Protein tyrosine phosphatase inhibitors and methods of use thereof

Abstract

The present invention provides compounds of Formula (I) and Formula (II) that are useful for modulating the biological activity of the protein tyrosine phosphatase-1b (PTP1B) enzyme. Compounds of this invention can be used to treat diseases and/or conditions in which the PTP1B enzyme is a factor. Such diseases and/or conditions include, but are not limited to, Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, atherosclerosis, vascular restenosis, inflammatory bowel disease, pancreatitis, adipose cell tumors, adipose cell carcinoma, liposarcoma, dyslipidemia, cancer, and neurodegenerative diseases.

1 - 51 . (canceled) 
   
   
       52 . A method of treating, preventing, or controlling one or more diseases or conditions selected from the group consisting of Type 1 diabetes, Type 2 diabetes, inadequate glucose tolerance, insulin resistance, obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, atherosclerosis, vascular restenosis, inflammatory bowel disease, pancreatitis, adipose cell tumors, adipose cell carcinoma, liposarcoma, dyslipidemia, cancer, and neurodegenerative disease, said method comprising the administration of an effective amount of a pharmaceutical composition comprising a compound of Formula IIe: 
     
       
         
         
             
             
         
       
       wherein R 26 , R 27  and R 29  are each independently H, halo, —OH, —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 CH 3 , —CH 2 CF 3 , —CF 2 CF 3 , —CH 2 Cl, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 SO 2 CH 3 , —OR 23 , —C(O)R 23 , —C(O)OR 23 , —C(O)N(R 23 )(R 24 ), —OC(O)R 23 , —OC(O)OR 23 , —OC(O)N(R 23 )(R 24 ), —N(R 23 )(R 24 ), —S(O) 2 R 23 , —S(O)R 23 , —SR 23 , —S(O) 2 N(R 23 )(R 24 ); —NR 23 C(O)R 24 , —NR 23 C(O)R 24 , —NR 23 SOOR 24 , —NR 23 C(O)N(R 24 )(R 25 ), —NR 23 SO 2 R 24 , —NR 23 SO 2 N(R 24 )(R 25 ) or optionally substituted C 1-6  alkyl, C 1-6  alkoxy, or aryl; where R 23 , R 24  and R 25  are each independently H, C 1-4  alkyl or C 3-8  cycloalkyl, heterocycloalkyl, aryl or heteroaryl; 
       R 31  and R 32  are each independently H, alkyl or C 5-6  aryl; 
       R 40  is H, alkyl, alkylene, —C(O)OR 39 , —C(O)N(R 37 )(R 38 ) or —N(NH 2 )C(O)NH(CH 2 ) n Ph; 
       R 37  and R 38  are each independently H, —C(O)OR 39 , —C(O)cycloalkyl-Ph, —S(O) 2 R 39 , —C(O)R 39 , —OC(O)R 39 , —C(O)(CH 2 ) q R 39 , —S(O) 1 NHR 39 , —S(O) 2 N(R 44 )(R 39 ), —N(R 44 )(R 39 ), —C(O)N(R 44 )(R 39 ) or —NHC(O)N(R 44 )(R 39 ); or 
       optionally substituted C 1-6  alkyl, C 3-8  cycloalkyl, C 5-8  aryl, 3 to 8 membered heterocycloalkyl or 5 to 8 membered heteroaryl; 
       R 39  is H, optionally substituted C 1-6  alkyl, aryl or heteroaryl; 
       R 43  is H, —NHR 39  or R 39 ; 
       wherein n is an integer from 0 to 4; and 
       wherein each of the phenyl ring A carbon atoms 3, 5 or 6 including its respective substituents are optionally replaced by N; or phenyl ring A carbons atoms 5 and 6 and their respective substituents are optionally replaced by S, N or O; or 
       a pharmaceutically acceptable salt, ester or prodrug thereof. 
     
   
   
       53 . A method of modulating the biological activity of PTP1B comprising contacting PTP1B with a compound of Formula IIa: 
     
       
         
         
             
             
         
       
       wherein R a  and R b  are independently H or halogen; 
       R 26 , R 27 , R 29  and R 30  are each independently H, halo, —OH, —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 CH 3 , —CH 2 CF 3 , —CF 2 CF 3 , —CH 2 Cl, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 SO 2 CH 3 , —OR 23 , —C(O)R 23 , —C(O)OR 23 , —C(O)N(R 23 )(R 24 ), —OC(O)R 23 , —OC(O)OR 23 , —OC(O)N(R 23 )(R 24 ), —N(R 23 )(R 24 ), —S(O) 2 R 23 , —S(O)R 23 , —SR 23 , —S(O) 2 N(R 23 )(R 24 ), —NR 23 C(O)R 24 , —NR 23 C(O)OR 24 , —NR 23 SOOR 24 , —NR 23 C(O)N(R 24 )(R 25 ), —NR 23 SO 2 R 24 , —NR 23 SO 2 N(R 24 )(R 25 ) or optionally substituted C 1-6  alkyl, C 1-6  alkoxy, or aryl; where R 23 , R 24  and R 25  are each independently H, C 1-4  alkyl or C 3-8  cycloalkyl, or heterocycloalkyl, aryl or heteroaryl; 
       R 31  and R 32  are each independently H, alkyl or C 5-6  aryl; 
       R 28  is H, halogen, —CN, —[CH 2 ] n —[C(H) 3-p ] x (R 33 ) p , —C(O)OH, —C(O)(CH 2 ) n NH 2 , —C(O)NH(CH 2 ) n R 33 , —C═N—N—S(O) 2 R 33 , —(CH 2 ) n —CH(R 34 )(R 35 ) or —CHNR 34 ; or R 28  taken together with either R 27  or R 29  form an optionally substituted ring comprising 3 to 8 carbon atoms or heteroatoms; with the proviso that R 27  and R 28  are not both H; 
       each R 33  is independently H, halogen, —C(O)OR 39 , —OH, —CN, —N═N—N, —N(R 37 )(R 38 ), —C(O)NH(CH 2 ) n R 39 , —C(R 39 )(NH 2 )C(O)O—R 39 , —CH 2 R 35  or —CH(R 35 )(NHS(O) 2 —R 39 ) or optionally substituted cycloalkyl, or aryl, heterocycloalkyl, or heteroaryl; 
       R 34  is H or —N(R 37 )(R 38 ); 
       R 35  is H, —C(O)R 34 , —C(O)OR 39  or —N(NH 2 )C(O)NH(CH 2 ) n Ph; 
       R 37  and R 38  are each independently H, —C(O)OR 39 , —C(O)cycloalkyl-Ph, —S(O) 2 R 39 , —C(O)R 39 , —OC(O)R 39 , —C(O)(CH 2 ) q R 39 , —S(O) 2 , —S(O) 2 NHR 39 , —S(O) 2 N(R 44 )(R 39 ), —N(R 44 )(R 39 ), —C(O)N(R 44 )(R 39 ) or —NHC(O)N(R 44 )(R 39 ); or 
       optionally substituted C 1-6  alkyl, C 3-8  cycloalkyl, C 5-8  aryl, 3 to 8 membered heterocycloalkyl or 5 to 8 membered heteroaryl; and 
       R 39  and R 44  are each independently H or optionally substituted C 1-6  alkyl, C 3-8  cycloalkyl, or C 3-8  aryl, 3 to 8 membered heterocycloalkyl or 5 to 8 membered heteroaryl; 
       wherein each of the phenyl ring A carbon atoms 2-6 including its respective substituents are optionally replaced by N; or any pair of adjacent phenyl ring A carbons atoms 2-6 and their respective substituents are optionally replaced by S, N or O; and 
       wherein n is an integer from 0 to 4; m is 0, 1 or 2; p is an integer from 1 to 3; q is an integer from 0 to 6; and x is either 0 or 1, provided that when x is 0, p is 1; 
       or pharmaceutically acceptable salt, ester or prodrug thereof. 
     
   
   
       54 . A method of modulating the biological activity of PTP1B in a mammal comprising administering a PTP1B-modulating amount of a compound of Formula IIe: 
     
       
         
         
             
             
         
       
       wherein R 26 , R 27  and R 29  are each independently H, halo, —OH, —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 CH 3 , —CH 2 CF 3 , —CF 2 CF 3 , —CH 2 Cl, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 SO 2 CH 3 , —OR 23 , —C(O)R 23 , —C(O)OR 23 , —C(O)N(R 23 )(R 24 ), —OC(O)R 23 , —OC(O)OR 23 , —OC(O)N(R 23 )(R 24 ), —N(R 23 )(R 24 ), —S(O) 2 R 23 , —S(O)R 23 , —SR 23 , —S(O) 2 N(R 23 )(R 24 ); —NR 23 C(O)R 24 , —NR 23 C(O)OR 24 , —NR 23 SOOR 24 , —NR 23 C(O)N(R 24 )(R 25 ), —NR 23 SO 2 R 24 , —NR 23 SO 2 N(R 24 )(R 25 ) or optionally substituted C 1-6  alkyl, C 1-6  alkoxy, or aryl; where R 23 , R 24  and R 25  are each independently H, C 1-4  alkyl or C 3-8  cycloalkyl or, heterocycloalkyl, aryl or heteroaryl; 
       R 31  and R 32  are each independently H, alkyl or C 5-6  aryl; 
       R 40  is H, alkyl, alkylene, —C(O)OR 39 , —C(O)N(R 37 )(R 38 ) or —N(NH 2 )C(O)NH(CH 2 ) n Ph; 
       R 37  and R 38  are each independently H, —C(O)OR 39 , —C(O)cycloalkyl-Ph, —S(O) 2 R 39 , —C(O)R 39 , —OC(O)R 39 , —C(O)(CH 2 ) q R 39 , —S(O) 2 , —S(O) 2 NHR 39 . —S(O) 2 N(R 44 )(R 39 ), —N(R 44 )(R 39 ), —C(O)N(R 44 )(R 39 ) or —NHC(O)N(R 44 )(R 39 ); or 
       optionally substituted C 1-6  alkyl, C 3-8  cycloalkyl, C 5-8  aryl, 3 to 8 membered heterocycloalkyl or 5 to 8 membered heteroaryl; 
       R 39  is H or optionally substituted C 1-6  alkyl, aryl or heteroaryl; 
       R 43  is H, —NHR 39  or R 39 ; 
       wherein n is an integer from 0 to 4; and 
       wherein each of the phenyl ring A carbon atoms 3, 5 or 6 including its respective substituents are optionally replaced by N; or phenyl ring A carbons atoms 5 and 6 and their respective substituents are optionally replaced by S, N or O; 
       or pharmaceutically acceptable salt, ester or prodrug thereof. 
     
   
   
       55 . A method of modulating the biological activity of PTP1B in a mammal comprising administering a PTP1B-modulating amount of {[2-bromo-4-(2-ethanesulfonylamino-2-methylcarbamoylethyl)phenyl]difluoromethyl}phosphonic acid, or pharmaceutically acceptable salt, ester or prodrug thereof. 
   
   
       56 . A method of modulating the biological activity of PTP1B in a mammal comprising administering a PTP1B-modulating amount of a compound of Formula IIa: 
     
       
         
         
             
             
         
       
       wherein R a  and R b  are independently H or halogen; 
       R 26 , R 27 , R 29  and R 30  are each independently H, halo, —OH, —NO 2 , —CN, —CF 3 , —CHF 2 , —CH 2 CH 3 , —CH 2 CF 3 , —CF 2 CF 3 , —CH 2 Cl, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 SO 2 CH 3 , —OR 23 , —C(O)R 23 , —C(O)OR 23 , —C(O)N(R 23 )(R 24 ), —OC(O)R 23 , —OC(O)OR 23 , —OC(O)N(R 23 )(R 24 ), —N(R 23 )(R 24 ), —S(O) 2 R 23 , —S(O)R 23 , —SR 23 , —S(O) 2 N(R 23 )(R 24 ), —NR 23 C(O)R 24 , —NR 23 C(O)OR 24 , —NR 23 SOOR 24 , —NR 23 C(O)N(R 24 )(R 25 ), —NR 23 SO 2 R 24 , —NR 23 SO 2 N(R 24 )(R 25 ) or optionally substituted C 1-6  alkyl, C 1-6  alkoxy, or aryl; where R 23 , R 24  and R 25  are each independently H, C 1-4  alkyl or C 3-8  cycloalkyl, or heterocycloalkyl, aryl or heteroaryl; 
       R 31  and R 32  are each independently H, alkyl or C 5-6  aryl; 
       R 28  is H, halogen, —CN, —[CH 2 ] n —[C(H) 3-p ] x (R 33 ) p , —C(O)OH, —C(O)(CH 2 ) n NH 2 , —C(O)NH(CH 2 ) n R 33 , —C═N—N—S(O) 2 R 33 , —(CH 2 ) n —CH(R 34 )(R 35 ) or —CHNR 34 ; or R 28  taken together with either R 27  or R 29  form an optionally substituted ring comprising 3 to 8 carbon atoms or heteroatoms; with the proviso that R 27  and R 28  are not both H; 
       each R 33  is independently H, halogen, —C(O)OR 39 , —OH, —CN, —N═N—N, —N(R 37 )(R 38 ), —C(O)NH(CH 2 ) n R 39 , —C(R 39 )(NH 2 )C(O)O—R 39 , —CH 2 R 35  or —CH(R 35 )(NHS(O) 2 —R 19 ) or optionally substituted cycloalkyl, or aryl, heterocycloalkyl, or heteroaryl; 
       R 34  is H or —N(R 37 )(R 38 ); 
       R 35  is H, —C(O)R 34 , —C(O)OR 39  or —N(NH 2 )C(O)NH(CH 2 ) n Ph; 
       R 37  and R 38  are each independently H, —C(O)OR 39 , —C(O)cycloalkyl-Ph, —S(O) 2 R 39 , —C(O)R 39 , —OC(O)R 39 , —C(O)(CH 2 ) q R 39 , —S(O) 2 , —S(O) 2 NHR 39 , —S(O) 2 N(R 44 )(R 39 ), —N(R 44 )(R 39 ), —C(O)N(R 44 )(R 39 ) or —NHC(O)N(R 44 )(R 39 ); or 
       optionally substituted C 1-6  alkyl, C 3-8  cycloalkyl or, C 5-8  aryl, 3 to 8 membered heterocycloalkyl or 5 to 8 membered heteroaryl; and 
       R 39  and R 44  are each independently H or optionally substituted C 1-6  alkyl, C 3-8  cycloalkyl, or C 3-8  aryl, 3 to 8 membered heterocycloalkyl or 5 to 8 membered heteroaryl; 
       wherein each of the phenyl ring A carbon atoms 2-6 including its respective substituents are optionally replaced by N; or any pair of adjacent phenyl ring A carbons atoms 2-6 and their respective substituents are optionally replaced by S, N or O; and 
       wherein n is an integer from 0 to 4; m is 0, 1 or 2; p is an integer from 1 to 3; q is an integer from 0 to 6; and x is either 0 or 1, provided that when x is 0, p is 1; or 
       pharmaceutically acceptable salt, ester or prodrug thereof. 
     
   
   
       57 - 63 . (canceled) 
   
   
       64 . The method of  claim 52  wherein R 26 , R 27  and R 29  are each H; R 39  is optionally substituted C 1-6  alkyl, aryl or heteroaryl; R 40  is —C(O)N(R 37 )(R 38 ); and R 43  is R 39 . 
   
   
       65 . The method of  claim 52  wherein the compound of Formula IIe is {[2-bromo-4-(2-ethanesulfonylamino-2-methylcarbamoylethyl)phenyl]difluoromethyl}phosphonic acid, or pharmaceutically acceptable salt, ester or prodrug thereof. 
   
   
       66 . The method of  claim 52  wherein the disease or condition is Type 2 diabetes.