Substituted imidazo[1,2b]pyridazine compounds as Trk kinase inhibitors

1. 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. A compound of claim 1 , wherein R 2 is NR b R c .

3. A compound 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. A compound 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, CF 3 and —O(1-4C alkyl).

5. A compound 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. A compound according to claim 1 , wherein X is null, —CH 2 — or —CH 2 CH 2 —.

7. A compound according to 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. A compound according to claim 1 , wherein Y has the absolute configuration of FIG. Ia:

9. A compound according to claim 1 , wherein R 3 is H.

10. A compound 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. A compound 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. A compound 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. A compound according to claim 12 , wherein Y is phenyl optionally substituted with one or more halogen atoms.

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

15. A compound according 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 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.

16. A compound according to claim 15 , 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.

17. A compound according to claim 16 , wherein Y is phenyl optionally substituted with one or more halogen atoms.

18. A compound according to claim 17 , wherein Y is phenyl optionally substituted with one or two fluorine atoms.

19. A compound according to claim 10 , wherein n is zero or one.

20. A compound according to claim 19 , wherein R 3 is hydrogen.

21. A compound according to claim 20 , wherein R 1 is hydrogen.

22. A compound of claim 1 , selected from:

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-phenylurea;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)morpholine-4-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)acetamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-(methyl sulfonamido)benzamide;

(R)-1-(3-cyanophenyl)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea;

(R)-1-(4-cyanophenyl)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea;

(R)-1-(2,4-dichlorophenyl)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea;

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-(3-(trifluoromethyl)phenyl)urea;

(R)-1-(3,5-dichlorophenyl)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea;

(S)—N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

(R)—N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxypyrrolidine-1-carboxamide;

(R)-tert-butyl 1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)piperidin-4-ylcarbamate;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxyazetidine-1-carboxamide;

(R)-tert-butyl 1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)azetidin-3-ylcarbamate;

(R)-tert-butyl 4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)piperazine-1-carboxylate;

(R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1,1-dimethylurea;

tert-Butyl 1-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)piperidin-3-ylcarbamate;

(R)-4-amino-N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)piperidine-1-carboxamide;

(R)-3-amino-N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)azetidine-1-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)piperazine-1-carboxamide;

3-Amino-N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)piperidine-1-carboxamide;

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-(4-fluorophenyl)urea;

tert-Butyl 3-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate;

N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3 , 8-diazabicyclo[3.2.1]octane-3-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-hydroxypiperidine-1-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)piperidine-1-carboxamide;

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea;

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-methylurea;

(R)-1-tert-butyl-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea;

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-(4-methoxyphenyl)urea;

(R)-ethyl 1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)piperidine-4-carboxylate;

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-(3,4,5-trimethoxyphenyl)urea;

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-(3,5-dimethylisoxazol-4-yl)urea;

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)piperidine-4-carboxylic acid;

N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,5-dimethylpiperazine-1-carboxamide;

(R)-tert-butyl 4-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate;

(S)-tert-butyl 4-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate;

(R)—N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-methylpiperazine-1-carboxamide;

(S)—N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-methylpiperazine-1-carboxamide; 4R)—N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,4-dihydroxypyrrolidine-1-carboxamide;

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)piperidin-4-sulfone;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-oxopiperazine-1-carboxamide;

N-(6-(2-(3-fluorophenyl)piperidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxyazetidine-1-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,3-difluoropyrrolidine-1-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,3-difluoroazetidine-1-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)azetidine-1-carboxamide;

(R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1-(2-hydroxyethyl)-1-methylurea;

(R)-tert-butyl 4-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-2,2-dimethylpiperazine-1-carboxylate;

(S)-tert-butyl 4-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)-2-isopropylpiperazine-1-carboxylate;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3,3-dimethylpiperazine-1-carboxamide;

(S)—N-(6-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-isopropylpiperazine-1-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-(hydroxymethyl)azetidine-1-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-methoxyazetidine-1-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide;

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-ylcarbamoyl)azetidin-3-yl isobutyrate;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-methylpiperazine-1-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxamide;

(R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-2,2,2-trifluoroacetamide; and

pharmaceutically acceptable salts thereof.

23. A pharmaceutical composition, which comprises a compound of Formula I as defined in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

24. A process for the preparation of a compound of claim 1 , which comprises:

(a) for a compound of Formula I wherein R 2 is NR b R c , reacting a corresponding compound of formula II

with a compound having the formula HNR b R c in the presence of a coupling reagent; or

(b) for a compound of Formula I wherein R 2 is NR b R c and R b is H, reacting a corresponding compound of formula II with a compound having the formula O═C═N—R c ; or

(c) for a compound of Formula I wherein R 2 is hetAr 2 or a phenyl ring which is optionally substituted with NHSO 2 (1-4C alkyl), reacting a corresponding compound of Formula II with a corresponding compound having the formula HOC(═O)R 2 in the presence of a coupling reagent and a base; or

(d) for a compound of Formula I wherein R 2 is (1-4C)alkyl, (1-4C)fluoroalkyl, CF 3 , (1-4C)hydroxyalkyl, 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, reacting a corresponding compound of Formula II with a corresponding compound having the formula (R 2 CO) 2 O in the presence of a base; and

removing or adding any protecting groups if desired, and forming a salt if desired.