Cathepsin inhibitors

Patent metadata

Field	Value
Publication number	US-11820734-B2
Application number	US-202117506096-A
Country	US
Kind code	B2
Filing date	Oct 20, 2021
Priority date	Dec 5, 2017
Publication date	Nov 21, 2023
Grant date	Nov 21, 2023

Abstract

This invention relates to compounds that are useful as inhibitors, in particular as inhibitors of Cathepsin K (CatK), and to a method of inhibiting cathepsin activity, comprising administering a compound or formulation comprising a compound according to the invention.

First claim

The invention claimed is:

1. A compound of formula II(b):

wherein:
R 2 is —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, or ═O;
R 3 is —C 2 -C 6 alkyl or —C 2 -C 6 haloalkyl;
R 4 and R 5 are independently selected from —H, —C 1 -C 3 alkyl, or —C 1 -C 3 haloalkyl, or R 4 and R 5 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl, or C 3 -C 6 cyclohaloalkyl;
R 6 is —H, —Y, —CH 3 , —CY 3 , —CHY 2 , or —CH 2 Y;
R a is —H, —C 1 -C 6 substituted or unsubstituted alkyl, —NH 2 , or —NR a R 10 ;
R 9 and R 10 are independently selected from —H, —C 1 -C 3 alkyl, or —C 1 -C 3 haloalkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached form a C 3 -C 6 heterocycloalkyl or C 3 -C 6 heterocyclohaloalkyl; and
Y is —F, —Cl, —Br, or —I;
or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound of claim 1 , wherein R a is —NR 9 R 10 , and
R 9 and R 10 are independently selected from —H, —C 1 -C 3 alkyl, or —C 1 -C 3 haloalkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached form a C 3 -C 6 heterocycloalkyl.

3. The compound of claim 1 , wherein R a is —CH 3 .

4. The compound of claim 1 , wherein R 2 is —CF 3 .

5. The compound of claim 1 , wherein R 3 is C 4 alkyl or C 4 haloalkyl.

6. The compound of claim 5 , wherein R 3 is CH 2 C(CH 3 ) 2 F or CH 2 C(CH 3 ) 2 H.

7. The compound of claim 1 , wherein:
R 4 is —H and R 5 is —CH 3 ; or
R 4 is —H and R 5 is H.

8. The compound of claim 1 , wherein:
R 2 is —C 1 -C 4 alkyl or —C 1 -C 4 haloalkyl;
R 3 is C 4 alkyl or C 4 haloalkyl;
R 4 and R 5 are independently selected from —H, —CH 3 , and —CH 2 CH 3 ;
R 6 is —H or —CH 3 ; and
R a is selected from —H and —C 1 -C 6 substituted or unsubstituted alkyl.

9. The compound of claim 1 , wherein:
R 2 is —C 1 haloalkyl;
R 3 is C 4 alkyl or C 4 haloalkyl;
R 4 and R 5 are independently selected from —H and —CH 3 ;
R 6 is —H or —CH 3 ; and
R a is —H, —CH 3 , or —CH 2 CH 3 .

10. The compound of claim 1 , wherein:
R a is —CH 3 ;
R 2 is —CF 3 ;
R 3 is C 4 alkyl or C 4 fluoroalkyl;
R 4 is —H and R 5 is —CH 3 , or R 4 is —H and R 5 is H; and
R 6 is H.

11. The compound of claim 1 , wherein the compound is a compound of formula IIIb:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 , wherein R a is —CH 3 .

13. The compound of claim 1 , wherein R 2 is —CF 3 .

14. The compound of claim 11 , wherein R 3 is C 4 alkyl or C 4 haloalkyl.

15. The compound of claim 14 , wherein R 3 is CH 2 C(CH 3 ) 2 F or CH 2 C(CH 3 ) 2 H.

16. The compound of claim 11 , wherein:
R 4 is —H and R 5 is —CH 3 ; or
R 4 is —H and R 5 is —H.

17. The compound of claim 11 , wherein:
R 2 is —C 1 -C 4 alkyl, or —C 1 -C 4 haloalkyl;
R 3 is C 4 alkyl or C 4 haloalkyl;
R 4 and R 5 are independently selected from —H, —CH 3 , and —CH 2 CH 3 ;
R 6 is —H or —CH 3 ; and
R a is selected from —H and —C 1 -C 6 substituted or unsubstituted alkyl.

18. The compound of claim 11 , wherein:
R 2 is —C 1 haloalkyl;
R 3 is C 4 alkyl or C 4 haloalkyl;
R 4 and R 5 are independently selected from —H and —CH 3 ;
R 6 is —H or —CH 3 ; and
R a is —H, —CH 3 , or —CH 2 CH 3 .

19. The compound of claim 1 , wherein:
R a is —CH 3 ;
R 2 is —CF 3 ;
R 3 is C 4 alkyl or C 4 fluoroalkyl;
R 4 is —H and R 5 is —CH 3 , or R 4 is —H and R 5 is —H; and
R 6 is —H.

20. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt or mixture thereof,
formulated with a pharmaceutically acceptable carrier, an organic bisphosphonate, an estrogen receptor modulator, an estrogen receptor beta modulator, an androgen receptor modulator, an inhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrin receptor antagonist, or an osteoblast anabolic agent.

21. A method of inhibiting cathepsin activity, the method comprising contacting a cysteine-based cathepsin with an effective amount of a compound of claim 1 .

22. A method of treating a cysteine-based cathepsin dependent condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of claim 1 to the subject.

23. The method of claim 22 , wherein the condition is selected from osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.

Assignees

• Academisch Ziekenhuis Leiden

Inventors

• Ovaa Huib
• Mons Maria Wilhelmina Elisabeth
• Van Boeckel Stan

Classifications

• C07C317/14 Primary

  having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings · CPC title

• A61P19/10

  for osteoporosis · CPC title

• C07C237/06

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• C07C237/22

  having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K) · CPC title

• C07C237/28

  having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton · CPC title