Piperidine substituted pyrazolo[1,5-a]pyrimidine derivatives with inhibitory activity on the replication of the respiratory syncytial virus (rsv)

Patent metadata

Field	Value
Publication number	US-2017349591-A1
Application number	US-201515534442-A
Country	US
Kind code	A1
Filing date	Dec 7, 2015
Priority date	Dec 8, 2014
Publication date	Dec 7, 2017
Grant date	—

Abstract

The invention concerns novel substituted bicyclic pyrazolo pyrimidine compounds of formula (I) having antiviral activity, in particular, having an inhibitory activity on the replication of the respiratory syncytial virus (RSV). The invention further concerns the preparation of such novel compounds, compositions comprising these compounds, and the compounds for use in the treatment of respiratory syncytial virus infection.

First claim

1 . A compound of formula (I), wherein

R 1 is selected from the group consisting of: hydrogen, hydroxy, C 1-4 alkyl, mono- or di(C 1-4 alkyl)amino, and Heterocyclyl 1 ;
R 2 is hydrogen or C 1-4 alkyl;
R 3 is selected from the group consisting of: C 1-4 alkyl, halo, C 3-6 cycloalkyl, mono- or di(C 1-4 alkyl)amino, and Heterocyclyl 2 ;
R 4 is selected from the group consisting of: hydrogen, C 1-6 alkyl, hydroxy, and halo;
Heterocyclyl 1 is selected from the group consisting of: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl; wherein each azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl is optionally substituted with one or two substituents each independently selected from the group consisting of: C 1-4 alkyl, hydroxy, halo, polyhaloC 1-4 alkyl, C 1-4 alkyloxycarbonyl, amino, C 1-4 alkylaminocarbonyl, and C 1-4 alkylsulfonyl;
Heterocyclyl 2 is selected from the group consisting of: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl; wherein each azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl is optionally substituted with one or two substituents each independently selected from the group consisting of: C 1-4 alkyl, hydroxy, halo, polyhaloC 1-4 alkyl, C 1-4 alkyloxycarbonyl, amino, C 1-4 alkyloxycarbonylamino, and C 1-4 alkylsulfonyl; and
Het is selected from the group consisting of: furanyl, thiophenyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, 9H-purinyl, thiazolo[5,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, oxazolo[5,4-d]pyrimidinyl, thieno[2,3-d]-pyrimidinyl, and thieno[3,2-d]pyrimidinyl; wherein each furanyl thiophenyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl 1,7-naphthyridinyl, 1,8-naphthyridinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, 9H-purinyl, thiazolo[5,4-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, oxazolo[5,4-d]pyrimidinyl, thieno[2,3-d]-pyrimidinyl, and thieno[3,2-d]pyrimidinyl is optionally substituted with one, two or three substituents each independently selected from the group consisting of: halo, C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 alkylthio, hydroxy, amino, mono- or di(C 1-4 alkyl)amino, hydroxycarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylsulfonylamino, aminocarbonyl, trifluoromethyl, C 1-4 alkyloxycarbonylamino, di(C 1-4 alkyloxycarbonyl)amino, C 1-4 alkylsulfonylaminocarbonyl, C 1-4 alkylaminocarbonyl, C 1-4 alkyloxyC 1-6 alkyloxycarbonylamino, di(C 1-4 alkyl)aminosulfonyl-aminocarbonyl, C 3-6 cycloalkylsulfonylaminocarbonyl, and HO—NH—(C═NH)—; and oxazolyl or triazolyl; wherein each oxazolyl or triazolyl is optionally substituted with one or two C 1-4 alkyl;
and pharmaceutically acceptable salts thereof.

2 . The compound as claimed in claim 1 wherein
R 1 is hydrogen, C 1-4 alkyl, mono- or di(C 1-4 alkyl)amino, or Heterocyclyl 1 ;
R 2 is hydrogen or C 1-4 alkyl;
R 3 is C 3-6 cycloalkyl or Heterocyclyl 2 ;
R 4 is hydrogen;
Heterocyclyl 1 is piperazinyl or morpholinyl; wherein each piperazinyl or morpholinyl is optionally substituted with one substituent selected from C 1-4 alkyloxycarbonyl, C 1-4 alkylaminocarbonyl, or C 1-4 alkylsulfonyl;
Heterocyclyl 2 is azetidinyl, or pyrrolidinyl; wherein each azetidinyl, or pyrrolidinyl is optionally substituted with one substituent selected from hydroxy or amino; and
Het is selected from quinazolinyl, pyrido[2,3-d]pyrimidinyl, thiazolo[5,4-d]-pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, oxazolo[5,4-d]pyrimidinyl, or thieno[2,3-d]pyrimidinyl; wherein each quinazolinyl, pyrido[2,3-d]pyrimidinyl, thiazolo[5,4-d]-pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, oxazolo[5,4-d]pyrimidinyl, or thieno[2,3-d]pyrimidinyl is optionally substituted with one, two or three substituents each independently selected from halo, C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 alkylthio, hydroxy, hydroxycarbonyl, C 1-4 alkyloxycarbonyl, C 1-4 alkylsulfonylamino, aminocarbonyl, trifluoromethyl, C 1-4 alkyloxy-carbonylamino, di(C 1-4 alkyloxycarbonyl)amino, C 1-4 alkylsulfonylamino-carbonyl, C 1-4 alkylaminocarbonyl, C 1-4 alkyloxyC 1-6 alkyloxycarbonylamino, di(C 1-4 alkyl)aminosulfonylaminocarbonyl, C 3-6 cycloalkylsulfonylamino-carbonyl, and HO—NH—(C═NH)—; and oxazolyl or triazolyl; wherein each oxazolyl or triazolyl is optionally substituted with one or two C 1-4 alkyl.

3 . The compound as claimed in claim 1 wherein R 1 is Heterocyclyl 1 , R 2 is hydrogen, and R 3 is Heterocyclyl 2 .

4 . The compound as claimed in claim 1 wherein R 1 is hydrogen, R 2 is C 1-4 alkyl, and R 3 is Heterocyclyl 2 .

5 . The compound as claimed in claim 1 wherein R 1 is hydrogen, R 2 is hydrogen, and R 3 is Heterocyclyl 2 .

6 . The compound as claimed in claim 1 wherein R 1 is C 1-4 alkyl, R 2 is hydrogen, and R 3 is Heterocyclyl 2 .

7 . The compound as claimed in claim 1 wherein R 1 is hydrogen, R 2 is hydrogen, and R 3 is C 1-4 alkyl.

8 . The compound as claimed in claim 1 wherein R 1 is hydrogen, R 2 is hydrogen, and R 3 is C 3-6 cycloalkyl.

9 . The compound as claimed in claim 1 wherein Het is quinazolinyl.

10 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

11 . A process for preparing a pharmaceutical composition as claimed in claim 8 wherein a therapeutically active amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier.

12 . (canceled)

13 . A method of treating a respiratory syncytial virus infection in a patient, comprising administering the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof to said patient.

14 . A compound selected from the group consisting of:
4-(5-(Azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; (S)-4-(5-(Azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; (R)-4-(5-(Azetidin-1-yl)-2-(1-(6-chloroquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; 4-(5-(Azetidin-1-yl)-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; 4-(5-(Azetidin-1-yl)-2-(1-(2-chloro-6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2 yl)-piperidin-1-yl)-6-methylquinazolin-2-yl)methanesulfonamide; (R)—N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazolin-2-yl)methanesulfonamide; (S)—N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2-yl)piperidin-1-yl)-6-methylquinazolin-2-yl)methanesulfonamide; N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2 yl)piperidin-1-yl)-5-methylquinazolin-2-yl)methanesulfonamide; N-(4-(2-(5-(Azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]pyrimidin-2 yl)piperidin-1-yl)quinazolin-2-yl)methanesulfonamide; 4-(2-(5-(Azetidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazoline; 1-(6-Methyl-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)py

Assignees

• Janssen Sciences Ireland Uc

Inventors

• Tahari Abdellah
• Vendeville Sandrine Marie Helene
• Jonckers Tim Hugo Maria
• Raboisson Pierre Jean-Marie Bernard
• Demin Samuël Dominique
• Hu Lili
• Cooymans Ludwig Paul

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title