Aldosterone synthase inhibitors

Patent metadata

Field	Value
Publication number	US-2017267688-A1
Application number	US-201515532126-A
Country	US
Kind code	A1
Filing date	Dec 1, 2015
Priority date	Dec 2, 2014
Publication date	Sep 21, 2017
Grant date	—

Abstract

The present invention relates to compounds of the formulas (IA) and (IB) and pharmaceutically acceptable salts thereof, wherein A and R 1 -R 6 , are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

First claim

1 . A compound of formula IA or IB

wherein:
A is selected from the group consisting of
benzoimidazolyl, benzo[d]isoxazolyl, benzooxazolyl, benzothiazolyl, benzotriazolyl, chromanyl, chromenyl, cyclohexen-1-yl, 2,3-dihydro-benzo[1,4]dioxinyl, 2,3-dihydro-5H-benzo[e][1,4]dioxepinyl, 3,4-dihydro-2H-benzo[1,4]dioxepinyl, 3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-onyl, 2,3-dihydro-benzofuranyl, 4,5-dihydro-1H-indazolyl, 1,3-dihydroindol-2-onyl, 1,3-dihydro-isoindolyl, 3,4-dihydro-2H-isoquinolin-1-onyl, 3,4-dihydro-2H-naphthalen-1-onyl, 3,4-dihydro-2H-[1,8]napthyridinyl, 7,8-dihydro-5H-pyrano[4,3-b]pyridinyl, 6,7-dihydro-[1]pyrindin-5-onyl, 3,4-dihydro-1H-quinolin-2-onyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, indanyl, indazolyl, indolyl, isochromanyl, isoquinolinyl, phenyl, pyrazolyl, pyrrolo[2,3-b]pyridinyl, quinolinyl, 1,3,4,5-tetrahydro-benzo[c]oxepinyl, 4, 5, 6, 7-tetrahydroindazolyl, thiazolyl and [1,2,4]triazolo[4,3-a]pyridinyl; wherein A is optionally substituted with one to three groups selected from C 1-6 alkyl, C 3-5 cycloalkyl, —OH, oxo, C 1-6 alkoxy, halogen, —CF 3 , —CN, —C(O)C 1-3 alkyl and —C(O)NH 2 ;
R 1 is selected from H and —C 1-3 alkyl;
R 2 is selected from —OH, —CN, —NH 2 , —N(C 1-3 alkyl) 2 , —NHC(O)C 1-3 alkyl, —NHC(O) C 3-5 cycloalkyl, —NHSO 2 C 1-3 alkyl and —NHC(O)CH 2 C(CH 3 ) 2 —OH;
R 3 is H;
R 4 is H; or
R 3 and R 4 together form a spiro cyclopropyl group;
R 5 is H or —C 1-3 alkyl; and
R 6 is —OH;

or a salt thereof.

2 . The compound of the formula IA according to claim 1 , or a salt thereof.

3 . The compounds of the formula IB according to claim 1 , wherein
A is selected from the group consisting of benzo[d]isoxazol-5-yl, benzotriazol-5-yl, chromen-6- or -7-yl, cyclohexen-1-yl, 4,5-dihydro-1H-indazol-6-yl, 3,4-dihydro-2H-[1,8]napthyridin-6-yl, imidazo[1,5-a]pyridine-6-yl, indan-5-yl, indazol-5- or -6-yl, isochroman-7-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, 2,3-dihydro-5H-benzo[1,4]dioxepin-7-yl, 3,4-dihydro-2H-naphthalen-1-on-6- or -7-yl, chroman-6- or -7-yl, 1,3,4,5-tetrahydro-benzo[c]oxepin-8-yl and 4, 5, 6, 7-tetrahydroindazol-6-yl; R 5 is H or —CH 3 ; and R 6 is OH;
or a salt thereof.

4 . The compound of the formula IA according to claim 1 , wherein
A is selected from the group consisting of benzoimidazol-5-yl, benzo[d]isoxazol-5-yl, benzooxazol-5-yl, benzothiazol-5-yl, benzotriazol-5-yl, chroman-6- or -7-yl, chromen-6- or -7-yl, cyclohexen-1-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,3-dihydro-5H-benzo[e][1,4]dioxepin-7-yl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, 4,5-dihydro-1H-indazol-6-yl, 1,3-dihydroindol-2-on-5-yl, 3,4-dihydro-2H-isoquinolin-1-on-6-yl, 3,4-dihydro-2H-naphthalen-1-on-6- or -7-yl, 3,4-dihydro-2H-[1,8]napthyridin-6-yl, 3,4-dihydro-1H-quinolin-2-on-6-yl, imidazo[1,2-a]pyridine-7-yl, imidazo[1,5-a]pyridine-6-yl, indan-5-yl, indazol-5- or -6-yl, isochroman-7-yl, isoquinolin-6-yl, phenyl, quinolin-3- or -6-yl and 4, 5, 6, 7-tetrahydroindazol-6-yl, indol-5 or 6-yl, 1,3,4,5-tetrahydro-benzo[c]oxepin-8-yl; wherein A is optionally substituted with one to three groups selected from C 1-3 alkyl, C 3-5 cycloalkyl, —OH, oxo, C 1-3 alkoxy, Cl, F, —CF 3 , —CN, —C(O)CH 3 and —C(O)NH 2 ; R 1 is selected from H and —CH 3 ; and R 2 is selected from —OH, —CN, —NH 2 , —N(CH 3 ) 2 , —NHC(O)C 1-3 alkyl, —NHC(O)cyclopropyl, —NHSO 2 C 1-3 alkyl and —NHC(O)CH 2 C(CH 3 ) 2 —OH;
or a salt thereof.

5 . The compound of the formula IA according to claim 1 , wherein
A is selected from the group consisting of benzo[d]isoxazol-5-yl, benzotriazol-5-yl, chromen-6- or -7-yl, cyclohexen-1-yl, 4,5-dihydro-1H-indazol-6-yl, 3,4-dihydro-2H-[1,8]napthyridin-6-yl, imidazo[1,5-a]pyridine-6-yl, indan-5-yl, indazol-5- or -6-yl, isochroman-7-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, 2,3-dihydro-5H-benzo[e][1,4]dioxepin-7-yl, 3,4-dihydro-2H-naphthalen-1-on-6- or -′7-yl, chroman-6- or -′7-yl, 1,3,4,5-tetrahydro-benzo[c]oxepin-8-yl and 4, 5, 6, 7-tetrahydroindazol-6-yl; wherein A is optionally substituted with one to three groups selected from C 1-3 alkyl, C 3-5 cycloalkyl, —OH, oxo, C 1-3 alkoxy, Cl, F, —CF 3 , —CN, —C(O)CH 3 and —C(O)NH 2 ; and R 2 is selected from —OH, —CN, —NHC(O)C 1-3 alkyl, —NHC(O)cyclopropyl, —NHSO 2 C 1-3 alkyl and —NHC(O)CH 2 C(CH 3 ) 2 —OH;
or a salt thereof.

6 . The compound according to claim 1 selected from the group consisting of

and the pharmaceutically acceptable salts thereof.

7 . The compound according to claim 6 selected from the group consisting of compound numbers
9, 12-18, 29, 34, 36-38, 43-45, 47, 48, 55, 60, 61, 65, 68, 69, 71, 73-77, 81, 83, 85, 89, 90, 92, 94, 96, 102-105, 107, 110, 112-114, 116, 118, 121, 123, 125-129, 131-133, 136, 142, 143, 148-150, 152-154, 157, 158, 160-164, 166, 168-172, 175-179, 183 and 185-199 and the pharmaceutically acceptable salts thereof.

8 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient or carrier.

9 . A m

Assignees

• Boehringer Ingelheim Int

Inventors

• Chen Zhidong
• Cogan Derek
• Guo Xin
• Marshall Daniel Richard
• Meyers Kenneth Michael
• Zhang Yunlong

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · 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

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

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