Macrocylic pyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-10017509-B2
Application number	US-201515300956-A
Country	US
Kind code	B2
Filing date	Apr 2, 2015
Priority date	Apr 3, 2014
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

The present invention relates to substituted macrocylic pyrimidine derivatives of Formula (I)

wherein the variables have the meaning defined in the claims. The compounds according to the present invention have EF2K inhibitory activity and optionally also Vps34 inhibitory activity. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

First claim

The invention claimed is:

1. A compound of Formula (I)

a tautomer or a stereoisomeric form thereof, wherein
X a , X b and X c each independently represent CH or N;
—X 1 — represents —(CHR 12 ) s —NR 1 —X e —C 1-4 alkanediyl-(SO 2 ) p3 —;
wherein said C 1-4 alkanediyl moiety is optionally substituted with hydroxyl or hydroxyC 1-4 alkyl;
—X e — represents —C(R 2 ) 2 — or —C(═O)—;
a represents —NR 4 —C(═O)—[C(R 5b ) 2 ] 1 — or —NR 4 —C(R 5b ) 2 —C(═O)— or —C(═O)—NR 4 —C(R 5b ) 2 —;
b represents

wherein said b ring may contain extra bonds to form a bridged ring system selected from 2,5-diazabicyclo[2.2.2]octanyl, 3, 8- diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3, 9- diazabicyclo[3.3.1]nonyl;
X d1 represents CH or N;
X d2 represents CH 2 or NH;
provided that at least one of X d1 and X d2 represents nitrogen;
c represents a bond, —[C(R 5a ) 2 ] m —, —C(═O)—, —O—, —NR 5a′ —, —SO 2 —, or —SO—;
ring

represents phenyl;
R 1 represents C 2-4 alkenyl, C 2-4 alkynyl, cyanoC 1-4 alkyl, —C(═O)—C 1-4 alkyl, —C(═O)-haloC 1-4 alkyl, hydroxyC 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, haloC 1-4 alkyloxyC 1-4 alkyl, —C(═O)NR 7 R 8 , —SO 2 —NR 7 R 8 , —SO 2 —R 9 , R 11 , C 1-4 alkyl substituted with R 11 , —C(═O)—R 11 , or —C(═O)—C 1-4 alkyl-R 11 ;
each R 2 independently represents hydrogen, C 1-4 alkyl, C 1-4 alkyl substituted with C 3-6 cycloalkyl, hydroxyC 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, carboxyl, —C(═O)—O—C 1-4 alkyl wherein C 1-4 alkyl is optionally substituted with C 1-4 alkyloxy, —C(═O)—NH 2 , —C(═O)—NH(C 1-4 alkyl) wherein C 1-4 alkyl is optionally substituted with C 1-4 alkyloxy, or —C(═O)—N(C 1-4 alkyl) 2 wherein each C 1-4 alkyl is optionally substituted with C 1-4 alkyloxy;
or R 1 and one R 2 are taken together to form C 1-4 alkanediyl or C 2-4 alkenediyl, each of said C 1-4 alkanediyl and C 2-4 alkenediyl optionally being substituted with 1 to 4 substituents each independently selected from hydroxyl, oxo, halo, cyano, N 3 , hydroxyC 1-4 alkyl, —NR 7 R 8 , —SO 2 —NR 7 R 8 , —NH—SO 2 —NR 7 R 8 , —C(═O)—NR 7 R 8 , or —NH—C(═O)—NR 7 R 8 ;
or R 1 and R 12 are taken together to form C 1-4 alkanediyl or C 2-4 alkenediyl, each of said C 1-4 alkanediyl and C 2-4 alkenediyl optionally being substituted with 1 to 4 substituents each independently selected from hydroxyl, oxo, halo, cyano, N 3 , hydroxyC 1-4 alkyl, —NR 7 R 8 , —SO 2 —NR 7 R 8 , —NH—SO 2 —NR 7 R 8 , —C(═O)—NR 7 R 8 , or —NH—C(═O)—NR 7 R 8 ;
each R 3 independently represents hydrogen; oxo; hydroxyl; carboxyl; —NR 3a R 3b ; —C(═O)—NR 3a R 3b ; hydroxyC 1-4 alkyl; haloC 1-4 alkyl; —(C═O)—C 1-4 alkyl; —C(═O)—O—C 1-4 alkyl wherein said C 1-4 alkyl may optionally be substituted with phenyl; C 1-4 alkyl optionally substituted with cyano, carboxyl, C 1-4 alkyloxy, —C(═O)—O—C 1-4 alkyl, —O—C(═O)—C 1-4 alkyl, —NR 3e R 3f , —C(═O)—NR 3e R 3f , —SO 2 —NR 3e R 3f , Q, —C(═O)-Q, or —SO 2 -Q; hydroxyC 1-4 alkyloxyC 1-4 alkyl; C 1-4 alkyloxyhydroxyC 1-4 alkyl;
hydroxyC 1-4 alkyloxyhydroxyC 1-4 alkyl; or C 1-4 alkyloxyC 1-4 alkyl optionally substituted with cyano, carboxyl, C 1-4 alkyloxy, —C(═O)—O—C 1-4 alkyl, —O—C(═O)—C 1-4 alkyl, —NR 3e R 3f , —C(═O)—NR 3e R 3f , —SO 2 —NR 3e R 3f , R 10 , —C(═O)—R 10 , or —SO 2 —R 10 ;
or two R 3 substituents attached to the same carbon atom are taken together to form C 2-5 alkanediyl or —(CH 2 ) p —O—(CH 2 ) p —;
each R 3a and R 3b independently represent hydrogen; —(C═O)—C 1-4 alkyl; —SO 2 —NR 3c R 3d ; or C 1-4 alkyl optionally substituted with C 1-4 alkyloxy; or
R 3a and R 3b are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 or 2 further heteroatoms selected from N, O or SO 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from C 1-4 alkyl, halo, hydroxyl, or haloC 1-4 alkyl;
each R 3c and R 3d independently represent hydrogen, C 1-4 alkyl or —(C═O)—C 1-4 alkyl; or
R 3c and R 3d are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 or 2 further heteroatoms selected from N, O or SO 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from C 1-4 alkyl, halo, hydroxyl, or haloC 1-4 alkyl;
each R 3e and R 3f independently represent hydrogen, C 1-4 alkyl optionally substituted with C 1-4 alkyloxy, —(C═O)—C 1-4 alkyl, or —SO 2 —NR 3c R 3d ;
R 4 represents hydrogen, C 1-4 alkyl or C 1-4 alkyloxyC 1-4 alkyl;
each R 5a independently represents hydrogen or C 1-4 alkyl; or
two R 5a substituents attached to the same carbon atom are taken together to form C 2-5 alkanediyl or —(CH 2 ) p —O—(CH 2 ) p —;
R 5a′ represents hydrogen or C 1-4 alkyl;
each R 5b independently represents hydrogen; C 1-4 alkyl; C 1-4 alkyl substituted with NR 5b1 R 5b2 ; C 1-4 alkyloxyC 1-4 alkyl; hydroxyC 1-4 alkyl; hydroxyl; C 3-6 cycloalkyl; or
phenyl optionally substituted with C 1-4 alkyl, halo, hydroxyl or C 1-4 alkyloxy; or
two R 5b substituents attached to the same carbon atom are taken together to form C 2-5 alkanediyl or —(CH 2 ) p —O—(CH 2 ) p —;
R 5b1 and R 5b2 independently represent hydrogen, C 1-4 alkyl optionally substituted with C 1-4 alkyloxy, —(C═O)—C 1-4 alkyl, or —SO 2 —NR 5b3 R 5b4 ;
R 5b3 and R 5b4 independently represent hydrogen, C 1-4 alkyl or —(C═O)—C 1-4 alkyl; or
R 5b3 and R 5b4 are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 or 2 further heteroatoms selected from N, O or SO 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from C 1-4 alkyl, halo, hydroxyl, or haloC 1-4 alkyl;
each R 6 independently represents hydrogen, halo, hydroxyl, carboxyl, cyano, C 1-4 alkyl, C 1-4 alkyloxyC 1-4 alkyl, hydroxyC 1-4 alkyl, haloC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl,
—NR 6a R 6b , or —C(═O)NR 6a R 6b ;
each R 6a and R 6b independently represent hydrogen or C 1-4 alkyl;
each R 7 and R 8 independently represent hydrogen, C 1-4 alkyl, haloC 1-4 alkyl, or C 3-6 cycloalkyl; or
R 7 and R 8 are taken together with the nitrogen to which they are attached to form a 4 to 7 membered saturated monocyclic heterocyclic ring which optionally contains 1 further heteroatom selected from N, O or SO 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from C 1-4 alkyl, halo, hydroxyl, or haloC 1-4 alkyl;
R 9 represents C 1-4 alkyl, haloC 1-4 alkyl, or C 3-6 cycloalkyl;
each R 10 independently represents a 4 to 7 membered saturated monocyclic heterocyclic ring containing up to 2 heteroatoms selected from N, O or SO 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from C 1-4 alkyl, halo, hydroxyl or haloC 1-4 alkyl;
each R 11 independently represents C 3-6 cycloalkyl, phenyl, or a 4 to 7 membered monocyclic heterocyclic ring containing up to 3 heteroatoms selected from N, O or SO 2 , said heterocyclic ring being optionally substituted with 1 to 4 substituents each independently selected from C 1-4 alkyl, halo, hydroxyl, or haloC 1-4 alkyl;
each R 12 independently represents hydrogen or C 1-4 alkyl;
Q represents a 4 to 7 membered saturated monocyclic heterocyclic r

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Diels Gaston Stanislas Marcella
• Schoentjes Bruno
• Versele Matthias Luc Aime
• Berthelot Didier Jean-Claude
• Willems Marc
• Viellevoye Marcel
• Embrechts Werner Constant Johan
• Wroblowski Berthold
• Meerpoel Lieven

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P25/24

  Antidepressants · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title