Purine inhibitors of human phosphatidylinositol 3-kinase delta

Patent metadata

Field	Value
Publication number	US-9730940-B2
Application number	US-201314443294-A
Country	US
Kind code	B2
Filing date	Nov 15, 2013
Priority date	Nov 16, 2012
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

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

The invention claimed is:

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

R 1a is selected from methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, and cyclopentyl, wherein R 1a is optionally substituted by 0, 1, 2, 3, or 4 groups independently selected from fluoro, chloro, methyl and amino;
R 2a is selected from cyclopropyl, isobutyl, 2-methylpropyl, methyl, ethyl, iodo, pyridazinyl, pyrimidinyl, pyrazinyl, pyridinyl, pyrrolidinyl, piperidinyl, ethoxycarbonyl, cyclohexyl, phenyl, quinazolinyl, isoquinolinyl, pyrazolyl, imidazolyl, indolyl, indazolyl, thiazolyl, pyrazolo[1,5-a]pyrimidinyl, 3,6-dihydro-2H-pyranyl, 1H-pyrrolo[2,3-b]pyridinyl, cyclobutyl, 1H-pyrazolo[3,4-b]pyridinyl], pyrrolo[2,3-b]pyridinyl, benzimidazolyl, morpholinyl, 4,5,6,7,-tetrahydropyrazolo[1,5-a]pyridinyl, 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl, wherein R 2a is substituted with 0, 1, 2, 3, or 4 R 3a substituents;
n is 0, 1, 2, 3, or 4;
A is selected from pyrrolidinyl, piperidinyl, cyclobutyl, cyclohexyl, azaspiro [2.4]hept-2-yl, azabicyclo[2.2.1]heptanyl, azetidinyl, and cyclopentyl;
L is selected from O, S, SO 2 , and —CH 2 ;
K is selected from a bond, NH, O, C(O), CH 2 , N((C 1-5 )alkyl) 1-2 , —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 3a is independently selected from: fluoro, chloro, methyl, ethyl, methoxy, pyrazolyl, hydroxyl, dimethylamino, morpholinyl, pyrrolidinyl, tert-butyl, methylsulfonyl, trifluoromethyl, phenyl, hydroxymethyl, cyclopropyl, imidazolyl, methylsulfonylamino, acetylamino, methylcarbonylamino, cyano, and amino, wherein R 3a is each substituted with 0, 1, 2, 3, or 4 R 4a substituents and each R 4a is independently selected from: halogen, methyl, ethyl, hydroxy, and amino;
R 3 is independently selected from:
halogen,
C 1-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
C 2-10 alkenyl(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 cycloalkylC 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 C 0-10 alkyl,
heteroarylC 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 1-10 )heteroalkylamino(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,
heteroarylC 0-10 alkylamino(carbonyl) 0-1 C 0-10 alkyl,
(C 3-12 )heterocycloalkylC 0-10 alkylamino(carbonyl) 0-1 C 0-10 alkyl,
C 1-10 alkyl(oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
C 1-10 heteroalkyl (oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
C 3-12 cycloalkyl C 0-10 alkyl (oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
aryl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
heteroaryl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
(C 3-12 )heterocycloalkyl C 0-10 alkyl(oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
—CO 2 (C 0-10 alkyl),
—(C 0-10 alkyl)CO 2 H,
Oxo (═O),
C 1-10 alkylS(O) 1-2 ,
heteroarylS(O) 1-2 ,
arylS(O) 1-2 ,
C 0-6 alkyl(amino) 0-1 S(O) 1-2 amino,
C 1-10 heteroalkyl(amino) 0-1 S(O) 1-2 amino,
(C 3-12 )cycloalkyl(amino) 0-1 S(O) 1-2 amino,
(C 3-12 )cycloheteroalkyl(amino) 0-1 S(O) 1-2 amino,
heteroaryl(amino) 0-1 S(O) 1-2 amino,
C 1-10 heteroalkylS(O) 1-2 , (C 3-12 )cycloalkylS(O) 1-2 ,
(C 3-12 )cycloheteroalkylS(O) 1-2 ,
heteroarylS(O) 1-2 , arylS(O) 1-2 ,
—SO 2 N(C 0-6 alkyl) 0-2 ,
—SO 2 CF 3 , amino,
(C 0-10 alkyl) 1-2 amino,
hydroxy,
(C 1-10 alkyl)OH,
C 0-10 alkylalkoxy,
cyano,
C 1-6 alkylcyano, and
C 1-6 haloalkyl; wherein R 3 is each substituted with 0, 1, 2, 3, or 4 substituents, R 4 ;

R 4 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 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 alkyl (oxy) 0-1 (carbonyl) 0-1 aminoC 0-10 alkyl,
Oxo (═O),
—SO 2 C 1-6 alkyl,
amino,
(C 0-10 alkyl) 1-2 amino,
(C 1-10 alkyl)OH,
C 1-10 alkoxy,
cyano, and
C 1-6 haloalkyl; wherein R 4 is substituted with 0, 1, 2, or 3 R 5 ;

R 5 is independently selected from hydroxy, (C 1-6 )alkyl, (C 1-6 )alkoxy, halogen, CO 2 H, —(C 0-6 )alkylCN, NO 2 , trifluoromethoxy, trifluoroethoxy, trifluoromethyl, trifluoroethyl, oxo (O═), —O (0-1) (C 1-10 )haloalkyl, amino(C 1-6 alkyl) 0-2 and NH 2 ; and R 5 is substituted with 0, 1, or 2 R 6 substituents; and
R 6 is independently selected from hydroxy, methyl, halogen, oxo (O═) and NH 2 .

2. A compound according to claim 1 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein the compound is selected from:
tert-butyl-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-6-[pyrrolidin-3-yloxy]-9H-purine;
tert-butyl-3-{[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
2-methylpropyl-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
naphthalen-2-yl-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
benzyl-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
4-methylphenyl-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
phenyl-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
2,2-dimethylpropyl-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
3-(trifluoromethyl)phenyl-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
4-methoxyphenyl-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
tert-butyl 4-{[8-(1-ethyl-5-methyl-1-pyrazol-3-yl)-9-methyl-9H-purin-6-yl]oxy}piperidine-1-carboxylate;
tert-butyl-3-{[8-(6-methoxy-5-methylpyridin-3-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
tert-butyl-3-{[9-methyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
tert-butyl-3-({9-methyl-8-[4-(1H-pyrazol-1-yl)phenyl]-9H-purin-6-yl}oxy)pyrrolidine-1-carboxylate;
tert-butyl-3-{[8-(1,3-dimethyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
tert-butyl-3-{[8-(1,2-dimethyl-1H-imidazol-5-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
tert-butyl-3-{[8-(4-hydroxyphenyl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
tert-butyl-3-{[9-methyl-8-(1H-pyrazol-4-yl)-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
tert-butyl-3-({8-[6-(dimethylamino)pyridin-3-yl]-9-methyl-9H-purin-6-yl}oxy)pyrrolidine-1-carboxylate;
tert-butyl-3-{[9-methyl-8-(2-methyl-1H-indol-7-yl)-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
tert-butyl-3-[(9-methyl-8-pyrazolo[1,5-a]pyrimidin-3-yl-9H-purin-6-yl)oxy]pyrrolidine-1-carboxylate;
tert-butyl-3-({8-[4-(acetylamino)phenyl]-9-methyl-9H-purin-6-yl}oxy)pyrrolidine-1-carboxylate;
tert-butyl-3-{[9-methyl-8-(6-morpholin-4-ylpyridin-3-yl)-9H-purin-6-yl]oxy}pyrrolidine-1-carboxylate;
tert-butyl-3-({8-[4-(1H-imidazol-1-yl)phenyl]-9-methyl-9H-purin-6-yl}oxy)pyrrolidine-1-carboxylate;
tert-butyl-3-{[9-methyl-8-(3-methyl-1-pyrazol-4-yl)-9H-purin-6-yl]oxy}pyrro

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

• Achab Abdelghani Abe
• Altman Michael D
• Deng Yongqi
• Guzi Timothy
• Kattar Solomon
• Katz Jason D
• Methot Joey L
• Zhou Hua
• Mcgowan Meredeth
• Christopher Matthew P
• Garcia Yudith
• Anthony Neville John
• Fradera Llinas Francesc Xavier
• Fong Kin Chiu
• Leng Xiansheng
• Mu Changwei
• Zhang Sixing
• Zhang Rong

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title