Method of treatment using substituted imidazo[1,2b]pyridazine compounds
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.
1. A compound of Formula II:
or a pharmaceutically acceptable salt thereof, 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 , 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 compound 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 .
3. The compound of claim 1 , wherein Y is phenyl optionally substituted with one or more halogen atoms.
4. The compound of claim 3 , wherein Y is phenyl optionally substituted with one or two fluorine atoms.
5. The compound of claim 1 , wherein X is —CH 2 —.
6. The compound of claim 1 , wherein R 3 is H.
7. The compound of claim 1 , wherein n is 0 or 1.
8. The compound of claim 1 , wherein:
Y is a phenyl ring optionally substituted with halogen;
X is —CH 2 —;
R 3 is H; and
n is 0.
9. A compound of Formula III:
or a pharmaceutically acceptable salt thereof, 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 , 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.
10. The compound of claim 9 , 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 .
11. The compound of claim 9 , wherein Y is phenyl optionally substituted with one or more halogen atoms.
12. The compound of claim 11 , wherein Y is phenyl optionally substituted with one or two fluorine atoms.
13. The compound of claim 9 , wherein X is —CH 2 —.
14. The compound of claim 9 , wherein R 3 is H.
15. The compound of claim 9 , wherein n is 0 or 1.
16. The compound of claim 9 , wherein:
Y is a phenyl ring optionally substituted with halogen;
X is —CH 2 —;
R 3 is H; and
n is 0.
17. A process for making a compound of Formula II:
or a pharmaceutically acceptable salt thereof, 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 , 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;
the process comprising reducing a corresponding compound of Formula III:
or a pharmaceutically acceptable salt thereof.
18. A process for preparing a compound of Formula III:
or a pharmaceutically acceptable salt thereof, 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 , 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;
the process comprising coupling a corresponding compound of Formula IV:
wherein Z is a leaving atom or group, with a corresponding compound of Formula V:
in the presence of a suitable solvent and at a temperature between 100° C. and 180° C.