally mono-, di-, or tri-substituted, and  
 optionally mono-, di-, or tri-substituted heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 7 ring members in each ring and, in at least one of said rings, from 1 to about 3 heteroatoms selected from the group consisting of N, O, and S;  
 
 R is oxygen or absent;  
 Z 2  is nitrogen;  
 Z 3  is CR 3 ;  
 R 1  and R 3  are independently chosen from hydrogen, halogen, amino, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted mono- or di-alkylamino, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkyl)oxy, optionally substituted (cycloalkyl)alkoxy, optionally substituted alkylthio, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, and optionally substituted mono- or dialkylcarboxamide; with the proviso that not all of R 1 , R 3 , and R 4  are hydrogen.  
 
     
     
         2 . A compound or salt according to  claim 1 , wherein 
 Ar 1  and Ar 2  are independently chosen from:    phenyl which is mono-, di-, or tri-substituted, and    1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, and triazolyl, each of which is optionally mono-, di-, or tri-substituted.    
     
     
         3 . A compound of Formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
 R is oxygen or absent;  
 Z 2  is nitrogen;  
 Z 3  is CR 3 ;  
 Ar 1  and Ar 2  are independently chosen from:  
 phenyl which is mono-, di-, or tri-substituted with R A , and  
 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, and triazolyl, each of which is optionally mono-, di-, or tri-substituted with R A ;  
 R 1  and R 3  are independently selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C 1 -C 6 alkyl 1 , C 1 -C 6 alkyl 1 -O—, mono- or di-(C 1 -C 6 alkyl 1 )amino, C 3 -C 7 cycloalkyl 2 (C 0 -C 4 alkyl 1 ), C 3 -C 7 cycloalkenyl 2 (C 0 -C 4 alkyll 1 ), C 3 -C 7 cycloalkyl 2 (C 0 -C 4 alkyl 1 )—O—, C 3 -C 7 cycloalkenyl 2 (C 0 -C 4 alkyl 1 )-O—, haloC 1 -C 6 alkyl 1 , haloC 1 -C 6 akyl 1 -O—, and —S(O) n (C 1 -C 6 alkyl 1 ), 
 where each alkyl 1  is independently straight or branched, contains 0 or 1 or more double or triple bonds, and is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxy, oxo, cyano, C 1 -C 4 alkoxy, amino, and mono- or di-(C 1 -C 4 alkyl)amino, and  
 where each C 3 -C 7 cycloalkyl 2  and C 3 -C 7 cycloalkenyl 2  is optionally substituted by one or more substituents independently chosen from halogen, hydroxy, oxo, cyano, C 1 -C 4 alkoxy, amino, and mono- or di-(C 1 -C 4 )alkylamino,  
 
 with the proviso that R 1 and R   3  are not both hydrogen;  
 R A  is independently selected at each occurrence from halogen, cyano, nitro, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl substituted with 0-2 R B , C 2 -C 6 alkenyl substituted with 0-2 R B , C 2 -C 6 alkynyl substituted with 0-2 R B , C 3 -C 7 cycloalkyl substituted with 0-2 R B , (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl substituted with 0-2 R B , 
 C 1 -C 6 alkoxy substituted with 0-2 R B , —NH(C 1 -C 6 alkyl) substituted with 0-2 R B , —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl) where each C 1 -C 6 alkyl is independently substituted with 0-2 R B , —XR C , and Y;  
 
 R B  is independently selected at each occurrence from halogen, hydroxy, cyano, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- or di-(C 1 -C 4 alkyl)amino, —S(O) n (alkyl), halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, —CO(C 1 -C 4 alkyl), —CONH(C 1 -C 4 alkyl), —CON(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —XR C , and Y;  
 R C  and R D , are the same or different, and are independently selected at each occurrence from: hydrogen, and 
 straight, branched, and cyclic alkyl groups, and (cycloalkyl)alkyl groups, having 1 to 8 carbon atoms, and containing zero or one or more double or triple bonds, each of which 1 to 8 carbon atoms may be further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy, mono- or di-(C 1 -C 4 alkyl)amino, —NHC(═O)(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(═O)(C 1 -C 6 alkyl),  
 —NHS(O) n (C 1 -C 6 alkyl), —S(O) n (C 1 -C 6 alkyl), —S(O) n NH(C 1 -C 6 alkyl), —S(O) n N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), and Z;  
 
 X is independently selected at each occurrence from the group consisting of —CH 2 —, —CHR D —, —O—, —C(═O)—, —C(═O)O—, —S(O) n —, —NH—, —NR D —, —C(═O)NH—, —C(═O)NR D —, —S(O) n NH—, —S(O) n NR D —, —OC(═S)S—, —NHC(═O)—, —NR D C(═O)—, —NHS(O) n —, and —NR D S(O) n —;  
 Y and Z are independently selected at each occurrence from: 3- to 7-membered carbocyclic or heterocyclic groups, which are saturated, partially unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- or di-(C 1 -C 4 alkyl)amino, and —S(O) n (alkyl), 
 wherein said 3- to 7-memberered heterocyclic groups contain from 1 to 3 heteroatom(s) independently selected from N, O, and S, with remaining ring members being carbon; and  
 
 n is independently selected at each occurrence from 0, 1, and 2.  
 
     
     
         4 - 6 . (canceled)  
     
     
         7 . A compound or salt according to  claim 3 , wherein: R is absent; Ar 2  is phenyl or pyridyl, each of which is mono-, di-, or tri-substituted with R A .  
     
     
         8 . A compound or salt according to  claim 3 , wherein: 
 R is absent;    R 1  and R 3  are independently selected from the group consisting of    i) hydrogen, ii)halogen, iii) C 1 -C 3 alkyl, iv) C 1 -C 3 alkoxy, v) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkyl, vi) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkoxy, vii) mono- or di-(C 1 -C 3 alkyl)amino, viii)C 1 -C 3 haloalkyl, and ix) C 1 -C 3 haloalkoxy wherein each of iii, iv, v, vi, and vii is unsubstituted or substituted by 1-3 groups independently chosen from hydroxy, amino, cyano, and halogen.    
     
     
         9 . A compound or salt according to  claim 8 , wherein: 
 Ar 2  is phenyl or pyridyl, each of which is substituted with R A  at at least 1 position ortho to the point of attachment of Ar in Formula I, and optionally substituted with up to 2 additional R A  groups.    
     
     
         10 . A compound or salt according to  claim 3 , wherein: 
 R is absent;    Ar 2  phenyl or pyridyl, each of which is substituted with R A  at at least 1 position ortho to the point of attachment of Ar in Formula I, and optionally substituted with up to 2 additional R A  groups; and    R C  and R D , which may be the same or different, are independently selected at each occurrence from 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.    
     
     
         11 . A compound or salt according to  claim 10 , wherein: 
 R 1  and R 3  are independently selected from the group consisting of 
 i) hydrogen, ii)halogen, iii) C 1 -C 3 alkyl, iv) C 1 -C 3 alkoxy, v) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkyl, vi) (C 3 -C 7 cycloalkyl)C 0 -C 3 alkoxy, vii) mono- or di-(C 0 -C 3 alkyl)amino, viii) C 1 -C 3 haloalkyl, and ix) C 1 -C 3 haloalkoxy wherein each of iii, iv, v, vi, and vii is unsubstituted or substituted by 1-3 groups independently chosen from hydroxy, amino, cyano, and halogen.  
   
     
     
         12 . A compound or salt according to  claim 3 , wherein 
 R is absent;    Ar 1  is chosen from phenyl which is mono-, di-, or tri-substituted with R A , and 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, and triazolyl, each of which is optionally mono-, di-, or tri-substituted with R A ; and    Ar 2  phenyl or pyridyl, each of which is substituted at at least 1 position ortho to the point of attachment of Ar in Formula I, and optionally substituted with up to 2 additional R A  groups.    
     
     
         13 . A compound or salt according to  claim 12 , wherein: 
 R 1  and R 3  are independently selected from hydrogen, cyano, amino, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 3 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 3 alkoxy, mono- or di-(C 1 -C 6 alkyl)amino, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, and —SO n (C 1 -C 6 alkyl);    R A  is independently selected at each occurrence from    i) halogen, cyano, nitro, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, hydroxy, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, (C 3 -C 7 cycloalkyl)C 1 -C 4 alkyl, C 1 -C 6 alkoxy, mono- or di-(C 1 -C 6 alkyl)amino, —CHO, and —C(═O)CH 3 ;    ii) C 1 -C 6 alkoxy and C 1 -C 6  alkyl which are unsubstituted or substituted with 1 or 2 groups independently selected from halogen, hydroxy, cyano, amino, oxo, C 1 -C 4 alkoxy, mono- or di-(C 1 -C 6 alkyl)amino, halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, C 1 -C 4 alkanoyl, morpholinyl, piperazinyl, piperidinyl, furanyl, and pyrrolidinyl, and    iii) 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, partially unsaturated, or aromatic, which may be further substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- or di-(C 1 -C 4 alkyl)amino; and    n is 0, 1, or 2.    
     
     
         14 . A compound or salt according to  claim 13 , wherein: 
 R 1  and R 3  are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 3 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 3 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 3 alkoxy, mono- or di-(C 1 -C 3 alkyl)amino, C 1 -C 3 haloalkyl, and C 1 -C 3 haloalkoxy; and    Ar 1  is selected from the group consisting of phenyl which is mono- di- or trisubstituted, and 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, tetrazolyl, and pyrazinyl, each of which is optionally mono- di- or trisubstituted with R A .    
     
     
         15 . A compound or salt according to  claim 14  of Formula II  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is nitrogen or CH;  
 R 1  and R 3  are independently chosen from hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, and methylamino;  
 R 4  and R 5 , are independently chosen from halogen, halo(C 1 -C 2 )alkyl, halo(C 1 -C 2 )alkoxy, hydroxy, amino, C 1 -C 3 alkyl, C 1 -C 2 alkoxy, and mono- or di-(C 1 -C 2 alkyl)amino;  
 R 6  is chosen from hydrogen, halogen, halo(C 1 -C 2 )alkyl, halo(C 1 -C 2 )alkoxy, hydroxy, amino, C 1 -C 3 alkyl, C 1 -C 2 alkoxy, and mono- or di-(C 1 -C 2 alkyl)amino.  
 
     
     
         16 . A compound or salt according to  claim 15  of Formula III  
       
         
           
           
               
               
           
         
       
       wherein R 7  and R 8  are independently chosen from methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, and halogen.  
     
     
         17 - 26 . (canceled)  
     
     
         27 . A compound according to  claim 1  which is selected from: 
 2-(2,4-Dimethoxy-phenyl)-5-(2-methoxy-4-trifluoromethoxy-phenyl)-3,6-dimethyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-5-(2,5-dimethyl-phenyl)-3,6-diethyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-phenyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-(2-methylphenyl)-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(2-trifluoromethyl-phenyl)-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(3-methylphenyl)-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(3-trifluoromethyl-phenyl)-pyrazine;    2-(2,4-Dimethoxy-phenyl)-5-(2,3-dimethyl-phenyl)-3,6-diethyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-5-(3,5-dimethyl-phenyl)-3,6-diethyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-5-(2,6-dimethyl-phenyl)-3,6-diethyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(2,4,6-trimethyl-phenyl)-pyrazine;    2,5-Bis-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(5-fluoro-2-methoxy-phenyl)-pyrazine;    2-(5-Chloro-2-methoxy-phenyl)-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-5-(2,5-dimethoxy-phenyl)-3,6-diethyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(5-isopropyl-2-methoxy-phenyl)-pyrazine;    2-(2,5-Dichloro-phenyl)-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(2,3,5-trichloro-phenyl)-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(4-fluoro-3-methyl-phenyl)-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(3-trifluoromethoxy-phenyl)-pyrazine;    2-(3,5-Bis-trifluoromethyl-phenyl)-5-(2,4-dimethoxy-phenyl)-3,6-diethyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-naphthalen-1-yl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-naphthalen-2-yl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-dimethyl-5-(2-methoxy-4-trifluoromethoxy-phenyl)-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-dimethyl-5-(2-methylphenyl)-pyrazine;    2-(2,5-Dimethyl-phenyl)-3,6-diethyl-5-[4-(1-fluoro-1-methyl-ethyl)-2,6-dimethoxy-phenyl]-pyrazine;    2-{4-[5-(2,5-Dimethyl-phenyl)-3,6-diethyl-pyrazin-2-yl]-3,5-dimethoxy-phenyl}-propan-2-ol;    1-{4-[5-(2,5-Dimethyl-phenyl)-3,6-diethyl-pyrazin-2-yl]-3,5-dimethoxy-phenyl}-ethanone;    2-(2,5-Dimethyl-phenyl)-3,6-diethyl-5-[4-(1-fluoro-ethyl)-2,6-dimethoxy-phenyl]-pyrazine;    1-{4-[5-(2,5-Dimethyl-phenyl)-3,6-diethyl-pyrazin-2-yl]-3,5-dimethoxy-phenyl}-ethanol;    2-(4-Difluoromethyl-2,6-dimethoxy-phenyl)-5-(2,5-dimethyl-phenyl)-3,6-diethyl-pyrazine;    2-(2,4-Dimethoxy-phenyl)-3,6-diethyl-5-(5-fluoro-2-methoxy-phenyl)-pyrazine:    4-[5-(2,5-Dimethyl-phenyl)-3,6-diethyl-pyrazin-2-yl]-3,5-dimethoxy-benzaldehyde; and    2-(2,5-Dimethyl-phenyl)-5-(4-[1,3]dioxolan-2-yl-2,6-dimethoxy-phenyl)-3,6-diethyl-pyrazine; or a pharmaceutically acceptable salt thereof.    
     
     
         28 . (canceled)  
     
     
         29 . A compound or salt according to  claim 3  wherein, in a standard in vitro CRF receptor binding assay the compound exhibits an IC 50  value for CRF receptors of less than or equal to 1 micromolar.  
     
     
         30 . A compound or salt according to  claim 3  wherein, in a standard in vitro CRF receptor binding assay the compound exhibits an IC 50  value for CRF receptors of less than or equal to 100 nanomolar.  
     
     
         31 . A compound or salt according to claims  3  wherein, in a standard in vitro CRF receptor binding assay, the compound exhibits an IC 50  value for CRF receptors of less than or equal to 10 nanomolar.  
     
     
         32 . A method for treating anxiety, depression, or stress comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt according to  claim 3 .  
     
     
         33 . A method for treating irritable bowel syndrome or Crohn's disease, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt according to  claim 3 .  
     
     
         34 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or salt of  claim 3 .  
     
     
         35 . A pharmaceutical composition according to  claim 34 , wherein the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch.  
     
     
         36 . A package comprising a pharmaceutical composition of  claim 34  in a container and further comprising indicia comprising at least one of: 
 instructions for using the composition to treat a patient suffering from anxiety, or    instructions for using the composition to treat a patient suffering from stress, or    instructions for using the composition to treat a patient suffering from depression.    
     
     
         37 . A package comprising a pharmaceutical composition of  claim 34  in a container and further comprising at least one of: instructions for using the composition to treat a patient suffering from irritable bowel syndrome or instructions for using the composition to treat a patient suffering from Crohn's disease.  
     
     
         38 . A method for demonstrating the presence or absence of CRF 1 receptors in a biological sample, said method comprising: 
 a) contacting the biological sample with a labeled compound according to  claim 3  under conditions that permit binding of the labeled compound to a CRF 1 receptor;    b) separating unbound labeled compound from bound labeled compound; and    c) detecting the labeled compound in the biological sample, and therefrom determining the presence or absence of CRF 1 receptors in the sample.    
     
     
         39 . The method of  claim 38  wherein the labeled is radiolabeled.  
     
     
         40 . The method of  claim 39  wherein the labeled compound is detected using autoradiography.  
     
     
         41 . A method of inhibiting the binding of CRF to a CRF 1 Receptor, which method comprises: 
 contacting a solution comprising CRF and a compound or salt of  claim 3  with a cell expressing the CRF receptor, wherein the compound or salt is present in the solution at a concentration sufficient to inhibit in vitro CRF binding to IMR32 cells.    
     
     
         42 . The method of  claim 41  wherein the cell expressing the CRF receptor is a neuronal cell that is contacted in vivo in an animal, and wherein the solution is a body fluid of said animal.  
     
     
         43 . The method of  claim 41  wherein the animal is a human patient.  
     
     
         44 . A method for detecting CRF 1 receptors in a first biological sample, said method comprising: 
 preparing said first biological sample;    preparing a second biological sample matched to said first sample;    contacting and incubating for a measured time interval said first sample with a solution comprising a first measured molar concentration of a labeled compound of  claim 3 , said contact being carried out in the absence of added CRF under a set of conditions that permit binding of the compound to a CRF 1 receptor and washing said first sample subsequent to said incubation;    contacting and incubating for said measured time interval the second sample with the a solution comprising said first measured molar concentration of the labeled compound and further comprising unlabelled CRF at a second molar concentration that is in excess to the first molar concentration, said contact and incubation being carried out under said set of conditions and washing said second sample subsequent to said incubation;    measuring a first amount of label remaining in the first biological sample after said washing of said first sample;    measuring a second amount of label remaining in the second biological sample after said washing of said second sample; and    comparing the first amount to the second amount;    wherein when said comparison shows that said first amount is greater than said second amount CRF1 receptors are present in the sample.