Heteroaryl - fused nitrogen heterocycles 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 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 - 10 . (canceled)  
     
     
         11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmacologically effective amount of the compound of Formula (I)  
       
         
           
           
               
               
           
         
         wherein  
         R 1  is  
         (a) alkyl; alkenyl; alkynyl; aryl;  
         (b) heterocyclyl; cycloalkyl;  
         (c) heteroaryl;  
         (d) -arylene-aryl; -arylene-heteroaryl; -heteroarylene-aryl; -heteroarylene-heteroaryl; -alkylene-aryl; -alkenylene-aryl;  
         (e) -alkynylene-aryl; -alkyloxy-aryl; -alkylene-heteroaryl; -alkenylene-heteroaryl; -alkynylene-heteroaryl; -alkoxy-heteroaryl; -alkylene-heterocyclyl;  
         (f) -alkylene-heterocyclyl; -alkenylene-heterocyclyl; -alkynylene-heterocyclyl; -alkylene-cycloalkyl, -alkenylene-cycloalkyl; -alkynylene-cycloalkyl;  
         (g) -arylene-L 1 -alkylene-aryl; -arylene-L 1 -alkylene-heteroaryl; -arylene-alkylene-L 1 -heteroaryl; -arylene-alkylene-L 1 -aryl; -alkylene-arylene-L 1 -alkylene-aryl; -alkylene-arylene-L 1 -alkylene-heteroaryl; -alkylene-arylene-alkylene-L 1 -aryl; -alkylene-arylene-alkylene-L 1 -heteroaryl; wherein L 1  comprises O, —C(O)—, S, —S(O)—, —S(O 2 )—, or a direct bond;  
         R 2  is  
         (a) hydrogen;  
         (b) alkyl; alkenyl; alkynyl;  
         (c) heterocyclyl; cycloalkyl;  
         (d) -alkylene-aryl; -alkenylene-aryl; -alkynylene-aryl; -alkyloxy-aryl,  
         (e) -alkylene-heteroaryl; -alkenylene-heteroaryl; -alkynylene-heteroaryl; -alkoxy-heteroaryl;  
         (f) -alkylene-heterocyclyl; -alkenylene-heterocyclyl; -alkynylene-heterocyclyl,  
         (g) —C(O)—OR 7 ; -alkylene-C(O)—OR 7 ; -alkenylene-C(O)—OR 7 ; -alkynylene-C(O)—OR 7 , —C(O)—NR 7 R 8 ; -alkylene-C(O)—NR 7 R 8 ; -alkenylene-C(O)—NR 7 R 8 ; -alkynylene-C(O)—NR 7 R 8 , -alkylene-O-aryl; -alkylene-O-alkylene-aryl; -alkylene-O-cycloalkyl; —(SO 2 )—R 7 ; -alkylene-S(O 2 )—R 7 ; -alkenylene-S(O 2 )—R 7 ; -alkynylene-S(O 2 )—R 7 ; -alkylene-S(O)—R 7 ; -alkenylene-S(O)—R 7 ; -alkynylene-S(O)—R 7 ; -alkylene-S(O 2 )—R 7 ; -alkenylene-S(O 2 )—R 7 ; -alkynylene-S(O 2 )—R 7 ; —S(O 2 )NR 7 R 8 ; -alkylene-S(O 2 )—NR 7 R 8 ; -alkenylene-S(O 2 )—NR 7 R 8 ; or -alkynylene-S(O 2 )—NR 7 R 8 ; wherein 
 R 7  and R 8  are independently selected from the group consisting of hydrogen, aryl, alkyl, and -alkylene-aryl, or R 7  and R 8  may be taken together to form a ring having the formula —(CH 2 ) m -T-(CH 2 ) n — bonded to the nitrogen atom to which R 7  and R 8  are attached, wherein 
 m and n are, independently, 1, 2, 3, or 4; T is —CH 2  —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O 2 )—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NH(SO 2 )—, —S(O 2 )N(H)—, —(O)CO—, —NHS(O 2 )NH—, —OC(O)—, —N(R 9 )—, —N(C(O)R 9 )—, —N(C(O)NHR 9 )—, —N(S(O 2 )NHR 9 )—, —N(SO 2 R 9 )—, or —N(C(O)OR 9 )—; or  
 
 R 7  and R 8  may be taken together, with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring.  
 R 3  is  
 
         (a) hydrogen;  
         (b) alkyl; alkenyl; alkynyl;  
         (c) -alkylene-aryl; -alkenylene-aryl; -alkynylene-aryl;  
         (d) -alkylene-heteroaryl; -alkenylene-heteroaryl; or -alkynylene-heteroaryl;  
         A 2  is —O—R 10 , —NR 10 R 11 , or —NR 10 A 4 ;  
         wherein  
         R 10  and R 11  are independently selected from the group consisting of: 
 (a) hydrogen;  
 (b) alkyl; alkenyl; alkynyl;  
 (c) heterocyclyl; cycloalkyl;  
 (d) aryl; heteroaryl; -arylene-aryl; -arylene-heteroaryl; -heteroarylene-aryl; -heteroarylene-heteroaryl; -alkylene-aryl; -alkenylene-aryl; -alkynylene-aryl; -alkyloxy-aryl; -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -alkoxy-heteroaryl,  
 (e) -alkylene-heterocyclyl; -alkenylene-heterocyclyl; -alkynylene-heterocyclyl;  
 (f) -arylene-L 2 -alkylene-aryl, -arylene-L 2 -alkylene-heteroaryl, -arylene-alkylene-L 2 -heteroaryl, -arylene-alkylene-L 2 -aryl, -alkylene-arylene-L 2 -alkylene-aryl, -alkylene-L 2 -aryl, -alkylene-L 2 -arylene-aryl, -alkylene-arylene-L 2 -alkylene-C(O)O-alkyl, -alkylene-arylene-L 2 -alkylene-C(O)OH, -alkylene-arylene-L 2 -alkylene-C(O)NH-alkyl, -alkylene-arylene-L 2 -alkylene-heteroaryl, -alkylene-arylene-alkylene-L 2 -aryl, -alkylene-arylene-alkylene-L 2 -heteroaryl, wherein L 2  comprises O, —C(O)—, S, —S(O)—, —S(O 2 )—, a direct bond;  
 (g) —C(O)—OR 12 , -alkylene-C(O)—OR 12 , -alkenylene-C(O)—OR 12 , -alkynylene-C(O)—OR 12 , —C(O)—NR 12 R 13 , -alkylene-C(O)—NR 12 R 13 , -alkenylene-C(O)—NR 12 R 13 , alkynylene-C(O)—NR 12 R 13 , -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-O-cycloalkyl, —S(O 2 )—R 12 , -alkylene-S(O 2 )—R 12 , -alkenylene-S(O 2 )—R 12 , -alkynylene-S(O 2 )—R 12 , -alkylene-S(O)—R 12 , -alkenylene-S(O)—R 12 , -alkynylene-S(O)—R 12 , -alkylene-S(O)—R 12 , -alkenylene-S(O)—R 12 , -alkynylene-S(O)—R 12 , —S(O 2 )—NR 12 R 13 , -alkylene-S(O 2 )—NR 12 R 13 , -alkenylene-S(O 2 )—NR 12 R 13 , and -alkynylene-S(O 2 )—NR 12 R 13 ;  
 
         wherein R 10  and R 11  may be taken together with the nitrogen atom to which they are attached, to form a heterocycyl or heteroaryl ring;  
         wherein 
 R 12  and R 13  are independently selected from the group consisting of hydrogen, aryl, alkyl, and alkylene-aryl; or  
 R 12  and R 13  may be taken together to form a ring having the formula —(CH 2 ) s -V-(CH 2 ) t — bonded to the nitrogen atom to which R 12  and R 13  are attached, wherein 
 s and t are, independently, 1, 2, 3, or 4; V is —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O 2 )—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NHS(O 2 ), —S(O 2 )N(H)—, —(O)CO—, —NHS(O 2 )NH—, —OC(O)—, —N(R 14 )—, —N(C(O)R 14 )—, —N(C(O)NHR 14 )—, —N(SO 2 NHR 14 )—, —N(S(O 2 )R 14 )—, or —N(C(O)OR 14 )—; or  
 
 R 12  and R 13  may be taken together with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring;  
 A 4  is  
                     
 
         wherein  
         L 3  is alkyline, alkenyline, heteroaryline, aryline, cycloalkyline, or heterocyclyline group;  
         L 4  is a direct bond, —C(O)—N(R 15 )—, —C(O)—O—, —C(O)—, —N(R 15 )—CO—N(R 16 )—, -alkylene-C(O)—N(R 15 )—, -alkylene-C(O)—O—, -alkylene-C(O)—, or -alkylene-N(R 15 )—CO—N(R 16 )—;  
         L 5  is hydrogen, alkyl, alkenyl, alkynyl, heterocyclyl, heteroaryl, alkylene-aryl; 
 L 6  is hydrogen, alkyl, alkenyl, alkynyl, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-O-alkylene-aryl, -alkylene-arylene-O-alkylene-aryl, -alkylene-S-alkylene-aryl, -alkylene-O-alkyl, -alkylene-S-alkyl, -alkylene-NH 2 , -alkylene-OH, -alkylene-SH, alkylene-cycloalkyl, alkylene-heterocyclyl, cycloalkyl, heterocyclyl, alkylene-arylene-aryl, arylene-aryl, -alkylene-C(O)—OR 17 , -alkylene-C(O)—NR 17 R 18 , -alkylene-NR 17 R 18 , -alkylene-N(R 17 )—C(O)—R 18 , or -alkylene-N(R 17 )—S(O 2 )—R 18 ;  
 
         wherein 
 R 17  and R 18  are independently selected from the group consisting of hydrogen, aryl, alkyl, and alkylene-aryl; or  
 R 17  and R 18  may be taken together to form a rind having the formula —(CH 2 ) o -P-(CH 2 ) w — bonded to the nitrogen atom to which R 17  and R 18  are attached, wherein 
 o and w are, independently, 1, 2, 3, or 4, P is —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O 2 )—, —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NHS(O 2 ), —S(O 2 )N(H)—, —(O)CO—, —NHS(O 2 )NH—, —OC(O)—, —N(R 19 )—, —N(C(O)R 19 )—, —N(C(O)NHR 19 )—, —N(SO 2 NHR 19 )—, —N(S(O 2 )R 19 )—, or —N(C(O)OR 19 )—; or  
 
 R 17  and R 18  may be taken together with the nitrogen atom to which they are attached to form a heterocyclyl or heteroaryl ring.  
 R 9 , R 14 , R 15 R 16 , and R 19  are independently selected from the group consisting of hydrogen, aryl, alkyl, and alkylene-aryl;  
 A 1  is O; S; or NR 20 , where R 20  is:  
 
         (a) hydrogen;  
         (b) alkyl;  
         (c) alkenyl; alkynyl; heterocyclyl; cycloalkyl; -alkylene-aryl; -alkenylene-aryl; -alkynylene-aryl; -alkyloxy-aryl; -alkylene-heteroaryl; -alkenylene-heteroaryl; -alkynylene-heteroaryl; -alkoxy-heteroaryl; -alkylene-heterocyclyl; -alkenylene-heterocyclyl; -alkynylene-heterocyclyl;  
         (d) -alkylene-C(O)—OR 21 ; -alkenylene-C(O)—OR 21 ; -alkynylene-C(O)—OR 21 ; —C(O)—NR 21 R 22 ; -alkylene-C(O)—NR 21 R 22 ; -alkenylene-C(O)—NR 21 R 22 ; -alkynylene-C(O)—NR 21 R 22 ; -alkylene-O-aryl; -alkylene-O-alkylene-aryl; -alkylene-O-cycloalkyl; —S(O 2 )—R 21 ; -alkylene-S(O 2 )—R 21 ; -alkenylene-S(O 2 )—R 21 ; -alkynylene-S(O 2 )—R 21 ; -alkylene-S(O)—R 21 ; -alkenylene-S(O)—R 21 ; -alkynylene-S(O)—R 21 ; alkylene-S(O)—R 21 ; -alkenylene-S(O)—R 21 ; -alkynylene-S(O)—R 21 ; —S(O 2 )—NR 21 R 22 ; -alkylene-S(O 2 )—NR 21 R 22 ; or -alkenylene-S(O 2 )—NR 21 R 22 ; -alkynylene-S(O 2 )—NR 21 R 22 ; wherein 
 R 21  and R 22  are independently selected from the group consisting of hydrogen, aryl, alkyl, and alkylene-aryl; or  
 R 21  and R 22  may be taken together to form a ring having the formula —(CH 2 ) x -Z-(CH 2 ) y — bonded to the nitrogen atom to which R 14  and R 15  are attached; wherein 
 x and y are, independently, 1, 2, 3, or 4, Z is —CH 2 —, —C(O)—, —O—, —N(H)—, —S—, —S(O)—, —S(O 2 )—, —C(O)N(H)—, —NHC(O)—, —NHC(O)N(H)—, —NHS(O 2 )—, —S(O 2 )N(H)—, —(O)CO—, —NHS(O 2 )H—, —OC(O)—, —N(R 23 )—, —N(C(O)R 23 )—, —N(C(O)NHR 23 )—, —N(S(O 2 )NHR 23 )—, —N(S(O 2 )R 23 )—, or —N(C(O)OR 23 )—; or  
 
 R 21  and R 22  may be taken together, with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring;  
 A 3  is —CH 2 —;  
 Ar 1  is, taken together with the double bond in Formula (I), aryl;  
 R 4 , R 5 , and R 6  are independently selected from the group consisting of  
 
         (a) hydrogen;  
         (b) aryl, heteroaryl;  
         (c) heterocyclyl; cycloalkyl, or  
         (d) -alkylene-Y-aryl; -alkenylene-Y-aryl; -alkynlene-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—H; —Y-alkyl; —Y-aryl; —Y-alkylene-aryl; —Y-alkylene-NR 24 R 25 ; —Y—O—Si-(alkyl) 3  and —Y—O—Si-(alkylene-aryl) 3 ; 
 wherein  
 Y is —CH 2 —, —O—, —N(H)—, —S—, —S(O)—, —S(O)—, —C(O)N(H)—, —NHC(O)—, —NHC(O)N(H)—, —NHS(O 2 ), —S(O 2 )N(H)—, —C(O)—O—, —C(NH)—O—, —NHS(O 2 )H—, or —O—C(O)—;  
 R 24  and R 25  are independently selected from the group consisting of hydrogen, aryl, alkyl, and alkylene-aryl; or  
 R 24  and R 25  may be taken together to form a ring having the formula —(CH 2 ) q -Q-(CH 2 ) r — bonded to the nitrogen atom to which R 24  and R 25  are attached, wherein 
 q and r are, independently, 1, 2, 3, or 4; Q is —CH 2 —, —O—, —N(H)—, —S—, —S(O)—, —S(O 2 ), —CON(H)—, —NHC(O)—, —NHC(O)N(H)—, —NHS(O 26 )—, —S(O 2 )N(H)—, —(O)CO—, —NHS(O 2 )H—, —OC(O)—, —N(R 26 )—, —N(C(O)R 26 )—, —N(C(O)NHR 26 )—, —N(S(O)NHR 26 )—, —N(S(O 2 )R 26 )—, or —N(C(O)OR 26 ); or  
 
 R 24  and R 25  may be taken together, with the nitrogen atom to which they are attached, to form a heterocyclyl or heteroaryl ring;  
 
         R 23  and R 26  are independently selected from the group consisting of hydrogen, aryl, alkyl, and alkylene-aryl;  
         or a pharmaceutically acceptable salt, or solvate thereof.  
       
     
     
         12 . The pharmaceutical composition of  claim 11 , in the form of an oral dosage or parenteral dosage unit.  
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein said compound is administered as a dose in a range from about 0.01 to 500 mg/kg of body weight per day.  
     
     
         14 . The pharmaceutical composition of  claim 11 , wherein said compound is administered as a dose in a range from about 0.1 to 200 mg/kg of body weight per day.  
     
     
         15 . The pharmaceutical composition of  claim 11 , wherein said compound is administered as a dose in a range from about 0.1 to 100 mg/kg of body weight per day.  
     
     
         16 . The pharmaceutical composition of  claim 11 , further comprising 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.  
     
     
         17 - 23 . (canceled)