Thienopyrimidines useful as aurora kinase inhibitors

Abstract

The present invention provides compounds having the formula: wherein R 1 , R 2 , X 1 , X 2 , L 1 , L 2 , Y and Z are as defined in classes and subclasses herein, and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of protein kinase (e.g., Aurora), and thus are useful, for example, for the treatment of Aurora mediated diseases.

1 - 46 . (canceled) 
   
   
       47 . A compound having the structure: 
     
       
         
         
             
             
         
       
       or pharmaceutically acceptable derivative thereof; 
       wherein one of   is a double bond, as valency permits; 
       one of X 1  and X 2  is S, the other is —C(R X1 )—; wherein R X1  is hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; 
       W 1  is O, S, NR W1  or —C(═O)NR W1  where R W1  is hydrogen, lower alkyl, C 3-6 cycloalkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; or R W1  together with a carbon atom present on Alk 1  forms an optionally substituted 5- to 6-membered heterocyclic ring; 
       Alk 1  is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO 2 —, —C(═O)C(═O)—, —C(═O)NR L1A —, —OC(═O)—, —OC(═O)NR L1A —, —NR L1A NR L1B —, —NR L1A NR L1B C(═O)—, —NR L1A C(═)—, —NR L1A CO 2 —, —NR L1A C(═)NR L1B —, —S(═O)—, —SO 2 —, —NR L1A SO 2 —, —SO 2 NR L1A —, —NR L1A SO 2 NR L1B —, —O—, —S—, or —NR L1A —; wherein each occurrence of R L1A  and R L1B  is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl; 
       L 2  is —NR W2 —, —N(R W2 )C(═O)G 2 -, —N(R W2 )C(═O)N(R W2 )CR W3 R W4 — or —CR W3 R W4 C(═O)N(R W2 )—; wherein G 2  is absent, O or NR G2 ; and R W2 , R W3 , R W4  and R G2  are independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; 
       Y is an optionally substituted phenyl or thiazolyl ring; 
       Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety. 
     
   
   
       48 . The compound of  claim 47  wherein X 1  is S and X 2  is CH. 
   
   
       49 . The compound of  claim 47  wherein X 1  is CH and X 2  is S. 
   
   
       50 . The compound of  claim 47  wherein L 2  is NH, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —NHC(═O)NHCH 2 —, or —CH 2 C(═O)NH—. 
   
   
       51 . The compound of  claim 47  having the structure: 
     
       
         
         
             
             
         
       
       wherein q is 1-4; one of X 1  and X 2  is S and the other is —CH—; and each occurrence of R Y1  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR Y3 , —SR Y3 , —NR Y2 R Y3 , —SO 2 NR Y2 R Y3 , —C(═O)NR Y2 R Y3 , halogen, —CN, —NO 2 , —C(═O)OR Y3 , —N(R Y2 )C(═O)R Y3 , wherein each occurrence of R Y2  and R Y3  is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Y2  and R Y3  taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring. 
     
   
   
       52 . The compound of  claim 51  having the structure: 
     
       
         
         
             
             
         
       
       wherein W 1  is O or NR W1 , where R W1  is hydrogen, lower alkyl, C 3-6 cycloalkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; and Alk 1  is a C 1-6 alkylene or C 2-6 alkenylene moiety; and each occurrence of R Y1  is independently hydrogen, halogen or lower alkyl. 
     
   
   
       53 . The compound of  claim 52  having the structure: 
     
       
         
         
             
             
         
       
       wherein L 2  is NH, —NHC(═O)—, —NHC(═O)O—, —NHC(═O)NH—, —NHC(═O)NHCH 2 —, or —CH 2 C(═O)NH—. 
     
   
   
       54 . The compound of  claim 53  wherein Z is a branched alkyl, alkenyl, alkynyl, heteroalkyl or heteroalkenyl moiety. 
   
   
       55 . The compound of  claim 53  wherein Z is one of: 
     
       
         
         
             
             
         
       
       wherein each occurrence of R Z1  is independently hydrogen, lower alkyl, lower alkenyl, aryl, heteroaryl or acyl. 
     
   
   
       56 . The compound of  claim 53  wherein Z is cycloalkyl, cycloalkenyl, or a heterocyclyl, aryl or heteroaryl moiety having one of the structures: 
     
       
         
         
             
             
         
       
       wherein the “A” cyclic moiety is a 6- to 10-membered mono- or fused bicyclic aromatic ring comprising from 0-4 nitrogen atoms; the “Het” moiety represents a fully or partially saturated or unsaturated 5- to 8-membered mono- or fused bicyclic ring comprising 1-4 heteroatoms selected from N, O and S; m is an integer from 0-6; and each occurrence of R Z1  is independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, -(alkyl)heterocyclyl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —N(R Z2 ) 2 , —SO 2 N(R Z2 ) 2 , —SO 2 R Z4 , —C(═O)N(R Z2 ) 2 , halogen, —CN, —NO 2 , —C(═O)OR Z2 , —N(R Z2 )C(═O)R Z3  or —N(R Z2 )SO 2 R Z4 ; wherein each occurrence of R Z2  and R Z3  is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl; or any two occurrences of R Z2 , taken together with the nitrogen atom to which they are attached (e.g., N(R Z2 ) 2 ), form a substituted or unsubstituted heterocyclic moiety; and R Z4  is alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; and wherein any two adjacent occurrence of R Z1  may form a fused 5- to 6-membered aryl, heteroaryl or heterocyclic ring. 
     
   
   
       57 . The compound of  claim 53  wherein Z is one of: 
     
       
         
         
             
             
         
       
       wherein m is an integer from 0 to 3; r is an integer from 1 to 4; X 3  is N or CR Z1 ; each occurrence of R Z1  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —NR Z2 R Z3 , —SO 2 NR Z2 R Z3 , —SO 2 R Z1 , —C(═O)NR Z2 R Z3 , halogen, —CN, —NO 2 , —C(═O)OR Z3 , —N(R Z2 )C(═O)R Z3 , wherein each occurrence of R Z2  and R Z3  is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2  and R Z3  taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring; and R Z4  is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl. 
     
   
   
       58 . The compound of  claim 57  wherein Z is one of: 
     
       
         
         
             
             
         
       
       wherein X 3  is N or CR Z1 ; R Z1  is hydrogen, halogen, lower alkyl, lower hydroxyalkyl or lower haloalkyl; R Z2  and R Z3  are independently hydrogen, lower alkyl, lower heteroalkyl, acyl, or R Z2  and R Z3  taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; and R Z4  is hydrogen or lower alkyl. 
     
   
   
       59 . The compound of  claim 57  wherein Z is one of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein X 3  is N or CR Z1 ; R Z1  is hydrogen, halogen, lower alkyl or lower haloalkyl; and R Z2  and R Z3  are independently hydrogen, lower alkyl, lower heteroalkyl, acyl, or R Z2  and R Z3  taken together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; X is halogen, R Z1A  is hydrogen, halogen, —CN, lower alkyl, lower alkoxy, lower haloalkyl or —SO 2 R Z4 ; wherein R Z4  is lower alkyl; and R Z2A  is hydrogen or lower alkyl. 
     
   
   
       60 . The compound of  claim 57  wherein Z is one of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein each occurrence of R Z1  is independently Cl, F, methyl or CF 3 ; R Z2  and R Z3  are each methyl or ethyl, or taken together with the nitrogen atom to which they are attached form a saturated or unsaturated pyrrolidinyl ring; and R Z2A  is hydrogen or methyl. 
     
   
   
       61 . The compound of  claim 60  wherein Z is one of: 
     
       
         
         
             
             
         
       
       wherein R Z1  is Cl, F, methyl or CF 3 . 
     
   
   
       62 . The compound of  claim 47  having the structure: 
     
       
         
         
             
             
         
       
       wherein X 1  and X 2  are as defined in  claim 47 ; Z is an aryl, heteroaryl or heterocyclic moiety; W 1  is O or NR W1 , where R W1  is hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl; Alk 1  is a substituted or unsubstituted C 1-6 alkylene or C 2-6 alkenylene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO 2 —, —C(═O)C(═O)—, —C(═O)NR L1A —, —OC(═O)—, —OC(═O)NR L1A —, —NR L1A NR L1B —, —NR L1A NR L1B C(═O)—, —NR L1A C(═)—, —NR L1A CO 2 —, —NR L1A C(═O)NR L1B —, —S(═O)—, —SO 2 —, —NR L1A SO 2 —, —SO 2 NR L1A —, —NR L1A SO 2 NR L1A —, —O—, —S—, or —NR L1A —; wherein each occurrence of R L1A  and R L1B  is independently hydrogen, lower alkyl, lower heteroalkyl, heterocyclyl, aryl, heteroaryl or acyl. 
     
   
   
       63 . The compound of  claim 62  having the structure: 
     
       
         
         
             
             
         
       
       wherein m is an integer from 0 to 3; and each occurrence of R Z1  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —NR Z2 R Z3 , —SO 2 NR Z2 R Z3 , —SO 2 R Z1 , —C(═O)NR Z2 R Z3 , halogen, —CN, —NO 2 , —C(═O)OR Z3 , —N(R Z2 )C(═O)R Z3 , wherein each occurrence of R Z2  and R Z3  is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2  and R Z3  taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring. 
     
   
   
       64 . The compound of  claim 63  having the structure: 
     
       
         
         
             
             
         
       
       wherein R Z1  is halogen, lower alkyl or lower haloalkyl. 
     
     
       
         
         
             
             
         
       
     
   
   
       65 . The compound of  claim 63  having the structure:
 wherein R X1  is hydrogen, lower alkyl or heterocyclyl; and R Z1  is halogen, lower alkyl or lower haloalkyl.   
   
   
       66 . The compound of  claim 64  wherein R Z1  is Cl, F, methyl or —CF 3 . 
   
   
       67 . The compound of  claim 62  having the structure: 
     
       
         
         
             
             
         
       
       wherein m is an integer from 0 to 3; and each occurrence of R Z1  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR Z2 , —SR Z2 , —NR Z2 R Z3 , —SO 2 NR Z2 R Z3 , —SO 2 R Z1 , —C(═O)NR Z2 R Z3 , halogen, —CN, —NO 2 , —C(═O)OR Z3 , —N(R Z2 )C(═O)R Z3 , wherein each occurrence of R Z2  and R Z3  is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl or acyl, or R Z2  and R Z3  taken together with the nitrogen or carbon atom to which they are attached form a 5-6 membered heterocyclic, aryl or heteroaryl ring. 
     
   
   
       68 . The compound of  claim 67  having the structure: 
     
       
         
         
             
             
         
       
       wherein R Z1  is halogen, lower alkyl or lower haloalkyl. 
     
   
   
       69 . The compound of  claim 67  having the structure: 
     
       
         
         
             
             
         
       
       wherein R X1  is hydrogen, lower alkyl or heterocyclyl; and R Z1  is halogen, lower alkyl or lower haloalkyl. 
     
   
   
       70 . The compound of  claim 68  wherein R Z1  is Cl, F, methyl or —CF 3 . 
   
   
       71 . The compound of  claim 51  wherein —W 1 -Alk 1 - is —NH—C 1-6 alkyl- or —O—C 1-6  alkyl-; wherein the C 1-6 alkyl moiety may be substituted or unsubstituted. 
   
   
       72 . The compound of  claim 71  wherein —W 1 -Alk 1 - is —NHCH 2 CH 2 —, —OCH 2 CH 2 — or —NH—CH 2 CH(CH 2 OH)—, or represents one of the structures: 
     
       
         
         
             
             
         
       
     
   
   
       73 . A composition comprising an effective amount of compound of  claim 47 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
   
   
       74 . The composition of  claim 73 , wherein the compound is in an amount to detectably inhibit Aurora protein kinase activity. 
   
   
       75 . The composition of  claim 73 , additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders. 
   
   
       76 . A method of inhibiting Aurora kinase activity in:
 (a) a subject; or   (b) a biological sample;   
     which method comprises administering to said patient, or contacting said biological sample with a compound of  claim 47 . 
   
   
       77 . The method of  claim 76 , wherein the method comprises inhibiting Aurora kinase activity. 
   
   
       78 . A method of treating or lessening the severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically mediated disorder, a viral disease, or a bone disorder, comprising the step of administering to said patient a compound of  claim 47 . 
   
   
       79 . The method according to  claim 78 , comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:
 said additional therapeutic agent is appropriate for the disease being treated; and   said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.