Covalent inhibitors of CDK-7

1. A compound of Formula (I), or an N-oxide thereof, or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, or an isotopic form thereof:

wherein

A is cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, fused hetero-bicyclic, or spiro-heterocyclic;

each of B, and C, independently, is cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl;

each of Z 1 , Z 2 , Z 3 , and Z 4 independently, is a bond, (CR a R b ) p , (CR a R b ) p N(R a )(CR a R b ) q , N(R a )(CR a R b ) q N(R a ), (CR a R b ) p O(CR a R b ) q , (CR a R b ) p C═C(CR a R b ) q , (CR a R b ) p C≡C(CR a R b ) q , C(R a )═N, O, S, C(O), N(R a ), S(O 2 ), OC(O), C(O)O, OSO 2 , S(O 2 )O, C(O)S, SC(O), C(O)C(O), C(O)N(R a ), N(R a )C(O), S(O 2 )N(R a ), N(R a )S(O 2 ), OC(O)O, OC(O)S, OC(O)N(R a ), OC(O)N(R a )(CR a R b ) p+1 N(R a )(CR a R b ) q , N(R a )C(O)O, N(R a )C(O)S, N(R a )C(O)N(R b ), (CR a R b ) p N(R a )C(O)(CR a R b ) q , or (CR a R b ) p C(O)N(R a )(CR a R b ) q ;

each of m, n, p, and q independently, is 0, 1, 2, 3, or 4;

Warhead is

L 1 is N(R 7 ) if the atom which L 1 connects to ring A is a carbon atom; or L 1 is a direct bond if ring A is a heterocycloalkyl, heterocycloalkenyl, or heteroaryl and the atom which L 1 connects to ring A is a nitrogen atom;

L 2 is (CR a R b ) s CH═HC(CR a R b ) r in which each of r, and s independently, is 1, 2, 3, or 4;

each of W 1 , and W 2 independently, is C(R 4 ) or N;

each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, —OR a , —SR a , —NR b R c , —C(O)R a , —S(O)R a , —SO 2 R a , —P(O)R b R c , —C(O)N(R b )R c , —N(R b )C(O)R c , —C(O)OR a , —OC(O)R a , —SO 2 N(R b )R c , —N(R b )SO 2 R c , -alkyl-R a , -alkyl-C(O)R a , -alkyl-NR b R c , -alkyl-C(O)N(R b )R c , -alkyl-N(R b )C(O), or -alkyl-N(R b )SO 2 R c ; and

each of R a , R b , R a , R b , and R c , independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, cyano, amine, nitro, hydroxy, —C(O)NHOH, alkoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylcarbonylamino, dialkylamino, or alkylamino.

2. The compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, or an isotopic form thereof, wherein the compound is represented by Formula (II)

in which each of Z 1 , Z 2 , Z 3 , and Z 4 independently, is a bond, (CH 2 ) p , (CH 2 ) p NR a (CH 2 ) q , NR a (CH 2 ) q NR a , (CH 2 ) p O(CH 2 ) q , CH═N, O, S, C(O), NH, S(O 2 ), OC(O), C(O)O, OSO 2 , S(O 2 )O, C(O)S, SC(O), C(O)C(O), C(O)NH, NHC(O), S(O 2 )NH, NHS(O 2 ), OC(O)O, OC(O)S, OC(O)NH, OC(O)NH(CH 2 ) p+1 NH(CH 2 ) q , NHC(O)O, NHC(O)S, NHC(O)NH, (CH 2 ) p NHC(O)(CH 2 ) q , or (CH 2 ) p C(O)NH(CH 2 ) q ; R 1 is H, alkyl, or alkyl-NR b R c ; and each of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, halo, nitro, oxo, cyano, —OR a , —SR a , —NR b R c , —C(O)R a , —SO 2 R a , —C(O)NHR c , —NHC(O)R c , —SO 2 NHR c , —NHSO 2 R c , -alkyl-R a , -alkyl-C(O)R a , -alkyl-NHR c , -alkyl-C(O)NHR c , -alkyl-NHC(O), or -alkyl-NHSO 2 R c .

3. The compound according to claim 2 or an N-oxide thereof, or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, or an isotopic form thereof, wherein the compound is represented by Formula (III)

in which t is 0, 1, 2, 3 or 4; R 1 is H, low alkyl, or low alkyl-NR b R c ; each of R 3 , R 4 , and R 5 , independently, is H, alkyl, alkenyl, alkynyl, halo, or haloalkyl; and M is (CH 2 ) p , O, or N(R a ).

4. The compound according to claim 3 or an N-oxide thereof, or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, or an isotopic form thereof, wherein the compound is represented by Formula (IV)

5. The compound according to claim 4 or an N-oxide thereof, or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, or an isotopic form thereof, wherein R 1 is H, —CH 3 , or CH 2 —N(CH 3 )CH 3 ; R 4 is H, CH 3 , CF 3 , CN, or halo.

6. The compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, or an isotopic form thereof, wherein the compound is

7. The compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, or an isotopic form thereof, wherein the compound is

8. The compound according to claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, or an isotopic form thereof, wherein the compound is

9. A pharmaceutical composition comprising a compound of Formula (I) or an N-oxide thereof as defined in claim 1 , or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, or an isotopic form thereof, and a pharmaceutically acceptable diluent or carrier.

10. A compound or an N-oxide thereof, or a pharmaceutically acceptable salt, polymorph, tautomer, stereoisomer, or an isotopic form thereof, wherein the compound is

11. A compound, wherein the compound is

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of claim 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

13. The compound according to claim 2 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (III)

in which t is 0, 1, 2, 3 or 4; R 1 is H, low alkyl, or low alkyl-NR b R c ; each of R 3 , R 4 , and R 5 , independently, is H, alkyl, alkenyl, alkynyl, halo, or haloalkyl; and M is 0 or N(R a ).

14. The compound according to claim 3 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IV)

15. The compound according to claim 4 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is H, —CH 3 , or CH 2 —N(CH 3 )CH 3 ; R 4 is H, CH 3 , CF 3 , CN, or halo.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is