Cyclin-dependent kinase 7 (CDK7) non-covalent inhibitors

1 . A compound of formula (Va) or (Vb), a tautomeric form, a stereochemically isomeric form, an isotopically labeled form, or a pharmaceutically acceptable salt or solvate thereof:

wherein,

R 2 is hydrogen; haloC 1-6 alkyl; C 1-6 alkoxy; C 1-6 alkyloxycarbonyl; C 2-6 alkenyl; C 2-6 alkynyl; —C(═O)—NH 2 ; —C(═O)—NH(C 1-4 alkyl); —C(═O)—N(C 1-4 alkyl) 2 ; C 3-6 cycloalkyl; phenyl; a 4 to 7 membered monocyclic heterocyclyl containing at least one heteroatom that is N, O or S; or C 1-6 alkyl optionally substituted with deuterium, hydroxyl, C 1-6 alkoxy, cyano, C 3-6 cycloalkyl, phenyl, or with a 4 to 7 membered monocyclic heterocyclyl containing at least one heteroatom that is N, O or S;

each R 5a , R 5b , R 6a , R 6b , R 7a , and R 7b , independently, is hydrogen; C 1-6 alkyl; haloC 1-6 alkyl; or R 5a and R 5b form a C 3-6 cycloalkyl together with the carbon atom to which they are bound; or R 6a and R 6b form a C 3-6 cycloalkyl together with the carbon atom to which they are bound; or R 5b and R 6a form a cyclopropyl together with the carbon atoms to which they are bound;

R 8 is a direct bond, C 1-4 alkanediyl optionally substituted with hydroxy, halo, deuterium, or C 1-4 alkoxy; —CH 2 —C(═O)—; a spiro-C 3-6 cycloalkyl; or a 4 to 7 membered spiro-monocyclic heterocyclyl containing at least one heteroatom that I s N, O or S;

A is a C 3-6 cycloalkyl; aryl; a 5 to 12 membered heteroaryl containing at least one heteroatom that is N, O or S; or a 3 to 12 membered heterocyclyl containing at least one heteroatom that is N, O or S;

R 9 is C 1-6 alkyl optionally substituted with C 3-6 cycloalkyl; cyano, halo; haloC 1-6 alkyl; C 1-6 alkoxy optionally substituted with C 3-6 cycloalkyl; haloC 1-6 alkoxy; hydroxyl; hydroxyC 1-6 alkyl; oxo; —SO 2 —C 1-4 alkyl; —SO 2 —C 3-6 cycloalkyl; —SO 2 —NH 2 , —SO 2 —NH(C 1-4 alkyl); —SO 2 —N(C 1-4 alkyl) 2 ; —NH—C(═O)—C 2-6 alkenyl; —C(═O)—C 1-6 alkyl; —C(═O)—C 1-6 alkyl-C 3-6 cycloalkyl; —C(═O)—C 3-6 cycloalkyl; —C(═O)—C 2-6 alkenyl; C 3-6 cycloalkyl; spiro-C 3-6 cycloalkyl; phenyl; a 4 to 7 membered monocyclic heterocyclyl containing at least one heteroatom that is N, O or S; or a 4 to 7 membered Spiro monocyclic heterocyclyl containing at least one heteroatom that is N, O or S;

n is 0, 1, 2, 3, 4, or 5;

R 10 is hydrogen, halo, hydroxy, mercapto, carboxyl, haloC 1-6 alkyl, mono- or di(C 1-6 alkyl)amino, mono- or di(C 1-6 alkyl)aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkylthio, cyano, nitro, haloC 1-6 alkoxy, aminocarbonyl, C 3-6 cycloalkyl, or C 1-6 alkyl optionally substituted with deuterium, amino, hydroxy, mono- or di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylamino, [(mono- or diC 1-6 alkyl)amino-C 1-6 alkyl]carbonylamino, or with C 1-6 alkylsulfonylamino; and

p is 0, 1, 2, 3, 4, or 5.

2 . The compound according to claim 1 , the tautomeric form, the stereochemically isomeric form, the isotopically labeled form, or the pharmaceutically acceptable salt or solvate thereof, wherein;

R 2 is hydrogen; or C 1-6 alkyl optionally substituted with deuterium, hydroxyl, C 1-6 alkoxy, or with a 4 to 7 membered monocyclic heterocyclyl containing at least one heteroatom that is N, O or S;

each R 5a , R 5b , R 6a , R 6b , R 7a , and R 7b , independently, is hydrogen; C 1-6 alkyl; haloC 1-6 alkyl; or R 5a and R 5b form a C 3-6 cycloalkyl together with the carbon atom to which they are bound; or R 6a and R 6b form a C 3-6 cycloalkyl together with the carbon atom to which they are bound; or R 5b and R 6a form a cyclopropyl together with the carbon atoms to which they are bound;

R 8 is a direct bond, C 1-4 alkanediyl optionally substituted with hydroxy, deuterium, or C 1-4 alkoxy; —CH 2 —C(═O)—; a spiro-C 3-6 cycloalkyl; or a 4 to 7 membered spiro-monocyclic heterocyclyl containing at least one heteroatom that is N, O or S;

A is a C 3-6 cycloalkyl; aryl; a 5 to 12 membered heteroaryl containing at least one heteroatom that is N, O or S;

R 9 is C 1-6 alkyl optionally substituted with C 3-6 cycloalkyl; halo; haloC 1-6 alkyl; C 1-6 alkoxy optionally substituted with C 3-6 cycloalkyl; haloC 1-6 alkoxy; hydroxyl; hydroxyC 1-6 alkyl; oxo; —SO 2 —C 3-6 cycloalkyl; —C(═O)—C 1-6 alkyl-C 3-6 cycloalkyl; —C(═O)—C 3-6 cycloalkyl; C 3-6 cycloalkyl; spiro-C 3-6 cycloalkyl; a 4 to 7 membered monocyclic heterocyclyl containing at least one heteroatom that is N, O or S;

n is 0, 1, 2, 3, or 4;

R 10 is hydrogen, halo, hydroxy, mercapto, carboxyl, haloC 1-6 alkyl, mono- or di(C 1-6 alkyl)amino, mono- or di(C 1-6 alkyl)aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkylthio, cyano, nitro, haloC 1-6 alkoxy, aminocarbonyl, C 3-6 cycloalkyl, or C 1-6 alkyl optionally substituted with deuterium, amino, hydroxy, mono- or di(C 1-6 alkyl)amino, C 1-6 alkylcarbonylamino, [(mono- or diC 1-6 alkyl)amino-C 1-6 alkyl]carbonylamino, or with C 1-6 alkylsulfonylamino; and

p is 0, 1, 2, or 3.

3 . The compound according to claim 1 , the tautomeric form, the stereochemically isomeric form, the isotopically labeled form, or the pharmaceutically acceptable salt or solvate thereof, wherein R 5a is C 1-6 alkyl; or R 5a and R 5b form a cyclopropyl together with the carbon atom to which they are bound; or R 6a and R 6b form a cyclopropyl together with the carbon atom to which they are bound; or R 5b and R 6a form a cyclopropyl together with the carbon atoms to which they are bound.

4 . The compound according to claim 1 , the tautomeric form, the stereochemically isomeric form, the isotopically labeled form, or the pharmaceutically acceptable salt or solvate thereof, wherein:

R 8 is C 1-4 alkanediyl optionally substituted with hydroxy or deuterium;

A is a 5 to 12 membered heteroaryl containing at least one heteroatom that is N, O or S;

R 9 is C 1-6 alkyl; and

n is 1.

5 . The compound according to claim 1 , the tautomeric form, the stereochemically isomeric form, the isotopically labeled form, or the pharmaceutically acceptable salt or solvate thereof, wherein the compound is:

6 . A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

7 . A method for the treatment of a cancer having elevated or abnormal cyclin-dependent kinase 7 (CDK7) activity, wherein the method comprises administering to a subject in need thereof the compound of claim 1 .

8 . The method of claim 7 , wherein the cancer is leukemia, lymphoma, melanoma, multiple myeloma, bone cancer, Ewing's sarcoma, triple-negative breast cancer (TNBC), brain cancer, neuroblastoma, or lung cancer.

9 . The method of claim 7 , wherein the subject is a mammal.

10 . An in vitro method of modulating CDK7 activity comprising contacting the CDK7 protein, or portion thereof, with the compound, or the pharmaceutically acceptable salt or solvate thereof, according to claim 1 .

11 . A method for inhibiting the activity of cyclin-dependent kinase 7 (CDK7) in a subject in need thereof, wherein the method comprises administering the compound of claim 1 to the subject.

12 . The method of claim 8 , wherein the leukemia is chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML), or acute myeloid leukemia (AML).

13 . The method of claim 8 , wherein the lymphoma is Hodgkin's lymphoma or non-Hodgkin's lymphoma.

14 . The method of claim 8 , wherein the lung cancer is small cell lung cancer (SCLC) or large cell lung cancer.

15 . The method of claim 8 , wherein the bone cancer is osteosarcoma.