N-[4-(1H-PYRAZOLO[3,4-b]PYRAZIN-6-YL)-PHENYL]-SULFONAMIDES AND THEIR USE AS PHARMACEUTICALS

Patent metadata

Field	Value
Publication number	US-2016175304-A1
Application number	US-201514949758-A
Country	US
Kind code	A1
Filing date	Nov 23, 2015
Priority date	Sep 19, 2011
Publication date	Jun 23, 2016
Grant date	—

Abstract

The present invention relates to N-[4-(1H-pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides of the formula I,

wherein Ar, R1, R2 and n 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

1 . A method of treating a disease selected from the group consisting of a degenerative joint disorder, diabetes, a cardiovascular disease, fibrosis, an inflammatory process, a pain, a tumor, and a cerebral infarction in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof,

wherein
Ar is selected from the series consisting of phenyl and a 5-membered or 6-membered monocyclic aromatic heterocycle comprising 1, 2 or 3 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and bonded via a ring carbon atom, which are all unsubstituted or substituted by one or more identical or different substituents R10;
n is selected from the series consisting of 0, 1 and 2;
R1 is selected from the series consisting of hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O) 2 —R15, —N(R13)-C(O)—NH—R14, —C(O)—N(R16)-R17, —CN, (C 1 -C 4 )-alkyl and —(C 1 -C 4 )-alkyl-O—R18;
R2 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl and —CN;
R10 is selected from the series 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, —N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO 2 , —C(O)—N(R23)-R24 and —CN,
and two groups R10 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 8-membered unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl and —CN;
R11 and R12 are independently of one another selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl and —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl,
or R11 and R12, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 7-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R11 and R12, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;
R13 is selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl;
R14 and R15 are independently of one another selected from the series 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, Het and —(C 1 -C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30;
R16 is selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl;
R17 is selected from the series consisting of hydrogen, (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, Het and —(C 1 -C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30,
or R16 and R17, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 7-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;
R18 is selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;
R19 is selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl;
R20 is selected from the series consisting of hydrogen, (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, Het and —(C 1 -C 4 )-alkyl-Het, wherein phenyl and Het all are unsubstituted or substituted by one or more identical or different substituents R30,
or R19 and R20, together with the nitrogen atom carrying them, form a monocyclic, 4-membered to 7-membered, saturated heterocycle which, in addition to the nitrogen atom carrying R19 and R20, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;
R21 is selected from the series consisting of hydrogen, (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl;
R22 is selected from the series consisting of (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl and —(C 1 -C 4 )-alkyl-(C 3 -C 7 )-cycloalkyl;
R23 and R24 are independently of one another selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl;
R30 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl and —CN; and
Het is a monocyclic, 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocycle which comprises 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is bonded via a ring carbon atom;
wherein all cycloalkyl groups can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;
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 method of claim 1 , wherein
Ar is selected from the series consisting of phenyl and a 5-membered or 6-membered monocyclic aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and bonded via a ring carbon atom, which are all unsubstituted or substituted by one or more identical or different substituents R10; n is selected from the series consisting of 0, 1 and 2; R1 is selected from the series consisting of hydrogen, —N(R11)-R12, —N(R13)-C(O)—R14, —N(R13)-S(O) 2 —R15, —N(R13)-C(O)—NH—R14, (C 1 -C 4 )-alkyl and —(C 1 -C 4 )-alkyl-O—R18; R2 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and —CN; R10 is selected from the series consisting of halogen, (C 1 -C 4 )-alkyl, —O—(C 1 -C 4 )-alkyl, —N(R19)-R20, —N(R21)-N(R19)-R20, —N(R21)-C(O)—R22, —NO 2 , —C(O)—N(R23)-R24 and —CN, and two groups R10 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 7-membered unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and —CN; R11 and R12 are independently of one another selected from the series consisting of hydrogen and (C 1 -C 4 )-alkyl, or R11 and R12, together with the nitrogen atom carrying them

Assignees

• Sanofi Sa

Inventors

• Nazare Marc
• Halland Nis
• Schmidt Friedemann
• Weiss Tilo
• Dietz Uwe
• Hofmeister Armin
• Carry Jean-Christophe

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · 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

• 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