IP Library › Granted Patent US 10,208,024
Granted Patent B2
US 10,208,024 · App. 15/333,148 · Granted Feb 19, 2019

2-aryl- and 2-heteroaryl-substituted 2-pyridazin-3(2H)-one compounds as inhibitors of FGFR tyrosine kinases

Inventors: Steven W. Andrews (Boulder, CO); James F. Blake (Boulder, CO); Adam Cook (Boulder, CO); Indrani W. Gunawardana (Boulder, CO); Kevin W. Hunt (Longmont, CO); Andrew T. Metcalf (Boulder, CO); David Moreno (Boulder, CO); Li Ren (Boulder, CO); Tony P. Tang (Boulder, CO)
Assignee: Array BioPharma Inc.
C07D403/14A61K31/501A61K31/5377A61K45/06C07D401/14C07D413/14C12Q1/6886G01N33/574
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Quick Facts
Patent No.
US 10,208,024
App. No.
15/333,148
Granted
Feb 19, 2019
Kind
B2
Abstract

Provided herein are compounds of the general Formula I: and stereoisomers and pharmaceutically acceptable salts or solvates thereof, in which X, R 1 , R 2 , R 3 , Ring A and z have the meanings given in the specification, which are inhibitors of FGFR1, FGFR2, FGFR3 and/or FGFR4 and are useful in the treatment and prevention of diseases which can be treated with an FGFR inhibitor, including diseases or disorders mediated by FGFR1, FGFR2, FGFR3 and/or FGFR4.

Claims (231)

1. A compound of the general Formula I:

and pharmaceutically acceptable salts thereof, wherein:

X is N or CH;

Ring A is a 5-membered heteroaryl ring having 1-2 ring nitrogen atoms;

z is 1, 2 or 3;

each R 1 is independently selected from the group consisting of:

(a) hydrogen;

(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,

(c) hydroxy(C1-C6 alkyl)- optionally substituted with 1-3 fluoros,

(d) dihydroxy(C1-C6 alkyl)- optionally substituted with 1-3 fluoros,

(e) cyano(C1-C6 alkyl)-,

(f) R a R b N(C1-C6 alkyl)-,

(g) (C1-C3 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros,

(h) (C3-C6 cycloalkyl)(CH 2 ) n — where n is 0-3 and said cycloalkyl is optionally substituted with CN, OH, R a R b N—, (1-3C)alkyl, or (1-3C)alkoxy;

(i) hetCyc 1 (CH 2 ) m — where m is 0-3,

(j) hetCyc 2 (CH 2 ) p — where p is 0 or 1,

(k) hetAr 1 (CH 2 ) q — where q is 1 or 2,

(l) halogen, and

(m) hetCyc 1 C(═O)CH 2 —;

hetCyc 1 is a 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, HO, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R c R d N- and (C1-C6 alkyl)C(═O)—;

hetCyc 2 is a 7-10 membered heterospirocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein said heterospirocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R c R d N- and (C1-C6 alkyl)C(═O)—;

hetAr 1 is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms, wherein said ring is optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen;

R 2 is AO or hetAr 2 ;

Ar 1 is phenyl substituted with one or more groups independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (cyclopropyl)C(═O)NH— and (cyclopropyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3 alkoxy portions is optionally substituted with 1-3 fluoros;

hetAr 2 is a 6-10 membered heteroaryl ring having 1-2 ring nitrogen atoms, wherein said ring is optionally substituted with one or more groups independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, (C1-C3 alkyl)NHC(═O)—, (C1-C3 alkyl)C(═O)NH—, (C3-C4 cycloalkyl)C(═O)NH- and (C3-C4 cycloalkyl)NHC(═O)—, wherein each of said C1-C3 alkyl and C1-C3 alkoxy portions is optionally substituted with 1-3 fluoros;

R 3 is H, C1-C4 alkyl or (C3-C4)cycloalkyl; and

R a , R b , R c and R d are independently hydrogen or C1-C6 alkyl optionally substituted with F, OH or C1-C6 alkoxy.

2. A compound according to claim 1 , wherein X is N.

3. A compound according to claim 1 , wherein X is CH.

4. A compound according to claim 1 , wherein R 2 is Ar 1 .

5. A compound according to claim 1 , wherein R 2 is hetAr 2 .

6. A compound according to claim 1 , wherein Ring A is pyrazolyl.

7. A compound according to claim 1 , wherein R 3 is hydrogen.

8. A compound according to claim 1 , wherein R 3 is C1-C4 alkyl.

9. A compound according to claim 1 , wherein R 3 is (C3-C4)cycloalkyl.

10. A compound according to claim 1 , wherein each occurrence of R 1 is hydrogen.

11. A compound according to claim 1 , wherein each occurrence of R 1 is C1-C6 alkyl optionally substituted with 1-3 fluoros.

12. A compound according to claim 1 , wherein each occurrence of R 1 is hydroxy(C1-C6 alkyl)- optionally substituted with 1-3 fluoros.

13. A compound according to claim 1 , wherein each occurrence of R 1 is dihydroxy(C1-C6 alkyl)- optionally substituted with 1-3 fluoros.

14. A compound according to claim 1 , wherein each occurrence of R 1 is cyano(C1-C6 alkyl)-.

15. A compound according to claim 1 , wherein each occurrence of R 1 is R a R b N(C1-C6 alkyl)-, where R a and R b are independently hydrogen or C1-C6 alkyl optionally substituted with F, OH or C1-C6 alkoxy.

16. A compound according to claim 1 , wherein each occurrence of R 1 is (C1-C3 alkoxy)C1-C6 alkyl- optionally substituted with 1-3 fluoros.

17. A compound according to claim 1 , wherein each occurrence of R 1 is (C3-C6 cycloalkyl)(CH 2 ) n — where n is 0-3 and said cycloalkyl is optionally substituted with CN, OH, R a R b N—, (1-3C)alkyl or (1-3C)alkoxy.

18. A compound according to claim 1 , wherein each occurrence of R 1 is hetCyc 1 (CH 2 ) m —, where m is 0-3, and hetCyc 1 is a 4-7 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of fluoro, HO, C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R c R d N- and (C1-C6 alkyl)C(═O)—.

19. A compound according to claim 1 , wherein each occurrence of R 1 is hetCyc 2 (CH 2 ) p — where p is 0 or 1, and hetCyc 2 is a 7-10 membered heterospirocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein said heterospirocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), (C3-C6 cycloalkoxy)C1-C6 alkyl-, hydroxy(C1-C6 alkyl)-, R c R d N- and (C1-C6 alkyl)C(═O)—.

20. A compound according to claim 1 , wherein each occurrence of R 1 is hetAr 1 (CH 2 ) q — where q is 1 or 2 and hetAr 1 is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms, wherein said ring is optionally substituted with one or more substituents independently selected from C1-C6 alkyl and halogen.

21. A compound according to claim 1 , wherein each occurrence of R 1 is halogen.

22. A compound according to claim 1 , wherein each occurrence of R 1 is hetCyc 1 C(═O)CH 2 —.

23. A compound according to claim 10 , wherein z is 2 or 3.

24. A compound according to claim 1 , wherein z is 1.

25. A compound of claim 1 , wherein the compound is selected from the group consisting:

Ex-

ample

#

Structure

Name

1

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

2

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3- methoxyphenyl)pyridazin-3(2H)- one

3

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,4- dimethoxyphenyl)pyridazin-3(2H)- one

4

1-((4-(5-amino-6-(1-(3,5- dimethoxyphenyl)-6-oxo-1,6- dihydropyridazin-3-yl)pyrazin-2- yl)-1H-pyrazol-1- yl)methyl)cyclopropane-1- carbonitrile

5

6-(3-amino-6-(1-(4,4,4-trifluoro-2- hydroxybutyl)-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

6

2-(4-(5-amino-6-(1-(3,5- dimethoxyphenyl)-6-oxo-1,6- dihydropyridazin-3-yl)pyrazin-2- yl)-1H-pyrazol-1-yl)-2- methylpropanenitrile

7

6-(3-amino-6-(1-(1-hydroxy-2- methylpropan-2-yl)-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

8

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3- methoxy-5- (trifluoromethoxy)phenyl)pyridazin- 3(2H)-one 2,2,2-trifluoroacetate salt

9

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3- ethoxy-5- (trifluoromethoxy)phenyl)pyridazin- 3(2H)-one 2,2,2-trifluoroacetate salt

10

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3- methoxy-5- (trifluoromethyl)phenyl)pyridazin- 3(2H)-one 2,2,2-trifluoroacetate salt

11

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2- chloro-3-methoxyphenyl)pyridazin- 3(2H)-one 2,2,2-trifluoroacetate salt

12

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(o- tolyl)pyridazin-3(2H)-one 2,2,2- trifluoroacetate salt

13

3-(3-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-6- oxopyridazin-1(6H)-yl)-5- methoxybenzonitrile 2,2,2- trifluoroacetate salt

14

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2- chloro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one (2,2,2-trifluoroacetate) salt

15

6-(3-amino-6-(1-isopropyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one 2,2,2-trifluoroacetate

16

6-(3-amino-6-(1-(pentan-3-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one 2,2,2-trifluoroacetate salt

17

6-(3-amino-6-(1- (cyclopropylmethyl)-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one 2,2,2-trifluoroacetate salt

18

6-(3-amino-6-(1-(2-hydroxy-2- methylpropyl)-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one 2,2,2-trifluoroacetate salt

19

6-(3-amino-6-(1-(2- morpholinoethyl)-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

20

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3- isopropoxy-5- methoxyphenyl)pyridazin-3(2H)- one

21

6-(3-amino-6-(1-isobutyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

22

6-(3-amino-6-(1-cyclobutyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

23

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6- dichloro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one

24

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2- bromo-3,5- dimethoxyphenyl)pyridazin-3(2H)- one 2,2,2-trifluoroacetate salt

25

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6- dibromo-3,5- dimethoxyphenyl)pyridazin-3(2H)- one 2,2,2-trifluoroacetate salt

26

(R)-6-(3-amino-6-(1-((5,5- dimethylmorpholin-2-yl)methyl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-2- (3,5-dimethoxyphenyl)pyridazin- 3(2H)-one

27

(S)-6-(3-amino-6-(1-((5,5- dimethylmorpholin-2-yl)methyl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-2- (3,5-dimethoxyphenyl)pyridazin- 3(2H)-one

28

6-(3-amino-6-(1-(((2S,5R)-5- methylmorpholin-2-yl)methyl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

29

(R)-6-(6-(1-((7-oxa-4- azaspiro[2.5]octan-6-yl)methyl)- 1H-pyrazol-4-yl)-3-aminopyrazin-2- yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

30

6-(3-amino-6-(1-(((2R,5R)-5- methylmorpholin-2-yl)methyl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

31

6-(3-amino-6-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-2- (3,5-dimethoxyphenyl)pyridazin- 3(2H)-one

32

6-(3-amino-6-(1-(1- methylpiperidin-4-yl)-1H-pyrazol- 4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

33

6-(3-amino-6-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

34

6-(3-amino-6-(1-(1-(2- (trifluoromethoxy)ethyl)piperidin-4- yl)-1H-pyrazol-4-yl)pyrazin-2-yl)- 2-(3,5-dimethoxyphenyl)pyridazin- 3(2H)-one 2,2,2-trifluoroacetate salt

35

6-(3-amino-6-(1-(1-(2,2- difluoroethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one 2,2,2-trifluoroacetate salt

36

6-(3-amino-6-(1-(1-(2,2,2- trifluoroethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

37

6-(3-amino-6-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-2-(5- methoxy-2-methylphenyl)pyridazin- 3(2H)-one

38

6-(3-amino-6-(1-(1- methylpiperidin-4-yl)-1H-pyrazol- 4-yl)pyrazin-2-yl)-2-(5-methoxy-2- methylphenyl)pyridazin-3(2H)-one

39

6-(3-amino-6-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(5- methoxy-2-methylphenyl)pyridazin- 3(2H)-one 2,2,2-trifluoroacetate salt

40

6-(3-amino-6-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2- fluoro-5-methoxyphenyl)pyridazin- 3(2H)-one

41

6-(3-amino-6-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-2-(2- fluoro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one

42

6-(3-amino-6-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2- fluoro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one 2,2,2-trifluoroacetate salt

43

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)-4- methylpyridazin-3(2H)-one

44

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)-4-ethylpyridazin- 3(2H)-one 2,2,2-trifluoroacetate salt

45

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)-4- propylpyridazin-3(2H)-one 2,2,2- trifluoroacetate salt

46

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)-4- isobutylpyridazin-3(2H)-one 2,2,2- trifluoroacetate salt

47

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)-4- isopropylpyridazin-3(2H)-one

48

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-4- cyclopropyl-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

49

6-(3-amino-6-(1-methyl-1H- pyrazol-4-yl)pyrazin-2-yl)-4- cyclobutyl-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

50

6-(3-amino-6-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-2- (3,5-dimethoxyphenyl)-4- methylpyridazin-3(2H)-one dihydrochloride salt

51

6-(3-amino-6-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxyphenyl)-4- methylpyridazin-3(2H)-one

52

3-(3-(3-amino-6-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-5- methyl-6-oxopyridazin-1(6H)-yl)- N,4-dimethylbenzamide dihydrochloride salt

53

6-(2-amino-5-(1-methyl-1H- pyrazol-4-yl)pyridin-3-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

54

6-(2-amino-5-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)pyridin-3-yl)-2- (3,5-dimethoxyphenyl)pyridazin- 3(2H)-one

55

6-(2-amino-5-(1-(1- methylpiperidin-4-yl)-1H-pyrazol- 4-yl)pyridin-3-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

56

6-(2-amino-5-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyridin-3-yl)-2-(3,5- dimethoxyphenyl)pyridazin-3(2H)- one

57

6-(2-amino-5-(1-methyl-1H- pyrazol-4-yl)pyridin-3-yl)-2-(2,6- dichloro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one

58

6-(2-amino-5-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)pyridin-3-yl)-2- (2,6-dichloro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one

59

6-(2-amino-5-(1-(1- methylpiperidin-4-yl)-1H-pyrazol- 4-yl)pyridin-3-yl)-2-(2,6-dichloro- 3,5-dimethoxyphenyl)pyridazin- 3(2H)-one

60

6-(2-amino-5-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyridin-3-yl)-2-(2,6- dichloro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one

61

3-(3-(2-amino-5-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)pyridin-3-yl)-6- oxopyridazin-1(6H)-yl)-N- methylbenzamide

62

3-(3-(2-amino-5-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyridin-3-yl)-6- oxopyridazin-1(6H)-yl)-N- methylbenzamide 2,2,2- trifluoroacetate salt

63

6-(3-amino-6-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-2-(3- methylquinolin-7-yl)pyridazin- 3(2H)-one bis(2,2,2- trifluoroacetate)

64

6-(3-amino-6-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3- methylquinolin-7-yl)pyridazin- 3(2H)-one

65

(S)-6-(3-amino-6-(1-((4,5,5- trimethylmorpholin-2-yl)methyl)- 1H-pyrazol-4-yl)pyrazin-2-yl)-2- (3,5-dimethoxyphenyl)pyridazin- 3(2H)-one 2,2,2-trifluoroacetate

66

6-(3-amino-6-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6- dichloro-3,5-dimethoxyphenyl)-4- methylpyridazin-3(2H)-one

67

6-(3-amino-6-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(3,5- dimethoxy-2- methylphenyl)pyridazin-3(2H)-one

68

6-(3-amino-6-(1-(2-oxo-2- (piperidin-1-yl)ethyl)-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(2,6-dichloro- 3,5-dimethoxyphenyl)pyridazin- 3(2H)-one

69

6-(3-amino-6-(1-(2- (dimethylamino)ethyl)-1H-pyrazol- 4-yl)pyrazin-2-yl)-2-(2,6-dichloro- 3,5-dimethoxyphenyl)pyridazin- 3(2H)-one

70

6-(3-amino-6-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(2,6-dichloro- 3,5-dimethoxyphenyl)pyridazin- 3(2H)-one

71

6-(3-amino-6-(1,3,5-trimethyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6- dichloro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one

72

6-(3-amino-6-(1-(1-hydroxy-2- methylpropan-2-yl)-1H-pyrazol-4- yl)pyrazin-2-yl)-2-(2,6-dichloro- 3,5-dimethoxyphenyl)pyridazin- 3(2H)-one

73

6-(3-amino-6-(1-isopropyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6- dichloro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one

74

6-(3-amino-6-(1-cyclopropyl-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6- dichloro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one

75

6-(3-amino-6-(1-(azetidin-3-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6- dichloro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one

76

6-(3-amino-6-(1-(2- (dimethylamino)ethyl)-1H-pyrazol- 4-yl)pyrazin-2-yl)-2-(2,6-dichloro- 3,5-dimethoxyphenyl)-4- methylpyridazin-3(2H)-one

77

6-(3-amino-6-(1-(azetidin-3-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6- dichloro-3,5-dimethoxyphenyl)-4- methylpyridazin-3(2H)-one

78

6-(3-amino-6-(1-(1-(2- methoxyethyl)azetidin-3-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6- dichloro-3,5-dimethoxyphenyl)-4- methylpyridazin-3(2H)-one

79

6-(3-amino-6-(1-(1-(2- ethoxyethyl)azetidin-3-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6- dichloro-3,5-dimethoxyphenyl)-4- methylpyridazin-3(2H)-one

80

3-(3-(3-amino-6-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-5- methyl-6-oxopyridazin-1(6H)-yl)- N,4-dimethylbenzamide

81

6-(2-amino-5-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)pyridin-3-yl)-2- (3,5-dimethoxyphenyl)-4- methylpyridazin-3(2H)-one dihydrochloride

82

6-(3-amino-6-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2,6- difluoro-3,5- dimethoxyphenyl)pyridazin-3(2H)- one

83

6-(3-amino-6-(1-(1-(2- methoxyethyl)piperidin-4-yl)-1H- pyrazol-4-yl)pyrazin-2-yl)-2-(2- chloro-6-fluoro-3- methoxyphenyl)pyridazin-3(2H)- one

or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition, comprising a compound according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

27. A process for the preparation of a compound of Formula 1 or a pharmaceutically acceptable salt thereof according to claim 1 , comprising:

(a) reacting a compound having the formula 5:

where X, R 1 , Ring A and z are as defined for Formula I, with a compound having the formula 4:

where R 2 is as defined for Formula I, in the presence of a palladium (II) catalyst and an inorganic base; or

(b) for a compound of Formula I where X, R 2 and R 3 are as defined in claim 1 , z is 1 and R 1 is a piperidine substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C3 alkoxy)C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxy(C1-C6 alkyl), reacting a compound having the formula 9A:

where X, R 2 and Ring A are as defined in claim 1 , with a compound having the formula R x -Y, where R x is C1-C6 alkyl (optionally substituted with 1-3 fluoros), (C1-C3 alkoxy)C1-C6 alkyl (optionally substituted with 1-3 fluoros) or hydroxy(C1-C6 alkyl), and Y is a leaving group, under standard alkylation reaction conditions; and

removing any protecting groups if present and optionally forming a pharmaceutically acceptable salt.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 25, 2017
From: ANDREWS, STEVEN W.; BLAKE, JAMES F.; COOK, ADAM; GUNAWARDANA, INDRANI W.; HUNT, KEVIN W.; METCALF, ANDREW T.; MORENO, DAVID; REN, LI; TANG, TONY P.
To: ARRAY BIOPHARMA, INC.
Reel/Frame 042137/0160 →
Continuity (2)
Provisional Application 62245956 · Oct 23, 2015
Related Publication 20170260168A1 · Sep 14, 2017
Cited By (7)
US 12,247,071 US 12,351,571 US 12,428,420 US 12,473,286 US 12,534,463 US 12,552,792 US 12,552,804