Aminopyrimidine derivatives for use as modulators of kinase activity

Patent metadata

Field	Value
Publication number	US-10080750-B2
Application number	US-201715490370-A
Country	US
Kind code	B2
Filing date	Apr 18, 2017
Priority date	Sep 12, 2011
Publication date	Sep 25, 2018
Grant date	Sep 25, 2018

Abstract

The invention provides novel heterocyclic amine compounds according to Formula (I) and their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

First claim

The invention claimed is:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt, solvate, or solvate of salt thereof, wherein:
X is N or CH;
Y is N;
E is

R 1 is H,
Hal is F, Cl, Br or I;
each LA is independently an unbranched or branched, linear saturated or partially unsaturated hydrocarbon chain having 1, 2, 3 4, 5 or 6 C atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal or OH;
each Ar is independently a mono- or bicyclic aromatic homo- or heterocycle having 0, 1, 2, 3 or 4 N, O and/or S atoms and 5, 6, 7, 8, 9, or 10 skeleton atoms, which may be unsubstituted or, independently of one another, mono- or disubstituted by Hal, LA, OH, SH, O(LA), NH 2 , NH(LA), N(LA) 2 , NO 2 , CN, OCN, COOH, COO(LA), CONH 2 , CONH(LA), CON(LA) 2 , NHCO(LA), NHCONH(LA), NHCONH 2 , CHO and CO(LA), and/or monosubstituted by Cyc 2 or O-Cyc 2 ;
each Cyc 1 is independently a 3, 4, 5 or 6 membered monocyclic aliphatic homo- or heterocycle having 0-2 heteroatoms, selected from O, S and N, which may be mono- or disubstituted by Hal, LA, NH 2 , NH(LA), N(LA) 2 , HO(LA)-;
each Cyc 2 is independently a 5 or 6 membered monocyclic aromatic homo- or heterocycle having 0-3 heteroatoms, selected from O, S and N, which may be mono- or di-substituted by Hal or LA; and
n is 1 or 2.

2. The compound according to claim 1 wherein
X is N,
or a pharmaceutically acceptable salt, solvate, or solvate of salt thereof.

3. The compound according to claim 1 , selected from:
6-{4-[1-(3-trifluoromethyl-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine (“71”);
6-{4-[1-(3-trifluoromethyl-phenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine (“73”);
6-{4-[1-(3-fluorophenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine (“76”);
6-{4-[1-(4-fluorophenyl)-2-pyrrolidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine (“78”); and
6-{4-[1-(4-fluoro-phenyl)-2-piperidin-1-yl-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine (“79”);
or a pharmaceutically acceptable salt, solvate, or solvate of salt thereof.

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

5. A method for treating cancer, comprising administering to a subject a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or solvate of salt thereof.

6. W The method of claim 5 , wherein said cancer is 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 such as acute myelogenous leukemia, multiple myeloma, chronic myelogneous leukemia, myeloid cell leukemia, glioma and Kaposi's sarcoma.

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

8. The compound according to claim 1 , wherein Ar is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by Hal, LA or O(LA), or a pharmaceutically acceptable salt, solvate, or solvate of salt, thereof.

9. The compound according to claim 1 , wherein
X is N,
Ar is phenyl or pyridyl, which is unsubstituted or mono- or disubstituted by Hal, LA or O(LA),
or a pharmaceutically acceptable salt, solvate, or solvate of salt thereof.

10. A compound selected from:
6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-bromo-pyrimidin-4-ylamine (“1”)
6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine (“2”)
6-{4-[(R)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine (“4”)
6-[4-(2-Amino-1-phenyl-ethyl)-piperazin-1-yl]-5-bromo-pyrimidin-4-ylamine (“5”)
6-[4-(2-Amino-1-phenyl-ethyl)-piperazin-1-yl]-5-(4-fluoro-phenyl)-pyrimidin-4-ylamine (“6”)
6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1H-pyrazol-4-yl)-pyrimidin-4-ylamine (“7”)
(R)-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrazol-4-yl)pyrimidin-4-amine (“9”),
5-(4-fluorophenyl)-6-(4-(2-(pyrrolidin-1-yl)-1-(4-(trifluoromethyl)-phenyl)-ethyl)-piperazin-1-yl)-pyrimidin-4-amine (“10”)
5-bromo-6-(4-(2-(piperidin-1-yl)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine (“11”)
5-(4-Fluoro-phenyl)-6-{4-[2-piperidin-1-yl-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-pyrimidin-4-ylamine (“12”)
5-(4-Fluoro-phenyl)-6-[4-(4-trifluoromethyl-benzyl)-piperazin-1-yl]-pyrimidin-4-ylamine (“13”)
5-bromo-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine (“14”)
(S)-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine (“16”)
(R)-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(4-fluorophenyl)pyrimidin-4-amine (“17”)
5-(6-aminopyridin-3-yl)-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)-phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine (“20”)
6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-vinylpyrimidin-4-amine (“21”)
2-(4-(4-amino-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)-piperazin-1-yl)pyrimidin-5-yl)phenyl)propan-2-ol (“22”)
Methyl 4-(4-amino-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl) piperazin-1-yl)pyrimidin-5-yl)benzoate (“23”)
6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(cyclohex-1-en-1-yl)pyrimidin-4-amine (“24”)
6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(cyclopent-1-en-1-yl)pyrimidin-4-amine (“25”)
4-(4-amino-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-5-yl)benzoic acid (“26”)
5-Cyclopropyl-6-(4-(2-(dimethylamino)-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)pyrimidin-4-amine (“28”)
5-Bromo-6-{4-[(1-methyl-1H-imidazol-2-yl)-phenyl-methyl]-piperazin-1-yl}-pyrimidin-4-ylamine (“29”)
5-(4-Fluoro-phenyl)-6-{4-[(1-methyl-1H-imidazol-2-yl)-phenyl-methyl]-piperazin-1-yl}-pyrimidin-4-ylamine (“30”)
6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-methoxypyrimidin-4-amine (“31”)
6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidin-4-amine (“33”)
6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(benzyloxy)pyrimidin-4-amine (“34”)
(35) 4-amino-6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl) pyrimidin-5-ol (“35”)
4-Amino-6-{4-[2-amino-l-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-pyrimidine-5-carbonitrile (“36”)
6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(1H-pyrrol-3-yl)pyrimidin-4-amine (“37”)
6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(isoxazol-4-yl)pyrimidin-4-amine (“38”)
6-(4-(2-amino-1-(4-(trifluoromethyl)phenyl)ethyl)piperazin-1-yl)-5-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-4-amine (“39”)
6-{4-[2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-ylamine (“40”)
6-{4-[(S)-2-Amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-5-(1-methy

Assignees

• Merck Patent Gmbh

Inventors

• Lan Ruoxi
• Huck Bayard R
• Chen Xiaoling
• Deselm Lizbeth C
• Qiu Hui
• Xiao Yufang
• Neagu Constantin
• Mochalkin Igor
• Johnson Theresa L

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title