Piperidine substituted tricyclic 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-2017349602-A1
Application number	US-201515534458-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 tricyclic pyrazolo pyrimidine compounds of formula (I-a) or (I-b) 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 Sin the treatment of respiratory syncytial virus infection.

First claim

1 . A compound of formula (I-a) or formula (I-b), wherein

n is an integer 0, 1 or 2;
X is selected from the group consisting of: CH 2 , O, CH 2 O and NR 4 , wherein R 4 is hydrogen, C 1-4 alkyl or benzyl;
Z is selected from the group consisting of: CH 2 , O and NR 4 , wherein R 4 is hydrogen, C 1-4 alkyl or benzyl;
and at least one of X or Z is CH 2 ;
R 1 is selected from the group consisting of: hydrogen, hydroxy, C 1-4 alkyl, amino, mono- or di(C 1-4 alkyl)amino, and Heterocyclyl 1 ;
Heterocyclyl 1 is selected from the group consisting of: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; wherein each azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl is optionally substituted with one or two substituents each independently selected from the group consisting of: C 1-4 alkyl, hydroxy, halo, trifluoromethyl, C 1-4 alkyloxycarbonyl, amino, C 1-4 alkylaminocarbonyl, and C 1-4 alkylsulfonyl;
R 2 is phenyl-(CO)— wherein the phenyl is substituted with one or two substituents each independently selected from the group consisting of: hydrogen, halo, trifluoromethyl, C 1-4 alkyl, C 1-4 alkyloxy, and C 1-4 alkylsulfonylamino;
or R 2 is a bicyclic heterocycle selected from cinnolinyl, quinazolinyl, or quinoxalinyl, wherein said cinnolinyl, quinazolinyl, or quinoxalinyl is substituted with one or two substituents each independently selected from the group consisting of: hydrogen, halo, trifluoromethyl, C 1-4 alkyl, C 1-4 alkyloxy, and C 1-4 alkylsulfonylamino; and
R 3 is selected from the group consisting of: hydrogen, C 1-6 alkyl, hydroxy, and halo;
and a pharmaceutically acceptable salt thereof.

2 . The compound as claimed in claim 1 wherein
n is an integer 0, 1 or 2;
X is CH 2 , O, CH 2 O or NR 4 , wherein R 4 is C 1-4 alkyl;
Z is CH 2 , O or NR 4 , wherein R 4 is C 1-4 alkyl;
and at least one of X or Z is CH 2 ;
R 1 is hydrogen, hydroxy, C 1-4 alkyl, amino, mono- or di(C 1-4 alkyl)amino, or Heterocyclyl 1 ;
Heterocyclyl 1 is pyrrolidiny, or morpholinyl;
R 2 is phenyl-(CO)— wherein the phenyl is substituted with one or two substituents each independently selected from hydrogen, C 1-4 alkyl, or C 1-4 alkylsulfonylamino;
or R 2 is a bicyclic heterocycle selected from cinnolinyl, quinazolinyl, or quinoxalinyl, wherein said bicyclic heterocycle is substituted with one or two substituents each independently selected from hydrogen, halo, trifluoromethyl, C 1-4 alkyl, C 1-4 alkyloxy, and C 1-4 alkylsulfonylamino; and
R 3 is hydrogen;
or a pharmaceutically acceptable salt thereof.

3 . The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 0; X is CH 2 ; and Z is CH 2 .

4 . The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 1; X is CH 2 ; and Z is CH 2 .

5 . The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 2; X is CH 2 ; and Z is CH 2 .

6 . The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 0; X is CH 2 ; and Z is O.

7 . The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 1; X is CH 2 ; and Z is O.

8 . The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is Heterocyclyl 1 ; n is 2; X is CH 2 ; and Z is O.

9 . The compound as claimed in claim 1 wherein the compound is of formula (I-a) wherein R 1 is di(C 1-4 alkyl)amino; n is 1; X is NR 4 ; R 4 is C 1-4 alkyl; and Z is CH 2 .

10 . The compound as claimed in claim 1 wherein the compound is of formula (I-a) R 1 is C 1-4 alkyl; n is 1; X is CH 2 ; and Z is CH 2 .

11 . The compound as claimed in claim 1 wherein the compound is of formula (I-b) wherein R 1 is C 1-4 alkyl; n is 1; X is CH 2 ; and Z is CH 2 .

12 . 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.

13 . A process for preparing a pharmaceutical composition as claimed in claim 12 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.

14 . (canceled)

15 . 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.

16 . 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)pyrarazolo[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)pyrazolo[1,5-a]pyrimidin-5-yl)azetidin-3-ol; 1-(6-Methyl-2-(1-(6-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)azetidin-3-amine; 2-Methoxyethyl 4-(2-(5-(azetidin-1-yl)-7-morpholinopyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-6-morpholinoquinazolin-2-ylcarbamate; 4-(5-(Azetidin-1-yl)-2-(1-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; 4-(5-(Azetidin-1-yl)-2-(1-(2-ethoxypyrido[2,3-d]pyrimidin-4-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; 4-(5-(Azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; (R)-4-(5-(Azetidin-1-yl)-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; (S)-4-(5-(Azetidin-1-yl)-2-(1-(5 methylquinazolin-4-yl)piperidin-2-yl)-pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; 4-(5-(Azetidin-1-yl)-2-(1-(2-methylthiazolo[5,4-d]pyrimidin-7-yl)-piperidin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)morpholine; 4-(2-(5-(Azetidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidin-2-yl)-piperidin-1-yl)-6-methylquinazoline; 4-(2-(5-(Azetidin-1-yl)-6-methyl-7-(piperidin-1-yl)pyrazolo[1,5-a]-pyrimidin-2-yl)piperidin-1-yl)-6-methylquinazoline; 1-(6-Methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-yl)pyrazolo-[1,5-a]pyrimidin-5-yl)azetidin-3-ol; (R)-1-(6-Methyl-2-(1-(5-methylquinazolin-4-yl)piperidin-2-y

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

Classifications

• C07D487/14

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title