Compounds for the treatment and prophylaxis of respiratory syncytial virus disease

Patent metadata

Field	Value
Publication number	US-RE49481-E
Application number	US-202017075948-A
Country	US
Kind code	E1
Filing date	Oct 21, 2020
Priority date	Aug 11, 2011
Publication date	Apr 4, 2023
Grant date	Apr 4, 2023

Abstract

A compound of formula (I)as well as pharmaceutically acceptable salt thereof, wherein R1 to R10, A, Q, X and Y are as defined in the specification and claims, and their use as a pharmaceutical for the treatment or prophylaxis of respiratory syncytial virus disease.

First claim

The invention claimed is:

1. A compound of formula (I)

Wherein
R 1 is hydrogen, halogen, or C 1-6 alkyl;
R 2 is hydrogen, halogen, or C 1-6 alkyl;
R 3 is hydrogen, halogen, or C 1-6 alkyl;
R 4 is hydrogen, or C 1-6 alkyl;
R 5 is hydrogen, or halogen;
R 6 is hydrogen, halogen, hydroxy, C 1-6 alkoxy, carboxy, morpholinyl, or 4-C 0-6 alkylpiperazin-1-yl;
R 7 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylaminocarbonyl, diC 1-6 alkylaminocarbonyl, C 1-6 alkylsulfonyl, phenoxy, or hydroxy(CH 2 ) 2-6 —O—;
R 8 is hydrogen, halogen, or C 1-6 alkoxy;
R 9 is hydrogen, C 1-6 alkyl, or ═O;
R 10 is hydrogen, or ═O, provided that R 9 and R 10 are not ═O simultaneously;
A is nitrogen, or —C—R 11 , wherein R 11 is hydrogen, halogen, C 1-6 alkyl, cycloalkyl, C 1-6 alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, C 1-6 alkoxy(CH 2 ) 1-6 —O—, difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl, hydroxy(CH 2 ) 2-6 —O—, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, hydroxy(CH 2 ) 1-6 , deuteratedC 1-6 alkyl, carboxyl, C 1-6 alkoxycarbonyl, hydroxy, difluoromethyl, —CH(hydroxy) C 1-6 alkyl, or C 1-6 alkylsulfanyl;
X is —CH 2 —, —O—, —NH—, —CF 2 —, —C(C 1-6 alkyl)(OH)—, —S—, —C(═O)—, —C(═NOC 0-6 alkyl)-, —S(═O)—, —S(O 2 )— or —S(═O)(NH)—;
Y is —CH—, or nitrogen;
Q is hydrogen; halogen; C 1-6 alkyl, unsubstituted or once or twice substituted by amino or hydroxy, provided that di-substitution is not on the same carbon; amino(CH 2 ) 2-6 aminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazol-4-yl(CH 2 ) 1-6 ; carboxy(CH 2 ) 1-6 ; phenylsulfonyl; piperidin-4-yl-carbonyl; 1H-pyrazol-3-yl; pyrrolidin-3-yloxy; piperidin-4-yloxy; amino(CH 2 ) 2-6 —O—; or NR 12 R 13 , wherein one of R 12 and R 13 is hydrogen, C 1-6 alkyl, or hydroxy(CH 2 ) 2-6 , and the other one is {1-[amino(CH 2 ) 0-6 ]-3,3-difluorocyclobutyl}(CH 2 ) 1-6 ; guanidino(CH 2 ) 2-6 ; (S—C 1-6 alkylsulfonimidoyl)(CH 2 ) 2-6 ; 2-oxa-6-aza-spiro[3.4]oct-8-yl; {3-[amino(CH 2 ) 0-6 ]tetrahydrofuran-3-yl}(CH 2 ) 1-6 ; 3-aminomethyl-1,1-dioxidothietan-3-ylmethyl; 3-amino-1,1-dioxidothietan-3-ylmethyl; 3-(aminomethyl)thietan-3-ylmethyl;(1,1-dioxidothiomorpholin-4-yl)ethyl; C 0-6 alkyl(oxetanyl)N(CH 2 ) 2-6 ; 4,5-dihydro-1H-imidazol-2-yl; amino(CH 2 ) 2-6 —O—(CH 2 ) 2-6 ; amino(CH 2 ) 2-10 ; amino(CH 2 ) 1-6 difluoromethyl(CH 2 ) 1-6 ; amino(CH 2 ) 1-6 difluoromethyldifluoromethyl(CH 2 ) 1-6 ; amino(CH 2 ) 1-6 fluoromethyl(CH 2 ) 1-6 ; amino(CH 2 ) 1-6 oxetanyl(CH 2 ) 0-6 ; amino(CH 2 ) 0-6 oxetanyl(CH 2 ) 1-6 ; amino(CH 2 ) 2-6 sulfanyl(CH 2 ) 2-6 ; amino(CH 2 ) 2-6 sulfonyl(CH 2 ) 2-6 ; amino(CH 2 ) 0-6 carbonyl(CH 2 ) 0-6 ; aminocycloalkyl(CH 2 ) 0-6 ; 2-aminodihydrooxazol-4-yl(CH 2 ) 1-6 ; 2-aminodihydrooxazol-5-yl(CH 2 ) 1-6 ; (2-amino-5-methyl-4,5-dihydro-1,3-oxazol-5-yl)methyl; aminophenyl; 4-aminotetrahydropyran-4-yl(CH 2 ) 1-6 ; azetidin-2-yl(CH 2 ) 1-6 ; azetidin-3-yl(CH 2 ) 0-6 ; azetidinylcarbonyl; C 1-6 alkoxy(CH 2 ) 2-6 ; C 1-6 alkoxy(CH 2 ) 2-6 amino(CH 2 ) 2-6 ; C 1-6 alkyl; C 1-6 alkylamino(CH 2 ) 2-6 ; C 1-6 alkylaminocarbonyl(CH 2 ) 0-6 ; C 1-6 alkylaminooxetanyl(CH 2 ) 1-6 ; C 1-6 alkylcarbonyl; C 1-6 alkylcarbonylamino(CH 2 ) 2-6 ; C 1-6 alkylcarbonylamino(CH 2 ) 1-6 oxetanyl(CH 2 ) 0-6 ; C 1-6 alkylsulfinyl(CH 2 ) 2-6 ; C 1-6 alkylsulfonyl; carboxy(CH 2 ) 1-6 ; cyano(CH 2 ) 1-6 ; diC 1-6 alkylamino(CH 2 ) 2-6 ;diC 1-6 alkylaminocarbonyl; difluoromethyl(CH 2 ) 1-6 amino(CH 2 ) 2-6 ; hydrogen; hydroxy(CH 2 ) 2-10 ; hydroxy(CH 2 ) 2-6 amino(CH 2 ) 2-6 ; hydroxy(CH 2 ) 1-6 carbonyl; hydroxy(CH 2 ) 0-6 oxetanyl(CH 2 ) 1-6 ; hydroxy(CH 2 ) 1-6 oxetanyl(CH 2 ) 0-6 ; hydroxycycloalkyl; isoxazolyl; morpholin-2-yl(CH 2 ) 1-6 ; morpholin-4-yl(CH 2 ) 2-6 ; oxetanyl(CH 2 ) 0-6 ; N-oxetanylpyrrolidin-3-yl; oxo-pyrrolidinylcarbonyl; phenylaminocarbonyl; phenyl(CH 2 ) 0-6 aminooxetanyl(CH 2 ) 1-6 ; phenylcarbonyl; piperazinyl(CH 2 ) 2-6 ; piperidin-1-yl(CH 2 ) 2-6 ; piperidin-2-yl(CH 2 ) 1-6 ; piperidin-3-yl(CH 2 ) 0-6 ; piperidin-4-yl(CH 2 ) 0-6 ; piperidinylcarbonyl; pyrazinylcarbonyl; pyrazol-3-yl; pyridazinylcarbonyl; pyridinyl(CH 2 ) 0-6 carbonyl; pyridinylamino(CH 2 ) 2-6 ; pyrrolidin-3-yl, unsubstituted or 4-substituted by halogen; pyrrolidin-4-yl, unsubstituted or 3-substituted by hydroxy or C 1-6 alkoxy; pyrrolidin-2-yl(CH 2 ) 1-6 ; pyrrolidinylcarbonyl; tetrahydrofuran-3-yl; tetrahydropyran-4-yl; tetrazolyl(CH 2 ) 2-6 ; trifluoromethylcarbonylamino(CH 2 ) 1-6 oxetanyl; trifluoromethylsulfonyl;

 wherein R 14 is hydrogen, C 1-6 alkyl or hydroxy(CH 2 ) 1-6 ; R 15 is hydroxy, C 1-6 alkyl, hydroxy(CH 2 ) 1-6 or amino; and R 16 is C 1-6 alkyl, trifluoromethyl, hydroxy(CH 2 ) 1-6 , amino(CH 2 ) 1-6 , aminocarboxy or carboxy(CH 2 ) 1-6 ;

 wherein R 17 is hydrogen, C 1-6 alkyl or hydroxy(CH 2 ) 1-6 ; R 18 is hydroxy(CH 2 ) 1-6 or C 1-6 alkyl; R 19 is hydroxy(CH 2 ) 1-6 , amino(CH 2 ) 1-6 , carboxy or aminocarboxy(CH 2 ) 0-6 ; or

 wherein R 20 is hydrogen or C 1-6 alkyl; R 21 is C 1-6 alkyl; R 22 is C 1-6 alkoxy or amino;
R 12 and R 13 , with the nitrogen atom to which they are attached, may form a pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, azetidinyl, diazepanyl or oxopyrrolidinyl ring; which may be unsubstituted, once or twice substituted by a group selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, gemdimethyl, amino, aminocarbonyl, hydroxy, oxetanylamino, C 1-6 alkylpiperazinyl, and amino(CH 2 ) 1-6 ;
R 12 and R 13 , with the nitrogen atom to which they are attached may form a bridge ring or a spiral ring selected from 2-oxa-6-aza-spiro[3.4]octan-6-yl, 2-oxa-5,7-diazaspiro[3.4]octan-6-one-5-yl, (4aS,7aR)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d][1,3]oxazol-5-yl, 2-aza -bicyclo[2.1.1]hexan-2-yl, and 3-aza-bicyclo[3.1.0]hexan-3-yl; which may be unsubstituted or further substituted by amino;
and pharmaceutically acceptable salt and stereoisomers thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 is hydrogen, halogen or C 1-6 alkyl;
R 2 is hydrogen, halogen or C 1-6 alkyl;
R 3 is hydrogen, halogen or C 1-6 alkyl;
R 4 is hydrogen or C 1-6 alkyl;
R 5 is hydrogen;
R 6 is hydrogen, halogen, hydroxy, C 1-6 alkoxy, morpholinyl or 4-C 0-6 alkylpiperazin-1-yl;
R 7 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, phenoxy or hydroxy(CH 2 ) 2-6 —O—;
R 8 is hydrogen, halogen or C 1-6 alkoxy;
R 9 is hydrogen or C 1-6 alkyl;
R 10 is hydrogen;
A is nitrogen or —C—R 11 , wherein R 11 is hydrogen, halogen, C 1-6 alkyl, cycloalkyl, C 1-6 alkoxy, trifluoromethyl, trifluoromethoxy, pyridinyloxy, C 1-6 alkoxy(CH 2 ) 1-6 —O—, difluoromethoxy, cyano, nitro, amino, vinyl, acetylenyl, aminocarbonyl, hydroxy(CH 2 ) 2-6 —O—, C 1-6 alkylsulfinyl, hydroxy(CH 2 ) 1-6 , deuteratedC 1-6 alkyl, carboxyl, alkoxycarbonyl, hydroxy, difluoromethyl, —CH(hydroxy)C 1-6 alkyl or C 1-6 alkylsulfanyl;
X is S, S═O, SO 2 or S(O)NH;
Y is —CH— or nitrogen;
Q is C 1-6 alkyl, unsubstituted or once substituted by amino; amino(CH 2 ) 2-6 aminosulfonyl; 2-amino-4,5-dihydro-1,3-oxazol-4-ylethyl; carboxy(CH 2 ) 1-6 ; phenylsulfonyl; piperidin-4-yl-carbonyl; 1H-pyrazol-3-yl; pyrrolidin-3-yloxy; piperidin-4-yloxy; amino(CH 2 ) 2-6 —O—; or
NR 12 R 13 , wherein one of R 12 and R 13 is hydrogen, C 1-6 alkyl or hydroxy(CH 2 ) 2-6 , and the other one is {1-[amino(CH 2 ) 0-6 ]-3,3-difluorocyclobutyl}(CH 2 ) 1-6 ; (S—C 1-6 alkylsulfonimidoyl)(

Assignees

• Hoffmann La Roche

Inventors

• Chen Li
• Feng Lichun
• Feng Song
• Gao Lu
• Guo Tao
• Huang Mengwei
• Liang Chungen
• Liu Yongfu
• Wang Lisha
• Wong Jason Christopher
• Wu Jim Zhen
• Wu Xihan
• Yun Hongying
• Zheng Xiufang

Classifications

• C07D413/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title