Inhibitors of cyclin-dependent kinase 7 (cdk7)

Abstract

The present invention provides novel compounds described herein, such as of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.

What is claimed is: 
     
         1 . A compound having the structural formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
 G is selected from: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein a hydrogen on G is replaced by a bond to R 2 , and:
 each R 1  is independently selected from hydrogen, halogen, optionally substituted C 1 -C 6  alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —OR a , —NR b R c , —C(O)R a , —C(O)NR b R c , —S(O) x R a , and —S(O) x NR b R c ; 
 R A6  is hydrogen, halogen, heterocyclyl, C 1 -C 6  alkyl, carbocyclyl, —OR a , —NR b R c , —C(O)R a , —C(O)NR b R c , —S(O) x R a , or —S(O) x NR b R c ; 
 R A7  is hydrogen, halogen, heterocyclyl, C 1 -C 6  alkyl, carbocyclyl, —OR a , —NR b R c , —C(O)R a , —C(O)NR b R c , —S(O) x R a , or —S(O) x NR b R c ; 
 each R a  is independently selected from hydrogen, C 1 -C 6  alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; 
 each R b  and R c  is independently selected from hydrogen and —C 1 -C 6  alkyl, or 
 R b  and R c  taken together with the atom to which they are attached form a 3-7-membered ring; 
 Y is N or CH; 
 K is bond, aryl, heteroaryl, carbocyclyl, or heterocyclyl; 
 R B1  is hydrogen or —C(O)R a ; 
 J is —NH— or —O—; 
 T is a 5-membered aryl or heteroaryl; 
 p is 0, 1, 2, 3, 4, or 5; 
 x is 0, 1, or 2; 
 R 2  is a bond, an optionally substituted C 1 -C 4  alkylene or an optionally substituted C 2 -C 4  alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, —C(O)—, or —N(R 6 )—, wherein R 6  is hydrogen or a C 1 -C 6  alkyl chain; 
 Q is selected from a bond, an optionally substituted divalent carbocyclyl, an optionally substituted divalent heterocyclyl, an optionally substituted divalent aryl, and an optionally substituted divalent heteroaryl; 
 R 3  is selected from a bond, an optionally substituted C 1 -C 4  alkylene, and an optionally substituted C 2 -C 4  alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene is optionally and independently replaced with —O—, —S—, —N(R 6 )—, —NHC(O)—, —C(O)NH—, —C(O)—, or —S(═O) 2 —; 
 each R 6  is independently selected from hydrogen, and optionally substituted —C 1 -C 6  alkyl; 
 Z is selected from a bond; a monocyclic or bicyclic aryl, carbocyclyl, heterocyclyl and heteroaryl, wherein when Z is other than a bond, Z is optionally substituted; 
 R 4  is any one of the Formulae (ii-0)-(ii-19): 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           wherein:
 L 3  is a bond, an optionally substituted C 1 -C 7  alkylene, or an optionally substituted C 2 -C 7  alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, —S(O)—, —S(O) 2 , —N— or —N(R 6 )—; 
 L 4  is a bond, an optionally substituted C 1 -C 4  alkylene, or an optionally substituted C 2 -C 4  alkenylene or alkynylene; 
 each of R E1 , R E2  and R E3  is independently selected from hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR 9 , —CH 2 N(R 9 ) 2 , —CH 2 SR 9 , —CN, —OR 9 , —N(R 9 ) 2 , and —SR 9 , wherein each occurrence of R 9  is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or 
 R E1  and R E3 , or R E2  and R E3 , or R E1  and R E2  are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring; 
 R E4  is a leaving group; 
 Y is O, S, or N(R 6 ); and 
 z is 0, 1, 2, 3, 4, 5, or 6; 
 
           when Q is phenyl, Z is other than a bond; and 
           except in the case wherein R 4  is (ii-0), no more than one of Q, R 3 , and Z is a bond. 
         
       
     
     
         2 . The compound of  claim 1 , having the structural formula (IIb): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of formula (IIb) of  claim 2 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , having the structural formula (IIg): 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of formula (IIg) of  claim 4 , wherein the compound has the structural formula (IIh): 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of formula (IIh)  claim 5 , having the structural formula (IIi): 
       
         
           
           
               
               
           
         
         wherein A is optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; R B  is C 1 -C 6  alkyl or halogen; and q is 0, 1, 2, or 3. 
       
     
     
         7 . The compound of formula (IIi) of  claim 6 , having the structural formula (IIj): 
       
         
           
           
               
               
           
         
         wherein R 2B  is a bond or optionally substituted —CH 2 ; and B is optionally substituted divalent aryl, optionally substituted divalent heteroaryl, or optionally substituted divalent heterocyclyl. 
       
     
     
         8 . The compound of formula (IIj) of  claim 7 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of formula (IIj)  claim 7 , having the structural formula (IIk): 
       
         
           
           
               
               
           
         
         wherein A is optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl; C is optionally substituted monocyclic aryl, optionally substituted monocyclic heteroaryl, or optionally substituted monocyclic heterocyclyl; R B  is C 1 -C 6  alkyl or halogen; R 3B  is a bond, optionally substituted —NHC(O)—, optionally substituted —CH 2 —, optionally substituted —NH—, optionally substituted —NHCH 2 —, or optionally substituted —CH 2 NH—; each of R E1B  and R E2B  is independently selected from hydrogen or —CH 2 N(CH 3 ) 2 ; and q is 0, 1, 2, or 3. 
       
     
     
         10 . The compound of formula (IIk)  claim 9 , having the structural formula (IIm): 
       
         
           
           
               
               
           
         
         wherein C is optionally substituted monocyclic aryl, optionally substituted monocyclic heteroaryl, or optionally substituted monocyclic heterocyclyl; R 3B  is a bond, optionally substituted —NHC(O)—, optionally substituted —CH 2 —, optionally substituted —NH—, optionally substituted —NHCH 2 —, or optionally substituted —CH 2 NH—; and each of R E1B  and R E2B  is independently selected from hydrogen or —CH 2 N(CH 3 ) 2 . 
       
     
     
         11 . The compound of formula (IIm) of  claim 10 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , having the structural formula (IIIa): 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of formula (IIIa)  claim 12 , having the structural formula (IIIb): 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of formula (IIIb)  claim 13 , having the structural formula (IIIc): 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound of formula (IIIc) of  claim 14 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of formula (IIIc)  claim 14 , having the structural formula (IIId): 
       
         
           
           
               
               
           
         
         wherein R 3C  is a bond, optionally substituted —CH 2 —, optionally substituted —NH—, —C(O), —N(CH 3 )—, or optionally substituted —CH(CH 3 )—; and D is optionally substituted monocyclic or bicyclic aryl or heteroaryl. 
       
     
     
         17 . The compound of formula (IIId)  claim 16 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of formula (IId)  claim 16 , having the structural formula (IIIe): 
       
         
           
           
               
               
           
         
         wherein each of R E1C  and R E2C  is independently selected from hydrogen or —CH 2 N(CH 3 ) 2 . 
       
     
     
         19 . The compound of formula (IIIe)  claim 18 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of any one of  claims 1 ,  2 ,  4 - 7 ,  9 ,  10 ,  12 - 14 ,  16 , and  18 , wherein R 2  is selected from a bond, †—NH—, †—C(O), †—CH 2 —, and †-NHC(O)—, wherein “†” represents a portion of R 2  bound to G. 
     
     
         21 . The compound of any one of  claims 1 ,  2 ,  4 - 7 ,  9 ,  10 ,  12 - 14 ,  16 ,  18 , and  20  wherein Q is selected from a bond, divalent 1,3,4-oxadiazole; divalent 1-oxa-3-azaspiro[4.5]dec-2-ene; divalent cyclohexyl; divalent 4-thia-1,2-diazaspiro[4.5]dec-2-ene; divalent oxazole; divalent phenyl; divalent piperidine and divalent pyrrolidine, wherein Q is optionally substituted with up to three independently selected substituents. 
     
     
         22 . The compound of  claim 16 , wherein Q is selected from 1,3,4-oxadiazol-2,5-diyl; 1-oxa-3-azaspiro[4.5]dec-2-en-7,2-diyl; 4-fluorocyclohex-1,4-diyl; 4-hydroxycyclohex-1,4-diyl; 4-thia-1,2-diazaspiro[4.5]dec-2-en-7,3-diyl; cyclohex-1,3-diyl; cyclohex-1,4-diyl; oxazol-2,5-diyl; benzene-1,2-diyl; benzene-1,3-diyl; piperidin-1,3-diyl; piperidin-1,3-diyl; piperidin-4,1-diyl; piperidin-1,4-diyl; and pyrrolidin-3,1-diyl. 
     
     
         23 . The compound of any one of  claims 1 ,  2 ,  4 - 7 ,  9 ,  10 ,  12 - 14 ,  16 ,  18 , and  20 - 22  wherein R 3  is selected from a bond, †—C(O)—(CH 2 ) 3 —, †—CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 —, †—C(O)—, †—NH—C(O)—, †—C(O)—NH—, †t-NH—C(O)—CF 2 —CH 2 —, †—CH 2 —, †—NH—, †—NH—CH 2 —, †—CH 2 —NH—, †—NH—C(O)—CH(CF 3 )—, †—N(CH 3 )—CH 2 —, †—NH—C(O)—CH 2 —CH 2 —, †-CH(CH 3 )—, †—N(CH 3 )— and †—NH—CH 2 —CH(CF 3 )—, wherein “†” represents a portion of R 3  bound to Q. 
     
     
         24 . The compound of any one of  claims 1 ,  2 ,  4 - 7 ,  9 ,  10 ,  12 - 14 ,  16 ,  18 ,  20 - 23 , wherein Z is selected from a bond, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 “1” represents a portion of Z bound to R 3 ; 
 “2” represents a portion of Z bound to R 4 ; 
 each instance of R 5 , if present, is independently selected from deuterium, 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, —OR D1 , —N(R D1 ) 2 , and —SR D1  wherein each occurrence of R D1  is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, and optionally substituted aryl, optionally substituted heteroaryl; 
 and m is 0, 1, 2, 3 or 4. 
 
       
     
     
         25 . The compound of  claim 24 , wherein Z is selected from a bond, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claims 24  and  25 , wherein Z is selected from a bond, cyclohex-1,4-diyl, piperidin-3,1-diyl, piperidin-4,1-diyl, piperidin-1,2-diyl, piperidin-2,1-diyl, pyridin-2,5-diyl, pyridin-2,4-diyl, bicyclo[1.1.1]pent-1,3-diyl, pyrimidin-2,5-diyl, pyrazol-1,4-diyl, pyrrolidin-2,1-diyl, 4,4-difluoropyrrolidin-2,1-diyl, isoindolin-2,5-diyl, 6-azaspiro[2.5]octan-6,1-diyl, 2,8-diazaspiro[4.5]decan-2,8-diyl, pyrrolidin-3,1-diyl, 5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazol-3,6-diyl, 1,1-dioxobenzo[d]isothiazol-3,6-diyl, piperazin-1,4-diyl, pyrrolidin-1,3-diyl, piperidin-1,4-diyl, pyrrolidin-2,4-diyl, 2,2-difluorocyclopent-1,1-diyl, 3-fluoroazetidin-3,1-diyl, 3,3-difluoropiperidin-4,1-diyl, benzene-1,2-diyl, benzene-1,3-diyl, benzene-1,4-diyl, and 4-hydroxypyrrolidin-3,1-diyl. 
     
     
         27 . The compound of any one of  claims 1 - 26 , wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of  claim 27 , wherein L 3  is selected from a bond, —NH—, —CH 2 —NH—**, —S(O) 2 —NH—**, and —NH—S(O) 2 —NH—**, wherein “**” represents a portion of L 3  bound to —C(═Y)—. 
     
     
         29 . The compound of  claims 27  and  28 , wherein R 4  is selected from: —CH 2 —NH—C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —NH—C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —NH—C(O)—CH═CH 2 , —C(O)—CH═CH 2 , —S(O) 2 —NH—C(O)—CH═CH 2 , and —NH—S(O) 2 —NH—C(O)—CH═CH 2 —NH—C(O)—CH═CH 2 . 
     
     
         30 . The compound of any one of  claims 1 - 26 , wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         31 . The compound of  claim 30 , wherein R 4  is —CH═CH 2 . 
     
     
         32 . The compound of any one of  claims 1 - 26 , wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         33 . The compound of  claim 32 , wherein R 4  is —N(C(O)—CH═CH 2 ) 2 . 
     
     
         34 . The compound of any one of  claims 1 - 33 , wherein the compound is selected from any one of the compounds depicted in  FIGS. 1A-1C . 
     
     
         35 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 34  and a pharmaceutically acceptable excipient. 
     
     
         36 . The composition of  claim 35  for use in treating a subject suffering from a disease or condition associated with aberrant activity of a CDK. 
     
     
         37 . The composition of  claim 36 , wherein the subject is suffering from a disease or condition associated with aberrant activity of CDK7. 
     
     
         38 . The composition of  claims 36  or  37 , wherein the disease or condition is selected from cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, autoimmune disease, or an infectious disease. 
     
     
         39 . The composition of any one of  claims 36 - 38 , wherein the subject is a mammal. 
     
     
         40 . The composition of any one of  claims 36 - 39 , wherein the disease is cancer. 
     
     
         41 . The composition of  claim 40 , wherein the cancer is selected from a blood cancer, melanoma, a bone cancer, a breast cancer, a brain cancer, or a lung cancer. 
     
     
         42 . The composition of  claim 41 , wherein the cancer is a blood cancer selected from chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CMIL), acute myelogenous leukemia (ANIL), lymphoma, and multiple myeloma. 
     
     
         43 . The composition of  claim 41 , wherein the disease is a bone cancer selected from osteosarcoma and Ewing's sarcoma. 
     
     
         44 . The composition of  claim 41 , wherein the disease is triple-negative breast cancer (TNBC). 
     
     
         45 . The composition of  claim 41 , wherein the disease is neuroblastoma. 
     
     
         46 . The composition of  claim 41 , wherein the disease is small cell lung cancer (SCLC). 
     
     
         47 . The composition of any one of  claims 36 - 46 , comprising the additional step of administering to the subject in need thereof one or more additional agents independently selected from anti-proliferative agents, anti-cancer agents, immunosuppressant agents, and pain-relieving agents.