Fused ring compound containing furan or salt thereof and pharmaceutical composition comprising same

Patent metadata

Field	Value
Publication number	US-9493478-B2
Application number	US-201314416079-A
Country	US
Kind code	B2
Filing date	Jul 23, 2013
Priority date	Jul 23, 2012
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

The present invention provides a fused ring compound containing furan or a pharmaceutically acceptable salt thereof, a method for preparing same, a pharmaceutical composition comprising same, and a use thereof. The fused ring compound containing furan or a pharmaceutically acceptable salt thereof inhibits the activity of phosphatidylinositol 3-kinase (PI3K) and can therefore be used in a pharmaceutical composition for treating and preventing respiratory diseases, inflammatory diseases, proliferative diseases, cardiovascular diseases, or central nervous system diseases which occur due to the over-activation of PI3K.

First claim

What is claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein,
A is hydrogen or —(CH 2 ) m Q,
B is hydrogen; —(C≡C)R 1 ; —(CH 2 ) m Q; —(CH═CH)(CH 2 ) m Q; —(C≡C)(CH 2 ) m Q; —NH(CH 2 ) p Q; —(CONH)(CH 2 ) m Q; or —CONR 1 R 2 , wherein, one of A and B is hydrogen, and A and B cannot be hydrogen at the same time,
m is an integer from 0 to 3,
p is an integer from 0 to 3,
Q is phenyl; pyridyl; pyrazolyl; thiophenyl; pyrimidinyl; thiazolyl; pyridazinyl; piperazinyl; morpholinyl; piperidinyl; tetrahydropyridyl; naphthyl; benzothiophenyl; benzodioxolyl; dihydrobenzofuranyl; dihydrobenzoxazinyl; benzodioxinyl; benzothiadiazolyl; quinolyl; indazolyl; benzoimidazolyl; dihydrobenzodioxinyl; benzothiazolyl; or indolyl,
wherein Q is optionally substituted with one or more substituents selected from the group consisting of hydroxy; amino; halogen; cyano; C 1 -C 10 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 6 alkoxy and C 1 -C 6 alkylcarbonyloxy; C 2 -C 10 alkenyl; 4-oxo-2-thioxothiazolidin-5-ylidenyl; C 2 -C 10 alkynyl; C 3 -C 10 cycloalkyl; 5- to 7-membered heterocycloalkyl-C 1 -C 4 alkyl, wherein, said heterocycloalkyl is optionally substituted with C 1 -C 4 alkyl; C 6 -C 12 aryl; 5- to 12-membered heteroaryl optionally substituted with C 1 -C 4 alkyl; 3- to 12-membered heterocycloalkyl optionally substituted with C 1 -C 6 alkyl; C 1 -C 10 alkoxy optionally substituted with one or more substituents selected from halogen and cyano; C 3 -C 10 cycloalkyloxy; C 6 -C 12 aryl-C 1 -C 10 alkyloxy, wherein, said aryl is optionally substituted with C 1 -C 3 alkoxy; C 6 -C 12 aryloxy optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, hydroxycarbonyl, cyano and nitro; 5- to 12-membered heteroaryloxy optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, hydroxycarbonyl, cyano and nitro; C 1 -C 10 alkylcarbonyloxy; C 1 -C 10 alkylthio; mono- or di-C 1 -C 10 alkylamino; mono- or di-C 3 -C 7 cycloalkylamino; C 6 -C 12 arylamino; 5- to 12-membered heteroarylamino; C 1 -C 10 alkylsulfonylamino; C 6 -C 12 arylsulfonylamino; 5- to 12-membered heteroarylsulfonylamino; C 1 -C 10 alkylcarbonylamino; C 6 -C 12 arylcarbonylamino; 5- to 12-membered heteroarylcarbonylamino; formyl; C 1 -C 10 alkylcarbonyl; C 6 -C 12 arylcarbonyl; 5- to 12-membered heteroarylcarbonyl; C 1 -C 10 alkoxycarbonyl; hydroxycarbonyl; C 6 -C 12 aryloxycarbonyl; 5- to 12-membered heteroaryloxycarbonyl; aminocarbonyl; mono- or di-C 1 -C 10 alkylaminocarbonyl, wherein said alkyl is optionally substituted with hydroxy; C 6 -C 12 arylaminocarbonyl; 5- to 12-membered heteroarylaminocarbonyl; aminosulfonyl; mono- or di-C 1 -C 10 alkylaminosulfonyl, wherein, said alkyl is optionally substituted with hydroxy; C 3 -C 7 cycloalkylaminosulfonyl; C 1 -C 10 alkylsulfonyl optionally substituted with hydroxy; 5- to 7-membered heterocycloalkyl-sulfonyl, wherein, said heterocycloalkyl is optionally substituted with C 1 -C 4 alkyl; C 6 -C 12 arylaminosulfonyl; 5- to 12-membered heteroarylaminosulfonyl; C 1 -C 10 alkylsulfinyl; C 1 -C 10 alkylcarbamoyloxy; and C 1 -C 10 alkylureido,
R 1 and R 2 are each independently hydrogen; C 1 -C 10 alkyl optionally substituted with one or more substituents selected from hydroxy and C 1 -C 6 alkoxy; C 3 -C 10 cycloalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1 -C 6 alkoxy and C 1 -C 6 alkylcarbonyloxy; C 1 -C 10 alkoxycarbonyl; C 1 -C 10 alkylcarbonyl; or R 1 and R 2 join together to form a 5- to 12-membered ring optionally containing a heteroatom selected from N and O,
R is a substituent selected from the group consisting of the following chemical formulae,

* indicates the binding site in which the compound of formula (I) is connected to,
D is NR 7 , O or S,
E is O or S,
R 3 is hydrogen; or C 1 -C 10 alkyl optionally substituted with hydroxy,
R 4 is 3- to 12-membered heterocycloalkyl (said heterocycloalkyl is optionally substituted with C 1 -C 10 alkyl or halogen); C 1 -C 10 alkoxy; C 1 -C 10 alkylthio; or NR 8 R 9 ,
R 6 is hydrogen or C 1 -C 10 alkyl,
R 7 is hydrogen or C 1 -C 10 alkyl,
R 8 and R 9 are each independently hydrogen; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from C 1 -C 6 alkoxycarbonyl and C 6 -C 12 aryl, wherein said aryl is optionally substituted with halogen or C 1 -C 6 alkoxy; C 6 -C 12 aryl optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy; or 5- to 12-membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, C 1 -C 6 alkyl and C 1 -C 6 alkoxy.

2. The compound of claim 1 , wherein
A is hydrogen or —(CH 2 ) m Q,
B is hydrogen; —(C≡C)R 1 ; —(CH 2 ) m Q; —(CH═CH)(CH 2 ) m Q; —(C≡C)(CH 2 ) m Q; —NH(CH 2 ) p Q; —(CONH)(CH 2 ) m Q; or —CONR 1 R 2 , wherein, one of A and B is hydrogen, and A and B cannot be hydrogen at the same time,
m is an integer from 0 to 3,
p is an integer from 0 to 3,
Q is phenyl; pyridyl; pyrazolyl; thiophenyl; pyrimidinyl; thiazolyl; pyridazinyl; piperazinyl; morpholinyl; piperidinyl; tetrahydropyridyl; naphthyl; benzothiophenyl; benzodioxolyl; dihydrobenzofuranyl; dihydrobenzoxazinyl; benzodioxinyl; benzothiadiazolyl; quinolyl; indazolyl; benzoimidazolyl; dihydrobenzodioxinyl; benzothiazolyl; or indolyl,
wherein Q is optionally substituted with one or more substituents selected from the group consisting of hydroxy; amino; halogen; cyano; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C 1 -C 6 alkoxy and C 1 -C 6 alkylcarbonyloxy; C 2 -C 6 alkenyl; 4-oxo-2-thioxothiazolidin-5-ylidenyl; C 2 -C 6 alkynyl; C 3 -C 7 cycloalkyl; 5- to 7-membered heterocycloalkyl-C 1 -C 4 alkyl, wherein, said heterocycloalkyl is optionally substituted with C 1 -C 4 alkyl; C 6 -C 12 aryl; 5- to 12-membered heteroaryl optionally substituted with C 1 -C 4 alkyl; 3- to 12-membered heterocycloalkyl optionally substituted with C 1 -C 3 alkyl; C 1 -C 6 alkoxy optionally substituted with one or more of halogen and cyano; C 3 -C 7 cycloalkyloxy; C 6 -C 12 aryl-C 1 -C 6 alkyloxy, wherein, said aryl is optionally substituted with C 1 -C 3 alkoxy; C 6 -C 12 aryloxy optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, hydroxycarbonyl, cyano and nitro; 5- to 12-membered heteroaryloxy, wherein, said heteroaryl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, halogen, hydroxycarbonyl, cyano and nitro; C 1 -C 6 alkylcarbonyloxy; C 1 -C 6 alkylthio; mono- or di-C 1 -C 6 alkylamino; mono- or di-C 3 -C 7 cycloalkylamino; C 6 -C 12 arylamino; 5- to 12-membered heteroarylamino; C 1 -C 6 alkylsulfonylamino; C 6 -C 12 arylsulfonylamino; 5- to 12-membered heteroarylsulfonylamino; C 1 -C 6 alkylcarbonylamino; C 6 -C 12 arylcarbonylamino; 5- to 12-membered heteroarylcarbonylamino; formyl; C 1 -C 6 alkylcarbonyl; C 6 -C 12 arylcarbonyl; 5- to 12-membered heteroarylcarbonyl; C 1 -C 6 alkoxycarbonyl; hydroxycarbonyl; C 6 -C 12 aryloxycarbonyl; 5- to 12-membered heteroaryloxycarbonyl; aminocarbonyl; mono- or di-C 1 -C 6 alkylaminocarbonyl, wherein, said alkyl is optionally subst

Assignees

• Yuhan Corp

Inventors

• Seo Hyoung Sig
• Kim Tae Kyun
• Lee Hyun Joo
• Kim Dong Hoon
• Lee Gyu Jin
• Park Jun Chul
• Gal Ji Yeong
• Kim Tae-Hoon
• Hyun Kwan Hoon
• Ahn Kyoung Kyu
• Park Kaapjoo
• Nam Su Youn
• Lee Ge Hyeong
• Lim Hee Jong

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D491/048 Primary

  the oxygen-containing ring being five-membered · CPC title

• A61K31/429

  condensed with heterocyclic ring systems · CPC title

• A61K31/4738

  ortho- or peri-condensed with heterocyclic ring systems · CPC title