N-(4-(azaindazol-6-yl)-phenyl)-sulfonamides and their use as pharmaceuticals

Patent metadata

Field	Value
Publication number	US-9718825-B2
Application number	US-201414775620-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Mar 13, 2013
Publication date	Aug 1, 2017
Grant date	Aug 1, 2017

Abstract

The present invention relates to N-(4-(azaindazol-6-yl)-phenyl)-sulfonamides of the formula I,

wherein Ar, n, X, Z, R1, R2 and R3 have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds which modulate protein kinase activity, specifically the activity of serum and glucocorticoid regulated kinase (SGK), in particular of serum and glucocorticoid regulated kinase isoform 1 (SGK-1, SGK1), and are suitable for the treatment of diseases in which SGK activity is inappropriate, for example degenerative joint disorders or inflammatory processes such as osteoarthritis or rheumatism. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use as pharmaceuticals, and pharmaceutical compositions comprising them.

First claim

The invention claimed is:

1. A compound of formula I, a stereoisomeric form thereof, or a pharmaceutically acceptable salt of any of the foregoing,

wherein
Ar is selected from the group consisting of phenyl and a 5-membered or 6-membered monocyclic, aromatic, heterocyclic group which comprises 1, 2 or 3 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom, which all are unsubstituted or substituted by one or more identical or different substituents R5;
n is selected from the group consisting of 0, 1 and 2;
X is selected from the group consisting of N and CH;
Z is selected from the group consisting of a direct bond, O, S and N(R10);
R1 is selected from the group consisting of H, —N(R11)-R12, —N(R13)-C(O)-R14, —N(R13)-S(O) 2 —R15, —N(R13)-C(O)—NH—R16, (C 1 -C 4 )-alkyl and —(C 1 -C 4 )-alkyl-O—R17;
R2 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl and —CN;
R3 is selected from the group consisting of H, (C 1 -C 8 )-alkyl, R30 and —(C 1 -C 4 )-alkyl-R30, wherein (C 1 -C 5 )-alkyl is unsubstituted or substituted by one or more identical or different substituents R31;
R5 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, —O—(C 1 -C 4 )-alkyl, —O—(C 3 -C 7 )-cycloalkyl, —O—(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, —C(O)—N(R6)-R7 and —CN,
or two groups R5 attached to adjacent ring carbon atoms of Ar, together with the carbon atoms to which they are attached, form a 5-membered to 8-membered monocyclic, unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents R8;
R6 and R7 are independently selected from the group consisting of H and (C 1 -C 4 )-alkyl;
R8 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl and —CN;
R10 is selected from the group consisting of H and (C 1 -C 4 )-alkyl;
R11 and R12 are independently selected from the group consisting of H, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, Het1, —(C 1 -C 4 )-alkyl-Het1 and —(C 1 -C 4 )-alkyl-phenyl, wherein phenyl is unsubstituted or substituted by one or more identical or different substituents R50,
or R11 and R12, together with the nitrogen atom to which they are attached, form a 4-membered to 7-membered monocyclic, saturated, heterocyclic group which, in addition to the nitrogen atom to which R11 and R12 are attached, comprises 0 or 1 further ring heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl;
R13 is selected from the group consisting of H, (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl;
R14 and R16 are independently selected from the group consisting of (C 1 -C 8 )-alkyl, (C 3 -C 7 )-cycloalkyl, —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, phenyl, —(C 1 -C 4 )-alkyl-phenyl, Het2 and —(C 1 -C 4 )-alkyl-Het2, wherein (C 1 -C 8 )-alkyl and (C 3 -C 7 )-cycloalkyl all are unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of —OH and —O—(C 1 -C 4 )-alkyl, and wherein phenyl and Het2 all are unsubstituted or substituted by one or more identical or different substituents R50;
R15 is selected from the group consisting of (C 1 -C 8 )-alkyl, phenyl and Het3, wherein phenyl and Het3 all are unsubstituted or substituted by one or more identical or different substituents R50;
R17 is selected from the group consisting of H and (C 1 -C 4 )-alkyl;
R30 is a 3-membered to 12-membered monocyclic or bicyclic, saturated or partially unsaturated cyclic group which comprises 0 ring heteroatoms, which is unsubstituted or substituted by one or more identical or different substituents R32, or
R30 is a 3-membered to 12-membered monocyclic or bicyclic, saturated, partially unsaturated or aromatic, cyclic group which comprises 1, 2 or 3 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which is unsubstituted or substituted by one or more identical or different substituents R32;
R31 is selected from the group consisting of halogen, —OH, —O—(C 1 -C 4 )-alkyl, —O—(C 3 -C 7 )-cycloalkyl, —O—(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, —N(R33)-R34, —CN and —C(O)—N(R35)-R36;
R32 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl, —(C 1 -C 4 )-alkyl-O—R37, —(C 1 -C 4 )-alkyl-N(R38)-R39, —(C 1 -C 4 )-alkyl-CN, —C(O)—(C 1 -C 4 )-alkyl, —CN, —OH, ═O, —O—(C 1 -C 4 )-alkyl, —N(R40)-R41, —C(O)—O—(C 1 -C 4 )-alkyl and —C(O)—N(R42)-R43;
R33, R34, R35, R36, R37, R38, R39, R40, R41, R42 and R43 are independently selected from the group consisting of H and (C 1 -C 4 )-alkyl;
R50 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl and —CN;
Het1 is a 4-membered to 7-membered monocyclic, saturated, heterocyclic group which comprises 1 or 2 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom, and which is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl;
Het2 is a 4-membered to 7-membered monocyclic, saturated, partially unsaturated or aromatic, heterocyclic group which comprises 1 or 2 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom; and
Het3 is a 5-membered or 6-membered monocyclic, aromatic, heterocyclic group which comprises 1, 2 or 3 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom;
wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical or different substituents selected from the group consisting of fluorine and (C 1 -C 4 )-alkyl; and
wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.

2. The compound of claim 1 , a stereoisomeric form thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein
Ar is selected from the group consisting of phenyl and a 5-membered or 6-membered monocyclic, aromatic, heterocyclic group which comprises 1 or 2 identical or different ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and is bonded via a ring carbon atom, which all are unsubstituted or substituted by one or more identical or different substituents R5;
R1 is selected from the group consisting of H, —N(R11)-R12, —N(R13)-C(O)-R14, —N(R13)-S(O) 2 —R15, —N(R13)-C(O)—NH—R16 and (C 1 -C 4 )-alkyl;
R5 is selected from the group consisting of halogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl, —O—(C 1 -C 4 )-alkyl, —O—(C 3 -C 7 )-cycloalkyl, —C(O)—N(R6)-R7 and —CN,
or two groups R5 attached to adjacent ring carbon atoms of Ar, together with the carbon atoms to which they are attached, fo

Assignees

• Sanofi Sa

Inventors

• Nazare Marc
• Halland Nis
• Schmidt Friedemann
• Kleemann Heinz-Werner
• Weiss Tilo
• Saas Joachim
• Struebing Carsten

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title