# US 10,865,205 B2 · Degradation of cyclin-dependent kinase 8 (CDK8) by conjugation of CDK8 inhibitors with E3 ligase ligand and methods of use

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- Number: US 10,865,205 B2
- Document ID: US10865205B2
- Status: Granted
- Kind: B2
- Application number: 16/094,105
- Filed: 2017-04-21
- Published: 2019-04-18
- 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
- Web page: https://patentgrep.com/patent/US10865205B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 47/18: Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- 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 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- A61P 31/22: for herpes viruses
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/10: Spiro-condensed systems
- A61P 35/00: Antineoplastic agents
- 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

## Abstract

The present application provides bifunctional compounds of Formula (Ia) or (Ib): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 8 (CDK8). The present application also relates to methods for the targeted degradation of CDK8 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK8 which can be utilized in the treatment of disorders modulated by CDK8.

## Claims

### Claim 1

A bifunctional compound of Formula X:
wherein:
the Targeting Ligand is of Formula TL-I:
wherein:
A is
X is N or CH;
X2 is N or CH;
X3 is N or CH;
X4 is N or CH;
each R1 is independently (C1-C4) alkyl or (C1-C4) haloalkyl;
each R2 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2;
each R3 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2;
each R4 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, OH, or NH2; and
t, n, o, and r are each independently 0, 1, 2, or 3;
wherein the Targeting Ligand is bonded to the Linker via the next to
the Linker is a bond or a carbon chain that serves to link the Targeting Ligand with the Degron,
wherein,
the carbon chain optionally comprises one, two, three, or more heteroatoms selected from N, O, and S,
and wherein,
one or more chain carbon atoms in the carbon chain are optionally substituted with one or more substitutents selected from oxo, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C3) alkoxy, OH, halogen, NH2, NH(C1-C3) alkyl, N(C1-C3)2, CN, (C3-C8) cycloalkyl, heterocyclyl, and phenyl; and
the Degron is of Formula D1:
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
or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The bifunctional compound of claim 1, wherein A is

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

The bifunctional compound of claim 1, wherein X2 is N.

### Claim 5 (depends on 1)

The bifunctional compound of claim 1, wherein X3 is N.

### Claim 6 (depends on 1)

The bifunctional compound of claim 1, wherein r is 1 and R4 is (C1-C4) haloalkyl.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

The bifunctional compound of claim 1, wherein the Linker 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), (CH2)JC(O)NH, CH2, O, NH, or NR19;
each R19 is independently (C1-C3) alkyl;
j is 1, 2, or 3; 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.

### Claim 9 (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 10 (depends on 1)

A method of treating cancer, wherein the cancer is leukemia or lymphoma, comprising administering to a subject in need thereof an effective amount of bifunctional compound or pharmaceutically acceptable salt or stereoisomer of claim 1.

### Claim 11 (depends on 1)

The bifunctional compound of claim 1, which is
or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

The bifunctional compound of claim 11, which is
or a stereoisomer or pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 10)

The method of claim 10, wherein the cancer is leukemia.

### Claim 14 (depends on 10)

The method of claim 10, wherein the cancer is lymphoma.