# US 10,865,204 B2 · Degradation of cyclin-dependent kinase 4/6 (CDK4/6) by conjugation of CDK4/6 inhibitors with E3 ligase ligand and methods of use

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- Number: US 10,865,204 B2
- Document ID: US10865204B2
- Status: Granted
- Kind: B2
- Application number: 16/094,098
- Filed: 2017-04-21
- Published: 2019-03-28
- Granted: 2020-12-15
- Earliest claimed: 2016-04-22
- Assignees: Dana-Farber Cancer Institute, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.
- Inventors: Nathanael S. Gray; Tinghu Zhang; Calla M. Olson; Yanke Liang; Nicholas Kwiatkowski; Baishan Jiang; Eric Wang
- Web page: https://patentgrep.com/patent/US10865204B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 401/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present application provides bifunctional compounds of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 4 (CDK4) and/or cyclin-dependent kinase 6 (CDK6). The present application also relates to methods for the targeted degradation of CDK4 and/or CDK6 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK4 and/or CDK6 which can be utilized in the treatment of disorders modulated by CDK4 and/or CDK6.

## Claims

### Claim 1

A bifunctional compound of Formula X:
wherein:
the Targeting Ligand is capable of binding to CDK4 and/or CDK6, and is of Formula TL-I:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
A is absent or C(R4)2;
A′ is NR5 or O;
B is
X is N or CH;
X2 is N or CR5;
each R1 is independently (C1-C4) alkyl or (C1-C4) haloalkyl;
R2 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, OH, or NH2;
R3 is (C6-C10) aryl or a monocyclic or bicyclic heteroaryl comprising one to four heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R7; or
R2 and R3 together with the carbon atoms to which they are attached form a 5- or 6-membered heterocycloalkyl comprising one or two heteroatoms selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with one or more R8; or R2 and R3 together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaryl comprising one or two heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more R9;
each R4 is independently H or (C1-C4) alkyl;
R5 is H or (C1-C4) alkyl;
each R6 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2;
each R7 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; or
each R8 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, C(O)(C1-C4) alkyl, C(O)NH2, C(O)NH(C1-C4) alkyl, C(O)N((C1-C4) alkyl)2, (C3-C7) cycloalkyl, or heterocycloalkyl, or two R8 together with the carbon to which they are attached form C(O);
each R9 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, C(O)(C1-C4) alkyl, C(O)NH2, C(O)NH(C1-C4) alkyl, C(O)N((C1-C4) alkyl)2, (C3-C7) cycloalkyl, or heterocycloalkyl; and
n and t are independently 0, 1, 2, or 3,
wherein the Targeting Ligand is bonded to the Linker via the
next to
the Linker is a group that covalently binds to the Targeting Ligand and the Degron, and is of Formula L0:
or a stereoisomer thereof, wherein:
p1 is an integer selected from 0 to 12;
p2 is an integer selected from 0 to 12;
p3 is an integer selected from 1 to 6;
each W is independently absent, CH2, O, S, NH, or NR19;
Z1 is absent, C(O), CH2C(O)NH, CH2, O, NH, or NR19;
each R19 is independently (C1-C3) alkyl; and
Q is absent or NHC(O)CH2,
wherein the Linker is covalently bonded to a Degron via the
next to Q, and covalently bonded to a Targeting Ligand via the
next to Z1; and
the Degron is capable of binding to a ubiquitin ligase, and is of Formula D1:
or a stereoisomer thereof, wherein:
Y is a bond, (CH2)1-6, (CH2)0-6—O, (CH2)0-6—C(O)NR11, (CH2)0-6—NR11C(O), (CH2)0-6—NH, or (CH2)0-6—NR12;
Z is C(O) or C(R13)2;
R11 is H or (C1-C6) alkyl;
R12 is (C1-C6) alkyl or C(O)—(C1-C6) alkyl;
each R13 is independently H or (C1-C3) alkyl;
each R14 is independently (C1-C3) alkyl;
R15 is H, deuterium, (C1-C3) alkyl, F or Cl;
each R16 is independently halogen, OH, (C1-C6) alkyl, or (C1-C6) alkoxy;
q is 0, 1, or 2; and
v is 0, 1, 2, or 3,
wherein the Degron is covalently bonded to the Linker via the

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The bifunctional compound of claim 1, wherein A is absent.

### Claim 4 (depends on 1)

The bifunctional compound of claim 1, wherein A is CH2.

### Claim 5 (depends on 1)

The bifunctional compound of claim 1, wherein A′ is NH.

### Claim 6 (depends on 1)

The bifunctional compound of claim 1, wherein B is

### Claim 7 (depends on 1)

The bifunctional compound of claim 1, wherein R2 is halogen.

### Claim 8 (depends on 1)

The bifunctional compound of claim 1, wherein R3 is a bicyclic heteroaryl comprising one to four heteroatoms selected from N, O, and S, optionally substituted with one or more R7.

### Claim 9 (depends on 1)

The bifunctional compound of claim 1, wherein R2 and R3 together with the carbon atoms to which they are attached form a 6-membered heterocycloalkyl comprising one or two heteroatoms selected from N, O, and S, optionally substituted with one or more R8.

### Claim 10 (depends on 1)

The bifunctional compound of claim 1, wherein R2 and R3 together with the carbon atoms to which they are attached form a 5-membered heteroaryl comprising one or two heteroatoms selected from N, O, and S, optionally substituted with one or more R9.

### Claim 11 (depends on 1)

The bifunctional compound of claim 1, wherein the Targeting Ligand is of Formula TL-Ia or TL-Ib:

### Claim 12 (depends on 1)

The bifunctional compound of claim 1, wherein the Targeting Ligand is of Formula TL-Ic or TL-Id:

### Claim 13 (depends on 1)

The bifunctional compound of claim 1, wherein the Targeting Ligand is of Formula TL-Ie or TL-If:

### Claim 14 (depends on 1)

The bifunctional compound of claim 1, wherein the Targeting Ligand is of Formula TL-Ig, TL-Ih, or TL-Ii:

### Claim 15 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the bifunctional compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 16

A bifunctional compound, which is
or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 17

A bifunctional compound, which is
or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 18

A bifunctional compound, which is
or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 19

A bifunctional compound, which is
or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 20

A bifunctional compound, which is
or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 1)

A method for treating a cancer comprising administering to a subject in need thereof an effective amount of the bifunctional compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the cancer is selected from breast cancer, brain cancer, endometrial cancer, head and neck cancer, gastrointestinal cancer, lung cancer, ovarian cancer, prostate cancer, uterine cancer, hepatocellular carcinoma, liposarcoma, melanoma, multiple myeloma, neuroblastoma, leukemia, lymphoma, and teratoma.

### Claim 22 (depends on 21)

The method of claim 21, wherein the cancer is a lymphoma or leukemia.

### Claim 23 (depends on 1)

The bifunctional compound of claim 1, wherein the Linker is selected from:

### Claim 24 (depends on 1)

The bifunctional compound of claim 1, wherein the Degron is of Formula D1a or D1b:

### Claim 25 (depends on 21)

The method of claim 21, wherein the cancer is brain cancer.

### Claim 26 (depends on 25)

The method of claim 25, wherein the brain cancer is glioblastoma.

### Claim 27 (depends on 21)

The method of claim 21, wherein the cancer is breast cancer.

### Claim 28 (depends on 21)

The method of claim 21, wherein the cancer is lung cancer.

### Claim 29 (depends on 28)

The method of claim 28, wherein the lung cancer is non-small cell lung cancer (NSCLC).

### Claim 30 (depends on 22)

The method of claim 22, wherein the leukemia is acute-myeloid leukemia (AML) or acute lymphatic leukemia (ALL).