# US 11,306,070 B2 · Inhibitors of cyclin-dependent kinase 12 (CDK12) and uses thereof

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- Number: US 11,306,070 B2
- Document ID: US11306070B2
- Status: Granted
- Kind: B2
- Application number: 16/462,892
- Filed: 2017-11-22
- Published: 2020-11-19
- Granted: 2022-04-19
- Earliest claimed: 2016-11-22
- Assignees: Dana-Farber Cancer Institute, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.
- Inventors: Nathanael S. Gray; Tinghu Zhang; Baishan Jiang; Nicholas Paul Kwiatkowski
- Web page: https://patentgrep.com/patent/US11306070B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61P 35/00: Antineoplastic agents
- C07D 401/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides novel compounds of Formulae (I′) and (II), 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., CDK12), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.

## Claims

### Claim 1

A compound of Formula (II):
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 (ii-1)-(ii-5):
or an optionally substituted 6-membered aryl or heteroaryl ring;
each instance of V1, V2, V3, V4, V5, V6, V7, V8, V9, V10, V11, V12, V13, and V14 is independently O, S, N, N(RA1), C, or C(RA2);
each instance of RA1 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;
each instance of RA2 is independently selected from hydrogen, 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(RA2b)2, and —SRA2a, wherein each instance of RA2a 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, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
wherein each occurrence of RA2b 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, optionally substituted heteroaryl, and a nitrogen protecting group, or optionally two instances of RA2b are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; 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;
R1b is independently selected from hydrogen, 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(RB1b)2, and —SRB1a, wherein of RB1a is selected from 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, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom,
wherein each occurrence of RB1b 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, optionally substituted heteroaryl, and a nitrogen protecting group, or optionally two instances of RB1b are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
each instance of R3, if present, is independently selected from 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, —ORC1, -N(RC1a)2 and —SRC1, wherein each occurrence of RC1 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, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom,
wherein each occurrence of RC1a 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, optionally substituted heteroaryl, and a nitrogen protecting group, or optionally two instances of RC1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; or
two R3 groups bound to the same ring carbon atom are taken together to form ═O, or
two R3 groups bound to the same or different ring carbon atoms are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring;
R6 is selected from hydrogen and -C1-C6 alkyl;
R7 is a warhead of formula:
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 each instance of RL3a is independently 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 instance 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(REE)2, —CH2SREE, —OREE, —N(REE)2, —Si(REE)3, or —SREE, wherein each instance 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;
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;
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits; and
each instance of R8, if present, is independently selected from hydrogen, 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(RD1a)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, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom,
wherein each occurrence of RD1a 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, optionally substituted heteroaryl, and a nitrogen protecting group, or optionally two instances of RD1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; or
two R8 groups are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring;
n is 0, 1, 2, 3, 4, 5 or 6; and
p is 0, 1, 2, 3, 4, or 5.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is of formula:

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R1b is halogen.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein at least one instance of R8 is halogen, —O(alkyl), or optionally substituted alkyl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R7 is of formula:

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound is of formula:
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

### Claim 7 (depends on 1)

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

### Claim 8 (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, solvate, hydrate, tautomer, or stereoisomer thereof.

### Claim 9 (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, solvate, hydrate, tautomer, or stereoisomer thereof.

### Claim 10 (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, solvate, hydrate, tautomer, or stereoisomer thereof.

### Claim 11 (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, solvate, hydrate, tautomer, or stereoisomer thereof.

### Claim 12 (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, solvate, hydrate, tautomer, or stereoisomer thereof.

### Claim 13 (depends on 1)

The compound of claim 1, wherein the compound is a compound of Formula (II):
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R6 is H.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is of formula:

### Claim 16 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein Ring A is of formula:

### Claim 17 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R1b is Cl.

### Claim 18 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein n is 0.

### Claim 19 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein p is 0.

### Claim 20 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R1b is Br.