IP Library › Granted Patent US 10,183,928

Granted Patent B2

US 10,183,928 · App. 15/462,255 · Granted Jan 22, 2019

Inhibitors of RET

Inventors: Joseph L. Kim (Wayland, MA); Kevin J. Wilson (Boston, MA); Jason D. Brubaker (Cambridge, MA)

Assignee: BLUEPRINT MEDICINES CORPORATION

C07D401/14 C07D403/14

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Quick Facts

Patent No.: US 10,183,928
App. No.: 15/462,255
Granted: Jan 22, 2019
Kind: B2

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Abstract

Described herein are compounds that inhibit wild-type RET and its resistant mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.

Claims (100)

1. A compound having the structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

ring A is an aryl or heteroaryl ring;

each of X 1 and X 2 is independently N or C(R 6 );

each R 1 and each R 7 is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halo, C 1 -C 6 heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, —C(O)R, —OC(O)R, —C(O)OR, —(C 1 -C 6 alkylene)-C(O)R, —SR, —S(O) 2 R, —(O) 2 —N(R)(R), —(C 1 -C 6 alkylene)—S(O) 2 R, —(C 1 -C 6 alkylene)-S(O) 2 —N(R)(R), —N(R)(R), —C(O)—N(R)(R), —N(R)—C(O)R, —N(R)—C(O)OR, —(C 1 -C 6 alkylene)-N(R)—C(O)R, —N(R)S(O) 2 R, and —P(O)(R)(R), wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a , or two R 1 or two R 7 are taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R b ;

each of R 2 , R 3a , R 3b , R 4 , R 8a , and R 8b is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, hydroxyl, C 1 -C 6 heteroalkyl, and —N(R)(R), wherein each alkyl, alkoxy, and heteroalkyl is optionally and independently substituted with 0-5 occurrences of R a ;

each of R 5 and R 9 is independently hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl, wherein each alkyl and heteroalkyl is optionally and independently substituted with 0-5 occurrences of R a ;

R 6 is selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo, C 1 -C 6 heteroalkyl, and —N(R)(R), wherein each alkyl, alkoxy, and heteroalkyl is optionally and independently substituted with 0-5 occurrences of R a ;

each R is independently selected from hydrogen, hydroxyl, halo, thiol, C 1 -C 6 alkyl, C 1 -C 6 thioalkyl, C 1 -C 6 alkoxy, C 1 -C 6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each of alkyl, thioalkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of R a , or two R together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of R b ;

each R a and each R b is independently selected from C 1 -C 6 alkyl, halo, hydroxyl, C 1 -C 6 heteroalkyl, C 1 -C 6 alkoxy, cycloalkyl, heterocyclyl, and cyano, wherein each of alkyl, heteroalkyl, alkoxy, cycloalkyl, and heterocyclyl is independently substituted with 0-5 occurrences of R′;

each R′ is independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, halo, hydroxyl, cycloalkyl, and cyano, or two R′ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring;

m is 0, 1, or 2; and

n is 0, 1, 2, or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 1; R 1 is located at the 5-position; and R 1 is C 1 -C 4 alkyl substituted with 0-3 occurrences of R a .

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 .

4. The compound of any of claims 1 - 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, hydroxyl, halo, or O—C 1 -C 4 alkyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, hydroxyl, fluoro, and OCH 3 .

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each of R 3a , R 3b , R 8a , and R 8b is hydrogen.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, C 1 -C 4 alkyl, and O—C 1 -C 4 alkyl, wherein each alkyl portion of R 4 is substituted with 0-3 occurrences of R a .

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, CH 3 , or OCH 3 .

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or C 1 -C 4 alkyl substituted with 0-3 occurrences of R 8 .

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen or CH 3 .

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently hydrogen, halo, or C 1 -C 4 alkyl substituted with 0-3 occurrences of R a .

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein each R 6 is independently hydrogen, chloro, or CH 3 .

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered monocyclic heteroaryl comprising at least one nitrogen ring atom.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein ring A is

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1; and R 7 is pyrazol-1-yl substituted with 0-3 occurrences of R a .

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R 7 is 4-fluoropyrazol-1-yl or pyrazol-1-yl.

17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen or C 1 -C 4 alkyl substituted with 0-3 occurrences of R a .

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen or methyl.

19. The compound of claim 1 having the structural Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein ring A, X 1 , X 2 , R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9 , m, and n are as defined as for structural Formula (I).

20. The compound of claim 1 having the structural Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein ring A, X 1 , X 2 , R 1 , R 2 , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8a , R 8b , R 9 , m, and n are as defined as for structural Formula (I).

21. A compound having the structural Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is N, CH, or C(halo);

X 2 is N or CH;

X 3 is N or CH;

R 12 is selected from hydrogen, hydroxyl, halo, and optionally substituted O—C 1 -C 4 alkyl;

R 14 is hydrogen, optionally substituted C 1 -C 4 alkyl, or optionally substituted O—C 1 -C 4 alkyl;

R 15 is hydrogen or optionally substituted C 1 -C 4 alkyl;

R 16 is hydrogen or optionally substituted C 1 -C 4 alkyl;

R 17 is hydrogen or halo; and

R 19 is hydrogen or optionally substituted C 1 -C 4 alkyl.

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein:

X 1 is N, CH, or C(Cl);

R 12 is selected from hydrogen, hydroxyl, fluoro, and O—CH 3 ;

R 14 is hydrogen, CH 3 , or OCH 3 ;

R 15 is hydrogen or CH 3 ;

R 16 is hydrogen or CH 3 ;

R 17 is hydrogen or fluoro; and

R 19 is hydrogen or CH 3 .

23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein when X 1 is CH, R 16 is CH 3 .

24. The compound of claim 21 having the structural Formula (IIa):

or a pharmaceutically acceptable salt thereof,

wherein X 1 , X 2 , X 3 , R 12 , R 14 , R 15 , R 16 , R 17a , R 17b , R 17c , R 18a , R 18b , and R 19 are as defined as for structural Formula (II).

25. The compound of claim 3 having the structural Formula (IIb):

or a pharmaceutically acceptable salt thereof,

wherein X 1 , X 2 , X 3 , R 12 , R 13a , R 13b , R 14 , R 15 , R 16 , R 17a , R 17b , R 17c , R 18a , R 18b , and R 19 are as defined as for structural Formula (II).

26. A compound chosen from:

and pharmaceutically acceptable salts thereof.

27. A method for treating a subject suffering from non-small cell lung cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

28. A method for treating a subject suffering from papillary thyroid cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

29. A method for treating a subject suffering from medullary thyroid cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

30. A method for treating a subject suffering from colorectal cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

31. A method for treating a subject suffering from multiple endocrine neoplasia, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising: a pharmaceutically acceptable carrier; and

at least one compound chosen from compounds of claim 1 or 26 and pharmaceutically acceptable salts thereof.

33. The compound