Imidazo[1,5-a]pyrazine derivatives as PI3Kdelta inhibitors

Patent metadata

Field	Value
Publication number	US-11220506-B2
Application number	US-201816643040-A
Country	US
Kind code	B2
Filing date	Sep 7, 2018
Priority date	Sep 8, 2017
Publication date	Jan 11, 2022
Grant date	Jan 11, 2022

Abstract

Disclosed is a compound of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions comprising thereof. Also disclosed is a method of treating PI3Kδ related disorders or diseases by using the compound disclosed herein.

First claim

The invention claimed is:

1. A compound of Formula (I),

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is —NR a R b , wherein R a and R b are each independently hydrogen or C 1-6 alkyl;
R 2 is hydrogen, F, Cl, Br, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , —OR 12 , —SO 2 R 12 , —COR 12 , —CO 2 R 12 , —CONR 12 R 13 , —C(═NR 12 )NR 13 R 14 , —NR 12 R 13 , —NR 12 COR 13 , —NR 12 CONR 13 R 14 , —NR 12 CO 2 R 13 , —NR 12 SONR 13 R 14 , —NR 12 SO 2 NR 13 R 14 , or —NR 12 SO 2 R 13 ; wherein said —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally substituted with at least one substituent R 11a ;
R 3 and R 4 , which may be the same or different, are each independently hydrogen, —C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R 5 and R 6 , which may be the same or different, are each independently hydrogen, halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , —OR 12 , —SO 2 R 12 , —COR 12 , —CO 2 R 12 , —CONR 12 R 13 , —C(═NR 12 )NR 13 R 14 , —NR 12 R 13 , —NR 12 COR 13 , —NR 12 CONR 13 R 14 , —NR 12 CO 2 R 13 , —NR 12 SONR 13 R 14 , —NR 12 SO 2 NR 13 R 14 , or —NR 12 SO 2 R 13 ; wherein said —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally substituted with at least one substituent R 11b ;
R 7 , R 8 and R 10 , which may be the same or different, are each independently hydrogen, halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , —OR 12 , —SO 2 R 12 , —COR 12 , —CO 2 R 12 , —CONR 12 R 13 , —C(═NR 12 )NR 13 R 14 , —NR 12 R 13 , —NR 12 COR 13 , —NR 12 CONR 13 R 14 , —NR 12 CO 2 R 13 , —NR 12 SONR 13 R 14 , —NR 12 SO 2 NR 13 R 14 , or —NR 12 SO 2 R 13 ; wherein said —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally substituted with at least one substituent R 11c ;
R 9 is —CN, —NO 2 , —OR 12 , —SO 2 R 12 , —SO 2 NR 12 R 13 , —COR 12 , —CO 2 R 12 , —CONR 12 R 13 , —C(═NR 12 )NR 13 R 14 , —NR 12 COR 13 , —NR 12 CONR 13 R 14 , —NR 12 CO 2 R 13 , —NR 12 SONR 13 R 14 , —NR 12 SO 2 NR 13 R 14 , or —NR 12 SO 2 R 13 ;
R 11a , R 11b , and R 11c , which may be the same or different, are each independently hydrogen, halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, haloC 1-6 alkyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , oxo, —OR 12 , —SO 2 R 12 , —COR 12 , —CO 2 R 12 , —CONR 12 R 13 , —C(═NR 12 )NR 13 R 14 , —NR 12 R 13 , —NR 12 COR 13 , —NR 12 CONR 13 R 14 , —NR 12 CO 2 R 13 , —NR 12 SONR 13 R 14 , —NR 12 SO 2 NR 13 R 14 , or —NR 12 SO 2 R 13 ; and
R 12 , R 13 , and R 14 , which may be the same or different, are each independently hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently optionally substituted with at least one substituent R 15 ;
Alternatively, (R 12 and R 13 ), or (R 13 and R 14 ), or (R 12 and R 14 ), together with the atom(s) to which they are attached, form a 3- to 12-membered saturated, partially or fully unsaturated ring comprising 0, 1 or 2 additional heteroatoms independently selected from —NH, —O—, —S—, —SO— or —SO 2 —, and said ring is optionally substituted with at least one substituent R 15 ;
R 15 , at each of its occurrences, is independently hydrogen, halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —CN, —NO 2 , oxo, —OR 16 , —SO 2 R 16 , —COR 16 , —CO 2 R 16 , —CONR 16 R 17 , —C(═NR 16 )NR 17 R 18 , —NR 16 R 17 , —C 1-6 alkyl-NR 16 R 17 , —NR 16 COR 17 , —NR 16 CONR 17 R 18 , —NR 16 CO 2 R 17 , —NR 16 SONR 17 R 18 , —NR 16 SO 2 NR 17 R 18 , or —NR 16 SO 2 R 17 , wherein said C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently optionally substituted with halogen, R 19 , —OR 19 , —COR 19 , —SO 2 R 19 , or —CO 2 R 19 ;
wherein each of R 16 , R 17 , or R 18 is independently hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, haloC 1-6 alkyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
(R 16 and R 17 ), or (R 16 and R 18 ), or (R 17 and R 18 ), together with the atom(s) to which they are attached, form a 3- to 12-membered saturated, partially or fully unsaturated ring comprising 0, 1 or 2 additional heteroatoms independently selected from —NH, —O—, —S—, —SO— or —SO 2 —, and said ring is optionally substituted with at least one substituent R 19 ; and
wherein R 19 is independently hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, haloC 1-6 alkyl, haloC 2-6 alkenyl, haloC 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl, or heteroaryl are each optionally substituted with halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, haloC 1-6 alkyl, haloC 2-6 alkenyl, or haloC 2-6 alkynyl; and

wherein said —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, haloC 1-6 alkyl, haloC 2-6 alkenyl, or haloC 2-6 alkynyl are each optionally substituted with cycloalkyl, heterocyclyl, aryl, or heteroaryl.

2. The compound of claim 1 , wherein:
(a) R 1 is —NH 2 ; or
(b) R 2 is independently hydrogen, halogen, —C 1-6 alkyl, C 3-6 cycloalkyl or C 6-10 aryl, wherein —C 1-6 alkyl, C 3-6 cycloalkyl and C 6-10 aryl are each independently optionally substituted with at least one substituent R 11a ; or
(c) R 3 and R 4 are each independently hydrogen or —C 1-6 alkyl; or
(d) R 5 and R 6 , which may be the same or different, are each independently hydrogen, halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally substituted with at least one substituent R 11b , wherein R 11b is halogen; or
(e) R 7 , R 8 and R 10 , which may be the same or different, are each independently hydrogen, halogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or —OR 12 ; wherein said —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally substituted with at least one substituent R 11c , wherein R 11c is halogen.

3. The compound of claim 2 , wherein:
(a) R 2 is C 1-6 alkyl; or
(b) R 3 is hydrogen, and R 4 is —C 1-6 alkyl; or
(c) R 5 and R 6 are both hydrogen; or
(d) R 7 and R 8 are each independently hydrogen, halogen or —C 1-6 alkyl; or
(e) R 10 is methoxy, ethoxy, propoxy, or isopropoxy.

4. The compound of claim 1 , wherein R 9 is —CONR 12 R 13 .

5. The compound of claim 4 , wherein:
R 12 is hydrogen;
R 13 is C 1-6 alklyl optionally substituted with one substituent R 15 ; and
R 15 is heterocyclyl optionally substituted with halogen, R 19 , —OR 19 , —COR 19 , —SO 2 R 19 , or —CO 2 R 19 .

6. The compound of claim 5 , wherein the heterocyclyl is a 4-, 5-, 6-, 7- or 8-membered saturated monocyclic ring comprising one nitrogen heteroatom or a 5-, 6-, 7- or 8-membered saturated monocyclic ring comprising one nitrogen atom and 1 additional heteroatom selected from —NH, —O—, —S—, —SO— or —SO 2 —, wherein the heterocyclyl is optionally substituted with halogen, R 19 , —OR 19 , —COR 19 , —SO 2 R 19 ,

Assignees

• Beigene Ltd

Inventors

• Li Jing
• Zhao Haibo
• Wang Zhiwei

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D233/64 Primary

  with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title