Indolizine derivatives and their use in neurodegenerative diseases

Patent metadata

Field	Value
Publication number	US-9546166-B2
Application number	US-201514814659-A
Country	US
Kind code	B2
Filing date	Jul 31, 2015
Priority date	Jul 31, 2014
Publication date	Jan 17, 2017
Grant date	Jan 17, 2017

Abstract

The present invention relates to indolizine compounds, and pharmaceutically acceptable compositions thereof, useful as antagonists of P2X7, and for the treatment of P2X7-related disorders.

First claim

We claim:

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein:
X is -halogen, -haloalkyl, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; or X is a C 1-6 aliphatic, C 5-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
Y is O, S, SO 2 , SO, C(O), CO 2 , C(O)N(R), NRC(O), NRC(O)N(R), NRSO 2 , or N(R);
Ring A is C 5-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or a 6-18 membered bicyclic, fused bicyclic, spiro bicyclic, or polycyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each of which is optionally substituted;
each R 1 is independently —R, halogen, -haloalkyl, -hydroxyalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ; or
two R 1 groups, together with the atom or atoms to which each is attached, may form a fused or spiro ring selected from C 5-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
Z is —R, halogen, -haloalkyl, -hydroxyalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ,
each R a is independently —R, halogen, -haloalkyl, -hydroxyalkyl, —OR, —SR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;
each R is independently hydrogen, C 1-6 aliphatic, C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or
two R groups on the same atom are taken together with the atom to which they are attached to form a C 3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;
m is 1 or 2;
n is 0, 1, 2, or 3; and
p is 0, 1, or 2.

2. The compound of claim 1 , wherein X is -halogen, -haloalkyl, or an optionally substituted C 1-6 aliphatic.

3. The compound of claim 1 , wherein Y is C(O), CO 2 , C(O)NH, NHC(O), or NHSO 2 .

4. The compound of claim 3 , wherein Y is

5. The compound of claim 1 , wherein Ring A is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

6. The compound of claim 5 , wherein Ring A is

7. The compound of claim 6 , wherein each R 1 is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, straight chain or branched pentyl, straight chain or branched hexyl, OH, F, Cl, Br, I, or CF 3 ; or two R 1 groups, together with the atom or atoms to which each is attached, may form a fused or spiro ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

8. The compound of claim 5 , wherein Ring A is

9. The compound of claim 1 , wherein Z is H or I.

10. The compound of claim 1 , wherein Z is C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

11. The compound of claim 10 , wherein Z is

12. The compound of claim 1 , of formula III:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , of formula V:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 , selected from

15. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

16. A process for manufacturing a compound of formula I, comprising the steps of:
reacting a compound of formula A:

wherein X, Z, R a , and p are as defined in claim 1 ;
with a compound of formula

Assignees

• Merck Patent Gmbh

Inventors

• Karra Srinivasa R
• Goutopoulos Andreas

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · 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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title