# US 10,308,648 B2 · Inhibitors of cyclin-dependent kinase 7 (CDK7)

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- Number: US 10,308,648 B2
- Document ID: US10308648B2
- Status: Granted
- Kind: B2
- Application number: 15/519,484
- Filed: 2015-10-15
- Published: 2017-11-16
- Granted: 2019-06-04
- 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; Arshad M. Siddiqui; Kevin Sprott; Dana K. Winter; Amy Ripka; Dansu Li; Guoli Zhang
- Web page: https://patentgrep.com/patent/US10308648B2

## 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 compound having the structural formula I:
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
ring A is an optionally substituted heteroaryl ring of any one of the Formulae (i-1)-(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 selected from the group consisting of hydrogen, deuterium, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
each instance of RA2 is independently selected from the group consisting of 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, and —SRA2a, wherein each occurrence of RA2a is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and 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 selected from the group consisting of N and CH, wherein at least one X is N;
W is selected from the group consisting of N and C(R1a);
each of R1a, if present, and R1b is independently selected from the group consisting of 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, and —SRB1a, wherein each occurrence of RB1a is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and 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 selected from the group consisting of a bond, an optionally substituted C1-C4 alkylene, and 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 selected from the group consisting of —NH2, —NH—C(O)—(CH2)3—N(CH3)2, —NH—C(O)—CH2—CH(OH)—CH2—N(CH3)2,
—NH—CH3, and —NH—C(O)—C(O)—NH2;
each R5, if present, is independently selected from the group consisting of 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, and —SRD1, wherein each occurrence of RD1 is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, and optionally substituted aryl, optionally substituted heteroaryl;
each R6, if present, is independently selected from the group consisting of 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, and —SRC1, wherein each occurrence of RC1 is independently selected from the group consisting of 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, and 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 selected from the group consisting of hydrogen and optionally substituted —C1-C6 alkyl;
n is 0, 1, 2, 3, 4, 5 or 6; and
p is 0, 1, 2 or 3,
wherein the compound is other than
and stereoisomers and enantiomers thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein ring A is selected from the group consisting of:

### Claim 3 (depends on 2)

The compound of claim 2, wherein, ring A is selected from the group consisting of:

### Claim 4 (depends on 1)

The compound of claim 1, wherein each X is N.

### Claim 5 (depends on 1)

The compound of claim 1, wherein W is C(R1a).

### Claim 6 (depends on 5)

The compound of claim 5, wherein R1a is selected from the group consisting of hydrogen, halo, —OH, —C1-C3 alkyl, halo-substituted —C1-C3 alkyl, —O—C1-C3 alkyl, halo-substituted —O—C1-C3 alkyl, —CN, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, and C3-C6 cycloalkyl.

### Claim 7 (depends on 6)

The compound of claim 6, wherein R1a is selected from the group consisting of hydrogen, chloro, fluoro, —CN, —CF3, and cyclopropyl.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R1b is hydrogen.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R2 is selected from the group consisting of —NH—; —N(C1-C3 alkyl)-; —NH—CH2-*; and C1-C2 alkylene optionally substituted with 1 to 4 substituents independently selected from the group consisting of halo, —OH, —C1-C3 alkyl, halo-substituted —C1-C3 alkyl, —O—C1-C3 alkyl, halo-substituted —O—C1-C3 alkyl, —CN, —NH2, —NH(C1-C3 alkyl), —N(C1-C3 alkyl)2, wherein “*” represents a portion of R2 bound to a cyclohexyl ring.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R2 is —NH—.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R3 is selected from the group consisting of †-NH—C(O)—, †-C(O)—NH—, †-NH—S(O)2—, †-NH—CH(CF3)—, and —N(CH3)—CH2—, wherein “†” represents a portion of R3 bound to a cyclohexyl ring.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R4 is —NH2.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R5 is absent or each R5 is independently selected from the group consisting of fluoro, chloro and morpholin-4-yl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R6 or each R6 is independently selected from the group consisting of —OH, fluoro, and 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 1)

The compound of claim 1, having the Formula (Ia):

### Claim 16 (depends on 1)

The compound of claim 1, having the Formula (Ib):
wherein:
ring A is selected from
R1a is selected from the group consisting of hydrogen, chloro, fluoro, —CN, —CF3, and cyclopropyl;
R3 is selected from the group consisting of †-NH—C(O)—, †-C(O)—NH—, †-NH—S(O)2—, †-NH—CH(CF3)—, and —N(CH3)—CH2—, wherein “†” represents a portion of R3 bound to a cyclohexyl ring;
R5 is absent, or each R5 is independently selected from the group consisting of fluoro, chloro, and morpholin-4-yl; and
R6 is absent, or each R6 is independently selected from the group consisting of —OH, halo, and 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 1)

The compound of claim 1, selected from the group consisting of any one of Compounds 100-101 and 103-126.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising (a) the compound of claim 1, or the pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and (b) a pharmaceutically acceptable excipient.

### Claim 19 (depends on 1)

The compound of claim 1, wherein the compound is the pharmaceutically acceptable salt of the compound of formula I.

### Claim 20 (depends on 18)

The pharmaceutical composition of claim 18, wherein the composition comprises the pharmaceutically acceptable salt of the compound of formula I.