Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as raf kinase inhibitors

Abstract

The present invention provides compounds having the formula: wherein A-B together represent one of the following structures: and n, R 1 , R 2 , R 3 , R 4 , 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., RAF), and thus are useful, for example, for the treatment of RAF mediated diseases.

1 - 57 . (canceled) 
     
     
         58 . A method of inhibiting RAF kinase activity in:
 (a) a patient; or   (b) a biological sample;   which method comprises administering to said patient, or contacting said biological sample with,   a compound of formula (I):   
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof; 
         wherein A-B together represent: 
       
       
         
           
           
               
               
           
         
           represents a single or double bond as valency permits; 
         n is an integer from 0-4; 
         R 1  and R 2  are independently hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; 
         R 3  is hydrogen or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; 
         L 1  is —O—, —S—, —NR L1A — or 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(═O)—, —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 L1B , —O—, —S—, or —NR L1A —; wherein each occurrence of R L1A  and R L1B  is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; 
         L 2  is a single bond, —O—, —S—, —NR L2A —, a heteroalicyclic or heteroaromatic moiety, or 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(═O)—, —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 L1B —, —O—, —S—, or —NR L1A —; wherein each occurrence of R L1A  and R L1B  is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; 
         Y is a cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl moiety; and 
         Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; 
         or a composition comprising said compound and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
       
     
     
         59 . The method of  claim 58 , wherein the method comprises inhibiting RAF kinase activity. 
     
     
         60 . 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 formula I:   
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof; 
         wherein A-B together represent: 
       
       
         
           
           
               
               
           
         
            represents a single or double bond as valency permits; 
         n is an integer from 0-4; 
         R 1  and R 2  are independently hydrogen, halogen, cyano, nitro, or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; 
         R 3  is hydrogen or an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; 
         L 1  is —O—, —S—, —NR L1A — or 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(═O)—, —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 L1B —, —O—, —S—, or —NR L1A —; wherein each occurrence of R L1A  and R L1B  is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; 
         L 2  is a single bond, —O—, —S—, —NR L2A —, a heteroalicyclic or heteroaromatic moiety, or 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(═O)—, —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 L1B —, —O—, —S—, or —NR L1A —; wherein each occurrence of R L1A  and R L1B  is independently hydrogen, alkyl, heteroalkyl, heterocyclyl, aromatic, heteroaromatic or acyl; 
         Y is a cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl moiety; and 
         Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; 
         or a composition comprising said compound and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 
       
     
     
         61 . The method according to  claim 60 , 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.   
     
     
         62 . A method of synthesizing a compound of formula: 
       
         
           
           
               
               
           
         
       
       wherein:
    represents a single or double bond; and 
 Z is an aliphatic, heteroaliphatic, alicyclic, heteroalicyclic, aromatic or heteroaromatic moiety; 
 the method comprising: 
 (a) providing a carboxylic acid of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
    represents a single or double bond; 
 and reacting the compound with an amine of formula: 
 
       
         
           
           
               
               
           
         
         to form an amide of formula: 
       
       
         
           
           
               
               
           
         
         (b) reacting the amide formed in step (a) with a suitable base to form an intermediate of formula: 
       
       
         
           
           
               
               
           
         
       
       and
 (c) reacting the intermediate formed in step (b) with H 2 N—Z to form the compound of formula: 
 
       
         
           
           
               
               
           
         
       
     
     
         63 . The method of  claim 62 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         64 . The method of  claim 62 , wherein the compound of formula: 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         65 . The method of  claim 62 , wherein the suitable base is lithium hydroxide. 
     
     
         66 . A method of synthesizing a compound of formula: 
       
         
           
           
               
               
           
         
       
       wherein:
    represents a single or double bond; 
 m is an integer from 0 to 3; 
 each 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 Z4 , —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 alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, or -(alkyl)heteroaryl; 
 the method comprising steps of: 
 (a) providing a carboxylic acid of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
    represents a single or double bond; 
 and reacting the compound with an amine of formula: 
 
       
         
           
           
               
               
           
         
         to form an amide of formula: 
       
       
         
           
           
               
               
           
         
         (b) reacting the amide formed in step (a) with a suitable base to form an intermediate of formula: 
       
       
         
           
           
               
               
           
         
         (c) reacting the intermediate formed in step (b) with a diaminobenzene of formula: 
       
       
         
           
           
               
               
           
         
         to form diamide of formula: 
       
       
         
           
           
               
               
           
         
       
       and
 (d) treating the diamide formed in step (c) with a suitable acid. 
 
     
     
         67 . The method of  claim 66 , wherein the compound is of formula: 
       
         
           
           
               
               
           
         
       
     
     
         68 . The method of  claim 66 , wherein the suitable base is lithium hydroxide. 
     
     
         69 . The method of  claim 66 , wherein the suitable acid is acetic acid.