Fused morpholinopyrimidines and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9771378-B2
Application number	US-201615210927-A
Country	US
Kind code	B2
Filing date	Jul 15, 2016
Priority date	Jan 15, 2014
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.

First claim

We claim:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof,
wherein:
R is phenyl, —C1-C4 alkylene-phenyl, oxetanyl, C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, —C1-C4 alkylene-C3-C8 monocyclic cycloalkyl, 3- to 7-membered monocyclic heterocycle, —C1-C4 alkylene 3- to 7-membered monocyclic heterocycle, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —CN, —NH2, —OH, oxo, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, amino-substituted C1-C4 alkyl, —NH—C1-C4 alkyl, —NHC(O)—C1-C4 alkyl, —C(O)NH—C1-C4 alkyl, —C(O)N(C1-C4 alkyl)2, hydroxy-substituted C1-C4 alkyl, —S(O)2-C1-C4 alkyl, —S(O)2-halo-substituted C1-C4 alkyl, —S(O)2-NH—C1-C4 alkyl, —S(O)2-N(C1-C4 alkyl)2, —NH—S(O)2-C1-C4 alkyl, —N(C1-C4 alkyl)-S(O)2-C1-C4 alkyl, C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, 3- to 7-membered monocyclic heterocycle, —C3-C8 monocyclic cycloalkyl, —C(O)NH2 and -phenoxy, provided that phenyl is not substituted with one or more oxo;
Y is phenyl or pyridinyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, amino-substituted C1-C4 alkoxy, —CN, (C1-C4 alkyl)2N—C1-C4-alkoxy, —NH—C1-C4 alkyl, —OH and —NH2; and
Z is —CN or nitrogen-containing 3- to 7-membered monocyclic heterocycle which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —CN, —NH2, —OH, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, —C1-C4 alkoxy, —OCF3 and 3- to 7-membered monocyclic heterocycle.

2. A compound of claim 1 , wherein:
R is phenyl, —C1-C4 alkylene-phenyl, oxetanyl, C1-C6 alkyl, —C3-C8 monocyclic cycloalkyl, 3- to 7-membered monocyclic heterocycle, —C1-C4 alkylene 3- to 7-membered monocyclic heterocycle or —C1-C4 alkylene-C3-C8 monocyclic cycloalkyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —CN, —NH2, —OH, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, amino-substituted C1-C4 alkyl, —NH—C1-C4 alkyl, —NHC(O)—C1-C4 alkyl, —C(O)NH—C1-C4 alkyl, —C(O)N(C1-C4 alkyl)2, hydroxy-substituted C1-C4 alkyl, —S(O)2-C1-C4 alkyl, —S(O)2-halo-substituted C1-C4 alkyl, —S(O)2-NH—C1-C4 alkyl, —S(O)2-N(C1-C4 alkyl)2, —NH—S(O)2-C1-C4 alkyl, —N(C1-C4 alkyl)-S(O)2-C1-C4 alkyl, C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, 3- to 7-membered monocyclic heterocycle, —C3-C8 monocyclic cycloalkyl, —C(O)NH2;
Y is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, amino-substituted C1-C4 alkoxy, —CN, (C1-C4 alkyl)2N—C1-C4 alkoxy, —NH—C1-C4 alkyl, —OH and —NH2; and
Z is pyridinyl or imidazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of -halo, —NH2, —OH, —C1-C4 alkyl, halo-substituted C1-C4 alkyl, —C1-C4 alkoxy, —OCF3 and 3- to 7-membered monocyclic heterocycle;
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein:
R is phenyl, tetrahydropyranyl, —C1-C4 alkyl, —C1-C4 alkylene-phenyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, —C1-C4 alkyl, halo-substituted C1-C4 alkyl and halo-substituted C1-C4 alkoxy;
Y is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo and —C1-C4 alkoxy; and
Z is pyridinyl or imidazolyl, each of which is substituted with one —C1-C4 alkyl or halo;
or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , wherein:
R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo and —C1-C4 alkyl;
Y is phenyl substituted with one or more substituents independently selected from the group consisting of halo and —C1-C4 alkoxy; and
Z is imidazolyl substituted with methyl or halo;
or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 , wherein:
R is phenyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo and —C1-C4 alkyl;
Y is phenyl substituted with one or more substituents independently selected from the group consisting of halo and —C1-C4 alkoxy; and
Z is pyridinyl substituted with methyl or chloro;
or a pharmaceutically acceptable salt thereof.

6. A compound selected from the group consisting of:
(S)—N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-methyl-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(S)—N-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)-8-methyl-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(R)—N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-methyl-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(R)—N-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)-8-methyl-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
7-(3,5-difluorophenyl)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(+)-7-(3, 5-difluorophenyl)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl) phenyl)-7, 8-dihydro-6H-pyrimido [5, 4-b] [1, 4] oxazin-2-amine;
8-methyl-N-(4-(2-methylpyridin-4-yl)phenyl)-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(+)-8-methyl-N-(4-(2-methylpyridin-4-yl)phenyl)-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
N-(3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-methyl-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(+)-N-(3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-methyl-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(+)-8-methyl-N-(4-(4-methyl-1H-imidazol-1-yl)phenyl)-7-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
7-(3,5-difluorophenyl)-8-methyl-N-(4-(2-methylpyridin-4-yl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(+)-7-(3,5-difluorophenyl)-8-methyl-N-(4-(2-methylpyridin-4-yl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(+)-8-methyl-N-(4-(2-methylpyridin-4-yl)phenyl)-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
7-(3,5-difluorophenyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(−)-7-(3,5-difluorophenyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(+)-7-(3,5-difluorophenyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-methyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-methyl-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(−)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-methyl-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(+)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-methyl-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
N-(3-fluoro-4-(2-methylpyridin-4-yl)phenyl)-8-methyl-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
(+)-N-(3-fluoro-4-(2-methylpyridin-4-yl)phenyl)-8-methyl-7-(o-tolyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-2-amine;
7-(3,5-difluorophenyl)-N-(3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-meth

Assignees

• Denali Therapeutics Inc

Inventors

• Burnett Duane A
• Bursavich Matthew Gregory
• Mcriner Andrew J

Classifications

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07D498/10

  Spiro-condensed systems · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D498/20

  Spiro-condensed systems · CPC title