Protease inhibitors

Patent metadata

Field	Value
Publication number	US-10723709-B2
Application number	US-201916449850-A
Country	US
Kind code	B2
Filing date	Jun 24, 2019
Priority date	Sep 24, 2008
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

Abstract

Compounds of the formula II:

wherein
R 1 and R 2 are independently H, F or CH 3 ; or R 1 forms an ethynyl bond and R 2 is H or C 3 -C 6 cycloalkyl which is optionally substituted with one or two substituents independently selected from methyl, CF 3 , OMe or halo; R 3 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, either of which is optionally substituted with one or two methyl and/or a fluoro, trifluoromethyl or methoxy, when R 3 is C 3 -C 6 cycloalkyl it may alternatively be gem substituted with fluoro; R 4 is methyl or fluoro; m is 0, 1 or 2; E is a bond, or thiazolyl, optionally substituted with methyl or fluoro; A 1 is CH or N, A 2 is CR 6 R7 or NR 6 , provided at least one of A 1 and A 2 comprises N; R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkyl-O—C 1 -C 3 alkyl, or when A 2 is C, R 6 can also be C 1 -C 4 alkoxy or F; R 7 is H, C 1 -C 4 alkyl or F

or a pharmaceutically acceptable salt, N-oxide or hydrate thereof, have utility in the treatment of disorders characterized by inappropriate expression or activation of cathepsin K, such as osteoporosis, osteoarthritis, rheumatoid arthritis or bone metastases.

First claim

The invention claimed is:

1. A compound of the formula II:

wherein:
A 1 is CH or N;
A 2 is CR 6 R 7 or NR 6 , provided at least one of A 1 and A 2 comprises N;
E is thiazolyl, optionally substituted with methyl or fluoro;
m is 0, 1 or 2;
n is 0 or 1, such that the ring containing A 1 and A 2 is a saturated, nitrogen-containing ring of 5 or 6 ring atoms;
R is H, methyl, CF 3 , OMe or halo, located at any of the 1, 2 or 3 positions on the depicted cyclopropyl in Formula II,
R 3 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, either of which is optionally substituted with one or two methyl and/or a fluoro, trifluoromethyl or methoxy, when R 3 is C 3 -C 6 cycloalkyl it may alternatively be gem substituted with fluoro;
R 4 is methyl or fluoro;
R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkyl-O—C 1 -C 3 alkyl, or when A 2 is C, R 6 can also be C 1 -C 4 alkoxy or F;
R 7 is H, C 1 -C 4 alkyl or F;

or a pharmaceutically acceptable salt, N-oxide or hydrate thereof.

2. The compound according to claim 1 , wherein the orientation of the thiazolyl ring is as shown in the partial structure:

where R 5 is H methyl or fluoro.

3. The compound according to claim 1 , wherein R 3 is the side chain of leucine.

4. The compound according to claim 1 , wherein m represents 0 and R 5 represents F.

5. The compound according to claim 1 , wherein m represents 1, R 4 is F and R 5 is H.

6. The compound according to claim 5 , wherein R 4 is positioned as shown by the partial structure:

7. The compound according to claim 1 , wherein R 6 is CH 3 .

8. The compound according to claim 1 , selected from the group consisting of
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-carbonyl)-3-methyl-butyl]-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-yl)-1-cyclohexyl-2-oxo-ethyl]-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-yl)-1-cyclopentyl-2-oxo-ethyl]-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-carbonyl)-2-methyl-butyl]-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-carbonyl)-3-methyl-butyl]-4-[5-methyl-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-yl)-1-cyclohexyl-2-oxo-ethyl]-4-[5-methyl-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-yl)-1-cyclohexyl-2-oxo-ethyl]-4-[5-methyl-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-carbonyl)-2-methyl-butyl]-4-5-methyl-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-carbonyl)-3-methyl-butyl]-4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-yl)-1-cyclohexyl-2-oxo-ethyl]-4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-yl)-1-cyclopentyl-2-oxo-ethyl]-4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-carbonyl)-2-methyl-butyl]-4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-carbonyl)-3-methyl-butyl]-3-fluoro-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-yl)-1-cyclohexyl-2-oxo-ethyl]-3-fluoro-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-yl)-1-cyclopentyl-2-oxo-ethyl]-3-fluoro-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-carbonyl)-2-methyl-butyl]-3-fluoro-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;

and pharmaceutically acceptable salts, N-oxides and hydrates thereof.

9. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier or diluent therefor.

10. A method for the treatment of osteoarthritis, comprising the administration to a patient in need thereof a safe and effective amount of a compound of the formula II:

wherein:
A 1 is CH or N;
A 2 is CR 6 R 7 or NR 6 , provided at least one of A 1 and A 2 comprises N;
E is thiazolyl, optionally substituted with methyl or fluoro;
m is 0, 1 or 2;
n is 0 or 1, such that the ring containing A 1 and A 2 is a saturated, nitrogen-containing ring of 5 or 6 ring atoms;
R is H, methyl, CF 3 , OMe or halo, located at any of the 1, 2 or 3 positions on the depicted cyclopropyl in Formula II;
R 3 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl, either of which is optionally substituted with one or two methyl and/or a fluoro, trifluoromethyl or methoxy, when R 3 is C 3 -C 6 cycloalkyl it may alternatively be gem substituted with fluoro;
R 4 is methyl or fluoro;
R 6 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 3 alkyl-O—C 1 -C 3 alkyl, or when A 2 is C, R 6 can also be C 1 -C 4 alkoxy or F;
R 7 is H, C 1 -C 4 alkyl or F;

or a pharmaceutically acceptable salt, N-oxide or hydrate thereof, to a subject in need thereof.

11. The method according to claim 10 , wherein the orientation of the thiazolyl ring is as shown in the partial structure:

where R 5 is H methyl or fluoro.

12. The method according to claim 10 , wherein R 3 is the side chain of leucine.

13. The method according to claim 10 , wherein m represents 0 and R 5 represents F.

14. The method according to claim 10 , wherein m represents 1, R 4 is F and R 5 is H.

15. The method according to claim 14 , wherein R 4 is positioned as shown by the partial structure:

16. The method according to claim 10 , wherein R 6 is CH 3 .

17. The method according to claim 10 , wherein the compound of formula II is selected from the group consisting of
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-carbonyl)-3-methyl-butyl]-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-yl)-1-cyclohexyl-2-oxo-ethyl]-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-yl)-1-cyclopentyl-2-oxo-ethyl]-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-carbonyl)-2-methyl-butyl]-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide;
N-[1-(6-(cyclopropylethynyl)-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-carbonyl)-3-methyl-butyl]-4-

Assignees

• Medivir Ab

Inventors

• Oden Lourdes Salvador
• Nilsson Magnus
• Kahnberg Pia
• Samuelsson Bertil
• Grabowska Urszula

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61P19/00

  Drugs for skeletal disorders · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P29/00

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