Tropomyosin-related kinase (TRK) inhibitors

Patent metadata

Field	Value
Publication number	US-11406644-B2
Application number	US-202017032692-A
Country	US
Kind code	B2
Filing date	Sep 25, 2020
Priority date	Dec 10, 2013
Publication date	Aug 9, 2022
Grant date	Aug 9, 2022

Abstract

Tropomyosin-related kinase inhibitors (Trk inhibitors) are small molecule compounds useful in the treatment of disease. Trk inhibitors can be used as pharmaceutical agents and in pharmaceutical compositions. Trk inhibitors are useful in the treatment of inflammatory diseases, autoimmune disease, defects of bone metabolism and/or cancer, and are particularly useful in the treatment of osteoarthritis (OA), pain, and pain associated with OA. Trk inhibitors are also useful for inhibiting tropomyosin-related kinase A (TrkA), tropomyosin-related kinase B (TrkB), tropomyosin-related kinase C (TrkC), and/or c-FMS (the cellular receptor for colony stimulating factor-1 (CSF-1)).

First claim

The invention claimed is:

1. A method of inhibiting tropomyosin-related kinase A in a patient, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I) in order to inhibit tropomyosin-related kinase A in the patient, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof; wherein:
n is 1, 2, 3, 4 or 5;
m is 0, 1, 2, 3 or 4;
Q 1 is (C 2 -C 9 )heteroaryl optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 , R 7 R 8 N—, R 7 R 8 N(O)C—, R 7 (O)CR 8 N—, F 3 C—, NC—, (C 3 -C 10 )alkyl-S—, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 3 -C 10 )alkyl(O)S—, (C 3 -C 10 )cycloalkyl(O)S—, (C 6 -C 14 )aryl(O)S—, (C 2 -C 9 )heteroalkyl(O)S—, (C 2 -C 9 )heterocycloalkyl(O)S—, (C 2 -C 9 )heteroaryl(O)S—, (C 3 -C 10 )alkyl-O 2 S—, (C 3 -C 10 )cycloalkyl-O 2 S—, (C 6 -C 14 )aryl-O 2 S—, (C 2 -C 9 )heteroalkyl-O 2 S—, (C 2 -C 9 )heterocycloalkyl-O 2 S—, (C 2 -C 9 )heteroaryl-O 2 S—, or R 7 R 8 NO 2 S—,
wherein R 7 and R 8 is each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, or (C 2 -C 9 )heteroaryl;

Q 2 is (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, or (C 2 -C 9 )heterocycloalkyl,
wherein the (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, or (C 2 -C 9 )heterocycloalkyl is optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, COOH—(C 1 -C 10 )alkyl, COOH—(C 3 -C 10 )cycloalkyl, (C 1 -C 10 )alkyl-O—, —OH, —NH 2 , R 7 R 8 N—, R 7 R 8 N(O)C—, R 7 (O)CR 8 N—, F 3 C—, NC—, (C 3 -C 10 )alkyl-S—, (C 3 -C 10 )cycloalkyl-S—, (C 6 -C 14 )aryl-S—, (C 2 -C 9 )heteroalkyl-S—, (C 2 -C 9 )heterocycloalkyl-S—, (C 2 -C 9 )heteroaryl-S—, (C 3 -C 10 )alkyl(O)S—, (C 3 -C 10 )cycloalkyl(O)S—, (C 6 -C 14 )aryl(O)S—, (C 2 -C 9 )heteroalkyl(O)S—, (C 2 -C 9 )heterocycloalkyl(O)S—, (C 2 -C 9 )heteroaryl(O)S—, (C 3 -C 10 )alkyl-O 2 S—, (C 3 -C 10 )cycloalkyl-O 2 S—, (C 6 -C 14 )aryl-O 2 S—, (C 2 -C 9 )heteroalkyl-O 2 S—, (C 2 -C 9 )heterocycloalkyl-O 2 S—, (C 2 -C 9 )heteroaryl-O 2 S—, or R 7 R 8 NO 2 S—,
wherein R 7 and R 8 is each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 6 -C 14 )aryl, or (C 2 -C 9 )heteroaryl;

X is CH, N, or CR 9 , wherein R 9 is (C 1 -C 10 )alkyl;
R 1 is H, (C 1 -C 10 )alkylamine, or NH 2 ;
R 2 is (C 1 -C 10 )alkylamine or (C 1 -C 10 )alkyl-O—;
R 3 and R 4 are each independently H or (C 1 -C 10 )alkyl; and
R 5 and R 6 are each independently H or (C 1 -C 10 )alkyl.

2. The method of claim 1 , wherein Q 1 is (C 2 -C 9 )heteroaryl substituted by (C 1 -C 10 )alkyl.

3. The method of claim 1 , wherein Q 2 is (C 6 -C 14 )aryl substituted by (C 1 -C 10 )alkyl-O—.

4. The method of claim 2 , wherein Q 2 is (C 6 -C 14 )aryl substituted by (C 1 -C 10 )alkyl-O—.

5. The method of claim 1 , wherein X is N.

6. The method of claim 4 , wherein X is N.

7. The method of claim 1 , wherein R 1 is NH 2 .

8. The method of claim 6 , wherein R 1 is NH 2 .

9. The method of claim 1 , wherein R 2 is (C 1 -C 10 )alkyl-O—.

10. The method of claim 8 , wherein R 2 is (C 1 -C 10 )alkyl-O—.

11. The method of claim 1 , wherein the compound is represented by Formula II:

or a pharmaceutically acceptable salt thereof, wherein:
n is 1, 2, or 3;
m is 0, 1, 2, or 3;
Q 1 is (C 2 -C 9 )heteroaryl optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, (C 1 -C 10 )alkyl-O—, —OH, or —NH 2 ;
Q 2 is (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, or (C 2 -C 9 )heterocycloalkyl,
wherein the (C 6 -C 14 )aryl, (C 2 -C 9 )heteroaryl, (C 3 -C 10 )cycloalkyl, or (C 2 -C 9 )heterocycloalkyl is optionally substituted by one to four groups selected from (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 3 -C 10 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-C(O)O—, (C 1 -C 10 )alkyl-O—, —OH, or —NH 2 ;

X is CH, N, or CR 9 , wherein R 9 is (C 1 -C 10 )alkyl;
R 1 is (C 1 -C 10 )alkylamine or NH 2 ; and
R 2 is (C 1 -C 10 )alkylamine or (C 1 -C 10 )alkyl-O—.

12. The method of claim 11 , wherein Q 1 is (C 2 -C 9 )heteroaryl substituted by (C 1 -C 10 )alkyl.

13. The method of claim 11 , wherein Q 2 is (C 6 -C 14 )aryl substituted by (C 1 -C 10 )alkyl-O—.

14. The method of claim 12 , wherein Q 2 is (C 6 -C 14 )aryl substituted by (C 1 -C 10 )alkyl-O—.

15. The method of claim 11 , wherein X is N.

16. The method of claim 14 , wherein X is N.

17. The method of claim 11 , wherein R 1 is NH 2 .

18. The method of claim 16 , wherein R 1 is NH 2 .

19. The method of claim 11 , wherein R 2 is (C 1 -C 10 )alkyl-O—.

20. The method of claim 18 , wherein R 2 is (C 1 -C 10 )alkyl-O—.

21. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

Assignees

• Genzyme Corp

Inventors

• Kane Jr John L
• Matthews Gloria
• Metz Markus
• Kothe Michael
• Liu Jinyu
• Scholte Andrew

Classifications

• A61K31/66

  Phosphorus compounds · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• A61K31/4725

  containing further heterocyclic rings · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title