Tropomyosin-related kinase (Trk) inhibitors

Patent metadata

Field	Value
Publication number	US-10166239-B2
Application number	US-201715436195-A
Country	US
Kind code	B2
Filing date	Feb 17, 2017
Priority date	Dec 10, 2013
Publication date	Jan 1, 2019
Grant date	Jan 1, 2019

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 treating osteoarthritis in a patient in need thereof, the method comprising administering to the patient a compound of the structure of Formula (I):

wherein:
n is 1, 2, 3, 4 or 5;
m is 0, 1, 2, 3 or 4;
Q 1 is H, halo, (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(O)P—, (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(O)P—, (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, (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, or —NH 2 ;

R 1 is H, halo, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 1 -C 10 )alkylamine, or NH 2 ;
R 2 is H, halo, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 1 -C 10 )alkylamine, (C 1 -C 10 )alkyl-O—, or NH 2 ;
R 3 and R 4 are each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 1 -C 10 )alkylamine, O—(C 1 -C 10 )alkyl, or NH 2 or R 3 and R 4 are taken together with the carbon to which they are attached to form a 3 to 10 member ring,
wherein the 3 to 10 member ring 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, or —NH 2 ; and

R 5 and R 6 are each independently H, (C 1 -C 10 )alkyl, (C 2 -C 9 )heteroalkyl, (C 1 -C 10 )alkylamine, O—(C 1 -C 10 )alkyl, or NH 2 or R 5 and R 6 are taken together with the carbon to which they are attached to form a 3 to 10 member ring,
wherein the 3 to 10 member ring 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, or —NH 2 ;

or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein n is 1, 2 or 3.

3. The method according to claim 2 , wherein n is 1.

4. The method according to claim 1 , wherein m is 0, 1, or 2.

5. The method according to claim 4 , wherein m is 1.

6. The method according to claim 1 , wherein n is 1 and m is 1.

7. The method according to claim 1 , wherein Q 1 is H or (C 6 -C 14 )aryl or (C 2 -C 9 )heteroaryl,
wherein the (C 6 -C 14 )aryl or (C 2 -C 9 )heteroaryl 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(O)P—, (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.

8. The method according to claim 6 , wherein 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(O)P—, (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.

9. The method according to claim 1 , wherein Q 2 is (C 6

Assignees

• Genzyme Corp

Inventors

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

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

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

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title