Inhibitors of cyclin dependent kinase 7 (CDK7)
The present invention provides, inter alia, compounds having the structures of formulas described herein; pharmaceutically acceptable salts, solvates, hydrates, tautomers, and isotopic forms thereof; and compositions (e.g., pharmaceutical compositions and kits) containing one or more of the foregoing. Also provided are methods of administering and uses involving the compounds and/or pharmaceutical compositions for treating or preventing disease. The disease can be a proliferative disease, such as a cancer (e.g., a blood cancer (e.g., a leukemia or lymphoma), a brain cancer, a breast cancer, melanoma, multiple myeloma, or an ovarian cancer) a benign neoplasm, pathologic angiogenesis, or a fibrotic disease. While no aspect of the invention is limited by the biological events that may transpire, administering a compound or other composition described herein may selectively inhibit the aberrant expression or activity of cyclin-dependent kinase 7 (CDK7) and, thereby, induce cellular apoptosis and/or inhibit the transcription of disease-related genes in the patient (or in a biological sample).
1. A compound of Formula I:
or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein:
X is N, CH, or C(R 10 ), wherein R 10 is halo or —P(O)(CH 3 ) 2 ;
Y is N or CH;
R 1 is —OH, —CN, —C(O)NH 2 , or one of the following heteroaryl groups
wherein any heteroaryl portion of R 1 is optionally substituted at up to two substitutable carbon atoms with a substituent independently selected from halo, —CN, —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), and —S(O) 2 —(C 1 -C 4 alkyl);
R 2 is fluoro, chloro, —CN, or C 1 -C 4 alkyl optionally substituted with fluoro;
R 3 , R 4 , and R 5 are as follows:
(i) R 3 is C or CH and R 4 is C or CH, wherein R 3 and R 4 are taken together to form an optionally substituted and optionally benzofused cycloalkyl, and R 5 is hydrogen, C 1 -C 4 alkyl, or is taken together with R 6 to form an optionally substituted and optionally benzofused saturated monocyclic or bicyclic heterocyclyl; or
(ii) R 3 is C or CH, R 4 is C, CH, or CH 2 , and R 5 is C, CH or CH 2 , wherein R 3 and R 5 are taken together with R 4 and the intervening nitrogen atom to form a saturated monocyclic heterocyclyl other than piperidine, wherein the saturated monocyclic heterocyclyl is optionally substituted and optionally fused to a cycloalkyl, saturated heterocyclyl, or phenyl ring, wherein R 5 and R 6 are optionally taken together to form a ring that is fused to the saturated monocyclic heterocyclyl formed when R 3 and R 5 are taken together; or
(iii) R 3 is CH 2 , R 4 is C or CH, and R 5 is C, CH or CH 2 , wherein R 4 and R 5 are taken together with the intervening nitrogen atom to form an optionally substituted and optionally benzofused saturated monocyclic or bicyclic heterocyclyl;
R 6 is hydrogen, —C 1 -C 4 alkyl, —C(O)—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-N(R 7 ) 2 , —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —C(O)-aryl, or —S(O) 2 -aryl;
each R 7 is, independently, halo, —CN, —OH, —NH 2 , —NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , —C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl) or —S(O) 2 —(C 1 -C 4 alkyl);
n is 0, 1, 2, 3 or 4;
each saturated heterocyclyl, cycloalkyl, or aryl is optionally substituted with up to four substituents independently selected from halo, —CN, —OH, —NH 2 , —NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , —C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), and an optionally substituted phenyl; and
each C 1 -C 4 alkyl and C 1 -C 4 alkylene is optionally substituted with up to five substituents independently selected from halo, —CN, —OH, —NH 2 , —NH(unsubstituted C 1 -C 4 alkyl), N(unsubstituted C 1 -C 4 alkyl) 2 , and —O-(unsubstituted C 1 -C 4 alkyl).
2. The compound of claim 1 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein R 1 is —OH, —CN, —C(O)NH 2 ,
3. The compound of claim 1 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein R 2 is -chloro or —CF 3 .
4. The compound of claim 1 , wherein the compound is a compound of Formula Ia:
or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein:
ring A is an optionally substituted and optionally benzofused cycloalkyl;
X, Y, R 1 , R 2 , R 5 , R 6 , R 7 , and n are as defined in claim 1 ; and
p is 0, 1, 2, 3, 4, or 5.
5. The compound of claim 4 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein R 1 is hydrogen or —CH 3 , and R 6 is hydrogen, —C 1 -C 4 alkyl, halo-substituted —C 1 -C 4 alkyl, hydroxy-substituted —C 1 -C 4 alkyl, or —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), or R 5 and R 6 are taken together with the nitrogen atom to which they are bound to form a saturated heterocyclyl optionally substituted with 1-4 substituents independently selected from halo, —OH, —C 1 -C 4 alkyl, and —O—(C 1 -C 4 alkyl).
6. The compound of claim 1 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein the compound is a compound of Formula Ib:
wherein:
ring B is an optionally substituted, saturated monocyclic heterocyclyl optionally fused to a cycloalkyl, saturated heterocyclyl, or phenyl ring
X, Y, R 1 , R 2 , R 6 , R 7 , and n are as defined in claim 1 ; and
m is 0, 1, 3, or 4.
7. The compound of claim 1 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein Y is CH and/or X is N, CH, C(Cl), or —C(P(O)(CH 3 ) 2 ).
8. The compound of claim 1 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein n is 0.
9. The compound of claim 6 , wherein the compound is a compound of Formula II:
or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein:
ring B is optionally substituted;
ring C is optionally substituted;
X is N, CH, or C(R 10 ), wherein R 10 is halo or —P(O)(CH 3 ) 2 ;
Y is N or CH;
R 1 is —OH, —CN, —C(O)NH 2 , or one of the following heteroaryl groups
wherein any heteroaryl portion of R 1 is optionally substituted at up to two substitutable carbon atoms with a substituent independently selected from halo, —CN, —OH, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), and —S(O) 2 —(C 1 -C 4 alkyl);
R 2 is fluoro, chloro, —CN, or C 1 -C 4 alkyl optionally substituted with fluoro;
R 6 is hydrogen, —C 1 -C 4 alkyl, —C(O)—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-N(R 7 ) 2 , —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —C(O)-aryl, or —S(O) 2 -aryl;
each R 7 is, independently, halo, —CN, —OH, —NH 2 , —NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , —C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl) or —S(O) 2 —(C 1 -C 4 alkyl);
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
o is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
wherein m+p does not equal 2;
each saturated heterocyclyl, cycloalkyl, or aryl is optionally substituted with up to four substituents independently selected from halo, —CN, —OH, —NH 2 , —NH(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl) 2 , —C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), and an optionally substituted phenyl; and
each C 1 -C 4 alkyl and C 1 -C 4 alkylene is optionally substituted with up to five substituents independently selected from halo, —CN, —OH, —NH 2 , —NH(unsubstituted C 1 -C 4 alkyl), N(unsubstituted C 1 -C 4 alkyl) 2 , and —O-(unsubstituted C 1 -C 4 alkyl).
10. A compound selected from any one of the compounds set forth below or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof:
11. A pharmaceutical composition comprising the compound of claim 1 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof; and a pharmaceutically acceptable excipient.
12. A method of treating a patient suffering from a disease associated with aberrant activity of CDK7, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 1 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof.
13. The method of claim 12 , wherein the disease is a proliferative disease, an infectious disease, or a disease caused by or associated with expanded repeats of simple nucleotide tracts.
14. The method of claim 13 , wherein the proliferative disease is cancer, a benign neoplasm, pathologic angiogenesis, or a fibrotic disease; the infectious disease is a viral infection caused by an influenza virus, a human immunodeficiency virus (HIV), a herpes virus, or a human papilloma virus (HPV)); and the disease caused by or associated with expanded repeats of simple nucleotide tracts is Huntington's Disease, myotonic dystrophy, or a form of amyotrophic lateral sclerosis (ALS).
15. The method of claim 14 , wherein the proliferative disease is a cancer selected from the group consisting of a blood cancer, a bone cancer, a brain cancer, a breast cancer, a lung cancer, melanoma, neuroblastoma, and an ovarian cancer.
16. The method of claim 15 , wherein the blood cancer is chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia (CMML), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), lymphoma, or multiple myeloma.
17. The method of claim 15 , wherein the bone cancer is osteosarcoma or Ewing's sarcoma; the breast cancer is triple-negative breast cancer (TNBC); the brain cancer is a glioblastoma; and the lung cancer is small cell lung cancer (SCLC).
18. The method of claim 12 , further comprising administering a second agent to the patient, wherein the second agent is an anti-proliferative agent, an anti-cancer agent, an immunosuppressant, or a pain-relieving agent.
19. A pharmaceutical composition comprising the compound of claim 10 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof; and a pharmaceutically acceptable excipient.
20. A method of treating a patient suffering from a disease associated with aberrant activity of CDK7, the method comprising administering to the patient a therapeutically effective amount of the compound of claim 10 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof.
21. The method of claim 20 , wherein the disease is a proliferative disease, an infectious disease, or a disease caused by or associated with expanded repeats of simple nucleotide tracts.
22. The method of claim 21 , wherein the proliferative disease is cancer, a benign neoplasm, pathologic angiogenesis, or a fibrotic disease; the infectious disease is a viral infection caused by an influenza virus, a human immunodeficiency virus (HIV), a herpes virus, or a human papilloma virus (HPV); and the disease caused by or associated with expanded repeats of simple nucleotide tracts is Huntington's Disease, myotonic dystrophy, or a form of amyotrophic lateral sclerosis (ALS).
23. The method of claim 22 , wherein the proliferative disease is a cancer selected from the group consisting of a blood cancer, a bone cancer, a brain cancer, a breast cancer, a lung cancer, melanoma, neuroblastoma, and an ovarian cancer.
24. The method of claim 23 , wherein the blood cancer is chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia (CMML), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), lymphoma, or multiple myeloma.
25. The method of claim 23 , wherein the bone cancer is osteosarcoma or Ewing's sarcoma; the breast cancer is triple-negative breast cancer (TNBC); the brain cancer is a glioblastoma; and the lung cancer is small cell lung cancer (SCLC).
26. The method of claim 10 , further comprising administering a second agent to the patient, wherein the second agent is an anti-proliferative agent, an anti-cancer agent, an immunosuppressant, or a pain-relieving agent.