N,6-bis(aryl or heteroaryl)-1,3,5-triazine-2,4-diamine compounds as IDH2 mutants inhibitors for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9724350-B2
Application number	US-201414904032-A
Country	US
Kind code	B2
Filing date	Jul 10, 2014
Priority date	Jul 11, 2013
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

Provided are compounds of formula (I), Wherein: ring A and ring B are each independently an optionally substituted 5-6 membered monocyclic aryl or heteroaryl. The compounds are inhibitors of isocitrate dehydrogenase 2 (IDH2) mutants useful for treating cancer.

First claim

The invention claimed is:

1. A compound having Formula II:

or a pharmaceutically acceptable salt thereof, wherein:
ring A′ is selected from phenyl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, oxazol-4-yl, isoxazol-3-yl, thiazol-2-yl, pyridin-3-yl and pyridin-2-yl, wherein ring A′ is optionally substituted with one or two substituents independently selected from 1-propenyl, -cyclopropyl-OH, chloro, fluoro, —CF 3 , —CHF 2 , —CH 3 , —CH 2 CH 3 , —CF 2 CH 3 , —S(O)CH 3 , —S(O) 2 CH 3 , —CH 2 OH, —CH(OH)CH 3 , —CH(OH)CF 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —C(O)—NH 2 , —CH 2 NH 2 , —NH(CH 3 ), —CN and —N(CH 3 ) 2 ; and
ring B′ is selected from phenyl, pyridin-3-yl, pyridin-4-yl, pyridazin-4-yl, isoxazol-4-yl, isoxazol-3-yl, thiazol-5-yl, pyrimidin-5-yl and pyrazol-4-yl, wherein ring B′ is optionally substituted with one to two substituents independently selected from halo; —CN; —OH; C 1 -C 4 alkyl optionally substituted with halo, CN or —OH; —S(O) 2 —C 1 -C 4 alkyl; —S(O)—C 1 -C 4 alkyl; —S(O) 2 —NH—C 1 -C 4 alkyl; —S(O) 2 —NH—CH 2 —CF 3 ; —S(O) 2 —N(C 1 -C 4 alkyl) 2 ; —S(O) 2 -azetidin-1-yl; —O—C 1 -C 4 alkyl; —CH 2 —O—CH 3 , morpholin-4-yl, cyclopropyl, cyclopropyl-C 1 -C 4 alkyl, cyclopropyl-C 1 -C 4 alkoxy, cyclopropyl-CN, —S(O) 2 —NH-cyclopropyl; —S(O) 2 —NH—CH 2 -cyclopropyl; —C(O)—C 1 -C 4 alkyl, —C(O)—O—CH 3 ;

wherein:
a. ring A′ and ring B′ are not both an optionally substituted phenyl;
b. when ring A′ is unsubstituted pyridyl, then ring B′ is not phenyl optionally substituted with one to three groups independently selected from methyl, ethyl, t-butyl, methoxy, CH(OH)CH 3 , Cl, Br, and CF 3 ;
c. when ring A′ is oxazol-4-yl, isoxazol-3-yl, or thiazol-2-yl, then ring B′ is not phenyl optionally substituted with one to two groups independently selected from F, Cl, SO 2 CH 3 , C(O)OCH 3 , methyl, ethyl, t-butyl, methoxy, ethoxy, CF 3 , and OH;
d. the compound is not:
(1) N 2 -2-pyridinyl-6-(3-pyridinyl)-1,3,5-triazine-2,4-diamine;
(2) 6-(6-methoxy-3-pyridinyl)-N 2 -(4-methylphenyl)-1,3,5-triazine-2,4-diamine;
(3) 6-(2-methoxy-3-pyridinyl)-N 2 -(4-methylphenyl)-1,3,5-triazine-2,4-diamine;
(4) N 2 -(3-chlorophenyl)-6-(2-chloro-4-pyridinyl)-1,3,5-triazine-2,4-diamine;
(5) 3-[[4-[[4-amino-6-[(3-chlorophenyl)amino]-1,3,5-triazin-2-yl]-2-pyridinyl]amino]-1-propanol;
(6)N-[34[4-amino-6-(2-methyl-4-pyrimidinyl)-1,3,5-triazin-2-yl]amino]-4-methylphenyl]-N′-[4-chloro-3-(trifluoromethyl)phenyl]-urea;
(7) 2,6-bis[6-(2-amino-4-phenylamino-1,3,5-triazinyl)]pyridine; or
(8) 2,6-bis[6-(2-amino-4-phenylamino-1,3,5-triazinyl)]pyrazine.

2. The compound of claim 1 , wherein ring A′ is selected from 2-chlorophenyl, 2-fluorophenyl, 2-methoxyphenyl, 3-hydroxyphenyl, 3-amidophenyl, 3-methylsulfinylphenyl, 3-methyl sulfonylphenyl, 3-(1-methanol)phenyl, 3-methanaminephenyl, 3-methoxy-2-fluorophenyl, 5-methoxy-2-fluorophenyl, 3-hydroxy-2-fluorophenyl, 5-hydroxy-2-fluorophenyl, 5-hydroxy-3-fluorophenyl, 3-methanolphenyl, 3,5-dihydroxyphenyl, 3-trifluoromethyl-5-chlorophenyl, 3-(1-hydoxy-2,2,2-trifluoroethyl)phenyl, 3-(1-hydoxyethyl)phenyl, 3-(1-hydoxycyclopropyl)phenyl, 3-hydroxymethyl-5-phenol, pyridin-2-yl, 3-fluoropyridin-2-yl, 3-cyanopyridin-2-yl, 3,6-difluoropyridin-2-yl, 3-fluoro-6-methoxypyridin-2-yl, 3-fluoro-6-hydroxypyridin-2-yl, 3-fluoro-6-aminopyridin-2-yl, 4-fluoro-6-aminopyridin-2-yl, 6-propen-1-ylpyridin-2-yl, 6-methylaminopyridin-2-yl, 3-fluoro-6-trifluoromethylpyridin-2-yl, 4-chloro-6-aminopyridin-2-yl, 4-fluoro-6-aminopyridin-2-yl, 4-chloro-6-methoxypyridin-2-yl, 6-aminopyridin-3-yl, 2-methoxypyridin-3-yl, 6-aminopyridin-2-yl, 6-chloropyridin-2-yl, 6-trifluoromethylpyridin-2-yl, 6-difluoromethylpyridin-2-yl, 4-(CH 2 OH)-6-trifluoromethyl-pyridin-2-yl, 4-(CH 2 OH)-6-chloro-pyridin-2-yl, 6-(1,1-difluoroethyl)-4-fluoropyridin-2-yl, 4-trifluoromethylpyrimidin-2-yl, 4-aminopyrimidin-2-yl, 6-trifluoromethyl-4-aminopyrimidin-2-yl, 4-trifluoromethyl-6-aminopyrimidin-2-yl, 4-aminopyrimidin-2-yl, 2-aminopyrimidin-4-yl, 2-aminopyrimidin-5-yl, 4,6-dichloropyridin-2-yl, 3,5-dichlorophenyl, 2,6-difluorophenyl, 2-methyloxazol-4-yl, 4-trifluoromethyl-thiazol-2-yl, 4-methylthiazol-2-yl and phenyl.

3. The compound of claim 1 , wherein ring B′ is selected from 2-(morpholin-4-yl)pyridin-4-yl, 3,5-difluorophenyl, 3-chlorophenyl, 3-cyanomethylphenyl, 3-cyanophenyl, 3-(cyclopropylmethyl)phenyl, 3-cyclopropylaminosulfonylphenyl, 3-dimethylaminosulfonylphenyl, 3-ethyl sulfonylphenyl, 3-fluorophenyl, 3-methyl sulfonylphenyl, 4-fluorophenyl, 3-(1-hydroxyisopropyl)phenyl, 3-methylsulfonyl-5-chlorophenyl, 3-methylsulfonyl-5-fluorophenyl, 3-(N-2,2,2,-trifluoroethylaminosulfonyl)phenyl, 5-chloropyridin-3-yl, 5-cyanopyridin-3-yl, 5-cyanopyridin-3-yl, 5-cyanopyridin-4-yl, 5-fluoropyridin-3-yl, 5-trifluoromethypyridin-3-yl, 2-trifluoromethylpyridin-4-yl, 2-difluoromethylpyridin-4-yl, 2-chloropyridin-4-yl, 6-chloropyridin-4-yl, 6-cyanopyridin-4-yl, 2-cyanopyridin-4-yl, 6-cyclopropylpyridin-4-yl, 6-ethoxypyridin-4-yl, 6-fluoropyridin-3-yl, 2-fluoropyridin-4-yl, 5,6-difluoropyridin-3-yl, 6-fluoropyridin-4-yl, 6-methylpyridin-4-yl, 2-difluoromethylpyridin-4-yl, 6-trifluoromethylpyridin-4-yl, 2-(1-methoxycyclopropyl)pyridin-4-yl, 2-cyclopropylpyridin-4-yl, 2-(propan-1-one)pyridin-4-yl, 2-(1-methylcyclopropyl)pyridin-4-yl, 2-(1-cyanocyclopropyl)pyridin-4-yl, 2-(1-cyanoisopropyl)pyridin-4-yl, isoxazol-4-yl, phenyl, pyridin-4-yl, picolinat-2-yl, pyrimidin-5-yl, 1-propylpyrazol-4-yl, 6-methyl-pyridazin-4-yl, and thiazol-5-yl.

4. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising the compound of claim 4 , and a pharmaceutically acceptable carrier.

7. A method of treating a glioblastoma characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the NADPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate in a patient, comprising the step of administering to the patient a therapeutically effective amount of the compound of claim 1 .

8. The method of claim 7 , wherein the IDH2 mutation is an IDH2 R140Q or R172K mutation.

9. The method of claim 7 , wherein the IDH2 mutation is an IDH2 R140Q mutation.

10. The method of claim 7 , further comprising administering to the patient in need thereof a second therapeutic agent useful in the treatment of glioblastoma.

11. A method of treating a glioblastoma characterized by the presence of an IDH2 mutation, wherein the IDH2 mutation results in a new ability of the enzyme to catalyze the NADPH-dependent reduction of a-ketoglutarate to R(−)-2-hydroxyglutarate in a patient, comprising the step of administering to the patient a therapeutically effective amount of the compound of claim 2 .

12. The method of claim 11 , wherein the IDH2 mutation is an IDH2 R140Q or R172K mutation.

13. The method of claim 11 , wherein the IDH2 mutation is an IDH2 R140Q mutation.

14. The method of claim 11 , further comprising administering to the patient in need thereof a second therapeutic agent useful in the treatment of glioblastoma.

Assignees

• Agios Pharmaceuticals Inc

Inventors

• Travins Jeremy
• Utley Luke

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/53 Primary

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title