Purine inhibitors of human phosphatidylinositol 3-kinase delta

Patent metadata

Field	Value
Publication number	US-10100064-B2
Application number	US-201515318483-A
Country	US
Kind code	B2
Filing date	Jun 9, 2015
Priority date	Jun 13, 2014
Publication date	Oct 16, 2018
Grant date	Oct 16, 2018

Abstract

The instant invention provides compounds of formula (I) which are PI3K-delta inhibitors, and as such are useful for the treatment of PI3K-delta-mediated diseases such as inflammation, asthma, COPD and cancer.

First claim

What is claimed is:

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

A, B, D, E and G are independently selected from carbon and nitrogen, wherein at least two of A, B, D, E and G are carbon and wherein A, B, D, E and G form an aromatic ring;
R 1 is selected from hydrogen, C 1-5 alkyl, and —(C 0-3 alkyl)C 3-4 cycloalkyl, wherein R 1 is optionally substituted by 0, 1, 2, 3, or 4 groups independently selected from hydrogen, fluoro, chloro, methyl, C 1-3 haloalkyl, amino, O(C═O)R a , O(C═O)OR a and NH(C═O)R a ;
R a is independently selected from C 1-3 alkyl, C 1-3 haloalkyl and —(C 0-3 alkyl)C 3-4 cycloalkyl;
R 2 is selected from pyridinyl, pyrimidinyl, fluoro, pyrazolyl, phenyl, imidazolyl, iodo, and trifluoroethyl, wherein R 2 is substituted with 0, 1, 2, 3, or 4 R 6 substituents;
R 4 is selected from halogen, C 1-10 alkyl, C 2-10 alkynyl, and C 1-10 alkoxy, wherein R 4 is substituted with 0, 1, 2, 3, or 4 substituents selected from OH, halogen, and —CO 2 H;
n is 0, 1, 2, or 3;
v is 0, 1, 2, or 3;
p is 0 or 1;
L is selected from —O—, —NH—, and —N(C 1-3 alkyl)-;
K is selected from a bond, NH, O, C(O), CH 2 , N(C 1 s)alkyl, —C(O)N(R b )—(CH 2 ) m —, S, SO 2 , and C 2-10 alkynylene;
R b is H or C 1-10 alkyl,
m is 0, 1, 2, or 3;
R 3 is independently selected from:
halogen,
C 1-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
aryl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 -C 0-10 alkyl,
C 3-12 cycloalkylC 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
heteroaryl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
(C 1-10 alkyl) 1-2 aminoC 0-10 alkyl,
C 0-10 alkylamino(carbonyl) 0-1 C 0-10 alkyl,
(C 1-10 alkyl) 1-2 aminoC 0-10 alkyl carbonylC 0-10 alkyl,
C 0-10 alkylsulfonylC 0-10 alkyl,
(C 1-10 alkyl)OH, and
C 1-6 haloalkyl;

wherein R 3 is each substituted with 0, 1, 2, 3, or 4 R 5 substituents and each R 5 is independently selected from:
halogen, C 1-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl, C 1-10 heteroalkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl, aryl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl, C 3-12 cycloalkyl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl, heteroaryl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl, (C 3-12 )heterocycloalkyl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl, C 1-10 alkylamino(carbonyl) 0-1 C 0-10 alkyl, C 3-12 cycloalkyl C 0-10 alkylamino(carbonyl) 0-1 C 0-10 alkyl, aryl C 0-10 alkylamino(carbonyl) 0-1 C 0-10 alkyl, heteroaryl C 0-10 alkylamino(carbonyl) 0-1 C 0-10 alkyl, (C 3-12 )heterocycloalkyl C 0-10 alkylamino(carbonyl) 0-1 C 0-10 alkyl, C 0-10 alkylsulfonylC 0-10 alkyl, (C 3-12 )cycloalkylC 0-10 alkylsulfonylC 0-10 alkyl, (C 3-12 )cycloheteroalkylC 0-10 alkylsulfonylC 0-10 alkyl, heteroarylC 0-10 alkylsulfonylC 0-10 alkyl, arylC 0-10 alkylsulfonylC 0-10 alkyl, —CO 2 (C 0-10 alkyl), —(C 0-10 alkyl)CO 2 H, Oxo (═O), —SO 2 N(C 1-6 alkyl) 1-2 , —SO 2 C 1-6 alkyl, —SO 2 CF 3 , —SO 2 CF 2 H, amino, (C 0-10 alkyl) 1-2 amino, hydroxy, (C 1-10 alkyl)OH, C 1-10 alkoxy, cyano, and C 1-6 haloalkyl;
R 6 is independently selected from:
halogen,
C 1-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
C 1-10 haloalkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
C 1-10 heteroalkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
aryl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
C 3-12 cycloalkyl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
heteroaryl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
(C 3-12 )heterocycloalkyl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
C 0-10 alkyl(oxy) 0-1 carbonylaminoC 0-10 alkyl,
C 0-10 alkylamino(oxy) 0-1 carbonylC 0-10 alkyl,
(C 1-10 )heteroalkylamino(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
C 3-12 cycloalkylamino(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
aryl C 0-10 alkylamino(oxy) 0-1 (carbonyl) 0-1 C 10 alkyl,
heteroaryl C 0-10 alkylamino(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
(C 3-12 )heterocycloalkylamino(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
—CO 2 (C 0-10 alkyl),
—(C 0-10 alkyl)CO 2 H,
oxo (═O),
C 0-10 alkylsulfonylC 0-10 alkyl,
C 1-10 heteroalkylsulfonylC 0-10 alkyl,
(C 3-12 )cycloalkylC 0-10 alkylsulfonylC 0-10 alkyl,
(C 3-12 )cycloheteroalkylC 0-10 alkylsulfonylC 0-10 alkyl,
heteroarylC 0-10 alkylsulfonylC 0-10 alkyl,
arylC 0-10 alkylsulfonylC 0-10 alkyl,
—SO 2 NH 2 ,
—SO 2 NH(C 1-10 alkyl),
—SO 2 N(C 1-10 alkyl) 2 ,
—SO 2 CF 3 ,
—SO 2 CF 2 H,
amino,
(C 1-10 alkyl) 1-2 amino,
-(oxy) 0-1 (carbonyl) 0-1 N(C 0-10 alkyl) 1-2
hydroxy,
(C 1-10 alkyl)OH,
C 1-10 alkoxy,
(C 1-10 alkyl)cyano,
cyano, and
C 1-6 haloalkyl; and

wherein R 5 and R 6 are each independently substituted with 0, 1, 2, or 3 R 7 substituents and each R 7 substituent is independently selected from hydroxy, (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 5-6 )aryl, (C 5-6 )heteroaryl, (C 1-10 alkyl)OH, halogen, CO 2 H, —(C 0-6 )alkylCN, —O(C═O)C 1 -C 6 alkyl, —(C═O)OC 1 -C 6 alkyl, NO 2 , trifluoromethoxy, trifluoroethoxy, trifluoromethyl, trifluoroethyl, —N—C(O)O(C 0-6 )alkyl, C 1-10 alkylsulfonyl, oxo (O═), aminosulfonyl, —SO 2 N(C 1-6 alkyl) 1-2 , —SO 2 C 1-6 alkyl, —SO 2 CF 3 , —SO 2 CF 2 H, —C 1-10 alkylsulfinyl, —O (0-1) (C 1-10 )haloalkyl, amino(C 1-6 alkyl) 1-2 and NH 2 .

2. A compound according to claim 1 , or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 1 is hydrogen or C 1-5 alkyl optionally substituted by 0, 1, 2, 3, or 4 groups independently selected from hydrogen, C 1-3 haloalkyl, fluoro, chloro, methyl, amino, O(C═O)R a , O(C═O)OR a and NH(C═O)R a .

3. A compound according to claim 2 , or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein

is selected from:

4. A compound according to claim 3 , or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein v is 0 or 1; and n is 0, 1, or 2.

5. A compound according to claim 4 , or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein K is selected from a bond, NH, CH 2 , and —C(O)N(R b )—(CH 2 ) m —.

6. A compound according to claim 5 , or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein K is a bond.

7. A compound according to claim 6 , a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein L is —NH— or —O—.

8. A compound according to claim 7 , a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or isopentyl, wherein R 1 is substituted by 0, 1, 2, 3, or 4 groups independently selected from hydrogen, fluoro, chloro, methyl, C 1-3 haloalkyl, amino, O(C═O)R a , O(C═O)OR a and NH(C═O)R a .

9. A compound or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein said compound is selected from:
N-(3-cyclopropyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-6-yl)-9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-amine;
9-ethyl-8-(2-methylpyrimidin-5-yl)-N-[3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-6-yl]-9H-purin-6-amine;
9-ethyl-N-[3-(1-methylethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-6-yl]-8-(2-methylpyrimidin-5-yl)-9H-purin-6-amine;
9-ethyl-N-[3-ethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-

Assignees

• Merck Sharp & Dohme

Inventors

• Mcgowan Meredeth Ann
• Fong Kin Chiu
• Anthony Neville John
• Zhou Hua
• Katz Jason D
• Yang Lihu
• Li Chaomin
• Tian Yuan
• Mu Changwei
• Ye Baijun
• Shi Feng
• Zhao Xiaoli
• Fu Jianmin
• Li Yabin

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D519/00 Primary

  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

• C07D473/30

  attached in position 6, e.g. hypoxanthine · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title