Thiolactams and uses thereof

Abstract

This invention provides compounds of formula I: wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as described in the specification. The compounds are inhibitors of PLK and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is selected from hydrogen, —CN, halogen, optionally substituted C 1-6 aliphatic, or —YR 1a ,
 wherein Y is —O—, —S—, or —NR 1a , and each occurrence of R 1a  is independently hydrogen, or optionally substituted C 1-6 aliphatic; 
 
 R 2  is selected from hydrogen, halogen, —ZR 2a , or —OR 2b ,
 wherein Z is an optionally substituted C 1-6  alkylene chain, and R 2a  is —OR 2b , —N(R 2b ) 2 , —SR 2b , —C(O)N(R 2b ) 2 , —N(R 2b )C(O)R 2b , —SO 2 N(R 2b ) 2 , —NR 2b SO 2 R 2b , NR 2b  C(O)N(R 2b ) 2 , or —NR 2b SO 2 N(R 2b ) 2 , wherein each occurrence of R 2b  is independently hydrogen or optionally substituted C 1-6 alkyl, or two occurrences of R 2b , taken together with a nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring; 
 
 R 3  is selected from hydrogen, halogen, optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 alkoxy; 
 R 4  is selected from hydrogen, optionally substituted C 1-6 aliphatic, an optionally substituted 3-7-membered heterocyclyl ring, —(CH 2 ) x NR 4a R 4b , —(CH 2 ) x NR 4a C(O)R 4b , —(CH 2 ) X NR 4a S(O) 2 R 4b , —(CH 2 ) x C(O)R 4b , —(CH 2 ) x C(O)NR 4a R 4b , —(CH 2 ) x S(O) 2 NR 4a R 4b , or —(CH 2 ) x OR 4b , 
 wherein 
 each occurrence of x is independently 0-6; 
 wherein R 4a  is hydrogen or optionally substituted C 1-6 aliphatic, and 
 R 4b  is hydrogen, optionally substituted C 1-6 aliphatic, optionally substituted C 3-7 -heterocyclyl or C 3-7 carbocyclyl ring, or is W—R 4c , wherein W is an optionally substituted C 2-6  alkylene chain, and R 4c  is an optionally substituted C 3-7 -heterocyclyl ring, —OR 4d , —N(R 4d ) 2 , —C(O)N(R 4d ) 2 , —N(R 4d )C(O)R 4d , SO 2 N(R 4d ) 2 , —NR 4d SO 2 R 4d , —NR 4d C(O)N(R 4d ) 2 , or —NR 4d SO 2 N(R 4d ) 2 , wherein each occurrence of R 4d  is independently hydrogen or optionally substituted C 1-6 aliphatic, or two occurrences of R 4d , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring; 
 or wherein R 4a  and R 4b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring; 
 R 5  is hydrogen, optionally substituted C 1-6 aliphatic, an optionally substituted C 3-7 -heterocyclyl ring, or is X—R 5a , wherein X is an optionally substituted C 2-6  alkylene chain or —NR 5c ,
 wherein when X is an optionally substituted C 2-6  alkylene chain R 5a  is —OR″, —N(R 5b ) 2 , —SR 5b , —C(O)N(R 5b ) 2 ,—N(R 5b )C(O)R 5b , —SO 2 N(R″) 2 , —NR 5b SO 2 R 5b , —NR 5b C(O)N(R 5b ) 2 , or —NR 5b SO 2 N(R 5b ) 2 ; and 
 when X is R 5a  is hydrogen or optionally substituted C 1-6 aliphatic, or R 5a  and R″, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring; 
 wherein each occurrence of R″ and R″ is independently hydrogen or optionally substituted C 1-6 aliphatic, or two occurrences of R 5b , or R 5a  and R″, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring; or 
 
 wherein R 4  and R 5 , taken together, form an optionally substituted 5-7-membered cycloaliphatic or heterocyclyl ring; and 
 R 6  is selected from hydrogen, halogen, optionally substituted C 1-4 alkyl, or optionally substituted C 1-4 alkoxy. 
 
     
     
         2 . The compound of  claim 1 , wherein R 2 , R 4 , and R 6  are each hydrogen. 
     
     
         3 . The compound of  claim 1 , wherein R 2 , R 5 , and R 6  are each hydrogen. 
     
     
         4 . The compound of  claim 1 , wherein R 1  is optionally substituted C 1-4 aliphatic, halogen, —CN, or -OMe. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is methyl, ethyl, —CF 3 , Cl, —CN, —OMe, or cyclopropyl. 
     
     
         6 . The compound of  claim 1 , wherein R 2  is hydrogen or —Z—R 2a , wherein Z is —(CH 2 ) 2-4  and R 2a  is N(R 2b ) 2 , wherein each occurrence of R 2b  is selected from hydrogen or C 1-4 alkyl, or two occurrences of R 2b , taken together with the nitrogen atom to which they are bound, form an optionally substituted C 3-7 -heterocyclyl ring. 
     
     
         7 . The compound of  claim 1 , wherein R 3  is methyl or CF 3 . 
     
     
         8 . The compound of  claim 1 , wherein R 4  is methyl, or -meta R 4b , wherein R 4a  and R 4b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring, or wherein R 4a  is hydrogen or C 1-4 alkyl, and R 4b  is an optionally substituted C 3-7 -heterocyclyl ring or is W—R 4c , wherein W is an optionally substituted C 2-6  alkylene chain, and R 4c  is an optionally substituted C 3-7 -heterocyclyl ring. 
     
     
         9 . The compound of  claim 1 , wherein R 5  is an optionally substituted C 3-7 -heterocyclyl ring or is X—R 5a , wherein X is an optionally substituted C 2-6  alkylene chain, and R 5a  is —N(R 5b ) 2 , wherein each occurrence of leis independently hydrogen or C 1-6 alkyl, or two occurrences of R 5b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring. 
     
     
         10 . The compound of  claim 1 , wherein R 4  and R 5  are taken together to form a ring selected from: 
       
         
           
           
               
               
           
         
         wherein 
         G 1  is —NH—, —O— or —N(CH 3 )— 
         R 7  is selected from hydrogen or optionally substituted C 1-6 aliphatic, 
         R 8  is selected from fluoro, optionally substituted C 1-6 aliphatic, or —YR 1a , wherein Y is —O—, —S—, or —NR 1a , and each occurrence of R 1a  is independently hydrogen, or optionally substituted C 1-6 aliphatic; and 
         y is 0-4. 
       
     
     
         11 . The compound of  claim 1  having the structure of formula I-A: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 11 , wherein R 1  is optionally substituted C 1-4 aliphatic, halogen, —CN, or -OMe. 
     
     
         13 . The compound of  claim 11 , wherein R 1  is methyl, ethyl, —CF 3 , Cl, —CN, —OMe, or cyclopropyl. 
     
     
         14 . The compound of  claim 11 , wherein R 3  is methyl or CF 3 . 
     
     
         15 . The compound of  claim 11 , wherein R 5  is an optionally substituted C 3-7 -heterocyclyl ring or is X—R 5a , wherein X is an optionally substituted C 2-6  alkylene chain, and R 5a  is —N(R 5b ) 2 , wherein each occurrence of R 5b is independently hydrogen or C 1-6 alkyl, or two occurrences of R 5b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring. 
     
     
         16 . The compound of  claim 15 , wherein R 5  is an optionally substituted pyrrolidinyl, morpholinyl, piperidinyl, or piperazinyl group, or is X—R 5a , wherein X is a C 2-4 alkylene chain, and R 5a  is —N(R 5b ) 2 , wherein each occurrence of R 5b is independently hydrogen or C 1-6 alkyl, or two occurrences of R 5b , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl group. 
     
     
         17 . The compound of  claim 16 , wherein the pyrrolidinyl, morpholinyl, piperidinyl, or piperazinyl group is optionally substituted with 1-4 occurrences of C 1-4 alkyl or C 1-4 haloalkyl. 
     
     
         18 . The compound of  claim 11 , wherein:
 a) R 1  is methyl, ethyl, propyl, —CF 3 , Cl, —CN, —OMe, or cyclopropyl;   b) R 3  is methyl or CF 3 ; and   c) R 5  is an optionally substituted pyrrolidinyl, morpholinyl, piperidinyl, or piperazinyl group, or is X—R 5a , wherein X is a C 2-4 alkylene chain, and R 5a  is —N(R 5b ) 2 , wherein each occurrence of R 5b is independently hydrogen or C 1-6 alkyl, or two occurrences of R 5b , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl group.   
     
     
         19 . The compound of  claim 18 , wherein R 1  is Cl or CF 3 , and R 3  is methyl. 
     
     
         20 . The compound of  claim 1  having the structure of formula I-B: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 20 , wherein R 1  is optionally substituted C 1  aliphatic, halogen, —CN, or -OMe. 
     
     
         22 . The compound of  claim 21 , wherein R 1  is methyl, ethyl, —CF 3 , Cl, —CN, —OMe, or cyclopropyl. 
     
     
         23 . The compound of  claim 20 , wherein R 3  is methyl or CF 3 . 
     
     
         24 . The compound of  claim 20 , wherein R 4  is —NR 4a R 4b , wherein R 4a  and R 4b , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring, or wherein R 4a  is hydrogen or C 1-4 alkyl, and R 4b  is an optionally substituted C 3-7 -heterocyclyl ring or is W—R 4c , wherein W is an optionally substituted C 2-4  alkylene chain, and R 4c  is an optionally substituted C 3-7 -heterocyclyl ring, or —N(R 4d ) 2 , wherein each occurrence of R 4d  is independently hydrogen or C 1-6 alkyl, or two occurrences of R 4d , taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring. 
     
     
         25 . The compound of  claim 24 , wherein R 4  is —NR 4a R 4b , wherein R 4a  and R 4b , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or wherein R 4a  is hydrogen or C 1-4 alkyl, and R 4b  is an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or is W—R 4c , wherein W is an optionally substituted C 2-4  alkylene chain, and R 4c  is an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or —N(R 4d ) 2 , wherein each occurrence of R 4d  is independently hydrogen or C 1-6 alkyl, or two occurrences of R 4d , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring. 
     
     
         26 . The compound of  claim 20 , wherein:
 a) R 1  is methyl, ethyl, propyl, —CF 3 , Cl, —CN, —OMe, or cyclopropyl;   b) R 3  is methyl or CF 3 ; and   c)R 4  is —NR 4a R 4b , wherein R 4a  and R 4b , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or wherein R 4a  is hydrogen or C 1-4 alkyl, and R 4b is an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or is W—R 4c , wherein W is an optionally substituted C 2-4  alkylene chain, and R 4c  is an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring, or —N(R 4d ) 2 , wherein each occurrence of R 4d  is independently hydrogen or C 1-6 alkyl, or two occurrences of R 4d , taken together with the nitrogen atom to which they are bound, form an optionally substituted pyrrolidinyl, piperazinyl, piperidinyl, or morpholinyl ring.   
     
     
         27 . The compound of  claim 26 , wherein R 1  is Cl or CF 3 , and R 3  is methyl. 
     
     
         28 . The compound of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         29 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         30 . A method for inhibiting PLK activity in a patient comprising administering a composition comprising an amount of a compound of  claim 1  or a composition of  claim 29 , effective to inhibit PLK activity in the patient. 
     
     
         31 . A method for treating a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to a patient a compound of  claim 1  or a composition of  claim 29 . 
     
     
         32 . A method of treating cancer in a patient comprising the step of administering to a patient a compound of  claim 1  or a composition of  claim 29 . 
     
     
         33 . The method of  claim 32 , wherein the cancer is melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic. 
     
     
         34 . The method of  claim 32 , wherein the method comprises the step of disrupting mitosis of the cancer cells by inhibiting PLK with a compound of  claim 1 . 
     
     
         35 . The method of  claim 32 , further comprising administering to the patient a cytotoxic agent selected from the group consisting of chemotherapeutic agents and radiation therapy.