阅读说明：本技术 Raf激酶的抑制剂 (Inhibitors of RAF kinase ) 是由 史蒂芬·W·卡尔多 陶菲克·卡努尼 埃里克·A·墨菲 李·D·阿诺德 约翰·泰霍纳斯 于 2020-03-20 设计创作，主要内容包括：本文提供了受体酪氨酸激酶效应物RAF的抑制剂,包含所述化合物的药物组合物,以及使用所述化合物治疗疾病的方法。(Provided herein are inhibitors of the receptor tyrosine kinase effector RAF, pharmaceutical compositions comprising the compounds, and methods of treating diseases using the compounds.)

1. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (I):

wherein the content of the first and second substances,

g is C ═ O or SO₂；

R is C1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH)₂- (C1-C8 optionally substituted alkylene) -S (O) NHMe, C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl alkyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH)₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2; or optionally, if q is 2, then two R ¹The groups are joined to form a fused ring;

R²h, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxy;

R⁶h, D, Cl or F;

R^cis H or D;

z is selected from:

(a)-NR^aR^bwherein R is^aSelected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; and is

R^bSelected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

(b)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-S-alkyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R ¹¹The groups together form oxo;

(c)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl); and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(d)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; n1 is 0, 1 or 2, provided that both m1 and n1 are not 0; p is 0, 1 or 2; and q is 0, 1 or 2;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substitutedSubstituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R ¹¹The groups together form oxo;

(e)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 1 or 2; p is 0, 1, 2 or 3; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹、-CH₂-CH₂-、-CH₂-CHR¹¹-、-CH₂-C(R¹¹)₂-、-CHR¹¹-CH₂-、-C(R¹¹)₂-CH₂-、-NH-CH₂-、-NH-CHR¹¹-、-NH-C(R¹¹)₂-、-CH₂-NH-、-CHR¹¹-NH-、-C(R¹¹)₂-NH-、-N(R¹¹)-CH₂-、-N(R¹¹)-CHR¹¹-、-N(R¹¹)-C(R¹¹)₂-、-CH₂-N(R¹¹)-、-CHR¹¹-N(R¹¹)-、-C(R¹¹)₂-N(R¹¹)-、-O-CH₂-or-CH₂-O-; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(f)wherein m is 0, 1 or 2; n is 0, 1 or 2;m1 is 0, 1 or 2; p is 0, 1 or 2;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂；

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R ¹¹The groups together form oxo;

and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(g)wherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3, with the proviso that both m and n are not 0; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(h)wherein m is 1, 2 or 3; n is 1, 2 or 3; p is 0, 1 or 2; and is

Each R¹³Or R¹⁴Independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substitutedis-SO of₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;

(i)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO ₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two geminal R¹¹The groups together form oxo.

2. A compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (II):

wherein the content of the first and second substances,

g is C ═ O or SO₂；

R is C1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH)₂- (C1-C8 optionally substituted alkylene) -S (O) NHMe, C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl alkyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH)₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2; or optionally, if q is 2, then two R¹The groups are joined to form a fused ring;

R²h, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxy;

R⁶h, D, Cl or F;

R^cis H or D;

z is selected from:

(a)-NR^aR^bwherein R is^aSelected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; and is

R^bSelected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

(b)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-S-alkyl, optionally substituted-SO ₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo;

(c)wherein m is0. 1, 2 or 3; p is 0, 1, 2, 3 or 4;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl); and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(d)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; n1 is 0, 1 or 2, provided that both m1 and n1 are not 0; p is 0, 1 or 2; and q is 0, 1 or 2;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO ₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(e)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 1 or 2; p is 0, 1, 2 or 3; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹、-CH₂-CH₂-、-CH₂-CHR¹¹-、-CH₂-C(R¹¹)₂-、-CHR¹¹-CH₂-、-C(R¹¹)₂-CH₂-、-NH-CH₂-、-NH-CHR¹¹-、-NH-C(R¹¹)₂-、-CH₂-NH-、-CHR¹¹-NH-、-C(R¹¹)₂-NH-、-N(R¹¹)-CH₂-、-N(R¹¹)-CHR¹¹-、-N(R¹¹)-C(R¹¹)₂-、-CH₂-N(R¹¹)-、-CHR¹¹-N(R¹¹)-、-C(R¹¹)₂-N(R¹¹)-、-O-CH₂-or-CH₂-O-; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(f)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂；

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO ₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(g)wherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3, with the proviso that both m and n are not 0; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(h)wherein m is 1, 2 or 3; n is 1, 2 or 3; p is 0, 1 or 2; and is

Each R¹³Or R¹⁴Independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;

(i)Wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylAlkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two geminal R¹¹The groups together form oxo.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein G is C ═ O.

4. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R^cIs hydrogen.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R^cIs deuterium.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R²Is hydrogen or deuterium.

7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is hydrogen or deuterium.

8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R²Is F.

9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is F.

10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

11. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-H or C-D.

12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-F.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is an optionally substituted C1 alkyl group.

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.

16. The compound of any one of claims 1-13 or 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is CH₃Q is 1, and R¹Positioned to provide 3-methylmorpholino.

17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl.

18. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R is- (C1-C8 optionally substituted alkylene) -OPO (OH)₂。

19. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted cycloalkyl.

20. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R is C4-C6 optionally substituted cycloalkylalkyl.

21. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R is heterocyclyl optionally substituted with C3-C6.

22. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted heterocyclylalkyl.

23. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein the C1-C8 optionally substituted alkyl is C2 optionally substituted alkyl.

24. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein said- (C1-C8 optionally substituted alkylene) -OPO (OH)₂Is C2 optionally substituted alkylene.

25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is halogen.

26. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is optionally substituted C1-C3 alkyl.

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is methyl.

28. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is-NR^aR^bWherein R is^aIs selected from HOptionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; and is

R^bIs selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R^aIs H.

30. The compound of claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R^aIs an optionally substituted alkyl group.

31. The compound of any one of claims 28-30, or a pharmaceutically acceptable salt or solvate thereof, wherein R^bIs an optionally substituted alkyl group.

32. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R ¹¹The groups together form oxo.

33. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

34. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1.

35. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2.

36. The compound of claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3.

37. The compound of any one of claims 32-36, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

38. The compound of any one of claims 32-36, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

39. The compound of any one of claims 32-36, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

40. The compound of any one of claims 32-36, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

41. The compound of any one of claims 32-40, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹Is optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

42. The compound of claim 41, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl is substituted with at least one halogen.

43. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl); and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo.

44. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein W is O.

45. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein W is S.

46. The compound of any one of claims 43-45, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1.

47. The compound of any one of claims 43-45, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 2.

48. The compound of any one of claims 43-47, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹¹Is optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

49. The compound of claim 48, or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl is substituted with at least one halogen.

50. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; n1 is 0, 1 or 2, provided that both m1 and n1 are not 0; p is 0, 1 or 2; and q is 0, 1 or 2;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO ₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo.

51. The compound of claim 50, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1.

52. The compound of any one of claims 50-51, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0 and n is 2.

53. The compound of any one of claims 50-52, or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 0 and n1 is 2.

54. The compound of any one of claims 50-53, or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1 and n1 is 1.

55. The compound of any one of claims 50-54, or a pharmaceutically acceptable salt or solvate thereof, wherein W is O.

56. The compound of any one of claims 50-54, or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH₂。

57. The compound of any one of claims 50-54, or a pharmaceutically acceptable salt or solvate thereof, wherein W is CHR ¹¹。

58. The compound of any one of claims 50-54, or a pharmaceutically acceptable salt or solvate thereof, wherein W is C (R)¹¹)₂。

59. The compound of any one of claims 57-58, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹¹Is halogen and q is 1.

60. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 1 or 2; p is 0, 1, 2 or 3; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹、-CH₂-CH₂-、-CH₂-CHR¹¹-、-CH₂-C(R¹¹)₂-、-CHR¹¹-CH₂-、-C(R¹¹)₂-CH₂-、-NH-CH₂-、-NH-CHR¹¹-、-NH-C(R¹¹)₂-、-CH₂-NH-、-CHR¹¹-NH-、-C(R¹¹)₂-NH-、-N(R¹¹)-CH₂-、-N(R¹¹)-CHR¹¹-、-N(R¹¹)-C(R¹¹)₂-、-CH₂-N(R¹¹)-、-CHR¹¹-N(R¹¹)-、-C(R¹¹)₂-N(R¹¹) -; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl.

61. The compound of claim 60, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0, n is 1, and m1 is 1; and W is-O-CH ₂-or-CH₂-O-。

62. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl.

63. The compound of claim 62, or a pharmaceutically acceptable salt or solvate thereof, wherein W is O.

64. The compound of any one of claims 62-63, or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH₂Or CHR¹¹。

65. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 0.

66. The compound of any one of claims 62-64, or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1.

67. The compound of any one of claims 62-66, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1.

68. The compound of any one of claims 62-66, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 0.

69. The compound of any one of claims 62-66, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0 and n is 1.

70. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3, with the proviso that both m and n are not 0; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl.

71. The compound of claim 70, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1.

72. The compound of claim 70, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 2.

73. The compound of any one of claims 70-72, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

74. The compound of any one of claims 70-72, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.

75. The compound of any one of claims 70-74, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R¹¹Attached to the olefin carbon.

76. The compound of any one of claims 70-74, or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R¹¹Not attached to the olefin carbon.

77. The compound of any one of claims 70-76, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹¹Is optionally substitutedC1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

78. The compound of any one of claims 70-72, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

79. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 1, 2 or 3; n is 1, 2 or 3; p is 0, 1 or 2; and each R¹³Or R¹⁴Independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl.

80. The compound of claim 79, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2 and n is 1.

81. The compound of claim 79 or 80, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

82. The compound of claim 79 or 80, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

83. The compound of any one of claims 79-82, or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹³Or R¹⁴One of which is not hydrogen.

84. The compound of any one of claims 79-83, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹³Or R¹⁴One is optionally substituted C1-C6 alkyl.

85. The compound of claim 84, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹³Is optionally substituted C1-C6 alkyl.

86. The compound of claim 84, or a pharmaceutically acceptable salt or solvate thereof, wherein R¹⁴Is optionally substituted C1-C6 alkyl.

87. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two geminal R ¹¹The groups together form oxo.

88. The compound of claim 87, or a pharmaceutically acceptable salt or solvate thereof, wherein W is O.

89. The compound of claim 87 or 88, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2 and n is 1.

90. The compound of any one of claims 87-89, or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1 or 2.

91. The compound of any one of claims 87-90, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0 or 1 and q is 0 or 1.

92. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from the compounds described in table 1.

93. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1 or 3-91, or a pharmaceutically acceptable salt or solvate thereof.

94. A pharmaceutical composition comprising a compound of formula (II) as described in any one of claims 2-91, or a pharmaceutically acceptable salt or solvate thereof.

95. A pharmaceutical composition comprising the compound of claim 92, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

96. A pharmaceutical composition comprising a compound of formulae (III) - (VI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

97. A process for preparing a pharmaceutical composition comprising mixing a compound of any one of claims 1-92, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

98. A compound according to any one of claims 1 to 92, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

99. A compound according to any one of claims 1-92, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of cancer or a neoplastic disease.

100. Use of a compound of any one of claims 1-92, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

101. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (I) as described in any one of claims 1 or 3-91, or a pharmaceutically acceptable salt or solvate thereof.

102. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1 or 3-91, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

103. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (II) as described in any one of claims 2-91, or a pharmaceutically acceptable salt or solvate thereof.

104. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (II) as described in any one of claims 2-91, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

105. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of claim 92, or a pharmaceutically acceptable salt or solvate thereof.

106. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising the compound of claim 92, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

107. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formulae (III) - (VI), or a pharmaceutically acceptable salt or solvate thereof.

108. A method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formulae (III) - (VI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

109. The method of any one of claims 101-108, wherein the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

Background

RAF kinases function in the Ras-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway (also known as the MAPK/ERK pathway) by phosphorylating and activating MEK. MAPK leads to altered transcription of genes critical to the cell cycle by altering the levels and activity of transcription factors. Dysregulation of MAPK activity often occurs in tumors. Thus, there is a need for therapies that target RAF kinase activity for the treatment of cancer and other disorders characterized by aberrant MAPK/ERK pathway signaling.

Disclosure of Invention

Provided herein are inhibitors of the receptor tyrosine kinase effector, raf (raf), pharmaceutical compositions comprising the compounds, and methods of treating diseases using the compounds.

One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (I):

Wherein the content of the first and second substances,

g is C ═ O or SO₂；

R is C1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH)₂- (C1-C8 optionally substituted alkylene) -S (O) NHMe, C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl alkyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH)₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2; or optionally, if q is 2, then two R¹The groups are joined to form a fused ring;

R²h, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxyA group;

R⁶h, D, Cl or F;

R^cis H or D;

z is selected from:

(a)-NR^aR^bwherein R is^aSelected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; and R is^bSelected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

(b)Wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-S-alkyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo;

(c)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl); and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylSubstituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(d)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; n1 is 0, 1 or 2, provided that both m1 and n1 are not 0; p is 0, 1 or 2; and q is 0, 1 or 2;

W is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(e)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 1 or 2; p is 0, 1, 2 or 3; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹、-CH₂-CH₂-、-CH₂-CHR¹¹-、-CH₂-C(R¹¹)₂-、-CHR¹¹-CH₂-、-C(R¹¹)₂-CH₂-、-NH-CH₂-、-NH-CHR¹¹-、-NH-C(R¹¹)₂-、-CH₂-NH-、-CHR¹¹-NH-、-C(R¹¹)₂-NH-、-N(R¹¹)-CH₂-、-N(R¹¹)-CHR¹¹-、-N(R¹¹)-C(R¹¹)₂-、-CH₂-N(R¹¹)-、-CHR¹¹-N(R¹¹)-、-C(R¹¹)₂-N(R¹¹)-、-O-CH₂-or-CH₂-O-; each R¹¹Independently selectSelected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(f)Wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂；

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(g)wherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3, with the proviso that both m and n are not 0; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, orTwo of R¹¹The groups together form oxo;

(h)wherein m is 1, 2 or 3; n is 1, 2 or 3; p is 0, 1 or 2; and is

Each R¹³Or R¹⁴Independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;

(i)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two geminal R¹¹The groups together form oxo.

One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (II):

Wherein the content of the first and second substances,

g is C ═ O or SO₂；

R isC1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH)₂- (C1-C8 optionally substituted alkylene) -S (O) NHMe, C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl alkyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH)₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2; or optionally, if q is 2, then two R¹The groups are joined to form a fused ring;

R²h, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxy;

R⁶h, D, Cl or F;

R^cis H or D;

z is selected from:

(a)-NR^aR^bwherein R is^aSelected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; and R is^bSelected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

(b)Wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substitutedOptionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-S-alkyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo;

(c)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl); and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(d)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; n1 is 0, 1 or 2, provided that both m1 and n1 are not 0; p is 0, 1 or 2; and q is 0, 1 or 2;

W is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(e)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 1 or 2; p is 0, 1, 2 or 3; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹、-CH₂-CH₂-、-CH₂-CHR¹¹-、-CH₂-C(R¹¹)₂-、-CHR¹¹-CH₂-、-C(R¹¹)₂-CH₂-、-NH-CH₂-、-NH-CHR¹¹-、-NH-C(R¹¹)₂-、-CH₂-NH-、-CHR¹¹-NH-、-C(R¹¹)₂-NH-、-N(R¹¹)-CH₂-、-N(R¹¹)-CHR¹¹-、-N(R¹¹)-C(R¹¹)₂-、-CH₂-N(R¹¹)-、-CHR¹¹-N(R¹¹)-、-C(R¹¹)₂-N(R¹¹)-、-O-CH₂-or-CH₂-O-; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(f)Wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂；

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy,Optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(g)wherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3, with the proviso that both m and n are not 0; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(h)wherein m is 1, 2 or 3; n is 1, 2 or 3; p is 0, 1 or 2; and is

Each R¹³Or R¹⁴Independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;

(i)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two geminal R¹¹The groups together form oxo.

One embodiment provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

One embodiment provides a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

Another embodiment provides the method, wherein the disease or disorder is cancer.

One embodiment provides a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

One embodiment provides a method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof. Another embodiment provides the method, wherein the disease or disorder is cancer.

Is incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purpose to which this specification pertains.

Detailed Description

As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties such as molecular weight or chemical properties such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments herein are intended to be included. The term "about" when used in reference to a number or numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus in some cases the number or numerical range will vary from 1% to 15% of the number or numerical range. The term "comprising" (and related terms such as "comprises" or "having" or "including") is not intended to exclude that, in certain other embodiments, for example, an embodiment of any material composition, method, or process, etc., described herein "consists of or" consists essentially of the recited feature.

Definition of

As used in this specification and the appended claims, the following terms have the meanings indicated below, unless the contrary is indicated.

"amino" means-NH₂A group.

"cyano" refers to the group-CN.

"nitro" means-NO₂A group.

"oxa" refers to an-O-group.

"oxo" refers to an ═ O group.

"thio" refers to ═ S groups.

"imino" refers to an ═ N-H group.

"oximino" refers to the group ═ N-OH.

"hydrazino" refers to ═ N-NH₂A group.

"alkyl" means consisting only of carbon and hydrogen atoms, free of unsaturation, having 1 to 15 carbon atoms (e.g., C)₁-C₁₅Alkyl) or a branched or unbranched hydrocarbon chain group. In certain embodiments, the alkyl group comprises 1 to 13Carbon atoms (e.g. C)₁-C₁₃Alkyl groups). In certain embodiments, the alkyl group contains 1 to 8 carbon atoms (e.g., C)₁-C₈Alkyl groups). In other embodiments, the alkyl group contains 1 to 5 carbon atoms (e.g., C)₁-C₅Alkyl groups). In other embodiments, the alkyl group contains 1 to 4 carbon atoms (e.g., C)₁-C₄Alkyl groups). In other embodiments, the alkyl group contains 1 to 3 carbon atoms (e.g., C)₁-C₃Alkyl groups). In other embodiments, the alkyl group contains 1 to 2 carbon atoms (e.g., C) ₁-C₂Alkyl groups). In other embodiments, the alkyl group contains one carbon atom (e.g., C)₁Alkyl groups). In other embodiments, the alkyl group contains 5 to 15 carbon atoms (e.g., C)₅-C₁₅Alkyl groups). In other embodiments, the alkyl group contains 5 to 8 carbon atoms (e.g., C)₅-C₈Alkyl groups). In other embodiments, the alkyl group contains 2 to 5 carbon atoms (e.g., C)₂-C₅Alkyl groups). In other embodiments, the alkyl group contains 3 to 5 carbon atoms (e.g., C)₃-C₅Alkyl groups). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl group is attached to the rest of the molecule by a single bond. Unless expressly stated otherwise in the specification, alkyl is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, hydroxyimino, -trimethylsilyl, -OR^a、-SR^a、-OC(O)-R^a、-N(R^a)₂、-C(O)R^a、-C(O)OR^a、-C(O)N(R^a)₂、-N(R^a)C(O)OR^a、-OC(O)-N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)S(O)_tR^a(wherein t is 1 or 2), -S (O)_tOR^a(wherein t is 1 or 2), -S (O)_tR^a(wherein t is 1 or 2) and-S (O)_tN(R^a)₂(wherein t is 1 or 2) wherein each R^aIndependently is hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"alkoxy" refers to a group bonded through an oxygen atom of the formula-O-alkyl, wherein alkyl is an alkyl chain as defined above.

"alkenyl" means a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In certain embodiments, alkenyl groups contain 2 to 8 carbon atoms. In other embodiments, alkenyl groups contain 2 to 4 carbon atoms. The alkenyl group is attached to the remainder of the molecule by a single bond, for example, vinyl, prop-1-enyl (i.e., allyl), but-1-enyl, pent-1, 4-dienyl, and the like. Unless expressly stated otherwise in the specification, an alkenyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, hydroxyimino, -trimethylsilyl, -OR^a、-SR^a、-OC(O)-R^a、-N(R^a)₂、-C(O)R^a、-C(O)OR^a、-C(O)N(R^a)₂、-N(R^a)C(O)OR^a、-OC(O)-N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)S(O)_tR^a(wherein t is 1 or 2), -S (O)_tOR^a(wherein t is 1 or 2), -S (O)_tR^a(wherein t is 1 or 2) and-S (O)_tN(R^a)₂(wherein t is 1 or 2) wherein each R^aIndependently is hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"alkynyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from 2 to 12 carbon atoms. In certain embodiments, alkynyl groups contain 2 to 8 carbon atoms. In other embodiments, alkynyl groups contain 2 to 6 carbon atoms. In other embodiments, alkynyl groups contain 2 to 4 carbon atoms. The alkynyl group is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless expressly stated otherwise in the specification, alkynyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, hydroxyimino, -trimethylsilyl, -OR^a、-SR^a、-OC(O)-R^a、-N(R^a)₂、-C(O)R^a、-C(O)OR^a、-C(O)N(R^a)₂、-N(R^a)C(O)OR^a、-OC(O)-N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)S(O)_tR^a(wherein t is 1 or 2), -S (O)_tOR^a(wherein t is 1 or 2), -S (O)_tR^a(wherein t is 1 or 2) and-S (O)_tN(R^a)₂(wherein t is 1 or 2) wherein each R^aIndependently hydrogen, alkyl (optionally substituted by halogen, hydroxy, methoxy orTrifluoromethyl substituted), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the remainder of the molecule to a group, consisting only of carbon and hydrogen, containing no unsaturation, and having from 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is connected to the rest of the molecule by a single bond and to the group by a single bond. The point of attachment of the alkylene chain to the rest of the molecule and to the group is through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, the alkylene group contains 1 to 8 carbon atoms (e.g., C)₁-C₈Alkylene). In other embodiments, the alkylene group contains 1 to 5 carbon atoms (e.g., C)₁-C₅Alkylene). In other embodiments, the alkylene group contains 1 to 4 carbon atoms (e.g., C)₁-C₄Alkylene). In other embodiments, the alkylene group contains 1 to 3 carbon atoms (e.g., C)₁-C₃Alkylene). In other embodiments, the alkylene group contains 1 to 2 carbon atoms (e.g., C)₁-C₂Alkylene). In other embodiments, the alkylene group contains 1 carbon atom (e.g., C)₁Alkylene). In other embodiments, the alkylene group contains 5 to 8 carbon atoms (e.g., C) ₅-C₈Alkylene). In other embodiments, the alkylene group contains 2 to 5 carbon atoms (e.g., C)₂-C₅Alkylene). In other embodiments, the alkylene packetContaining 3 to 5 carbon atoms (e.g. C)₃-C₅Alkylene). Unless otherwise explicitly stated in the specification, the alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, hydroxyimino, -trimethylsilyl, -OR^a、-SR^a、-OC(O)-R^a、-N(R^a)₂、-C(O)R^a、-C(O)OR^a、-C(O)N(R^a)₂、-N(R^a)C(O)OR^a、-OC(O)-N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)S(O)_tR^a(wherein t is 1 or 2), -S (O)_tOR^a(wherein t is 1 or 2), -S (O)_tR^a(wherein t is 1 or 2) and-S (O)_tN(R^a)₂(wherein t is 1 or 2) wherein each R^aIndependently is hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain connecting the rest of the molecule to a group, consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. The alkenylene chain is connected to the rest of the molecule by a single bond and to the group by a single bond. In certain embodiments, alkenylene contains 2 to 8 carbon atoms (e.g., C)₂-C₈Alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (e.g., C)₂-C₅Alkenylene). In other embodiments, alkenylene contains 2 to 4 carbon atoms (e.g., C)₂-C₄Alkenylene). In other embodiments, alkenylene contains 2 to 3 carbon atoms (e.g., C)₂-C₃Alkenylene). In other embodiments, alkenylene contains 2 carbon atoms (e.g., C)₂Alkenylene). In other embodiments, alkenylene contains 5 to 8 carbon atoms (e.g., C)₅-C₈Alkenylene). In other embodiments, alkenylene contains 3 to 5 carbon atoms (e.g., C)₃-C₅Alkenylene). Unless explicitly stated otherwise in the specification, alkenylene chains are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, hydroxyimino, -trimethylsilyl, -OR ^a、-SR^a、-OC(O)-R^a、-N(R^a)₂、-C(O)R^a、-C(O)OR^a、-C(O)N(R^a)₂、-N(R^a)C(O)OR^a、-OC(O)-N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)S(O)_tR^a(wherein t is 1 or 2), -S (O)_tOR^a(wherein t is 1 or 2), -S (O)_tR^a(wherein t is 1 or 2) and-S (O)_tN(R^a)₂(wherein t is 1 or 2) wherein each R^aIndependently is hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"alkynylene group"or" alkynylene chain "refers to a straight or branched divalent hydrocarbon chain connecting the remainder of the molecule to a group, consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. The alkynylene chain is connected to the rest of the molecule by a single bond and to the group by a single bond. In certain embodiments, alkynylene comprises 2 to 8 carbon atoms (e.g., C) ₂-C₈Alkynylene). In other embodiments, alkynylene contains 2 to 5 carbon atoms (e.g., C)₂-C₅Alkynylene). In other embodiments, alkynylene contains 2 to 4 carbon atoms (e.g., C)₂-C₄Alkynylene). In other embodiments, alkynylene contains 2 to 3 carbon atoms (e.g., C)₂-C₃Alkynylene). In other embodiments, the alkynylene group contains 2 carbon atoms (e.g., C)₂Alkynylene). In other embodiments, alkynylene contains 5 to 8 carbon atoms (e.g., C)₅-C₈Alkynylene). In other embodiments, the alkynylene group contains 3 to 5 carbon atoms (e.g., C)₃-C₅Alkynylene). Unless explicitly stated otherwise in the specification, an alkynylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thio, imino, hydroxyimino, -trimethylsilyl, -OR^a、-SR^a、-OC(O)-R^a、-N(R^a)₂、-C(O)R^a、-C(O)OR^a、-C(O)N(R^a)₂、-N(R^a)C(O)OR^a、-OC(O)-N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)S(O)_tR^a(wherein t is 1 or 2), -S (O)_tOR^a(wherein t is 1 or 2), -S (O)_tR^a(wherein t is 1 or 2) and-S (O)_tN(R^a)₂(wherein t is 1 or 2) wherein each R^aIndependently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) Halogen, hydroxy, methoxy, or trifluoromethyl substituted), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by the removal of a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from 5 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, i.e. it comprises a cyclic, delocalized (4n +2) pi-electron system according to houckel theory. Ring systems from which the aryl group is derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise explicitly stated in the specification, the term "aryl" or the prefix "aryl" (as in "aralkyl") is intended to include aryl groups optionally substituted with one or more substituents independently selected from: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b-OR^a、-R^b-OC(O)-R^a、-R^b-OC(O)-OR^a、-R^b-OC(O)-N(R^a)₂、-R^b-N(R^a)₂、-R^b-C(O)R^a、-R^b-C(O)OR^a、-R^b-C(O)N(R^a)₂、-R^b-O-R^c-C(O)N(R^a)₂、-R^b-N(R^a)C(O)OR^a、-R^b-N(R^a)C(O)R^a、-R^b-N(R^a)S(O)_tR^a(wherein t is 1 or 2),-R^b-S(O)_tR^a(wherein t is 1 or 2), -R^b-S(O)_tOR^a(wherein t is 1 or 2) and-R^b-S(O)_tN(R^a)₂(wherein t is 1 or 2), wherein each R^aIndependently is hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, methoxy or trifluoromethyl), fluoroalkyl, or arylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R is independently^bIndependently is a direct bond or a linear or branched alkylene or alkenylene chain, and R^cIs a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted, unless otherwise specified.

"aralkyl" means a group of the formula-R^c-a radical of an aryl radical, wherein R^cIs an alkylene chain as defined above, e.g., methylene, ethylene, and the like. The alkylene chain portion of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for aryl.

"aralkenyl" means a group of formula-R^d-a radical of an aryl radical, wherein R^dIs an alkenylene chain as defined above. The aryl moiety of the aralkenyl group is optionally substituted as described above for aryl. The alkenylene chain portion of the aralkenyl group is optionally substituted as described above for alkenylene.

"aralkynyl" means the formula-R^e-a radical of an aryl radical, wherein R^eIs an alkynylene chain as defined above. The aryl moiety of the aralkynyl radical is as hereinbefore specifiedSaid for aryl is optionally substituted. The alkynylene moiety of the arylalkynyl group is optionally substituted as described above for the alkynylene chain.

"aralkoxy" means a compound of the formula-O-R^c-a group of aryl groups bonded through an oxygen atom, wherein R^cIs an alkylene chain as defined above, e.g., methylene, ethylene, and the like. The alkylene chain portion of the aralkyl group is optionally substituted as described above for the alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for aryl.

"carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms, including fused or bridged ring systems, having 3 to 15 carbon atoms. In certain embodiments, carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, carbocyclyl contains 5 to 7 carbon atoms. The carbocyclyl group is attached to the rest of the molecule by a single bond. Carbocyclyl groups are either saturated (i.e., contain only a single C-C bond) or unsaturated (i.e., contain one or more double or triple bonds). The fully saturated carbocyclyl group is also referred to as a "cycloalkyl". Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyl groups are also known as "cycloalkenyl". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo [ 2.2.1)]Heptylalkyl), norbornenyl, decahydronaphthyl, 7-dimethyl-bicyclo [2.2.1 ]]Heptalkyl, and the like. Unless otherwise specifically stated in the specification, the term "carbocyclyl" is intended to include carbocyclyl groups optionally substituted with one or more substituents independently selected from: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b-OR^a、-R^b-OC(O)-R^a、-R^b-OC(O)-OR^a、-R^b-OC(O)-N(R^a)₂、-R^b-N(R^a)₂、-R^b-C(O)R^a、-R^b-C(O)OR^a、-R^b-C(O)N(R^a)₂、-R^b-O-R^c-C(O)N(R^a)₂、-R^b-N(R^a)C(O)OR^a、-R^b-N(R^a)C(O)R^a、-R^b-N(R^a)S(O)_tR^a(wherein t is 1 or 2), -R^b-S(O)_tR^a(wherein t is 1 or 2), -R^b-S(O)_tOR^a(wherein t is 1 or 2) and-R^b-S(O)_tN(R^a)₂(wherein t is 1 or 2), wherein each R^aIndependently is hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, methoxy or trifluoromethyl), fluoroalkyl, or arylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R is independently^bIndependently is a direct bond or a linear or branched alkylene or alkenylene chain, and R^cIs a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted, unless otherwise specified.

"carbocyclylalkyl" refers to the formula-R^c-a carbocyclic group, wherein R^cIs an alkylene chain as defined above. The alkylene chain and carbocyclyl group are optionally substituted as described above.

"carbocyclylalkynyl" refers to the formula-R^c-a carbocyclic group, wherein R^cIs an alkynylene chain as defined above. The alkynylene chain and carbocyclyl group are optionally substituted as described above.

"carbocyclylalkoxy" means a radical of the formula-O-R^c-a carbocyclic group bonded via an oxygen atom, wherein R^cIs an alkylene chain as defined above. The alkylene chain and carbocyclyl group are optionally substituted as described above.

As used herein, "carboxylic acid bioisosteres" refers to functional groups or moieties that exhibit similar physical, biological, and/or chemical properties as carboxylic acid moieties. Examples of carboxylic acid bioisosteres include, but are not limited to:

and the like.

"halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

"fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the fluoroalkyl group is optionally substituted as described above for alkyl.

"heterocyclyl" refers to a stable 3 to 18-membered non-aromatic cyclic group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in the specification, a heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. Heterocyclyl groups are partially or fully saturated. The heterocyclyl is attached to the remainder of the molecule through any atom in the ring. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thiopheneRadical [1,3 ]]Dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl. Unless otherwise explicitly stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl groups as defined above optionally substituted with one or more substituents selected from: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b-OR^a、-R^b-OC(O)-R^a、-R^b-OC(O)-OR^a、-R^b-OC(O)-N(R^a)₂、-R^b-N(R^a)₂、-R^b-C(O)R^a、-R^b-C(O)OR^a、-R^b-C(O)N(R^a)₂、-R^b-O-R^c-C(O)N(R^a)₂、-R^b-N(R^a)C(O)OR^a、-R^b-N(R^a)C(O)R^a、-R^b-N(R^a)S(O)_tR^a(wherein t is 1 or 2), -R^b-S(O)_tR^a(wherein t is 1 or 2), -R^b-S(O)_tOR^a(wherein t is 1 or 2) and-R^b-S(O)_tN(R^a)₂(wherein t is 1 or 2), wherein each R^aIndependently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl(s) ((R))Optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R^bIndependently is a direct bond or a linear or branched alkylene or alkenylene chain, and R^cIs a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted, unless otherwise specified.

"N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl group as defined above that contains at least one nitrogen, and wherein the point of attachment of the heterocyclyl group to the remainder of the molecule is through a nitrogen atom in the heterocyclyl group. The N-heterocyclyl group is optionally substituted as described above for the heterocyclyl group. Examples of such N-heterocyclyl groups include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

"C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl group as defined above that contains at least one heteroatom, and wherein the point of attachment of the heterocyclyl group to the remainder of the molecule is through a carbon atom in the heterocyclyl group. The C-heterocyclyl group is optionally substituted as described above for the heterocyclyl group. Examples of such C-heterocyclyl groups include, but are not limited to, 2-morpholinyl, 2-or 3-or 4-piperidinyl, 2-piperazinyl, 2-or 3-pyrrolidinyl, and the like.

"Heterocyclylalkyl" means a compound of the formula-R^c-a group of heterocyclic groups, wherein R^cIs an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heterocyclylalkyl group is optionally taken as described above for the alkylene chain And (4) generation. The heterocyclyl portion of the heterocyclylalkyl group is optionally substituted as described above for heterocyclyl.

"Heterocyclylalkoxy" means a compound of the formula-O-R^c-a group of heterocyclic groups bonded via an oxygen atom, wherein R^cIs an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy group is optionally substituted as described above for the alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy group is optionally substituted as described above for heterocyclyl.

"heteroaryl" refers to a group derived from a 3 to 18 membered aromatic ring group containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one ring in the ring system is fully unsaturated, i.e., it comprises a cyclic, delocalized (4n +2) pi-electron system according to houckel's theory. Heteroaryl groups include fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heteroaryl group is attached to the rest of the molecule through any atom in the ring. Examples of heteroaryl groups include, but are not limited to, aza A group selected from the group consisting of acridinyl, benzimidazolyl, benzindolyl, 1, 3-benzodioxolyl, benzofuranyl, benzoxazolyl and benzo [ d]Thiazolyl, benzothiadiazolyl, benzo [ b ]][1,4]Dioxa medicineRadical, benzo [ b][1,4]Oxazinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothiophenyl, benzothienofuranyl, benzonaphthofuranyl, and benzothiophenyl[3,2-d]Pyrimidinyl, benzotriazolyl, benzo [4,6 ]]Imidazo [1,2-a ]]Pyridyl, carbazolyl, cinnolinyl, cyclopenta [ d ]]Pyrimidinyl, 6, 7-dihydro-5H-cyclopenta [4,5 ]]Thieno [2,3-d ]]Pyrimidinyl, 5, 6-dihydrobenzo [ h ]]Quinazolinyl, 5, 6-dihydrobenzo [ h ]]Cinnolinyl, 6, 7-dihydro-5H-benzo [6,7 ]]Cyclohepta [1,2-c ]]Pyridazinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanonyl, furo [3,2-c ]]Pyridyl, 5,6,7,8,9, 10-hexahydrocycloocta [ d ]]Pyrimidinyl, 5,6,7,8,9, 10-hexahydrocycloocta [ d]Pyridazinyl, 5,6,7,8,9, 10-hexahydrocycloocta [ d ] ]Pyridyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, 5, 8-methano-5, 6,7, 8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl (1,6-naphthyridinonyl), oxadiazolyl, 2-oxo-azaazazolinylAlkyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10 a-octahydrobenzo [ h ]]Quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo [3,4-d]Pyrimidinyl, pyridinyl, pyrido [3,2-d ]]Pyrimidinyl, pyrido [3,4-d ]]Pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7, 8-tetrahydroquinazolinyl, 5,6,7, 8-tetrahydrobenzo [4,5 ] tetrahydroquinoline]Thieno [2,3-d ]]Pyrimidinyl, 6,7,8, 9-tetrahydro-5H-cyclohepta [4,5 ]]Thieno [2,3-d ]]Pyrimidinyl, 5,6,7, 8-tetrahydropyrido [4,5-c]Pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno [2,3-d ]]Pyrimidinyl, thieno [3,2-d]Pyrimidinyl, thieno [2, 3-c) ]Pyridyl and thienyl (thiophenyl) (i.e., thienyl (thiophenyl)). Unless otherwise explicitly stated in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above optionally substituted with one or more substituents selected from: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, optionally substitutedAryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R^b-OR^a、-R^b-OC(O)-R^a、-R^b-OC(O)-OR^a、-R^b-OC(O)-N(R^a)₂、-R^b-N(R^a)₂、-R^b-C(O)R^a、-R^b-C(O)OR^a、-R^b-C(O)N(R^a)₂、-R^b-O-R^c-C(O)N(R^a)₂、-R^b-N(R^a)C(O)OR^a、-R^b-N(R^a)C(O)R^a、-R^b-N(R^a)S(O)_tR^a(wherein t is 1 or 2), -R^b-S(O)_tR^a(wherein t is 1 or 2), -R^b-S(O)_tOR^a(wherein t is 1 or 2) and-R^b-S(O)_tN(R^a)₂(wherein t is 1 or 2), wherein each R^aIndependently is hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, methoxy or trifluoromethyl), fluoroalkyl, or arylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R is independently ^bIndependently is a direct bond or a linear or branched alkylene or alkenylene chain, and R^cIs a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted, unless otherwise specified.

"N-heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen, and wherein the point of attachment of the heteroaryl group to the remainder of the molecule is through the nitrogen atom in the heteroaryl group. The N-heteroaryl group is optionally substituted as described above for the heteroaryl group.

"C-heteroaryl" refers to a heteroaryl group as defined above, wherein the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. The C-heteroaryl group is optionally substituted as described above for the heteroaryl group.

"Heteroarylalkyl" means a compound of the formula-R^c-a radical of heteroaryl, wherein R^cIs an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkyl group is optionally substituted as defined above for heteroaryl.

"Heteroarylalkoxy" means a compound of the formula-O-R^c-a group of heteroaryl groups bonded via an oxygen atom, wherein R^cIs an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkoxy group is optionally substituted as defined above for heteroaryl.

In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms defined as (R) -or (S) -according to absolute stereochemistry. Unless otherwise indicated, the present disclosure is intended to refer to all stereoisomeric forms of the compounds disclosed herein. When the compounds described herein contain olefinic double bonds, the present invention is intended to include both E and Z geometric isomers (e.g., cis or trans), unless otherwise indicated. Likewise, all possible isomers are also intended to be included, as well as racemic and optically pure forms thereof, and all tautomeric forms. The term "geometric isomer" refers to an E or Z geometric isomer (e.g., cis or trans) of an olefinic double bond. The term "positional isomers" refers to structural isomers around a central ring, such as the ortho, meta, and para isomers around the phenyl ring.

"tautomer" refers to molecules in which it is possible for a proton to move from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds presented herein exist as tautomers. In situations where tautomerism is likely to occur, there will be a chemical equilibrium of the tautomers. The exact ratio of tautomers depends on several factors including physical state, temperature, solvent and pH. Some examples of tautomeric equilibrium include:

in some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, e.g., enriched in²H、³H、¹¹C、¹³C and/or¹⁴In the form of C content. In a particular embodiment, the compound is deuterated at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Pat. nos. 5,846,514 and 6,334,997. As described in U.S. patent nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and/or efficacy, thereby increasing the duration of action of the drug.

Unless otherwise indicated, structures shown herein are intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, except for replacement of hydrogen by deuterium or tritium or replacement of carbon by deuterium or tritium ¹³C-or¹⁴Compounds having the present structure in addition to C-rich carbon substitution are also within the scope of the present disclosure.

The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, isotopes may be usedSuch as deuterium (²H) Tritium (a)³H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) The compound is labeled. By using²H、¹¹C、¹³C、¹⁴C、¹⁵C、¹²N、¹³N、¹⁵N、¹⁶N、¹⁶O、¹⁷O、¹⁴F、¹⁵F、¹⁶F、¹⁷F、¹⁸F、³³S、³⁴S、³⁵S、³⁶S、³⁵Cl、³⁷Cl、⁷⁹Br、⁸¹Br、¹²⁵Isotopic substitution by I is contemplated. In some embodiments, the use is contemplated¹⁸F is isotopically substituted. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

In certain embodiments, some or all of the compounds disclosed herein¹H atom quilt²H atom substitution. Methods of synthesis of deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

Deuterium substituted compounds are synthesized using various methods, such as those described in: dean, Dennis c. eds. Recent Advances in the Synthesis and Applications of radio ported Compounds for Drug Discovery and Development, [ curr., pharm.des., 2000; 6(10) ]2000,110 pp; george w.; varma, Rajender S.the Synthesis of radio bound Compounds via Organometallic Intermediates, Tetrahedron,1989,45(21), 6601-21; and Evans, E.Anthony.Synthesis of radiolaboratory compounds, J.Radioactive. chem.,1981,64(1-2), 9-32.

Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium containing compounds. Large amounts of deuterium containing reagents and building blocks are commercially available from Chemical suppliers such as Aldrich Chemical co.

Deuterium transferring reagents suitable for nucleophilic substitution reactions, e.g. iodomethane-d₃(CD₃I) Are readily available and can be used to transfer deuterium-substituted carbon atoms to a reaction substrate under nucleophilic substitution reaction conditions.

By way of example only, CDs₃The use of I is shown in the reaction scheme below.

Using deuterium transferring agents, e.g. lithium aluminium deuteride (LiAlD)₄) Deuterium is transferred to the reaction substrate under reducing conditions. By way of example only, LiAlD₄The use of (a) is shown in the following reaction scheme.

By way of example only, as shown in the reaction scheme below, deuterium gas and palladium catalysts are used to reduce unsaturated carbon-carbon bonds and to effect reductive substitution of aryl carbon-halogen bonds.

In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compounds disclosed herein are completely substituted with deuterium atoms and do not contain non-exchangeable moieties ¹H hydrogen atom. In one embodiment, the level of deuterium incorporation is determined by the synthetic method using the deuterated synthetic building block as starting material.

"pharmaceutically acceptable salts" include acid addition salts and base addition salts. Any pharmaceutically acceptable salt of a heteroaromatic RAF inhibiting compound described herein is intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"pharmaceutically acceptable acid addition salts" refers to those salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, and the like. Also included are salts formed with the following organic acids: such as aliphatic mono-and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, malate, tartrate, mesylate, and the like. Also contemplated are Salts of amino acids such as arginate, gluconate, and galacturonate (see, e.g., Berge S.M et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science,66:1-19 (1997)). In some embodiments, acid addition salts of basic compounds are prepared by contacting their free base form with a sufficient amount of the desired acid to produce the salt, according to methods and techniques familiar to the skilled artisan.

"pharmaceutically acceptable base addition salts" refers to those salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from organic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts derived from organic bases include, but are not limited to, the following salts of organic bases: primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine (theobromine), purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al, supra.

"pharmaceutically acceptable solvate" refers to a composition of matter that is in the form of a solvent addition. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of solvent and is formed during manufacture with a pharmaceutically acceptable solvent such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed in the processes described herein. The compounds provided herein optionally exist in unsolvated as well as solvated forms.

The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalia class: humans, non-human primates, such as chimpanzees, and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

As used herein, "treat" or "treating" or "alleviating" or "improving" are used interchangeably. These terms refer to a route by which a beneficial or desired result, including but not limited to a therapeutic benefit and/or a prophylactic benefit, is obtained. By "therapeutic benefit" is meant the elimination or amelioration of the underlying disorder being treated. In addition, therapeutic benefits may also be achieved as follows: one or more physiological symptoms associated with the underlying condition are eradicated or ameliorated such that coloration is observed in the patient, although the patient is still afflicted with the underlying condition. For prophylactic benefit, in some embodiments, the composition is administered to a patient at risk of developing a particular disease, or a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not been made.

RAF kinase family

RAF kinases are a family of serine/threonine protein kinases that constitute the core component of the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling cascade, also known as the MAPK/ERK pathway, which mediates the transmission of signals from cell surface receptors to the nucleus of the cell to regulate cell growth, differentiation and survival. The RAF proteins are associated with retroviral oncogenes and are structurally conserved from metazoan to mammalian, as are the MAPK/ERK pathways. Their deregulation leads to uncontrolled cell proliferation, survival and dedifferentiation. Thus, in most cancers, RAF kinase is altered or inappropriately activated.

The MAPK/ERK signaling pathway is a network of proteins in the cell that transmit signals from receptors on the cell surface to DNA in the nucleus. The signal begins when the signal molecule binds to a receptor on the cell surface, and ends when the DNA in the nucleus expresses the protein and produces some change in the cell, such as cell division. This pathway comprises a number of proteins that are delivered by adding phosphate groups to adjacent proteins, acting as molecular "on" or "off" switches, and in general, can be divided into 3 steps: (I) ras activation, (ii) kinase signaling cascades, and (iii) regulation of translation and transcription. Briefly, an extracellular mitogen or signal molecule binds to a membrane receptor. This allows Ras, a small gtpase, to exchange its GDP for GTP and become active. Activated Ras activates the protein kinase activity of RAF kinase. RAF kinases phosphorylate and activate MEK (MEK1 and MEK 2). MEK then phosphorylates and activates MAPK (also known as ERK). MAPK activation regulates the activity of several transcription factors and also alters translation of mRNA into protein. MAPK leads to altered transcription of genes critical to the cell cycle by altering the levels and activity of transcription factors.

There are three known mammalian RAF isoforms: C-RAF (also known as RAF-1 or C-RAF-1), B-RAF and A-RAF. All RAF kinases share a common modular structure consisting of 3 conserved regions (CR1, CR2 and CR3) with distinct functions. CR1 contains (i) a Ras-binding domain (RBD) necessary for interaction with Ras and membrane phospholipids required for membrane recruitment, and (ii) a cysteine-rich domain (CRD) which is a secondary Ras-binding site, also necessary for CR1 to interact with a kinase domain to achieve RAF autoinhibition. CR2 contains important inhibitory phosphorylation sites that are involved in Ras binding and negative regulation of RAF activation. CR3 is characterized by a kinase domain, including the activation segment, whose phosphorylation is critical for kinase activation.

Functionally, the RAF structure can be divided into a regulatory N-terminal region, which contains the RBD critical for activation and an inhibitory phosphorylation site, and a catalytic C-terminal region, which contains the phosphorylation site necessary for kinase activation. The regulatory domain inhibits the activity of the kinase domain, the removal of which results in constitutive oncogenic activation. However, the activity of the isolated C-RAF kinase domain is further regulated and can be stimulated by phorbol esters, v-Src and phosphorylation.

A common and critical step in the activation of all 3 RAF kinase isoforms is membrane recruitment of Ras family proteins. RAF kinase is localized in the cytosol in an inactive state when bound to 14-3-3 protein. In the presence of active Ras, they translocate to the plasma membrane. Membrane translocation triggers further activation events such as binding of PP2A to dephosphorylate the inhibitory pS259 site in RAF-1 (and possibly the corresponding sites in a-RAF and B-RAF) and co-localization with the kinases responsible for multiple activation phosphorylation. The sequences that form the binding interface are well conserved in the RAF as well as the Ras family, indicating that several members of the Ras family have the ability to bind to RAF kinase. H-Ras, N-Ras and K-Ras stimulate all 3 RAF isoforms and are the only Ras proteins that activate B-RAF. In contrast, A-RAF is also activated by R-Ras3, while C-RAF responds weakly to R-Ras3, Rit and TC 21. However, all RAF kinases share MEK1/2 kinase as a substrate. MEK1/2 in turn activates ERK1/2, a pathway that regulates many cellular functions such as cell proliferation, differentiation, migration or apoptosis.

C-RAF

C-RAF was first identified as a ubiquitously expressed isoform. In humans, C-RAF is encoded by the RAF1 gene. C-RAF also has a known splice variant that is preferentially expressed in muscle and brain. C-RAF plays a key role in mediating the cellular effects of growth factor signaling. In the inactive state, the C-RAF exists in a closed conformation in which the N-terminal regulatory region folds and blocks the catalytic region. This conformation is stabilized by the 14-3-3 dimer binding to the N-terminal site phospho-S259 (pS259) and the C-terminal site pS 621. Dephosphorylation of pS259 by specific phosphatases (PP2A, PP1) at the cell membrane releases 14-3-3 from its N-terminal binding site in C-RAF, allowing a conformational change to occur that uncovers the RBD and CRD domains in the CR1 region, enabling Ras binding and membrane recruitment to occur.

B-RAF

B-RAF is encoded in humans by the BRAF gene, which is also known as the proto-oncogene B-RAF and the v-RAF murine sarcoma virus oncogene homolog B. Alternative splicing produces multiple B-RAF isoforms that are differentially expressed in various tissues. Activation of a-RAF and C-RAF requires phosphorylation and dephosphorylation of certain residues and binding to other proteins, whereas B-RAF is activated immediately after translocation to the plasma membrane. B-RAF exhibits higher basal kinase activity than A-RAF and C-RAF. B-RAF requires binding of Ras and 14-3-3 for activation and is inhibited or activated by PKA, depending on the level of 14-3-3 expression, and high expression levels are required to allow activation. B-RAF activity is also regulated by splicing. The B-RAF isoform containing exon 8B is more phosphorylated at the inhibitory S365 site, resulting in increased interaction with 14-3-3 and potentiating the inhibitory interaction between the N-terminal regulatory domain and the kinase domain, which together results in lower kinase activity.

A-RAF

The serine/threonine-protein kinases A-RAF or A-RAF are in humans enzymes encoded by the ARAF gene. There are 2 known splice isoforms of A-RAF-DA-RAF 1 and D-RAF 2. They lack the kinase domain and act as dominant inhibitory mutants of Ras and ARF gtpases. DA-RAF1 is a positive regulator of myogenic differentiation by mediating inhibition of the ERK pathway required for differentiation. a-RAF differs from other RAF kinases in several ways. a-RAF is the only RAF isoform regulated by steroid hormones. In addition, the a-RAF protein has amino acid substitutions in the negatively charged region upstream of the kinase domain (N-region), which results in its low basal activity. a-RAF is also only weakly activated by oncogenic H-Ras and Src, and also exhibits low kinase activity against MEK (the lowest kinase activity against MEK proteins in the RAF kinase family). In addition to phosphorylation of MEK, a-RAF also inhibits MST2, a tumor suppressor and pro-apoptotic kinase not found in the MAPK pathway. By inhibiting MST2, a-RAF prevented the onset of apoptosis. However, this inhibition occurs only when the splicing factor intranuclear heterogeneous ribonucleoprotein H (hnRNP H) maintains expression of the full-length A-RAF protein. Tumor cells often overexpress hnRNP H, which results in full-length expression of A-Raf, which then inhibits apoptosis, keeping cancer cells alive that should be destroyed. A-RAF also binds to pyruvate kinase M2(PKM2), also outside the MAPK pathway. PKM2 is an isozyme of pyruvate kinase and is responsible for the Warburg effect in cancer cells. a-RAF up-regulates PKM2 activity by promoting conformational changes in PKM 2. This results in the conversion of PKM2 from its less active dimeric form to its more active tetrameric form. This results in the conversion of more of the glucose carbon to pyruvate and lactate, producing energy for the cell, linking a-Raf to the regulation of energy metabolism and cellular transformation, both of which are important in tumorigenesis.

RAF kinase inhibitors

Aberrant activation of the MAPK/ERK pathway is frequently found in various cancers and is a target for cancer therapy. In particular, B-RAF has become one of the most attractive molecular targets in cancer therapy, since somatic mutations of B-RAF are often found in human tumors. About 20% of all cancer samples tested to date carry the B-RAF mutation. B-RAF-V600E is a missense mutation in the kinase domain resulting from the substitution of the 600 th glutamic acid with valine, and is the most common B-RAF mutation. About 1% of the various tumor types tested underwent C-RAF mutation, while the mutation rate of a-RAF was even lower. B-RAF and C-RAF form homo-and heterodimers as part of their activation mechanism, while a-RAF stabilizes the B-RAF: C-RAF complex to maintain signaling efficiency. In addition, C-RAF transmits signals from oncogenic RAS to MEK, whereas B-RAF does not. Thus, in different cases, each RAF isoform serves as a potential therapeutic target.

Sorafenib is the first RAF inhibitor to enter clinical trials. Sorafenib is a broad specificity drug that inhibits other kinases, including the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3), the platelet-derived growth factor receptor family (PDGFR-b and KIT), and FLT 3. Clinical trials showed no correlation between clinical response and B-RAF mutational status, indicating that it is a poor inhibitor of B-RAF. This has led to the development of a new generation of B-RAF inhibitors, including but not limited to vemurafenib (vemurafenib), SB-590885, and dabrafenib (GSK 2118436). Although preliminary results of clinical studies of B-RAF mutant melanoma are encouraging, it is clear that tumors of different cell types carrying the B-RAF mutation respond differently to selective B-RAF inhibition as clinical trials of other B-RAF mutant cancers (such as thyroid and colorectal cancers) begin. Furthermore, the presence of primary and secondary resistance to RAF inhibition is one of the greatest challenges in the progression of RAF kinase inhibitor therapy. Resistance mechanisms fall into two broad categories. Approximately 50% of patients exhibit intrinsic/primary resistance. The other 50% of patients initially respond to RAF inhibitors (> 30% tumor shrinkage), but subsequently develop disease progression associated with acquired/secondary resistance to RAF inhibitors. These two classes are not mutually exclusive, as almost all responders have the remaining disease and therefore may exhibit intrinsic resistance. Determinants of primary RAF inhibitor resistance appear to vary from tumor type to tumor type, and also involve alterations in RTK signaling. Potential mechanisms of secondary B-RAF inhibitor resistance include, but are not limited to, reactivation of the ERK1/2 pathway, upregulation of RTK signaling, upregulation of receptor tyrosine kinases, mutations in RAS, and upregulation of COT. The B-Raf alternative splicing and amplification of B-RAF-V600E also involved about 30% and 20% of patients, respectively. In addition, RAF kinase inhibitors cause abnormal activation of MAPK pathways, which in some cases can lead to the development of malignancies driven by secondary RAS mutations. Thus, there is a need in the art for novel RAF kinase inhibitors that overcome the existing deficiencies and challenges of existing inhibitors.

Heteroaromatic RAF inhibiting compounds

In one aspect, provided herein are heteroaromatic RAF inhibitory compounds.

One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (I):

wherein the content of the first and second substances,

g is C ═ O or SO₂；

R is C1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH)₂- (C1-C8 optionally substituted alkylene) -S (O) NHMe, C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl alkyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH)₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2; or optionally, if q is 2, then two R¹The groups are joined to form a fused ring;

R²h, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxy;

R⁶h, D, Cl or F;

R^cis H or D;

z is selected from:

(a)-NR^aR^bwherein R is^aSelected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; and R is ^bSelected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

(b)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-S-alkyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo;

(c)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl); and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R ¹¹The groups together form oxo;

(d)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; n1 is 0, 1 or 2, provided that both m1 and n1 are not 0; p is 0, 1 or 2; and q is 0, 1 or 2;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(e)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 1 or 2; p is 0, 1, 2 or 3; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹、-CH₂-CH₂-、-CH₂-CHR¹¹-、-CH₂-C(R¹¹)₂-、-CHR¹¹-CH₂-、-C(R¹¹)₂-CH₂-、-NH-CH₂-、-NH-CHR¹¹-、-NH-C(R¹¹)₂-、-CH₂-NH-、-CHR¹¹-NH-、-C(R¹¹)₂-NH-、-N(R¹¹)-CH₂-、-N(R¹¹)-CHR¹¹-、-N(R¹¹)-C(R¹¹)₂-、-CH₂-N(R¹¹)-、-CHR¹¹-N(R¹¹)-、-C(R¹¹)₂-N(R¹¹)-、-O-CH₂-or-CH₂-O-; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R ¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(f)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂；

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(g)wherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3, with the proviso that both m and n are not 0; p is 0, 1, 2, 3 or4; and is

Each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R ¹¹The groups together form oxo;

(h)wherein m is 1, 2 or 3; n is 1, 2 or 3; p is 0, 1 or 2; and is

Each R¹³Or R¹⁴Independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;

(i)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two geminal R¹¹The groups together form oxo.

One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (II):

Wherein the content of the first and second substances,

g is C ═ O or SO₂；

R is C1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH)₂- (C1-C8 optionally substituted alkylene) -S (O) NHMe, C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl alkyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH)₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2; or optionally, if q is 2, then two R¹The groups are joined to form a fused ring;

R²h, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxy;

R⁶h, D, Cl or F;

R^cis H or D;

z is selected from:

(a)-NR^aR^bwherein R is^aSelected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; and R is^bSelected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

(b)Wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-S-alkyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo;

(c)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl); and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(d)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; n1 is 0, 1 or 2, provided that both m1 and n1 are not 0; p is 0, 1 or 2; and q is 0, 1 or 2;

W is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkylOptionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(e)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 1 or 2; p is 0, 1, 2 or 3; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹、-CH₂-CH₂-、-CH₂-CHR¹¹-、-CH₂-C(R¹¹)₂-、-CHR¹¹-CH₂-、-C(R¹¹)₂-CH₂-、-NH-CH₂-、-NH-CHR¹¹-、-NH-C(R¹¹)₂-、-CH₂-NH-、-CHR¹¹-NH-、-C(R¹¹)₂-NH-、-N(R¹¹)-CH₂-、-N(R¹¹)-CHR¹¹-、-N(R¹¹)-C(R¹¹)₂-、-CH₂-N(R¹¹)-、-CHR¹¹-N(R¹¹)-、-C(R¹¹)₂-N(R¹¹)-、-O-CH₂-or-CH₂-O-; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(f)Wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2;

w is O, S, S: (O)、SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂；

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(g)wherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3, with the proviso that both m and n are not 0; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(h)wherein m is 1, 2 or 3; n is 1, 2 or 3; p is 0, 1 or 2; and is

Each R¹³Or R¹⁴Independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkylA group;

(i)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two geminal R¹¹The groups together form oxo.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein G is C ═ O.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R^cIs hydrogen. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R^cIs deuterium.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R²Is hydrogen or deuterium. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R²Is F.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is hydrogen or deuterium. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is F.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-H or C-D. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-F.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is an optionally substituted C1 alkyl group. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is CH₃Q is 1, and R¹Positioned to provide 3-methylmorpholino.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl, C3-C6 optionally substituted cycloalkyl, C4-C6 optionally substituted cycloalkylalkyl, C3-C6 optionally substituted heterocyclyl, or C3-C6 optionally substituted heterocyclylalkyl.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the C1-C8 optionally substituted alkyl is C2 optionally substituted alkyl.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is- (C1-C8 optionally substituted alkylene) -OPO (OH)₂. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein- (C1-C8 optionally substituted alkylene) -OPO (OH)₂Is C2 optionally substituted alkylene.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted cycloalkyl. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C4-C6 optionally substituted cycloalkylalkyl. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is heterocyclyl optionally substituted with C3-C6. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is heterocyclylalkyl optionally substituted with C3-C6.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴Is halogen. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is optionally substituted C1-C3 alkyl. One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is methyl.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is-NR^aR^bWherein R is^aSelected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; and R is^bIs selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R^aIs H. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ^aIs an optionally substituted alkyl group. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R^bIs an optionally substituted alkyl group.

One embodiment provides a compound of formula (I) or (II)Or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹Is optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl is substituted with at least one halogen.

One embodiment provides a compound of formula (I) or (II)(II) the compound, or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl); and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is S. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 2. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹¹Is optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl is substituted with at least one halogen.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; n1 is 0, 1 or 2, with the proviso that m1 and n1Both are not 0; p is 0, 1 or 2; and q is 0, 1 or 2;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0 and n is 2. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 0 and n1 is 2. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1 and n1 is 1. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is O. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH ₂. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CHR¹¹. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is C (R)¹¹)₂. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹¹Is halogen and q is 1.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 1 or 2; p is 0, 1, 2 or 3; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹、-CH₂-CH₂-、-CH₂-CHR¹¹-、-CH₂-C(R¹¹)₂-、-CHR¹¹-CH₂-、-C(R¹¹)₂-CH₂-、-NH-CH₂-、-NH-CHR¹¹-、-NH-C(R¹¹)₂-、-CH₂-NH-、-CHR¹¹-NH-、-C(R¹¹)₂-NH-、-N(R¹¹)-CH₂-、-N(R¹¹)-CHR¹¹-、-N(R¹¹)-C(R¹¹)₂-、-CH₂-N(R¹¹)-、-CHR¹¹-N(R¹¹)-、-C(R¹¹)₂-N(R¹¹) -; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0, n is 1, and m1 is 1; and W is-O-CH ₂-or-CH₂-O-。

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is O. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH₂Or CHR¹¹. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 0. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 0. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0 and n is 1.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3, with the proviso that both m and n are not 0; p is 0, 1, 2, 3 or 4; and each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkylOptionally substituted heterocyclyl or optionally substituted heterocyclylalkyl. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 2. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R ¹¹Attached to the olefin carbon. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein at least one R¹¹Not attached to the olefin carbon. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹¹Is optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 1, 2 or 3; n is 1, 2 or 3; p is 0, 1 or 2; and each R¹³Or R¹⁴Independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl. Another embodiment provides a compound of formula (I) or (II) Or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2 and n is 1. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹³Or R¹⁴One of which is not hydrogen. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹³Or R¹⁴One is optionally substituted C1-C6 alkyl. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹³Is optionally substituted C1-C6 alkyl. In another embodiment, there is provided a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹⁴Is optionally substituted C1-C6 alkyl.

One embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO ₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two geminal R¹¹The groups together form oxo. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides a compound of formula (I) or (II),or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2 and n is 1. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1 or 2. Another embodiment provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0 or 1 and q is 0 or 1.

One embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ia):

Wherein the content of the first and second substances,

g is C ═ O or SO₂；

R is C1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH)₂C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl alkyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH)₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2;

R²h, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxy;

R⁶h, D, Cl or F;

R^cis H or D;

z is selected from:

(a)-NR^aR^bwherein R is^aSelected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkylOptionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; and R is^bSelected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

(b)Wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo;

(c)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl); and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(d)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; n1 is 0, 1 or 2, provided that both m1 and n1 are not 0; p is 0, 1 or 2; and q is 0, 1 or 2;

W is O, S, S (O),SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(e)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 1 or 2; p is 0, 1, 2 or 3; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹、-CH₂-CH₂-、-CH₂-CHR¹¹-、-CH₂-C(R¹¹)₂-、-CHR¹¹-CH₂-、-C(R¹¹)₂-CH₂-、-NH-CH₂-、-NH-CHR¹¹-、-NH-C(R¹¹)₂-、-CH₂-NH-、-CHR¹¹-NH-、-C(R¹¹)₂-NH-、-N(R¹¹)-CH₂-、-N(R¹¹)-CHR¹¹-、-N(R¹¹)-C(R¹¹)₂-、-CH₂-N(R¹¹)-、-CHR¹¹-N(R¹¹)-、-C(R¹¹)₂-N(R¹¹) -; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(f)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2;

W is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂；

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(g)wherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3, with the proviso that both m and n are not 0; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(h)wherein m is 1, 2 or 3; n is 1, 2 or 3; p is 0, 1 or 2; and is

Each R¹³Or R¹⁴Independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; each R ¹¹Independently selected from-OHHalogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or

(i)Wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two geminal R¹¹The groups together form oxo.

One embodiment provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIa):

wherein the content of the first and second substances,

g is C ═ O or SO₂；

R is C1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH) ₂C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl alkyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH)₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2;

R²h, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxy;

R⁶h, D, Cl or F;

R^cis H or D;

z is selected from:

(a)-NR^aR^bwherein R is^aSelected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; and R is^bSelected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl;

(b)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo;

(c)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; w is O, S, S (O), SO2, NH or N (optionally substituted C1-C6 alkyl); and is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(d)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; n1 is 0, 1 or 2, provided that both m1 and n1 are not 0; p is 0, 1 or 2; and q is 0, 1 or 2;

w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH ₂、CHR¹¹Or C (R)¹¹)₂(ii) a And is

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(e)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 1 or 2; p is 0, 1, 2 or 3; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹、-CH₂-CH₂-、-CH₂-CHR¹¹-、-CH₂-C(R¹¹)₂-、-CHR¹¹-CH₂-、-C(R¹¹)₂-CH₂-、-NH-CH₂-、-NH-CHR¹¹-、-NH-C(R¹¹)₂-、-CH₂-NH-、-CHR¹¹-NH-、-C(R¹¹)₂-NH-、-N(R¹¹)-CH₂-、-N(R¹¹)-CHR¹¹-、-N(R¹¹)-C(R¹¹)₂-、-CH₂-N(R¹¹)-、-CHR¹¹-N(R¹¹)-、-C(R¹¹)₂-N(R¹¹) -; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(f)wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2;

W is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂；

Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl;

(g)wherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3, with the proviso that both m and n are not 0; p is 0, 1, 2, 3 or 4; and is

Each R¹¹Independently selected from-OH, a,Halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo;

(h)wherein m is 1, 2 or 3; n is 1, 2 or 3; p is 0, 1 or 2; and is

Each R¹³Or R¹⁴Independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; each R ¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or

(i)Wherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two geminal R¹¹The groups together form oxo.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein G is C ═ O.

In one embodimentCompounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided, wherein R ^cIs hydrogen. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R^cIs deuterium.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is²Is hydrogen or deuterium. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is²Is F.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is⁶Is hydrogen or deuterium. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is⁶Is F.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-H or C-D. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-F.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is ¹Is an optionally substituted C1 alkyl group. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is¹Is CH₃Q is 1, and R¹Positioned to provide 3-methylmorpholino.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl, C3-C6 optionally substituted cycloalkyl, C4-C6 optionally substituted cycloalkylalkyl, C3-C6 optionally substituted heterocyclyl, or C3-C6 optionally substituted heterocyclylalkyl.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein the C1-C8 optionally substituted alkyl is C2 optionally substituted alkyl.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is- (C1-C8 optionally substituted alkylene) -OPO (OH)₂. In another embodiment, there is provided a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein- (C1-C8 optionally substituted alkylene) -OPO (OH)₂Is C2 optionally substituted alkylene.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted cycloalkyl. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C4-C6 optionally substituted cycloalkylalkyl. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted heterocyclyl. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C3-C6 optionally substituted heterocyclylalkyl.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is ⁴Is halogen. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is⁴Is optionally substituted C1-C3 alkyl. One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R is⁴Is methyl.

One embodiment provides a compound of formula (Ia) or (IIa), orA pharmaceutically acceptable salt or solvate thereof, wherein Z is-NR^aR^bWherein R is^aSelected from H, optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; and R is^bIs selected from optionally substituted alkyl, optionally substituted C3-C6 alkenyl, optionally substituted C3-C6 alkynyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted C4-C6 heterocyclyl or optionally substituted heterocyclylalkyl. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R^aIs H. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R ^aIs an optionally substituted alkyl group. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R^bIs an optionally substituted alkyl group.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. In another embodiment, there is provided a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt thereofAn acceptable salt or solvate, wherein m is 2. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R ¹¹Is optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl is substituted with at least one halogen.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl); and each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein W is O. In another embodiment, there is provided a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt thereof Or a solvate, wherein W is S. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 2. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R¹¹Is optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein the optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl is substituted with at least one halogen.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; n1 is 0, 1 or 2, provided that both m1 and n1 are not 0; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO ₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0 and n is 2. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 0 and n1 is 2.Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1 and n1 is 1. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein W is O. In another embodiment, there is provided a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH₂. In another embodiment, there is provided a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CHR ¹¹. In another embodiment, there is provided a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein W is C (R)¹¹)₂. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R¹¹Is halogen and q is 1.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 1 or 2; p is 0, 1, 2 or 3; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹、-CH₂-CH₂-、-CH₂-CHR¹¹-、-CH₂-C(R¹¹)₂-、-CHR¹¹-CH₂-、-C(R¹¹)₂-CH₂-、-NH-CH₂-、-NH-CHR¹¹-、-NH-C(R¹¹)₂-、-CH₂-NH-、-CHR¹¹-NH-、-C(R¹¹)₂-NH-、-N(R¹¹)-CH₂-、-N(R¹¹)-CHR¹¹-、-N(R¹¹)-C(R¹¹)₂-、-CH₂-N(R¹¹)-、-CHR¹¹-N(R¹¹)-、-C(R¹¹)₂-N(R¹¹) -; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl,Optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0, n is 1, and m1 is 1; and W is-O-CH ₂-or-CH₂-O-。

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a Each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two R¹¹The groups together form oxo; and R is¹²And R¹³Each independently selected from H or optionally substituted C1-C6 alkyl. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein W is O. In another embodiment, there is provided a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH₂Or CHR¹¹. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 0. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1. Another embodiment provides Compounds of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, are described wherein m is 1 and n is 1. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 0. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0 and n is 1.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1, 2 or 3; n is 0, 1, 2 or 3, with the proviso that both m and n are not 0; p is 0, 1, 2, 3 or 4; and each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 1. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 2. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein at least one R ¹¹Attached to the olefin carbon. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein at least one R¹¹Not attached to the olefin carbon. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R¹¹Is optionally substitutedC1-C6 alkyl or optionally substituted C3-C6 cycloalkyl. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

In another embodiment, there is provided a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 1, 2 or 3; n is 1, 2 or 3; p is 0, 1 or 2; and each R¹³Or R¹⁴Independently selected from hydrogen, halogen, -CN, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl; each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2 and n is 1. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R ¹³Or R¹⁴One of which is not hydrogen. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R¹³Or R¹⁴One is optionally substituted C1-C6 alkyl. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R¹³Is optionally substituted C1-C6 alkyl. In another embodiment, compounds of formula (Ia) or (IIa), or pharmaceutically acceptable salts or solvates thereof, are provided wherein R¹⁴Is optionally substituted C1-C6 alkyl.

One embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z isWherein m is 0, 1 or 2; n is 0, 1 or 2; m1 is 0, 1 or 2; p is 0, 1 or 2; and q is 0, 1 or 2; w is O, S, S (O), SO₂NH or N (optionally substituted C1-C6 alkyl), CH₂、CHR¹¹Or C (R)¹¹)₂(ii) a And each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, or two geminal R ¹¹The groups together form oxo. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2 and n is 1. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1 or 2. Another embodiment provides a compound of formula (Ia) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0 or 1 and q is 0 or 1.

One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (III):

wherein the content of the first and second substances,

g is C ═ O or SO₂；

R is C1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH)₂C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl alkyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH) ₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2;

R²h, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxy;

R⁶h, D, Cl or F;

R^cis H or D;

z is selected from:

(a)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and W is O, NH or N (optionally substituted C1-C6 alkyl); each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-S-alkyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo;

(b)wherein m is 1, 2 or 3; n is 1, 2 or 3; m1 is 0, 1, 2 or 3; p is 0, 1 or 2; q is 0, 1 or 2; each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted Heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo; and each R¹²Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹²The groups together form oxo.

One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IV):

wherein the content of the first and second substances,

g is C ═ O or SO₂；

R is C1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH)₂C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl alkyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH)₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2;

R²H, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxy;

R⁶h, D, Cl or F;

R^cis H or D;

z is selected from:

(a)wherein m is 0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; and W is O, NH or N (optionally substituted C1-C6 alkyl); each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-S-alkyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo;

(b)wherein m is 1, 2 or 3; n is 1, 2 or 3; m1 is 0, 1, 2 or 3; p is 0, 1 or 2; q is 0, 1 or 2; each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R ¹¹The groups together form oxo; and each R¹²Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹²The groups together form oxo.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein G is C ═ O.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R^cIs hydrogen. In another embodiment, there is provided a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R^cIs deuterium.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R²Is hydrogen or deuterium. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R²Is F.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁶Is hydrogen or deuterium. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is F.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-H or C-D. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-F.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is an optionally substituted C1 alkyl group. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is CH₃Q is 1, and R¹Positioned to provide 3-methylmorpholino.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl, C3-C6 optionally substituted cycloalkyl, C4-C6 optionally substituted cycloalkylalkyl, C3-C6 optionally substituted heterocyclyl, or C3-C6 optionally substituted heterocyclylalkyl.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the C1-C8 optionally substituted alkyl is C2 optionally substituted alkyl.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is- (C1-C8 optionally substituted alkylene) -OPO (OH)₂. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein- (C1-C8 optionally substituted alkylene) -OPO (OH)₂Is C2 optionally substituted alkylene.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is cycloalkyl optionally substituted with C3-C6. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C4-C6 optionally substituted cycloalkylalkyl. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is heterocyclyl optionally substituted with C3-C6. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R is heterocyclylalkyl optionally substituted with C3-C6.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is halogen. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is optionally substituted C1-C3 alkyl. One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is methyl.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is

Wherein m is 0, 1, 2 or 3; p is 0, 1,2. 3 or 4; and W is O, NH or N (optionally substituted C1-C6 alkyl); each R¹¹Independently selected from amino, alkylamino, dialkylamino, -OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-S-alkyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 or 2. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein W is O. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein W is NH. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein W is N (optionally substituted C1-C6 alkyl). Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In another embodiment, there is provided a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein two R ¹¹The groups together form oxo.

One embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is

Wherein m is 1, 2 or 3; n is 1, 2 or 3; m1 is 0, 1, 2 or 3; p is 0, 1 or 2; q is 0, 1 or 2; each R¹¹Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substitutedC1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹¹The groups together form oxo; and each R¹²Independently selected from-OH, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkynyl, optionally substituted-SO₂Alkyl, optionally substituted C3-C6 cycloalkylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl; or two R¹²The groups together form oxo. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1 and n is 2. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 0, 1, or 2. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1, n is 2, and m1 is 0, 1, or 2. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1, n is 2, and m1 is 0. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0 or 1. Another embodiment provides a compound of formula (III) or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0 or 1.

One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (V):

wherein the content of the first and second substances,

g is C ═ O or SO₂；

R is C1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH)₂C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂、C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH)₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2;

R²h, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxy;

R⁶h, D, Cl or F;

R^cis H or D;

z is optionally substituted N-linked pyrrole, optionally substituted-NH-pyrazole or optionally substituted-N (optionally substituted C1-C6 alkyl) -pyrazole.

One embodiment provides a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (VI):

wherein the content of the first and second substances,

g is C ═ O or SO ₂；

R is C1-C8 optionally substituted alkyl, - (C1-C8 optionally substituted alkylene) -OPO (OH)₂C3-C6 optionally substituted cycloalkyl, - (C3-C6 optionally substituted cycloalkylene) -OPO (OH)₂C4-C6 optionally substituted cycloalkylalkyl, - (C3-C6 optionally substituted cycloalkylidenyl alkyl) -OPO (OH)₂C3-C6 optionally substituted heterocyclyl, - (C3-C6 optionally substituted heterocyclyl) -OPO (OH)₂Heterocyclylalkyl optionally substituted with C3-C6, - (C3-C6 optionally substituted heterocyclylalkyl) -OPO (OH)₂；

X is N, C-H, C-D, C-F or C-CH₃；

R¹Is C1-C3 optionally substituted alkyl, and q is 0, 1 or 2;

R²h, D or F;

R⁴is halogen, optionally substituted C1-C3 alkyl, -CD₃Or optionally substituted C1-C3 alkoxy;

R⁶h, D, Cl or F;

R^cis H or D;

z is optionally substituted N-linked pyrrole, optionally substituted-NH-pyrazole or optionally substituted-N (optionally substituted C1-C6 alkyl) -pyrazole.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein G is C ═ O.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R^cIs hydrogen. In another embodiment, there is provided a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R is ^cIs deuterium.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R²Is hydrogen or deuterium. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R²Is F.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is hydrogen or deuterium. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁶Is F.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-H or C-D. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C-F.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R¹Is an optionally substituted C1 alkyl group. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹Is CH₃Q is 1, and R¹Positioned to provide 3-methylmorpholino.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl, C3-C6 optionally substituted cycloalkyl, C4-C6 optionally substituted cycloalkylalkyl, C3-C6 optionally substituted heterocyclyl, or C3-C6 optionally substituted heterocyclylalkyl.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C1-C8 optionally substituted alkyl. Another embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein the C1-C8 optionally substituted alkyl is C2 optionally substituted alkyl.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R is- (C1-C8 optionally substituted alkylene) -OPO (OH)₂. In another embodiment, there is provided a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein said- (C1-C8 optionally substituted alkylene) -OPO (OH)₂Is C2 optionally substituted alkylene.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R is cycloalkyl optionally substituted with C3-C6. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C4-C6 optionally substituted cycloalkylalkyl. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R is heterocyclyl optionally substituted with C3-C6. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R is heterocyclylalkyl optionally substituted with C3-C6.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is halogen. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is optionally substituted C1-C3 alkyl. One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R⁴Is methyl.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is an optionally substituted N-linked pyrrole.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is optionally substituted-NH-pyrazole.

One embodiment provides a compound of formula (V) or (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is optionally substituted-N (optionally substituted C1-C6 alkyl) -pyrazole.

In some embodiments, a heteroaromatic RAF kinase inhibitory compound as described herein has the structure provided in table 1.

TABLE 1

In some embodiments, a heteroaromatic RAF kinase inhibitory compound as described herein has the structure provided below.

Preparation of the Compounds

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "commercially available Chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and Fluka), Apin Chemical Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemserace Inc. (West Chemicals, PA), Scent Chemical Co., Haupage, NY), EastOrganic Chemical, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co., Pittsburgh, Pironshi, Parkinshi Chemical, Australine Chemical Co., Inc, Chemical Co., Inc., mineral Co., Inc, Chemical Co., Inc, mineral Co., Inc, Chemical Co., Inc, mineral Co., R, mineral Co., Inc, mineral Co., R, mineral Co., R, mineral, germany), Spectrum Quality Product, Inc (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc (Rockville, MD), and Wako Chemicals USA, Inc.

Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide reference to articles describing the preparation include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, inc., New York; sandler et al, "Organic Functional Group Preparations," 2 nd edition, Academic Press, New York, 1983; h.o. house, "Modern Synthetic Reactions", 2 nd edition, w.a. benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2 nd edition, John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: Reactions, mechanics and Structure", 4 th edition, Wiley-Interscience, New York, 1992. Other suitable reference books and treatises that detail the Synthesis of reactants useful in the preparation of the compounds described herein or provide reference to articles describing the preparation include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: conjugates, Methods, Starting Materials", Second Revised Edition (Second, Revised and Enlarged Edition) (1994) John Wiley & Sons ISBN: 3-527-; hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2 nd edition (1999) Wiley-VCH, ISBN: 0-471-; march, J. "Advanced Organic Chemistry: Reactions, mechanics, and Structure" 4 th edition (1992) John Wiley & Sons, ISBN: 0-471-; otera, J. (eds) "Modern carbon Chemistry" (2000) Wiley-VCH, ISBN: 3-527-; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-; solomons, T.W.G. "Organic Chemistry", 7 th edition (2000) John Wiley & Sons, ISBN: 0-471-; stowell, J.C., "Intermediate Organic Chemistry" 2 nd edition (1993) Wiley-Interscience, ISBN: 0-471-; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-; "Organic Reactions" (1942-2000) John Wiley & Sons, more than volume 55; and "Chemistry of Functional Groups" John Wiley & Sons, volume 73.

Specific and similar reactants are optionally identified by known Chemical indexes compiled by the Chemical abstracts Service of the American Chemical Society, which is available from most public libraries and college libraries and through online databases (contacting the American Chemical Society, Washington, d.c. for more details). Known but not commercially available chemicals in the catalog are optionally prepared by custom chemical synthesis rooms (houses) where many standard chemical supply rooms (e.g., those listed above) provide custom synthesis services. References useful for the preparation and selection of pharmaceutically acceptable Salts of the compounds described herein are p.h.stahl and c.g.wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical composition

In certain embodiments, the heteroaromatic RAF kinase inhibitory compounds described herein are administered as pure chemicals. In other embodiments, The heteroaromatic RAF kinase inhibitory compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also herein a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on The chosen route of administration and standard pharmaceutical Practice, for example, as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21 st edition. Mack pub.co., Easton, PA (2005)).

Provided herein is a pharmaceutical composition comprising at least one heteroaromatic RAF kinase inhibitory compound described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, and one or more pharmaceutically acceptable carriers. The carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject or patient) of the composition.

One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formulae (I) - (VI) or a pharmaceutically acceptable salt or solvate thereof.

One embodiment provides a process for preparing a pharmaceutical composition comprising admixing a compound of formulae (I) - (VI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, the heteroaromatic RAF kinase inhibitory compounds described by formulas (I) - (VI) or pharmaceutically acceptable salts or solvates thereof are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products, e.g., produced in one or more steps of the synthetic process.

Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that readily dissolves in the digestive tract. In some embodiments, suitable non-toxic solid carriers are used, including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (see, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 st edition. Mack pub. Co., Easton, PA (2005)).

In some embodiments, the heteroaromatic RAF kinase inhibitory compounds described by formulas (I) - (VI) or a pharmaceutically acceptable salt or solvate thereof are formulated for administration by injection. In some cases, the injectable formulation is an aqueous formulation. In some cases, the injectable formulation is a non-aqueous formulation. In some cases, the injectable formulation is a formulation based on an oil such as sesame oil.

The dosage of a composition comprising at least one heteroaromatic RAF kinase inhibitory compound described herein varies depending on the condition of the subject or patient (e.g., human). In some embodiments, such factors include overall health, age, and other factors.

The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage and the appropriate duration and frequency of administration will depend upon factors such as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient and the method of administration. Generally, the appropriate dosage and treatment regimen provide the composition in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., improved clinical outcome, such as more frequent complete or partial remission, or longer disease-free and/or overall survival, or reduction in severity of symptoms). The optimal dosage is typically determined using experimental models and/or clinical trials. The optimal dosage depends on the body mass, body weight or blood volume of the patient.

Oral dosages typically range from about 1.0mg to about 1000mg, one to four or more times per day.

Method of treatment

One embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

One embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or a neoplastic disease.

One embodiment provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

One embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

One embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or a neoplastic disease.

One embodiment provides the use of a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

One embodiment provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

One embodiment provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or a neoplastic disease.

One embodiment provides the use of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

One embodiment provides a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

One embodiment provides a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or a neoplastic disease.

One embodiment provides the use of a compound of formula (IIa) or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (IIa) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

One embodiment provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

One embodiment provides a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or a neoplastic disease.

One embodiment provides the use of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

One embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

One embodiment provides a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or a neoplastic disease.

One embodiment provides the use of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

One embodiment provides a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

One embodiment provides a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or a neoplastic disease.

One embodiment provides the use of a compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (V), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (V) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

One embodiment provides a compound of formula (VI), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treatment of the human or animal body.

One embodiment provides a compound of formula (VI), or a pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer or a neoplastic disease.

One embodiment provides the use of a compound of formula (VI) or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer or a neoplastic disease.

In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (VI), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of formula (VI) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the cancer is breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, or lung cancer.

Provided herein are the methods wherein the pharmaceutical compositions are administered orally. Provided herein are the methods wherein the pharmaceutical compositions are administered by injection.

Other embodiments and uses will be apparent to those skilled in the art in light of this disclosure. The following examples are provided merely to illustrate various embodiments and should not be construed as limiting the invention in any way.

Examples

I. Chemical synthesis

In some embodiments, the heteroaromatic RAF kinase inhibitory compounds disclosed herein are synthesized according to the following examples. As used throughout the specification of the present invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

DEG C

δ_HChemical shift from tetramethylsilane to low field (downfield), parts per million

DCM dichloromethane (CH)₂Cl₂)

DMF dimethyl formamide

DMSO dimethyl sulfoxide

EA Ethyl acetate

ESI electrospray ionization

Et Ethyl group

G gram

h hours

HPLC high performance liquid chromatography

Hz

J coupling constant (in NMR spectroscopy)

LCMS liquid chromatography mass spectrometry

Medicine for treating diseases and symptoms

m multiple peaks (spectra); rice; hao-mi

M mol

M⁺Parent molecule ion

Me methyl group

Mhz megahertz

min for

mol; molecule (e.g. in mol wt)

mL of

MS mass spectrometry

nm nanometer

NMR nuclear magnetic resonance

pH value; measurement of acidity or alkalinity of aqueous solutions

PE Petroleum Ether

RT Room temperature

s singlet (Spectrum)

t triplet (spectrum)

T temperature

TFA trifluoroacetic acid

THF tetrahydrofuran

Intermediate 1: 2-fluoro-4-methyl-5- (5-morpholino-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) Pyridin-3-yl) Aniline

Step 1: 4- (5-bromo-2-fluoropyridin-3-yl) morpholine

To a solution of 5-bromo-2-fluoropyridin-3-amine (6.00g, 31.41mmol) in DMF (60.00mL) at 0 deg.C was added NaH (3.77g, 94.24mmol, 60%). The reaction mixture was stirred for 15 min. To the above mixture was added 1-bromo-2- (2-bromoethoxy) ethane (10.93g, 47.12 mmol). The reaction mixture was heated to 85 ℃ and stirred for 0.5 h. The resulting mixture was poured into water (250 mL). The resulting precipitate was collected by vacuum filtration. The filter cake was rinsed twice with water and heptane. The solid was dried under high vacuum to give 4- (5-bromo-2-fluoropyridin-3-yl) morpholine as a yellow solid (5.6g, 68%). For C ₉H₁₀FBrN₂O[M+H]⁺MS ESI of (a) calculated 261.00, 262.99, found 261.05,263.00.¹H-NMR(400MHz,d₆-DMSO)δ7.86(d,J＝2.0Hz,1H),7.64(dd,J＝9.2,2.4Hz,1H),3.82-3.64(m,4H),3.10-3.05(m,4H)。

Step 2: 4- [ 5-bromo-2- [2- (tetrahydropyran-2-yloxy) ethoxy]Pyridin-3-yl]Morpholine

To a solution of 2- (tetrahydropyran-2-yloxy) ethanol (4.62g, 31.60mmol) in 1, 4-dioxane (60.00mL) was added NaH (1.26g, 31.60mmol, 60%) at 0 ℃. The reaction mixture was stirred at room temperature for 20 min. To the above mixture was added 4- (5-bromo-2-fluoropyridin-3-yl) morpholine (1.65g, 6.32mmol) and the reaction mixture was heated to 105 ℃ and stirred for 3 h. The resulting mixture was cooled to room temperature and quenched with water (30mL)And (6) extinguishing. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (2 × 10mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (EtOAc: EtOH ═ 3:1)/PE (10-50%). The fractions containing the desired product were combined and concentrated to give 4- [ 5-bromo-2- [2- (tetrahydropyran-2-yloxy) ethoxy ] ethanol as a yellow oil]Pyridin-3-yl]Morpholine (1.8g, 73%). For C₁₆H₂₃BrN₂O₂[M+H]⁺MS ESI calculated values 387.08, 389.08; found 387.10,389.10.¹H-NMR(400MHz,d₆-DMSO)δ7.82(d,J＝2.0Hz,1H),7.29(d,J＝2.4Hz,1H),4.65(d,J＝3.6Hz,1H),4.48-4.28(m,2H),3.93-3.90(m,1H),3.78-3.65(m,6H),3.47-3.42(m,1H),3.09-3.03(m,4H),1.64-1.60(m,2H),1.49-1.45(m,4H)。

And step 3: 2-fluoro-4-methyl-5- [5- (morpholin-4-yl) -6- [2- (tetrahydropyran-2-yloxy) ethoxy ]Pyridine (II) Pyridin-3-yl]Aniline

To 4- [ 5-bromo-2- [2- (tetrahydropyran-2-yloxy) ethoxy]Pyridin-3-yl]Morpholine (550.00mg, 1.42mmol) and 2-fluoro-4-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (534.93mg, 2.13mmol) in 1, 4-dioxane (0.5mL) and H₂To a solution in O (0.1mL) was added Na₂CO₃(301.05mg, 2.84mmol) and 1, 1-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (463.91mg, 0.57 mmol). The reaction mixture was degassed three times with nitrogen and stirred at 80 ℃ for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH (1-10%) in DCM. The fractions containing the desired product were combined and concentrated to give 2-fluoro-4-methyl-5- [5- (morpholin-4-yl) -6- [2- (tetrahydropyran-2-yloxy) ethoxy ] ethoxy as a yellow solid]Pyridin-3-yl]Aniline (580mg, 95%). For C₂₃H₃₀FN₃O₄[M+H]⁺Calculated MS ESI of 432.22; found 432.30.¹H-NMR(400MHz,d₆-DMSO)δ7.63(d,J＝2.0Hz,1H),7.05(d,J＝2.0Hz,1H),6.93(d,J＝12.4Hz,1H),6.65(d,J＝9.6Hz,1H),4.96(s,2H),4.48-4.44(m,2H),3.92(s,1H),3.82-3.68(m,6H),3.50-3.46(m,1H),3.10-3.06(m,4H),2.08(s,3H),1.73-1.58(m,2H),1.57-1.45(m,5H)。

Intermediate 2: 2-fluoro-4-methyl-5- (5-morpholino-6- ((tetrahydro-2H-pyran-4-yl) oxy) pyridin-3-yl) Aniline

Step 1: 4- [ 5-bromo-2- (tetrahydropyran-4-yloxy) pyridin-3-yl]Morpholine

To a solution of tetrahydropyran-4-ol (1.96g, 19.15mmol) in dioxane (40.0mL) at 0 deg.C was added NaH (0.77g, 19.15mmol, 60%). The reaction mixture was stirred at 0 ℃ for 30 min. To the above mixture was added 4- (5-bromo-2-fluoropyridin-3-yl) morpholine (1.00g, 3.83mmol) and the reaction mixture was allowed to warm to 105 ℃ and stirred for 2 h. The resulting mixture was quenched with water (100mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20-50% EtOAc/PE. The fractions containing the desired product were combined and concentrated to give 4- [ 5-bromo-2- (tetrahydropyran-4-yloxy) pyridin-3-yl as an off-white solid]Morpholine (0.95g, 72%). For C₁₄H₁₉BrN₂O₃[M+H]⁺MS ESI of (a) calculated 343.06, 345.06, found 343.05,345.05.¹H-NMR(300MHz,d6-DMSO)δ7.83(d,J＝2.1Hz,1H),7.30(d,J＝2.1Hz,1H),5.24(t,J＝8.1Hz,1H),3.90-3.68(m,6H),3.58-3.51(m,2H),3.14-2.96(m,4H),2.02-1.97(m,2H),1.72-1.62(m,2H)。

Step 2: 2-fluoro-4-methyl-5- [5- (morpholin-4-yl) -6- (tetrahydropyran-4-yloxy) pyridin-3-yl]Benzene and its derivatives Amines as pesticides

To 4- [ 5-bromo-2- (tetrahydropyran-4-yloxy) pyridin-3-yl]Morpholine (940.00mg, 2.74mmol) and 2-fluoro-4-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (894.05mg, 3.56mmol) in dioxane (15.00mL) and H₂To a solution in O (3.00mL) was added Na₂CO₃(580.55mg, 5.48mmol) and 1, 1-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (223.66mg, 0.27 mmol). The reaction mixture was degassed three times with nitrogen and stirred at 80 ℃ for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH₂Cl₂0-10% MeOH in (E). The fractions containing the desired product were combined and concentrated to give 2-fluoro-4-methyl-5- [5- (morpholin-4-yl) -6- (tetrahydropyran-4-yloxy) pyridin-3-yl as an off-white solid ]Aniline (0.86g, 81%). For C₂₁H₂₆FN₃O₃[M+H]⁺Calculated MS ESI of 388.20; found 388.20.¹H-NMR(400MHz,d6-DMSO)δ7.62(d,J＝2.0Hz,1H),7.04(d,J＝2.0Hz,1H),6.91(d,J＝12.4Hz,1H),6.63(d,J＝9.2Hz,1H),5.31-5.30(m,1H),4.96(brs,2H),3.89-3.79(m,2H),3.75-3.73(m,4H),3.58-3.53(m,2H),3.07-3.05(m,4H),2.11-1.95(m,5H),1.72-1.65(m,2H)。

Intermediate 3: 4-methyl-3- (5-morpholino-6- ((tetrahydro-2H-pyran-4-yl) oxy) pyridin-3-yl) aniline

The title compound was prepared using a procedure analogous to that described for intermediate 2, substituting 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline for 2-fluoro-4-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline to give the title compound as a solid.

Intermediate 4: 2-fluoro-4-methyl-5- (2-morpholino-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) Pyridin-4-yl) anilines

Step 1: 4- (6-fluoro-4-iodopyridin-2-yl) morpholine

To a stirred solution of 2, 6-difluoro-4-iodopyridine (16.00g, 66.40mmol) in DMSO (240.00mL) was added morpholine (5.49mL, 63.04mmol) and DIEA (12.07mL, 93.40mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 70 ℃ for 3 h. The resulting mixture was diluted with water (150mL) and extracted with EA (3 × 300 mL). The combined organic layers were washed with brine (4 × 100mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 30% EA in PE. Fractions containing the desired product were combined and concentrated to give 4- (6-fluoro-4-iodopyridin-2-yl) morpholine as an off-white solid (17.6g, 86%). For C ₉H₁₀FIN₂O[M+H]⁺MS ESI of 308.98, found 309.10. H-NMR (300MHz, CDCl)₃)δ6.77-6.76(m,1H),6.60-6.59(m,1H),3.78(t,J＝4.8Hz,4H),3.49(t,J＝5.0Hz,4H)。

Step 2: 4- [ 4-iodo-6- [2- (tetrahydropyran-2-yloxy) ethoxy]Pyridin-2-yl]Morpholine

At 0 ℃ and nitrogenTo a stirred solution of 4- (6-fluoro-4-iodopyridin-2-yl) morpholine (5.00g, 16.23mmol) and 2- (tetrahydropyran-2-yloxy) ethanol (9.49g, 64.92mmol) in dioxane (100mL) under atmosphere was added NaH (2.60g, 64.92mmol, 60%) in portions. The reaction mixture was stirred at 100 ℃ for 1 h. The resulting mixture was quenched with water (500mL) at 0 ℃ and extracted with EA (3 × 300 mL). The combined organic layers were washed with brine (3 × 200mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 30% EA in PE. The fractions containing the desired product were combined and concentrated to give 4- [ 4-iodo-6- [2- (tetrahydropyran-2-yloxy) ethoxy ] ethanol as a yellow oil]Pyridin-2-yl]Morpholine (5.85g, 83%). For C₁₆H₂₃IN₂O₄[M+H]⁺MS ESI of 434.07, found 435.10. H-NMR (400MHz, CDCl)₃)δ6.56(s,1H),6.50(s,1H),4.67(t,J＝3.6Hz,1H),4.50-4.36(m,2H),4.03-3.98(m,1H),3.91-3.85(m,1H),3.80-3.70(m,5H),3.53-3.49(m,1H),3.45(t,J＝4.9Hz,4H),1.87-1.51(m,6H)。

And step 3: 2-fluoro-4-methyl-5- [2- (morpholin-4-yl) -6- [2- (tetrahydropyran-2-yloxy) ethoxy]Pyridine (II) Pyridin-4-yl]Aniline

To 4- [ 4-iodo-6- [2- (tetrahydropyran-2-yloxy) ethoxy ]Pyridin-2-yl]Morpholine (5.75g, 13.24mmol) and a solution of 2-fluoro-4-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (3.66g, 14.56mmol) in dioxane (170mL) and water (40mL) were added Na₂CO₃(4.21g, 39.72mmol) and 1, 1-bis (diphenylphosphino) ferrocene-palladium (II) dichloride dichloromethane complex (1.08g, 1.32 mmol). The reaction mixture was degassed three times with nitrogen and stirred at 80 ℃ for 1 h. The resulting mixture was diluted with water (100mL) and extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (3 × 100mL) and dried over anhydrous Na₂SO₄Dried and filtered. Decompressing the filtrateAnd (5) concentrating. The residue was purified by silica gel column chromatography eluting with 0-40% EA in PE. The fractions containing the desired product were combined and concentrated to give 2-fluoro-4-methyl-5- [2- (morpholin-4-yl) -6- [2- (tetrahydropyran-2-yloxy) ethoxy as a yellow oil]Pyridin-4-yl]Aniline (4.4g, 77%). For C₂₃H₃₀FN₃O₄[M+H]⁺Calculated MS ESI of 432.22; found 432.25. H-NMR (300MHz, CDCl)₃)δ6.87(d,J＝11.7Hz,1H),6.65(d,J＝9.0Hz,1H),6.11-6.07(m,2H),4.70(t,J＝3.6Hz,1H),4.54-4.41(m,2H),4.11-4.02(m,1H),3.94-3.77(m,6H),3.54-3.47(m,5H),2.14(s,3H),1.89-1.43(m,6H)。

Intermediate 5: 4-methyl-3- (2-morpholino-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) pyridine- 4-yl) anilines

Using a procedure analogous to that described for intermediate 4, the title compound was prepared from 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline and 4- (4-iodo-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) pyridin-2-yl) morpholine to give the title compound as an oil.

Intermediate 6: 2-fluoro-4-methyl-5- (2- ((R) -3-methylmorpholino) -6- (2- ((tetrahydro-2H-pyran-2-yl) Oxy) ethoxy) pyridin-4-yl) aniline

The title compound was prepared using a procedure similar to that described for intermediate 4, substituting morpholine with (R) -3-methylmorpholine to give the title compound as a solid.

Intermediate 7: 3- (2- [ [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl)]Methoxy radical]-6- (morpholine-4-) Yl) pyridin-4-yl) -4-methylaniline

The title compound was prepared using a procedure similar to that described for intermediate 4, substituting [ (4S) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methanol for 2- (tetrahydropyran-2-yloxy) ethanol to give the title compound as a solid.

Intermediate 8: 3- (2- [ [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl)]Methoxy radical]-6- (morpholine-4-) Yl) pyridin-4-yl) -4-methylaniline

The title compound was prepared using a procedure similar to that described for intermediate 4, substituting [ (4R) -2, 2-dimethyl-1, 3-dioxolan-4-yl ] methanol for 2- (tetrahydropyran-2-yloxy) ethanol to give the title compound as a solid.

Intermediates 9 and 10: (2S) -1- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]Propane-2-ol and (2S) -2- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl ]Oxy radical]Propane-1-ol

The title compound was prepared using a procedure similar to that described for intermediate 4, substituting (S) -1, 2-propanediol for 2- (tetrahydropyran-2-yloxy) ethanol to give the title compound as a solid.

Intermediates 11 and 12: (2R) -1- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]Propane-2-ol and (2R) -2- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]Propane-1-ol

The title compound was prepared using a procedure similar to that described for intermediate 4, substituting (R) -1, 2-propanediol for 2- (tetrahydropyran-2-yloxy) ethanol to give the title compound as a solid.

Intermediate 13: 4- (4-iodo-6- [ [ 2-methyl-1- (tetrahydropyran-2-yloxy) propan-2-yl)]Oxy radical]Pyridine- 2-yl) morpholine

Step 1: 2- (tetrahydropyran-2-yloxy) acetic acid methyl ester

To a stirred solution of methyl 2-hydroxyacetate (6.30g, 69.94mmol) in DCM (100mL) at 0 deg.C under nitrogen was added dihydropyran (8.93mL, 97.88mmol) and 4-methylbenzene-1-sulfonate; pyridin-1-ium (175.76mg, 0.70 mmol). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was quenched by addition of water (100mL) at room temperature. The resulting mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with NaHCO ₃(saturated, 2X200mL) and brine (300mL), over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc (0-50%) in PE to give methyl 2- (tetrahydropyran-2-yloxy) acetate (8.6g, 70%) as a colorless oil. H-NMR (400MHz, CDCl)₃)δ4.76-4.74(m,1H),4.24(s,2H),3.90-3.76(m,1H),3.75(s,3H),3.56-3.51(m,1H),1.91-1.71(m,3H),1.66-1.52(m,3H)。

Step 2: 2-methyl-1- (tetrahydropyran-2-yloxy) propan-2-ol

To methyl 2- (tetrahydropyran-2-yloxy) acetate (1.00g, 5.74mmol) in Et at-70 ℃ under a nitrogen atmosphere₂To a stirred solution in O (14mL) CH was added dropwise₃MgBr (5.74mL, 17.220mmol, 1M). The resulting mixture was stirred at room temperature for 3h under nitrogen atmosphere. By addition of NH₄Cl (sat, 20mL) quenched the reaction. The resulting mixture was washed with Et₂O (3 × 20 mL). The combined organic layers were washed with brine (50mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA (0-100%) in PE, to give 2-methyl-1- (tetrahydropyran-2-yloxy) propan-2-ol (860mg, 86%) as a colorless oil. H-NMR (400MHz, CDCl)₃)δ4.62-4.60(m,1H),3.94-3.88(m,1H),3.61-3.53(m,2H),3.36-3.34(m,1H),2.70(brs,1H),1.93-1.74(m,3H),1.68-1.53(m,3H),1.22(s,6H)。

And step 3: 4- (4-iodo-6- [ [ 2-methyl-1- (tetrahydropyran-2-yloxy) propan-2-yl)]Oxy radical]Pyridine-2- Base) morpholine

To a stirred mixture of 2-methyl-1- (tetrahydropyran-2-yloxy) propan-2-ol (848.31mg, 4.87mmol) in DMF (1.50mL) at 0 deg.C under nitrogen was added NaH (38.95mg, 0.97mmol, 60%) in portions. To the above mixture was added 4- (6-fluoro-4-iodopyridin-2-yl) morpholine (300.00mg, 0.97mmol) at room temperature. The resulting mixture was stirred at 100 ℃ for a further 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50mL) and over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 25% EA in PE to give 4- (4-iodo-6- [ [ 2-methyl-1- (tetrahydropyran-2-yloxy) propan-2-yl) as a pale yellow oil]Oxy radical]Pyridin-2-yl) morpholine (190mg42%). For C₁₈H₂₇IN₂O₄[M+H]⁺MS ESI of 463.10, found 463.10. H-NMR (400MHz, CDCl)₃)δ6.52-6.51(m,2H),4.64-4.63(m,1H),3.96-3.94(m,1H),3.85-3.79(m,5H),3.72-3.70(m,1H),3.53-3.42(m,5H),1.83-1.47(m,12H)。

Intermediate 14: 1- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]-2-methylpropan-2-ol

The title compound was prepared using a procedure similar to that described for intermediate 4, step 2, substituting 2-methyl-propane-1, 2-diol for 2- (tetrahydropyran-2-yloxy) ethanol to give the title compound as a solid.

Intermediate 15: 1- ((4-iodo-6-morpholinopyridin-2-yl) oxy) -3-methoxypropan-2-ol

The title compound was prepared using a procedure similar to that described for intermediate 4, step 2, substituting 3-methoxypropane-1, 2-diol for 2- (tetrahydropyran-2-yloxy) ethanol to give the title compound as a solid.

Intermediate 16: (3R) -N- [ 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- Radical) phenyl]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide

Step 1: (3R) -N- [ 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzene Base of]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide

To a stirred solution of (3R) -3- (trifluoromethoxy) pyrrolidine hydrochloride (150mg, 0.64mmol) and DIEA (415.80mg, 3.22mmol) in THF (5mL) was added triphosgene (76.38mg, 0.26mmol) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. To this was added (3R) -3- (trifluoromethoxy) pyrrolidine hydrochloride (135.60mg, 0.708mmol) at room temperature. The solution was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography on silica eluting with EA/PE (0 to 60%) to give (3R) -N- [ 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl as an off-white solid ]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide (250mg, 94%). For C₁₉H₂₆BF₃N₂O₄[M+H]⁺MS ESI of 415.19, found 415.25. H-NMR (400MHz, CDCl)₃)δ7.73-7.71(m,1H),7.46-7.45(m,1H),7.16-7.14(m,1H),6.14(s,1H),4.95-4.92(m,1H),3.80-3.71(m,2H),3.64-3.61(m,2H),2.51(s,3H),2.37-2.20(m,2H),1.37(s,12H)。F-NMR(376MHz,CDCl₃)δ-58.70(3F)。

Intermediate 17: (3S) -N- [ 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- Radical) phenyl]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide

The title compound was prepared using a procedure similar to that described for intermediate 16, substituting (3S) -3- (trifluoromethoxy) pyrrolidine hydrochloride for (3R) -3- (trifluoromethoxy) pyrrolidine hydrochloride to give the title compound as a solid.

Intermediate 18: 3-methyl-1- [ 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-) Radical) phenyl]-3- [1- (trifluoromethyl) pyrazol-4-yl]Urea

The title compound was prepared using a procedure similar to that described for intermediate 16, substituting N-methyl-1- (trifluoromethyl) pyrazol-4-amine for (3R) -3- (trifluoromethoxy) pyrrolidine hydrochloride to give the title compound as a solid.

Intermediate 19: n- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)

Phenyl) -3- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxamide

The title compound was prepared using a procedure similar to that described for intermediate 16 substituting 3- (2,2, 2-trifluoroethyl) pyrrolidine for (3R) -3- (trifluoromethoxy) pyrrolidine hydrochloride to give the title compound as a solid.

Intermediate 20: 3- (1, 1-difluoroethyl) pyrrolidine hydrochloride

Step 1: 3- (1, 1-Difluoroethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To 3-acetylpyrrolidine-1-carboxylic acid tert-butyl ester (600.00mg, 2.81mmol) in CHCl at 0 ℃ under nitrogen₃To a stirred solution in (12.00mL) was added BAST (2.49g, 11.26mmol) dropwise. The reaction mixture was stirred at 60 ℃ overnight. The resulting mixture was washed with NaHCO at 0 deg.C₃(saturation) quench and extract with EA (3 × 40 mL). MergingWas washed with brine (3 × 30mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EA (3: 1). Fractions containing the desired product were combined and concentrated to give tert-butyl 3- (1, 1-difluoroethyl) pyrrolidine-1-carboxylate (360mg, 54%) as a yellow oil. H-NMR (400MHz, CDCl)₃)δ3.57(s,2H),3.33-3.28(m,2H),2.64-2.60(m,1H),2.04-1.92(m,2H),1.61(t,J＝18.8Hz,3H),1.46(s,9H)。

Step 2: 3- (1, 1-difluoroethyl) pyrrolidine hydrochloride

To a stirred solution of tert-butyl 3- (1, 1-difluoroethyl) pyrrolidine-1-carboxylate (360mg, 1.53mmol) in EA (1.00mL) was added HCl (10mL, 2M in EA) dropwise at 0 ℃ under nitrogen. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give 3- (1, 1-difluoroethyl) pyrrolidine hydrochloride (320mg) as a yellow oil. It was used in the next step without further purification. H-NMR (400MHz, CDCl) ₃)δ3.65-3.32(m,4H),2.91-2.87(m,1H),2.25-2.09(m,2H),1.63(t,J＝18.0Hz,3H)。

Intermediate 21: 2- (1, 1-Difluoroethyl) morpholine hydrochloride

The title compound was prepared using a procedure similar to that described for intermediate 20, substituting tert-butyl 2-acetylmorpholine-4-carboxylate for tert-butyl 3-acetylpyrrolidine-1-carboxylate to give the title compound as a yellow oil.

Intermediate 22: 3- (trifluoromethyl) -2, 5-dihydro-1H-pyrrole hydrochloride

Step 1: 3- (trifluoromethyl) -2, 5-dihydro-1H-pyrrole hydrochloride

A solution of tert-butyl 3- (trifluoromethyl) -2, 5-dihydropyrrole-1-carboxylate (100mg, 0.42mmol) and HCl (gaseous) in 1, 4-dioxane (2mL, 65.82mmol, 2N) was stirred at room temperature under nitrogen for 16 h. The resulting mixture was concentrated under reduced pressure to give 3- (trifluoromethyl) -2, 5-dihydro-1H-pyrrole hydrochloride (80mg, crude) as a yellow solid. It was used in the next step without further purification. For C₅H₇ClF₃N[M+H-HCl]⁺MS ESI of 138.05, found 138.20.

Intermediate 23: 3- (1,1,2,2, 2-pentafluoroethyl) pyrrolidine hydrochloride

Step 1: 3-hydroxy-3- (1,1,2,2, 2-pentafluoroethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

TBAF (14.58mL, 14.58mmol) was added dropwise to a stirred solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (2.00g, 10.80mmol) and trimethyl (1,1,2,2, 2-pentafluoroethyl) silane (3.11g, 16.20mmol) in THF (20mL) at-40 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under nitrogen for 16 h. The resulting mixture was diluted with EA (100 mL). The resulting solution was washed with water (3X100mL) and brine (100mL) over anhydrous Na ₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 3-hydroxy-3- (1,1,2,2, 2-pentafluoroethyl) pyrrolidine-1-carboxylate as a light brown oil (3.3g,80%). For C₁₁H₁₆F₅NO₃[M-Boc+H]⁺MS ESI of 206.11, found 206.05.

Step 2: 3- (1,1,2,2, 2-pentafluoroethyl) -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester

To a stirred solution of 3-hydroxy-3- (1,1,2,2, 2-pentafluoroethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (2.10g, 6.88mmol) in pyridine (20mL) at room temperature under a nitrogen atmosphere was added dropwise SOCl₂(4.09g, 34.40 mmol). The resulting mixture was stirred at 80 ℃ for 4h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA (0-30%) in PE. Fractions containing the desired product were combined and concentrated to give tert-butyl 3- (1,1,2,2, 2-pentafluoroethyl) -2, 5-dihydropyrrole-1-carboxylate as a yellow oil (1.25g, 63%). For C₁₁H₁₄F₅NO₂[M-Boc+H]⁺MS ESI of 188.04, found 187.85. H-NMR (400MHz, CDCl)₃)δ6.43-6.38(m,1H),4.35-4.30(m,4H),1.51(s,9H)。F-NMR(376MHz,d₆-DMSO)δ-83.57(3F),-113.39(2F)。

And step 3: 3- (1,1,2,2, 2-Pentafluoroethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 3- (1,1,2,2, 2-pentafluoroethyl) -2, 5-dihydropyrrole-1-carboxylate (1.25g, 4.35mmol) and Pd/C (wet) (0.50g, 4.70mmol) in MeOH (15mL) was stirred under an atmosphere of hydrogen (2atm) at room temperature for 2 h. The resulting mixture was filtered and the filter cake was washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 3- (1,1,2,2, 2-pentafluoroethyl) pyrrolidine-1-carboxylate as a pale yellow oil (1.2g, 95%). For C ₁₁H₁₆F₅NO₂[M-Boc+H]⁺MS ESI of 190.06, found 189.90. H-NMR (400MHz, d)₆-DMSO)δ3.59-3.44(m,2H),3.28-3.25(m,3H),2.10-1.95(m,2H),1.41(s,9H)。F-NMR(376MHz,d₆-DMSO)δ-83.29(3F),-119.74-122.14(2F)。

And 4, step 4: 3- (1,1,2,2, 2-pentafluoroethyl) pyrrolidine hydrochloride

To a stirred solution of tert-butyl 3- (1,1,2,2, 2-pentafluoroethyl) pyrrolidine-1-carboxylate (1.20g, 4.15mmol) in dioxane (10.00mL) at 0 deg.C was added dropwise HCl (gaseous) in 1, 4-dioxane (10.00 mL). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure to give 3- (1,1,2,2, 2-pentafluoroethyl) pyrrolidine hydrochloride as a yellow solid (930mg, crude). It was used in the next step without further purification. For C₆H₉ClF₅N[M-HCl+H]⁺MS ESI of 190.06, found 190.10. H-NMR (400MHz, d)₆-DMSO)δ9.72(brs,2H),3.55-3.50(m,1H),3.43-3.30(m,2H),3.24-3.15(m,2H),2.30-2.22(m,1H),2.02-1.92(m,1H)。F-NMR(376MHz,d₆-DMSO)δ-83.30(3F),-118.90,-121.75(2F)。

Intermediate 24: 3- (trifluoromethyl) -1,2,5, 6-tetrahydropyridine hydrochloride

Step 1: 3- (trifluoromethyl) -5, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 4-hydroxy-3- (trifluoromethyl) piperidine-1-carboxylate (0.50g, 1.86mmol) in pyridine (10mL) at 0 deg.C under nitrogenAdding SOCl dropwise into the solution₂(1.35mL, 18.61 mmol). The reaction mixture was stirred at 80 ℃ for 1 h. The resulting mixture was quenched with water (50mL) and extracted with EA (3 × 40 mL). The combined organic layers were washed with 1M HCl (3X30mL) and brine (30mL) over anhydrous Na ₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative-TLC (PE/EA ═ 3/1) to give 3- (trifluoromethyl) -5, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester as a yellow oil (0.30g, 64%). H-NMR (400MHz, CDCl)₃)δ6.47(d,J＝3.6Hz,1H),4.02(s,2H),3.50(t,J＝5.6Hz,2H),2.27-2.24(m,2H),1.48(s,9H)。F-NMR(376MHz,CDCl₃)δ-68.27。

Step 2: 3- (trifluoromethyl) -1,2,5, 6-tetrahydropyridine hydrochloride

To a stirred solution of 3- (trifluoromethyl) -5, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.17g, 0.68mmol) in EA (1mL) at 0 ℃ under nitrogen was added dropwise 2M HCl in EA (5 mL). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to give 3- (trifluoromethyl) -1,2,5, 6-tetrahydropyridine hydrochloride (0.13g, 100%) which was used in the next step without further purification. H-NMR (400MHz, CDCl)₃)δ6.60(s,1H),3.88(s,2H),3.42-3.38(m,2H),2.69-2.65(m,2H)；F-NMR(376MHz,CDCl₃)δ-68.58。

Intermediate 25: 3- (2,2, 2-trifluoroethyl) -2, 5-dihydro-1H-pyrrole hydrochloride

Step 1: 3- (2,2, 2-trifluoroethyl) -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydropyrrole-1-carboxylate (0.50g, 1.69mmol) and 1,1, 1-trifluoro-2-iodoethane (1.07g, 5.08mmol) in 1, 4-dioxane (10mL) at room temperature was added Cs₂CO₃(2.21g, 6.77mmol) and XantPhos (0.196g, 0.34mmol) and Pd ₂(dba)₃.CHCl₃(0.35g, 0.34 mmol). The reaction mixture was degassed three times with nitrogen and stirred at 80 ℃ overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (1: 2). The fractions containing the desired product were combined and concentrated to give tert-butyl 3- (2,2, 2-trifluoroethyl) -2, 5-dihydropyrrole-1-carboxylate (0.12g, 25%) as a colorless oil. For C₁₁H₁₆F₃NO₂[M+H–t-Bu]⁺MS ESI of 196.11, found 196.10.

Step 2: 3- (2,2, 2-trifluoroethyl) -2, 5-dihydro-1H-pyrrole hydrochloride

To a stirred solution of tert-butyl 3- (2,2, 2-trifluoroethyl) -2, 5-dihydropyrrole-1-carboxylate (0.12g, 0.48mmol) in DCM (2.00mL) was added dropwise HCl (gaseous) (4M, 2.00mL, 0.05mmol) in 1, 4-dioxane at 0 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under reduced pressure to give 3- (2,2, 2-trifluoroethyl) -2, 5-dihydro-1H-pyrrole hydrochloride (85mg, 100%) as a yellow solid. It was used in the next step without further purification. For C₆H₉ClF₃N[M+H]⁺Calculated MS ESI of 152.06; found 152.10.¹H NMR(400MHz,CDCl₃)δ10.43(brs,2H),5.84(s,1H),4.24-4.20(m,2H),4.18-4.10(m,2H),3.05(q,J＝10.4Hz,2H)。

Intermediate 26: 3- (1,1,2,2, 2-pentafluoroethyl) -2, 5-dihydro-1H-pyrrole hydrochloride

Step 1: 3- (1,1,2,2, 2-pentafluoroethyl) -2, 5-dihydro-1H-pyrrole hydrochloride

To a stirred solution of tert-butyl 3- (1,1,2,2, 2-pentafluoroethyl) -2, 5-dihydropyrrole-1-carboxylate (0.1g, 0.35mmol) in dioxane (1mL, 11.80mmol) was added dropwise HCl (gaseous) (1mL, 32.91mmol) in 1, 4-dioxane (4M) at 0 ℃. The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure to give 3- (1,1,2,2, 2-pentafluoroethyl) -2, 5-dihydro-1H-pyrrole hydrochloride as a yellow solid (79mg, 91%). It was used in the next step without further purification. For C₆H₇ClF₅N[M-HCl+H]⁺MS ESI of 188.11, found 187.90. H-NMR (400MHz, CDCl)₃)δ10.19(brs,2H),6.82(s,1H),4.21-4.17(m,4H)。

Intermediate 27: 1, 1-difluoro-6-azaspiro [3.4]Octane

Step 1: 1, 1-difluoro-6-azaspiro [3.4]Octane-6-carboxylic acid benzyl ester

To 1-oxo-6-azaspiro [3.4 ] at 0 ℃ under argon atmosphere]Octane-6-carboxylic acid benzyl ester (2.00g, 7.71mmol) in CHCl₃To a stirred solution in (20.00mL) was added BAST (6.83g, 30.852mmol) dropwise. The reaction mixture was stirred at 60 ℃ for 20h under argon atmosphere. With saturated NaHCO₃Mixing the obtained mixtureNeutralized to pH 7. The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (3: 1). The fractions containing the desired product were combined and concentrated to give 1, 1-difluoro-6-azaspiro [3.4 ] as a yellow oil ]Octane-6-carboxylic acid benzyl ester (1g, 46.09%). For C₁₅H₁₇F₂NO₂[M+H]⁺Calculated MS ESI of 282.1, found 282.3.

Step 2: 1, 1-difluoro-6-azaspiro [3.4]Octane

1, 1-difluoro-6-azaspiro [3.4 ]]Octane-6-carboxylic acid benzyl ester (75.00mg, 0.267mmol) in CF₃The solution in COOH (5.00mL) was stirred at 70 ℃ for 2h under argon. The solution was concentrated under reduced pressure. The residue was diluted with EA (10 mL). The resulting mixture was taken up in saturated NaHCO₃Aqueous (10mL x 2) wash. The organic layer was passed over anhydrous Na₂SO₄Dried and filtered. Concentrating the filtrate under reduced pressure to obtain 1, 1-difluoro-6-azaspiro [3.4 ] as off-white semisolid]Octane (35mg, 90%). The crude product was used in the next step without further purification.¹H NMR(400MHz,DMSO-d6)δ3.12-2.99(m,2H),3.02-2.90(m,2H),2.10-1.83(m,3H),1.82-1.67(m,4H)。

Intermediate 28: (Z) -3- (2,2, 2-trifluoroethylidene) pyrrolidine hydrochloride

Step 1: (3Z) -3- (bromomethylidene) pyrrolidine-1-carboxylic acid tert-butyl esterAnd(3E) -3- (bromomethylidene) pyrrolidine- 1-Carboxylic acid tert-butyl ester

To (bromomethyl) triphenylphosphonium bromide (30.61 g) at-78 deg.C70.18mmol) in THF (220mL) was added t-BuOK (1M in THF) (64.78mL, 64.78mmol) dropwise. The reaction mixture was stirred at-78 ℃ for 1.5 h. To the above solution was added 3-oxopyrrolidine-1-carboxylic acid tert-butyl ester (10g, 53.99mmol) in THF (40 mL). The reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The resulting mixture was quenched by addition of water (500mL) at room temperature and extracted with DCM (2 × 500 mL). The combined organic layers were washed with brine (2 × 300mL) and dried over anhydrous Na ₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA/PE (0 to 20%). The fractions containing the desired product were combined and concentrated to give tert-butyl (3Z) -3- (bromomethylidene) pyrrolidine-1-carboxylate (1.5g, 11%) as a yellow oil and tert-butyl (3E) -3- (bromomethylidene) pyrrolidine-1-carboxylate (1.8g, 13%) as a yellow oil. (3Z) -3- (bromomethylidene) pyrrolidine-1-carboxylic acid tert-butyl ester for C₁₀H₁₆BrNO₂[M-t-Bu]⁺MS ESI of (a) calculated 205.97, 207.97, found 205.85, 207.85.¹H-NMR(400MHz,d₆-DMSO) delta 6.43-6.40(m,1H),3.93-3.91(m,2H),3.45-3.42(m,2H),2.58-2.55(m,2H),1.41(s, 9H). (3E) -3- (bromomethylidene) pyrrolidine-1-carboxylic acid tert-butyl ester for C₁₀H₁₆BrNO₂[M-t-Bu]⁺MS ESI of (a) calculated 205.97, 207.97, found 205.85, 207.85.¹H-NMR(400MHz,d₆-DMSO)δ6.37-6.34(m,1H),3.87-3.84(m,2H),3.47-3.44(m,2H),2.60-2.57(m,2H),1.42(s,9H)。

Step 2: (3Z) -3- (2,2, 2-trifluoroethylidene) pyrrolidine-1-carboxylic acid tert-butyl ester

To a mixture of tert-butyl (3Z) -3- (bromomethylidene) pyrrolidine-1-carboxylate (0.39g, 1.49mmol) and CuI (0.68g, 3.571mmol) in HMPA (2.50mL, 14.29mmol) and DMF (2.50mL, 32.30mmol) at 75 deg.C over 1h was added dropwise a solution of methyl 2, 2-difluoro-2-sulfoacetate (2.86g, 14.88mmol) and DMF (2.50mL, 0.034 mmol). With nitrogen The reaction mixture was degassed and stirred at 75 ℃ for 3 days. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (4: 1). The fractions containing the desired product were combined and concentrated to give tert-butyl (3Z) -3- (2,2, 2-trifluoroethylidene) pyrrolidine-1-carboxylate as a colorless oil (66mg, 18%). For C₁₁H₁₆F₃NO₂[M-tBu]⁺MS ESI of 195.11, found 195.90.

And step 3: (Z) -3- (2,2, 2-trifluoroethylidene) pyrrolidine hydrochloride

To a mixture of (3Z) -3- (2,2, 2-trifluoroethylene) pyrrolidine-1-carboxylic acid tert-butyl ester (66.00mg, 0.263mmol) in 1, 4-dioxane (2.00mL, 23.608mmol) was added HCl (gaseous) (1.00mL, 32.912mmol) in 1, 4-dioxane. The reaction mixture was stirred at room temperature under nitrogen overnight. The resulting mixture was concentrated in vacuo to give (3Z) -3- (2,2, 2-trifluoroethylene) pyrrolidine hydrochloride as a pale yellow solid (48mg, 97.41%). The crude product was used in the next step without further purification. For C₆H₉ClF₃N[M+H-HCl]⁺Calculated MS ESI of 152.06; found 151.90.

Intermediate 29: (3E) -3- (2,2, 2-trifluoroethylidene) pyrrolidine hydrochloride

The title compound was prepared using a procedure similar to that described for intermediate 28, substituting (3E) -3- (bromomethylidene) pyrrolidine-1-carboxylate for (3Z) -3- (bromomethylidene) pyrrolidine-1-carboxylate to give the title compound as a yellow solid.

Intermediate 30: (Z) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine hydrochloride

Step 1: 2,2, 2-trifluoro-1- [3- (2,2, 2-trifluoroacetyl) pyrrolidin-1-yl]Ethanones

To a stirred mixture of pyrrolidine-3-carboxylic acid (4.00g, 34.74mmol) in toluene (60.00mL) was added TFAA (26.58mL, 126.55mmol) dropwise and pyridine (22.37mL, 282.835mmol) dropwise at 0 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 50 ℃ for 48 h. The resulting mixture was quenched with water (50mL) at 0 ℃ and stirred for an additional 2h at 45 ℃. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated in vacuo to give 2,2, 2-trifluoro-1- [3- (2,2, 2-trifluoroacetyl) pyrrolidin-1-yl as a brown oil]Ethanone (10g, crude). The crude product was used in the next step without further purification. For C₈H₇F₆NO₂[M+H+H₂O]⁺MS ESI of 282.04, found 282.00.

Step 2: 3- (2,2, 2-Trifluoroacetyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred mixture of 2,2, 2-trifluoro-1- [3- (2,2, 2-trifluoroacetyl) pyrrolidin-1-yl group at room temperature under a nitrogen atmosphere]Ethanone (2.30g, 8.74mmol), MeOH (15.00mL), and H₂To a mixture of O (0.47mL, 26.222mmol) was added K ₂CO₃(2.42g, 17.481 mmol). The reaction mixture was stirred at room temperature for 2 h. To the above mixture was added dropwise (Boc) at room temperature₂O (2.29g, 10.493 mmol). Mixing the obtained mixture inStirring is carried out for a further 16h at room temperature. The resulting mixture was concentrated and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA/PE (0 to 70%). Fractions containing the desired product were combined and concentrated to give tert-butyl 3- (2,2, 2-trifluoroacetyl) pyrrolidine-1-carboxylate as a brown oil (1.87g, 80%). For C₁₁H₁₆F₃NO₃[M-t-Bu+H]⁺MS ESI of 212.05, found 212.05.

And step 3: 3- (1,1, 1-trifluoro-2-hydroxypropan-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 3- (2,2, 2-trifluoroacetyl) pyrrolidine-1-carboxylate (5.8g, 21.70mmol) in THF (60.00mL) under nitrogen at-70 deg.C was added dropwise MeMgBr (21.70mL, 65.109 mmol). The reaction mixture was stirred at room temperature under nitrogen for 16 h. By addition of NH₄The reaction was quenched with Cl (aq) (sat, 200 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (1 × 500mL) and dried over anhydrous Na ₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc/PE (0-100%). Fractions containing the desired product were combined and concentrated to give tert-butyl 3- (1,1, 1-trifluoro-2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate as a pale yellow solid (0.87g, 14%). For C₁₂H₂₀F₃NO₃[M-t-Bu+H]⁺MS ESI of 228.14, found 228.05. H-NMR (400MHz, d)₆-DMSO)δ6.02-5.99(m,1H),3.43-3.40(m,2H),3.18-3.01(m,2H),2.45-2.41(m,1H),1.92-1.80(m,2H),1.40(s,9H),1.27(s,3H)。

And 4, step 4: (3Z) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine-1-carboxylic acid tert-butyl ester and (3E) -3- (1, 1, 1-trifluoropropan-2-ylidene) pyriPyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 3- (1,1, 1-trifluoro-2-hydroxypropan-2-yl) pyrrolidine-1-carboxylate (1.13g, 3.99mmol) in pyridine (11.00mL) was added SOCl dropwise at room temperature under a nitrogen atmosphere₂(2372.76mg, 19.944 mmol). The reaction mixture was stirred at 80 ℃ for 1h under nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA (0-30%) in PE. The fractions containing the desired product were combined and concentrated to give tert-butyl (3Z) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine-1-carboxylate (0.20g, 19%) as a yellow oil and tert-butyl (3E) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine-1-carboxylate (0.70g, 66%) as a yellow oil. (3Z) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine-1-carboxylic acid tert-butyl ester: for C ₁₂H₁₈F₃NO₂[M-t-Bu+H]⁺MS ESI of 210.13, found 209.95. H-NMR (400MHz, d)₆-DMSO)δ4.23-4.19(m,2H),3.56-3.54(m,2H),2.68-2.66(m,2H),1.82(s,3H),1.56(s,9H)。

(3E) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine-1-carboxylic acid tert-butyl ester: for C₁₂H₁₈F₃NO₂[M-t-Bu+H]⁺MS ESI of 210.13, found 209.95. H-NMR (400MHz, d)₆-DMSO)δ4.08-4.06(m,2H),3.59-3.57(m,2H),2.84-2.82(m,2H),1.80(s,3H),1.53(s,9H)。

And 5: (3Z) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine hydrochloride

To a stirred solution of tert-butyl (3Z) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine-1-carboxylate (80.00mg, 0.302mmol) in dioxane (1.50mL) at 0 deg.CHCl (gaseous) in 1, 4-dioxane (1.50mL) was added dropwise. The reaction solution was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure to give (3Z) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine hydrochloride as a yellow solid (58 mg). The crude product was used in the next step without further purification. For C₇H₁₁ClF₃N[M-HCl+H]⁺MS ESI of 166.08, found 166.10. H-NMR (400MHz, d)₆-DMSO)δ9.57(brs,2H),4.02-3.99(m,2H),3.58-3.40(m,2H),2.74-2.72(m,2H),1.85(s,3H)。

Intermediate 31: (E) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine hydrochloride

The title compound was prepared using a procedure similar to that described for intermediate 30, step 5, substituting (3Z) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine-1-carboxylic acid tert-butyl ester with (3E) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine-1-carboxylic acid tert-butyl ester to give the title compound as a light yellow solid.

Intermediate 32: 3- (2,2, 2-trifluoroethyl) -2, 5-dihydro-1H-pyrrole hydrochloride

Step 1: 3- (2,2, 2-trifluoroethyl) -2, 5-dihydropyrrole-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydropyrrole-1-carboxylate (0.50g, 1.69mmol) and 1,1, 1-trifluoro-2-iodoethane (1.07g, 5.08mmol) in 1, 4-dioxane (10mL) at room temperature was added Cs₂CO₃(2.21g, 6.78mmol), XantPhos (0.196g, 0.339mmol) and Pd₂(dba)₃.CHCl₃(0.35g, 0.339 mmol). The reaction mixture was degassed three times with nitrogen and stirred at 80 ℃ overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (1: 2). Fractions containing the desired product were combined and concentrated to give tert-butyl 3- (2,2, 2-trifluoroethyl) -2, 5-dihydropyrrole-1-carboxylate as a white oil (0.12g, 25%). For C₁₁H₁₆F₃NO₂[M+H-tBu]^-MS ESI of 196.05, found 196.10.

Step 2: 3- (2,2, 2-trifluoroethyl) -2, 5-dihydro-1H-pyrrole hydrochloride

To a stirred solution of tert-butyl 3- (2,2, 2-trifluoroethyl) -2, 5-dihydropyrrole-1-carboxylate (0.12g, 0.48mmol) in DCM (2.00mL) was added HCl (gaseous) (2.00mL, 0.055mmol) in 1, 4-dioxane (4M) at 0 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under reduced pressure to give 3- (2,2, 2-trifluoroethyl) -2, 5-dihydro-1H-pyrrole hydrochloride (90mg, 100%) as a yellow solid. The crude product was used in the next step without further purification. For C ₆H₉ClF₃N[M+H-HCl]⁺Calculated MS ESI of 152.06; found 152.10.

Intermediate 33: (Z) -2- (pyrrolidin-3-ylidene) propionitrile hydrochloride

Step 1: (3Z) -3- (1-cyanoethylidene) pyrrolidine-1-carboxylic acid ester/(3E) -3- (1-cyanoethylidene) Pyrrolidine-1-carboxylic acid ester

To a solution of diethyl 1-cyanoethylphosphonate (1.15g, 5.99mmol) in THF (30mL) at 0 deg.C was added t-BuOK (0.81g, 7.19 mmol). The reaction mixture was stirred for 10 min. Thereafter, tert-butyl 3-oxopyrrolidine-1-carboxylate (1.11g, 5.99mmol) in THF (6mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 20-35% EA in PE. The fractions containing the desired product were combined and concentrated to give tert-butyl (3E) -3- (1-cyanoethylidene) pyrrolidine-1-carboxylate (0.50g, 38%) as a colorless oil and tert-butyl (3Z) -3- (1-cyanoethylidene) pyrrolidine-1-carboxylate (0.48g, 36%) as a colorless oil. (3E) -3- (1-cyanoethylidene) pyrrolidine-1-carboxylic acid tert-butyl ester: for C₁₂H₁₈N₂O₂[M+H]+ MS ESI calculation 223.14; found 223.05.¹H-NMR (400MHz, d6-DMSO) δ 4.03(m,2H),3.46(t, J ═ 7.2Hz,2H),2.79(s,2H),1.84-1.78(m,3H),1.41(s, 9H). (3Z) -3- (1-cyanoethylidene) pyrrolidine-1-carboxylic acid tert-butyl ester: for C ₁₂H₁₈N₂O₂[M+H]+ MS ESI calculation 223.14; found 223.05.¹H-NMR(400MHz,d6-DMSO)δ4.02(s,2H),3.40(t,J＝7.2Hz,2H),2.64(s,2H),1.78(s,3H),1.34(s,9H)。

Step 2: (Z) -2- (pyrrolidin-3-ylidene) propionitrile hydrochloride

To a stirred solution of (3Z) -3- (1-cyanoethylidene) pyrrolidine-1-carboxylic acid tert-butyl ester (0.23g, 1.03mmol) in dioxane (5.75mL, 65.26mmol) was added HCl (4M in 1, 4-dioxane) (5.75mL) dropwise at 25 ℃. The reaction mixture was stirred for 16 h. The resulting mixture was concentrated in vacuo to give (Z) -2- (pyrrolidin-3-ylidene) propionitrile hydrochloride (165mg, 100%) as a yellow solid. The crude product was taken without further work-upThe purification was used directly in the next step. For C₇H₁₁ClN₂[M+H-HCl]⁺Calculated MS ESI of 123.08; found 123.20.

Intermediate 34: (E) -2- (pyrrolidin-3-ylidene) propionitrile hydrochloride

The title compound was prepared using a procedure similar to that described for intermediate 33, step 2, substituting tert-butyl (3Z) -3- (1-cyanoethylidene) pyrrolidine-1-carboxylate with tert-butyl (3E) -3- (1-cyanoethylidene) pyrrolidine-1-carboxylate to give the title compound as a light yellow solid.Intermediate 35: 2-methyl-2- (pyrrolidin-3-yl) propionitrile hydrochloride

Step 1: 3- (1-cyano-1-methylethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of tert-butyl 3- (cyanomethyl) pyrrolidine-1-carboxylate (0.5g, 2.38mmol) in THF (4mL) at-5 ℃ under nitrogen was added KHMDS (1.43mL, 1.43mmol) dropwise. The reaction mixture was stirred for 10 minutes, after which CH was added slowly over a period of 10 minutes ₃A solution of I (0.776g, 5.47mmol) in THF (0.70 mL). The reaction mixture was stirred for a further 1 h. The resulting mixture was reacted with NH at 0 deg.C₄Cl (saturated) was quenched and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (2 × 30mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 30% EA in PE. The fractions containing the desired product were combined and concentrated to give 3- (1-cyano-1-methylethyl) pyriproxyfen as a colorless oilPyrrolidine-1-carboxylic acid tert-butyl ester (0.23g, 41%). H-NMR (400MHz, CDCl)₃)δ3.60(s,2H),3.31-3.15(m,2H),2.20-1.85(m,3H),1.47(s,9H),1.40(s,3H),1.37(s,3H)。

Step 2: 2-methyl-2- (pyrrolidin-3-yl) propionitrile hydrochloride

To a stirred solution of tert-butyl 3- (1-cyano-1-methylethyl) pyrrolidine-1-carboxylate (0.23g, 0.98mmol) in EA (1.00mL, 10.22mmol) at 0 deg.C under nitrogen was added dropwise 4M HCl in 1, 4-dioxane. The reaction mixture was stirred at ambient temperature for 3 h. The resulting mixture was concentrated under reduced pressure to give 2-methyl-2- (pyrrolidin-3-yl) propionitrile hydrochloride (0.16g, 94%) as an off-white solid. H-NMR (400MHz, CDCl)₃)δ3.66-3.62(m,1H),3.54-3.50(m,1H),3.44-3.40(m,1H),3.12-3.08(m,1H),2.26-2.24(m,1H),2.01-1.93(m,2H),1.43-1.42(m,6H)。

Intermediate 36: 3- (1,1, 1-trifluoropropan-2-yl) pyrrolidine hydrochloride

Step 1: 3- (1,1, 1-trifluoropropan-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl (3E) -3- (1,1, 1-trifluoropropan-2-ylidene) pyrrolidine-1-carboxylate (0.35g, 1.32mmol) in MeOH (5.00mL) was added Pd/C (10%) (0.15g, 1.41 mmol). The reaction mixture was degassed with hydrogen and stirred at room temperature for 1h under a hydrogen atmosphere (1 atm). The resulting mixture was filtered and the filter cake was washed with MeOH (4x5 mL). The filtrate was concentrated under reduced pressure. This gave 3- (1,1, 1-trifluoropropan-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oilButyl ester (320 mg). The crude product was used in the next step without further purification. For C₁₂H₂₀F₃NO₂[M-Boc+H]⁺MS ESI of 168.09, found 167.95.¹H-NMR(400MHz,CDCl₃)δ3.68-3.51(m,2H),3.32-3.18(m,1H),3.04-2.94(m,1H),2.35-2.03(m,3H),1.74-1.52(m,1H),1.51(s,9H),1.22-1.08(m,3H)。

Step 2: 3- (1,1, 1-trifluoropropan-2-yl) pyrrolidine hydrochloride

To a stirred solution of tert-butyl 3- (1,1, 1-trifluoropropan-2-yl) pyrrolidine-1-carboxylate (0.32g, 1.20mmol) in dioxane (3.00mL) at 0 deg.C was added dropwise HCl (gaseous, 2M) in 1, 4-dioxane (3.00 mL). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure to give 3- (1,1, 1-trifluoropropan-2-yl) pyrrolidine hydrochloride (280mg) as a colorless oil. The crude product was used in the next step without further purification. For C₇H₁₃ClF₃N[M-HCl+H]⁺MS ESI of 168.09, found 168.15. H-NMR (400MHz, d) ₆-DMSO)δ9.44-9.37(m,2H),3.52-3.40(m,2H),3.14-3.03(m,1H),2.90-2.81(m,1H),2.68-2.57(m,1H),2.39-2.25(m,1H),2.09-2.04(m,1H),1.75-1.61(m,1H),1.12-1.08(m,3H)。

Intermediate 37: 3- (2, 2-Difluorocyclopropyl) pyrrolidine hydrochloride

Step 1: 3- (2, 2-Difluorocyclopropyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a mixture of tert-butyl 3-vinylpyrrolidine-1-carboxylate (0.20g, 1.01mmol) and NaI (30.39mg, 0.20mmol) in THF (1.00mL) was added trifluoromethyl trimethylsilane (0.36g, 2.53 mmol). The reaction mixture was stirred at 80 ℃ overnight under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography on silica eluting with EA/PE (0 to 55%). Fractions containing the desired product were combined and concentrated to give tert-butyl 3- (2, 2-difluorocyclopropyl) pyrrolidine-1-carboxylate as a yellow oil (74mg, 50% purity, 30% yield). It was used in the next step without further purification. For C₁₂H₁₉F₂NO₂[M-tBu+CH₃CN+H]⁺MS ESI of 233.14, found 233.05.

Step 2: 3- (2, 2-Difluorocyclopropyl) pyrrolidine hydrochloride

To a stirred solution of tert-butyl 3- (2, 2-difluorocyclopropyl) pyrrolidine-1-carboxylate (74.00mg, 0.299mmol) in dioxane (1.00mL) at 0 deg.C was added 4M HCl in 1, 4-dioxane (1.00mL) dropwise. The reaction solution was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure to give 3- (2, 2-difluorocyclopropyl) pyrrolidine hydrochloride (55mg, 100%) as a yellow oil. For C ₇H₁₂ClF₂N[M-HCl+H]⁺MS ESI of 148.09, found 148.10.

Intermediate 38: 3- [ (trifluoromethyl) thio group]Pyrrolidine hydrochloride

Step 1: 3- [ (trifluoromethyl) thio group]Pyrrolidine-1-carboxylic acid tert-butyl ester

To a mixture of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.60g, 3.20mmol), tetrabutylammonium iodide (14.2g, 38.45mmol, 12.00 equiv.), KI (4.2g, 25.64mmol) in toluene (30mL) was added [ (trifluoromethyl) sulfanyl group]Silver (0.89g, 4.27 mmol). The reaction mixture was stirred at 120 ℃ for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA/PE (0 to 15%). The fractions containing the desired product were combined and concentrated to give 3- [ (trifluoromethyl) thio ] thio as a brown oil]Pyrrolidine-1-carboxylic acid tert-butyl ester (1g, crude). For C₁₀H₁₆F₃NO₂S[M+H–t-Bu]⁺MS ESI of 216.09, found 215.95.

Step 2: 3- [ (trifluoromethyl) thio group]Pyrrolidine hydrochloride

To 3- [ (trifluoromethyl) thio group]To a mixture of pyrrolidine-1-carboxylic acid tert-butyl ester (1.00g, 3.69mmol) in MeOH (4.00mL) was added 4M HCl in 1, 4-dioxane (4.00 mL). The reaction mixture was stirred at room temperature for a further 16 h. The resulting mixture was concentrated under reduced pressure to give 3- [ (trifluoromethyl) thio group as a brown oil ]Pyrrolidine hydrochloride (1g, crude). The crude product was used in the next step without further purification. For C₅H₉ClF₃NS[M+H–HCl]⁺MS ESI of (d) calculated 172.03, found 172.05.

Intermediate 39: (3R) -3- (2,2, 2-trifluoroethoxy) pyrrolidine

Step 1: 3- [ (trifluoromethyl) thio group]Pyrrolidine-1-carboxylic acid tert-butyl ester

The reaction mixture was washed with (3R) -pyrrolidine-3-ol hydrochloride (5.00g, 40.46mmol), 4-methoxybenzyl chloride (6336.38mg, 40.46mmol) and K₂CO₃A mixture of (16775.23mg, 121.38mmol) in acetone (50mL) was stirred at 60 deg.C under nitrogen for 16 h. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using a column containing 10%

NH₃.H₂O/DCM (0 to 8%) in MeOH to give (3R) -1- [ (4-methoxyphenyl) methyl ] as a brown oil]Pyrrolidin-3-ol (6.4g, 76%). For C₁₂H₁₇NO₂[M+H–

t-Bu]⁺MS ESI of 208.13, found 208.00.

Step 2: (3R) -1- [ (4-methoxyphenyl) methyl group]-3- (2,2, 2-trifluoroethoxy) pyrrolidine

To (3R) -1- [ (4-methoxyphenyl) methyl at 0 ℃ under a nitrogen atmosphere]A stirred solution of pyrrolidin-3-ol (4.80g, 23.16mmol) and THF (50mL) was added NaH (926mg, 23.16mmol, 60%) in portions. The resulting mixture was stirred at room temperature for 0.5h under nitrogen atmosphere. To the above mixture was added 2,2, 2-trifluoroethyl trifluoromethanesulfonate (88.06g, 34.74mmol) dropwise over 5min at 0 ℃. The resulting mixture was stirred at 60 ℃ for an additional 4 h. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography on silica eluting with MeOH/DCM (0 to 8%) to give (3R) -1- [ (4-methoxyphenyl) methyl) as a brown oil ]-3- (2,2, 2-trifluoroethoxy) pyrrolidine (4g, 60%). For C₁₄H₁₈F₃NO₂[M+H]⁺MS ESI of 290.13, found 290.00.

And step 3: (3R) -3- (2,2, 2-trifluoroethoxy) pyrrolidine

Reacting (3R) -1- [ (4-methoxyphenyl) methyl]-3- (2,2, 2-trifluoroethoxy) pyrrolidine (1.00g, 3.46mmol), ammonium formate (1089.81mg, 17.28mmol), Pd (OH)₂A mixture of/C (24mg, 0.03mmol, 20%) and MeOH (1.00mL) was stirred at 60 deg.C for 16 h. The solid was filtered off and washed with MeOH (3 × 10 mL). The resulting mixture was concentrated in vacuo to give (3R) -3- (2,2, 2-trifluoroethoxy) pyrrolidine as a brown oil (580mg, crude). For C₆H₁₀F₃NO[M+H]⁺MS ESI of 170.07, found 169.90.

Intermediate 40: (3S) -3- (2,2, 2-trifluoroethoxy) pyrrolidine

Intermediate 27 was prepared using a procedure similar to that described for intermediate 39, using the appropriate starting materials.

Intermediate 41: 3-trifluoromethanesulfonyl pyrrolidine hydrochloride

Step 1: 3-Trifluoromethanesulfonylpyrrolidine-1-carboxylic acid tert-butyl ester

Reacting 3- [ (trifluoromethyl) thio group]A solution of pyrrolidine-1-carboxylic acid tert-butyl ester (200.00mg, 0.74mmol) and MCPBA (299.33mg, 1.47mmol, 85%) in DCM (2.00mL) was stirred at 25 deg.C for 16 h. The resulting mixture was concentrated under vacuum. To the residue was added MCPBA (299.33) in DCM (2.00mL) mg, 1.47mmol, 2.00 equiv, 85%), the resulting mixture was stirred at 25 ℃ for 16 h. Subjecting the obtained mixture to CH₂Cl₂Diluted (20mL) with saturated NaHCO₃Washing with anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (4:1) to give tert-butyl 3-trifluoromethanesulfonylpyrrolidine-1-carboxylate as an off-white solid (120mg, 54%). For C₁₀H₁₆F₃NO₄S[M+H]⁺Calculated MS ESI of 304.08; found 304.10.¹H-NMR(400MHz,d₆-DMSO)δ4.69(s,1H),3.76-3.67(m,2H),3.48(t,J＝10.4Hz,1H),2.41(s,3H),1.41(s,9H)。

Step 2: (3R) -1- [ (4-methoxyphenyl) methyl group]-3- (2,2, 2-trifluoroethoxy) pyrrolidine

A mixture of tert-butyl 3-trifluoromethanesulfonylpyrrolidine-1-carboxylate (120.00mg, 0.40mmol), HCl (4N in 1, 4-dioxane, 4.00mL), and MeOH (4.00mL) was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification. For C₅H₉ClF₃NO₂S[M+H-Cl]⁺Calculated MS ESI of 204.02; found 204.10.

Intermediate 42: (3S) -3-Isopropoxypyrrolidine

Step 1: (3S) -3-Isopropoxypyrrolidine-1-carboxylic acid benzyl ester

Will be stirred(3S) -3-Hydroxypyrrolidine-1-carboxylic acid benzyl ester (3.00g, 13.56mmol), Ag₂A mixture of O (6284.19mg, 27.12mmol) and 2-iodopropane (30mL) was stirred at 40 deg.C under nitrogen for 48 h. The resulting mixture was concentrated under vacuum. The residue was purified by column chromatography on silica eluting with EA/PE (0 to 30%) to give benzyl (3S) -3-isopropoxypyrrolidine-1-carboxylate (2g, 56%) as a pale yellow oil. For C ₁₅H₂₁NO₃[M+H]⁺Calculated MS ESI of 264.15; found 264.00.¹H-NMR(400MHz,d₆-DMSO)δ

7.40-7.32(m,5H),5.16-5.15(m,2H),4.15-4.14(m,1H),3.66-3.64(m,1H),3.57-3.46(m,4H),1.98-1.95(m,2H),1.18-1.15(m,6H)。

Step 2: (3S) -3-Isopropoxypyrrolidine

Benzyl (3S) -3-isopropoxypyrrolidine-1-carboxylate (500.00mg, 1.90mmol), ammonium formate (598.62mg, 9.49mmol), Pd (OH)₂A mixture of/C (266.64mg, 0.38mmol, 20%) and MeOH (5.00mL) was stirred at 60 deg.C for 1 h. The solid was filtered off. The resulting filtrate was concentrated in vacuo to give (3S) -3-isopropoxypyrrolidine as a pale yellow oil (320mg, crude). For C₇H₁₅NO[M+H]⁺Calculated MS ESI of 130.12; found 129.95.

Intermediate 43: (3S) -3- (1, 1-Difluoroethoxy) pyrrolidine

Step 1: (3S) -1- [ (4-methoxyphenyl) methyl group]Pyrrolidin-3-ols

The reaction mixture was washed with (3S) -pyrrolidine-3-ol hydrochloride (20g, 161.84mmol), 4-methoxybenzyl chloride (25345.53mg, 161.84mmol) and K₂CO₃A mixture of (67100.91mg, 485.51mmol) in acetone (200mL) was stirred at 60 deg.C under nitrogen for 3 h. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure to give (3S) -1- [ (4-methoxyphenyl) methyl group as a brown oil]Pyrrolidin-3-ol (35g, crude). For C₁₂H₁₇NO₂[M+H]⁺Calculated MS ESI of 208.13; found 208.00.

Step 2: (3S) -1- [ (4-methoxyphenyl) methyl group]Pyrrolidin-3-yl acetate

To (3S) -1- [ (4-methoxyphenyl) methyl group at 0 ℃ under a nitrogen atmosphere]Ac was added dropwise to a solution of pyrrolidin-3-ol (35g, crude) in pyridine (350mL)₂O (34477.24mg, 337.72 mmol). The resulting mixture was stirred at room temperature under nitrogen for 16 h. The reaction solution was concentrated under reduced pressure. The residue was diluted with EA (500mL) and saturated Na₂CO₃(3x250mL) washing. The organic layer was passed over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with DCM/MeOH (10:1) to give (3S) -1- [ (4-methoxyphenyl) methyl) as a brown oil]Pyrrolidin-3-yl acetate (17g, 40%). For C₁₄H₁₉NO₃[M+H]⁺Calculated MS ESI of 250.14; found 250.00.¹H-NMR(400MHz,CDCl₃)δ7.27-7.23(m,2H),6.89-6.86(m,2H),5.20-5.16(m,1H),3.82(s,3H),3.82-3.52(m,2H),2.81-2.83(m,2H),2.66-2.63(m,1H),2.43-2.41(m,1H),2.30-2.25(m,1H),2.05(s,3H),1.88-1.84(m,1H)。

And step 3: (3S) -1- [ (4-methoxyphenyl) methyl group]Pyrrolidin-3-yl thioacetate

Reacting (3S) -1- [ (4-methoxyphenyl) methyl]Pyrrolidin-3-yl acetate (1g, 4.01mmol), hexamethyldisiloxane (3907.88mg, 24.07mmol), P₂S₅A mixture of (1069.86mg, 4.81mmol) and toluene (20mL) was stirred at 120 deg.C under nitrogen for 16 h. The residue was purified by column chromatography on silica eluting with MeOH/DCM (0 to 7%) to give (3S) -1- [ (4-methoxyphenyl) methyl ] amine as a yellow oil ]Pyrrolidin-3-yl thioacetate (120mg, 11%). For C₁₄H₁₉NO₂S[M+H]⁺Calculated MS ESI of 266.11; found 266.05.¹H-NMR(400MHz,CDCl₃)δ7.35-7.33(m,2H),6.92-6.90(m,2H),5.73-5.71(m,1H),3.83(s,3H),3.76-3.73(m,3H),3.05-2.95(m,3H),2.57(s,3H),2.48-2.42(m,1H),2.15-2.05(m,1H)。

And 4, step 4: (3S) -3- (1, 1-Difluoroethoxy) -1- [ (4-methoxyphenyl) methyl group]Pyrrolidine as a therapeutic agent

To (3S) -1- [ (4-methoxyphenyl) methyl group at room temperature under a nitrogen atmosphere]A stirred solution of pyrrolidin-3-yl thioacetate (120.00mg, 0.45mmol) and tetrabutylammonium dihydrogen fluoride (408.99mg, 1.36mmol) in DCM (4.00mL) was added NBS (32.19mg, 0.18mmol) in portions. The resulting mixture was stirred at room temperature for 1h under nitrogen atmosphere. By adding saturated NaHCO at 0 deg.C₃The reaction was quenched (50 mL). The resulting mixture was extracted with DCM (2 × 50 mL). The combined organic layers were passed over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with MeOH/DCM (0 to 5%) to give (3S) -3- (1, 1-difluoroethoxy) -1- [ (4-methoxyphenyl) methyl ] p]Pyrrolidine (50mg, 41%). For C₁₄H₁₉F₂NO₂[M+H]⁺Calculated MS ESI of 272.14; found 272.20.¹H-NMR(400MHz,CDCl₃)δ7.28-7.25(m,2H),6.90-6.87(m,2H),4.85-4.83(m,1H),3.83(s,3H),2.86-2.22(m,5H),1.95-1.75(m,1H),1.73(t,J＝13.2Hz,1H)。F-NMR(376MHz,CDCl₃)δ-66.52(2F)。

And 5: (3S) -3- (1, 1-Difluoroethoxy) pyrrolidine

Reacting (3S) -3- (1, 1-difluoroethoxy) -1- [ (4-methoxyphenyl) methyl]Pyrrolidine (50.00mg, 0.18mmol), ammonium formate (116.21mg, 1.84mmol), Pd (OH) ₂A mixture of/C (25.88mg, 0.04mmol, 20%) and MeOH (2.00mL) was stirred at 60 deg.C for 1 h. The solid was filtered off. The filtrate was concentrated under reduced pressure to give (3S) -3- (1, 1-difluoroethoxy) pyrrolidine as a yellow oil (40mg, crude). For C₆H₁₁F₂NO[M+H]⁺Calculated MS ESI of 152.08; found 152.05.

Intermediate 44: (3S) -3- (1, 1-Difluoroethoxy) pyrrolidine

Step 1: n- [1- (trifluoromethyl) pyrazol-4-yl]Carbamic acid tert-butyl ester

To a stirred solution of 1- (trifluoromethyl) pyrazol-4-amine (0.30g, 1.99mmol) and di-tert-butyl dicarbonate (0.69g, 3.18mmol) in THF (9mL) at room temperature was added NaHCO₃(417.0mg, 4.96mmol) in water (3 mL). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The mixture was diluted with water (25mL) and extracted with EtOAc (3 × 40 mL). The combined organic layers were passed over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatographyPurification by elution with PE/EtOAc (9:1) afforded N- [1- (trifluoromethyl) pyrazol-4-yl as a yellow solid]Tert-butyl carbamate (0.46g, 92%). For C₉H₁₂F₃N₃O₂[M+H]⁺MS ESI of 252.09, found 252.10. H-NMR (400MHz, chloroform-d) delta 8.11(s,1H),7.63(s,1H),6.42(s,1H),1.54(s, 9H). F-NMR (376MHz, CDCl) ₃)δ-60.69(3F)。

Step 2: N-methyl-N- [1- (trifluoromethyl) pyrazol-4-yl]Carbamic acid tert-butyl ester

To a stirred solution of NaH (99.35mg, 4.14mmol, 60%) in THF (5.00mL) was added N- [1- (trifluoromethyl) pyrazol-4-yl in THF (2.0mL) dropwise at 0 deg.C]Tert-butyl carbamate (0.52g, 2.07 mmol). The resulting mixture was stirred at 0 ℃ for 1 h. MeI (0.59g, 4.14mmol) was added to the above mixture at 0 ℃. The resulting mixture was stirred at room temperature for a further 1 h. The resulting mixture was quenched with water (20mL) and extracted with EA (3 × 60 mL). The combined organic layers were passed over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EA (5:1) to give N-methyl-N- [1- (trifluoromethyl) pyrazol-4-yl) as a yellow solid]Tert-butyl carbamate (0.50g, 91%). For C₁₀H₁₄F₃N₃O₂[M+H]⁺MS ESI of 266.10, found 266.20. H-NMR (400MHz, chloroform-d) delta 8.10(s,1H),7.83(s,1H),3.27(s,3H),1.54(s, 9H).

And step 3: (3S) -1- [ (4-methoxyphenyl) methyl group]Pyrrolidin-3-yl thioacetate

To N-methyl-N- [1- (trifluoromethyl) pyrazol-4-yl at room temperature]Tert-butyl carbamate (0.60g, 2.26mmol) in dioxane (1.0mL) HCl (4M in dioxane, 5.00mL) was added. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give N-methyl-1- (trifluoromethyl) pyrazol-4-amine hydrochloride (0.40g, crude) as a yellow solid. For C ₅H₇ClF₃N₃[M+H-HCl]⁺Calculated MS ESI of 166.05, found 166.00. H-NMR (400MHz, d)₆-DMSO)δ8.77(s,2H),8.38(s,1H),7.98(s,1H),2.81(s,3H)。

Intermediate 45: 4- (2,2, 2-trifluoroethyl) pyrrolidine-3-benzoic acid ester

Step 1: 3-hydroxy-4-methylenepyrrolidine-1-carboxylic acid tert-butyl ester

Stirring (CH) at-10 ℃ under nitrogen atmosphere₃)₃To a mixture of Si (24.46g, 119.86mmol) in THF (225.00mL) was added n-BuLi (44.35mL, 110.88mmol) dropwise. The reaction mixture was stirred at-10 ℃ for 30min under nitrogen atmosphere. Adding 6-oxa-3-azabicyclo [3.1.0 ] dropwise to the mixture at-10 deg.C]Hexane-3-carboxylic acid tert-butyl ester (5.55g, 29.96mmol) in THF (45.00 mL). The reaction mixture was allowed to warm slowly to room temperature over 1h, then stirred at room temperature under nitrogen for 3 h. The resulting mixture was quenched by the addition of water (300 mL). The resulting mixture was extracted with EA (3 × 200 mL). The combined organic layers were washed with brine (300mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA (0-100%) in PE. The fractions containing the desired product were combined and concentrated to give tert-butyl 3-hydroxy-4-methylenepyrrolidine-1-carboxylate (2.5g, 42%) as a light brown oil. For C ₁₀H₁₇NO₃[M-t-Bu+H]⁺MS ESI of 144.06, found 144.10.

Step 2: 3-hydroxy-4- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a mixture of tert-butyl 3-hydroxy-4-methylenepyrrolidine-1-carboxylate (1.00g, 5.02mmol), tris (2, 2-bipyridine) ruthenium dichloride (0.16g, 0.25mmol) and 8- (trifluoromethyl) -8-thiatricyclo [7.4.0.0^ [2,7 ^ a ]]]Tridec-1 (13),2,4,6,9, 11-hexaen-8-ium; to a solution of trifluoromethanesulfonic acid (2.43g, 6.02mmol) in MeOH (15.00mL) was added pyridine (0.48g, 6.02 mmol). The reaction mixture was irradiated with a fluorescent lamp and stirred at room temperature under argon atmosphere for 16 h. By adding NaHCO₃The resulting mixture was quenched with aqueous solution (saturated, 100 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with water (50mL) and brine (1 × 50mL) over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EA (0-100%). The fractions containing the desired product were combined and concentrated to give tert-butyl 3-hydroxy-4- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxylate as a yellow oil (480mg, 36%). For C₁₁H₁₈F₃NO₃[M–t-Bu+H]⁺MS ESI of 214.06, found 214.05.

And step 3: 3- (benzoyloxy) -4- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxylic acid tert-butyl ester

To a stirred solution of 3-hydroxy-4- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (65.00mg, 0.24mmol) in DCM (3.50mL) was added TEA (122.14mg, 1.207mmol), DMAP (32.44mg, 0.266mmol) and benzoyl chloride (67.87mg, 0.483mmol) at 0 ℃ under nitrogen. The reaction mixture was put under nitrogen atmosphereStir at rt for 16 h. The resulting mixture was quenched by the addition of water (20 mL). The resulting mixture was extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA (0-50%) in PE. Fractions containing the desired product were combined and concentrated to give tert-butyl 3- (benzoyloxy) -4- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxylate as a pale yellow solid (60mg, 67%). For C₁₈H₂₂F₃NO₄[M–t-Bu+H]⁺MS ESI of 318.09, found 318.05.

And 4, step 4: 4- (2,2, 2-trifluoroethyl) pyrrolidine-3-benzoic acid ester; trifluoroacetic acid

To a stirred solution of 3- (benzoyloxy) -4- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (60.00mg, 0.161mmol) in DCM (2.50mL) was added TFA (0.50mL) dropwise at room temperature. The reaction solution was stirred at room temperature for 2 h. Concentrating the resulting mixture under reduced pressure to give 4- (2,2, 2-trifluoroethyl) pyrrolidine-3-benzoic acid ester as a brown oil; trifluoroacetic acid (65 mg). The product was used in the next step without further purification. For C ₁₅H₁₅F₆NO₄[M-TFA+H]⁺MS ESI of 274.10, found 274.05.

Intermediate 46: (3R) -3- (trifluoromethoxy) pyrrolidine hydrochloride

Step 1: (3R) -3- (trifluoromethoxy) pyrrolidine-1-carboxylic acid benzyl ester

To a stirred mixture of AgOTf (34.84g, 135.59mmol) and KF (10.50g, 180.79mmol), Selectfluor (24.02g, 67.79mmol), (3R) -3-hydroxypyrrolidine-1-carboxylic acid benzyl ester (10.00g, 45.20mmol) in EtOAc (270mL) was added 2-fluoropyridine (13.16g, 135.54mmol) and TMSCF dropwise at 0 deg.C under a nitrogen atmosphere₃(19.28g, 135.59 mmol). The resulting mixture was stirred at room temperature under nitrogen for 12 h. The resulting mixture was filtered and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (5:1) to give benzyl (3R) -3- (trifluoromethoxy) pyrrolidine-1-carboxylate (2.6g, 15%) as a colorless oil. For C₁₃H₁₄F₃NO₃[M+H]⁺MS ESI of 290.09, found 290.10.¹H-NMR(400MHz,d₆-DMSO):δ7.38-7.30(m,5H),5.13-5.03(m,3H),3.66-3.22(m,4H),2.20-2.13(m,2H)。¹⁹F-NMR(376MHz,d₆-DMSO):-56.83。

Step 2: (3R) -3- (trifluoromethoxy) pyrrolidine hydrochloride

To a stirred solution of benzyl (3R) -3- (trifluoromethoxy) pyrrolidine-1-carboxylate (1.00g, 3.28mmol) in MeOH (10mL) at room temperature under a nitrogen atmosphere was added Pd (OH)₂C (46.12mg, 0.33mmol, 20%). The resulting mixture was stirred at room temperature under hydrogen atmosphere for 1 h. The resulting mixture was filtered and the filter cake was washed with MeOH (5 × 10 mL). The filtrate was treated with HCl (2mL, 4M in dioxane) and concentrated under reduced pressure to give (3R) -3- (trifluoromethoxy) pyrrolidine hydrochloride as a pale yellow solid (600mg, crude). For C ₅H₉ClF₃NO[M+H-HCl]⁺MS ESI of 156.12, found 156.10. H-NMR (400MHz, DMSO-d)₆)δ9.97-9.77(m,2H),5.25-5.22(m,1H),3.50-3.18(m,4H),2.26-2.15(m,2H)。

Intermediate 47: (3S) -3- (trifluoro-3Methoxy) pyrrolidine hydrochloride

The title compound was prepared using a procedure analogous to that described for intermediate 35, substituting (3R) -3-hydroxypyrrolidine-1-carboxylic acid benzyl ester with (3S) -3-hydroxypyrrolidine-1-carboxylic acid benzyl ester to give the title compound as a solid.

Intermediate 48: 3-cyclopropropylidene pyrrolidine hydrochloride

Step 1: 3-Cyclopropylenepyrrolidine-1-carboxylic acid tert-butyl ester

To a mixture of (3-bromopropyl) triphenylphosphonium bromide (10.02g, 21.60mmol) in DME (23.00mL) at 0 deg.C was added NaH (1.73g, 43.25mmol, 60%). The reaction mixture was stirred at 65 ℃ for 6 h. To the above mixture was added 3-oxopyrrolidine-1-carboxylic acid tert-butyl ester (1.00g, 5.40mmol) at 65 ℃. The resulting mixture was stirred at 65 ℃ for a further 22 h. The reaction was quenched by addition of water/ice (30mL) at 0 ℃. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (10mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (5: 1). The fractions containing the desired product were combined and concentrated to give tert-butyl 3-cyclopropylylidenepyrrolidine-1-carboxylate as a pale yellow oil (0.49g, 39%). For C ₁₂H₁₉NO₂[M+H-56]⁺MS ESI of 154.14, found 153.90.

Step 2: 3-cyclopropropylidene pyrrolidine hydrochloride

To a stirred mixture of tert-butyl 3-cyclopropylidene pyrrolidine-1-carboxylate (0.49g, 2.34mmol) in 1, 4-dioxane (2.00mL) was added dropwise HCl (gaseous) in 1, 4-dioxane (2.00mL) at 0 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under nitrogen for 2 h. The resulting mixture was concentrated under vacuum. This gave 3-cyclopropylidene pyrrolidine hydrochloride as a brown oil (0.46g, 67%). For C₇H₁₂ClN[M+H-HCl]⁺Calculated MS ESI of 110.09; found 110.20.

Intermediate 49: 4- (trifluoromethoxy) pyrazolidine-1-carboxylic acid benzyl ester 2,2, 2-trifluoroacetate salt

Step 1: n- (tert-butyloxycarbonyl) benzyloxy carbohydrazide

To a stirred solution of benzyloxycarbohydrazide (5.00g, 30.09mmol) and TEA (3.65g, 36.11mmol) in THF (15.00mL) at room temperature under nitrogen was added dropwise (Boc)₂A solution of O (7.88g, 36.11mmol) in THF (10.00 mL). The reaction mixture was stirred at room temperature under nitrogen overnight. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with hexane (100mL) to give N- (tert-butoxycarbonyl) benzyloxycarbohydrazide as an off-white solid (7.1g, 89%). For C ₁₃H₁₈N₂O₄[M-Boc+H]⁺MS ESI of 167.07, found 167.10.

Step 2: tert-butyl [ (1, 3-dibromopropan-2-yl) oxy]Dimethyl siliconAlkane (I) and its preparation method

To a stirred solution of 1, 3-dibromo-2-propanol (10.00g, 45.90mmol) in DCM (50.00mL) was added 1H-imidazole (3.28g, 48.19mmol), TBS-Cl (7.26g, 48.19mmol), and DMAP (0.56g, 4.59mmol) at 0 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at room temperature under nitrogen for 16 h. The reaction was quenched by addition of water (100mL) at room temperature. The resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with water (100mL) and brine (100mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA/PE (0-20%). The fractions containing the desired product were combined and concentrated to give tert-butyl [ (1, 3-dibromopropan-2-yl) oxy ] as a pale yellow oil]Dimethylsilane (14.3g, 94%). H-NMR (400MHz, CDCl)₃)δ4.08-4.01(m,1H),3.55-3.48(m,4H),0.94(s,9H),0.17(s,6H)。

And step 3: 1-benzyl-2-tert-butyl-4-hydroxypyrazolidine-1, 2-dicarboxylate

To a stirred mixture of NaH (3.61g, 90.32mmol) in DMF (30.00mL) at 0 deg.C under nitrogen was added dropwise a solution of N- (tert-butoxycarbonyl) benzyloxycarbohydrazide (10.58g, 39.74mmol) in DMF (48.00 mL). The reaction mixture was stirred at room temperature under nitrogen for 45 min. To the above mixture was added dropwise tert-butyl [ (1, 3-dibromopropan-2-yl) oxy group at room temperature ]Dimethylsilane (12.00g, 36.13 mmol). The reaction mixture was stirred at room temperature for an additional 36 h. With NH at room temperature₄The reaction was quenched with aqueous Cl (sat, 500 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (300mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gelPurification by chromatography, eluting with EA (0-50%) in PE. Fractions containing the desired product were combined and concentrated to give 1-benzyl 2-tert-butyl 4-hydroxypyrazolidine-1, 2-dicarboxylate (2.3g, 20%) as a light brown oil. For C₂₂H₃₆N₂O₅Si[M–Boc+H]⁺MS ESI of (a) calculated 337.20, found 337.10.

And 4, step 4: 1-benzyl-2-tert-butyl-4-hydroxypyrazolidine-1, 2-dicarboxylate

To 1-benzyl 2-tert-butyl 4- [ (tert-butyldimethylsilyl) oxy) at 0 ℃ under nitrogen atmosphere]TBAF (6.05mL, 6.05mmol) was added dropwise to a stirred solution of pyrazolidine-1, 2-dicarboxylate (2.2g, 5.04mmol) in THF (30.00 mL). The reaction solution was stirred at room temperature under nitrogen atmosphere for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EA (0-100%) in PE. Fractions containing the desired product were combined and concentrated to give 1-benzyl 2-tert-butyl 4-hydroxypyrazolidine-1, 2-dicarboxylate (1.55g, 95%) as a yellow oil. For C ₁₆H₂₂N₂O₅[M+H]⁺MS ESI of (a) calculated 323.15, found 323.10.

And 5: 1-benzyl 2-tert-butyl 4- (trifluoromethoxy) pyrazolidine-1, 2-dicarboxylic acid ester

To argentio trifluoromethanesulfonate (3.71g, 14.44mmol) and KF (1.12g, 19.28mmol), 4- (chloromethyl) -1-fluoro-1, 4-diazabicyclo [2.2.2 ] under nitrogen at room temperature]Octane-1, 4-diimmonium; to a stirred solution of bis (tetrafluoroborate) (2.56g, 7.23mmol), 1-benzyl 2-tert-butyl 4-hydroxypyrazolidine-1, 2-dicarboxylate (1.55g, 4.81mmol) in EA (25.00mL) was added 2-fluoropyridine (1.40g, 14.42mmol) and TMSCF dropwise₃(2.05g，14.42 mmol). The reaction mixture was stirred at room temperature under nitrogen for 12 h. The resulting mixture was filtered. The filter cake was washed with EtOAc (3 × 25 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA (0-40%) in PE. Fractions containing the desired product were combined and concentrated to give 1-benzyl 2-tert-butyl 4- (trifluoromethoxy) pyrazolidine-1, 2-dicarboxylate (0.35g, 19%) as a colorless oil. For C₁₇H₂₁F₃N₂O₅[M–Boc+H]⁺MS ESI of 291.09, found 291.05.

Step 6: 4- (trifluoromethoxy) pyrazolidine-1-carboxylic acid benzyl ester 2,2, 2-trifluoroacetate salt

To a stirred solution of 1-benzyl 2-tert-butyl 4- (trifluoromethoxy) pyrazolidine-1, 2-dicarboxylate (70.00mg, 0.18mmol) in DCM (2.50mL) was added TFA (0.50mL) dropwise at room temperature. The reaction solution was stirred at room temperature for 2 h. The resulting solution was concentrated under reduced pressure to give benzyl 4- (trifluoromethoxy) pyrazolidine-1-carboxylate 2,2, 2-trifluoroacetate salt as a light brown oil (65mg, 93%). For C ₁₄H₁₄F₆N₂O₅[M–TFA+H]⁺MS ESI of 291.09, found 290.95.

Intermediate 50: 2-fluoro-4-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)

Aniline

In N₂To a solution of 5-bromo-2-fluoro-4-methylaniline (2.0g, 9.8mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (2.7g, 10.8mmol) and KOAc (2.9g, 29.4mmol) in dioxane (20mL) was added Pd (dppf) Cl₂(359mg，0.49mmol) and the mixture was stirred at 100 ℃ for 16 h. The reaction was cooled to room temperature and the mixture was filtered. The filtrate was concentrated to give 2-fluoro-4-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (crude) which was used in the next step without any further purification. MS calculated: 251, found value of MS 252([ M + H)]⁺)。

Intermediate 51: 4- (6- (3- (benzyloxy) cyclobutoxy) -4-iodopyridin-2-yl) morpholine

The title compound was prepared using a procedure similar to that described for intermediate 54, step 2, substituting 3- (benzyloxy) cyclobutane-1-ol for 2- (tetrahydropyran-2-yloxy) ethanol to give the title compound as a solid.

Intermediate 52: 3- ((4-iodo-6-morpholinopyridin-2-yl) oxy) cyclopentan-1-ol

The title compound was prepared using a procedure similar to that described for intermediate 54, step 2, substituting cyclopentane-1, 3-diol for 2- (tetrahydropyran-2-yloxy) ethanol to give the title compound as a solid.

Intermediates 53 and 54: (1S,4S) -4- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]-1-methylcyclohexane Alk-1-ols (cis) and (1R,4R) -4- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]-1-methylcyclohexane-1- Alcohol (trans)

Step 1: 4- (benzyloxy) -1-methylcyclohexane-1-ol

To a stirred solution of 4- (benzyloxy) cyclohexan-1-one (2.50g, 12.24mmol) in THF (25.00mL) at-70 deg.C under a nitrogen atmosphere was added dropwise 1MCH in THF₃MgBr (3.18mL, 3.18 mmol). The reaction mixture was stirred at room temperature under nitrogen for 16 h. The resulting mixture was reacted with NH at 0 deg.C₄Aqueous Cl (saturated, 100ml) was quenched. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA in PE (50%). The fractions containing the desired product were combined and concentrated to give 4- (benzyloxy) -1-methylcyclohexan-1-ol as a pale yellow oil (1.05g, 39%). H-NMR (400MHz, CDCl)₃)δ7.40-7.33(m,5H),4.59-4.52(m,2H),3.61-3.55(m,1H),1.90-1.69(m,6H),1.50-1.40(m,2H),1.29-1.25(m,3H)。

Step 2: 1-methylcyclohexane-1, 4-diol

A mixture of 4- (benzyloxy) -1-methylcyclohexan-1-ol (1.05g, 4.77mmol), Pd/C (0.50g, 0.47mmol, 10%), HCOOH (0.75mL), and MeOH (5.00mL) was stirred under an atmosphere of hydrogen (2atm) at room temperature for 16 h. The resulting mixture was filtered. The filter cake was washed with MeOH (4 × 10 mL). The combined filtrates were concentrated under reduced pressure to give 1-methylcyclohexane-1, 4-diol (0.60g, 97%) as a pale yellow oil. H-NMR (400MHz, CDCl) ₃)δ3.93-3.62(m,1H),2.50-1.43(m,8H),1.30-1.25(m,3H)。

And step 3: (1S,4S) -4- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]-1-methylcyclohexan-1-ol (cis); (1R,4R) -4- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]-1-methylcyclohexane-1-ol (trans)

To a stirred mixture of NaH (0.16g, 3.90mmol) in DMF (4.00mL) at 0 deg.C under nitrogen was added dropwise a solution of 1-methylcyclohexane-1, 4-diol (0.51g, 3.90mmol) in DMF (4.00 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 h. To the above mixture was added a solution of 4- (6-fluoro-4-iodopyridin-2-yl) morpholine (0.40g, 1.30mmol) in DMF (2.00mL) at room temperature. The reaction mixture was stirred at 100 ℃ for a further 2 h. The resulting mixture was allowed to cool to room temperature and quenched with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA (0-70%) in PE. The fractions containing the desired product were combined and concentrated to give (1S,4S) -4- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl) as an off-white solid]Oxy radical]-1-methylcyclohexan-1-ol (0.13g, 46%) (cis). For C ₁₆H₂₃IN₂O₃[M+H]⁺MS ESI of 419.08, found 419.05. H-NMR (400MHz, d)₆-DMSO). delta.6.68-6.65 (m,1H),6.44-6.39(m,1H),4.84-4.75(m,1H),4.14(s,1H),3.72-3.66(m,4H),3.42-3.37(m,4H),1.77-1.67(m,4H),1.62-1.58(m,2H),1.45-1.33(m,2H),1.12(s, 3H). In addition, (1R,4R) -4- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl) is obtained as an off-white solid]Oxy radical]-1-methylcyclohexan-1-ol (0.10g, 37%) (trans). For C₁₆H₂₃IN₂O₃[M+H]⁺MS ESI of 419.08, found 419.10. H-NMR (400MHz, d)₆-DMSO)δ6.66-6.65(m,1H),6.44-6.43(m,1H),4.98-4.92(m,1H),4.10(s,1H),3.72-3.66(m,4H),3.42-3.39(m,4H),1.94-1.84(m,2H),1.62-1.52(m,4H),1.45-1.39(m,2H),1.15(s,3H)。

Intermediate 55: (4- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl)]Oxy radical]-1-methylcyclobutan-1-ol

Step 1: [3- (benzyloxy) -1-methylcyclobutoxy group](tert-butyl) diphenylsilane

To a stirred solution of 3- (benzyloxy) -1-methylcyclobutan-1-ol (1.00g, 5.20mmol) and imidazole (0.71g, 10.40mmol) in DMF (10.00mL) at 0 deg.C was added tert-butyl (chloro) diphenylsilane (2.02mL, 7.79 mmol). The reaction mixture was stirred at 20 ℃ for 18 h. The resulting mixture was diluted with water (100mL) and extracted with EA (4x100 mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA/PE (0-12%). The fractions containing the desired product were combined and concentrated to give [3- (benzyloxy) -1-methylcyclobutoxy) -1-methyl cyclobutoxy as a colorless crude oil ](tert-butyl) diphenylsilane (1.25g, 56%). H-NMR (400MHz, DMSO-d)₆)δ7.76-7.27(m,15H),4.33-4.31(m,2H),3.60-3.53(m,1H),2.27-2.16(m,4H),1.19-1.18(m,3H),1.06-1.05(m,9H)。

Step 2: 3- [ (tert-butyldiphenylsilyl) oxy group]-3-methylcyclobutan-1-ol

To [3- (benzyloxy) -1-methylcyclobutoxy group]To a mixture of (tert-butyl) diphenylsilane (1.25g, 2.90mmol) and Pd/C (0.31g, 0.29mmol, 10%) in MeOH (20.00mL) was added HCO₂H (1.00 mL). By H₂The reaction mixture was degassed three times and stirred at room temperature for 2 days. The resulting mixture was filtered and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EtOAc (4: 1). Combining the fractions containing the desired product andconcentration gave 3- [ (tert-butyldiphenylsilyl) oxy) as a colorless oil]-3-methylcyclobutan-1-ol (0.60g, 61%). H-NMR (400MHz, CDCl)₃)δ7.76-7.71(m,4H),7.47-7.38(m,6H),3.81-3.74(m,1H),2.31-2.25(m,2H),2.13-2.07(m,2H),1.21(m,3H),1.06-1.04(m,9H)。

And step 3: 4- (6- [3- [ (tert-butyldiphenylsilyl) oxy)]-3-methylcyclobutoxy group]-4-iodopyridine- 2-yl) morpholine and 3- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]-1-methylcyclobutan-1-ol

To 3- [ (tert-butyldiphenylsilyl) oxy group at 0 ℃ under a nitrogen atmosphere]To a stirred solution of-3-methylcyclobutan-1-ol (0.35g, 1.03mmol) in DMF (3.00mL) was added NaH (41.11mg, 1.03mmol, 60%). The reaction mixture was stirred at room temperature for 1 h. To the above mixture was added 4- (6-fluoro-4-iodopyridin-2-yl) morpholine (0.10g, 0.34mmol) at room temperature. The reaction mixture was stirred at room temperature for a further 16 h. By addition of saturated NaHCO at room temperature ₃The resulting mixture was quenched with aqueous solution (100 mL). The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (3 × 50mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EA (2: 1). The fractions containing the desired product were combined and concentrated to give 4- (6- [3- [ (tert-butyldiphenylsilyl) oxy) as an off-white solid]-3-methylcyclobutoxy group]-4-iodopyridin-2-yl) morpholine (0.13g, 18%). For C₃₀H₃₇IN₂O₃Si[M+H]⁺MS ESI of 629.16, found 629.00.

And 4, step 4: 3- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]-1-methylcyclobutan-1-ol and 3- [ [4- Iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]-1-methylcyclobutan-1-ol

To 4- (6- [3- [ (tert-butyldiphenylsilyl) oxy) at ℃ under nitrogen atmosphere]-3-methylcyclobutoxy group]To a stirred solution of-4-iodopyridin-2-yl) morpholine (0.15g, 0.24mmol) in THF (2.00mL) was added TBAF (0.36mL, 0.36mmol, 1M). The reaction mixture was stirred at 80 ℃ for 3h under nitrogen atmosphere. The resulting mixture was quenched by the addition of water (100 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (3 × 50mL) and dried over anhydrous Na ₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/(EA/EtOH ═ 3:1) (2: 1). The fractions containing the desired product were combined and concentrated to give 3- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl) as an off-white solid]Oxy radical]-1-methylcyclobutan-1-ol (30mg, 32%). For C₁₄H₁₉IN₂O₃[M+H]⁺MS ESI of 391.04, found 390.90.¹H-NMR(400MHz,DMSO-d₆)δ6.67(s,1H),6.42(s,1H),5.08(s,1H),4.68-4.61(m,1H),3.68-3.65(m,4H),3.41-3.39(m,4H),2.48-2.43(m,2H),2.09-2.04(m,2H),1.25(s,3H)。

Intermediate 56: 1- ([ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl)]Oxy radical]Methyl) cyclopropane-1-ol

Step 1: 1- (hydroxymethyl) cyclopropane-1-ol

To a stirred solution of 1-hydroxycyclopropane-1-carboxylic acid (0.6g, 5.88mmol) in THF (10.00mL) at 0 deg.C under nitrogen was added LiAlH in portions₄(0.33g, 8.82 mmol). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was washed successively with water (0.6) at 0 deg.C6mL), NaOH (10% aq, 1.32mL), and water (1.98 mL). The resulting mixture was filtered and the filter cake was washed with THF (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA/EtOH (3/1) in PE (60%). Fractions containing the desired product were combined and concentrated to give 1- (hydroxymethyl) cyclopropane-1-ol as a colorless oil (0.62g, 60%). H-NMR (400MHz, d) ₆-DMSO)δ5.14(s,1H),4.53(t,J＝5.6Hz,1H),3.40(d,J＝5.6Hz,2H),0.51-0.42(m,4H)。

Step 2: 1- [ [ (6-fluoro-4-iodopyridin-2-yl) oxy ] group]Methyl radical]Cyclopropane-1-ols

To a stirred solution of 1- (hydroxymethyl) cyclopropane-1-ol (0.62g, 7.05mmol) in DMF (8.00mL) was added t-BuOK (1M in THF, 7.03mL, 7.03mmol) dropwise at 0 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. To the above mixture was added a solution of 2, 6-difluoro-4-iodopyridine (1.70g, 7.03mmol) in DMF (5.00mL) at room temperature. The reaction mixture was stirred at room temperature for a further 16 h. The resulting mixture was quenched with water (150 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 32% EA in PE. The fractions containing the desired product were combined and concentrated to give 1- [ [ (6-fluoro-4-iodopyridin-2-yl) oxy ] as a yellow oil]Methyl radical]Cyclopropane-1-ol (0.32g, 13%). For C₉H₉INO₂[M+H]⁺MS ESI of 309.97, found 309.90.

And step 3: 1- ([ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl)]Oxy radical]Methyl) cyclopropane-1-ol

To 1- [ [ (6-fluoro-4-iodopyridin-2-yl) oxy group at room temperature under a nitrogen atmosphere]Methyl radical ]To a stirred solution of cyclopropane-1-ol (0.32g, 1.02mmol) in DMSO (6.00mL) was added morpholine (97.67mg, 1.12mmol) and DIEA (0.16g, 1.22 mmol). The reaction mixture was stirred at 70 ℃ for 16 h. The resulting mixture was diluted with water (60mL) and extracted with EA (3 × 30 mL). The combined organic layers were washed with brine (50mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA in PE (50%). The fractions containing the desired product were combined and concentrated to give 1- ([ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl) as a pale yellow solid]Oxy radical]Methyl) cyclopropane-1-ol (0.28g, 73%). For C₁₃H₁₇IN₂O₃[M+H]⁺MS ESI of 377.03, found 377.00. H-NMR (400MHz, d)₆-DMSO)δ6.67(s,1H),6.48(s,1H),5.49(s,1H),4.18(s,2H),3.67-3.65(m,4H),3.42-3.39(m,4H),0.66-0.57(m,4H)。

Intermediate 57: 4- [6- [ (3, 3-difluorocyclopentyl) oxy]-4-iodopyridin-2-yl]Morpholine

To a stirred solution of 3, 3-difluorocyclopent-1-ol (0.24g, 1.95mmol) in NMP (2.00mL) at 0 deg.C under nitrogen was added NaH (46.73mg, 1.95 mmol). The reaction mixture was stirred at 25 ℃ for 1 h. To the above mixture was added 4- (6-fluoro-4-iodopyridin-2-yl) morpholine (0.20g, 0.65mmol) at 25 ℃. The reaction mixture was stirred at 100 ℃ for a further 3 h. By adding saturated NaHCO at 0 deg.C ₃The reaction was quenched with aqueous solution (100 mL). The resulting mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with saturated brine (3 × 50mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with PE/EA (2: 1). The fractions containing the desired product were combined and concentrated to give 4- [6- [ (3, 3-difluorocyclopentyl) oxy ] as an off-white solid]-4-iodopyridin-2-yl]Morpholine (0.14g, 52%). For C₁₄H₁₇F₂IN₂O₂[M+H]⁺MS ESI of 411.03, found 411.05.¹H-NMR(400MHz,DMSO-d₆)δ6.71(m,1H),6.45(m,1H),5.36-5.31(m,1H),3.69-3.65(m,4H),3.46-3.41(m,4H),2.70-2.56(m,1H),2.31-2.12(m,3H),1.96-1.85(m,2H)。

⁶Intermediate 58: imino (2- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl)]Oxy radical]Ethyl) methyl-lambda-sulfur Alkanone (sulfanone)

Step 1: 4- [ 4-iodo-6- [2- (methylthio) ethoxy]Pyridin-2-yl]Morpholine

To a stirred solution of 2- (methylthio) ethanol (1g, 11.04mmol) in dioxane (20mL) was added NaH (0.44g, 11.04mmol, 60%) at 0 deg.C under nitrogen. The reaction mixture was stirred at room temperature for 0.5 h. To the above mixture was added 4- (6-fluoro-4-iodopyridin-2-yl) morpholine (0.85g, 2.76mmol) at room temperature. The reaction mixture was stirred at 100 ℃ for a further 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA/PE (0 to 100%). The fractions containing the desired product were combined and concentrated to give 4- [ 4-iodo-6- [2- (methylsulfanyl) ethoxy ] ethyl as a gray solid ]Pyridin-2-yl]Morpholine (1g, 95%). For C₁₂H₁₇IN₂O₂S[M+H]⁺MS ESI of 381.01, found 380.95.

Step 2: 4- [ 4-iodo-6- (2-methanesulfinyl-ethoxy) pyridin-2-yl]Morpholine

To 4- [ 4-iodo-6- [2- (methylthio) ethoxy group at 0 ℃ under nitrogen atmosphere]Pyridin-2-yl]To a stirred solution of morpholine (1g, 2.63mmol) in DCM (20mL) was added m-CPBA (0.59g, 2.89mmol, 85%). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA to EtOH 3:1/PE (0 to 100%). The fractions containing the desired product were combined and concentrated to give 4- [ 4-iodo-6- (2-methanesulfinyl-ethoxy) pyridin-2-yl as a gray solid]Morpholine (0.90g, 86%). For C₁₂H₁₇IN₂O₃S[M+H]⁺MS ESI of 397.00, found 396.90.

⁶And step 3: imino (2- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl)]Oxy radical]Ethyl) methyl-lambda-sulfanyl ketone

To 4- [ 4-iodo-6- (2-methanesulfinyl-ethoxy) pyridin-2-yl]Morpholine (0.5g, 1.26mmol) and ammonium acetate (0.39g, 5.05mmol) in MeOH (2.5mL) was added PhI (OAc)₂(1.2g, 3.79 mmol). The reaction mixture was stirred at room temperature for 0.5h under nitrogen atmosphere. The resulting mixture was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CAN aqueous solution, gradient 20% to 50% within 20 min; detector, UV 254/220 nm. The fractions containing the desired product were combined and concentrated to give imino (2- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl) as a brown solid ]Oxy radical]Ethyl) methyl-lambda⁶Sulfanones (80mg, 15%). For C₁₂H₁₈IN₃O₃S[M+H]⁺Calculated MS ESI of 412.01; found 411.95.

Intermediate 59: 3- ((4-iodo-6-morpholinopyridin-2-yl) oxy) -1-methylcyclopentan-1-ol

The title compound was prepared using a procedure similar to that described for intermediate 4, step 2, substituting 1-methylcyclopentane-1, 3-diol for 2- (tetrahydropyran-2-yloxy) ethanol to give the title compound as a solid.

Intermediate 60: 3- (((4-iodo-6-morpholinopyridin-2-yl) oxy) methyl) oxetan-3-ol

The title compound was prepared using a procedure similar to that described for intermediate 54, step 2, substituting 3- (hydroxymethyl) oxetan-3-ol for 2- (tetrahydropyran-2-yloxy) ethanol to give the title compound as a solid.

Intermediate 61: 3- (2- ((4-iodo-6-morpholinopyridin-2-yl) oxy) ethyl) oxetan-3-ol

The title compound was prepared using a procedure similar to that described for intermediate 54, step 2, substituting 3- (2-hydroxyethyl) oxetan-3-ol for 2- (tetrahydropyran-2-yloxy) ethanol to give the title compound as a solid.

Intermediates 12 and 13: 4- [ 6-chloro-2- [ (3, 3-difluorocyclopentyl) oxy]Pyrimidin-4-yl ]Morpholine

Step 1: (2R) -1- [ (6-fluoro-4-iodopyridin-2-yl) oxy]Propan-2-ol and (2R) -2- [ (6-fluoro-4-iodo) Pyridin-2-yl) oxy]Propane-1-ol

To a solution of R-1, 2-propanediol (5.00g, 65.707mmol, 1.10 equiv.) in DMF (120mL) at 0 deg.C was added NaH (2.63g, 65.756mmol, 1.10 equiv., 60%). The mixture was stirred for 45 min. 2, 6-difluoro-4-iodopyridine (14.40g, 59.756mmol, 1.00 eq.) was added and the mixture was allowed to warm to room temperature and stirred for 3 h. By adding saturated NH at 0 deg.C₄The reaction was quenched with Cl (aq) (100 mL). The resulting mixture was extracted with DCM (4 × 80 mL). The combined organic layers were washed with brine (400mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with 30% EtOAc in PE to give (2R) -1- [ (6-fluoro-4-iodopyridin-2-yl) oxy) as a pale yellow oil]Propan-2-ol (4.8g, 27%) and (2R) -2- [ (6-fluoro-4-iodopyridin-2-yl) oxy]Mixture of propane-1-ols (7.0g, 40%, ratio 2: 1). For C₈H₉FINO₂[M+H]⁺Calculated MS ESI of 297.97; found 298.00.

Step 2: (2R) -1- [ (6-fluoro-4-iodopyridin-2-yl) oxy]Propan-2-ol and (2R) -2- [ (6-fluoro-4-iodo) Pyridin-2-yl) oxy]Propane-1-ol

To (2R) -1- [ (6-fluoro-4-iodopyridin-2-yl) oxy]Propan-2-ol and (2R) -2- [ (6-fluoro-4-iodopyridin-2-yl) oxy]To a mixture of propan-1-ol (1.00g, 3.366mmol, 1.00 equiv) in DMSO (10mL) was added (2S) -2-methylmorpholine (340.49mg, 3.366mmol, 1.00 equiv) and DIEA (522.08mg, 4.039mmol, 1.20 equiv). The resulting mixture was stirred at 70 ℃ for 2 h. Subjecting the mixture to hydrogenation with hydrogen₂O (100mL) was quenched and then extracted with EtOAc (4 × 50 mL). Combined organic layerWashed with brine (5X50mL) over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and extracted with PE/EtOAc (4:1) to give (2R) -2- ([ 4-iodo-6- [ (2S) -2-methylmorpholin-4-yl) as a milky white oil]Pyridin-2-yl]Oxy) propan-1-ol and (2R) -1- ([ 4-iodo-6- [ (2S) -2-methylmorpholin-4-yl]Pyridin-2-yl]Oxy) propan-2-ol mixture (1.2g, 93%). For C₁₃H₁₉IN₂O₃[M+H]⁺Calculated MS ESI of 379.04; found 378.95.

Intermediate 64: (R) -1- ((4-iodo-6- ((R) -2-methylmorpholino) pyridin-2-yl) oxy) propan-2-ol

The title compound was prepared using a procedure similar to that described for intermediates 63 and 2, substituting (2R) -2-methylmorpholine for (2S) -2-methylmorpholine to give the title compound as a solid.

Intermediate 65: (2R) -1- ((6- (2-oxa-5-azabicyclo [ 4.1.0)]Heptane-5-yl) -4-iodopyridine-2- Yl) oxy) propan-2-ol

The title compound was prepared using a procedure analogous to that described for intermediates 63 and 2, substituting 2-oxa-5-azabicyclo [4.1.0] heptane hydrochloride for (2S) -2-methylmorpholine to give the title compound as a solid.

Intermediate 66: (S) -N- (3- (2-chloro-6- ((R) -2-hydroxypropoxy) pyridin-4-yl) -4-methylphenyl) -3- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxamide

Step 1:(R) -1- ((6-chloro-4-iodopyridin-2-yl) oxy) propan-2-ol and (R) -2- ((6-chloro-4-iodopyridin-2-yl) oxy) propan-1-ol

To a solution of R-1, 2-propanediol (1.53g, 20.082mmol, 1.10 equiv.) in DMF (50mL) at 0 deg.C was added NaH (0.80g, 20.082mmol, 1.10 equiv., 60%). The mixture was stirred at 25 ℃ for 1 h. 2, 6-dichloro-4-iodopyridine (5.00g, 18.256mmol, 1.00 eq.) was added and the mixture was stirred at 25 ℃ for 2 h. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE/EtOAc (1:1) to give a mixture of (R) -1- ((6-chloro-4-iodopyridin-2-yl) oxy) propan-2-ol and (R) -2- ((6-chloro-4-iodopyridin-2-yl) oxy) propan-1-ol as an off white oil (1.2g, 21%). For C ₈H₉ClINO₂[M+H]⁺MS ESI of 313.94, found 313.95. H-NMR (300MHz, chloroform-d) δ 7.33-7.27 (m,1H),7.12(dd, J ═ 12.6,1.1Hz,1H),6.82(d, J ═ 5.4Hz,1H), 4.25-4.09 (m,2H),1.49(d, J ═ 6.4Hz,1H), 1.36-1.26 (m, 3H).

Step 2: (3S) -N- (3- [ 2-chloro-6- [ (2R) -2-hydroxypropoxy group)]Pyridin-4-yl]-4-methylphenyl) -3- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxamide

Reacting (2R) -1- [ (6-chloro-4-iodopyridin-2-yl) oxy]Propan-2-ol and (2R) -2- [ (6-fluoro-4-iodopyridin-2-yl) oxy]Propan-1-ol (1.20g, 3.828mmol, 1.00 equiv), (3S) -N- [ 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-3- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxamide (1.58g, 3.828 m)mol, 1 equivalent), Pd (dppf) Cl₂-CH₂Cl₂(0.31g, 0.383mmol, 0.1 equiv.) and Na₂CO₃(1.22g, 11.483mmol, 3 equiv.) in dioxane (12.00mL) and H₂The mixture in O (1.20mL) was stirred at 80 ℃ for 2h under nitrogen. The reaction mixture was concentrated under reduced pressure. The compounds were separated by preparative chiral HPLC using the following conditions: (column: CHIRALPAK IG, 5X 25cm, 10 um; mobile phase A: CO₂And the mobile phase B: MeOH (0.1% 2M NH)₃-MeOH); flow rate: 180 mL/min; gradient: 45% of B; 220 nm; RT 1: 5.32 of; RT 2: 6.85; injection volume: 2.5 ml; the operation number is as follows: 16). The collected fractions were combined and concentrated under reduced pressure to give (3S) -N- (3- [ 2-chloro-6- [ (2R) -2-hydroxypropoxy) as a pale yellow solid ]Pyridin-4-yl]-4-methylphenyl) -3- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxamide (650mg, 36%). For C₂₂H₂₅ClF₃N₃O₃[M+H]⁺MS ESI of 472.15, found 472.15. H-NMR (300MHz, chloroform-d) δ 7.37-7.28 (m,2H),7.20(d, J ═ 8.3Hz,1H),6.92(d, J ═ 1.1Hz,1H),6.67(d, J ═ 1.1Hz,1H),6.27(s,1H),4.38(t, J ═ 7.5Hz,1H), 4.30-4.15 (m,2H),3.82(t, J ═ 8.6Hz,1H),3.65(t, J ═ 9.0Hz,1H),3.45(q, J ═ 9.2Hz,1H),3.13(t, J ═ 9.4Hz,1H),2.56(d, J ═ 9.5, 2H), 2.34-2.23 (m, 1.24, 24 (m,2H), 3.6 (t, 3.6H, 1H),3.6 (t, J ═ 9.6Hz, 1H).

Intermediate 67: (2R,3R) -3- ((4-iodo-6-morpholinopyridin-2-yl) oxy) butan-2-ol

Step 1: 4- (6-fluoro-4-iodopyridin-2-yl) morpholine

To a stirred solution of 2, 6-difluoro-4-iodopyridine (16.00g, 66.40mmol) in DMSO (240mL) at room temperature under a nitrogen atmosphere was added morpholine (5.49mL, 63.04 mmo)l) and DIEA (12.07mL, 93.40 mmol). The reaction mixture was stirred at 70 ℃ for 3 h. The resulting mixture was cooled to room temperature, diluted with water (150mL) and extracted with EA (300mL x 3). The combined organic layers were washed with brine (100 mL. times.4) and over anhydrous Na₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 30% EA in PE to give 4- (6-fluoro-4-iodopyridin-2-yl) morpholine as an off white solid (17.60g, 86%). For C ₉H₁₀FIN₂O[M+H]⁺MS ESI of 308.98, found 309.10.

Step 2: (2R,3R) -3- ((4-iodo-6-morpholinopyridin-2-yl) oxy) butan-2-ol

To a solution of (2R,3R) -butane-2, 3-diol (1.40g, 16.31mmol) in DMF (20mL) at 0 deg.C was added NaH (260mg, 60%, 6.50 mmol). The reaction mixture was stirred at 0 ℃ for 30 min. 4- (6-fluoro-4-iodopyridin-2-yl) morpholine (1.00g, 3.20mmol) was then added to the reaction mixture. The mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water (30mL) and extracted with DCM (30mL × 2). The combined organic layers were washed with Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 20% EA in PE to give (2R,3R) -3- ((4-iodo-6-morpholinopyridin-2-yl) oxy) butan-2-ol (1.20g, 80%) as a yellow oil. For C₁₉H₁₉IN₂O₃[M+H]⁺MS ESI of 379.04, found 379.10.

Intermediate 68: (S) -3- (difluoromethoxy) -N- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxan Boroacropin-2-yl) phenyl) pyrrolidine-1-carboxamide

Step 1: (S) -3- (difluoromethoxy) pyrrolidine

To a solution of (S) -3- (difluoromethoxy) pyrrolidine-1-carboxylic acid benzyl ester (7.00g, 25.80mmol) in DCM (100mL) was added TFA (20 mL). The reaction mixture was stirred at room temperature overnight. The solution was concentrated in vacuo to give the TFA salt of (S) -3- (difluoromethoxy) pyrrolidine as a yellow oil (7.01g, crude).

Step 2: (S) -3- (difluoromethoxy) -N- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan) Cyclopentan-2-yl) phenyl) pyrrolidine-1-carboxamide

To a solution of 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (1.01g, 4.29mmol) and DIEA (2.80g, 21.50mmol) in THF (50mL) at 0 deg.C under a nitrogen atmosphere was added BTC (510mg, 1.72 mmol). The reaction mixture was stirred at 0 ℃ for 30 min. To the mixture was then added the TFA salt of (S) -3- (difluoromethoxy) pyrrolidine (2.10g, 8.33 mmol). The mixture was stirred at 0 ℃ for a further 1 h. The mixture was concentrated and purified by silica gel column chromatography eluting with 50% EA in PE to give (S) -3- (difluoromethoxy) -N- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyrrolidine-1-carboxamide as a white solid (300mg, 17%). For C₁₆H₂₃IN₂O₄[M+H]⁺Calculated MS ESI of 397.20, found 397.30

Intermediate 69: n- (3-bromo-4-methylphenyl) -3- (tert-butyl) -1H-pyrrole-1-carboxamide

N- (3-bromo-4-methylphenyl) -3- (tert-butyl) -1H-pyrrole-1-carboxamide

To a solution of 3- (tert-butyl) -1H-pyrrole (300mg, 2.44mmol) in THF (20mL) at 0 deg.C was added n-BuLi (1.07mL, 2.68 mmol). The reaction mixture was then stirred at room temperature for 30 min. To another flask were added BTC (288mg, 1.04mmol), DIEA (1.26g, 9.76mmol) and THF (20 mL). The mixture was then stirred at-78 ℃ for 5 min. After stirring, the mixture was added to the previous solution and stirred at-78 ℃ for 30 min. The mixture was then stirred at room temperature for a further 30 min. The resulting mixture was quenched with water (100mL) and extracted with EtOAc (50 mL. times.3). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na ₂SO₄Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA in PE (0-50%) to give N- (3-bromo-4-methylphenyl) -3- (tert-butyl) -1H-pyrrole-1-carboxamide (117mg, 14%) as a yellow solid. For C₁₆H₁₉BrN₂O[M+H]⁺MS ESI of 335.07, found 335.10.

Intermediate 70: (R) -4- (6- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy) -4-iodopyridine-2- Base) morpholine

The title compound was prepared using a procedure similar to that described for intermediate 67, step 2, using (R) - (2, 2-dimethyl-1, 3-dioxolan-4-yl) methanol to give the title compound as a solid.

Intermediate 71: (S) -4- (6- ((2, 2-dimethyl-1, 3-dioxolan-4-yl) methoxy) -4-iodopyridine-2- Base) morpholine

The title compound was prepared using a procedure similar to that described for intermediate 67, step 2, using (S) - (2, 2-dimethyl-1, 3-dioxolan-4-yl) methanol to give the title compound as a solid.

Intermediate 72: n- (4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzene 3- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxamide

The title compound was prepared using a procedure similar to that described for intermediate 68, step 2, using 3- (2,2, 2-trifluoroethyl) pyrrolidine to give the title compound as a solid.

Intermediate 73: 4- (4-iodo-6- (((2S) -1- ((tetrahydro-2H-pyran-2-yl) oxy) propan-2-yl) oxy) Pyridin-2-yl) morpholine

The title compound was prepared using a procedure analogous to that described for intermediate 67, step 2, using (2S) -1- ((tetrahydro-2H-pyran-2-yl) oxy) propan-2-ol to give the title compound as a solid.

Intermediate 74: (R) -3- ((4-iodo-6-morpholinopyridin-2-yl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared using a procedure similar to that described for intermediate 67, step 2, using tert-butyl (R) -3-hydroxypyrrolidine-1-carboxylate to give the title compound as a solid.

Intermediate 75: 3- ((4-iodo-6-morpholinopyridin-2-yl) oxy) azetidine-1-carboxylic acid tert-butyl ester

The title compound was prepared using a procedure analogous to that described for intermediate 67, using tert-butyl 3-hydroxyazetidine-1-carboxylate to give the title compound as a solid.

Example 1 and example 2: (R) -N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) - 4-methylphenyl) -3- (trifluoromethyl) pyrrolidine-1-carboxamide; (S) -N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholino) Synthesis of linopyridin-4-yl) -4-methylphenyl) -3- (trifluoromethyl) pyrrolidine-1-carboxamide

Step 1:

DIEA (10.7g, 83.0mmol) was added to a solution of 2, 6-difluoro-4-iodopyridine (10.0g, 41.5mmol) and morpholine (3.6g, 41.5mmol) in DMSO (100mL) at room temperature. The mixture was stirred in a sealed tube at 130 ℃ for 16 h. The reaction was cooled to room temperature, diluted with water (200mL) and extracted with DCM (200mL × 3). Combined organic layers with H₂O (200 mL. multidot.2) and brine (200mL), washed over Na₂SO₄Dried, filtered and concentrated. The residue was purified by flash silica gel chromatography (PE: EA ═ 20:1 to PE: EA ═ 10:1) to give 4- (6-fluoro-4-iodopyridin-2-yl) morpholine (10.4g, 81.7%). MS calculated: 308, MS found: 309([ M + H ]]⁺)。

Step 2:

to a solution of 2- ((tetrahydro-2H-pyran-2-yl) oxy) ethanol (24.8g, 169.5mmol) in dioxane (150mL) at 0 deg.C was added NaH (6.8g, 169.5mmol, 60% in mineral oil), and the mixture was mixedThe mixture was stirred at room temperature for 15min, 4- (6-fluoro-4-iodopyridin-2-yl) morpholine (10.4g, 33.9mmol) was added and the mixture was stirred at 100 ℃ for 2 h. The reaction was cooled to room temperature, diluted with water (200mL) and extracted with DCM (200mL × 3). Combined organic layers with H₂O (200 mL. multidot.2) and brine (200mL), washed over Na₂SO₄Dried, filtered and concentrated. The residue was purified by flash silica gel chromatography (PE: EA ═ 20:1 to PE: EA ═ 5:1) to give 4- (4-iodo-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) pyridin-2-yl) morpholine (10.7g, 72.8%). MS calculated: 434, MS found: 435([ M + H) ]⁺)。

And step 3:

at room temperature and N₂Next, to 4- (4-iodo-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) pyridin-2-yl) morpholine (3.9g, 8.9mmol), 2-fluoro-4-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (crude, 9.8mmol) and Cs₂CO₃(8.7g, 26.7mmol) to a solution in dioxane (100mL) and water (10mL) was added Pd (dppf) Cl₂(652mg, 0.89 mmol). The mixture was stirred at 100 ℃ for 16 h. The reaction was cooled to room temperature, filtered and concentrated. The residue was purified by flash silica gel chromatography (PE: EA ═ 5:1 to PE: EA ═ 2:1) to give 2-fluoro-4-methyl-5- (2-morpholino-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) pyridin-4-yl) aniline (2.7g, 69.3%). MS calculated: 431 measured value: 432([ M + H)]⁺)。

And 4, step 4:

to a solution of 2-fluoro-4-methyl-5- (2-morpholino-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) pyridin-4-yl) aniline (492mg, 1.14mmol) in THF (20mL) at 0 ℃ were added DIEA (221mg, 1.71mmol) and 4-nitrophenyl chloroformate (230mg, 1.14mmol), and the mixture was stirred at room temperature for 1H. The reaction was cooled to 0 ℃ and DIEA (442mg, 3.42mmol) and 3- (trifluoromethyl) pyrrolidine hydrochloride (200mg, 1.14mmol) were added. The reaction mixture was stirred at room temperature for 1h, then concentrated. The residue was purified by flash silica gel chromatography (PE: EA ═ 5:1 to PE: EA ═ 2:1) to give N- (2-fluoro-4-methyl-5- (2-morpholino-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) pyridin-4-yl) phenyl) -3- (tris- (phenyl) methyl-l-hydroxy-ethyl) phenyl) -2- (trifluoromethyl-phenyl) propan-2-ol Fluoromethyl) pyrrolidine-1-carboxamide (480mg, 70.6%). MS calculated: 596MS measured values: 597([ M + H)]⁺)。

And 5:

to a solution of N- (2-fluoro-4-methyl-5- (2-morpholino-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) pyridin-4-yl) phenyl) -3- (trifluoromethyl) pyrrolidine-1-carboxamide (280mg, 0.47mmol) in EtOAc (15mL) was added HCl/EtOAc (10mL, 2M) at room temperature and the reaction was stirred for 30 min. The mixture was concentrated and the residue was purified by flash silica gel chromatography (PE: EA ═ 2:1 to PE: EA ═ 1:1) to give a racemic mixture (120mg, 49.8%). The mixture was then resolved by chiral HPLC (Daicel Chiralpak IH: 20X 250mm L, 5 μm; CO)₂MeOH 75:25, 50g/min, 230nm) to give two enantiomers: 50.8mg (21.1%) of the first isomer (ee) eluting at 7.18min>98%) and 51.6mg (21.5%) of the second isomer (ee) eluting at 9.03min>98％)。¹H NMR(400MHz,DMSO-d₆) First eluting isomer: δ 1.98-2.03(m,1H),2.17-2.20(m,4H),3.43-3.53(m,8H),3.64-3.72(m,7H),4.24(t, J ═ 5.6Hz,2H),4.78(t, J ═ 5.6Hz,1H),5.98(s,1H),6.19(s,1H),7.13(d, J ═ 11.6Hz,1H),7.32(d, J ═ 8.4Hz,1H),8.04(s, 1H). MS calculated: 512, found: 513([ M + H)]⁺)。¹H NMR(400MHz,DMSO-d₆) Second eluting isomer: δ 1.98-2.03(m,1H),2.17-2.20(m,4H),3.43-3.53(m,8H),3.68-3.72(m,7H),4.24(t, J ═ 5.6Hz,2H),5.98(s,1H),6.02(brs,1H),6.19(s,1H),7.13(d, J ═ 11.6Hz,1H),7.32(d, J ═ 8.0Hz,1H),8.04(s, 1H). MS calculated: 512, found: 513([ M + H) ]⁺)。

Example 3: (RS) -N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylbenzene 3- (trifluoromethyl) pyrrolidine-1-carboxamide

To N- (2-fluoro-4-methyl-5- (2-morpholino-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethoxy) pyridin-4-yl) phenyl at room temperature) To a solution of-3- (trifluoromethyl) pyrrolidine-1-carboxamide (280mg, 0.47mmol) in EtOAc (15mL) was added HCl/EtOAc (10mL, 2M) and the mixture was stirred for 30 min. The mixture was concentrated and the residue was purified by preparative-HPLC (Gilson-5 Xbridge, C85 μm 19 x 150mm 30-70% B, A: H)₂O(0.1％NH₄HCO₃) And B: ACN, UV: 214nm, flow 15mL/min, GT 8min) to give N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylphenyl) -3- (trifluoromethyl) pyrrolidine-1-carboxamide (106.6mg, 45.9%).¹H NMR(400MHz,DMSO-d₆) δ 1.98-2.04(m,1H),2.17-2.20(m,4H),3.43-3.54(m,8H),3.64-3.72(m,7H),4.24(t, J ═ 5.6Hz,2H),4.78(t, J ═ 5.6Hz,1H),5.98(s,1H),6.19(s,1H),7.14(d, J ═ 11.6Hz,1H),7.32(d, J ═ 8.4Hz,1H),8.04(s, 1H). MS calculated: 512, found: 513([ M + H)]⁺)。

Example 4: (RS) -N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylbenzene 3- (trifluoromethyl) piperidine-1-carboxamide

Step 1:

2-fluoro-4-methyl-5- { 2-morpholin-4-yl-6- [2- (tetrahydro-pyran-2-yloxy) -ethoxy]A solution of-pyridin-4-yl } -phenylamine (150mg, 0.34mmol), CDI (74mg, 0.45mmol) and DIEA (147mg, 1.14mmol) in DMF (10mL) was stirred at 50 ℃ for 2 h. 3-trifluoromethyl-piperidine (59mg, 0.38mmol) was added and the reaction was stirred at 50 ℃ overnight. The mixture was concentrated and the residue was purified by flash silica gel chromatography (PE: EA ═ 5:1 to PE: EA ═ 2:1) to give 3-trifluoromethyl-piperidine-1-carboxylic acid (2-fluoro-4-methyl-5- { 2-morpholin-4-yl-6- [2- (tetrahydro-pyran-2-yloxy) -ethoxy-2-yl-ethoxy-piperidine-1-carboxylic acid]-pyridin-4-yl } -phenyl) -amide (101mg, 47.6%). MS calculated: 610, found: 611([ M + H)]⁺)。

Step 2:

to N- (2-fluoro-4-methyl-5- (2-morpholino-6- (2- ((tetrahydro-2H-pyran-2-yl) oxy) at room temperature) Ethoxy) pyridin-4-yl) phenyl) -3- (trifluoromethyl) piperidine-1-carboxamide (101mg, 0.16mmol) to a solution in dioxane (10mL) was added HCl/dioxane (3mL, 2M) and the mixture was stirred for 30 min. The mixture was concentrated and the residue was purified by preparative-HPLC (Waters-2 Sunfire, C85 μm 19 x 150mm 35-70% B, A: H₂O (0.1% HCOOH), B: ACN, UV: 214nm, flow 15mL/min, GT ═ 10min) to give N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylphenyl) -3- (trifluoromethyl) piperidine-1-carboxamide (38.3mg, 44.5%). ¹H NMR(400MHz,DMSO-d₆): δ 1.44-1.52(m,2H),1.70-1.73(m,1H),1.94-1.96(m,1H),2.20(s,3H),2.79-2.87(m,2H),3.43-3.45(m,5H),3.67-3.70(m,7H),3.97-4.01(m,1H),4.20-4.25(m,2H),4.76-4.79(m,1H),5.97(s,1H),6.18(s,1H),7.12(d, J ═ 11.6Hz,1H),7.22(d, J ═ 8.4Hz,1H),8.41(s, 1H). MS calculated: 526; MS found: 527([ M + H)]⁺)

Example 5: (RS) -3- (tert-butyl) -N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridine-4-) 4-methylphenyl) -pyrrolidine-1-carboxamide

The title compound was prepared using the general procedure for N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylphenyl) -3- (trifluoromethyl) pyrrolidine-1-carboxamide.¹H NMR(400MHz,DMSO-d₆) δ 0.90(s,9H),1.54-1.65(m,1H),1.80-1.86(m,1H),1.99-2.07(m,1H),2.20(s,3H),3.05(t, J ═ 10.2Hz,1H),3.20-3.27(m,1H),3.43-3.47(m,5H),3.54(t, J ═ 9.2Hz,1H),3.68-3.72(m,6H),4.24(t, J ═ 5.6Hz,2H),4.78(t, J ═ 5.6Hz,1H),5.98(s,1H),6.19(s,1H),7.12(d, J ═ 12.0Hz,1H),7.36(d, J ═ 8.4, 1H),7.79(s, 1H). MS calculated: 500, a step of; MS found: 501([ M + H ]]⁺)。

Example 6: 1- (3, 3-dimethylbutyl) -3- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridine- 4-yl) -4-methylphenyl) urea

The title compound was prepared using the general procedure for N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylphenyl) -3- (trifluoromethyl) pyrrolidine-1-carboxamide. ¹H NMR(400MHz,DMSO-d₆) δ 0.89(s,9H),1.32-1.36(m,2H),2.15(s,3H),3.05-3.10(m,2H),3.44(t, J ═ 4.8Hz,4H),3.68-3.72(m,6H),4.24(t, J ═ 5.2Hz,2H),4.78(t, J ═ 5.6Hz,1H),5.95(s,1H),6.17(s,1H),6.46(t, J ═ 5.4Hz,1H),7.10(d, J ═ 12.4Hz,1H),7.97(d, J ═ 8.8Hz,1H),8.20(s, 1H). MS calculated: 474; MS found: 475([ M + H)]⁺)。

Example 7: (RS) -N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylbenzene 3- (trifluoromethyl) piperazine-1-carboxamide

The title compound was prepared using the general procedure for N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylphenyl) -3- (trifluoromethyl) piperidine-1-carboxamide.¹H NMR(400MHz,DMSO-d₆) δ 2.20(s,3H),2.64-2.67(m,1H),2.90-2.99(m,4H),3.43-3.46(m,4H),3.68-3.70(m,6H),3.77-3.81(m,1H),4.03(dd, J ═ 2.8,12.4Hz,1H),4.24(t, J ═ 5.2Hz,2H),4.78(t, J ═ 5.6Hz,1H),5.98(s,1H),6.19(s,1H),7.13(d, J ═ 11.6Hz,1H),7.23(d, J ═ 8.0Hz,1H),8.41(s, 1H). MS calculated: 527; MS found: 528([ M + H ]]⁺)。

Example 8: (RS) -3- (tert-butyl) -N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridine-4-) 4-methylphenyl) piperidine-1-carboxamide

The title compound was prepared using the general procedure for N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylphenyl) -3- (trifluoromethyl) piperidine-1-carboxamide. ¹H NMR(400MHz,DMSO-d₆) δ 0.87(s,9H),1.11-1.18(m,2H),1.40-1.43(m,1H),1.66-1.69(m,1H),1.79-1.82(m,1H),2.19(s,3H),2.42-2.50(m,1H),2.62-2.66(m,1H),3.43-3.46(m,4H),3.68-3.69(m,6H),4.03(d, J-13.2, 1H),4.16(d, J-12.8 Hz,1H),4.24(d, J-5.6 Hz,2H),4.77(brs,1H),5.97(s,1H),6.19(s,1H),7.11(d, J-11.6 Hz,1H), 7.8H (d, 1H), 8H, 1H). MS calculated: 514; MS found: 515([ M + H)]⁺)。

Example 9: 2- (tert-butyl) -N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4- Methylphenyl) morpholine-4-carboxamide

The title compound was prepared using the general procedure for N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylphenyl) -3- (trifluoromethyl) piperidine-1-carboxamide.¹H NMR(400MHz,DMSO-d₆) δ 0.91(s,9H),2.20(s,3H),2.57-2.68(m,1H),2.81-2.88(m,1H),2.96-2.99(m,1H),3.39-3.46(m,5H),3.68-3.72(m,6H),3.83-3.92(m,2H),3.96(d, J ═ 12.8Hz,1H),4.24(t, J ═ 5.6Hz,2H),4.78(t, J ═ 5.6Hz,1H),5.98(s,1H),6.19(s,1H),7.13(d, J ═ 12.0Hz,1H),7.24(d, J ═ 8.4Hz,1H),8.33(s, 1H). MS calculated: 516; MS found: 517([ M + H)]⁺)。

Example 10: (RS) -N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylbenzene 2- (trifluoromethyl) morpholine-4-carboxamide

Using N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylphenyl) General procedure for (E) -3- (trifluoromethyl) piperidine-1-carboxamide the title compound was prepared.¹H NMR(400MHz,DMSO-d₆) δ 2.21(s,3H),2.93-3.07(m,2H),3.44(t, J-4.8 Hz,4H),3.58-3.64(m,1H),3.68-3.72(m,6H),3.93(d, J-13.6 Hz,1H),4.00(d, J-10.4 Hz,1H),4.15-4.24(m,4H),4.78(t, J-5.6 Hz,1H),5.98(s,1H),6.19(s,1H),7.15(d, J-12.0 Hz,1H),7.25(d, J-8.4 Hz,1H),8.54(s, 1H). MS calculated: 528 of the raw material; MS found: 529([ M + H)]⁺)。

Example 11: (RS) -3- (tert-butyl) -N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridine-4-) 4-methylphenyl) piperazine-1-carboxamide

The title compound was prepared using the general procedure for N- (2-fluoro-5- (2- (2-hydroxyethoxy) -6-morpholinopyridin-4-yl) -4-methylphenyl) -3- (trifluoromethyl) piperidine-1-carboxamide.¹H NMR(400MHz,DMSO-d₆):δ0.90(s,9H),2.14-2.20(m,4H),2.44(t,J＝11.8Hz,1H),2.54-2.60(m,1H),2.67-2.73(m,1H),2.93(d,J＝11.6Hz,1H),3.44(t,J＝4.8Hz,4H),3.68-3.72(m,6H),3.90(d,J＝12.4Hz,1H),4.02(d,J＝12.0Hz,1H),4.24(t,J＝5.6Hz,2H),4.78(t,J＝5.6Hz,1H),5.98(s,

1H) 6.19(s,1H),7.12(d, J ═ 12.0Hz,1H),7.23(d, J ═ 8.4Hz,1H),8.19(s, 1H). MS calculated: 515; MS found: 516([ M + H)]⁺)。

Examples 12 and 13: (3R) -N- [ 2-fluoro-5- [6- (2-hydroxyethoxy) -5- (morpholin-4-yl) pyridin-3- Base of]-4-methylphenyl radical]-3- (trifluoromethyl) pyrrolidine-1-carboxamide and (3S) -N- [ 2-fluoro-5- [6- (2-hydroxyethoxy) ethanol -5- (morpholin-4-yl) pyridin-3-yl]-4-methylphenyl radical]-3- (trifluoromethyl) pyrrolidine-1-carboxamide

Step 1: n- [ 2-fluoro-4-methyl-5- [5- (morpholin-4-yl) -6- [2- (tetrahydropyran-2-yloxy) ethoxy] Pyridin-3-yl]Phenyl radical]-3- (trifluoromethyl) pyrrolidine-1-carboxamide

To 2-fluoro-4-methyl-5- [5- (morpholin-4-yl) -6- [2- (tetrahydropyran-2-yloxy) ethoxy under nitrogen atmosphere]Pyridin-3-yl]To a solution of aniline (560.00mg, 1.30mmol) in THF (25.00mL) was added triphosgene (154.04mg, 0.52mmol) and DIEA (838.64mg, 6.49 mmol). The reaction mixture was stirred at room temperature for 0.5 h. To the above mixture was added 3- (trifluoromethyl) pyrrolidine hydrochloride (227.86mg, 1.30mmol) and the reaction mixture was stirred at room temperature for 4 h. The resulting mixture was concentrated under vacuum. The residue was diluted with water (20mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with brine (20mL) and dried over anhydrous Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH (1-10%) in DCM. The fractions containing the desired product were combined and concentrated to give N- [ 2-fluoro-4-methyl-5- [5- (morpholin-4-yl) -6- [2- (tetrahydropyran-2-yloxy) ethoxy ] as a yellow solid ]Pyridin-3-yl]Phenyl radical]-3- (trifluoromethyl) pyrrolidine-1-carboxamide (550mg, 71%). For C₂₉H₃₆F₄N₄O₅[M+H]⁺MS ESI of 597.26, found 597.25.¹H-NMR(300MHz,d6-DMSO)δ8.07(s,1H),7.68(d,J＝2.0Hz,1H),7.33(d,J＝8.4Hz,1H),7.17(d,J＝11.2Hz,1H),7.10(d,J＝2.0Hz,1H),4.70(d,J＝3.6Hz,1H),4.50-4.46(m,2H),4.02-3.90(m,1H),3.83-3.63(m,7H),3.48(m,5H),3.13-3.08(m,4H),2.25-2.20(m,4H),2.07-2.02(m,1H),1.82-1.56(m,2H),1.52-1.46(m,4H)。

Step 2: n- [ 2-fluoro-5- [6- (2-hydroxyethoxy) -5- (morpholin-4-yl) pyridin-3-yl]-4-methylbenzene Base of]-3- (trifluoromethyl) pyrrolidine-1-carboxamide

To the N- [ 2-fluoro-4-methyl-5- [5- (morpholin-4-yl) -6- [2- (tetrahydropyran-2-yloxy) ethoxy group]Pyridin-3-yl]Phenyl radical]To a solution of-3- (trifluoromethyl) pyrrolidine-1-carboxamide (300.00mg, 0.50mmol) in MeOH (4.50mL) was added HCl (4M in 1, 4-dioxane) (1.50 mL). The reaction solution was stirred at 25 ℃ for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, CH₃An aqueous solution of CN, 0% to 100% gradient over 25 min; detector, UV 254 nm. The fractions containing the desired product were combined and concentrated to give N- [ 2-fluoro-5- [6- (2-hydroxyethoxy) -5- (morpholin-4-yl) pyridin-3-yl as an off-white solid]-4-methylphenyl radical]-3- (trifluoromethyl) pyrrolidine-1-carboxamide (210mg, 90%). For C₂₄H₂₈F₄N₄O₄[M+H]⁺Calculated MS ESI of 513.20; found 513.35.

And step 3: (3R) -N- [ 2-fluoro-5- [6- (2-hydroxyethoxy) -5- (morpholin-4-yl) pyridin-3-yl ]-4-methyl group Phenyl radical]-3- (trifluoromethyl) pyrrolidine-1-carboxamideAnd (3S) -N- [ 2-fluoro-5- [6- (2-hydroxyethoxy) ethoxyBase) -5- (morpholine- 4-yl) pyridin-3-yl]-4-methylphenyl radical]-3- (trifluoromethyl) pyrrolidine-1-carboxamide

N- [ 2-fluoro-5- [6- (2-hydroxyethoxy) -5- (morpholin-4-yl) pyridin-3-yl]-4-methylphenyl radical]-3- (trifluoromethyl) pyrrolidine-1-carboxamide (210mg) was separated by preparative chiral HPLC using the following conditions: column: CHIRAL ART Cellulose-SB, 2 x 25cm, 5 um; mobile phase A: hexane: DCM ═ 5:1(10mM NH3-MEOH), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 10B to 10B within 11 min; 254/220 nm. The fractions containing the desired product were concentrated to give two enantiomers: (71.8mg) first isomer (ee) eluting at 8.296min>98%) and (75.9mg) the second isomer (ee) eluting at 9.553min>98％)。¹H-NMR(400MHz,d₆-DMSO) first eluting isomer: δ 8.04(s,1H),7.65(d, J ═ 1.6Hz,1H),7.32(d, J ═ 8.0Hz,1H),7.16(d, J ═ 11.6Hz,1H),7.06(d, J ═ 1.6Hz,1H),4.79(t, J ═ 4.2Hz,1H),4.36(t, J ═ 4.2Hz,2H),3.77-3.74(m,7H),3.69-3.57(m,3H),3.34-3.28(m,1H),3.09-3.07(m,4H),2.33-2.15(m,4H),2.05-1.98(m, 1H). For C₂₄H₂₈F₄N₄O₄[M+H]⁺MS ESI of 513.20, found 513.15. ¹H-NMR(400MHz,d₆-DMSO) second eluting isomer: δ 8.04(s,1H),7.65(d, J ═ 1.6Hz,1H),7.32(d, J ═ 8.0Hz,1H),7.16(d, J ═ 11.6Hz,1H),7.06(d, J ═ 1.6Hz,1H),4.79(t, J ═ 4.2Hz,1H),4.36(t, J ═ 4.2Hz,2H),3.77-3.74(m,7H),3.69-3.57(m,3H),3.34-3.28(m,1H),3.09-3.07(m,4H),2.33-2.15(m,4H),2.05-1.98(m, 1H). For C₂₄H₂₈F₄N₄O₄[M+H]⁺MS ESI of 513.20, found 513.15.

The following compounds in table 3 were prepared using procedures similar to those described in examples 12 and 13, using the appropriate starting materials. The racemic product was resolved using the chiral column specified in table 3.

TABLE 3

Example 149: (3R) -N- [3- [2- (2-hydroxy-2-methylpropoxy) -6- (morpholin-4-yl) pyridin-4-yl]- 4-methylphenyl radical]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide

(3R) -N- [3- [2- (2-hydroxy-2-methylpropoxy) -6- (morpholin-4-yl) pyridin-4-yl]-4-methylbenzene Base of]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide

1- [ [ 4-iodo-6- (morpholin-4-yl) pyridin-2-yl]Oxy radical]-2-methylpropan-2-ol (100.00mg, 0.26mmol), (3R) -N- [ 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide (120.48mg, 0.29mmol), Pd (dppf) Cl ₂.CH₂Cl₂(21.59mg，0.03mmol)、Na₂CO₃A mixture of (84.07mg, 0.79mmol), 1, 4-dioxane (4mL) and water (1mL) was stirred at 80 ℃ for 2h under nitrogen. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EA: EtOH (3:1)/PE (0 to 100%). The crude product was purified by prep-HPLC using the following conditions: column: XBridge BEH C18 OBD Prep column, 5um, 19mm x 250 mm; mobile phase A: water (10mmol/L NH)₄HCO₃) And the mobile phase B: acetonitrile; flow rate: 20 mL/min; gradient of gradient: 35B to 65B within 5 min; 254 nm; RT 1: 4.5min, (3R) -N- [3- [2- (2-hydroxy-2-methylpropoxy) -6- (morpholin-4-yl) pyridin-4-yl) is obtained as an off-white solid]-4-methylphenyl radical]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide (66.7mg, 47%). For C₂₆H₃₃F₃N₄O₆[M+H]⁺MS ESI of 539.24, found 539.20. H-NMR (400MHz, d)₆-DMSO)δ8.25(s,1H),7.46-7.43(m,1H),7.38-7.37(m,1H),7.15(d,J＝8.4Hz,1H),6.21(s,1H),5.99(s,1H),5.15-5.14(m,1H),4.57(s,1H),4.01(s,2H),3.71-3.55(m,7H),3.45-3.40(m,5H),2.24-2.17(m,5H),1.18(s,6H)。F-NMR(376MHz,d₆-DMSO)δ-56.71(3F)。

The following compounds in table 4 were prepared using procedures analogous to those described in example 149, using the appropriate starting materials. The racemic product was resolved using the chiral column specified in table 4.

TABLE 4

Example 170: (3S) -N- (3- [2- [ (1-hydroxy-2-methylpropan-2-yl) oxy)]-6- (morpholin-4-yl) pyri dine Pyridin-4-yl]-4-methylphenyl) -3- (trifluoromethoxy) pyrrolidine-1-carboxamide

Step 1: (3S) -N- [ 4-methyl-3- (2- [ [ 2-methyl-1- (tetrahydropyran-2-yloxy) propan-2-yl)]Oxygen gas Base of]-6- (morpholin-4-yl) pyridin-4-yl) phenyl]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide

Reacting 4- (4-iodo-6- [ [ 2-methyl-1- (tetrahydropyran-2-yloxy) propan-2-yl)]Oxy radical]Pyridin-2-yl) morpholine (100.00mg, 0.22mmol), (3S) -N- [ 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide (98.56mg, 0.24mmol), Pd (dppf) Cl₂.CH₂Cl₂(17.66mg，0.02mmol)、Na₂CO₃A mixture of (68.77mg, 0.65mmol), 1, 4-dioxane (4.00mL), and water (1.00mL) was stirred at 80 ℃ under nitrogen for 2 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA/PE (0 to 100%) to give (3S) -N- [ 4-methyl-3- (2- [ [ 2-methyl-1- (tetrahydropyran-2-yloxy) propan-2-yl) as a pale yellow solid]Oxy radical]-6- (morpholin-4-yl) pyridin-4-yl) phenyl]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide (100mg, 74.25%). For C₃₁H₄₁F₃N₄O₆[M+H]⁺MS ESI of 623.30, found 623.20.

Step 2: (3S) -N- (3- [2- [ (1-hydroxy-2-methylpropan-2-yl) oxy)]-6- (morpholin-4-yl) pyridine- 4-radical]-4-methylphenyl) -3- (trifluoromethoxy) pyrrolidine-1-carboxamide

To (3S) -N- [ 4-methyl-3- (2- [ [ 2-methyl-1- (tetrahydropyran-2-yloxy) propan-2-yl) at room temperature]Oxy radical]-6- (morpholin-4-yl) pyridin-4-yl) phenyl]-3- (trifluoromethoxy) pyrrolidine-1-carboxamide (100.00 mg)0.16mmol) in MeOH (3mL) HCl (gaseous) in 1, 4-dioxane (1.00mL, 4M) was added dropwise. The resulting solution was stirred at room temperature for 0.5 h. With saturated NaHCO₃(aqueous solution) the reaction solution was basified to pH-8. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100mL) and dried over anhydrous Na₂SO₄And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC using the following conditions: column: XBridge C18 OBD Prep Column,10 μm, 19mm x 250 mm; mobile phase A: water (10mmoL/L NH)₄HCO₃) And the mobile phase B: ACN; flow rate: 20 mL/min; gradient: 50B to 80B within 5.8 min; 254/210 nm; RT 1: 5.75min, (3S) -N- (3- [2- [ (1-hydroxy-2-methylpropan-2-yl) oxy) as an off-white solid]-6- (morpholin-4-yl) pyridin-4-yl]-4-methylphenyl) -3- (trifluoromethoxy) pyrrolidine-1-carboxamide (35.3mg, 41%). For C ₂₆H₃₃F₃N₄O₅[M+H]⁺MS ESI of 539.24, found 539.20. H-NMR (400MHz, d)₆-DMSO)δ8.25(s,1H),7.46-7.43(m,1H),7.39-7.38(m,1H),7.15(d,J＝8.4Hz,1H),6.22(s,1H),5.93(s,1H),5.15-5.14(m,1H),4.86(t,J＝6.0Hz,1H),3.74-3.56(m,9H),3.48-3.40(m,5H),2.25-2.19(m,5H),1.51(s,6H)。F-NMR(376MHz,d₆-DMSO)δ-56.71(3F)。

The following compounds in table 5 were prepared using procedures analogous to those described in example 149 and related examples, using the appropriate starting materials. The racemic product was resolved using the chiral column specified in table 5.

TABLE 5

Example 227: (3S) -N- (3- [2- [ (2R) -2-Hydroxypropoxy group)]-6- [ (2S) -2-methylmorpholin-4-yl]Pyridine (II) Pyridin-4-yl]-4-methylphenyl) -3- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxamide

Step 1: (3S) -N- (3- [2- [ (2R) -2-Hydroxypropoxy group)]-6- [ (2S) -2-methylmorpholin-4-yl]Pyridine- 4-radical]-4-methylphenyl) -3- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxamide

Mixing (2R) -1- ([ 4-iodo-6- [ (2S) -2-methylmorpholin-4-yl)]Pyridin-2-yl]Oxy) propane-2-ol (240mg, 0.635mmol, 1.00 eq.) and (3S) -N- [ 4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]-3- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxamide (261.61mg, 0.635mmol, 1.00 eq), 1, 4-dioxane (4.00mL), H₂O(1.00mL)、Na₂CO₃(201.77mg, 1.904mmol, 3.00 equiv.) and Pd (dppf) Cl₂A mixture of DCM (51.82mg, 0.063mmol, 0.10 eq.) in N₂Stirring at 80 ℃ for 2h under an atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 60% EtOAc in PE. The crude product was purified under the following conditions: column: GreenSep Basic, 30 × 150mm5 um; mobile phase A: CO2, mobile phase B: IPA (0.5% 2M NH 3-MeOH); flow rate: 50 mL/min; gradient: 35% of B; 254 nm; RT 1: 5.08 of; RT 2: 5.45 of; injection volume: 0.6 ml; the operation number is as follows: 20; (3S) -N- (3- [2- [ (2R) -2-hydroxypropoxy group) is obtained as a white solid ]-6- [ (2S) -2-methylmorpholin-4-yl]Pyridin-4-yl]-4-methylphenyl) -3- (2,2, 2-trifluoroethyl) pyrrolidine-1-carboxamide (39.9mg, 12%). For C₂₇H₃₅F₃N₄O₄[M+H]⁺MS ESI of 537.26, found 537.30.

The following compounds in table 6 were prepared using procedures analogous to those described in example 227, using the appropriate starting materials. The racemic product was resolved using the chiral column specified in the table.

TABLE 6

Biological evaluation

Example 1: kinase assay protocol

Protein kinase assay: the kinase/inhibitor interaction was measured using an assay platform as previously described (antassiadis et al, 2011). Briefly, for each reaction, the kinase was combined with a substrateThe substances were mixed in a buffer containing 20mM HEPES (pH 7.5), 10mM MgCl2, 1mM EGTA, 0.02% Brij35, 0.02mg/mL BSA, 0.1mM Na3VO4, 2mM DTT and 1% DMSO. All compounds were dissolved in DMSO. Compounds were then added to each reaction mixture by acoustic dispensing using an ECHO 550 nanoliter dispenser. For the human RAF1 test, human MEK1(K97R) was used as substrate at a concentration of 3 micromolar with a final ATP concentration of 10 micromolar. For the human BRAF test, human MEK1(K97R) was used as the substrate at a concentration of 1 micromolar with a final ATP concentration of 25 micromolar. Compounds at 10 dose IC ₅₀Mode testing was performed with 3-fold serial dilutions starting at 10 micromolar. After 20 min incubation, ATP (Sigma-Aldrich, St. Louis, MO 63178) and [ g33P, purchased from Perkinelmer (Boston, MA, 02118 Cat. BLU 003H250UC) were added at a final total concentration of 10mM]ATP (specific activity 10. mu. Ci/. mu.l). The Reaction was carried out at room temperature for 2 hours and then spotted on P81 ion-exchange cellulose chromatography paper (Reaction Biology). The filter paper was washed in 0.75% phosphoric acid to remove unincorporated ATP. The remaining percentage of kinase activity relative to the vehicle-containing (DMSO) kinase reaction was calculated for each kinase/inhibitor pair. IC calculation Using Prism 5(GraphPad)₅₀The value is obtained.

Representative data for exemplary compounds are presented in table 5.

TABLE 5

Note that: biochemical assay IC₅₀The data are given in the following ranges:

a: less than or equal to 0.010 mu M C: 0.10 mu M to less than or equal to 1.0 mu M

B: 0.010 mu M to less than or equal to 0.10 mu M D: 1.0 to 10 mu M

Preparation of pharmaceutical dosage forms

Example 1: oral capsule

The active ingredient is a compound of table 1, or a pharmaceutically acceptable salt or solvate thereof. Capsules for oral administration are prepared by mixing 1-1000mg of the active ingredient with starch or other suitable powder blends. The mixture is incorporated into an oral dosage unit suitable for oral administration, such as a hard gelatin capsule.

Example 2: solution for injection

The active ingredient is a compound of table 1 or a pharmaceutically acceptable salt thereof, and is formulated into a solution having a concentration of 50mg-eq/mL in sesame oil.

The examples and embodiments described herein are for illustrative purposes only and various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.