Sulfoximine substituted quinazolines for pharmaceutical compositions

Patent metadata

Field	Value
Publication number	US-9139577-B2
Application number	US-201414315399-A
Country	US
Kind code	B2
Filing date	Jun 26, 2014
Priority date	Jun 28, 2013
Publication date	Sep 22, 2015
Grant date	Sep 22, 2015

Abstract

This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I

wherein Ar, R 1 and R 2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.

First claim

The invention claimed is:

1. A compound of formula I

wherein
Ar is selected from a group consisting of:

 wherein X is CH;
R 3 is H, halogen, CN or —C(═O)—NH 2 ; and
R 4 is selected from a group consisting of:

wherein R 7 is selected from a group consisting of H, CN, C 1-6 -alkyl, —O—(C 1-3 -alkyl), C 2-4 -alkynyl, C 3-7 -cycloalkyl, heterocyclyl, —(C 1-3 -alkyl)-heterocyclyl, —(C 1-3 -alkyl)-O-heterocyclyl, aryl, —(C 1-3 -alkyl)-aryl, 5- or 6-membered heteroaryl, —(C 1-3 -alkyl)-heteroaryl, —COOH, —(C═O)—O—(C 1-6 -alkyl), —(C═O)—N═S(═O)(C 1-3 -alkyl) 2 and —(C═O)—NR N1 R N2 ;
wherein R N1 is H or C 1-3 -alkyl; and
R N2 is selected from a group consisting of H, C 1-6 -alkyl, C 2-5 -alkynyl, C 3-7 -cycloalkyl, heterocyclyl, —(C 1-3 -alkyl)-heterocyclyl, —(C 1-3 -alkyl)-aryl and —SO 2 —(C 1-3 -alkyl);
or R N1 and R N2 together with the N-atom to which they are attached form a azetidinyl, pyrrolidinyl, piperidinyl, 4-oxo-piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl or 1-imino-1,4-thiazinane-1-oxide ring, which may be substituted with one OH, C 1-3 -alkyl or —O—C 1-3 -alkyl; and
wherein in R 4 , each heterocyclyl is selected from a group consisting of 4-, 5- or 6-membered saturated monocyclic ring systems containing 1, 2 or 3 heteroatoms independently of each other selected from the group consisting on O, S, N and NH, wherein one —CH 2 — group may be replaced by a —C(═O)— group and wherein each heterocyclyl group is optionally substituted with C 1-3 -alkyl;
wherein in R 4 , each aryl is phenyl or naphthyl;
wherein in R 4 , each heteroaryl is selected from a group consisting of 5- or 6-membered monocyclic heteroaromatic ring systems containing 1, 2 or 3 heteroatoms independently of each other selected from the group consisting on O, S, N and NH and is optionally substituted with C 1-3 -alkyl;
wherein in R 4 , each alkyl is optionally substituted with 1 or more F or with one or two substituents independently selected from the group consisting of CN, OH, —O—(C 1-3 -alkyl), —O-tetrahydrofuranyl, NH 2 , —NH—(C═O)—(C 1-3 -alkyl), —NH—(C═O)—NH—(C 1-3 -alkyl) or —NH—SO 2 —(C 1-3 -alkyl); and
wherein in R 4 , each cycloalkyl is optionally substituted with 1 or more F or one CN, OH, CF 3 , —O—(C 1-3 -alkyl) or ═O; and
R 8 and R 9 are independently of each other selected from the group consisting of:
H and C 1-3 -alkyl optionally substituted with 1-3 F or one OH or NH 2 ;
R 1 is selected from a group consisting of:

wherein R 5 is selected from the group consisting of:
a) C 1-3 -alkyl, which is optionally substituted with a substituent selected from the group consisting of —O—(C 1-3 -alkyl), —O—C 3-7 -cycloalkyl, —O-heterocyclyl, C 3-7 -cycloalkyl, heterocyclyl and phenyl,

wherein each alkyl group is optionally substituted with one or more F; and
b) C 2-3 -alkenyl, C 2-3 -alkynyl, C 3-7 -cycloalkyl, heterocyclyl, heteroaryl, and aryl; and

R 6 is C 1-3 -alkyl which is optionally substituted with one or more F,
or wherein R 5 and R 6 together with the sulfur atom to which they are attached form a 4 to 7-membered saturated or partly unsaturated heterocycle that further to the sulfur atom may contain one additional heteroatom selected from the group consisting of O, S and NR N ,
wherein R N is H, C 1-3 -alkyl, —C(═O)—(C 1-3 -alkyl), —C(═O)—O—(C 1-4 -alkyl), —C(═O)—(C 1-3 -alkyl)-O—(C 1-4 -alkyl), —C(═O)—NH 2 , —C(═O)—NH(C 1-3 -alkyl), —C(═O)—N(C 1-3 -alkyl) 2 or —SO 2 (C 1-4 -alkyl);
and wherein R 5 , R 6 and the heterocycles formed by R 5 and R 6 together with the sulfur atom to which they are attached may each be independently substituted with halogen, CN, OH, NH 2 , —NH(C 1-4 -alkyl), —N(C 1-4 -alkyl) 2 , —NH—C(═O)—(C 1-4 -alkyl), —NH—C(═O)—O—(C 1-4 -alkyl), —NH—C(═O)—NH 2 , —NH—C(═O)—NH—(C 1-4 -alkyl), —NH—C(═O)—N(C 1-4 -alkyl) 2 , —N(C 1-4 -alkyl)-C(═O)—(C 1-4 -alkyl), —N(C 1-4 -alkyl)-C(═O)—O—(C 1-4 -alkyl), —N(C 1-4 -alkyl)-C(═O)—NH 2 , —N(C 1-4 -alkyl)-C(═O)—NH—(C 1-4 -alkyl), —N(C 1-4 -alkyl)-C(═O)—N(C 1-4 -alkyl) 2 , —O—(C 1-4 -alkyl), C 1-6 -alkyl, C 3-7 -cycloalkyl, heterocyclyl, heteroaryl, —C(═O)—NH 2 , —C(═O)—NH(C 1-4 -alkyl), —C(═O)—N(C 1-4 -alkyl) 2 , —COOH, —C(═O)—O—(C 1-4 -alkyl), —(C 1-4 -alkyl)-NH—C(═O)—(C 1-4 -alkyl); —SO—(C 1-4 -alkyl) or —SO 2 —(C 1-4 -alkyl); and
R 2 is selected from a group consisting of halogen, CN, OH, NH 2 , C 1-3 -alkyl, C 2-3 -alkenyl, C 2-3 -alkynyl, C 3-5 -cycloalkyl, —O—(C 1-3 -alkyl), —O-cyclopropyl and —S—C 1-3 -alkyl, wherein each alkyl group is optionally substituted with one or more F; and
wherein, if not otherwise specified, each alkyl group in the above definitions is linear or branched and may be substituted with one to three F;
or a stereoisomer or salt thereof.

2. The compound according to claim 1 , wherein R 1 is selected from a group consisting of:

wherein R 5 is selected from the group consisting of:
a) C 1-3 -alkyl, which is optionally substituted with —O—(C 1-3 -alkyl), —O—C 3-7 -cycloalkyl, C 3-7 -cycloalkyl, or phenyl,

wherein each alkyl group is optionally substituted with one or more F; and
b) C 3-7 -cycloalkyl, pyridinyl, and phenyl; and

R 6 is C 1-3 -alkyl which is optionally substituted with one or more F;
or wherein R 5 and R 6 together with the sulfur atom to which they are attached form a 4- to 7-membered saturated or partly unsaturated heterocycle that further to the sulfur atom may contain one additional heteroatom selected from the group consisting of O, S and NR N ,
wherein R N is H, C 1-3 -alkyl, —C(═O)—(C 1-3 -alkyl), —C(═O)—O—(C 1-4 -alkyl), —C(═O)—(C 1-3 -alkyl)-O—(C 1-4 -alkyl), —C(═O)—NH 2 , —C(═O)—NH(C 1-3 -alkyl), —C(═O)—N(C 1-3 -alkyl) 2 or —SO 2 (C 1-4 -alkyl);
or a salt thereof.

3. The compound according to claim 1 , wherein R 2 is selected from a group consisting of F, Cl, Br, CH 3 , CF 3 , cyclopropyl and —O—CH 3 ,
or a salt thereof.

4. The compound according to claim 1 , wherein
R 3 is F, Cl, Br, CN or —C(═O)—NH 2 ;
or a salt thereof.

5. The compound according to claim 4 , wherein R 3 is F,
or a salt thereof.

6. The compound according to claim 1 , wherein R 4 is selected from a group consisting of:

wherein R 7 is selected from a group consisting of CN; C 1-6 -alkyl, —O—(C 1-3 -alkyl), C 2-4 -alkynyl, C 3-7 -cycloalkyl, heterocyclyl, —(C 1-3 -al kyl)-heterocyclyl, —(C 1-3 -alkyl)-O-heterocyclyl, aryl, —(C 1-3 -alkyl)-aryl, 5- or 6-membered heteroaryl, —(C 1-3 -alkyl)-heteroaryl, —COOH, —(C═O)—O—(C 1-6 -alkyl), —(C═O)—N═S(═O)(C 1-3 -alkyl) 2 and —(C═O)—NR N1 R N2 ;
wherein R N1 is H or C 1-3 -alkyl; and
R N2 is selected from a group consisting of H, C 1-6 -alkyl, C 2-5 -alkynyl, C 3-7 -cycloalkyl, heterocyclyl, —(C 1-3 -alkyl)-heterocyclyl, —(C 1-3 -alkyl)-aryl, —SO 2 —(C 1-3 -alkyl);
or R N1 and R N2 together with the N-atom to which they are attached form a azetidinyl, pyrrolidinyl, piperid

Assignees

• Blum Andreas
• Gottschling Dirk
• Heckel Armin
• Hehn Joerg P
• Schmid Bernhard
• Wiedenmayer Dieter
• Boehringer Ingelheim Int

Inventors

• Blum Andreas
• Gottschling Dirk
• Heckel Armin
• Hehn Joerg P
• Schmid Bernhard
• Wiedenmayer Dieter

Classifications

• A61P43/00

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title