# US 11,993,595 B2 · Compounds

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- Number: US 11,993,595 B2
- Document ID: US11993595B2
- Status: Granted
- Kind: B2
- Application number: 17/901,390
- Filed: 2022-09-01
- Published: 2023-02-16
- Granted: 2024-05-28
- Earliest claimed: 2014-09-23
- Assignees: Mission Therapeutics Limited
- Applicants: Mission Therapeutics Limited
- Inventors: Alison Jones; Mark Ian Kemp; Martin Lee Stockley; Karl Richard Gibson; Gavin Alistair Whitlock; Andrew Madin
- Web page: https://patentgrep.com/patent/US11993595B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 25/00: Drugs for disorders of the nervous system
- 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 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 513/04: Ortho-condensed systems
- 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 invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase L1 (UCHL1). The invention further relates to the use of DUB inhibitors in the treatment of cancer and other indications. Compounds of the invention include compounds having the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 to R8 are as defined herein.

## Claims

### Claim 1

A compound of formula (I):
a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, wherein:
R1 represents a 9-membered bicyclic heteroaryl ring comprising 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulphur, and which is substituted with 1 to 4 Q1-(R9)n;
R2, R3, R4, R5, R6 and R8 are each independently selected from hydrogen, C1-C3 alkyl and C1-C3 alkoxy, wherein said alkyl and alkoxy are optionally substituted with halo, C1-C3 alkyl or C1-C3 alkoxy;
R7 is selected from hydrogen, methyl, CF3, phenyl, pyridyl and pyrimidyl;
n is 0 or 1;
when n is 0, Q1 is selected from hydrogen, halogen, cyano, oxo, nitro, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, —SO2R11, —NR11R12, —NR11COR12, —NR10CONR11R12, —CO2R11, —NR11CO21R12, —SO2NR11R12, —C(O)R11, —NR11SO2R12, NR11SO2NR13R14, SO2NR11, —C1-C6 alkyl and C1-C2 haloalkyl;
when n is 1, Q1 is selected from a covalent bond, —CONR10—, —NR10CO—, an oxygen atom, —S(O)m—, —CO—, C1-C6 alkylene and —C2-C6 alkenylene;
m is 0, 1 or 2;
R9 represents a 3 to 10-membered heterocyclyl, heteroaryl, aryl or cycloalkyl ring;
R10, R11 and R12 are each independently selected from hydrogen, C1-C6 alkyl and C1-C6 alkylene;
wherein R9 is optionally substituted with one or more substituents selected from halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, oxo, cyano, nitro, -Q2-NR13CONR14R15, -Q2-NR13R14, -Q2-NR13COR14, -Q2-COR13, -Q2-SO2R13, -Q2-CONR13, Q2-CONR13R14, -Q2-CO2R13, -Q2-SO2NR13R14, -Q2-NR13SO2R14 and -Q2-NR13SO2NR14R15; wherein said alkyl and alkoxy are optionally substituted with halo, deutero, C1-3 alkyl, hydroxy, C1-3 alkoxy, cyano, amino, nitro, oxo, C1-3 alkylamino, C2-6 alkenylamino, di-C1-3 alkylamino, C1-3 acylamino, di-C1-3 acylamino, carboxy, C1-3 alkoxycarbonyl, carbamoyl, mono-C1-3 carbamoyl or di-C1-3 carbamoyl, or any of the above in which a hydrocarbyl moiety is itself substituted by halo;
or R9 is optionally substituted with a 3 to 10-membered heterocyclyl, heteroaryl, aryl or cycloalkyl ring, either directly attached or via linking group selected from oxygen, carbonyl, C1-C6 alkylene and C1-C6 alkyleneoxy;
Q2 represents a covalent bond, C1-C6 alkylene or C2-C6 alkenylene; and
R13, R14 and R15 are each independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein the ring of R1 is selected from indazolyl, benzothiazolyl, benzoimidazolyl, imidazopyridinyl, pyrazolopyridinyl and thiazolopyridinyl.

### Claim 3 (depends on 1)

The compound according to claim 1 wherein for each Q1-(R9)n where n is 0, each Q1 substituent is independently selected from halogen, C1-C4 alkyl, C1-C2 haloalkyl, C1-C2 alkoxy, —COR11, —SO2R11, cyano, CONR11R12 and C1-C2 haloalkoxy; and wherein for each Q1-(R9) where n is 1, each Q1 substituent is independently selected from a covalent bond, —CO—, C1-C6 alkylene, C2-C6 alkenylene and —NR10—.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein R2, R3, R4, R5, R6, R7 and R8 are each hydrogen.

### Claim 5 (depends on 1)

The compound according to claim 1 wherein R3 is methyl.

### Claim 6 (depends on 1)

The compound according to claim 1 wherein the ring of R9 is a 5 or 6-membered monocyclic, or a 9 or 10-membered bicyclic, heterocyclyl, aryl, heteroaryl or cycloalkyl ring.

### Claim 7 (depends on 6)

The compound according to claim 6 wherein the ring of R9 is selected from morpholinyl, piperidinyl, pyrrolidinyl, diazepanyl, piperazinyl, pyridazinyl, pyrazinyl, pyrazolyl, cyclopropyl, cyclohexyl, cyclopentyl, pyridinyl, imidazolyl, indolinyl, isoindolinyl, pyrimidinyl, isoxazolyl, dihydroindenyl, dihydroisoquinolinyl, tetrahydropyranyl, phenyl, oxadiazolyl, triazolyl, isoquinolinyl, indazolyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazolpyridinyl, imidazopyrimidinyl, imidazopyrazinyl, oxazolyl and quinolinyl.

### Claim 8 (depends on 1)

The compound according to claim 1 wherein:
R9 is optionally substituted with one or more substituents selected from halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 hydroxyalkyl, oxo, cyano, nitro, -Q2-NR13C0NR14R15, -Q2-NR13R14, -Q2-NR13C0R14, -Q2-COR13, -Q2-SO2R13, -Q2-CONR13, Q2-CONR13R14, -Q2-CO2R13, -Q2-SO2NR13R14, -Q2-NR13SO2R14 and -Q2-NR13SO2NR14R15; wherein said alkyl and alkoxy are optionally substituted with halo, deutero, C1-3 alkyl, hydroxy, C1-3 alkoxy, cyano, amino, nitro or oxo;
or R9 is optionally substituted with a 3 to 10 membered heterocyclyl, heteroaryl, aryl or cycloalkyl ring, either directly attached or via linking group selected from oxygen, carbonyl, C1-C6 alkylene and C1-C6 alkyleneoxy;
Q2 represents a covalent bond, C1-C6 alkylene or C2-C6 alkenylene; and
R13, R14 and R15 are each independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl; wherein said alkyl is optionally substituted with halo, deutero, Ci-3 alkyl, hydroxy, C1-3 alkoxy, cyano, amino, nitro or oxo.

### Claim 9 (depends on 8)

The compound according to claim 8 wherein R9 is optionally substituted with 1 to 3 substituents selected from halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy,
C1-C6 alkyl, C2-C6 alkynyl, oxo, cyano, NR13R14, NR13COR14, CH2NR13COR14, COR13, CONR13R14, SO2NR13R14 and NR13SO2R14;
or R9 is optionally substituted with a 3 to 10-membered heterocyclyl, heteroaryl, aryl or cycloalkyl ring, either directly attached or via linking group selected from oxygen, carbonyl, C1-C6 alkylene and C1-C6 alkyleneoxy; and
R13, R14 and R15 are each independently selected from hydrogen and C1-C6 alkyl.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, together with one or more pharmaceutically acceptable excipients.