Method of treatment using substituted imidazo[1,2B]pyridazine compounds

Patent metadata

Field	Value
Publication number	US-9227975-B2
Application number	US-201213614968-A
Country	US
Kind code	B2
Filing date	Sep 13, 2012
Priority date	Sep 22, 2008
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

Methods for treating a disease or disorder selected from pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection and osteolytic disease in a mammal, which comprise administering to said mammal a therapeutically effective amount of a compound of Formula I

in which R 1 , R 2 , R 3 , R 4 , X, Y and n have the meanings given in the specification.

First claim

What is claimed is:

1. A method for inhibiting a Trk kinase in a cell, the method comprising contacting the cell with an effective amount of a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H or (1-6C alkyl);
R 2 is NR b R c , (1-4C)alkyl, (1-4C)fluoroalkyl, CF 3 , (1-4C)hydroxyalkyl, -(1-4C alkyl)hetAr 1 , -(1-4C alkyl)NH(1-4C alkyl), hetAr 2 , hetCyc 1 , hetCyc 2 , phenyl which is optionally substituted with NHSO 2 (1-4C alkyl), or (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl), CN, OH, CF 3 , CO 2 (1-4C alkyl) or CO 2 H;
R b is H or (1-6C alkyl);
R c is H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr 3 , or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF 3 and —O(1-4C alkyl),
or NR b R c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, —OC(═O)(1-4C alkyl), NH 2 , —NHC(═O)O(1-4C alkyl), and (1-4C)hydroxyalkyl,
or NR b R c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO 2 , wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF 3 , (1-4C)alkyl, CO 2 (1-4C alkyl), CO 2 H, NH 2 , NHC(═O)O(1-4C alkyl) and oxo,
or NR b R c forms a 7-8 membered bridged heterocyclic ring having 1-2 ring nitrogen atoms and optionally substituted with CO 2 (1-4C alkyl);
hetAr 1 is a 5-membered heteroaryl ring having 1-3 ring nitrogen atoms;
hetAr 2 is 5-6 membered heteroaryl ring having at least one nitrogen ring atom and optionally having a second ring heteroatom independently selected from N and S, wherein said heteroaryl ring is optionally substituted with one or more substituents independently selected from (1-4C alkyl), halogen, -(1-4 C)alkoxy, and NH(1-4C alkyl);
hetCyc 1 is a carbon-linked 4-6 membered azacyclic ring optionally substituted with one or more substituents independently selected from (1-4C alkyl), CO 2 H and CO 2 (1-4C alkyl);
hetCyc 2 is a pyridinone or pyridazinone ring substituted with a substituent selected from (1-4C)alkyl;
hetAr 3 is a 5-6 membered heteroaryl ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from (1-4C)alkyl;
Y is a phenyl ring optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF 3 and CHF 2 , or a 5-6 membered heteroaryl ring having a ring heteroatom selected from N and S;
X is null, —CH 2 —, —CH 2 CH 2 —, —CH 2 O—, or —CH 2 NR d —
R d is H or (1-4C alkyl);
R 3 is H or (1-4C alkyl);
each R 4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4 C)alkoxy, NH 2 , NH(1-4C alkyl) and CH 2 OH; and
n is 0, 1, 2, 3, 4, 5 or 6.

2. The method of claim 1 , wherein R 2 is NR b R c .

3. The method of claim 2 , wherein:
NR b R c forms a 4 membered heterocyclic ring having a ring nitrogen atom optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, —OC(═O)(1-4C alkyl), NH 2 , —NHC(═O)O(1-4C alkyl), and (1-4C)hydroxyalkyl,
or NR b R c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO 2 , wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF 3 , (1-4C)alkyl, CO 2 (1-4C alkyl), CO 2 H, NH 2 , NHC(═O)O(1-4C alkyl) and oxo,
or NR b R c forms a 7-8 membered bridged heterocyclic ring having 1-2 ring nitrogen atoms and optionally substituted with CO 2 (1-4C alkyl).

4. The method of claim 2 , wherein:
R b is H or (1-6C alkyl); and
R c is H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr 3 , or phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen, CN, CF3 and —O(1-4C alkyl).

5. The method of claim 1 , wherein R 2 is (1-4C)alkyl, (1-4C)fluoroalkyl, CF 3 , -(1-4C alkyl)hetAr 1 , or -(1-4C alkyl)NH(1-4C alkyl).

6. The method of claim 1 , wherein X is null, —CH 2 — or —CH 2 CH 2 —.

7. The method of claim 1 , wherein Y is a phenyl ring optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF 3 and CHF 2 .

8. The method of claim 1 , wherein Y has the absolute configuration of Figure Ia:

9. The method of claim 1 , wherein R 3 is H.

10. The method according to claim 1 , wherein:
R 1 is H or (1-6C alkyl);
R 2 is NR b R c ;
NR b R c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from halogen, OH, (1-4C alkyl), (1-4 C)alkoxy, —OC(═O)(1-4C alkyl), NH 2 , —NHC(═O)O(1-4C alkyl) and (1-4C)hydroxyalkyl,
or NR b R c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO 2 , wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF 3 , (1-4C)alkyl, CO 2 (1-4C alkyl), CO 2 H, NH 2 , NHC(═O)O(1-4C alkyl) and oxo;
Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF 3 and CHF 2 ;
X is null, —CH 2 —, or —CH 2 CH 2 —;
R 3 is H or (1-4C alkyl);
each R 4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4 C)alkoxy, NH 2 , NH(1-4C alkyl) and CH 2 OH; and
n is 0, 1, or 2.

11. The method according to claim 10 , wherein:
R 1 is H or (1-6C alkyl);
R 2 is NR b R c ;
NR b R c forms a 5-6 membered heterocyclic ring having a ring heteroatom which is nitrogen and optionally having a second ring heteroatom or group selected from N, O and SO 2 , wherein the heterocyclic ring is optionally substituted with one or more substituents independently selected from OH, halogen, CF 3 , (1-4C)alkyl, CO 2 (1-4C alkyl), CO 2 H, NH 2 , NHC(═O)O(1-4C alkyl) and oxo;
Y is phenyl optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkoxy, CF 3 and CHF 2 ;
X is —CH 2 —;
R 3 is H or (1-4C alkyl);
each R 4 is independently selected from halogen, (1-4C)alkyl, OH, (1-4 C)alkoxy, NH 2 , NH(1-4C alkyl) and CH 2 OH; and
n is 0, 1, or 2.

12. The method according to claim 11 , wherein the heterocyclic ring formed by NR b R c is optionally substituted with one or two substituents independently selected from OH, F, NH 2 , CO 2 H, CO 2 Et, NHCO 2 C(CH 3 ) 3 , CF 3 , methyl, ethyl, isopropyl, CO 2 C(CH 3 ) 3 and oxo.

13. The method according to claim 12 , wherein Y is phenyl optionally substituted with one or more halogen atoms.

14. The method according to claim 13 , wherein Y is phenyl optionally substituted with one or two fluorine atoms.

15. The method according to claim 10 , wherein:
R 1 is H or (1-6C alkyl);
R 2 is NR b R c ;
NR b R c forms a 4 membered heterocyclic ring having a ring nitrogen atom, wherein said ring is optionally substituted

Assignees

• Andrews Steven W
• Haas Julia
• Jiang Yutong
• Zhang Gan
• Array Biopharma Inc

Inventors

• Andrews Steven W
• Haas Julia
• Jiang Yutong
• Zhang Gan

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P33/10

  Anthelmintics · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title

• A61P43/00

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