Purine inhibitors of human phosphatidylinositol 3-kinase delta

Patent metadata

Field	Value
Publication number	US-9938281-B2
Application number	US-201314443314-A
Country	US
Kind code	B2
Filing date	Nov 15, 2013
Priority date	Nov 16, 2012
Publication date	Apr 10, 2018
Grant date	Apr 10, 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

The invention claimed is:

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

R 1 is selected from methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl, 2-2-difluoroethyl, and 2-2-2-trifluoroethyl;
R 2 is selected from pyrimidinyl, pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolidinyl, oxetanyl, cyclohexyl, azetidinyl, phenyl, pyrazolyl, imidazolyl, indolyl, indazolyl, thiazolyl, hydrogen, 1H-pyrazolo[3,4-b]pyridinyl], benzimidazolyl, cyclopropyl, tert-butyl, ethyl, methyl, methylpropyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, and morpholinyl, wherein R 2 is substituted with 0, 1, 2, 3, or 4 independently selected R 3 substituents;
n is 0, 1, 2, 3, or 4;
A is selected from pyrrolidinyl, piperidinyl, azetidinyl, azaspiro[2.4]hept-7-yl, and azepanyl;
L is selected from NH, and N(C 1-10 alkyl);
K is selected from a bond, NH, O, C(O), CH 2 , N(C 1-5 )alkyl, —C(O)N(R b )—(CH 2 ) m —, N, 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:
fluoro, chloro, methyl, ethyl, propyl, methoxy, methoxymethyl, methylethyl, 2-methylbuten-4-yl, 2-methylpropyl, 1,3,4-oxadiazolyl, pyridinyl, isoquinolinyl, cyclopropylmethyl, cyclopropylethyl, isopropyl, hydroxy, oxo, dimethylamino, tert-butyl, trifluoromethyl, trifluoroethyl, carboxy, tert-butylcarboxy, fluoroethylcarboxy, tetrahydrothiophenylcarboxy, methylpropylcarboxy, propylcarboxy, benzylcarboxy, 2,2-dimethylpropylcarboxy, methylcarboxy, ethylcarboxy, methylethylcarboxy, cyclopentylcarbonyl, cyclohexylcarboxy, cyclobutylcarbonyl, 2,2,2-trifluoroethylcarboxy, spiro[2.4]hept-1-ylcarbonyl, spiro[2.5]oct-1-ylcarbonyl, benzylcarbonyl, imidazolylcarbonyl, ethylcarbonyl, piperidinylcarbonyl, pyrrolidinylcarbonyl, cyclohexylcarbonyl, isopropylcarbonyl, tetrahydro-2H-pyran-4-ylcarbonyl, oxazolylcarbonyl, cyclopropylcarbonyl, azetidinylcarbonyl, cyclopropylaminocarbonyl, tetrahydrofuranylcarbonyl, isoxazolylcarbonyl, triazolylcarbonyl, thiadiazolylcarbonyl, cyclobutylaminocarbonyl, furanylmethylaminocarbonyl, aminocarbonyl, pyrazolylcarbonyl, hydroxymethyl, oxadiazolylcarbonyl, ethylsulfonyl, methylsulfonyl, (cyclopropylmethyl)aminocarbonyl, azabicyclo[3.1.0]hex-6-ylcarbonyl, trifluoroethylaminocarbonyl, (tetrahydrothiophenylmethyl)aminocarbonyl, cyclohexylaminocarbonyl, ethylaminocarbonyl, (1,1,3,3-tetramethylbutyl)aminocarbonyl, oxazolylcarbonylamino, dimethylpropylaminocarbonyl, methylcarbonylamino, bicyclo[1.1.1]pent-1-ylcarbonyl, methylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, phenyl, pyrimidinyl, thieno[3,2-c]pyridinyl, morpholinylcarbonyl, butylaminocarbonyl,
2-methylprop-1-enyl, cyano, (methylamino)methylcarbonyl, amino, hydroxyisopropyl, 2-hydroxypropyl, hydroxycarbonyl, methoxycarbonyl, and isobutylcarbonyl; wherein R 3 is each substituted with 0, 1, 2, 3, or 4 substituents, R 4 ;
wherein R 3 is each substituted with 0, 1, 2, 3, or 4 R 4 substituents and each R 4 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,
aryl C 2-10 alkynyl(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(carbonyl) 0-1 oxyC 0-10 alkyl,
C 1-10 heteroalkyl(carbonyl) 0-1 oxyC 0-10 alkyl,
aryl C 0-10 alkyl (carbonyl) 0-1 oxyC 0-10 alkyl,
(C 3-12 )cycloalkyl C 0-10 alkyl(carbonyl) 0-1 oxyC 0-10 alkyl,
heteroarylC 0-10 alkyl(carbonyl) 0-1 oxyC 0-10 alkyl,
(C 3-12 )heterocycloalkyl C 0-10 alkyl(carbonyl) 0-1 oxyC 0-10 alkyl,
((C 0-10 )alkyl) 1-2 aminocarbonyloxy,
aryl (C 0-10 )alkylaminocarbonyloxy,
(C 3-12 )cycloalkyl(C 0-10 )alkylaminocarbonyloxy,
heteroaryl(C 0-10 )alkylaminocarbonyloxy,
(C 3-12 )heterocycloalkyl(C 0-10 )alkylaminocarbonyloxy,
C 1-10 alkylaminocarbonylC 0-10 alkyl,
C 3-12 cycloalkyl C 0-10 alkylaminocarbonylC 0-10 alkyl,
aryl C 0-10 alkylaminocarbonylC 0-10 alkyl,
heteroaryl C 0-10 alkylaminocarbonylC 0-10 alkyl,
(C 3-12 )heterocycloalkyl C 0-10 alkylaminocarbonylC 0-10 alkyl,
C 1-10 alkyl (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 ,
C 1-10 heteroalkyl S(O) 1-2 ,
(C 3-12 )cycloalkyl S(O) 1-2 ,
(C 3-12 )cycloheteroalkylS(O) 1-2 ,
heteroarylS(O) 1-2 ,
aryl S(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,
aryl(amino) 0-1 S(O) 1-2 amino,
—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,
-(oxy) 0-1 (carbonyl) 0-1 N(C 0-10 alkyl) 1-2 ,
hydroxy,
(C 1-10 alkyl)OH,
C 1-10 alkoxy,
cyano, and
C 1-6 haloalkyl;

R 4 is substituted with 0, 1, 2, or 3 R 5 substituents and each R 5 substituent is independently selected from hydroxy, (C 1-6 )alkyl, (C 1-6 )alkoxy, (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, C 1-10 heteroalkyl, aryl, (C 3-12 )cycloalkyl, heteroaryl, (C 3-12 )heterocycloalkyl, C 1-10 heteroalkylsulfonyl, oxo (O═), (C 3-12 )cycloalkylsulfonyl, (C 3-12 )cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, 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) 0-2 and NH 2 ; and
R 5 is substituted with 0, 1, or 2 R 6 substituents and each R 6 substituent is independently selected from hydroxy, (C 1-6 )alkyl, (C 1-6 )alkoxy, (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, C 1-10 heteroalkylsulfonyl, oxo (O═), (C 3-12 )cycloalkylsulfonyl, (C 3-12 )cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, 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, —O (0-1) (C 1-10 )haloalkyl, amino(C 1-6 alkyl) 0-2 and NH 2 .

2. A compound 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]amino}pyrrolidine-1-carboxylate;
tert-butyl 3-((8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl)(methyl)amino)pyrrolidine-1-carboxylate;
tert-butyl 3-((9-ethyl-8-(6-methoxy-5-methylpyridin-3-yl)-9H-purin-6-yl)(methyl)amino)pyrrolidine-1-carboxylate;
tert-butyl 3-((9-ethyl-8-(6-methoxy-5-methylpyridin-3-yl)-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate;
tert-butyl 3-((8-(2-(tert-butyl)thiazol-5-yl)-9-ethyl-9H-purin-6-yl)amino)pyrrolidine-1-carboxylate;
tert-butyl 3-((8-(2-(tert-butyl)thiazol-5-yl)-9-ethyl-9H-purin-6-yl)(methyl)amino)pyrrolidine-1-carboxylate;
tert-butyl 3-((8-(6-methoxy-5

Assignees

• Merck Sharp & Dohme

Inventors

• Achab Abdelghani Abe
• Altman Michael D
• Deng Yongqi
• Kattar Solomon
• Katz Jason D
• Methot Joey L
• Zhou Hua
• Mcgowan Meredeth
• Christopher Matthew P
• Garcia Yudith
• Anthony Neville John
• Fradera Llinas Francesc Xavier
• Yang Liping
• Mu Changwei
• Wang Xiaona
• Shi Feng
• Ye Baijun
• Zhang Sixing
• Zhao Xiaoli
• Zhang Rong
• Fong Kin Chiu
• Leng Xiansheng

Classifications

• A61P37/08

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · 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