Substituted acetylenic pyrazolo[1,5-a]pyridine compounds as kinase inhibitors

Abstract

This invention relates to compounds of the general formula:in which the variable groups are as defined herein, and to their preparation and use.

1 . A compound of the Formula I 
       
         
           
           
               
               
           
         
       
       or a tautomer, or an individual isomer or a mixture of isomers thereof wherein:
 Ring T is a 5-membered heteroaryl ring containing 1 or 2 nitrogens with the remaining ring atoms being carbon, substituted on at least two ring atoms with R 1  groups, at least two of which being located on adjacent ring atoms, and, together with the atoms to which they are attached, forming a saturated, partially saturated or unsaturated 5- or 6-membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, and S and being optionally substituted with 1-4 R e  groups: 
 Ring B represents a 5- or 6-membered aryl or heteroaryl ring; 
 L 1  is selected from NR 1 C(O), C(O)NR 1 , NR 1 C(O)O, NR 1 C(O)NR 1 , and OC(O)NR 1 ; 
 each occurrence of R a , R b  and R t  is independently selected from the group consisting of halo, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3  and —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —; 
 R e , at each occurrence, is independently selected from the group consisting of halo, ═O, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NR 2 SO 2 R 2l , —S(O)   t R 2 , —SO 2 NR 2 R 3  and —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —; 
 R 1 , R 2  and R 3  are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; 
 alternatively, R 2  and R 3 , taken together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(O) r ; 
 each occurrence of R 4  is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; 
 each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties is optionally substituted; 
 is 0, 1, 2, 3 or 4; 
 n is 2 or 3; 
 p is 0, 1, 2, 3, 4 or 5; and, 
 r is 0, 1 or 2; 
 or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
 
     
     
         2 . A compound of  claim 1  wherein Ring T has the following structure: 
       
         
           
           
               
               
           
         
         in which Ring E is a 5- or 6-membered unsaturated rind comprising 0-3 heteroatoms selected from O, N, and S, and s is 0, 1, 2, 3 or 4. 
       
     
     
         3 . A compound according to  claim 1  wherein Ring T is a bicyclic heteroaryl ring selected from: 
       
         
           
           
               
               
           
         
         and s is 0, 1, 2, 3 or 4. 
       
     
     
         4 . A compound of claim of the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         Ring C is a 5- or 6-membered heterocyclic or heteroaryl ring, comprising carbon atoms and 1-3 heteroatoms independently selected from 0, N and S(O); 
         R c , at each occurrence, is independently selected from halo, ═O, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —Si(R 2 ) 3 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3  and —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —; and, 
         v is 0, 2, 3, 4 or 5. 
       
     
     
         5 . A compound of  claim 4  wherein Ring T has the following structure: 
       
         
           
           
               
               
           
         
         and s is 0, 1, 2, 3 or 4. 
       
     
     
         6 . A compound of  claim 5  wherein Rings A and B are aryl. 
     
     
         7 . A compound of  claim 5  or  6  wherein Ring C is an imidazole ring 
     
     
         8 . A compound of  claim 7  selected from Formulae IIa, IIb, and IIc: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound of  claim 8  wherein s is 0; m, p and v are R a  and R c  are methyl; and R b  is CF 3 . 
     
     
         10 . A compound of  claim 1  having the formula: 
       
         
           
           
               
               
           
         
         wherein; 
         Ring D represents a 5-, 6-heterocyclic or heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O) r ; 
         L 2  is (CH 2 ) x , O(CH 2 ) x , NR 3 (CH 2 ) x , S(CH 2 ) x  or (CH 2 ) x NR 3 C(O)(CH 2 ) x  in either direction; 
         R d , at each occurrence, is selected from the group consisting of H, halo, ═O, —CN, —NO 2 , —R 4 , —OR 2 , —NR 2 R 3 , —C(O)YR 2 , —OC(O)YR 2 , —NR 2 C(O)YR 2 , —SC(O)YR 2 , —NR 2 C(═S)YR 2 , —OC(═S)YR 2 , —C(═S)YR 2 , —YC(═NR 3 )YR 2 , —YP(═O)(YR 4 )(YR 4 ), —Si(R 2 ) 3 , —NR 2 SO 2 R 2 , —S(O) r R 2 , —SO 2 NR 2 R 3  and —NR 2 SO 2 NR 2 R 3 , wherein each Y is independently a bond, —O—, —S— or —NR 3 —; 
         R 2  and R 3  are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; 
         alternatively, R 2  and R 3 , taken together with the atom to which they are attached, form a 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 heteroatoms selected from N, O and S(O) r ; 
         each occurrence of R 4  is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; 
         each of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl moieties in this Section 1 is optionally substituted; 
         w is 0, 1, 2, 3, 4 or 5; 
         x is 0, 1, 2 or 3; and, 
         z is 1, 2, 3 or 4. 
       
     
     
         11 . A compound of  claim 10  wherein Ring T has the following structure: 
       
         
           
           
               
               
           
         
         and s is 0, 1, 2, 3 or 4. 
       
     
     
         11 . A compound of  claim 11 , wherein Rings A and B are aryl. 
     
     
         13 . A compound of  claim 11  or  12  wherein Ring T is a bicyclic heteroaryl ring selected from: 
       
         
           
           
               
               
           
         
         and s is 0, 1, 2, 3 or 4. 
       
     
     
         14 . A compound of  claim 13 , wherein Ring D is a piperazine ring and L 2  is CH 2 . 
     
     
         15 . A compound of  claim 14  selected from Formulae IIIa, IIIb, and IIIc: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound of  claim 15  wherein s is 0, m is 1, p is 1, R a  is methyl, R b  is CF 3 , and R d  is methyl or —CH 2 CH 2 OH. 
     
     
         17 . A method for treating cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of any of  claim 1 - 6  or  10 - 12  or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
     
     
         18 . A method for treating cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of  claim 7  or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
     
     
         19 . A method for treating cancer in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of  claim 13  or a pharmaceutically acceptable salt, solvate or hydrate thereof. 
     
     
         20 . A composition comprising a compound of any of  claim 1 - 8  or  10 - 12  or a pharmaceutically acceptable salt, solvate or hydrate thereof and a pharmaceutical acceptable carrier, diluent or vehicle. 
     
     
         21 . A composition comprising a compound of  claim 7  or a pharmaceutically acceptable salt, salivate or hydrate thereof and a pharmaceutical acceptable carrier, diluent or vehicle. 
     
     
         22 . A composition comprising a compound of  claim 13  or a pharmaceutically acceptable salt, solvate or hydrate thereof and a pharmaceutical acceptable carrier, diluent or vehicle.