Bis-heteroaryl alkanes as therapeutic agents

Abstract

This invention provides compounds which are useful as inhibitors of protein tyrosine phosphatases (PTPases). As inhibitors of PTPases the compounds of the invention are useful for the management, treatment, control and adjunct treatment of diseases in mammals mediated by PTPase activity. Such diseases include type I diabetes, type II diabetes, immune dysfunction, AIDS, autoimmunity, glucose intolerance, obesity, cancer, psoriasis, allergic diseases, infectious diseases, inflammatory diseases, diseases involving the modulated synthesis of growth hormone or the modulated synthesis of growth factors or cytokines which affect the production of growth hormone, or Alzheimer's disease.

1 . A method of inhibiting a protein tyrosine phosphatase comprising: administering to a subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of a compound of the Formula:  
     
       
         
         
             
             
         
       
       wherein  
       R 1  and R 2  are independently selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       and  
       
         
           
           
               
               
           
         
       
       R 3  is  
       (a) hydrogen;  
       (b) alkyl;  
       (c) alkenyl; or  
       (d) alkynyl;  
       R 4  is heteroarylene;  
       wherein 
 R 4  is optionally substituted with a substituent of the formula  
                     wherein 
 L 1  is a direct bond, alkylene, —O-alkylene-, alkylene-O—, —NH—C(O)—, —C(O)—NH— or —NH—CO—NH—;  
 L 2  is alkyline, alkenyline, heteroaryline, aryline, or heterocyclyline;  
 L 3  is —O—, —C(O)—N(R 19 )—, —C(O)—O—, —C(O)—, or —N(R 19 )—CO—N(R 20 )—;  
 L 4  is H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, alkylene-aryl;  
 L 5  is hydrogen, alkyl, alkenyl, alkynyl, -alkylene-aryl, -alkylene-heteroaryl, alkylene-O-alkylene-aryl, -alkylene-S-alkylene-aryl, -alkylene-O-alkyl, -alkylene-S-alkyl, -alkylene-NH 2 , -alkylene-OH, -alkylene-SH, -alkylene-C(O)—OR 9 , -alkylene-C(O)—NR 9 R 10 , -alkylene-NR 9 R 10 , -alkylene-N(R 9 )—C(O)—R 10 , -alkylene-N(R 9 )—S(O 2 )—R 10 ; or  
                     
 may be taken together to constitute a direct bond;  
 R 5  is  
   
 
       (a) hydrogen;  
       (b) alkyl;  
       (c) alkenyl;  
       (d) alkynyl;  
       (e) aryl;  
       (f) heteroaryl;  
       (g) cycloalkyl;  
       (h) heterocyclyl;  
       (i) alkylene-OH;  
       (j) alkylene-COOH;  
       (k) alkylene-NH 2 ;  
       (l) COOH;  
       (m) CONH 2 ; or  
       (n) NH 2 ;  
       R 6 , R 6 ′, R 7 , R 7 ′, R 8 , and R 8 ′ are independently selected from the group consisting of  
       (a) hydrogen;  
       (b) aryl;  
       (c) heteroaryl;  
       (d) heterocyclyl;  
       (e) cycloalkyl;  
       (f) halogen;  
       (g) -alkylene-Y-aryl; -alkenylene-Y-aryl; -alkynylene-Y-aryl; -alkylene-Y-heteroaryl; -alkenylene-Y-heteroaryl; -alkynlene-Y-heteroaryl; -alkylene-Y-cycloalkyl-alkenylene-Y-cycloalkyl; -alkynlene-Y-cycloalkyl; -alkylene-Y-heterocyclyl; -alkenylene-Y-heterocyclyl; -alkynlene-Y-heterocyclyl; -Y-alkyl; -Y-aryl; -Y-alkylene-aryl; -Y-alkylene-NR 11 R 12 ; —Y—O—Si-(alkyl) 3 ; and —Y—O—Si-(alkylene-aryl) 3 ; 
 wherein 
 Y is —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O 2 )—, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHS(O 2 )—, —S(O 2 )N(H)—, —C(O)—O—, —NHS(O 2 )NH—, or —OCO—; and  
 R 11  and R 12  are independently selected from the group consisting of: hydrogen, aryl, alkyl, and alkylene-aryl; or  
 R 11  and R 12  are taken together to form a ring having the formula—(CH 2 ) q -Q-(CH 2 ) r -bonded to the nitrogen atom to which R 11  and R 12  are attached, wherein q and r are, independently, 1, 2, 3, or 4; Q is —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —(O)CO—, —NHSO 2 NH—, —OC(O)—, —N(R 13 )—, —N(C(O)R 3 )—, —N(C(O)NHR 13 )—, —N(SO 2 NHR 13 )—, —N(SO 2 R 13 )—, or —N(C(O)OR 13 )—; or  
 R 11  and R 12  are taken together, with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring;  
 R 9 , R 10 , R 13 , R 19 , and R 20  are independently selected from the group consisting of  
 
 
       hydrogen, aryl, alkyl, and alkylene-aryl;  
       A 1  and A 2  are N—R 14 , where R 14  is  
       (a) alkyl; or  
       (b) -alkylene-aryl;  
       R 17  and R 18  are independently selected from the group consisting of hydrogen, alkyl,  
       and halogen;  
       Ar 1  and Ar 2  are phenyl;  
       or a pharmaceutically acceptable salt, solvate or prodrug thereof.  
     
   
   
       2 . A method of treatment of a PTPase mediated human disease comprising: 
 administering to a human in need thereof a pharmaceutical composition of comprising a compound of the Formula:                          wherein    R 1  and R 2  are independently selected from the group consisting of                          and                          R 3  is    (a) hydrogen;    (b) alkyl;    (c) alkenyl; or    (d) alkynyl;    R 4  is heteroarylene;    wherein 
 R 4  is optionally substituted with a substituent of the formula  
                     wherein 
 L 1  is a direct bond, alkylene, —O-alkylene-, alkylene-O—, —NH—C(O)—, —C(O)—NH— or —NH—CO—NH—;  
 L 2  is alkyline, alkenyline, heteroaryline, aryline, or heterocyclyline;  
 L 3  is —O—, —C(O)—N(R 19 )—, —C(O)—O—, —C(O)—, or —N(R 19 )—CO—N(R 20 )—;  
 L 4  is H, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, alkylene-aryl;  
 L 5  is hydrogen, alkyl, alkenyl, alkynyl, -alkylene-aryl, -alkylene-heteroaryl, alkylene-O-alkylene-aryl, -alkylene-S-alkylene-aryl, -alkylene-O-alkyl, -alkylene-S-alkyl, -alkylene-NH 2 , -alkylene-OH, -alkylene-SH, -alkylene-C(O)—OR 9 , -alkylene-C(O)—NR 9 R 10 , -alkylene-NR 9 R 10 , -alkylene-N(R 9 )—C(O)—R 10 , -alkylene-N(R 9 )—S(O 2 )—R 10 ; or  
                     
 may be taken together to constitute a direct bond;  
 R 5  is  
   
   (a) hydrogen;    (b) alkyl;    (c) alkenyl;    (d) alkynyl;    (e) aryl;    (f) heteroaryl;    (g) cycloalkyl;    (h) heterocyclyl;    (i) alkylene-OH;    (j) alkylene-COOH;    (k) alkylene-NH 2 ;    (l) COOH;    (m) CONH 2 ; or    (n) NH 2 ;    R 6 , R 6 ′, R 7 , R 7 ′, R 8 , and R 8 ′ are independently selected from the group consisting of    (a) hydrogen;    (b) aryl;    (c) heteroaryl;    (d) heterocyclyl;    (e) cycloalkyl;    (f) halogen;    (g) -alkylene-Y-aryl; -alkenylene-Y-aryl; -alkynylene-Y-aryl; -alkylene-Y-heteroaryl; -alkenylene-Y-heteroaryl; -alkynlene-Y-heteroaryl; -alkylene-Y-cycloalkyl-alkenylene-Y-cycloalkyl; -alkynlene-Y-cycloalkyl; -alkylene-Y-heterocyclyl; -alkenylene-Y-heterocyclyl; -alkynlene-Y-heterocyclyl; —Y-alkyl; —Y-aryl; —Y-aryl; —Y-aryl; —Y-alkylene-aryl; —Y-alkylene-NR 11 R 12 ; —Y—O—Si-(alkyl) 3 ; and —Y—O—Si-(alkylene-aryl) 3 ; 
 wherein 
 Y is —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O 2 )—, —CON(H—), —NHC(O)—, —NHCON(H)—, —NHS(O 2 )—, —S(O 2 )N(H)—, —C(O)—O—, —NHS(O 2 )NH—, or —O—CO—; and  
 R 11  and R 12  are independently selected from the group consisting of: hydrogen, aryl, alkyl, and alkylene-aryl; or  
 R 11  and R 12  are taken together to form a ring having the formula—(CH 2 ) q -Q-(CH 2 ) r  -bonded to the nitrogen atom to which R 11  and R 12  are attached, wherein q and r are, independently, 1, 2, 3, or 4; Q is —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —SO 2 —, —CON(H)—, —NHC(O)—, —NHCON(H)—, —NHSO 2 —, —SO 2 N(H)—, —(O)CO—, —NHSO 2 NH—, —OC(O)—, —N(R 13 )—, —N(C(O)R 13 )—, —N(C(O)NHR 13 )—, —N(SO 2 NHR 13 )—, —N(SO 2 R 13 )—, or —N(C(O)OR 13 )—; or  
 R 11  and R 12  are taken together, with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring;  
 R 9 , R 10 , R 13 , R 19 , and R 20  are independently selected from the group consisting of  
 
   hydrogen, aryl, alkyl, and alkylene-aryl;    A 1  and A 2  are N—R 14 , where R 14  is    (a) alkyl; or    (b) -alkylene-aryl;    R 17  and R 18  are independently selected from the group consisting of hydrogen, alkyl,    and halogen;    Ar 1  and Ar 2  are phenyl;    or a pharmaceutically acceptable salt, solvate or prodrug thereof.    
   
   
       3 . The method of  claim 2 , further comprising administering to a human in need thereof one or more therapeutic agents selected from the group consisting of alkylating agents, antimetabolites, plant alkaloids, antibiotics, hormones, biologic response modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, insulin, cholinesterase inhibitors, antipsychotics, antidepressants, and anticonvulsants.  
   
   
       4 . The method of  claim 2 , wherein the PTPase mediated disease is acute and/or chronic inflammation.  
   
   
       5 . The method of  claim 2 , wherein the PTPase mediated disease is type I diabetes.  
   
   
       6 . The method of  claim 2 , wherein the PTPase mediated disease is type II diabetes.  
   
   
       7 . The method of  claim 2 , wherein the PTPase mediated disease is immune dysfunction.  
   
   
       8 . The method of  claim 2 , wherein the PTPase mediated disease is AIDS or an autoimmune disease.  
   
   
       9 . The method of  claim 2 , wherein the PTPase mediated disease is glucose intolerance.  
   
   
       10 . The method of  claim 2 , wherein the PTPase mediated disease is obesity.  
   
   
       11 . The method of  claim 2 , wherein the PTPase mediated disease is cancer.  
   
   
       12 . The method of  claim 2 , wherein the PTPase mediated disease is psoriasis.  
   
   
       13 . The method of  claim 2 , wherein the PTPase mediated disease is an allergic disease.  
   
   
       14 . The method of  claim 2 , wherein the PTPase mediated disease is an infectious disease.  
   
   
       15 . The method of  claim 2 , wherein the PTPase mediated disease is an inflammatory disease.  
   
   
       16 . The method of  claim 2 , wherein the PTPase mediated disease is a disease involving the modulated synthesis of growth hormone.  
   
   
       17 . The method of  claim 2 , wherein the PTPase mediated disease is a disease involving the modulated synthesis of growth factors or cytokines which affect the production of growth hormone.  
   
   
       18 . The method of  claim 2 , wherein the PTPase mediated disease is Alzheimer's disease.