Aldosterone synthase inhibitors

Patent metadata

Field	Value
Publication number	US-9745289-B2
Application number	US-201514882486-A
Country	US
Kind code	B2
Filing date	Oct 14, 2015
Priority date	Oct 15, 2014
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

The present invention relates to compounds of formula I:

and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 and R 3 , 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

What is claimed is:

1. A compound of the formula I

wherein:
R 1 is selected from —C(O)NH 2 , —C(O)NH(CH 3 ) and —CN;
R 2 is —(X)—R 4 , wherein
—(X)— is a bond, —CH 2 —, or —O—; and
R 4 is selected from
—H;
C 1-3 alkyl, optionally substituted with one to four groups selected from —F, —SO 2 C 1-3 alkyl, and —OH;
halogen;
—CN;
—SO 2 C 1-3 alkyl;
—C(O)N(C 1-3 alkyl) 2 , provided —(X)— is not —O—;
—NHC(O)R 5 or —N(CH 3 )C(O)R 5 , provided that —(X)— is —CH 2 — and wherein R 5 is selected from C 3-6 cycloalkyl and C 1-3 alkyl optionally substituted with one to three —F groups;
—NHSO 2 C 1-3 alkyl;
—CH(cyclopropyl)NHSO 2 C 1-3 alkyl;
—OCH 2 C(O)N(C 1-3 alkyl) 2 , provided that —(X)— is —CH 2 —;
—S(═O)(═NH)CH 3 , provided that —(X)— is —CH 2 —;
heterocyclyl selected from tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, 1,1-dioxo[1,2]-thiazine, morpholinyl, oxazolidinyl, piperidinyl, azetidinyl, wherein said heterocyclyl is optionally substituted with one to three groups selected from —C(O)C 1-3 alkyl, halogen, —OH, oxo and C 1-3 alkyl;
—C(O)-heterocyclyl, provided that —(X)— is —CH 2 , wherein said heterocyclyl is selected from morpholin-4-yl, pyrrolidin-1-yl and piperidin-1-yl, optionally substituted with one or two groups selected from —F and —OH;
C 3-6 cycloalkyl optionally substituted with —CN or —OH; and
phenyl, optionally substituted with —SO 2 NH 2 ; and
R 3 is H, or C 1-3 alkyl optionally substituted with —OH; or
R 2 and R 3 together form an annelated five-membered cycloalkyl ring optionally substituted with —OH;
or a salt or a stereoisomer thereof.

2. The compound according to claim 1 , wherein:
R 1 is —C(O)NH 2 or —CN;
R 2 is —(X)—R 4 , wherein
—(X)— is a bond, and
R 4 is selected from
—CH 3 ,
—CF 3 ;
—CHF 2 ;
—CH 2 OH;
—CH(OH)CH 3 ;
—CH(OH)CF 3 ;
—F;
—CN;
heterocyclyl selected from tetrahydropyranyl and pyrrolidinyl, wherein said heterocyclyl is optionally substituted with one to three groups selected from C 1-3 alkyl, halogen, —OH and oxo;
C 3-6 cycloalkyl optionally substituted with —CN or —OH; and
phenyl, optionally substituted with —SO 2 NH 2 ; or
—(X)— is O, and
R 4 is selected from
C 1-3 alkyl;
—CH 2 SO 2 C 1-3 alkyl; and
heterocyclyl selected from tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, and azetidinyl, wherein said heterocyclyl is optionally substituted with one to three groups selected from —C(O)C 1-3 alkyl, halogen, —OH, oxo and C 1-3 alkyl; or
X is (—CH 2 —), and
R 4 is selected from
—SO 2 C 1-3 alkyl;
—C(O)N(C 1-3 alkyl) 2 ;
—NHC(O)R 5 or —N(CH 3 )C(O)R 5 , wherein R 5 is selected from cyclopropyl and C 1-3 alkyl optionally substituted with one to three —F groups;
—OCH 2 C(O)N(C 1-3 alkyl) 2 ;
—NHSO 2 C 1-3 alkyl;
—S(═O)(═NH)CH 3 ;
heterocyclyl selected from pyrrolidinyl, 1,1-dioxo[1,21-thiazine, morpholinyl and oxazolidinyl, wherein said heterocyclyl is optionally substituted with one to three groups selected from —C(O)C 1-3 alkyl, halogen, —OH, oxo and C 1-3 alkyl; and
—C(O)-heterocyclyl, wherein the heterocyclyl is selected from morpholin-4-yl, pyrrolidin-1-yl and piperidin-1-yl, optionally substituted with one or two groups selected from —F and —OH; and
R 3 is H or C 1-3 alkyl optionally substituted with —OH;
or a salt or a stereoisomer thereof.

3. The compound according to claim 1 , wherein:
R 2 is —(X)—R 4 , wherein
—(X)— is a bond, and
R 4 is selected from
—CF 3 ;
—CHF 2 ;
—CH 2 OH;
—CH(OH)CH 3 ;
—CH(OH)CF 3 ;
—F;
—CN;
heterocyclyl selected from tetrahydropyranyl and pyrrolidinyl, wherein said heterocyclyl is substituted with one to three groups selected from C 1-3 alkyl, —F, —OH and oxo;
C 3-6 cycloalkyl, substituted with —CN or —OH; and
phenyl, optionally substituted with —SO 2 NH 2 ; and
R 3 is H, or C 1-3 alkyl optionally substituted with —OH;
or a salt or a stereoisomer thereof.

4. The compound according to claim 1 , wherein:
R 2 is —(X)—R 4 , wherein
—(X)— is O, and
R 4 is selected from
C 1-3 alkyl;
—CH 2 SO 2 C 1-3 alkyl; and
heterocyclyl selected from tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, and azetidinyl, wherein said heterocyclyl is optionally substituted with —C(O)C 1-3 alkyl; and
R 3 is H, or C 1-3 alkyl optionally substituted with —OH;
or a salt or a stereoisomer thereof.

5. The compound according to claim 1 , wherein:
R 2 is —(X)—R 4 , wherein
X is (—CH 2 —), and
R 4 is selected from
—SO 2 C 1-3 alkyl;
—C(O)N(C 1-3 alkyl) 2 ;
—NHC(O)R 5 or —N(CH 3 )C(O)R 5 , wherein R 5 is selected from cyclopropyl and C 1-3 alkyl optionally substituted with one to three —F groups;
—OCH 2 C(O)N(C 1-3 alkyl) 2 ;
—NHSO 2 C 1-3 alkyl;
—S(═O)(═NH)CH 3 ;
heterocyclyl selected from pyrrolidinyl, 1,1-dioxo[1,2]-thiazine, morpholinyl and oxazolidinyl, wherein said heterocyclyl is optionally substituted with one to two groups selected from oxo and C 1-3 alkyl; and
—C(O)-heterocyclyl, wherein the heterocyclyl is selected from morpholin-4-yl, pyrrolidin-1-yl and piperidin-1-yl, optionally substituted with one or two groups selected from —F and —OH; and
R 3 is H, or C 1-3 alkyl optionally substituted with —OH;
or a salt or a stereoisomer thereof.

6. The compound according to claim 1 , wherein:
R 1 is —C(O)NH 2 ;
or a salt or a stereoisomer thereof.

7. The compound according to claim 1 , wherein:
R 1 is —CN;
or a salt or a stereoisomer thereof.

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

or a pharmaceutically acceptable salt or a stereoisomer thereof.

9. The compound according to claim 8 selected from the group consisting of compound numbers 1, 5, 12, 29, 37, 43, 56, 61, and 62 or a pharmaceutically acceptable salt or a stereoisomer thereof.

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

11. A method of treating a disease or disorder that can be alleviated by inhibition of aldosterone synthase selected from diabetic nephropathy, glomerulosclerosis, glomerulonephritis, IGA nephropathy, nephritic syndrome, focal segmental glomerulosclerosis (FSGS), hypertension, systolic heart failure, diastolic heart fai

Assignees

• Boehringer Ingelheim Int

Inventors

• Hornberger Keith R
• Meyers Kenneth Michael
• Nemoto Peter Allen
• Surprenant Simon
• Yu Hui

Classifications

• 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

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title

• A61P5/42

  for decreasing, blocking or antagonising the activity of mineralocorticosteroids · CPC title