Cathepsin inhibitors

Patent metadata

Field	Value
Publication number	US-2020385341-A1
Application number	US-201816770200-A
Country	US
Kind code	A1
Filing date	Dec 5, 2018
Priority date	Dec 5, 2017
Publication date	Dec 10, 2020
Grant date	—

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

1 . A compound of formula I:

wherein:
R 1 is —S(O) 2 R a , —C(O)R a , —H, —X, —CN, —C 1 -C 6 substituted or unsubstituted alkyl, or —C 3 -C 6 substituted or unsubstituted cycloalkyl, —C 1 -C 6 alkoxy, —C 3 -C 6 cycloalkoxy, —NHC(O)R a , —NHC(O)NHR a , —C 2 -C 5 lactam, or —C 1 -C 4 cyclourea; and R 1 is located para or meta to the phenylene moiety;
R 2 is —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, or =0;
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 , —CH 2 Y;
each R 7 is independently selected from —H, —X, —CN, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, or —C 1 -C 3 alkoxy;
each R 8 is independently selected from —X, —C 1 -C 4 alkyl, or —C 1 -C 4 haloalkyl;
R a is —H, —C 1 -C 6 substituted or unsubstituted alkyl, or —NH 2 , or —NR 9 R 10 ;
each X is independently selected from —F, —C 1 , —Br, or —I;
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 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;
Y is —F, —C 1 , —Br, or —I;
m is 0, 1, 2, 3, or 4; and
n is 0, 1 or 2,
or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.

2 . The compound of claim 1 , wherein R 1 is —S(O) 2 R a or —CH 3 .

3 . The compound of claim 1 , wherein R a is —C 1 -C 4 alkyl.

4 . (canceled)

5 . The compound of claim 1 , wherein R 1 is located para to the phenylene moiety.

6 . The compound of claim 1 , wherein R 2 is —C 1 -C 4 haloalkyl, —C 1 -C 2 haloalkyl, or —CF 3 .

7 . The compound of claim 6 , wherein R 1 is the haloalkyl is fluoroalkyl.

8 . (canceled)

9 . The compound of claim 1 , wherein R 3 is —C 2 -C 6 haloalkyl, —C 4 haloalkyl, —CH 2 C(CH 3 ) 2 F.

10 . The compound of claim 9 , wherein the haloalkyl is fluoroalkyl.

11 . (canceled)

12 . The compound of claim 1 , wherein R 4 and/or R 5 is —H, —CH 3 , or —CH 2 CH 3 .

13 . (canceled)

14 . The compound of claim 1 , wherein R 4 and R 5 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl.

15 . The compound of claim 14 , wherein R 4 and R 5 together with the carbon atom to which they are attached form a C 3 cycloalkyl.

16 . The compound of claim 1 , wherein R 6 is —H, —CH 3 , —CY 3 , —CHY 2 , or —CH 2 Y.

17 . (canceled)

18 . The compound of claim 1 , wherein R 7 and/or R 8 is —X or —C 1 -C 4 alkyl.

19 . (canceled)

20 . The compound of claim 1 , wherein m is 0 and/or n is 0.

21 . (canceled)

22 . The compound of claim 1 , wherein the compound is a compound of formula IIIa:

or a pharmaceutically acceptable salt, or prodrug thereof.

23 . The compound of claim 1 , selected from:

or a pharmaceutically acceptable salt thereof.

24 . The compound of claim 1 , 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, and the pharmaceutically acceptable salts and mixtures thereof.

25 . (canceled)

26 . (canceled)

27 . (canceled)

28 . (canceled)

29 . A method of inhibiting cathepsin activity, comprising administering a compound of claim 1 .

30 . A method of treating a cathepsin dependent condition, the method comprising administering a compound of claim 1 .

31 . The method of claim 30 , wherein the disease 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 or multiple myeloma

Assignees

• Academisch Ziekenhuis Leiden

Inventors

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

Classifications

• C07C275/40

  being further substituted by nitrogen atoms not being part of nitro or nitroso groups · 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

• C07C237/22

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

• C07C237/06

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

• A61P19/10

  for osteoporosis · CPC title