Natriuretic peptide receptor a agonists useful for the treatment of cardiometabolic diseases, kidney disease and diabetes

Patent metadata

Field	Value
Publication number	US-12440496-B2
Application number	US-202017611540-A
Country	US
Kind code	B2
Filing date	May 18, 2020
Priority date	May 22, 2019
Publication date	Oct 14, 2025
Grant date	Oct 14, 2025

Abstract

The present invention relates to Compounds of Formula I:

and pharmaceutically acceptable salts or prodrug thereof. The present invention also relates to compositions comprising at least one compound of Formula I, and methods of using the compounds of Formula I for treatment of cardiometabolic diseases including high blood pressure, heart failure, kidney disease, and diabetes in a subject.

First claim

What is claimed is:

1. A compound of the formula I, or a pharmaceutically acceptable salt thereof:

wherein
X is N or CH;
R 1 is selected from phenyl, pyridyl, thiazolyl, imidazolyl, pyrazinyl, and oxadiazolyl, wherein R 1 is substituted by 0, 1, 2, or 3, R 5 ;
R 2 is independently selected from:
arylC 0-10 alkyl,
C 3-12 cycloalkylC 0-10 alkyl,
heteroarylC 0-10 alkyl,
heterocyclylC 0-10 alkyl,
C 1-10 alkylaminoC 0-10 alkyl,
heteroarylC 0-10 alkylaminoC 0-10 alkyl,
heterocyclylC 0-10 alkylaminoC 0-10 alkyl,
C 1-10 heteroalkyl aminoC 0-10 alkyl,
C 3-12 cycloalkyl C 0-10 alkylaminoC 0-10 alkyl,
aryl C 0-10 alkylaminoC 0-10 alkyl,
amino, and
(C 1-10 alkyl) 1-2 amino;

wherein R 2 is each substituted with 0, 1, 2, 3, or 4 R 4 substituents;
each R 3 is independently selected from hydrogen, halogen, C 1-6 alkyl, and C 3-12 cycloalkyl C 0-10 alkyl, and heterocyclylC 0-10 alkyl, wherein R 3 is substituted by 0, 1, 2 or 3 groups independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and halogen;
each R 4 is independently selected from:
halogen,
C 1-10 alkyl,
C 1-10 heteroalkyl,
aryl C 0-10 alkyl,
C 3-12 cycloalkyl C 0-10 alkyl,
heteroaryl C 0-10 alkyl,
heterocyclylC 0-10 alkyl,
amino C 0-10 alkyl,
((C 1-10 )alkyl) 1-2 amino,
—CO 2 (C 1-10 alkyl),
—(C 0-10 alkyl) CO 2 H,
OXO,
hydroxy,
—(C 1-10 alkyl)OH,
C 1-10 alkoxy,
cyano, and
C 1-6 haloalkyl;

wherein R 4 is each substituted with 0, 1, 2, 3, or 4 R 8 substituents and each R 8 is independently selected from: C 1-10 alkyl, —CO 2 (C 1-10 alkyl), —(C 0-10 alkyl) CO 2 H, C 1-10 alkoxy, halogen, C 1-6 haloalkyl, cyano, oxo, hydroxy, and amino;
R 5 is independently selected from:
halogen,
C 1-10 alkyl,
aryl C 0-10 alkyl,
C 3-12 cycloalkylC 0-10 alkyl,
heteroaryl C 0-10 alkyl,
heterocyclyl C 0-10 alkyl,
C 1-10 alkylcarbonylC 0-10 alkyl,
C 1-10 heteroalkylcarbonylC 0-10 alkyl,
arylcarbonylC 0-10 alkyl,
(C 3-12 )cycloalkyl carbonylC 0-10 alkyl,
heteroarylcarbonylC 0-10 alkyl,
heterocyclylcarbonylC 0-10 alkyl,
((C 0-10 )alkyl) 1-2 aminocarbonyl,
C 1-10 alkoxy,
aryl C 0-10 alkyloxy,
C 3-12 cycloalkyloxy,
heteroaryl C 0-10 alkyloxy,
heterocyclyl C 0-10 alkyloxy,
(C 0-10 )alkylaminocarbonyl,
(C 1-10 )heteroalkylaminocarbonyl,
aryl(C 0-10 )alkylaminocarbonyl,
(C 3-12 )cycloalkyl(C 0-10 )alkylaminocarbonyl,
heteroaryl(C 0-10 )alkylaminocarbonyl,
heterocyclyl(C 0-10 )alkylaminocarbonyl,
C 0-10 alkylcarbonylaminoC 0-10 alkyl,
C 1-10 heteroalkylcarbonylaminoC 0-10 alkyl,
C 3-12 cycloalkyl C 0-10 alkylcarbonylaminoC 0-10 alkyl,
aryl C 0-10 alkylcarbonylaminoC 0-10 alkyl,
heteroaryl C 0-10 alkylcarbonylaminoC 0-10 alkyl,
heterocyclyl C 0-10 alkylcarbonylamino,
—SO 2 N(C 1-6 alkyl) 0-2 ,
C 0-6 alkylS(O) 1-2 amino,
—SO 2 CF 3 ,
—SO 2 CF 2 H,
amino,
(C 0-10 alkyl) 1-2 amino,
hydroxy,
(C 1-10 alkyl)OH,
cyano,
C 1-6 haloalkyl,
—CO 2 (C 1-10 alkyl),
(C 0-10 alkyl) CO 2 H,
OXO,
C 1-10 alkylS(O) 1-2 ,
C 1-10 heteroalkyl S(O) 1-2 ,
(C 3-12 )cycloalkylS(O) 1-2 ,
heterocyclyl S(O) 1-2 ,
heteroarylS(O) 1-2 , and
arylS(O) 1-2 ;

wherein R 5 is each substituted with 0, 1, 2, 3, or 4 R 6 ;
each R 6 is independently selected from:
halogen,
C 1-10 alkyl,
C 1-6 haloalkyl,
C 1-10 heteroalkyl,
aryl C 0-10 alkyl,
C 3-12 cycloalkyl C 0-10 alkyl,
heteroaryl C 0-10 alkyl,
heterocyclyl C 0-10 alkyl,
amino C 0-10 alkyl,
((C 1-10 )alkyl) 1-2 amino,
—CO 2 (C 1-10 alkyl),
—(C 0-10 alkyl) CO 2 H,
OXO,
hydroxy,
—(C 1-10 alkyl)OH,
C 1-10 alkoxy,
cyano, and
aminocarbonyl; and

wherein R 6 is each substituted with 0, 1, 2, or 3, R 7 substituents and each R 7 is independently selected from: C 1-4 alkyl, hydroxy, —CO 2 (C 1-6 alkyl), —(C 0-6 alkyl) CO 2 H, C 1-6 alkoxy, halogen, C 1-6 haloalkyl, cyano, and amino.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is N.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is CH.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl or pyridyl, wherein R 1 is substituted by 0, 1, 2 or 3 R 5 .

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected from: halogen, C 1-10 alkyl, aryl C 0-10 alkyl, C 3-12 cycloalkylC 0 -10 alkyl, heteroaryl C 0-10 alkyl, heterocyclyl C 0-10 alkyl, C 1-10 alkylcarbonylC 0-10 alkyl, C 1-10 heteroalkylcarbonylC 0-10 alkyl, arylcarbonylC 0-10 alkyl, (C 3-12 )cycloalkyl carbonylC 0-10 alkyl, heteroarylcarbonylC 0-10 alkyl, heterocyclylcarbonylC 0-10 alkyl, ((C 0-10 )alkyl) 1-2 aminocarbonyl, C 1-10 alkoxy, aryl C 0-10 alkyloxy, C 3-12 cycloalkyloxy, heteroaryl C 0-10 alkyloxy, heterocyclyl C 0-10 alkyloxy, (C 0-10 )alkylaminocarbonyl, (C 1-10 )heteroalkylaminocarbonyl, aryl(C 0-10 )alkylaminocarbonyl, (C 3 -12)cycloalkyl(C 0-10 )alkylaminocarbonyl, heteroaryl(C 0-10 )alkylaminocarbonyl, heterocyclyl(C 0-10 )alkylaminocarbonyl, C 0-10 alkylcarbonylaminoC 0-10 alkyl, heterocyclyl C 0-10 alkylcarbonylamino, —SO 2 N(C 1-6 alkyl) 0-2 , C 0-6 alkylS(O) 1-2 amino, amino, (C 0-10 alkyl) 1-2 amino, hydroxy, —(C 1-10 alkyl)OH, cyano, C 1-6 haloalkyl, —(C 0-10 alkyl) CO 2 H, oxo, C 1-10 alkylS(O) 1-2 , wherein R 5 is each substituted with 0, 1, 2, 3, or 4 R 6 .

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected from: pyridyl, pyrimidinyl, furyl, pyrazolyl, thiophenyl, methylsulfonylamino, pyrrolidinylcarbamoyl, imidazolyl, triazoylyl, oxazolidinyl, azetidinylcarbamoyl, (pyrrolidinylmethyl) carbamoyl, diazaspiro[3.3]heptane-carbonyl, ethylcarbamoyl, azetidinylcarbonyl, aminocarbonyl, morpholinylcarbonyl, piperazinylcarbonyl, methylcarbamoyl, 1-oxa-3,8-diazaspiro[4.5]decanyl, imidazolidinyl, pyrrolidinylcarbonylamino, ethylcarbonylamino, thiophenyl, phenyl, 1-oxa-4,7-diazaspiro[4,4]nonane-carbonyl, 2,8-diazaspiro[3.5]nonane-carbonyl, piperidylcarbamoyl, octahydropyrrolo[2,3-b]pyrrole-carbonyl, (morpholinoethyl) carbamoyl, morpholinocarbonyl, octahydropyrrolo[3,4-b][1,4]oxazine-carbonyl, pyridazinyl, 1,2-dihydropyridazinyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, isoxazolyl, tetrazolyl, 1,2,3,4-tetrahydropyrimidinyl, 1,2,4-thiadiazolyl, pyrrolidinyl, pyrazolyloxy, ethoxy, phenoxy, 1,2-dihydropyridinyl, —NHS(O)2H, 1,3,4-oxathiazinanyl, halogen, and pyridazinyl, wherein R 5 is each substituted with 0, 1, 2, 3, or 4 R 6 .

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently selected from hydroxy, oxo, methyl, carboxy, fluoro, chloro, amino, hydroxyethyl, pyrrolidinylmethyl, 2,2,2-trifluoroethyl, benzyl, cyclopropyl, ethoxy, morpholinyl, cyano, trifluoromethyl, methylcarboxy, aminocarbonyl (carbamoyl), dimethylamino, dimethylsulfamoyl, ethylsulfonyl, and methoxy, wherein R 6 is each substituted with 0,1, or 2, R 7 substituents, and the other groups are provided in the general formula above, or as in the first through sixth embodiments.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from: piperidinyl, dimethylamino, tetrahydropyranylamino, 5-azaspiro[2.5]octanyl, cyclobutylamino, 2,7-diazaspiro[4.5]decanyl, azetidinyl, oxetanylamino, cyclohexylamino, cyclopentylamino, azabicyclo[3.1.0]hexanyl, pyrrolidinyl, diethylamino, tetrazolyl, 1-oxa-3-az

Assignees

• Merck Sharp & Dohme Llc
• Shi Changhong

Inventors

• Hong Qingmei
• Imbriglio Jason E
• Kerekes Angela D
• Khan Tanweer
• Lankin Claire
• Li Derun
• Liang Rui
• Shao Pengcheng Patrick
• Wu Zhicai
• Xiong Yusheng
• Ye Feng
• Youm Hyewon
• Yu Yang
• Kurissery Anthappan Tony
• Komanduri Venukrishnan

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title