# US 11,897,877 B2 · Inhibitor compounds

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- Number: US 11,897,877 B2
- Document ID: US11897877B2
- Status: Granted
- Kind: B2
- Application number: 17/319,231
- Filed: 2021-05-13
- Published: 2022-12-22
- Granted: 2024-02-13
- Earliest claimed: 2012-09-07
- Assignees: Cancer Research Technology Limited
- Applicants: Cancer Research Technology Limited
- Inventors: Swen Hoelder; Julian Blagg; Savade Solanki; Hannah Woodward; Sebastien Gaston Andre Naud; Vassilios Bavetsias; Peter Sheldrake; Paolo Innocenti; Kwai-Ming J. Cheung; Butrus Atrash
- Web page: https://patentgrep.com/patent/US11897877B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- 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 compounds of formula I wherein R1, R4, Ar, W, X and Z are all as defined herein. The compounds of the present invention are known to inhibit the spindle checkpoint function of Monospindle 1 (Mps1—also known as TTK) kinases either directly or indirectly via interaction with the Mps1 kinase itself. In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

## Claims

### Claim 1

A compound of formula Ic shown below:
wherein:
R1 is selected from heteroaryl, and NR7R8
and wherein R1 is optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O)qCH3 (where q is 0, 1, or 2), methylamino, dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, or (3-8C)cycloalkyl(1-2C)alkyl, and wherein any (1-4C)alkyl, (1-4C)alkoxy, aryl, heteroaryl, heterocyclyl, or (3-8C)cycloalkyl moiety present within a substituent group on R1 is optionally further substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NRaRb, ORa, C(O)Ra, C(O)ORa, OC(O)Ra, N(Rb)ORa, C(O)N(Rb)Ra, N(Rb)C(O)Ra, S(O)pRa (where p is 0, 1, or 2), SO2N(Rb)Ra, or N(Rb)SO2Ra, wherein Ra and Rb are each independently selected from H or (1-4C)alkyl;
R3 is hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl
R4 is hydrogen;
Ar has the formula:
wherein all of A1, A2, and A3 are CH;
R5 is (1-3C)alkoxy, or (1-3C)fluoroalkoxy;
R6 is selected from heteroaryl and heterocyclyl,
and wherein R6 is optionally further substituted by one or more substituent groups independently selected from oxo, halo, cyano, nitro, hydroxy, NR22R23, (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-5C)alkanoyl, (1-5C)alkylsulphonyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, CONR22R23, and SO2NR22R23; wherein R22 and R23 are each independently selected from hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl;
and wherein when said substituent group comprises an alkyl, cycloalkyl, heterocyclyl, or heteroaryl moiety then said moiety is optionally further substituted by hydroxy, fluoro, chloro, cyano, CF3, OCF3, (1-2C)alkyl, (1-2C)alkoxy, SO2(1-2C)alkyl, or NReRf (where Re and Rf are each independently selected from hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl);
R8 is selected from hydrogen, (1-6C)alkyl, (1-6C)alkoxy, (3-9C)cycloalkyl, (3-9C)cycloalkyl-(1-2C)alkyl, aryl, aryl-(1-2C)alkyl, heterocyclyl, heterocyclyl-(1-2C)alkyl, heteroaryl, or heteroaryl-(1-2C)alkyl, and wherein R8 is optionally further substituted by one or more substituents selected from hydroxy, fluoro, chloro, cyano, CF3, OCF3 (1-2C)alkyl, or (1-2C)alkoxy; and
R7 is selected from hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl-(1-2C)alkyl, and wherein R7 is optionally further substituted by one or more substituents selected from hydroxy, fluoro, chloro, cyano, CF3, OCF3, (1-2C)alkyl, or (1-2C)alkoxy;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R8 is selected from hydrogen, (1-6C)alkyl, (3-9C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, phenyl, 3 to 9 membered heterocyclyl, 3 to 9 membered heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, or 5 or 6 membered heteroaryl-(1-2C)alkyl, and wherein R8 optionally further substituted by one or more substituents selected from hydroxy, fluoro, chloro, cyano, CF3, OCF3, (1-2C)alkyl, or (1-2C)alkoxy.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R7 is hydrogen or (1-4C)alkyl.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein R1 is selected from 5 or 6 membered heteroaryl, 3 to 9 membered heterocyclyl, or NR7R8; and wherein R1 is optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O)qCH3 (where q is 0, 1, or 2), methylamino, dimethylamino, phenyl, 5 or 6 membered heteroaryl, 3 to 6 membered heterocyclyl, or (3-6C)cycloalkyl,
and wherein any (1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl, heterocyclyl, or (3-6C)cycloalkyl group present within a substituent group on R1 is optionally further substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NRaRb, ORa, C(O)Ra, C(O)ORa, OC(O)Ra, N(Rb)ORa, C(O)N(Rb)Ra, N(Rb)C(O)Ra, S(O)pRa (where p is 0, 1, or 2), SO2N(Rb)Ra, or N(Rb)SO2Ra, wherein Ra and Rb are each independently H or (1-4C)alkyl.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein R1 is a 3 to 9 membered nitrogen-linked heterocyclyl or NR7R8; and wherein the 3 to 9 membered nitrogen-linked heterocyclyl is optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1, or 2), methylamino, dimethylamino, phenyl, 5 or 6 membered heteroaryl, 3 to 6 membered heterocyclyl, or (3-6C)cycloalkyl;
R7 is hydrogen; and
R8 is (1-6C)alkyl or a 3 to 9 membered heterocyclyl, each of which is optionally substituted by one or more substituents selected from hydroxyl, fluoro, chloro, cyano, CF3, OCF3, (1-2C)alkyl, or (1-2C)alkoxy.

### Claim 7 (depends on 1)

A compound according to claim 1, wherein R1 is a 3 to 9 membered nitrogen-linked monocyclic, bicyclic, or spiro bicyclic heterocyclyl or NR7R8; and wherein the 3 to 9 membered nitrogen-linked heterocyclyl is optionally substituted by one or more substituent groups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(0)qCH3 (where q is 0, 1, or 2), methylamino, or dimethylamino;
R7 is hydrogen; and
R8 is (1-6C)alkyl or a 3 to 9 membered heterocyclyl, each of which is optionally substituted by one or more substituents selected from hydroxyl, fluoro, chloro, cyano, CF3, OCF3, (1-2C)alkyl, or (1-2C)alkoxy.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein R3 is hydrogen or methyl.

### Claim 9 (depends on 1)

A compound according to claim 1, wherein R5 is OCH3.

### Claim 10 (depends on 1)

A compound according to claim 1, wherein R6 is a 5 membered heteroaryl comprising 1, 2, or 3 nitrogen atoms;
and wherein R6 is optionally further substituted by one or more substituent groups independently selected from halo, cyano, hydroxy, NR22R23, (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3 to 6 membered heterocyclyl, 3 to 6 membered heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heteroaryl-(1-2C)alkyl, CONR22R23, and SO2NR22R23; wherein R22 and R23 are each independently hydrogen or (1-4C)alkyl.

### Claim 11 (depends on 4)

A pharmaceutical composition according to claim 4 in a form suitable for oral use.

### Claim 12 (depends on 1)

A method of treating a cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof; wherein the cancer is selected from lung, colon, breast, ovarian, liver or skin cancer.

### Claim 13 (depends on 12)

The method of claim 12, wherein the cancer is breast cancer.

### Claim 14 (depends on 12)

The method of claim 12, wherein the cancer is a human cancer.

### Claim 15 (depends on 1)

A method of inhibiting Mps1 kinase in a cell, said method comprising contacting the cell with an effective amount of a compound of formula Ic as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 16 (depends on 15)

The method of claim 15, wherein the method is in vitro or in vivo.

### Claim 17 (depends on 1)

A method of inhibiting Mps1 kinase activity in a human or animal subject in need of such inhibition, the method comprising administering to said subject an effective amount of a compound of formula Ic as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof.