Bone marrow on x chromosome kinase (bmx) inhibitors and uses thereof

Abstract

The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the compounds of Formula (I) or (II), or compositions thereof, for treating or preventing a wide range of diseases (e.g., proliferative diseases (e.g., cancers, benign neoplasms, angiogenesis, inflammatory diseases, autoimmune diseases) and metabolic diseases (e.g., diabetes (e.g., type 2 diabetes, gestational diabetes)) in a subject. Treatment of a subject with a disease using a compound of Formula (I) or (II), or compositions thereof, may downregulate the expression and/or inhibit the activity of a kinase (e.g., a tyrosine kinase, such as a Tec kinase, in particular, bone marrow on X chromosome kinase (BMX)), and therefore, suppress tyrosine kinase singling in the subject.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; 
       wherein:
 each instance of R A  is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A1 , —N(R A1 ) 2 , —SR A1 , —CN, —C(═O)R A1 , —C(═O)OR A1 , —C(═O)SR A1 , —C(═O)N(R A1 ) 2 , —C(═S)R A1 , —C(═S)OR A1 , —C(═S)SR A1 , C(═S)N(R A1 ) 2 , —C(═NR A1 )R A1 , —C(═NR A1 )OR A1 , —C(═NR A1 )SR A1 , —C(═NR A1 )N(R A1 ) 2 , —NO 2 , —N 3 , —N(R A1 ) 3   + X − , wherein X −  is a counterion, —N(OR A1 )R A1 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)SR A1 , —NR A1 C(═O)N(R A1 ) 2 , —NR A1 C(═S)R A1 , —NR A1 C(═S)OR A1 , —NR A1 C(═S)SR A1 , —NR A1 C(═S)N(R A1 ) 2 , —NR A1 C(═NR A1 )R A1 , —NR A1 C(═NR A1 )OR A1 , —NR A1 C(═NR A1 )SR A1 , —NR A1 C(═NR A1 )N(R A1 ) 2 , —NR A1 S(═O) 2 R A1 , —NR A1 S(═O) 2 OR A1 , —NR A1 S(═O) 2 SR A1 , —NR A1 S(═O) 2 N(R A1 ) 2 , —NR A1 S(═O)R A1 , —NR A1 S(═O)OR A1 , —NR A1 S(═O)SR A1 , NR A1 S(═O)N(R A1 ) 2 , —NR A1 P(═O), —NR A1 P(═O) 2 , —NR A1 P(═O)(R A1 ) 2 , —NR A1 P(═O)R A1 (OR A1 ), —NR A1 P(═O)(OR A1 ) 2 , —OC(═O)R A1 , —OC(═O)OR A1 , —OC(═O)SR A1 , —OC(═O)N(R A1 ) 2 , —OC(═NR A1 )R A1 , —OC(═NR A1 )OR A1 , —OC(═NR A1 )N(R A1 ) 2 , —OC(═S)R A1 , —OC(═S)OR A1 , —OC(═S)SR A1 , —OC(═S)N(R A1 ) 2 , —ON(R A1 ) 2 , —OS(═O)R A1 , —OS(═O)OR A1 , —OS(═O)SR A1 , —OS(═O)N(R A1 ) 2 , —OS(═O) 2 R A1 , —OS(═O) 2 OR A1 , —OS(═O) 2 SR A1 , —OS(═O) 2 N(R A1 ) 2 , —OP(═O) 2 , —OP(═O)(R A1 ) 2 , —OP(═O)R A1 (OR A1 ), —OP(═O)(OR A1 ) 2 , —OP(═O), —OP(R A1 ) 2 , —OPR A1 (OR A1 ), —OP(OR A1 ) 2 , —OSi(R A1 ) 3 , —OSi(R A1 ) 2 OR A1 , —OSi(R A1 )(OR A1 ) 2 , —OSi(OR A1 ) 3 , SSR A1 , —S(═O)R A1 , —S(═O)OR A1 , S(═O)N(R A1 ) 2 , S(═O) 2 R A1 , S(═O) 2 OR A1 , —S(═O) 2 N(R A1 ) 2 , —SC(═O)R A1 , —SC(═O)OR A1 , —SC(═O)SR A1 , —SC(═O)N(R A1 ) 2 , —SC(═S)R A1 , —SC(═S)OR A1 , —SC(═S)SR A1 , —SC(═S)N(R A1 ) 2 , —P(R A1 ) 2 , —PR A1 (OR A1 ), —P(OR A1 ) 2 , —P(═O), —P(═O)(R A1 ) 2 , —P(═O)(OR A1 ) 2 , —P(═O)R A1 (OR A1 ), —P(═O) 2 , —B(R A1 ) 2 , —B(OR A1 ) 2 , —BR A1 (OR A1 ), Si(R A1 ) 3 , —Si(R A1 ) 2 OR A1 , —SiR A1 (OR A1 ) 2 , and —Si(OR A1 ) 3 , provided that two R A  groups are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring; wherein each occurrence of R A1  is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R A1  groups are joined to form an optionally substituted heterocyclic ring; 
 k is 0, 1, 2, 3, 4, or 5; 
 M is a bond or an optionally substituted C 1-6  hydrocarbon chain; 
 Ring C is an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring; 
 each instance of R C  is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR C1 , —N(R C1 ) 2 , —SR C1 , —CN, —C(═O)R C1 , —C(═O)OR C1 , —C(═O)SR C1 , —C(═O)N(R C1 ) 2 , —C(═S)R C1 , —C(═S)OR C1 , —C(═S)SR C1 , —C(═S)N(R C1 ) 2 , —C(═NR C1 )R C1 , —C(═NR C1 )OR C1 , —C(═NR C1 )SR C1 , —C(═NR C1 )N(R C1 ) 2 , —NO 2 , —N 3 , —N(R C1 ) 3   + X − , wherein X −  is a counterion, —N(OR C1 )R C1 , —NR C1 C(═O)R C1 , —NR C1 C(═O)OR C1 , —NR C1 C(═O)SR C1 , —NR C1 C(═O)N(R C1 ) 2 , —NR C1 C(═S)R C1 , —NR C1 C(═S)OR C1 , —NR C1 C(═S)SR C1 , —NR C1 C(═S)N(R C1 ) 2 , —NR C1 C(═NR C1 )R C1 , —NR C1 C(═NR C1 )OR C1 , —NR C1 C(═NR C1 )SR C1 , —NR C1 C(═NR C1 )N(R C1 ) 2 , —NR C1 S(═O) 2 R C1 , —NR C1 S(═O) 2 OR C1 , —NR C1 S(═O) 2 SR C1 , —NR C1 S(═O) 2 N(R C1 ) 2 , —NR C1 S(═O)R C1 , —NR C1 S(═O)OR C1 , —NR C1 S(═O)SR C1 , —NR C1 S(═O)N(R C1 ) 2 , —NR C1 P(═O), —NR C1 P(═O) 2 , —NR C1 P(═O)(R C1 ) 2 , —NR C1 P(═O)R C1 (OR C1 ), —NR C1 P(═O)(OR C1 ) 2 , —OC(═O)R C1 , —OC(═O)OR C1 , —OC(═O)SR C1 , —OC(═O)N(R C1 ) 2 , —OC(═NR C1 )R C1 , —OC(═NR C1 )OR C1 , —OC(═NR C1 )N(R C1 ) 2 , —OC(═S)R C1 , —OC(═S)OR C1 , —OC(═S)SR C1 , —OC(═S)N(R C1 ) 2 , —ON(R C1 ) 2 , —OS(═O)R C1 , —OS(═O)OR C1 , —OS(═O)SR C1 , —OS(═O)N(R C1 ) 2 , —OS(═O) 2 R C1 , —OS(═O) 2 OR C1 , —OS(═O) 2 SR C1 , —OS(═O) 2 N(R C1 ) 2 , —OP(═O) 2 , —OP(═O)(R C1 ) 2 , —OP(═O)R C1 (OR C1 ), —OP(═O)(OR C1 ) 2 , —OP(═O), —OP(R C1 ) 2 , —OPR C1 (OR C1 ), —OP(OR C1 ) 2 , —OSi(R C1 ) 3 , —OSi(R C1 ) 2 OR C1 , —OSi(R C1 )(OR C1 ) 2 , —OSi(OR C1 ) 3 , —SSR C1 , —S(═O)R C1 , —S(═O)OR C1 , —S(═O)N(R C1 ) 2 , —S(═O) 2 R C1 , —S(═O) 2 OR C1 , —S(═O) 2 N(R C1 ) 2 , —SC(═O)R C1 , —SC(═O)OR C1 , —SC(═O)SR C1 , —SC(═O)N(R C1 ) 2 , —SC(═S)R C1 , —SC(═S)OR C1 , —SC(═S)SR C1 , —SC(═S)N(R C1 ) 2 , —P(R C1 ) 2 , —PR C1 (OR C1 ), —P(OR C1 ) 2 , —P(═O), —P(═O)(R C1 ) 2 , —P(═O)(OR C1 ) 2 , —P(═O)R C1 (OR C1 ), —P(═O) 2 , —B(R C1 ) 2 , —B(OR C1 ) 2 , —BR C1 (OR C1 ), —Si(R C1 ) 3 , —Si(R C1 ) 2 OR C1 , SiR C1 (OR C1 ) 2 , and —Si(OR C1 ) 3 , wherein each occurrence of R C1  is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R C1  groups are joined to form an optionally substituted heterocyclic ring or optionally substituted heteroaryl ring; 
 n is 0, 1, 2, 3, or 4; 
 L is a bond or an optionally substituted C 1-6  hydrocarbon chain; 
 R D  is any one of Formulae (i-1)-(i-17): 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R D1  is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —OR D1a , —N(R D1a ) 2 , —SR D1a , —CH 2 OR D1a , —CH 2 N(R D1a ) 2 , or —CH 2 SR D1a , —C(═O)R D1a , —C(═O)OR D1a , —C(═O)SR D1a , —C(═O)N(R D1a ) 2 , —C(═S)R D1a , —C(═S)OR D1a , —C(═S)SR D1a , —C(═S)N(R D1a ) 2 , —C(═NR D1a )R D1a , —C(═NR D1a )OR D1a , —C(═NR D1a )SR D1a , and —C(═NR D1a )N(R D1a ) 2 , wherein each occurrence of R D1a  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R D1a  groups are joined to form an optionally substituted heterocyclic ring; 
         R D2  is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —OR D2a , —N(R D2a ) 2 , —SR D2a , —CH 2 OR D2a , —CH 2 N(R D2a ) 2 , or —CH 2 SR D2a , C(═O)R D2a , C(═O)OR D2a , —C(═O)SR D2a , —C(═O)N(R D2a ) 2 , —C(═S)R D2a , —C(═S)OR D2a , —C(═S)SR D2a , —C(═S)N(R D2a ) 2 , —C(═NR D2a )R D2a , —C(═NR D2a )OR D2a , —C(═NR D2a )R D2a , —C(═NR D2a )OR D2a , —C(═NR D2a )SR D2a , and —C(═NR D2a )N(R D2a ) 2 , wherein each occurrence of R D2a  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R D2a  groups are joined to form an optionally substituted heterocyclic ring; 
         R D3  is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —OR D3a , —N(R D3a ) 2 , —SR D3a , —CH 2 OR D3a , —CH 2 N(R D3a ) 2 , or —CH 2 SR D3a , —C(═O)R D3a , —C(═O)OR D3a , —C(═O)SR D3a , —C(═O)N(R D3a ) 2 , —C(═S)R D3a , —C(═S)OR D3 a —C(═S)SR D3a , —C(═S)N(R D3a ) 2 , —C(═NR D3a )R D3a , —C(═NR D3a )OR D3a , —C(═NR D3a )SR D3a , and —C(═NR D3a )N(R D3a ) 2 , wherein each occurrence of R D3a  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R D3a  groups are joined to form an optionally substituted heterocyclic ring; 
         optionally R D1  and R D3 , or R D2  and R D3 , or R D1  and R D2  are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; 
         R D4  is a leaving group; 
         R D5  is hydrogen, C 1-6  alkyl, or a nitrogen protecting group; 
         Y is O, S, or NR D6 , wherein R D6  is hydrogen, C 1-6  alkyl, or a nitrogen protecting group; 
         a is 1 or 2; 
         z is 0, 1, 2, 3, 4, 5, or 6; and 
         optionally R D5  and one R C  are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring. 
       
     
     
         2 . The compound of  claim 1 , wherein R D  is of Formula (i-1): 
       
         
           
           
               
               
           
         
       
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein Ring C is an optionally substituted phenyl ring. 
     
     
         5 . The compound of  claim 1 , wherein L is a bond or —CH 2 —. 
     
     
         6 . (canceled) 
     
     
         7 . The compound of  claim 2 , wherein Y is O. 
     
     
         8 . The compound of  claim 1 , wherein the compound is of Formula (I-1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         9 . The compound of  claim 1 , wherein the compound is of Formula (I-2): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The compound of  claim 1 , wherein M is a bond or an optionally substituted C 2  hydrocarbon chain. 
     
     
         11 . (canceled) 
     
     
         12 . The compound of  claim 10 , wherein M is trans-CH═CH—. 
     
     
         13 . The compound of  claim 1 , wherein the compound is of Formula (I-3): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound of  claim 1 , wherein the compound is of Formula (I-4): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The compound of  claim 1 , wherein the compound is of Formula (I-5): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The compound of  claim 1 , wherein the compound is of Formula (I-6): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 - 28 . (canceled) 
     
     
         29 . The compound of  claim 1 , wherein:
 R C  is C 1-6  alkyl; and   n is 1.   
     
     
         30 - 35 . (canceled) 
     
     
         36 . The compound of  claim 1 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. 
     
     
         37 . (canceled) 
     
     
         38 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. 
     
     
         39 - 40 . (canceled) 
     
     
         41 . A kit comprising:
 a container comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof; and   instructions for administering the compound, or the pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.   
     
     
         42 . A method for treating a disease characterized by overexpression of bone marrow kinase on X chromosome (BMX), the method comprising:
 administering to a subject in need thereof a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, in an amount effective to treat the disease.   
     
     
         43 . A method for treating a disease associated with aberrant activity of bone marrow kinase on X chromosome (BMX), the method comprising:
 administering to a subject in need thereof a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, in an amount effective to treat the disease.   
     
     
         44 - 50 . (canceled) 
     
     
         51 . A method for treating a disease associated with insulin resistance, the method comprising:
 administering to a subject in need thereof a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, in an amount effective to treat the disease.   
     
     
         52 - 55 . (canceled) 
     
     
         56 . A method of suppressing kinase signaling in a biological sample or subject, the method comprising:
 administering to the biological sample or subject a compound of  claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, in an amount effective to suppress the kinase signaling.   
     
     
         57 - 81 . (canceled)