Inhibitors of cyclin-dependent kinase 7 (CDK7)
The present invention provides novel compounds of Formula (I) and Formula (II) 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.
1. A compound having the structural formula I:
or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein:
ring A is selected from
each X is N;
W is C(R 1a ), wherein R 1a is selected from —Cl, —CN, —CF 3 , —CH 3 , and —CH 2 CH 3 ;
R 1b is hydrogen;
R 2 is —NH—;
Q is selected from 3-hydroxycyclohex-1,3-diyl, cyclohex-1,3-diyl, and 3-methylcyclohex-1,3-diyl;
R 3 is selected from †—NH—C(O)—, †—NH—CH 2 —, and †—N(CH 3 )—CH 2 —, wherein “†” represents a portion of R 3 bound to Q;
Z is
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, optionally substituted aryl, and optionally substituted heteroaryl;
m is 0, 1, 2, 3 or 4; and
R 4 is selected from —NH—C(O)—CH═CH—CH 2 —N(CH 3 ) 2 , —NH—C(O)—CH═CH 2 , —NH—C(O)—CF═CH 2 , and —N(CH 3 )—C(O)—CH═CHCH 2 —N(CH 3 ) 2 .
2. The compound of claim 1 , having structural formula Ic:
or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein:
ring A″ is selected from
R 8 is hydrogen;
each of R 7 and R 10 is independently selected from hydrogen and methyl;
R 21a is selected from —Cl, —CN, —CF 3 , —CH 3 , and —CH 2 CH 3 ;
each R 12 if present is independently halogen; and
o is 0, 1, 2, or 3.
3. The compound of claim 2 , having the formula Ic′:
wherein R 7 , R 8 , R 10 , R 21a , R 12 and o are as defined in claim 2 .
4. The compound of any one of claim 2 or 3 , wherein each R 12 , if present, is fluoro.
5. The compound of any one of claim 2 or 3 , wherein o is 0.
6. The compound of claim 1 , selected from any one of the following compounds:
7. The compound of claim 1 , wherein ring A is
8. The compound of claim 1 , wherein W is C(R 1a ) and R 1a is —Cl, —CF 3 , or —CH 2 CH 3 .
9. The compound of claim 1 , wherein Q is cyclohex-1,3-diyl or 3-methylcyclohex-1,3-diyl.
10. The compound of claim 1 , wherein
ring A is
W is C(R 1a ) and R 1a is —Cl, —CF 3 , or —CH 2 CH 3 ; and
Q is cyclohex-1,3-diyl or 3-methylcyclohex-1,3-diyl.
11. The compound of claim 1 , wherein the compound is
12. The compound of claim 1 , wherein the compound is
13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
14. The pharmaceutical composition of claim 13 , wherein the compound has structural formula Ic:
or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein:
ring A″ is selected from
R 8 is hydrogen;
each of R 7 and R 10 is independently selected from hydrogen and methyl;
R 21a is selected from —Cl, —CN, —CF 3 , —CH 3 , and —CH 2 CH 3 ;
each R 12 if present is independently halogen; and
o is 0, 1, 2, or 3.
15. The pharmaceutical composition of claim 13 , wherein the compound has the formula Ic′:
wherein
ring A″ is selected from
R 8 is hydrogen;
each of R 7 and R 10 is independently selected from hydrogen and methyl;
R 21a is selected from —Cl, —CN, —CF 3 , —CH 3 , and —CH 2 CH 3 ;
each R 12 if present is independently halogen; and
o is 0, 1, 2, or 3.
16. The pharmaceutical composition of claim 13 , wherein, in the compound,
ring A is
W is C(R 1a ) and R 1a is —Cl, —CF 3 , or —CH 2 CH 3 ; and
Q is cyclohex-1,3-diyl or 3-methylcyclohex-1,3-diyl.
17. The pharmaceutical composition of claim 13 , wherein the compound is selected from any one of the following compounds:
18. The pharmaceutical composition of claim 17 , wherein the compound is
19. The pharmaceutical composition of claim 17 , wherein the compound is