# US 9,434,714 B2 · Pyrimidine imidazole amines as modulators of kinase activity

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- Number: US 9,434,714 B2
- Document ID: US9434714B2
- Status: Granted
- Kind: B2
- Application number: 14/618,122
- Filed: 2015-02-10
- Published: 2015-08-13
- Granted: 2016-09-06
- Earliest claimed: 2014-02-11
- Assignees: Merck Patent GmbH
- Applicants: Merck Patent GmbH
- Inventors: Ruoxi Lan; Xiaoling Chen; Yufang Xiao; Bayard R. Huck; Andreas Goutopoulos
- Web page: https://patentgrep.com/patent/US9434714B2

## CPC

- C07D 401/14: containing three or more hetero rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- 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 invention provides novel imidazole amine compounds according to formula (I) their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

## Claims

### Claim 1

A compound selected from:
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-ethyl-pyrimidin-4-ylamine (1);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-chloro-pyrimidin-4-ylamine (2);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropyl-pyrimidin-4-ylamine (3);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropyl-pyrimidin-4-ylamine (4);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-trifluoromethyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropyl-pyrimidin-4-ylamine (5);
5-Chloro-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(1-methyl-azetidin-3-ylmethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (6);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(2H-pyrazol-3-yl)-pyrimidin-4-ylamine (7);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-pyridin-4-yl-pyrimidin-4-ylamine (8);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-pyridin-3-yl-pyrimidin-4-ylamine (9);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-ethoxy-pyrimidin-4-ylamine (10);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-cyclobutyl-pyrimidin-4-ylamine (11);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropoxy-pyrimidin-4-ylamine (12);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-pyridin-4-yl-pyrimidin-4-ylamine (13);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-(2,2,2-trifluoro-ethoxy)-pyrimidin-4-ylamine (14);
4-Amino-6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbaldehyde (15);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-cyclopropyl-pyrimidin-4-ylamine (16);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-cyclopropyl-pyrimidin-4-ylamine (17);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-phenyl-pyrimidin-4-ylamine (18);
6-{4-[1-(2-Azetidin-1-yl-ethyl)-4-(2-isopropyl-pyridin-4-yl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-pyridin-3-yl-pyrimidin-4-ylamine (19);
5-Ethoxy-6-{4-(3-chloro-4-fluorophenyl)-1-2-(dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (20);
5-Bromo-6-{4-(3-methyl-4-fluorophenyl)-1-2-(dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (21);
5-Chloro-6-{4-(3-methyl-4-fluorophenyl)-1-2-(dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (22);
5-Chloro-6-{4-(3-trifluoromethyl-4-fluorophenyl)-1-2-(dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (23);
5-Chloro-6-{4-(3-trifluoromethyl-pyridin-4-yl)-1-2-(dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (24);
5-Bromo-6-{4-(3-trifluoromethyl-pyridin-4-yl)-1-2-(dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (25);
5-Ethoxy-6-{4-(3-trifluoromethyl-pyridin-4-yl)-1-2-(dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (26);
5-Ethyl-6-{4-(3-trifluoromethyl-pyridin-4-yl)-1-2-(dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (27);
5-Isoproxy-6-{4-(3-trifluoromethyl-pyridin-4-yl)-1-2-(dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine (28);
4-amino-6-{4-(3-trifluoromethyl-pyridin-4-yl)-1-2-(dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carbonitrile (29);
4-amino-6-{4-(3-trifluoromethyl-pyridin-4-yl)-1-2-(dimethylamino-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-5-carboxamide (30);
6-{4-[1-(2-Ethylamino-ethyl)-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropyl-pyrimidin-4-ylamine (31); and
6-{4-[1-[2-(3-Chloro-propylamino)-ethyl]-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-isopropyl-pyrimidin-4-ylamine (32);
and pharmaceutically acceptable salts, solvates, or solvates of salts thereof.

### Claim 2 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof, as active ingredient, together with a pharmaceutically acceptable carrier.

### Claim 3 (depends on 1)

A method for treating cancer selected from the group consisting of brain, lung, colon, epidermoid, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, uterine, rectal, oesophageal, testicular, gynecological, thyroid cancer, melanoma, hematologic malignancies, acute myelogenous leukemia, multiple myeloma, chronic myelogneous leukemia, myeloid cell leukemia, glioma and Kaposi's sarcoma, comprising administering to a subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, or solvate thereof.

### Claim 4 (depends on 1)

A kit consisting of separate packs of a) an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, or solvate thereof, and b) an effective amount of a further medicament active ingredient.

### Claim 5 (depends on 1)

A process for the preparation of the compounds of claim 1 and pharmaceutically usable salts, tautomers and stereoisomers thereof, comprising:
reacting a compound of formula (A), wherein, LG is a leaving group:
under basic conditions with compound of formula (B):
to yield the compound of the formula (I)