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

1. A method for attenuating or ameliorating one or more symptoms of a solid tumor exhibiting one or more of overexpression, activation, amplification, and mutation of a Trk kinase in a mammal in need thereof, the method comprising:

(a) detecting a tumor in a mammal that exhibits one or more of overexpression, activation, amplification, and mutation of a Trk kinase; and

(b) administering to the mammal a therapeutically effective amount of a compound having the general 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 the solid tumor is selected from the group consisting of: breast, prostate, lung, renal, thyroid, neuroblastoma, ovarian cancer, breast cancer, pancreatic cancer, astrocytoma and medulloblastoma, glioma, melanoma, lung adenocarcinoma, large cell neuroendocrine tumors, colorectal cancer, stomach, bladder, uterus, rectum, and kidney.

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

4. The method of claim 1 , 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).

5. The method of claim 1 , 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, CF 3 and —O(1-4C alkyl).

6. 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).

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

8. 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 .

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

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

11. The method of 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.

12. The method of claim 11 , 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.

13. The method of claim 12 , 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.

14. The method of claim 13 , wherein Y is phenyl optionally substituted with one or more halogen atoms.

15. The method of claim 14 , wherein Y is phenyl optionally substituted with one or two fluorine atoms.

16. The method of claim 11 , 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 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;

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.

17. The method of claim 16 , wherein the heterocyclic ring formed by NR b R c is optionally substituted with one or two substituents independently selected from F, OH, methyl, OMe, OC(═O)C(CH 3 ) 2 , NH 2 , —NHC(═O)OC(CH 3 ) 3 and CH 2 OH.

18. The method of claim 17 , wherein Y is phenyl optionally substituted with one or more halogen atoms.

19. The method of claim 18 , wherein Y is phenyl optionally substituted with one or two fluorine atoms.

20. The method of claim 11 , wherein n is zero or one.

21. The method of claim 20 , wherein R 3 is hydrogen.

22. The method of claim 21 , wherein R 1 is hydrogen.