# US 2019/0315747 A9 · Inhibitors of cyclin-dependent kinases

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- Number: US 2019/0315747 A9
- Document ID: US20190315747A9
- Status: Published application
- Kind: A9
- Application number: 15/561,729
- Filed: 2016-03-25
- Published: 2019-10-17
- Earliest claimed: 2015-03-27
- Assignees: Dana-Farber Cancer Institute, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.
- Inventors: Nathanael S. Gray; Tinghu Zhang; Nicholas Paul Kwiatkowski
- Web page: https://patentgrep.com/patent/US20190315747A9

## CPC

- C07D 473/16: two nitrogen atoms
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 473/34: attached in position 6, e.g. adenine
- C07D 487/04: Ortho-condensed systems
- C07K 14/4738: {Cell cycle regulated proteins, e.g. cyclin, CDC, INK-CCR (cell cycle dependent kinases C12N9/12)}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention provides novel compounds of Formula (I), (II), or (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing proliferative diseases (e.g., cancers (e.g., leukemia, acute lymphoblastic leukemia, lymphoma, Burkitt's lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, ovarian cancer, neuroblastoma, lung cancer, colorectal cancer), benign neoplasms, diseases associated with 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 a kinase, such as a cyclin-dependent kinase (CDK) (e.g., CDK7, CDK12, or CDK13), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —NRaRb, —ORb, —SRb, —C(═O)Rb, —C(═O)ORb, or —C(═O)NRaRb, wherein each instance of Ra and Rb is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group when attached to nitrogen, or an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur; or Ra and Rb are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
R3 is hydrogen, halogen, or optionally substituted C1-C6 alkyl;
R5 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
L1 is a bond, —NRL1—(CH2)t—, —O—, or —S—;
RL1 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
t is 0 or an integer between 1 and 5, inclusive;
Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
L2 is a bond, optionally substituted C1-4 alkylene, —C(═O)—, —NRL2—, —C(═O)NRL2—, —NRL2C(═O)—, —O—, or —S—, wherein RL2 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protection group;
Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R2 is any of Formulae (i-1)-(i-41):
wherein:
L3 is a bond or an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NRL3a—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═S)-, —C(═S)NRL3a—, trans-CRL3b═CRL3b—, cis-CRL3b═CRL3b—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NRL3a—, —NRL3aS(═O)—, —S(═O)2—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, or —NRL3aS(═O)2—, wherein RL3a is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of RL3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RL3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L4 is a bond or an optionally substituted, branched or unbranched C1-6 hydrocarbon chain;
each of RE1, RE2, and RE3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH2OREE, —CH2N(R)2, —CH2SREE, —OREE, —N(REE)2, —Si(REE)3, and —SREE, wherein each occurrence of REE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two REE groups are joined to form an optionally substituted heterocyclic ring;
or RE1 and RE3, or RE2 and RE3, or RE1 and RE2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
RE4 is a leaving group;
RE5 is halogen;
RE6 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
each instance of Y is independently O, S, or NRE7, wherein RE7 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits; and
provided that the compound is not

### Claim 2

A compound of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —NRaRb, —ORb, —SRb, —C(═O)Rb, —C(═O)ORb, or —C(═O)NRaRb, wherein each instance of Ra and Rb is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group when attached to nitrogen, or an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur; or Ra and Rb are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
each of R3 and R4 is independently hydrogen, halogen, or optionally substituted C1-C6 alkyl;
L1 is a bond, —NRL1—(CH2)t—, —O—, or —S—;
RL1 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
t is 0 or an integer between 1 and 5, inclusive;
Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
L2 is a bond, optionally substituted C1-4 alkylene, —C(═O)—, —NRL2—, —C(═O)NRL2—, —NRL2C(═O)—, —O—, or —S—, wherein RL2 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protection group;
Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R2 is any of Formulae (i-1)-(i-41):
wherein:
L3 is a bond or an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NRL3a—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═S)—, —C(═S)NRL3a—, trans-CRL3b═CRL3b—, cis-CRL3b═CRL3b—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NRL3a—, —NRL3aS(═O)—, —S(═O)2—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, or —NRL3aS(═O)2—, wherein RL3a is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of RL3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RL3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L4 is a bond or an optionally substituted, branched or unbranched C1-6 hydrocarbon chain;
each of RE1, RE2, and RE3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH2OREE, —CH2N(RE)2, —CH2SREE, —ORE, —N(REE)2, —Si(REE)3, and —SREE, wherein each occurrence of REE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two REE groups are joined to form an optionally substituted heterocyclic ring;
or RE1 and RE3, or RE2 and RE3, or RE1 and RE2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
RE4 is a leaving group;
RE5 is halogen;
RE6 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
each instance of Y is independently O, S, or NRE7, wherein RE7 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.

### Claim 3

A compound of Formula (III):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —NRaRb, —ORb, —SRb, —C(═O)Rb, —C(═O)ORb, or —C(═O)NRaRb, wherein each instance of Ra and Rb is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group when attached to nitrogen, or an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur; or Ra and Rb are joined to form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;
each of R3 and R4 is independently hydrogen, halogen, or optionally substituted C1-C6 alkyl;
L1 is a bond, —NRL1—(CH2)t—, —O—, or —S—;
RL1 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
t is 0 or an integer between 1 and 5, inclusive;
Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
L2 is a bond, optionally substituted C1-4 alkylene, —C(═O)—, —NRL2—, —C(═O)NRL2—, —NRL2C(═O)—, —O—, or —S—, wherein RL2 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protection group;
Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R2 is any of Formulae (i-1)-(i-41):
wherein:
L3 is a bond or an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NRL3a—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═S)—, —C(═S)NRL3a—, trans-CRL3b═CRL3b—, cis-CRL3b═CRL3b—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NRL3a—, —NRL3aS(═O)—, —S(═O)2—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, or —NRL3aS(═O)2—, wherein RL3a is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of RL3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RL3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L4 is a bond or an optionally substituted, branched or unbranched C1-6 hydrocarbon chain;
each of RE1, RE2, and RE3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH2OREE, —CH2N(RE)2, —CH2SREE, —ORE, —N(REE)2, —Si(REE)3, and —SREE, wherein each occurrence of REE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two REE groups are joined to form an optionally substituted heterocyclic ring;
or RE1 and RE3, or RE2 and RE3, or RE1 and RE2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
RE4 is a leaving group;
RE5 is halogen;
RE6 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
each instance of Y is independently O, S, or NRE7, wherein RE7 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.

### Claim 4 (depends on 1)

The compound of claim 1, wherein Ring A comprises an optionally substituted phenyl ring.

### Claim 5 (depends on 1)

The compound of claim 1, wherein Ring A comprises an optionally substituted cyclohexyl ring.

### Claim at position 6

6-7. (canceled)

### Claim 8 (depends on 1)

The compound claim 1, wherein L1 is —NRL1—.

### Claim at position 8

9-13. (canceled)

### Claim 14 (depends on 1)

The compound of claim 1, wherein L2 is —NRL2(C═O)—.

### Claim 15

(canceled)

### Claim 16 (depends on 1)

The compound of claim 1, wherein Ring B is absent.

### Claim 17 (depends on 1)

The compound of claim 1, wherein Ring B is an optionally substituted phenyl ring.

### Claim at position 13

18-20. (canceled)

### Claim 21 (depends on 1)

The compound of claim 1, wherein R1 is of Formula (n-1):
wherein:
each instance of R1a is independently hydrogen, halogen, optionally substituted C1-C6 alkyl, —N(RN1)2, or —ORO1;
each instance of RN1 is independently hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
RO1 is independently hydrogen, optionally substituted C1-C6 alkyl, or an oxygen protecting group; and
a1 is 0 or an integer between 1 and 6, inclusive.

### Claim at position 15

22-30. (canceled)

### Claim 31 (depends on 1)

The compound of claim 1, wherein R1 is of Formula (n-2):
wherein:
each instance of R1b is independently hydrogen, halogen, optionally substituted C1-C6 alkyl, —N(R N)2, or —ORO1;
each instance of RN1 is independently hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
RO1 is independently hydrogen, optionally substituted C1-C6 alkyl, or an oxygen protecting group; and
b1 is 0 or an integer between 1 and 6, inclusive.

### Claim at position 17

32-41. (canceled)

### Claim 42 (depends on 1)

The compound of claim 1, wherein the compound is of Formula (I-1):
or a pharmaceutically acceptable salt thereof, wherein
each instance of R1a is independently hydrogen, halogen, optionally substituted C1-C6 alkyl, —N(RN1)2, or —ORO1;
RO1 is independently hydrogen, optionally substituted C1-C6 alkyl, or an oxygen protecting group; and
a1 is 0 or an integer between 1 and 6, inclusive;
wherein the compound is of Formula (I-2):
or a pharmaceutically acceptable salt thereof, wherein:
each instance of R1b is independently hydrogen, halogen, optionally substituted C1-C6 alkyl, —N(RN1)2, or —ORO1;
each instance of RN1 is independently hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
RO1 is independently hydrogen, optionally substituted C1-C6 alkyl, or an oxygen protecting group; and
b1 is 0 or an integer between 1 and 6, inclusive; or
wherein the compound is of Formula (I-3):
or a pharmaceutically acceptable salt thereof, wherein
each instance of R1c is independently hydrogen, halogen, optionally substituted C1-C6 alkyl, —N(RN1)2, or —ORO1;
each instance of RN1 is independently hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
RO1 is independently hydrogen, optionally substituted C1-C6 alkyl, or an oxygen protecting group; and
c1 is 0 or an integer between 1 and 6, inclusive.

### Claim at position 19

43-100. (canceled)

### Claim 101 (depends on 1)

The compound of claim 1, wherein R2 is of Formula (i-1):

### Claim 102

(canceled)

### Claim 103

A compound of any one of the compounds in Tables A1 and A2, and
pharmaceutically acceptable salts thereon.

### Claim 104 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

### Claim 105

(canceled)

### Claim 106 (depends on 1)

A method of treating a proliferative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim at position 26

107-139. (canceled)

### Claim 140 (depends on 1)

A method of inhibiting the activity of a cyclin-dependent kinase (CDK) in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim at position 28

141-146. (canceled)

### Claim 147 (depends on 1)

A method of inhibiting transcription in a biological sample or subject, the method comprising:
administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 148

(canceled)

### Claim 149 (depends on 1)

A method of inhibiting cell growth in a biological sample or subject, the method comprising:
administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 150 (depends on 1)

A method of inducing apoptosis of a cell in a biological sample or subject, the method comprising:
administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim at position 33

151-161. (canceled)