Compounds for the inhibition of cyclophilins and uses thereof

Patent metadata

Field	Value
Publication number	US-9975902-B2
Application number	US-201715474193-A
Country	US
Kind code	B2
Filing date	Mar 30, 2017
Priority date	Mar 31, 2016
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

The present invention relates to compounds, and pharmaceutically acceptable compositions thereof, useful as inhibitors of cyclophilins, and for the treatment of cyclophilin-related disorders.

First claim

We claim:

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is

each R′ is independently —R, halogen, -haloalkyl, -hydroxyalkyl, —OR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, or —N(R) 2 ;
each R 1 is independently —H or C 1-6 aliphatic which is optionally substituted;
each R 1a is independently —H or C 1-6 aliphatic which is optionally substituted;
or R 1 and R 1a taken together with the atom to which they are attached form a 3-7 membered carbocyclic ring optionally having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is optionally substituted;
each R 2 is independently —H or C 1-6 aliphatic which is optionally substituted;
each R 2a is independently —H or C 1-6 aliphatic which is optionally substituted;
X is CH 2 ; or X and the bonds attached to X are absent;
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 1 or 2; and
p is 1, 2, 3, 4, or 5.

2. The compound of claim 1 , wherein each R′ is independently —R, —OR, or —N(R) 2 .

3. The compound of claim 2 , wherein each R′ is independently H, -Me, -Et, —OH, or —NH 2 .

4. The compound of claim 1 , wherein X is CH 2 .

5. The compound of claim 1 , wherein X, and the bonds attached to X, are absent.

6. The compound of claim 1 , wherein each R 1 is independently —H or -Me.

7. The compound of claim 1 , wherein R 1 and R 1a taken together with the atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted.

8. The compound of claim 1 , of formula II:

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , of formula VI:

or a pharmaceutically acceptable salt thereof.

11. A compound selected from:

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

13. The compound of claim 1 , wherein each R 1 is independently —H, -Me, or -Et.

14. The compound of claim 1 , wherein R 1 and R 1a taken together with the atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

15. A compound

Assignees

• Merck Patent Gmbh

Inventors

• Jorand-Lebrun Catherine
• Johnson Theresa L
• Graedler Ulrich
• Jiang Xuliang
• Kulkarni Santosh

Classifications

• A61P43/00

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

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title