Purine inhibitors of human phosphatidylinositol 3-kinase delta

Patent metadata

Field	Value
Publication number	US-10544147-B2
Application number	US-201716089509-A
Country	US
Kind code	B2
Filing date	Mar 24, 2017
Priority date	Mar 30, 2016
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

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:

wherein

is selected from the group consisting of

R 1 is selected from the group consisting of hydrogen, a 5- to 6-membered heteroaryl, C 1-6 alkyl, and C 1-6 haloalkyl, wherein said heteroaryl and alkyl is substituted with 0, 1, 2, or 3 moieties each independently selected from the group consisting of C 1-6 alkyl, halogen, and OH;
R 2 is hydrogen or C 1-6 alkyl;
R 3 is selected the group consisting of from hydrogen, C 1-6 alkyl, and cyano;
R 4 is selected from the group consisting of
hydrogen,
cyano,
C 1-6 alkyl,
C 1-6 heteroalkyl,
C 3-12 heterocycloalkylC 0-6 alkyl,
C 3-12 cycloalkylC 0-6 alkyl,
arylC 0-6 alkyl,
heteroarylC 0-6 alkyl,
spirocyclylC 0-6 alkyl,
C 3-12 cycloalkylC 0-10 alkyloxy,
amino,
-amino(C 1-10 alkyl) 1-2 ,
C 3-12 cycloalkylC 0-10 alkylamino,
heteroarylC 0-10 alkylamino,
C 3-12 heterocycloalkylC 0-10 alkylamino,
arylC 0-10 alkylamino,
hydroxy,
—(C 1-10 alkyl)OH, and
C 1-10 alkoxy;

wherein R 4 is substituted with 0, 1, 2, or 3 groups selected from the group consisting of C 1-6 alkyl, cyano, halogen, hydroxy, —O—C 1-6 alkyl, and —(C 1-10 alkyl)OH;
further wherein, optionally, R 3 and R 4 along with the carbon to which they are attached may join together to form a 4 to 6 membered saturated ring system substituted with 0, 1, or 2 moieties selected from the group consisting of C 1-6 alkyl, halogen, hydroxy, —O—C 1-6 alkyl, —(C 1-10 alkyl)OH, —SO 2 C 1-6 alkyl, —SO 2 CF 3 , —SO 2 CF 2 H, and C 3-12 cycloalkylC 0-10 alkylcarbonyl;
R 5 is selected from the group consisting of
hydrogen,
C 1-6 alkyl,
C 1-10 alkylcarbonyl,
C 3-12 cycloalkylC 0-10 alkyl,
C 3-12 heterocycloalkylC 0-10 alkyl,
arylC 0-10 alkyl, and
—(C 1-10 alkyl)OH; and

R 6 is hydrogen, oxo (═O), or C 1-3 alkyl.

2. The compound according to claim 1 , wherein R 1 is selected from the group consisting of hydrogen, difluoromethyl, pyrimidinyl, pyrazolyl wherein said pyrimidinyl and said pyrazolyl are each substituted with 0, 1, 2, or 3 moieties each independently selected from the group consisting of C 1-6 alkyl, halogen and OH.

3. The compound according to claim 2 , wherein R 2 is selected from the group consisting of hydrogen and C 1-6 alkyl.

4. The compound according to claim 3 , wherein R 2 is selected from the group consisting of methyl, ethyl, and hydrogen.

5. The compound according to claim 3 , wherein R 2 is hydrogen.

6. The compound according to claim 1 , wherein R 3 is selected from the group consisting of hydrogen, C 1-6 alkyl, and cyano.

7. The compound according to claim 6 , wherein R 3 is selected from the group consisting of hydrogen, methyl, and cyano.

8. The compound according to claim 1 , wherein R 4 is selected from the group consisting of
hydrogen,
cyano,
C 1-6 alkyl,
C 3-12 heterocycloalkylC 0-6 alkyl,
C 3-12 cycloalkylC 0-6 alkyl,
arylC 0-6 alkyl,
heteroarylC 0-6 alkyl,
spirocyclylC 0-6 alkyl,
C 3-12 cycloalkylC 0-10 alkyloxy,
-amino(C 1-10 alkyl) 1-2 ,
C 3-12 cycloalkylC 0-10 alkylamino,
heteroarylC 0-10 alkylamino,
C 3-12 heterocycloalkylC 0-10 alkylamino, and
—(C 1-10 alkyl)OH;

wherein said aryl is a 6-membered aryl and said heteroaryl is a 5- to 6-membered heteroaryl and further wherein R 4 is substituted with 0, 1, 2, or 3 groups selected from the group consisting of C 1-6 alkyl, cyano, halogen, hydroxy, and methoxy.

9. The compound according to claim 6 , wherein R 4 is selected from the group consisting of 2-methylpropyl, oxetanylmethyl, oxetan-3-ylmethyl, cyclopropylmethyl, benzyl, methylpyrimidinyl, methylpyrimidin-5-yl, tetrahydro-2H-pyranyl, phenyl, ethyl, 2-hydroxy-2-methylpropyl, azetidinyl, azetidin-1-yl, morpholinyl, oxa-6-azaspiro[3.3]heptyl, 1-oxa-6-azaspiro[3.3]hept-6-yl, pyridinylamino, hexahydro-4H-furo[3,2-b]pyrrol-4-yl, (1-cyclopropylethyl)amino, (methyl)(ethyl)amino, (methyl)(isopropyl)amino, (ethyl)amino, (1-cyclobutylethyl)amino, (cyclobutylmethyl)amino, (tetrahydrofuranylmethyl)amino, (tetrahydrofuran-2-ylmethyl)amino, 8-oxa-5-azaspiro[3.5]non-5-yl, 6,7-dihydropyrazolo[1.5-a]pyrazin-5(4H)-yl, tetrahydropyranylamino, tetrahydro-2H-pyra-4-ylamino, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, oxaazabicyclo[2.2.1]heptyl, 6-oxa-2-azaspiro[3.4]oct-2-yl, cyclobutylamino, isopropylamino, (cyclopropylmethyl)amino, tetrahydrofuranylamino, tetrahydrofuran-3-ylamino, isobutylamino, propylamino, azetidinyl, azetidin-1-yl, isobutoxy, cycloproylmethoxy, pyrrolidinyl, (oxetanylmethyl)amino, (oxetan-3-ylmethyl)amino, isopropoxy, cyclobutoxy, hydrogen, and 1-phenylethyl; wherein R 4 is substituted with 0, 1, 2, or 3 groups selected from the group consisting of C 1-4 alkyl, cyano, halogen, hydroxy, and methoxy.

10. The compound according to claim 1 , wherein R 3 and R 4 along with the carbon to which they are attached may join together to form a 4- to 6-membered saturated ring system selected from the group consisting of pyrrolidinyl, pyrrolidin-2-yl, piperidinyl, tetrahydrofuranyl, and cyclopentyl, said 4- to 6-membered saturated ring system is substituted with 0, 1, or 2 moieties selected from the group consisting of C 1-6 alkyl, halogen, —SO 2 C 1-6 alkyl, C 3-6 cycloalkylcarbonyl, and —SO 2 CF 3 .

11. The compound according to claim 9 , wherein R 5 is selected from the group consisting of hydrogen, methyl, methylcarbonyl, ethyl, isopropyl, morpholinoethyl, 2-hydroxy-2-methylpropyl, 2-hydroxyethyl, 1-phenylethyl, benzyl, tetrahydro-2H-pyranylmethyl, 1-cyclopropylethyl, and tetrahydro-2H-pyranyl.

12. The compound according to claim 11 , wherein R 6 is hydrogen or oxo.

13. The compound according to claim 1 , wherein

14. The compound or a pharmaceutically acceptable salt, wherein the compound is selected from the group consisting of
5-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]-3-methyl-3-(2-methylpropyl)-1,3-dihydro-2H-indol-2-one;
(R)-5-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]-3-methyl-3-(2-methylpropyl)-1,3-dihydro-2H-indol-2-one;
(S)-5-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]-3-methyl-3-(2-methylpropyl)-1,3-dihydro-2H-indol-2-one;
5-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]-3-methyl-3-(oxetan-3-ylmethyl)-1,3-dihydro-2H-indol-2-one;
(R)-5-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]-3-methyl-3-(oxetan-3-ylmethyl)-1,3-dihydro-2H-indol-2-one;
(S)-5-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]-3-methyl-3-(oxetan-3-ylmethyl)-1,3-dihydro-2H-indol-2-one;
5-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]-3-methyl-3-[(3-methyloxetan-3-yl)methyl]-1,3-dihydro-2H-indol-2-one;
(R)-5-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]-3-methyl-3-[(3-methyloxetan-3-yl)methyl]-1,3-dihydro-2H-indol-2-one;
(S)-5-[9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl]-3-methyl-3-[(3-methyloxetan-3-yl)methyl]-1,3-dihydro-2H-indol-2-one;
3-(cyclopropylmethyl)-5-(9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl)-3-methylindolin-2-one;
(R)-3-(cyclopropylmethyl)-5-(9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6-yl)-3-methylindolin-2-one;
(S)-3-(cyclopropylmethyl)-5-(9-ethyl-8-(2-methylpyrimidin-5-yl)-9

Assignees

• Merck Sharp & Dohme

Inventors

• Achab Abdelghani Abe
• Christopher Matthew P
• Fradera Llinas Francesc Xavier
• Katz Jason D
• Methot Joey L
• Zhou Hua
• Xu Shimin
• Fu Jianmin
• Fu Ning
• Li Yabin
• Wang Xichao

Classifications

• A61P11/06

  Antiasthmatics · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• 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

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title