Covalent inhibitors of CDK-7

A method of treating a neoplastic disease, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), or an N-oxide thereof, 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 Z1, Z2, Z3, and Z4 independently, is a bond, (CRaRb)p, (CRaRb)pN(Ra)(CRaRb)q, N(Ra)(CRaRb)qN(Ra), (CRaRb)pO(CRaRb)q, (CRaRb)pC═C(CRaRb)q, (CRaRb)pC≡C(CRaRb)q, C(Ra)═N, O, S, C(O), N(Ra), S(O2), OC(O), C(O)O, OSO2, S(O2)O, C(O)S, SC(O), C(O)C(O), C(O)N(Ra), N(Ra)C(O), S(O2)N(Ra), N(Ra)S(O2), OC(O)O, OC(O)S, OC(O)N(Ra), OC(O)N(Ra)(CRaRb)p+1N(Ra)(CRaRb)q, N(Ra)C(O)O, N(Ra)C(O)S, N(Ra)C(O)N(Rb), (CRaRb)pN(Ra)C(O)(CRaRb)q, or (CRaRb)pC(O)N(Ra)(CRaRb)q;
• each of m, n, p, and q independently, is 0, 1, 2, 3, or 4;
• Warhead is
• L1 is N(R7) if the atom which L1 connects to ring A is a carbon atom;
• or L1 is a direct bond if ring A is a heterocycloalkyl, heterocycloalkenyl, or heteroaryl and the atom which L1 connects to ring A is a nitrogen atom;
• L2 is (CRaRb)SCH═HC(CRaRb)r in which each of r, and s independently, is 1, 2, 3, or 4;
• each of W1, and W2 independently, is C(R4) or N;
• each of R1, R2, R3, R4, R5, R6, and R7, independently, is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, halo, nitro, oxo, cyano, —ORa, —SRa, —NRbRc, —C(O)Ra, —S(O)Ra, —SO2Ra, —P(O)RbRc, —C(O)N(Rb)Ra, —N(Rb)C(O)Rc, —C(O)ORa, —OC(O)Ra, —SO2N(Rb)Rc, —N(Rb)SO2Rc, -alkyl-Ra, -alkyl-C(O)Ra, -alkyl-NRbRc, -alkyl-C(O)N(Rb)Rc, -alkyl-N(Rb)C(O), or -alkyl-N(Rb)SO2Rc;
• and
• each of Ra, Rb, Ra, Rb, and Rc, 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.