Fused bicyclic imidazoles

Patent metadata

Field	Value
Publication number	US-9387204-B2
Application number	US-201314090367-A
Country	US
Kind code	B2
Filing date	Nov 26, 2013
Priority date	Aug 14, 2007
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

Compounds of formula (I)

a tautomer or stereoisomer thereof, or a salt thereof, wherein ring B and the imidazole to which it is fused, R4, R6 and R7 have the meanings as given in the description and the claims, are effective inhibitors of the Pi3K/Akt pathway.

First claim

We claim:

1. A compound of formula (I)

wherein ring B and the imidazole to which it is fused form a

wherein
R1 is hydrogen, 1-4C-alkyl, halogen, amino, —SR2, trifluoromethyl, cyano, 3-7C-cycloalkyl, 2-4C-alkenyl, 2-4C-alkynyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, mono- or di-1-4C-alkylamino, mono- or di-1-4C-alkylaminocarbonyl, —C(NH)NH2, —C(O)NH2 or —C(O)OR 10
R2 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl,
R3 is hydrogen, 1-4C-alkyl or halogen,
R4 is phenyl substituted by R5, unsubstituted phenyl, thienyl, pyridinyl, thiazolyl or oxazolyl,
R5 is 1-4C-alkyl, halogen or 1-4C-alkoxy,
R6 is hydrogen or 1-4C-alkyl,
R7 is —W—Y,
W is a monocyclic 5-membered heteroarylene comprising 1 nitrogen atom and optionally 1 or 2 further heteroatoms independently selected from oxygen, nitrogen and sulphur,
and wherein the heteroarylene is optionally substituted by R8,

R8 is 1-4C-alkyl or 3-7C-cycloalkyl,
Y is phenyl or a monocyclic 5- or 6-membered heteroaryl comprising 1 nitrogen atom and optionally 1 or 2 further heteroatoms independently selected from oxygen, nitrogen, sulphur,
and wherein the heteroaryl is optionally substituted by R9,

R9 is 1-4C-alkyl, 1-4C-alkoxy or halogen,
R10 is hydrogen or 1-4C-alkyl,
or a pharmaceutically acceptable salt, tautomer, or stereoisomer of said compound, or a pharmaceutically acceptable salt of said tautomer or said stereoisomer.

2. The compound according to claim 1 , wherein ring B and the imidazole to which it is fused form a

wherein
R1 is hydrogen, 1-4C-alkyl, halogen, amino, —SR2, trifluoromethyl, cyano, 3-7C-cycloalkyl, 2-4C-alkenyl, 2-4C-alkynyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, mono- or di-1-4C-alkylamino, mono- or di-1-4C-alkylaminocarbonyl, —C(NH)NH2, —C(O)NH2 or —C(O)OR 10
R2 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl,
R3 is hydrogen, 1-4C-alkyl or halogen,
R4 is phenyl substituted by R5, unsubstituted phenyl, thienyl, pyridinyl, oxazolyl or thiazolyl,
R5 is 1-4C-alkyl, halogen or 1-4C-alkoxy,
R6 is hydrogen or methyl,
R7 is —W—Y,
W is triazolylene, pyrazolylene, oxadiazolylene or imidazolylene, each of which is optionally substituted by R8,
R8 is 1-4C-alkyl or 3-7C-cycloalkyl,
Y is phenyl, furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is optionally substituted by R9,
R9 is 1-4C-alkyl, 1-4C-alkoxy or halogen,
R10 is hydrogen or 1-4C-alkyl,
or a pharmaceutically acceptable salt, tautomer, or stereoisomer of said compound, or a pharmaceutically acceptable salt of said tautomer or said stereoisomer.

3. The compound according to claim 1 , wherein ring B and the imidazole to which it is fused form a

wherein
R1 is hydrogen, 1-4C-alkyl, halogen, amino, —SR2, trifluoromethyl, cyano, 3-7C-cycloalkyl, 2-4C-alkenyl, 2-4C-alkynyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, mono- or di-1-4C-alkylamino, mono- or di-1-4C-alkylaminocarbonyl, —C(NH)NH2, —C(O)NH2 or —C(O)OR10
R2 is hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl,
R3 is hydrogen, 1-4C-alkyl or halogen,
R4 is phenyl substituted by R5, unsubstituted phenyl, thienyl, pyridinyl, oxazolyl or thiazolyl,
R5 is 1-4C-alkyl, halogen or 1-4C-alkoxy,
R6 is hydrogen or methyl,
R7 is —W—Y,
W is 1,2,4-triazolylene, pyrazolylene, 1,2,4-oxadiazolylene or imidazolylene,
Y is phenyl, furan-2-yl, thien-2-yl, pyrrol-2-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl, oxazol-2-yl, oxazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl, each of which is optionally substituted by R9,
R9 is 1-4C-alkyl, 1-4C-alkoxy or halogen,
R10 is hydrogen or 1-4C-alkyl,
or a pharmaceutically acceptable salt, tautomer, or stereoisomer of said compound, or a pharmaceutically acceptable salt of said tautomer or said stereoisomer.

4. The compound according to claim 1 , wherein ring B and the imidazole to which it is fused form a

wherein
R1 is hydrogen, 1-4C-alkyl, halogen, —SR2, amino, trifluoromethyl, cyano, 2-4C-alkenyl, 2-4C-alkynyl, 1-4C-alkoxy, mono- or di-1-4C-alkylamino, mono- or di-1-4C-alkylaminocarbonyl, —C(NH)NH2, —C(O)NH2 or —C(O)OR10
R2 is 1-4C-alkyl,
R3 is hydrogen or halogen,
R4 is phenyl substituted by R5, unsubstituted phenyl, thienyl, pyridinyl, oxazolyl or thiazolyl,
R6 is hydrogen,
R7 is —W—Y,
W is 1,2,4-triazolylene, pyrazolylene or 1,2,4-oxadiazolylene,
Y is phenyl, furan-2-yl, thien-2-yl, pyrrol-2-yl, pyridin-4-yl, thiazol-2-yl, pyridin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrazin-2-yl or pyridazin-3-yl, each of which is optionally substituted by R9,
R9 is 1-4C-alkyl, 1-4C-alkoxy or halogen,
R10 is hydrogen or 1-4C-alkyl,
or a pharmaceutically acceptable salt, tautomer, or stereoisomer of said compound, or a pharmaceutically acceptable salt of said tautomer or said stereoisomer.

5. A compound according to claim 1 , selected from the group consisiting of
3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
3-phenyl-2-(4-{[4-(3-pyrazin-2-yl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
6-bromo-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
3-(4-fluorophenyl)-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
7-methyl-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
3-(4-methoxyphenyl)-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
6-chloro-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
6-iodo-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
7-methoxy-3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)pipendin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)pipendin-1-yl]methyl}phenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine;
3-phenyl-2-(4-{[4-(3-pyridin-2-yl-pyrazol-5-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-(3-thienyl)imidazo[1,2-a]pyrimidine;
2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-(2-thienyl)imidazo[1,2-a]pyrimidine;
3-pyridin-4-yl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)-3-(1,3-thiazol-2-yl)imidazo[1,2-a]pyrimidine;
3-(2-fluorophenyl)-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine
3-phenyl-2-(4-{[4-(5-pyridin-4-yl-1H-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyrimidine;
2-[4

Assignees

• Bayer Ip Gmbh

Inventors

• HÖLDER Swen
• Zülch Armin
• Bär Thomas
• Maier Thomas
• Zimmermann Astrid
• Beckers Thomas
• Gekeler Volker
• Joshi Hemant
• Munot Yogesh
• Bhise Umesh
• Chavan Sunil
• Shivatare Sachin
• Patel Sarvesh
• Gore Vikas

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D417/04

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

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title