# US 10,865,206 B2 · Inhibitors of cyclin-dependent kinase 7 (CDK7)

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- Number: US 10,865,206 B2
- Document ID: US10865206B2
- Status: Granted
- Kind: B2
- Application number: 16/412,726
- Filed: 2019-05-15
- Published: 2019-11-07
- Granted: 2020-12-15
- Earliest claimed: 2014-10-16
- Assignees: Syros Pharmaceuticals, Inc.
- Applicants: Syros Pharmaceuticals, Inc.
- Inventors: Stephane Ciblat; Anzhelika Kabro; Melissa Leblanc; Serge Leger; Jason J. Marineau; Tom Miller; Stephanie Roy; Darby Schmidt; M. Arshad Siddiqui; Kevin Sprott; Dana K. Winter; Amy Ripka; Dansu Li; Guoli Zhang
- Web page: https://patentgrep.com/patent/US10865206B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, 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 cyclin-dependent kinase (e.g., CDK7), and therefore induce cellular apoptosis and/or inhibit transcription in the subject.

## Claims

### Claim 1

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the structural formula I:
or a pharmaceutically acceptable salt, isotopically labeled derivative, or stereoisomer thereof, wherein
ring A is an optionally substituted heteroaryl ring of Formula (i-1), (i-2), (i-3), (i-4), (i-5) or (i-6):
wherein
each instance of V1, V2, V3, V4, V5, V6, V7, V8, V9, V10, V11, V12, V13, V14 and V15 is, independently, O, S, N, N(RA1), C, or C(RA2);
each instance of RA1 is, independently, hydrogen, deuterium, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
each instance of RA2 is, independently, hydrogen, deuterium, halogen, —CN, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORA2a, —N(RA2a)2, or —SRA2a, wherein each occurrence of RA2a is, independently, hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or
any two RA1, any two RA2, or one RA1 and one RA2 are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
each X is, independently, N or CH, wherein at least one X is N;
W is N or C(R1a);
each of R1a, if present, and R1b is, independently, hydrogen, deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —ORB1a, —N(RB1a)2, or —SRB1a, wherein each occurrence of RB1a is, independently, hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or
R1a and R1b are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
R2 is an optionally substituted C1-C4 alkylene or an optionally substituted C2-C4 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, or —N(R7)—;
R3 is a bond, an optionally substituted C1-C4 alkylene, or an optionally substituted C2-C4 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene is optionally and independently replaced with —O—, —S—, —N(R7)—, or —S(O)2—;
R4 is —NH2, —NH—C(O)—(CH2)3—N(CH3)2, —NH—C(O)—CH2—CH(OH)—CH2—N(CH3)2, —NH—CH3, or —NH—C(O)—C(O)—NH2;
p is 0, 1, 2 or 3,
wherein the compound is other than
or a pharmaceutically acceptable salt, isotopically labeled derivative or stereoisomer thereof.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein, within the compound or the pharmaceutically acceptable salt, isotopically labeled derivative, or stereoisomer thereof, ring A is a heteroaryl ring of Formula (i-1), (i-2), (i-3), (i-4), (i-5) or (i-6) optionally substituted with methyl;
each instance of RA1 is, independently, hydrogen, deuterium, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl;
each instance of RA2 is, independently, hydrogen, deuterium, halogen, —CN, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —ORA2a, —N(RA2a)2, or —SRA2a, wherein each occurrence of RA2a is, independently, hydrogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl, or
any two RA1, any two RA2, or one RA1 and one RA2 are joined to form an unsubstituted carbocyclic, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl ring;
each X is, independently, N or CH, wherein at least one X is N;
W is N or C(R1a);
each of R1a, if present, and R1b is, independently, hydrogen, deuterium, halogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —ORB1a, —N(RB1a)2, or —SRB1a, wherein each occurrence of RB1a is, independently, hydrogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl, or
R1a and R1b are joined to form an unsubstituted carbocyclic, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl ring;
R2 is an unsubstituted C1-C4 alkylene or an unsubstituted C2-C4 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, or —N(R7)—;
R3 is a bond, a C1-C4 alkylene optionally substituted with ═O or ═S, or an unsubstituted C2-C4 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene is optionally and independently replaced with —O—, —S—, —N(R7)—, or —S(O)2—;
R4 is —NH2, —NH—C(O)—(CH2)3—N(CH3)2, —NH—C(O)—CH2—CH(OH)—CH2—N(CH3)2, —NH—CH3, or —NH—C(O)—C(O)—NH2;
each R5, if present, is, independently, deuterium, halogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —ORD1, —N(RD1)2, or —SRD1, wherein each occurrence of RD1 is, independently, hydrogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl;
each R6, if present, is, independently, deuterium, halogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, ═O, —CN, —ORC1, —N(RC1)2, or —SRC1, wherein each occurrence of RC1 is, independently, hydrogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RC1 groups are joined to form an unsubstituted heterocyclic ring; or
each R5, if present, is, independently, deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORD1, —N(RD1)2, or —SRD1, wherein each occurrence of RD1 is, independently, hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R6, if present, is, independently, deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, ═O, —CN, —ORC1, —N(RC1)2, or —SRC1, wherein each occurrence of RC1 is, independently, hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RC1 groups are joined to form an optionally substituted heterocyclic ring; or
two R6 are taken together to form a first 5-7 membered optionally substituted, heterocyclyl or carbocyclyl ring fused to the ring to which the R6 are bound, wherein two substituents on the substituted heterocyclyl or carbocyclyl ring, or one substituent on the substituted heterocyclyl or carbocyclyl ring and a third R6 may be taken together with the atoms to which they are bound to form a second optionally substituted, heterocyclyl or carbocyclyl ring fused to the ring to the first optionally substituted, heterocyclyl or carbocyclyl ring and/or the ring to which the third R6 is bound;
each R7 is, independently, hydrogen or optionally substituted —C1-C6 alkyl;
n is 0, 1, 2, 3, 4, 5 or 6; and
two R6 are taken together to form a first 5-7 membered unsubstituted, heterocyclyl or carbocyclyl ring fused to the ring to which the R6 are bound, wherein two substituents on the substituted heterocyclyl or carbocyclyl ring, or one substituent on the substituted heterocyclyl or carbocyclyl ring and a third R6 may be taken together with the atoms to which they are bound to form a second optionally substituted, heterocyclyl or carbocyclyl ring fused to the ring to the first optionally substituted, heterocyclyl or carbocyclyl ring and/or the ring to which the third R6 is bound; and
each R7 is, independently, hydrogen or unsubstituted —C1-C6 alkyl.

### Claim 3 (depends on 2)

The pharmaceutical composition of claim 2, wherein, ring A is

### Claim 4 (depends on 2)

The pharmaceutical composition of claim 2, wherein ring A is

### Claim 5 (depends on 2)

The pharmaceutical composition of claim 2, wherein ring A is; and/or each X is N; and/or W is C(R1a).

### Claim 6 (depends on 5)

The pharmaceutical composition of claim 5, wherein R1a is hydrogen, halo, —OH, —C1-C3 alkyl, —O—C1-C3 alkyl, —CN, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, or C3-C6 cycloalkyl.

### Claim 7 (depends on 6)

The pharmaceutical composition of claim 6, wherein R1a is hydrogen, chloro, fluoro, —CN, or cyclopropyl.

### Claim 8 (depends on 2)

The pharmaceutical composition of claim 2, wherein R1b is hydrogen.

### Claim 9 (depends on 8)

The pharmaceutical composition of claim 8, wherein R2 is —NH—; —N(C1-C3 alkyl)-; —NH—CH2—*; or C1-C2 alkylene, wherein “*” represents a portion of R2 bound to a cyclohexyl ring.

### Claim 10 (depends on 9)

The pharmaceutical composition of claim 9, wherein R2 is —NH—.

### Claim 11 (depends on 2)

The pharmaceutical composition of claim 2, wherein R3 is †—NH—C(O)—, †—C(O)—NH—, †—NH—S(O)2—, or —N(CH3)—CH2—, wherein “†” represents a portion of R3 bound to a cyclohexyl ring.

### Claim 12 (depends on 2)

The pharmaceutical composition of claim 2, wherein R4 is —NH2.

### Claim 13 (depends on 2)

The pharmaceutical composition of claim 2, wherein R5 is absent or each R5 is, independently, fluoro, chloro or morpholin-4-yl.

### Claim 14 (depends on 2)

The pharmaceutical composition of claim 2, wherein each R6 is, independently, —OH, fluoro, or methyl, or two or three R6 are taken together with the carbon atoms in the cyclohexyl ring depicted in Formula I to form:
wherein “2” represents a portion of the ring bound to R2, and “3” represents a portion of the ring bound to R3.

### Claim 15 (depends on 2)

The pharmaceutical composition of claim 2, wherein the compound or the pharmaceutically acceptable salt, isotopically labeled derivative, or stereoisomer thereof is of Formula (Ia):

### Claim 16 (depends on 2)

The pharmaceutical composition of claim 2, wherein the compound or the pharmaceutically acceptable salt, isotopically labeled derivative, or stereoisomer thereof is of Formula (Ib):
wherein:
ring A is
R1a is hydrogen, chloro, fluoro, —CN, or cyclopropyl;
R3 is †—NH—C(O)—, †—C(O)—NH—, †—NH—S(O)2—, or —N(CH3)—CH2—, wherein “t†” represents a portion of R3 bound to a cyclohexyl ring;
R4 is —NH2, —NH—C(O)—(CH2)3—N(CH3)2, —NH—C(O)—CH2—CH(OH)—CH2—N(CH3)2, —NH—CH3, or —NH—C(O)—C(O)—NH2;
R5 is absent, or each R5 is, independently, fluoro, chloro, or morpholin-4-yl; and
R6 is absent, or each R6 is, independently, —OH, halo, or C1-C3 alkyl; or two or three R6 bound to separate carbon atoms are taken together with the carbon atoms to form:
wherein “2” represents a portion of the ring bound to R2, and “3” represents a portion of the ring bound to R3.

### Claim 17 (depends on 2)

A method of treating a subject suffering from a disease or condition associated with aberrant activity of a cyclin-dependent kinase (CDK), wherein the disease or condition is cancer, a benign neoplasm, pathological angiogenesis, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease, and the method comprises the step of administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 2.

### Claim 18 (depends on 17)

The method of claim 17, wherein the subject is suffering from a cancer associated with aberrant activity of cyclin-dependent kinase 7 (CDK7).

### Claim 19 (depends on 18)

The method of claim 18, wherein the cancer is a breast cancer, brain cancer, Ewing's sarcoma, hematopoietic cancer, lung cancer, or ovarian cancer.

### Claim 20 (depends on 17)

The method of claim 17, wherein the subject is a human.

### Claim 21

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, isotopically labelled derivative, or stereoisomer thereof, wherein the compound is

### Claim 22 (depends on 21)

A method of treating a subject suffering from a disease or condition associated with aberrant activity of a CDK, wherein the disease or condition is cancer, a benign neoplasm, pathological angiogenesis, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, or an infectious disease, and the method comprises the step of administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 21.

### Claim 23 (depends on 22)

The method of claim 22, wherein the subject is suffering from a cancer associated with aberrant activity of CDK7.

### Claim 24 (depends on 23)

The method of claim 23, wherein the cancer is a breast cancer, brain cancer, Ewing's sarcoma, hematopoietic cancer, lung cancer, or ovarian cancer.

### Claim 25 (depends on 22)

The method of claim 22, wherein the subject is a human.