Substituted pyrimidine derivatives

Abstract

This invention relates to compounds of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, or a pharmaceutically acceptable salt of a prodrug thereof. The compounds interact with CRF 1 receptors, including human CRF 1 receptors. This invention also relates to methods of using the compounds of the invention to treat a disorder or condition, the treatment of which can be effected or facilitated by antagonizing a CRF receptor, such as CNS disorders or diseases, particularly anxiety-related disorders such as anxiety, and mood disorders such as major depression.

1 - 3 . (canceled)  
   
   
       4 . A method of inhibiting the binding of CRF to the CRF 1  receptor in vitro, the method comprising contacting, in the presence of CRF, a solution comprising a compound of Formula I,  
     
       
         
         
             
             
         
       
     
     a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof form free hydroxyl, amino or sulfhydry groups are bonded to any group that cleave to form free hydroxyl, amino or sulfhydryl group respectively, or a pharmaceutically acceptable salt of a prodrug thereof, wherein: 
 X is selected from —NR 3 R 4 , —OR 3 , —CR 3 R 5 R 5 , —C(O)R 3 , —S(O) m R 3 , —NR 3 C(O)R 4 , or —NR 3 S(O) m R 4 ;  
 m is 0, 1 or 2;  
 G is selected from N or C(R 2 );  
 R 1  and R 2  are independently selected from —H, —NH(alkyl), —N(alkyl) 2 —NH(substituted alkyl), —N(substituted alkyl) 2 , —O(alkyl), —O(substituted alkyl), halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, —CR 5 R 5 Ar, —OAr, —S(O) m Ar, —NR 5 Ar, —S(O) m alkyl, —S(O) m substituted alkyl, —CN, —NO 2 , —OH, —NH 2 , —SH, —C(O)NR 4 R 5  and —C(S)NR 4 R 5 ;  
 R 3  and R 4  are independently selected from heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, provided when both R 3  and R 4  are present one of the R 3  or R 4  selected from a group provided herein above and the other R 3  or R 4  is selected from —H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl, heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl;  
 Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and  
 R 5  each is independently selected from —H, alkyl, cycloalkyl, and haloalkyl, wherein alkyl may be substituted with 1-3 substituents selected from halogen, —O(alkyl), —NH(alkyl), —N(alkyl) 2 , —CO(O)NH(alkyl), —C(O)N(alkyl) 2 , —NHC(O)alkyl, —N(alkyl)C(O)alkyl, and —S(O) m alkyl, heterocycloalkyl, substituted heterocycloalkyl and Ar,  
 with cells expressing the CRF 1  receptor, wherein the compound is present in the solution at a concentration sufficient to reduce levels of CRF binding to the cells in vitro.  
 
   
   
       5 . A method of antagonizing a CRF 1  receptor in a mammal, comprising administering to the mammal, a therapeutically effective amount of a compound of Formula I,  
     
       
         
         
             
             
         
       
     
     a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof wherein hydroxyl, amine or sulfhydry groups are bonded to any group that cleaves to form free hydroxyl, amino or sulfhydry groups respectively, or a pharmaceutically acceptable salt of a prodrug thereof, wherein: 
 X is selected from —NR 3 R 4 , —OR 3 , —CR 3 R 5 R 5 , —C(O)R 3 , —S(O) m R 3 , —NR 3 C(O)R 4 , or —NR 3 S(O) m R 4 ;  
 m is 0, 1 or 2;  
 G is selected from N or C(R 2 );  
 R 1  and R 2  are independently selected from —H, —NH(alkyl), —N(alkyl) 2 , —NH(substituted alkyl), —N(substituted alkyl) 2 , —O(alkyl), —O(substituted alkyl), halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, —CR 5 R 5 Ar, —OAr, —S(O) m Ar, —NR 5 Ar, —S(O) m alkyl, —S(O) m substituted alkyl, —CN, —NO 2 , —OH, —NH 2 , —SH, —C(O) m Ar, —NR 5  and —C(S)NR 4 R 5 ;  
 R 3  and R 4  are independently selected from heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl, heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, provided when both R 3  and R 4  are present one of the R 3  or R 4  is selected from a group provided herein above and the other R 3  or R 4  is selected from —H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl;  
 Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and  
 R 5  each is independently selected from —H, alkyl, cycloalkyl, and haloalkyl, wherein alkyl may be substituted with 1-3 substituents selected from halogen, —O(alkyl), —NH(alkyl), —N(alkyl) 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —NHC(O)alkyl, —N(alkyl) C(O)alkyl, and —S(O) m alkyl, heterocycloalkyl, substituted heterocycloalkyl and Ar.  
 
   
   
       6 . A method for screening for ligands for CRF 1  receptors, which method comprises: a) carrying out a competitive binding assay with a CRF 1  receptor, a compound of Formula I,  
     
       
         
         
             
             
         
       
     
     a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof wherein hydroxyl, amine or sulfhydry groups are bonded to any group that cleaves to form free hydroxyl, amino or sulfhydryl group respectively, or a pharmaceutically acceptable salt of prodrug thereof, wherein: 
 X is selected from —NR 3 R 4 , —OR 3 , —CR 3 R 5 R 5 , —C(O)R 3 , —S(O) m R 3 , —NR 3 C(O)R 4 , or —NR 3 S(O) m R 4 ;  
 m is 0, 1 or 2;  
 G is selected from N or C(R 2 );  
 R 1  and R 2  are independently selected from —H, —NH(alkyl), —N(alkyl) 2 , —NH(substituted alkyl), —N(substituted alkyl) 2 , —O(alkyl), —O(substituted alkyl), halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroalkyl, —CR 5 R 5 Ar, —OAr, —S(O) m Ar, —NR 5 Ar, —S(O) m alkyl, —S(O) m substituted alkyl, —CN, —NO 2 , —OH, —NH 2 , —SH, —C(O)NR 4 R 5  and —C(S)NR 4 R 5 ;  
 R 3  and R 4  are independently selected from heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, provided when both R 3  and R 4  are present one of the R 3  or R 4  is selected from a group provided herein above and the other R 3  or R 4  is selected from —H, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, aryl cycloalkyl, substituted aryl, cycloalkyl, heteroaryl, cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl;  
 Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and  
 R 5  each is independently selected from —H, alkyl, cycloalkyl, and haloalkyl, wherein alkyl may be substituted with 1-3 substituents selected from halogen, —O(alkyl), —NH(alkyl), —N(alkyl) 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —NHC(O)alkyl, —N(alkyl)C(O)alkyl, and —S(O) m alkyl, heterocycloalkyl, substituted heterocycloalkyl and Ar, which is labeled with a detectable label, and a candidate ligand; and b) determining the ability of said candidate ligand to displace said labeled compound.  
 
   
   
       7 . A method of treating a disorder in a mammal the treatment of which disorder can be effected or facilitated by antagonizing CRF.  
   
   
       8 . The method according to  claim 7  wherein the disorder manifests hypersecretion of CRF.  
   
   
       9 . The method according to  claim 8  wherein the mammal is a human and the disorder is selected from anxiety-related disorders; mood disorders, post-traumatic stress disorder; supranuclear palsy; immune suppression; drug or alcohol withdrawal symptoms; inflammatory disorders; pain; asthma; psoriasis and allergies; phobias; sleep disorders induced by stress; fibromyalgia; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer; human immunodeficiency virus infections; neurodegenerative diseases; gastrointestinal diseases; eating disorders; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone; obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; cardiovascular and heart related disorders; immune dysfunctions; muscular spasms urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions; psychosocial dwarfism, hypoglycemia, and skin disorders; and hair loss.  
   
   
       10 . The method according to  claim 9  wherein the disorder is selected from anxiety-related disorders; mood disorders; bipolar disorders; post-traumatic stress disorder; inflammatory disorders; chemical dependencies and addictions; gastrointestinal disorders; and skin disorders.  
   
   
       11 . The method according to  claim 10  wherein the disorder is selected from anxiety-related disorders or mood disorders and wherein the anxiety-related disorder is generalized anxiety and wherein the mood disorder is depression.  
   
   
       12 . A method of promoting hair growth in a human, comprising administering to the human in need thereof an effective amount of a compound of Formula I,  
     
       
         
         
             
             
         
       
     
     a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof wherein hydroxyl, amine or sulfylhydry groups are bonded to any group that cleaves to form free hydroxyl, amino or sulfhydryl group respectively, or a pharmaceutically acceptable salt of a prodrug thereof, wherein; 
 X is selected from —NR 3 R 4 , —OR 3 , —CR 3 R 5 R 5 , —C(O)R 3 , —S(O) m R 3 , —NR 3 C(O)R 4 , or —NR 3 S(O) m R 4 ;  
 m is 0, 1 or 2;  
 G is selected from N or C(R 2 );  
 R 1  and R 2  are independently selected from —H, —NH(alkyl), —N(alkyl) 2 , —NH(substituted alkyl), —N(substituted alkyl) 2 , —O(alkyl), —O(substituted alkyl), halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, —CR 5 R 5 Ar, —OAr, —S(O) m Ar, —NR 5 Ar, —S(O) m alkyl, —S(O) m substituted alkyl, —CN, —NO 2 , —OH, —NH 2 , —SH, —C(O)NR 4 R 5  and —C(S)NR 4 R 5 ;  
 R 3  and R 4  are independently selected from heteroaryl substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, provided when both R 3  and R 4  are present one of the R 3  or R 4  is elected from a group provided herein above and the other R 3  or R 4  is selected from —H, alkyl, substituted, alkyl, haloalkyl, cycloalkyl, substituted, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl;  
 Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and  
 R 5  each is independently selected from —H, alkyl, cycloalkyl, and haloalkyl wherein alkyl may be substituted with 1-3 substituents selected from halogen, —O(alkyl), —NH(alkyl), —N(alkyl) 2 , —CO(O)NH(alkyl), —C(O)N(alkyl) 2 , —NHC(O)alkyl, —N(alkyl)C(O)alkyl, and —S(O) m alkyl, heterocycloalkyl, substituted heterocycloalkyl Ar.  
 
   
   
       13 . A method of promoting smoking cessation in a human, comprising administering to the human in need thereof an effective amount of a compound of Formula I,  
     
       
         
         
             
             
         
       
     
     a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof wherein hydroxyl, amine or sulfylhydry groups are bonded to any group that cleaves to form free hydroxyl, amino or sulfhydryl group respectively, or a pharmaceutically acceptable salt of a prodrug thereof, wherein: 
 X is selected from —NR 3 R 4 , —OR 3 , —CR 3 R 5 R 5 , —C(O)R 4 , —S(O) m R 3 , —NR 3 C(O)R 4 , or —NR 3 S(O) m R 4 ;  
 m is 0, 1 or 2;  
 G is elected from N or C(R 2 );  
 R 1  and R 2  are independently selected from —H, —NH(alkyl), —N(alkyl) 2 , —NH(substituted alkyl), —N(substituted alkyl) 2 , —O(alkyl), —O(substituted alkyl), halogen, alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl, —CR 5 R 5 Ar, —OAr, —S(O) m Ar, —NR 5 Ar, —S(O) m alkyl, —S(O) m substituted alkyl, —CN, —NO 2 , —NH 2 , —SH, —C(O)NR 4 R 5  and —C(S)NR 4 R 5 ;  
 R 3  and R 4  are independently selected from heteroaryl, substituted heteroaryl, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, heterocycloalkyl or substituted heterocycloalkyl, provided when both R 3  and R 4  are present one of the R 3  or R 4  is selected from a group provided herein above and the other R 3  or R 4  is selected from —H, alkyl, substituted alkyl, haloalkyl, cycloakyl, substituted cycloalkyl, aryl, heteroaryl heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, or substituted heteroaryl heterocycloalkyl;  
 Ar is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and  
 R 5  each is independently selected from —H, alkyl, cycloalkyl, and haloalkyl, wherein alkyl may be substituted with 1-3 substituents selected from halogen, —O(alkyl), —NH(alkyl), —N(alkyl) 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —NHC(O)alkyl, —N(alkyl)C(O)alkyl, and —S(O) m alkyl, heterocycloalkyl, substituted heterocycloalkyl and Ar.  
 
   
   
       14 . (canceled)  
   
   
       15 . (canceled)