Heterocyclic derivatives

Patent metadata

Field	Value
Publication number	US-9458163-B2
Application number	US-201514644953-A
Country	US
Kind code	B2
Filing date	Mar 11, 2015
Priority date	Jan 31, 2011
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

The invention relates to novel heterocyclic compounds of the formula

in which all of the variables are as defined in the specification, to their preparation, to their medical use, in particular to their use in the treatment of cancer and neurodegenerative disorders, and to medicaments comprising them.

First claim

The invention claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein
X represents CH;
R 1 represents

wherein
R 18 and R 22 independently represent hydrogen, halogen, hydroxy or hydroxy-C 1-3 alkyl-;
R 19 and R 21 independently represent hydrogen, amino, hydroxy, carboxy, C 1-3 alkoxy, amino-C 1-3 alkyl-, C 1-3 alkyl-C(═O)—NH—, C 1-3 alkyl-S(═O) m —NH— or hydroxy-C 1-3 alkyl-;
m represents 0, 1 or 2;
R 20 represents hydrogen, halogen or C 1-3 alkoxy; or

R 1 is selected from the group consisting of

wherein
R 23 represents hydrogen or methyl;
R 24 represents hydrogen, oxo or C 1-3 alkyl;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 independently represent hydrogen or methyl;
or R 2 and R 8 together form an ethylene bridge;
or R 2 and R 6 together form a methylene bridge;
or R 12 and R 14 together form an ethylene bridge; and
Y represents O, CHR 25 or CR 26 R 27
wherein
R 25 represents hydroxy or C 1-3 alkoxy; and
R 26 and R 27 independently represent hydrogen or halogen.

2. A compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein
X represents CH;
R 1 represents

wherein
R 18 and R 22 independently represent hydrogen, halogen, hydroxy or hydroxy-C 1-3 alkyl-;
R 19 and R 21 independently represent hydrogen, amino, hydroxy, carboxy, C 1-3 alkoxy, amino-C 1-3 alkyl-, C 1-3 alkyl-C(═O)—NH—, C 1-3 alkyl-S(═O) m —NH— or hydroxy-C 1-3 alkyl-;
m represents 0, 1 or 2;
R 20 represents hydrogen, halogen or C 1-3 alkoxy; or

R 1 is selected from the group consisting of

wherein
R 23 represents hydrogen or methyl;
R 24 represents hydrogen, oxo or C 1-3 alkyl;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 independently represent hydrogen or methyl; or R 5 and R 6 together form an ethylene bridge; and
Y represents O, CHR 25 or CR 26 R 27
wherein
R 25 represents hydroxy or C 1-3 alkoxy; and
R 26 and R 27 independently represent hydrogen or halogen.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 represents

wherein
R 18 and R 22 independently represent hydrogen, halogen, hydroxy or hydroxy-C 1-3 alkyl-;
R 19 and R 21 independently represent hydrogen, amino, hydroxy, carboxy, C 1-3 alkoxy, amino-C 1-3 alkyl-, C 1-3 alkyl-C(═O)—NH—, C 1-3 alkyl-S(═O) m —NH— or hydroxy-C 1-3 alkyl-;
m represents 0, 1 or 2; and
R 20 represents hydrogen, halogen or C 1-3 alkoxy.

4. A compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 18 , R 19 , R 20 , R 21 and R 22 is not hydrogen.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of

wherein
R 23 represents hydrogen or methyl; and
R 24 represents hydrogen, oxo or C 1-3 alkyl.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y represents O.

7. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y represents CHR 26 or CR 27 R 28 .

8. A compound according to claim 1 , which is selected from:
3-(2,4-Di-morpholin-4-yl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-phenol;
6-(1H-Indol-4-yl)-4-((R)-3-methyl-morpholin-4-yl)-2-((S)-3-methyl-morpholin-4-yl)-7H-yrrolo[2,3-d]pyrimidine; and
6-(1H-Indol-4-yl)-2,4-di-morpholin-4-yl-7H-pyrrolo[2,3-d]pyrimidine; and
pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent or carrier.

10. A combination comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a drug substance, for simultaneous or sequential administration.

11. A method for the treatment of a neurodegenerative disorder modulated by the inhibition of the mTOR enzyme comprising administration of an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need of treatment thereof.

Assignees

• Radetich Branko
• Yu Bing
• Zhu Yanyi
• Novartis Ag

Inventors

• Radetich Branko
• Yu Bing
• Zhu Yanyi

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/16

  Anti-Parkinson drugs · 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