NURR1 receptor modulators

文档序号：1878934 发布日期：2021-11-23 浏览：17次中文

阅读说明：本技术 Nurr1受体调节剂 (NURR1 receptor modulators ) 是由 P·M·英格兰 M·P·雅各布森 R·贝雷西斯于 2020-02-19 设计创作，主要内容包括：本文尤其描述了Nurr1受体调节剂和其用途。一方面,提供了一种用于治疗有需要的受试者的中枢神经系统的与多巴胺能神经元失调和/或变性相关的疾病的方法,所述方法包含向所述有需要的受试者施用治疗有效量的本文所描述的化合物。(Among other things, Nurr1 receptor modulators and uses thereof are described herein. In one aspect, there is provided a method for treating a disease of the central nervous system associated with dopaminergic neuronal imbalance and/or degeneration in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.)

1. A compound having the formula

Wherein

Ring a is aryl or heteroaryl;

L¹is L¹⁰¹-L¹⁰²-L¹⁰³；

L¹⁰¹Is a bond, -S (O)₂-、-N(R¹⁰¹)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰¹)-、-N(R¹⁰¹)C(O)-、-N(R¹⁰¹)C(O)NH-、-NHC(O)N(R¹⁰¹) -, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroaralkyleneBase, L¹⁰⁴-L¹⁰⁵、L¹⁰⁴-NH-L¹⁰⁵Or L¹⁰⁴-CH₂-L¹⁰⁵；

L¹⁰²Is a bond, -S (O)₂-、-N(R¹⁰²)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰²)-、-N(R¹⁰²)C(O)-、-N(R¹⁰²)C(O)NH-、-NHC(O)N(R¹⁰²) -, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L¹⁰³is a bond, -S (O)₂-、-N(R¹⁰³)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰³)-、-N(R¹⁰³)C(O)-、-N(R¹⁰³)C(O)NH-、-NHC(O)N(R¹⁰³) -, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L¹⁰⁴Is a bond, -O-, -NH-, -S-, -S (O)₂-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;

L¹⁰⁵is a bond, -O-, -NH-, -S-, -S (O)₂-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene;

R¹⁰¹、R¹⁰²and R¹⁰³Independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;

R¹is hydrogen, halogen, -CX¹ ₃、-CHX¹ ₂、-CH₂X¹、-OCX¹ ₃、-OCH₂X¹、-OCHX¹ ₂、-CN、 -N(O)_m1、 -N₃、SP(O)(OH)₂E, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

e is an electrophilic moiety;

R²independently halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、 -N(O)_m2、 -N₃Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R bound to adjacent atoms ²Substituents may be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

n1 and n2 are independently integers from 0 to 4;

m1, m2, v1 and v2 are independently 1 or 2;

X¹and X²Independently is-F, -Cl, -Br or-I; and is

z2 is an integer from 0 to 5.

2. The compound of claim 1, wherein the compound has formula (la)

Wherein

L¹⁰⁴Is a bond, -S (O)₂-, -C (O) -, -NHC (O) -, -OC (O) -, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;

L¹⁰⁵Is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene;

L¹⁰³is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and is

W is N or CH.

3. The compound of claim 2, wherein ring a is phenyl or 5-to 10-membered heteroaryl.

4. The compound of claim 2, wherein ring a is phenyl.

5. The compound of claim 2, wherein ring a is 3-quinolinyl.

6. The compound of claim 2, wherein the compound has formula (la)

And is

R^2X、R^2YAnd R^2ZIndependently hydrogen, halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、-N(O)_m2、 -N₃Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; bound to adjacent atomsAndsubstituents may be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; bound to adjacent atoms Andsubstituents may be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

7. The compound of claim 6, wherein

Independently halogen or unsubstituted heteroalkyl;

independently hydrogen or halogen; and is

Independently hydrogen, halogen, -CN,Unsubstituted heteroalkyl or substituted or unsubstituted heterocycloalkyl.

8. The compound of claim 6, wherein

Independently is halogen;

independently is halogen; and is

Independently hydrogen.

9. The compound of claim 6, wherein

Independently is-OCH₃；

Independently is hydrogen; and is

Independently is-OCH₃。

10. The compound of claim 6, wherein

Independently halogen or unsubstituted 2-to 4-membered heteroalkyl;

independently is hydrogen;

independently is halogen, -CN,Unsubstituted 2-to 4-membered heteroalkyl or substituted or unsubstituted 5-to 6-membered heterocycloalkyl;

independently is hydrogen; and is

Independently is unsubstituted C₁-C₂An alkyl group.

11. The compound of claim 2, wherein L¹⁰⁴is-C (O) -.

12. The compound of claim 2, wherein L¹⁰⁵Is unsubstituted alkylene.

13. The compound of claim 2, wherein L¹⁰⁵Is unsubstitutedC₁-C₄An alkylene group.

14. The compound of claim 2, wherein L¹⁰⁵Is composed of

15. The compound of claim 2, wherein W is N.

16. The compound of claim 2, wherein L¹⁰³Is unsubstituted alkylene.

17. The compound of claim 2, wherein L¹⁰³Is unsubstituted C₁-C₄An alkylene group.

18. The compound of claim 2, wherein L¹⁰³Is unsubstituted ethylene.

19. The compound of claim 2, whereinIs composed of

20. The compound of claim 1, wherein

R¹Is composed ofE. Unsubstituted alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl;

independently hydrogen or unsubstituted C₁-C₄An alkyl group;

independently hydrogen or unsubstituted C₁-C₄An alkyl group; and is

Independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂Or substituted or unsubstituted alkyl.

21. The compound of claim 1, wherein

R¹Is composed ofE. Unsubstituted C₁-C₄Alkyl radical, R¹⁰Substituted or unsubstituted phenyl or R ¹⁰Substituted or unsubstituted 5-to 6-membered heteroaryl;

independently hydrogen or unsubstituted C₁-C₄An alkyl group;

independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂、R¹⁰Substituted or unsubstituted C₁-C₄An alkyl group; and is

R¹⁰Is oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃Unsubstituted C₁-C₄Alkyl, unsubstituted 2-to 4-membered heteroalkyl, unsubstituted C₅-C₆Cycloalkyl, unsubstituted 5-to 6-membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5-to 6-membered heteroaryl.

22. The compound of claim 1, wherein R¹Is composed ofOr R¹⁰Substituted phenyl;

23. The compound of claim 1, wherein R¹is-SH, -SC (O) CH₃or-SSCH₃。

24. The compound of claim 1, wherein R¹Is E; and is

E is

25. The compound of claim 1, wherein the compound has formula (la)

L¹⁰⁴Is a bond; -O-, -NH-, -S-, or substituted or unsubstituted alkylene;

L¹⁰⁵is-S (O)₂-, -C (O) -, -NHC (O) -, or-OC (O) -; and is

L¹⁰³Is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

26. The compound of claim 25, wherein ring a is C₆-C₁₀Aryl or 5-to 10-membered heteroaryl.

27. The compound of claim 25, wherein ring a is phenyl.

28. The compound of claim 25, wherein the compound has formula (la)

L¹⁰⁴Is a bond, -O-, -NH-, -S-, or substituted or unsubstituted C₁-C₄An alkylene group;

L¹⁰⁵is-S (O)₂-, -C (O) -, -NHC (O) -, or-OC (O) -;

L¹⁰³is a bond, substituted or unsubstituted C₁-C₆Alkylene or substituted or unsubstituted 2-to 6-membered heteroalkylene; and is

Andindependently hydrogen, halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、 -N(O)_m2、 -N₃Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; bound to adjacent atomsAndsubstituents may be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

29. The compound of claim 28, whereinAndindependently a halogen.

30. The method of claim 28A compound of whichAndindependently is-Cl.

31. The compound of claim 25, wherein L¹⁰⁴is-O-.

32. The compound of claim 25, wherein L¹⁰⁵is-C (O) -.

33. The compound of claim 25, wherein L¹⁰³Is unsubstituted alkylene.

34. The compound of claim 25, wherein L¹⁰³Is unsubstituted C₁-C₆An alkylene group.

35. The compound of claim 25, wherein L¹⁰³Is unsubstituted C₁-C₄An alkylene group.

36. The compound of claim 25, wherein L¹⁰³Is a bond.

37. The compound of claim 25, wherein-L¹⁰⁴-CH₂-L¹⁰⁵-NH-L¹⁰³-is of

38. The compound of claim 25, wherein

R¹Is hydrogen,E. Substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted 2-to 6-membered heteroalkyl, substituted or unsubstituted C₅-C₆Cycloalkyl, substituted or unsubstituted 5-to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl;

e is an electrophilic moiety;

andindependently hydrogen, halogen, -CCl ₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted 2-to 6-membered heteroalkyl, substituted or unsubstituted C₅-C₆Cycloalkyl, substituted or unsubstituted 5-to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl.

39. The compound of claim 25, wherein

R¹Is hydrogen,E、R¹⁰Substituted or unsubstituted C₁-C₆Alkyl radical, R¹⁰Substituted or unsubstituted 2-to 6-membered heteroalkyl, R¹⁰Substituted or unsubstituted C₅-C₆Cycloalkyl radical, R¹⁰Substituted or unsubstituted 5-to 6-membered heterocycloalkyl, R¹⁰Substituted or unsubstituted phenyl or R¹⁰Substituted or unsubstituted 5-to 6-membered heteroaryl;

e is an electrophilic moiety;

andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹⁰Substituted or unsubstituted C₁-C₆Alkyl radical, R¹⁰Substituted or unsubstituted 2-to 6-membered heteroalkyl, R¹⁰Substituted or notSubstituted C₅-C₆Cycloalkyl radical, R¹⁰Substituted or unsubstituted 5-to 6-membered heterocycloalkyl, R¹⁰Substituted or unsubstituted phenyl or R¹⁰Substituted or unsubstituted 5-to 6-membered heteroaryl;

R¹⁰is oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃、R¹¹Substituted or unsubstituted C₁-C₄Alkyl radical, R¹¹Substituted or unsubstituted 2-to 4-membered heteroalkyl, R ¹¹Substituted or unsubstituted C₅-C₆Cycloalkyl radical, R¹¹Substituted or unsubstituted 5-to 6-membered heterocycloalkyl, R¹¹Substituted or unsubstituted phenyl or R¹¹Substituted or unsubstituted 5-to 6-membered heteroaryl;

R¹¹is oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃、R¹²Substituted or unsubstituted C₁-C₄Alkyl radical, R¹²Substituted or unsubstituted 2-to 4-membered heteroalkyl, R¹²Substituted or unsubstituted C₅-C₆Cycloalkyl radical, R¹²Substituted or unsubstituted 5-to 6-membered heterocycloalkyl, R¹²Substituted or unsubstituted phenyl or R¹²Substituted or unsubstituted 5-to 6-membered heteroaryl; and is

R¹²Is oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃Unsubstituted C₁-C₄Alkyl, unsubstituted 2-to 4-membered heteroalkyl, unsubstituted C₅-C₆Cycloalkyl, unsubstituted 5-to 6-membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5-to 6-membered heteroaryl.

40. The compound of claim 25, wherein R¹Is E; and is

E is

41. The compound of claim 1, wherein the compound is not

42. A pharmaceutical composition comprising a compound according to one of claims 1 to 41 and a pharmaceutically acceptable excipient.

43. A method for treating a disease of the central nervous system associated with dopaminergic neuronal imbalance and/or degeneration in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 41.

44. The method of claim 43, wherein the disease associated with dopaminergic neuronal dysfunction and/or degeneration is Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction.

45. The method of claim 43, wherein the disease associated with dopaminergic neuron imbalance and/or degeneration is Parkinson's disease.

46. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to one of claims 1 to 41.

47. The method of claim 46, wherein the cancer is breast cancer, pancreatic cancer, bladder cancer, mucoepidermoid cancer, gastric cancer, prostate cancer, colorectal cancer, lung cancer, adrenocortical cancer, or cervical cancer.

48. A method of modulating the Nurr1 activity level in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to one of claims 1 to 41.

49. A method of increasing the level of Nurr1 activity of a cell, the method comprising contacting the cell with a compound according to one of claims 1 to 41.

50. A method of increasing dopamine levels in a cell, the method comprising contacting the cell with a compound according to one of claims 1 to 41.

51. A pharmaceutical composition comprising 5, 6-Dihydroxyindole (DHI) and a pharmaceutically acceptable excipient.

52. A method for treating a disease associated with dopaminergic neuronal imbalance and/or degeneration in the central nervous system of a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of 5, 6-Dihydroxyindole (DHI).

53. The method of claim 52, wherein the disease associated with dopaminergic neuronal dysfunction and/or degeneration is Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction.

54. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of 5, 6-Dihydroxyindole (DHI).

55. The method of claim 54, wherein the cancer is breast cancer, pancreatic cancer, bladder cancer, mucoepidermoid cancer, gastric cancer, prostate cancer, colorectal cancer, lung cancer, adrenocortical cancer, or cervical cancer.

Background

Currently, over one million americans suffer from Parkinson's Disease (PD), and approximately 60,000 new cases are diagnosed each year. In an estimated 90% of PD patients, the cause of the disease is unknown, with no clear genetic or environmental origin. The most prominent neuropathological feature of PD is progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta and the consequent reduction of dopamine levels in the striatum, which is manifested by impaired motor function (e.g. rigidity, tremor, bradykinesia). Although the molecular basis of idiopathic PD is not fully understood, it has been proposed to include oxidative stress, mitochondrial dysfunction, and dopamine dyshomeostasis. Currently, there is no available therapeutic approach to prevent or even slow the progression of PD. Existing therapies alleviate PD symptoms by increasing dopaminergic signaling through one of three mechanisms: (1) increasing dopamine levels by increasing the amount of its biosynthetic precursor L-DOPA; (2) blocking dopamine decomposition by inhibiting dopamine metabolizing enzymes (monoamine oxidase (MAO), COMT); (3) dopamine activity is mimicked by direct agonism of dopamine receptors. However, these drugs only partially alleviate symptoms and can produce significant side effects, especially as the disease progresses. New therapies are urgently needed to combat the symptoms and progression of PD. Solutions to these and other problems in the art are disclosed herein, among other things.

Disclosure of Invention

In one aspect, there is provided a compound having the formula:

ring a is aryl or heteroaryl.

L¹Is L¹⁰¹-L¹⁰²-L¹⁰³。

L¹⁰¹Is a bond, -S (O)₂-、-N(R¹⁰¹)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰¹)-、-N(R¹⁰¹)C(O)-、-N(R¹⁰¹)C(O)NH-、-NHC(O)N(R¹⁰¹) -, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, L¹⁰⁴-L¹⁰⁵、L¹⁰⁴-NH-L¹⁰⁵Or L¹⁰⁴-CH₂-L¹⁰⁵。

L¹⁰²Is a bond, -S (O)₂-、-N(R¹⁰²)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰²)-、-N(R¹⁰²)C(O)-、-N(R¹⁰²)C(O)NH-、-NHC(O)N(R¹⁰²) -, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstitutedSubstituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

L¹⁰³Is a bond, -S (O)₂-、-N(R¹⁰³)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰³)-、-N(R¹⁰³)C(O)-、-N(R¹⁰³)C(O)NH-、-NHC(O)N(R¹⁰³) -, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

L¹⁰⁴Is a bond, -O-, -NH-, -S-, -S (O)₂-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

L¹⁰⁵Is a bond, -O-, -NH-, -S-, -S (O)₂-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene.

R¹⁰¹、R¹⁰²And R¹⁰³Independently hydrogen, oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

R¹Is hydrogen, halogen, -CX¹ ₃、-CHX¹ ₂、-CH₂X¹、-OCX¹ ₃、-OCH₂X¹、-OCHX¹ ₂、-CN、 -N(O)_m1、 -N₃、-SP(O)(OH)₂E, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

E is an electrophilic moiety.

R²Independently halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、 -N(O)_m2、 -N₃Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R bound to adjacent atoms ²Substituents may be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkaneA group, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

n1 and n2 are independently integers from 0 to 4.

m1, m2, v1 and v2 are independently 1 or 2.

X¹And X²Independently is-F, -Cl, -Br or-I.

z2 is an integer from 0 to 5.

In one aspect, a pharmaceutical composition is provided comprising a compound described herein and a pharmaceutically acceptable excipient.

In one aspect, there is provided a method for treating a disease of the central nervous system associated with dopaminergic neuronal imbalance and/or degeneration in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

In one aspect, there is provided a method of increasing the level of Nurr1 activity of a cell, the method comprising contacting the cell with a compound described herein.

In one aspect, a method of increasing dopamine levels in a cell is provided, the method comprising contacting the cell with a compound described herein.

Drawings

FIGS. 1A-1C: the crystal structure of the Nurr 1-screening hit complex revealed two different ligand binding sites and receptor conformations. FIG. 1A: the structures of hits 19.49 and 10.25 were screened. FIG. 1B: 19.49 covalently bound to Cys566 screened the hit structure. FIG. 1C: 10.25 covalently bound to Cys566 hit structures were screened.

FIGS. 2A-2B: both compounds 85 (figure 2A) and 87 (figure 2B) bound to the Nurr1 ligand binding domain with high nanomolar affinity. Binding was measured by micro thermophoresis.

FIGS. 3A-3B: compounds 85 (fig. 3A) and 87 (fig. 3B) stimulated transcription of the Nurr1 target gene in MN9D cells. Gene expression was normalized to Hprt.

FIGS. 4A-4D: reaction schemes for selecting compounds.

Detailed Description

I. Definition of

The abbreviations used herein have the conventional meaning in the chemical and biological fields. The chemical structures and formulae described herein are constructed according to standard rules of chemical valency known in the chemical art.

When a substituent is illustrated by a conventional formula written from left to right, the substituent equally encompasses chemically identical substituents resulting from writing the structure from right to left, e.g., -CH₂O-is equivalent to-OCH₂-。

Unless otherwise specified, the term "alkyl" by itself or as part of another substituent means a straight (i.e., unbranched) or branched carbon chain (or carbon) or combination thereof, which may be fully saturated, mono-unsaturated, or polyunsaturated, and may contain monovalent, divalent, and multivalent groups. The alkyl group can contain a specified number of carbons (e.g., C)₁-C₁₀Meaning one to ten carbons). Alkyl is an acyclic chain. Examples of saturated hydrocarbon groups include, but are not limited to, the followingThe group of (a): methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl, homologues and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. Unsaturated alkyl is alkyl having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers. An alkoxy group is an alkyl group attached to the rest of the molecule through an oxygen linker (-O-). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. An alkenyl group may contain more than one double bond and/or one or more triple bonds in addition to one or more double bonds. An alkynyl group may contain more than one triple bond and/or one or more double bonds in addition to one or more triple bonds.

Unless otherwise specified, the term "alkylene" by itself or as part of another substituent means a divalent group derived from alkyl, such as (but not limited to) through-CH₂CH₂CH₂CH₂The examples are given. Typically, the alkyl (or alkylene) groups will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein. "lower alkyl" or "lower alkylene" is a short chain alkyl or alkylene group typically having eight or fewer carbon atoms. Unless otherwise specified, the term "alkenylene" by itself or as part of another substituent means a divalent group derived from an alkene.

Unless otherwise specified, the term "heteroalkyl," by itself or in combination with another term, means a stable straight or branched chain or combination thereof containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. One or more heteroatoms (e.g., N, S, Si or P) may be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. The heteroalkyl being acyclic A chain of (2). Examples include, but are not limited to: -CH₂-CH₂-O-CH₃、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-CH₂-S-CH₂-CH₃、-S-CH₂-CH₂、-S(O)-CH₃、-CH₂-CH₂-S(O)₂-CH₃、-CH＝CH-O-CH₃、-Si(CH₃)₃、-CH₂-CH＝N-OCH₃、-CH＝CH-N(CH₃)-CH₃、-O-CH₃、-O-CH₂-CH₃and-CN. Up to two or three heteroatoms may be consecutive, e.g. -CH₂-NH-OCH₃and-CH₂-O-Si(CH₃)₃. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si or P). The heteroalkyl moiety may comprise two optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may comprise three optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may comprise four optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may comprise five optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may contain up to 8 optionally different heteroatoms (e.g., O, N, S, Si or P). Unless otherwise specified, the term "heteroalkenyl" by itself or in combination with another term means a heteroalkyl group containing at least one double bond. A heteroalkenyl group can optionally include more than one double bond and/or one or more triple bonds in addition to one or more double bonds. Unless otherwise specified, the term "heteroalkynyl" by itself or in combination with another term means a heteroalkyl group containing at least one triple bond. Heteroalkynyl groups can optionally contain more than one triple bond and/or one or more double bonds in addition to one or more triple bonds.

Similarly, unless otherwise specified, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from a heteroalkyl radical, such as (but not limited to) through-CH₂-CH₂-S-CH₂-CH₂-and-CH₂-S-CH₂-CH₂-NH-CH₂The examples are given. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply an orientation of the linking group. For example, of the formula-C (O)₂R' -represents-C (O)₂R '-and-R' C (O)₂-both. As described above, heteroalkyl as used herein includes those groups attached to the remainder of the molecule through a heteroatom, such as-C (O) R ', -C (O) NR', -NR 'R', -OR ', -SR', and/OR-SO₂R' is provided. It is understood that where a "heteroalkyl" is recited after a particular heteroalkyl, such as-NR 'R', the terms heteroalkyl and-NR 'R' are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are recited to increase clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude certain heteroalkyl groups, such as-NR' R ".

Unless otherwise specified, the terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms mean the cyclic forms of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl groups are not aromatic. Alternatively, for heterocycloalkyl, a heteroatom may occupy a position of the heterocycle that is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1, 2, 5, 6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. "cycloalkylene" and "heterocycloalkylene" alone or as part of another substituent means a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively.

Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Alternatively, e.g. "haloAlkyl "and like terms are meant to encompass monohaloalkyl and polyhaloalkyl groups. For example, the term "halo (C) ₁-C₄) Alkyl "includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

Unless otherwise indicated, the term "acyl" means-c (o) R, wherein R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Unless otherwise indicated, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent which may be a single ring or multiple rings (preferably, 1 to 3 rings) which are fused together (i.e., a fused ring aryl) or covalently linked. Fused ring aryl refers to multiple rings fused together, wherein at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl (or ring) containing at least one heteroatom (e.g., N, O or S), wherein the nitrogen and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. Thus, the term "heteroaryl" encompasses fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5, 6-fused ring heteroarylene refers to two rings fused together wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6, 6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And 6, 5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. The heteroaryl group may be attached to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuryl, indolyl, isoindolyl, benzothienyl, isoquinolyl, quinoxalyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, oxazolyl, pyridyl, 2-4-2-4-oxazolyl, 3-2-oxazolyl, 3, 2-oxazolyl, 2-4-oxazolyl, 2, 5-oxazolyl, 3-oxazolyl, and the like, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. The substituents for each of the above-indicated aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. By "arylene" and "heteroarylene", alone or as part of another substituent, is meant a divalent radical derived from an aryl and heteroaryl group, respectively. The heteroaryl substituent may be-O-attached to the nitrogen of a ring heteroatom.

Spiro is two or more rings in which adjacent rings are connected by a single atom. The individual rings within the spiro ring may be the same or different. Individual rings in the spirocyclic ring may be substituted or unsubstituted, and may have different substituents than other individual rings in the spirocyclic ring set. Possible substituents for each ring within a spiro ring are possible substituents for the same ring (when not part of a spiro ring) (e.g., substituents for cycloalkyl rings or heterocycloalkyl rings). The spirocyclic ring can be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and each ring within the spirocyclic group can be any ring of the previous list, including all rings having one type (e.g., all rings are substituted heterocycloalkylene, where each ring can be the same or different substituted heterocycloalkylene). When referring to a spiro ring system, heterocyclic spiro ring means a spiro ring in which at least one ring is heterocyclic and in which each ring may be a different ring. When referring to a spiro ring system, substituted spiro ring means that at least one ring is substituted and each substituent may optionally be different.

(symbol)Denotes the point of attachment of a chemical moiety to the rest of the molecule or formula.

As used herein, the term "oxo" means an oxygen double-bonded to a carbon atom.

The term "alkylarylene" is an arylene moiety covalently linked to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula:

the alkylarylene moiety may be substituted (e.g., with a substituent) on the alkylene moiety or arylene linker (e.g., at carbon 2, 3, 4, or 6) with: halogen, oxo, -N₃、-CF₃、-CCl₃、-CBr₃、-CI₃、-CN、-CHO、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₂CH₃、-SO₃H、-OSO₃H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂Substituted or unsubstituted C₁-C₅Alkyl or substituted or unsubstituted 2-to 5-membered heteroalkyl). In embodiments, the alkylarylene group is unsubstituted.

Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") encompasses both substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are provided below.

Substituents for alkyl and heteroalkyl radicals (packet)Containing those groups commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: -OR ', - (O), (NR', - (N-OR ',) -NR' R ', -SR', halogen, -SiR 'R "R', -oc (O) R ', -c (O) R', -CO ₂R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR″R″′、-NR″C(O)₂R′、-NR-C(NR′R″R″′)＝NR″″、-NR-C(NR′R″)＝NR″′、-S(O)R′、-S(O)₂R′、-S(O)₂NR′R″、-NRSO₂R′、-NR′NR″R″′、-ONR′R″、-NR′C(O)NR″NR″′R″″、-CN、-NO₂、-NR′SO₂R ', -NR ' C (O) -OR ', -NR ' OR ', where m ' is the total number of carbon atoms in such groups, ranges from zero to (2m ' + 1). R, R ', R ' and R ' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or aralkyl. When a compound described herein comprises more than one R group, for example, each of the R groups is independently selected as are each R 'group, R "group, R'" group, and R "" group when more than one of these groups is present. When R 'and R' are attached to the same nitrogen atom, they may combine with the nitrogen atom to form a 4-, 5-, 6-or 7-membered ring. For example, -NR' R "includes but is not limited to 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, those skilled in the art will understand that the term "alkyl" is intended to mean a group containing a carbon atom attached to a group other than hydrogen, such as haloalkyl (e.g., -CF) ₃and-CH₂CF₃) And acyl (e.g., -C (O) CH)₃、-C(O)CF₃、-C(O)CH₂OCH₃Etc.).

Similar toThe substituents described for alkyl, aryl and heteroaryl are varied and are selected, for example, from the following: -OR ', -NR ' R ', -SR ', halogen, -SiR ' R ' R ', -OC (O) R ', -C (O) R ', -CO₂R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR″R″′、-NR″C(O)₂R′、-NR-C(NR′R″R″′)＝NR″″、-NR-C(NR′R″)＝NR″′、-S(O)R′、-S(O)₂R′、-S(O)₂NR′R″、-NRSO₂R′、-NR′NR″R″′、-ONR′R″、-NR′C(O)NR″NR″′R″″、-CN、-NO₂、-R′、-N₃、-CH(Ph)₂Fluoro (C)₁-C₄) Alkoxy and fluoro (C)₁-C₄) Alkyl, -NR' SO₂R ', -NR ' C (O) -OR ', -NR ' OR ', numbers ranging from zero to the total number of open valences on the aromatic ring system; and wherein R ', R ", R'" and R "" are preferably independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein comprises more than one R group, for example, each of the R groups is independently selected as are each R 'group, R "group, R'" group, and R "" group when more than one of these groups is present.

Substituents of a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be depicted as substituents on a particular atom of the ring (often referred to as floating substituents) rather than the ring. In this case, a substituent may be attached to any of the ring atoms (following the rules of chemical valency), and in the case of a fused ring or spiro ring, a substituent depicted as being associated with one member of the fused ring or spiro ring (a floating substituent on a single ring) may be a substituent on either of the fused ring or spiro ring (a floating substituent on multiple rings). When a substituent is attached to a ring other than a particular atom (a floating substituent) and the subscript of the substituent is an integer greater than one, multiple substituents can be on the same atom, the same ring, different atoms, different fused rings, different spirorings, and each substituent can optionally be different. In the case where the point of attachment of the ring to the rest of the molecule is not limited to a single atom (floating substituent), the point of attachment may be any atom of the ring, and in the case of a fused ring or spiro ring, may be any atom of either of the fused ring or spiro ring (where the rules of chemical valency are followed). Where a ring, fused ring, or spiro ring contains one or more ring heteroatoms and the ring, fused ring, or spiro ring is shown with yet another floating substituent (including but not limited to the point of attachment to the rest of the molecule), the floating substituent may be attached to the heteroatom. When a ring heteroatom is shown bound to one or more hydrogens in a structure or formula with a floating substituent (e.g., a ring nitrogen with two bonds bound to the ring atom and a third bond bound to a hydrogen), when the heteroatom is attached to a floating substituent, the substituent will be understood to replace the hydrogen while following the chemical valence rules.

Two or more substituents may be optionally joined to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically (although not necessarily) attached to the cyclic base structure. In one embodiment, the ring-forming substituent is attached to a proximal member of the base structure. For example, two rings attached to adjacent members of a cyclic base structure form a substituent to create a fused ring structure. In another embodiment, the ring-forming substituent is attached to a single member of the base structure. For example, two rings attached to a single member of a cyclic base structure form a substituent resulting in a spiro ring structure. In yet another embodiment, the ring-forming substituent is attached to a non-adjacent member of the base structure.

Two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring of the formula-T-C (O) - (CRR')_q-U-, wherein T and U are independently-NR-, -O-, -CRR' -or a single bond, and q is an integer of 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted by a group of formula-A- (CH)₂)_rSubstituent of-B-Wherein A and B are independently-CRR' -, -O-, -NR-, -S (O) ₂-、-S(O)₂NR' -or a single bond, and r is an integer of 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a compound of the formula- (CRR')_s-X′-(C″R″R″′)_d-wherein S and d are independently integers from 0 to 3, and X 'is-O-, -NR' -, -S (O)₂-or-S (O)₂NR' -. Substituents R, R ', R ", and R'" are preferably independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

As used herein, the term "heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

As used herein, "substituent" means a group selected from the following moieties:

(A) oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCF₃、-OCBr₃、-OCI₃、-OCHCl₂、-OCHBr₂、-OCHI₂、-OCHF₂、-OCH₂Cl、-OCH₂Br、-OCH₂I、-OCH₂F、-N₃Unsubstituted alkyl (e.g. C) ₁-C₈Alkyl radical, C₁-C₆Alkyl or C₁-C₄Alkyl), unsubstituted heteroalkyl (e.g., 2-to 8-membered heteroalkyl, 2-to 6-membered heteroalkyl, or 2-to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C)₃-C₈Cycloalkyl radical, C₃-C₆Cycloalkyl or C₅-C₆Cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-to 8-membered heterocycloalkyl, 3-to 6-membered heterocycloalkyl, or 5-to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C)₆-C₁₀Aryl radical, C₁₀Aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, or 5-to 6-membered heteroaryl), and

(B) alkyl (e.g. C)₁-C₈Alkyl radical, C₁-C₆Alkyl or C₁-C₄Alkyl), heteroalkyl (e.g., 2-to 8-membered heteroalkyl, 2-to 6-membered heteroalkyl, or 2-to 4-membered heteroalkyl), cycloalkyl (e.g., C)₃-C₈Cycloalkyl radical, C₃-C₆Cycloalkyl or C₅-C₆Cycloalkyl), heterocycloalkyl (e.g., 3-to 8-membered heterocycloalkyl, 3-to 6-membered heterocycloalkyl, or 5-to 6-membered heterocycloalkyl), aryl (e.g., C)₆-C₁₀Aryl radical, C₁₀Aryl or phenyl), heteroaryl (e.g., 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, or 5-to 6-membered heteroaryl), substituted with at least one substituent selected from:

(i) oxo, halogen, -CCl ₃、-CBr₃、-CF₃、-CI₃、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCF₃、-OCBr₃、-OCI₃、-OCHCl₂、-OCHBr₂、-OCHI₂、-OCHF₂、-OCH₂Cl、-OCH₂Br、-OCH₂I、-OCH₂F、-N₃Unsubstituted alkyl (e.g. C)₁-C₈Alkyl radical, C₁-C₆Alkyl or C₁-C₄Alkyl), unsubstituted heteroalkyl (e.g., 2-to 8-membered heteroalkyl, 2-to 6-membered heteroalkyl, or 2-to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C)₃-C₈Cycloalkyl radical, C₃-C₆Cycloalkyl or C₅-C₆Cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-to 8-membered heterocycloalkyl, 3-to 6-membered heterocycloalkyl, or 5-to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C)₆-C₁₀Aryl radical, C₁₀Aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, or 5-to 6-membered heteroaryl), and

(ii) alkyl (e.g. C)₁-C₈Alkyl radical, C₁-C₆Alkyl or C₁-C₄Alkyl), heteroalkyl (e.g., 2-to 8-membered heteroalkyl, 2-to 6-membered heteroalkyl, or 2-to 4-membered heteroalkyl), cycloalkyl (e.g., C)₃-C₈Cycloalkyl radical, C₃-C₆Cycloalkyl or C₅-C₆Cycloalkyl), heterocycloalkyl (e.g., 3-to 8-membered heterocycloalkyl, 3-to 6-membered heterocycloalkyl, or 5-to 6-membered heterocycloalkyl), aryl (e.g., C)₆-C₁₀Aryl radical, C₁₀Aryl, or phenyl), heteroaryl (e.g., 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, or 5-to 6-membered heteroaryl), substituted with at least one substituent selected from:

(a) Oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCF₃、-OCBr₃、-OCI₃、-OCHCl₂、-OCHBr₂、-OCHI₂、-OCHF₂、-OCH₂Cl、-OCH₂Br、-OCH₂I、-OCH₂F、-N₃Unsubstituted alkyl (e.g. C)₁-C₈Alkyl radical, C₁-C₆Alkyl or C₁-C₄Alkyl), unsubstituted heteroalkyl (e.g., 2-to 8-membered heteroalkyl, 2-to 6-membered heteroalkyl, or 2-to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C)₃-C₈Cycloalkyl radical, C₃-C₆Cycloalkyl or C₅-C₆Cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-to 8-membered heterocycloalkyl, 3-to 6-membered heterocycloalkyl, or 5-to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C)₆-C₁₀Aryl radical, C₁₀Aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, or 5-to 6-membered heteroaryl), and

(b) alkyl (e.g. C)₁-C₈Alkyl radical, C₁-C₆Alkyl or C₁-C₄Alkyl), heteroalkyl (e.g., 2-to 8-membered heteroalkyl, 2-to 6-membered heteroalkyl, or 2-to 4-membered heteroalkyl), cycloalkyl (e.g., C)₃-C₈Cycloalkyl radical, C₃-C₆Cycloalkyl or C₅-C₆Cycloalkyl), heterocycloalkyl (e.g., 3-to 8-membered heterocycloalkyl, 3-to 6-membered heterocycloalkyl, or 5-to 6-membered heterocycloalkyl), aryl (e.g., C)₆-C₁₀Aryl radical, C₁₀Aryl or phenyl), heteroaryl (e.g., 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, or 5-to 6-membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, -CCl ₃、-CBr₃、-CF₃、-CI₃、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCF₃、-OCBr₃、-OCI₃、-OCHCl₂、-OCHBr₂、-OCHI₂、-OCHF₂、-OCH₂Cl、-OCH₂Br、-OCH₂I、-OCH₂F、-N₃Unsubstituted alkyl (e.g. C)₁-C₈Alkyl radical, C₁-C₆Alkyl or C₁-C₄Alkyl), unsubstituted heteroalkyl (e.g., 2-to 8-membered heteroalkyl, 2-to 6-membered heteroalkyl, or 2-to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C)₃-C₈Cycloalkyl radical, C₃-C₆Cycloalkyl or C₅-C₆Cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-to 8-membered heterocycloalkyl, 3-to 6-membered heterocycloalkyl, or 5-to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C)₆-C₁₀Aryl radical, C₁₀Aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, or 5-to 6-membered heteroaryl).

As used herein, "size-limited substituents (size-limited substituents/size-limited substituents group)" means a group selected from all substituents described above for "substituent", wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C₁-C₂₀Alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C₃-C₈Cycloalkyl, each substituted or unsubstituted heterocycloalkyl being substituted Substituted or unsubstituted 3-to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl being substituted or unsubstituted C₆-C₁₀Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-to 10-membered heteroaryl.

As used herein, "lower substituent" means a group selected from all substituents described above for "substituent", wherein each substituted or unsubstituted alkyl group is substituted or unsubstituted C₁-C₈Alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C₃-C₇Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-to 9-membered heteroaryl.

In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described herein is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is substituted or unsubstituted C₁-C₂₀Alkyl, each substituted or unsubstitutedSubstituted heteroalkyl is substituted or unsubstituted 2-to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl being substituted or unsubstituted C₃-C₈Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀Aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-to 10-membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is substituted or unsubstituted C₁-C₂₀Alkylene, each substituted or unsubstituted heteroalkylene being a substituted or unsubstituted 2-to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene being a substituted or unsubstituted C₃-C₈Cycloalkylene, each substituted or unsubstituted heterocycloalkylene being a substituted or unsubstituted 3-to 8-membered heterocycloalkylene, each substituted or unsubstituted arylene being a substituted or unsubstituted C ₆-C₁₀The arylene group, and/or each substituted or unsubstituted heteroarylene group is a substituted or unsubstituted 5-to 10-membered heteroarylene group.

In some embodiments, each substituted or unsubstituted alkyl is substituted or unsubstituted C₁-C₈Alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C₃-C₇Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C₁₀Aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-to 9-membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is substituted or unsubstituted C₁-C₈Alkylene, each substituted or unsubstituted heteroAlkyl is a substituted or unsubstituted 2-to 8-membered heteroalkylene, each substituted or unsubstituted cycloalkylene being a substituted or unsubstituted C₃-C₇Cycloalkylene, each substituted or unsubstituted heterocycloalkylene being a substituted or unsubstituted 3-to 7-membered heterocycloalkylene, each substituted or unsubstituted arylene being a substituted or unsubstituted C ₆-C₁₀The arylene group, and/or each substituted or unsubstituted heteroarylene group is a substituted or unsubstituted 5-to 9-membered heteroarylene group. In some embodiments, the compound is a chemical species described in the example section, figure, or table below.

In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroaryl, substituted or unsubstituted heteroalkylene, etc.), is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, substituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, substituted alkylene, etc., respectively), Unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, etc., respectively), Substituted cycloalkylene, substituted heterocycloalkylene, substituted heteroarylene, and/or substituted heteroalkylene).

In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one size-limited substituent, wherein each size-limited substituent may optionally be different if the substituted moiety is substituted with multiple size-limited substituents. In embodiments, if a substituted moiety is substituted with a plurality of size-limited substituents, each size-limited substituent is different.

In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if the substituted moiety is substituted with a plurality of groups selected from the group consisting of substituents, size-limited substituents and lower substituents; each substituent, size-limited substituent and/or lower substituent may optionally be different. In embodiments, if a substituted moiety is substituted with multiple groups selected from substituents, size-limited substituents, and lower substituents; each substituent, size-limited substituent and/or lower substituent is different.

Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, as well as individual isomers of (R) -or (S) -or (D) -or (L) -which may be defined as amino acids, in terms of absolute stereochemistry, are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art that are too unstable to be synthesized and/or isolated. The present disclosure is intended to encompass compounds in racemic and optically pure forms. Optically active (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is intended that these compounds contain both E and Z geometric isomers.

As used herein, the term "isomer" refers to compounds having the same number and kind of atoms, and thus having the same molecular weight, but differing in the structural arrangement or configuration of the atoms.

As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the present disclosure.

Unless otherwise specified, the structures depicted herein are also intended to encompass all stereochemical forms of the structures; i.e., the R configuration and the S configuration for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the present invention are within the scope of the disclosure.

Unless otherwise indicated, the structures depicted herein are also intended to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. E.g. having replacement of hydrogen by deuterium or tritium or by¹³C-or¹⁴Compounds of the structures of the present invention that have C-enriched carbon replacing carbon are within the scope of the present disclosure.

The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compound may be substituted with, for example, tritium (f) ³H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) And the like to be radiolabeled. All isotopic variations of the compounds of the present disclosure, whether radioactive or non-radioactive, are intended to be encompassed within the scope of the present disclosure.

It should be noted that throughout the application, alternatives are written in the Markush group, e.g. in each amino acid position containing more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered individually to include another example, and that the Markush group should not be understood as a single unit.

As used herein, the terms "bioconjugate" and "bioconjugate linker" refer to the association that results between atoms or molecules of a bioconjugate reactive group or bioconjugate reactive moiety. The association may be direct or indirect. For example, the first bioconjugate reactive group (e.g., -NH) provided herein₂Conjugation between-COOH, -N-hydroxysuccinimide or-maleimide) and the second bioconjugate reactive group (e.g., thiol, sulfur-containing amino acid, amine, amino acid-containing amine side chain or carboxylate) can be performed directly, e.g., through a covalent bond or linker (e.g., the first linker of the second linker), or indirectly, e.g., through non-covalent bonds (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole induced dipole, london dispersion), ring packing (pi effect), hydrophobic interactions, etc.). In embodiments, the bioconjugate or bioconjugate linker is formed using bioconjugate chemistry (i.e., association of two bioconjugate reactive groups) including, but not limited to, nucleophilic substitution (e.g., reaction of amines and alcohols with acid halides, active esters), electrophilic substitution (e.g., enamine reaction), and addition of carbon-carbon and carbon-heteroatom multiple bonds (e.g., michael reaction, diels-alder addition). These and other useful reactions are discussed in the following documents: for example, March, ADVANCED ORGANIC CHEMISTRY (ADVANCED ORGANIC CHEMISTRY), 3 rd edition, John Wiley father and son, John Wiley &Sons), New York (New York), 1985; hermanson, "BIOCONJUGATE technology (BioConjugate TECHNIQUES"), Academic Press, San Diego, 1996; and Feeney et al, MODIFICATION OF PROTEINS (PROTEINS); series of Chemical developments, first volume, 198, American Chemical Society, Washington, d.c., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently linked to the second bioconjugate reactive group (e.g., thiol). In the implementation ofIn an example, a first bioconjugate reactive group (e.g., a haloacetyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a thiol group). In embodiments, the first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently linked to the second bioconjugate reactive group (e.g., a sulfhydryl group). In embodiments, the first bioconjugate reactive group (e.g., N-hydroxysuccinimide moiety) is covalently linked to the second bioconjugate reactive group (e.g., sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently linked to the second bioconjugate reactive group (e.g., thiol). In embodiments, a first bioconjugate reactive group (e.g., -sulfo N-hydroxysuccinimide moiety) is covalently attached to a second bioconjugate reactive group (e.g., amino).

Useful bioconjugate reactive moieties for the bioconjugate chemistry herein include, for example:

(a) carboxyl groups and their various derivatives, including but not limited to N-hydroxysuccinimide esters, N-hydroxybenzotriazole esters, acid halides, acylimidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl, and aromatic esters;

(b) hydroxyl groups, which can be converted to esters, ethers, aldehydes, and the like;

(c) haloalkyl, wherein the halide can be subsequently replaced with a nucleophilic group such as an amine, carboxylate anion, thiol anion, carbanion, or alkoxide, thereby resulting in a new group covalently attached at the site of the halogen atom;

(d) (ii) an dienophile group capable of participating in a diels-alder reaction, such as, for example, a maleimide group or a maleimide group;

(e) an aldehyde or ketone group which allows subsequent derivatization by the formation of carbonyl derivatives such as, for example, imines, hydrazones, semi-carbazones or oximes, or by mechanisms such as Grignard (Grignard) addition or alkyllithium addition;

(f) sulfonyl halides for subsequent reaction with amines, e.g., to form sulfonamides;

(g) A thiol group which can be converted to a disulfide, reacted with an acid halide, or linked to a metal such as gold, or reacted with a maleimide;

(h) amine or thiol groups (e.g., present in cysteine) which may be, for example, acylated, alkylated, or oxidized;

(i) alkenes that can undergo, for example, cycloaddition, acylation, Michael addition, and the like;

(j) epoxides which can be reacted with, for example, amine and hydroxyl compounds;

(k) phosphoramidites and other standard functional groups useful for nucleic acid synthesis;

(l) A metal silicon oxide connection;

(m) metal attachment to a reactive phosphorus group (e.g., phosphine) to form, for example, a phosphodiester bond;

(n) linking the azide to the alkyne using copper-catalyzed cycloaddition click chemistry; and

(o) the biotin conjugate can be reacted with avidin or streptavidin (streptavidin) to form an avidin-biotin complex or streptavidin-biotin complex.

The bioconjugate reactive group can be selected such that it does not participate in or interfere with the chemical stability of the conjugates described herein. Alternatively, the reactive functional groups may be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugates include molecular entities derived from the reaction of unsaturated bonds such as maleimides with thiols.

"Analog/Analog" or "derivative" is used according to its ordinary general meaning in chemistry and biology and refers to a compound that is structurally similar to, but compositionally different from, another compound (i.e., a so-called "reference" compound), for example, in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or in the replacement of one functional group by another functional group, or in the absolute stereochemistry at one or more chiral centers of a reference compound. Thus, an analog is a compound that is similar or equivalent in function and appearance to a reference compound, but not similar or equivalent in structure or origin.

The terms "a" and "an", as used herein, mean one or more. Additionally, as used herein, the phrase "substituted with … …" means that the specified group can be substituted with one or more of any or all of the substituents of the named substituent. For example, when a group such as alkyl or heteroaryl is "unsubstituted C₁-C₂₀When alkyl or unsubstituted 2-to 20-membered heteroalkyl is substituted ", the group may contain one or more unsubstituted C ₁-C₂₀Alkyl, and/or one or more unsubstituted 2-to 20-membered heteroalkyl.

Further, where a moiety is substituted with an R substituent, the group may be referred to as "R-substituted". Where a moiety is substituted with R, the moiety is substituted with at least one R substituent, and each R substituent is optionally different. When a particular R group is present in the description of a chemical genus (as in formula (I)), the roman letter symbols may be used to distinguish each appearance of the particular R group. For example, in the presence of a plurality of R¹³In the case of a substituent, each R¹³Substituents can be distinguished asEtc. in which Each of which is at R¹³Is defined within the scope of the definition of (a) and is optionally different.

The description of the compounds of the present disclosure is limited by the principles of chemical ligation known to those skilled in the art. Thus, where a group may be substituted with one or more of a plurality of substituents, such substitution is selected so as to comply with the principles of chemical ligation and to yield a compound that is not inherently labile and/or would be known to one of ordinary skill in the art as potentially labile under environmental conditions (e.g., aqueous, neutral, and several known physiological conditions). For example, heterocycloalkyl or heteroaryl groups are attached to the rest of the molecule via a ring heteroatom according to chemical linking principles known to those skilled in the art, thereby avoiding inherently unstable compounds.

The term "pharmaceutically acceptable salts" is intended to encompass salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or the like. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid, neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include acid addition salts derived from the following inorganic acids: such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, etc.; and salts derived from the following relatively non-toxic organic acids: such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, and the like. Also included are Salts of amino acids such as arginine Salts, and Salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted into base addition salts or acid addition salts.

Thus, the compounds of the present disclosure may exist as salts with pharmaceutically acceptable acids. The present disclosure encompasses such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+) -tartrate, (-) -tartrate or a mixture thereof comprising a racemic mixture), succinate, benzoate and salts with amino acids such as glutamic acid and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

In addition to salt forms, the present disclosure also provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment (such as, for example, when contacted with a suitable enzyme or chemical reagent).

Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

A polypeptide or cell is "recombinant" when it is or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or non-wild-type) that is or is artificial or engineered or derived from an artificial or engineered protein or nucleic acid. For example, a polynucleotide inserted into a vector or any other heterologous location, e.g., into the genome of a recombinant organism, such that it is not associated with a nucleotide sequence that normally flanks the polynucleotide as it is found in nature, is a recombinant polynucleotide. Proteins expressed by recombinant polynucleotides in vitro or in vivo are examples of recombinant polypeptides. Similarly, polynucleotide sequences that do not occur in nature (e.g., variants of naturally occurring genes) are recombinant.

By "co-administration" is meant administration of a composition described herein simultaneously with, just before, or just after administration of one or more additional therapies. The compounds of the invention may be administered alone or may be co-administered to a patient. Co-administration is meant to encompass the simultaneous or sequential administration of a compound (more than one compound), either alone or in combination. Thus, the formulations may also be combined with other active substances (e.g. to reduce metabolic degradation) if desired.

As used herein, "cell" refers to a cell that performs a metabolic function or other function sufficient to maintain or replicate its genomic DNA. Cells can be identified by methods known in the art, including: for example, there is the ability to complete the membrane, stain with a particular dye, propagate offspring, or if a gamete is present, combine with a second gamete to produce viable offspring. The cells may comprise prokaryotic cells and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and plant and animal derived cells, such as mammalian cells, insect (e.g., noctuid) cells, and human cells. Cells may be useful when they are not adherent in nature or are treated to not adhere to a surface by, for example, trypsinization.

The term "treatment" refers to any indication of successful treatment or amelioration of an injury, disease, pathology, or condition, including any objective or subjective parameter, e.g., elimination; (iii) alleviating; alleviating symptoms or making the injury, pathology, or condition more tolerable to the patient; slow the rate of degeneration or decline; or less decline of the endpoint of degeneration; improving the physical or mental health of the patient. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including results of physical examination, neuropsychiatric examination, and/or psychiatric evaluation. For example, certain methods presented herein successfully treat cancer by reducing the incidence of cancer and/or causing remission of cancer. In some embodiments of the compositions or methods described herein, treating cancer comprises slowing the growth or spread rate of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term "treating" and its conjugation encompasses the prevention of injury, pathology, condition or disease. In an embodiment, the treatment is prophylaxis. In embodiments, the treatment does not comprise prophylaxis. In embodiments, the treatment (treating or treating) is not a prophylactic treatment.

An "effective amount" is an amount sufficient for the compound to achieve the stated purpose (e.g., achieve the effect it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, decrease signaling pathways, decrease one or more symptoms of a disease or condition) relative to the absence of the compound. An example of an "effective amount" when referred to in this context is an amount sufficient to cause treatment, prevention, or reduction of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount". "reducing" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of one or more symptoms, or eliminating one or more symptoms. A "prophylactically effective amount" of a drug is an amount of the drug that, when administered to a subject, will have the intended prophylactic effect, e.g., to prevent or delay the onset (or recurrence) of an injury, disease, pathology, or condition or to reduce the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of one dose, and may occur after administration of only a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of the enzyme relative to the absence of the antagonist. As used herein, "functionally disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. As used herein, "increased amount of activity" refers to the amount of agonist required to decrease the activity of an enzyme relative to the absence of agonist. As used herein, "functionally increased amount" refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of agonist. The precise amount will depend on The purpose of The treatment and will be determined by those skilled in The Art using known techniques (see, e.g., Lieberman, "Pharmaceutical Dosage Forms (volumes 1-3, 1992); Lloyd," Art, Science and Technology of Pharmaceutical Compounding (The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar Dosage calculation (Dosage Calculations) (1999); and Remington: The Science and Practice of medicine (20 th edition, 2003, Gennaro, Ed., Williams & Wilkins.).

"control" or "control experiment" is used in its ordinary and customary sense and refers to an experiment in which the subject or reagent of the experiment is treated as in a parallel experiment, except that the procedures, reagents or variables of the experiment are omitted. In some cases, controls were used as a standard of comparison in evaluating the effect of the experiment. In some embodiments, a control is a measure of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including examples, figures, or tables).

"contacting" is used in accordance with its ordinary general meaning and refers to the process of bringing at least two different species (e.g., chemical compounds comprising biomolecules or cells) into sufficient proximity to react, interact, or physically touch. However, it is to be understood that the resulting reaction product may result directly from the reaction between the added reagents, or from intermediates to one or more added reagents that may be produced in the reaction mixture.

The term "contacting" can encompass allowing two species to react, interact, or physically contact, wherein the two species can be a compound and a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) as described herein. In some embodiments, contacting comprises allowing a compound described herein to interact with a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) involved in a signaling pathway.

As defined herein, the term "activation/active/activating, etc." with respect to a protein refers to the conversion of the protein from an initial unactivated or inactivated state to a biologically active derivative. The terms refer to reduced activation or activation (activation), sensitization or upregulation of signal transduction or enzymatic activity or quantity of a protein in a disease.

The terms "agonist," "activator," "upregulator" and the like refer to an agent that is capable of detectably increasing the expression or activity of a given gene or protein. An agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% as compared to a control in the absence of the agonist. In certain instances, the expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or more greater than the expression or activity in the absence of the agonist.

As defined herein, the term "inhibit (inhibition/inhibiting)" or the like with respect to a cellular component-inhibitor interaction means negatively affecting (e.g., reducing) the activity or function of a cellular component relative to the activity or function of a cellular component in the absence of an inhibitor (e.g., reducing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)). In embodiments, inhibiting means negatively affecting (e.g., reducing) the concentration or level of a cellular component relative to the concentration or level of a cellular component in the absence of an inhibitor. In some embodiments, inhibition refers to a reduction in a disease or symptoms of a disease. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction pathway or signaling pathway (e.g., a decrease in a pathway involving a cellular component). Thus, inhibiting at least partially comprises partially or completely blocking stimulation, reducing, preventing or delaying activation, desensitization or down-regulation of a signaling pathway or enzymatic activity or amount of a cellular component.

Interchangeably, the terms "inhibitor", "repressor", "antagonist" or "downregulator" refer to a substance capable of detectably reducing the expression or activity of a given gene or protein. An antagonist can reduce expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% as compared to a control in the absence of the antagonist. In certain instances, the expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or less lower than the expression or activity in the absence of the antagonist.

The term "modulator" refers to a physical state of a target (e.g., the target can be a cellular component (e.g., a protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) that increases or decreases the level of the target molecule or the function of the target molecule or the target of the molecule relative to in the absence of the composition.

The term "expression" encompasses any step involved in the production of a polypeptide, including but not limited to transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting proteins (e.g., ELISA, western blot, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

The term "modulate" is used in its ordinary and customary sense and refers to an action that changes or modifies one or more properties. "Modulation" refers to the process of changing or altering one or more characteristics. For example, when applied to the effect of a modulator on a target protein, modulation means alteration by increasing or decreasing the identity or function of the target molecule or the amount of the target molecule.

A "patient" or "subject in need thereof" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human.

By "disease" or "condition" is meant a state or health condition in a patient or subject that can be treated with a compound or method provided herein. In some embodiments, the disease is a disease associated with (caused by) a cellular component (e.g., a protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule). In an embodiment, the disease is a neurodegenerative disease. In an embodiment, the disease is cancer.

As used herein, the term "neurodegenerative disease" refers to a disease or condition in which the nervous system function of a subject is impaired. Examples of neurodegenerative diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include Alexander's disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (bat disease), also known as spolier-woguet-schungren-Batten disease, Spielmeyer-Vogt-Sjogren-Batten disease, Bovine Spongiform Encephalopathy (BSE), Canavan disease (canavedisease), Cockayne syndrome (Cockayne syndrome), corticobasal degeneration, Creutzfeldt-Jakob disease, temporal dementia, schwann syndrome (Gerstmann-straussler-gecko-schwarfare syndrome)-Scheinker syndrome), Huntington's Disease (Huntington's Disease), HIV-associated dementia, Kennedy's Disease, Krabbe's Disease, kuru, Lewy body dementia (Lewy body dementia), Machado Joseph Disease (madado-Joseph Disease) (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, parkinson's Disease, Pelizaeus-Merzbacher Disease (Pelizaeus-Merzbacher Disease), Pick's Disease (Pick's Disease), primary lateral sclerosis, prion Disease, refm's Disease (schumschiff's Disease), Sandhoff's Disease, syphilis Disease (metabolic's Disease), spinal cord degeneration, spinal cord Disease secondary to acute subarachnoid Disease (spinal cord degeneration), spinal cord degeneration, spinal cord Disease secondary to acute subarachnoid Disease (spinal cord degeneration), spinal cord Disease secondary to acute subarachnoid Disease (lexy degeneration), spinal cord Disease secondary to acute subarachnoid Disease, and multiple system degeneration, Spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tuberculosis.

The term "inflammatory disease" as used herein refers to a disease or condition characterized by abnormal inflammation (e.g., an increased level of inflammation as compared to a control, such as a healthy human not having a disease). Examples of inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, Systemic Lupus Erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, type 1 diabetes, Guillain-Barre syndrome (Guillain-Barre syndrome), Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, vitiligo, Addison's disease, asthma, allergic rhinitis, multiple sclerosis, Hashimoto's encephalitis, Hashimoto's thyroiditis, Crohn's disease, psoriasis, Acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis).

As used herein, the term "cancer" refers to all types of cancers, tumors, or malignancies found in mammals (e.g., humans), including leukemias, lymphomas, carcinomas, and sarcomas. Exemplary cancers that can be treated with the compounds or methods provided herein include thyroid cancer, cancer of the endocrine system, cancer of the brain, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, medulloblastoma, colorectal cancer, or pancreatic cancer. Additional examples include: hodgkin's Disease, Non-Hodgkin's Lymphoma (Non-Hodgkin's Lymphoma), multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic cancer, malignant carcinoid cancer, bladder cancer, precancerous skin lesions, testicular cancer, Lymphoma, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortex cancer, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

The term "leukemia" refers to a progressive, malignant disease of the blood-forming organs and is generally characterized by the dysregulated proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias are generally classified clinically on the basis of: (1) the duration and nature of acute or chronic disease; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphoid) or monocytic; and (3) an increase or non-increase in the number of abnormal cells in the blood-leukemic or non-leukemic (sub-leukemic). Exemplary leukemias that can be treated with a compound or method provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, skin leukemia, embryonic leukemia, eosinophilic leukemia, galosmia (Gross' leukamia), hairy cell leukemia, hematopoietic leukemia (hemablastic leukemia), hemablastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphoid leukemia, lymphoblastic leukemia, leukemia with elevated blood pressure, and/or plasma pressure, Lymphocytic, lymphoid sarcoma cell, mast cell, megakaryocytic, small myeloblastic, monocytic, myeloblastic, myelomyeloblastic, myelomyelomyeloblastic, myelomonocytic, Negrel (Naegeli leukemia), plasma cell, multiple myeloma, plasma cell, promyelocytic, Lieder's cell, Rieder's cell, Hill's (Schilder's), Stem cell, sub-leukemia or undifferentiated cell.

As used herein, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphoid tissues. It begins with lymphocytes, which are blood cells found primarily in the lymph nodes, spleen, thymus, and bone marrow. The two major types of lymphoma are non-hodgkin's lymphoma and hodgkin's disease. Hodgkin's disease accounts for about 15% of all diagnosed lymphomas. This is a cancer associated with Reed-Sternberg malignant B lymphocytes (Reed-Sternberg malignant B lymphocytes). Non-hodgkin's lymphoma (NHL) can be classified based on the growth rate of the cancer and the cell types involved. There are aggressive (higher) and indolent (lower) types of NHL. Based on the cell type involved, there are B-cells and T-cells NHL. Exemplary B-cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extralymph node (MALT) lymphoma, nodal (monocyte-like B cell) lymphoma, spleen lymphoma, diffuse large cell B lymphoma, burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B lymphoblastic lymphoma. Exemplary T cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T cell lymphoma, peripheral T cell lymphoma, large cell lymphoma pleomorphic, mycosis fungoides, and precursor T lymphoblastic lymphoma.

The term "sarcoma" generally refers to a tumor that is composed of a substance similar to embryonic connective tissue, and is generally composed of tightly packed cells embedded in a fibrous or homogeneous substance. Sarcomas that can be treated with a compound or method provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abetis's sarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, green carcinosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' sarcoma, endometrium sarcoma, interstitial sarcoma, Ewing's sarcoma, fasciosarcoma, fibroblast sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple chromophoric hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jansen's sarcoma (Jensen's sarcoma), Kaposi's sarcoma (Kaposi's sarcoma), Kappapher cell sarcoma (Kupffer cell sarcoma), angiosarcoma, leukemic sarcoma, malignant stromal tumor sarcoma, extraperiosteal sarcoma, reticulocytic sarcoma, Rous sarcoma (Rous sarcoma), serous cyst sarcoma (serous sarcoma), synovial sarcoma, or capillary dilated sarcoma.

The term "melanoma" is understood to mean a tumor derived from the melanocytic system of the skin and other organs. Melanoma, which may be treated with a compound or method provided herein, includes, for example, acral lentigo melanoma, melanotic melanoma, benign juvenile melanoma, claudman melanoma (Cloudman' S melanoma), S91 melanoma, harting-pasque melanoma (Harding-Passey melanoma), juvenile melanoma, lentigo maligna, malignant melanoma, nodular melanoma, sub-formazan melanoma, or superficial spreading melanoma.

The term "cancer" refers to a malignant new growth consisting of epithelial cells that tends to infiltrate the surrounding tissues and cause metastasis. Exemplary cancers that can be treated with the compounds or methods provided herein include, for example, medullary thyroid cancer, familial medullary thyroid cancer, acinar cancer, alveolar cancer, cystic adenoid cancer, adenoid cystic cancer, adenocarcinoma, adrenocortical cancer, alveolar carcinoma, alveolar cell carcinoma, basal-like cytoma, basal-like carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchial carcinoma, brain carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid cancer, acne carcinoma, uterine corpus carcinoma, ethmoid carcinoma, thyroid carcinoma, canker (carcinoma cantaleum), columnar carcinoma, columnar cell carcinoma, ductal carcinoma, dural carcinoma, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, adenoid cell carcinoma, explanted carcinoma, ulcerative carcinoma (carcinoma ex ulceroce), fibrocarcinoma, colloidal carcinoma (gelatiforminaricarcinosi carcinoma), giant carcinoma (gelitinmachinery), giant carcinoma, and malignant carcinoma, Giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hairy mother carcinoma (hair-matrix carcinoma), leukemia (hematopoietic carcinoma), hepatocellular carcinoma, Schlemm cell carcinoma (Hurthle cell carcinoma), vitreous carcinoma (hyaline carcinoma), adenoid carcinoma of the kidney, juvenile embryonal carcinoma, carcinoma in situ, carcinoma in epidermis, carcinoma in epithelium, Klopacherer's carcinoma, Kulchitzky-cell carcinoma (Kulchitzky-cell carcinoma), large cell carcinoma, lenticular carcinoma (lentinular carcinoma), lenticular carcinoma (carcinosular carcinoma), lipomatous carcinoma (lipomatous carcinoma), lymphoepithelial carcinoma, medullary carcinoma (mucoid carcinoma), nasopharyngeal carcinoma (mucoid carcinoma, osteocarcinoma, mucoid carcinoma (mucoid carcinoma), mucoid carcinoma of the lung, and squamous cell carcinoma of the lung, Bone-like cancer (osteopoid carcinoma), papillary carcinoma, periportal carcinoma, invasive carcinoma, acanthoma, soft-pasty carcinoma (pultaceous carcinoma), renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma (schneiderian carcinoma), scleroma, scrotum carcinoma (carcinosa scroti), signet cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, globular cell carcinoma, fusiform cell carcinoma, medullary carcinoma (carcinosum), squamous carcinoma, squamous cell carcinoma, roping carcinoma, vasodilatory carcinoma (carcinospectomyomatosis), telangiectatic carcinoma (carcinosoma telangiectasias), transitional cell carcinoma, massive carcinoma (carcinosoma tubiformis), nodular skin carcinoma (wartus carcinosoma), warty carcinoma, or choriocarcinoma.

"pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that facilitates administration of an active agent to a subject and absorption by the subject, and that may be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solution, lactated Ringer's solution, common sucrose, common glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates (e.g., lactose, amylose, or starch), fatty acid esters, carboxymethylcellulose, polyvinylpyrrolidone, pigments, and the like. Such formulations can be sterilized and, if desired, mixed with adjuvants which do not deleteriously react with the compounds of the invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring and/or perfuming substances, etc. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

The term "formulation" is intended to encompass a formulation of an active compound with an encapsulating material in the form of a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier with which it is associated. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

As used herein, the term "about" means a range of values that includes the specified value, which one of ordinary skill in the art would consider reasonably similar to the specified value. In the examples, about means within the standard deviation using measurements generally accepted in the art. In embodiments, about refers to a range extending to +/-10% of the specified value. In an embodiment, the offer contains the specified value.

As used herein, the term "administering" means orally administering, administering in suppository form, topically contacting, intravenously, intraperitoneally, intramuscularly, intralesionally, intrathecally, intranasally, or subcutaneously, or implanting a slow release device (e.g., a mini osmotic pump) to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposome formulations, intravenous infusion, transdermal patches, and the like. By "co-administration" is meant that the compositions described herein are administered simultaneously with, just before, or just after the administration of one or more additional therapies (e.g., cancer therapies such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy). The compounds of the invention may be administered alone or may be co-administered to a patient. Co-administration is meant to encompass the simultaneous or sequential administration of a compound (more than one compound), either alone or in combination. Thus, the formulations may also be combined with other active substances (e.g. to reduce metabolic degradation) if desired. The compositions of the present invention may be delivered transdermally by a topical route formulated as a stick, solution, suspension, emulsion, gel, cream, ointment, paste, jelly, paint, powder, and aerosol.

The compounds described herein may be used in combination with each other, with other active agents known to be useful in the treatment of diseases associated with cells expressing disease-associated cellular components, or with adjuvants that may not be effective alone but may contribute to the efficacy of the active agent.

In some embodiments, co-administration comprises administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration comprises administering the two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration may be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition comprising both active agents. In other embodiments, the active agents may be formulated separately. In another embodiment, the active agent and/or adjuvant may be linked or conjugated to each other.

The compounds described herein may be co-administered with conventional neurodegenerative disease treatments including, but not limited to, parkinson's disease treatments such as levodopa (levodopa), carbidopa (carbidopa), selegiline (selegiline), amantadine (amantadine), donepezil (donepezil), galantamine (galanthamine), rivastigmine (rivastigmine), tacrine (tacrine), dopamine agonists (e.g., bromocriptine (bromocriptine), pergolide (pergolide), pramipexole (pramipexole), ropinirole (ropiniole)), anticholinergic drugs (e.g., trihexyphenidine), phenyltropine (benztropinine), biperiden (biperiden), pricyclidine (cycloproline), and catechol-O-methyltransferase inhibitors (e.g., tolcapone), capone (entacapone)).

The compounds described herein may also be co-administered with conventional anti-inflammatory disease treatments including, but not limited to, analgesics (e.g., acetaminophen (acetaminophen), duloxetine (duloxetine)), non-steroidal anti-inflammatory drugs (e.g., aspirin (aspirin), ibuprofen (ibuprofen), naproxen (naproxen), diclofenac sodium (diclofenac)), corticosteroids (e.g., prednisone, betamethasone, cortisone), dexamethasone (dexmethasone), hydrocortisone (hydrocortisone), methylprednisolone (methylprednisone), prednisolone (prednisone)), and opions (e.g., codeine, fentanyl, hydrocodone (hydrocodone)), hydromorphone (hydromorphone), morphine (morphine), piperidine (oxymorphone), oxycodone (oxycodone)).

"anti-cancer agent" is used in its ordinary general sense and refers to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) that has anti-tumor properties or the ability to inhibit cell growth or proliferation. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the anti-cancer agent is an agent identified herein having utility in a method of treating cancer. In some embodiments, the anti-cancer agent is an agent approved by the FDA or similar regulatory agency in countries other than the united states for the treatment of cancer. In embodiments, the anti-cancer agent is an agent with anti-tumor properties that has not been (e.g., has not been) approved by the FDA or similar regulatory agency in a country outside the united states for the treatment of cancer. Examples of anti-cancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, semetinib (selmetinib)/AZD 6244, GSK 1120212/trametinib (trametinib), GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil (chlorembucil), busulfan (busulfan), melphalan (melphalalan), mechlorethamine (mechlorethamine), uramustine (uramustine), thiotepa (thiotepa), nitrosoureas, mechlorethamine (e), melphalan (e.g., mechlorethamine), melphalan (e), melamine (e.g., hexamethyl), melamine (e.g., mechlorethamine), mechlorethamine (e.g., mechlorethamine), mechlorethamine (e.g., mechlorethamine), mechlorethamine (mechlorethamine), mechlorethamine (e, mechlorethamine (mechlorethamine), mechlorethamine (e.g., mechlorethamine), mechlorethamine (e, mechlorethamine), mechlorethamine (e.g., mechlorethamine), mechlorethamine (e.g., mechlorethamine), mechlorethamine (e.g., mechlorethamine), mechlorethamine (mechlorethamine), mechlorethamine (e.g., mechlorethamine), mechlorethamine (mechlorethamine), mechlorethamine (mechlorethamine ), mechlorethamine (e.g., mechlorethamine (mechlorethamine, mechlorethamine), mechlorethamine, lomustine (lomustine), semustine (semustine), streptozocin (streptozocin), triazene (dacarbazine), antimetabolites (e.g., 5-azathioprine, folinic acid, capecitabine (capecitabine), fludarabine (fludarabine), gemcitabine (gemcitabine), pemetrexed (pemetrexed), raltitrexed (raltitrexed), folic acid analogs (e.g., methotrexate), Or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin (pentostatin), etc.), plant alkaloids (e.g., vincristine (vincristine), vinblastine (vinblastine), vinorelbine (vinorelbine), vindesine (vindesine), podophyllotoxin (podophyllotoxin), paclitaxel (paclitaxel), docetaxel (docetaxel), etc.), topoisomerase inhibitors (e.g., irinotecan (irinotecan), topotecan (topotecan), amsacrine (amsacrine), etoposide (VP16), etoposide (etoposide), teniposide (teniposide), etc.), antitumor antibiotics (e.g., doxorubicin (doxocin), actinomycin (adriamycin), erythromycin (epirubicin), mitomycin (mitomycin), etc.), antitumor antibiotics (mitomycin), mitomycin (vincristine), etc, Plicamycin (plicamycin), etc.), platinum-based compounds (e.g., cisplatin (cispin), oxaliplatin (oxaloplatin), carboplatin (carboplatin)), anthraquinones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical hormone inhibitors (e.g., mitotane, aminoglutethimide), epipodophyllotoxin (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB 2363, SP600125, BAY 43-9006, tmocin (siamese), or mTOR 4002), or mTOR inhibitors such as mTOR 292 (R) or mTOR (R2), such as an antibody (e.g., a mitoxantronbin), an inhibitor (e.g., mitoxantronin), a mitoxantrone.g., a mitoxantrone, a, Gossypol (gossypol), ganesen (gensense), polyphenol E, chlorin (Chlorofusin), all-trans retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis inducing ligand (TRAIL), 5-aza-2' -deoxycytidine, all-trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec. RTM.), geldanamycin (geldanamycin), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), Frodropiridol (flavopiridol), LY294002, bortezomib (bortezomib), trastuzumab (trastuzumab), BAY 11-7082, PKC412, PD184352, 20-epi-1, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone (abiraterone); aclarubicin; asservate (acylfulvene); adenocyclopentanol (adecanol); adozelesin (adozelesin); aldesleukin (aldesleukin); ALL-TK antagonist; altretamine; ambamustine (ambamustine); amidox (amidox); amifostine (amifostine); (ii) aminolevulinic acid; amrubicin (amrubicin); amsacrine; anagrelide (anagrelide); anastrozole (anastrozole); andrographolide (andrographolide); angiogenesis inhibitors (angiogenisis inhibitor); an antagonist D; an antagonist G; andrelix (antarelix); anti-dorsal morphogenetic protein-1 (anti-dorsallizing morphogenetic protein-1); anti-androgens, prostate cancer; an antiestrogen; antineoplastic ketone (antineoplaston); an antisense oligonucleotide; aphidicolin (aphidicin glycinate); an apoptosis gene modulator; an apoptosis modulator; a purine-free nucleic acid; ara-CDP-DL-PTBA; arginine deaminase; avalanoline (asularnine); atamestane (atamestane); amoxicillin (atrimustine); asinastine 1 (axinatatin 1); asinastadine 2; asinastadine 3; azasetron (azasetron); azadoxine (azatoxin); diazotyrosine (azatyrosine); baccatin III derivatives (baccatin III deritive); balanol (balanol); batimastat (batimastat); a BCR/ABL antagonist; benzoxazole chloroxins (benzoxazolins); benzoylstaurosporine (benzoylstaurosporine); a beta-lactam derivative; beta-alidine (beta-alethine); aclacinomycin b (betamycin b); betulinic acid; a bFGF inhibitor; bicalutamide (bicalutamide); bissantrene; bisaziridinylspermimine (bisaziridinylspermine); bis-naphthalide (bisnafide); didetinyl a (bistetralene a); bizelesin (bizelesin); brefelone (brefflate); briprimine (bropirimine); butobactam (budotitane); buthionine sulfoximine (buthionine sulfoximine); calcipotriol (calcipotriol); calphos protein C; camptothecin (camptothecin) derivatives; canarypox IL-2(canarypox IL-2); card culture Capecitabine (capecitabine); carboxamide-amino-triazole (carboxamide-amino-triazole); carboxyamidotriazole (carboxyyamidotriazole); CaRest M3; CARN 700; a cartilage derived inhibitor; kazelesin (carzelesin); casein kinase Inhibitors (ICOS); castanospermine (castanospermine); cecropin b (cecropin b); cetrorelix (cetrorelix); porphines (chlorins); sulfonamide chloroquinoxalines (chloroquinoxalines sulfonamide); cicaprost (cicaprost); cis-porphyrin (cis-porphyrin); cladribine (cladribine); clomiphene analogs (clomiphene analogue); clotrimazole (clotrimazole); clindamycin a (colismicin a); clinostatin B; combretastatin a4(combretastatin a 4); combretastatin analogs (combretastatin analog); kanahuaning (connagenin); cladribine (crambescidin 816); clinatol (crisnatol); cryptophycin 8(cryptophycin 8); a nostoc a derivative; g is composed of rhodoxin A (curve A); cyclopentanelaquine (cyclopentanthraquinones); cycloplatin (cycloplatam); tipemicin (cypemycin); cytarabine phosphodiester (cytarabine ocfosfate); cytolytic factor (cytolytic factor); thiadessertine (cytostatin); daclizumab (daclizumab); decitabine (decitabine); dehydrated membrane ecteinascidin B (dehydrodidemnin B); deslorelin (deslorelin); dexamethasone (dexamethasone); west fosfamide (dexesfamide); dexrazoxane (dexrazoxane); dexverapamil (dexverapamul); mitoquinone (diaziquone); b (didemnin b); a second gram (didox); diethyl norspermine (diethylnorspermine); dihydro-5-azacytidine; 9-dioxamycin; diphenylspiromustine (diphenylspiromustine); behenyl alcohol; dolasetron (dolasetron); doxifluridine (doxifluridine); droloxifene (droloxifene); dronabinol (dronabinol); dacarbazine sa (duocarmycin sa); ebselen (ebselen); escomostine (ecomustine); edifovir (edelfosine); eculizumab (edrecolomab); eflornithine (eflornithine); elemene (elemene); ethirimuron (emiteflur); epirubicin; epristeride (epristeride); estramustine analogues (estramustine analogue); estrogen agonists (estrogen agonst); an estrogen antagonist; etanidazole (eta) nidazole); etoposide phosphate (etoposide phosphate); exemestane (exemestane); fadrozole (drozole); fazarabine (fazarabine); fenretinide (fenretinide); filgrastim (filgrastim); finasteride (finasteride); frataxinol (flavopiridol); flutemastine (flezelastine); formoterol (flusterone); fludarabine (fludarabine); fluorodaunorubicin hydrochloride (fluoroaurorunorubicin hydrochloride); formoterol (forfenimex); formestane (formestane); forstericin (fosstriicin); fotemustine (fotemustine); gadoteridine (gadolinium texaphyrin); gallium nitrate (gallium nitrate); galocitabine (gallocitabine); ganirelix (ganirelix); gelatinase inhibitors (gelatinase inhibitors); gemcitabine (gemcitabine); glutathione inhibitors (glutathione inhibitors); hepulan extract (hepsulfam); heregulin (heregulin); hexamethylene bisamide (hexamethyl bisacetamide); hypericin (hypericin); ibandronic acid (ibandronic acid); idarubicin (idarubicin); idoxifene (idoxifene); iloperidone (idramantone); ilofovir (ilmofosine); ilomastat (ilomastat); with idazoloxazerone (imidazoacridones); imiquimod (imiquimod); immunostimulatory peptides; insulin-like growth factor-1 receptor inhibitors (insulin-like growth factor-1 receptor inhibitors); an interferon agonist; an interferon; an interleukin; iodobenzylguanidine (iobengouane); doxorubicin iododoxorubicin (iododoxorubicin); 4-Ipomoea nigra alcohol (ipomoeanol, 4-); ipropyl (irolact); isradine (irsogladine); isobengazole (isobengazole); esomeprazole antagonist b (isohomohaliconidrin b); itasetron (itasetron); acragoline (jasplakinolide); kahalalide F (kahalalide F); lamellarin triacetate N (lamellarin-N triacetate); lanreotide (lanreotide); linamicin (leinamycin); leguminosis (lentigerstim); lentinan sulfate; leptin statin (leptin); letrozole (letrozole); leukemia inhibitory factor; leukocyte interferon alpha; leuprolide + estrogen + progesterone; dantong (leuprorelin); levamisole (levamisole); liazole; linear polyamine analogs; a lipophilic glycopeptide; a lipophilic platinum compound; exxocrin Ann 7(lissoclinamide 7); lobaplatin (lobaplatin); earthworm phospholipid (lombricine); lometrexol (lomerexol); lonidamine (lonidamine); losoxantrone (losoxantrone); lovastatin (lovastatin); loxoribine (loxoribine); lurtotecan (lurtotecan); texaphyrins (lutetium texaphyrin); lisophorine (lysofylline); a lytic peptide; maytansine (maitansine); moroxydine a (manostatin a); marimastat (marimastat); maoprocol (masoprocol); mammary silk profilin (maspin); matrix lytic factor inhibitors (matrilysin inhibitors); a matrix metalloproteinase inhibitor; melanoril (menogaril); mezzanine (merbarone); meterelin (meterelin); methioninase; metoclopramide; an inhibitor of MIF; mifepristone (mifepristone); miltefosine (miltefosine); milbemycin (mirimostim); mismatched double-stranded RNA; mitoguazone (mitoguzone); dibromodulcitol (mitolactol); mitomycin analogs; mitonafide (mitonafide); mitotoxin fibroblast growth factor-saporin (mitotoxin fibroblast growth factor-saporin); mitoxantrone (mitoxantrone); mofarotene (mofarotene); mogrammos (molgramostim); monoclonal antibodies, human chorionic gonadotropin; monophosphoryl lipid a + mycobacterial cell wall sk; mopidamol (mopidamol); multiple drug resistance gene inhibitors; multiple tumor suppressor 1-based therapies; mustard anti-cancer agents (mustard anticancer agents); oxacephem B (mycaperoxide B); a mycobacterial cell wall extract; myraprenone (myriaperone); n-acetyldinaline (N-acetyldinaline); n-substituted benzamides; nafarelin (nafarelin); nagreys (nagreskip); naloxone + tebuconazole (naloxone + pentazocine); naparlin (napavin); nalorphin (naphterpin); nartostim (nartograstim); nedaplatin (nedaplatin); nemorubicin (nemorubicin); neridronic acid (neridronic acid); neutral endopeptidase (neutral endopeptidase); nilutamide (nilutamide); nisamycin (nisamycin); nitric oxide modulators (nitric oxide modulators); nitroxide antioxidants (nitroxide antioxidants); nitrilyn (nitrilyn); o6-benzylguanine; octreotide (octreotide); okicenon (okicenone); an oligonucleotide; ao nationality of Olympic Nastone (onapristone); ondansetron (ondansetron); ondansetron; olacin (oracin); an inducer of an oral cytokine; ormaplatin; oxaterone (osaterone); oxaliplatin (oxaliplatin); orthodoxin (oxaunomycin); palatamine (palauaramine); pamidozoxine (palmitoyldizoxin); pamidronic acid (pamidronic acid); panaxytriol (panaxytriol); panomifen (panomifene); palatinoin (parabacin); pozenididine (pazelliptine); pemetrexed (pegasparase); peidisine (peldesine); wood sodium polysulphide (pentasan sodium); pentostatin (pentostatin); pentazolyl (pentazolyl); perfluobrone (perflukron); phosphoramide (perfosfamide); perillyl alcohol (perillyl alcohol); finazino-sine (phenazinomocin); phenyl acetate; a phosphatase inhibitor; bicibanil (picibanil); pilocarpine hydrochloride (pilocarpine hydrochloride); pirarubicin (pirarubicin); pirtricin (piritrexim); prallestine a (placetin a); praise B; a plasminogen activator inhibitor; a platinum complex; a platinum compound; a platinum-triamine complex; porfimer sodium (porfimer sodium); methyl mitomycin (porfiromycin); prednisone (prednisone); propylbisindanone (propyl bis-acridone); prostaglandin J2(prostaglandin J2); a proteasome inhibitor; protein a-based immunomodulators; inhibitors of protein kinase C; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurin (purpurins); pyrazoloacridine (pyrazoloacridine); pyridoxylated hemoglobin polyoxyethylene conjugates; a raf antagonist; raltitrexed (raltitrexed); ramosetron; ras farnesyl protein transferase inhibitors; (ii) a ras inhibitor; ras-GAP inhibitors; demethylated retetriptine (demethylated); rhenium (Re) 186 etidronate (rhenium 186 ethidronate); rhizomycin (rhizoxin); enzymatic nucleic acids (ribozymes); RII vitamin carboxamides (RII retinamides); roglutamide (rogletimide); rohituine (rohitukine); romurtide (romurtide); loquimex (roquinimex); rubiginone B1(rubiginone B1); a snorkel base (ruboxyl); saffingol (safingol); sarin pin (saintopin); SarCNU; sacochorphine A (sarcophylol A); sand Gerstromotim (sargramostim); a Sdi 1 mimetic; semustine (semustine); senescence-derived inhibitor 1; a sense oligonucleotide; a signal transduction inhibitor; a signal transduction modulator; a single-chain antigen-binding protein; azofurans (sizofurans); sobuzoxane (sobuzoxane); sodium boronate (sodium borocaptate); sodium phenyl acetate (sodium phenyl acetate); sovorol (solvol); a growth regulator binding protein; sonamin (sonermin); ospiramate acid (sparfosic acid); mycin d (spicamycin d); spiromustine (spiromustine); spandex (spandex); halichondrin 1; squalamine (squalamine); a stem cell inhibitor; inhibitors of stem cell division; stiipiamide; stromelysin inhibitors (stromelysin inhibitors); solifenacin (sulfinosine); a superactive vasoactive intestinal peptide antagonist; surasista (surasista); suramin (suramin); swainsonine (swainsoninone); synthetic glycosaminoglycans (mucopolysaccharides); tamoxifen (tallimustine); tamoxifen methiodide (tamoxifen methiodide); taulomustine (tauromustine); tazarotene (tazarotene); sodium tegaserod (tecogalan sodium); tegafur (tegafur); dai luralium (telluropyrylium); a telomerase inhibitor; temoporfin (temoporfin); temozolomide (temozolomide); teniposide (teniposide); tetrachloro-deoxyxide; tetrazolemine (tetrazolamine); salablastine (thalistatin); ciocaline (thiocoraline); thrombopoietin; thrombopoietin mimetics; thymalfasin (thymalfasin); a thymopoietin receptor agonist; thymotreonam (thymotrinan); thyroid stimulating hormone (thyroid stimulating hormone); tin ethyl protoporphyrin (tin ethyl ethylpururin); tirapazamine (tirapazamine); titanocene dichloride (titanocene bichloride); desmoplantin (topstein); toremifene (toremifene); a totipotent stem cell factor; a translation inhibitor; tretinoin (tretinoin); triacetyluridine (triacetyluridine); triciribine (triciribine); trimetrexate (trimetrexate); triptorelin (triptorelin); tropisetron (tropisetron); tolteromide (turosteride); tyrosine kinase inhibitors; a tyrosine phosphorylation inhibitor; an UBC inhibitor; ubenimex (ubenimex); urogenital sinus derived growth inhibitory factor; urine collection device A kinase receptor antagonist; vapreotide (vapreotide); warriolin b (variolin b); vector systems, red blood cell gene therapy; veratrilol (velaresol); veratramine (veramine); weilbins (verdins); verteporfin (verteporfin); vinorelbine (vinorelbine); vinblastine (vinxaline); vilatatin (vitaxin); vorozole (vorozole); zanoterone (zanoterone); zeniplatin (zeniplatin); benzalvitamin c (zilascorb); absolute stastatin stallinate, doxorubicin, Dactinomycin, bleomycin, vinblastine, cisplatin, acivicin (acivicin); aclarubicin; (ii) alcodazole hydrochloride (acodazole hydrochloride); crohn (acronine); (ii) Alexanox; aldesleukin; altretamine (altretamine); ambomycin (ambomacin); ametanone acetate; aminoglutethimide (aminoglutethimide); amsacrine (amsacrine); anastrozole; anthranilic acid (anthranycin); an asparaginase enzyme; triptyline (asperlin); azacitidine (azacitidine); azatepa (azetepa); azomycin (azotomycin); batimastat; benproperine (benzodepa); bicalutamide; bissantrenehydrochloride; bisnafide dimesylate (bisnafide dimesylate); bizelesin; bleomycin sulfate (bleomycin sulfate); brequinar sodium (brequinar sodium); briprimine; busulfan; actinomycin c (cactinomycin); carposterone (calusterone); carthamine (caracemide); carbathim (carbbeimer); carboplatin (carboplatin); carmustine (carmustine); caminomycin hydrochloride (carbacidin hydrochloride); folding to get new; cedefingol (cedefingol); cinchonine (chlorembuil); siromycin (cirolemycin); cladribine; cllinalto mesylate (crisnatol mesylate); cyclophosphamide (cyclophosphamide); cytarabine (cytarabine); dacarbazine (dacarbazine); daunorubicin hydrochloride (daunorubicin hydrochloride); decitabine; dexomaplatin (dexrmaplatin); dizaguanine (dezaguanine); dizyguanine mesylate (deazaguanine mesylate); a sulphinoquinone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate (droloxifene citrate); dromostanolone propionate; daptomycin (duazomycin); in accordance with Daqusand (edatrexate); eflornithine hydrochloride (eflornithine hydrochloride); elsamitrucin (elsamitrustin); enloplatin (enloplatin); enpromethane (enpromate); epipipidine (epidopidine); epirubicin hydrochloride (epirubicin hydrochloride); erbulozole (erbulozole); esorubicin hydrochloride (esorubicin hydrochloride); estramustine (estramustine); estramustine sodium phosphate; etanidazole; etoposide; etoposide phosphate; etoposide (etoprine); fadrozole (hydrochloric acid); fazarabine; fenretinide; floxuridine (floxuridine); fludarabine phosphate (fludarabine phosphate); fluorouracil; fluorocyclocytidine (fluoroocitabine) fluoroquinolone (fosquidone); fostricin sodium (fosstricin sodium); gemcitabine; gemcitabine hydrochloride (gemcitabine hydrochloride); a hydroxyurea; idarubicin hydrochloride (idarubicin hydrochloride); ifosfamide; imoramine (imicofosine); interleukin I1 (comprising recombinant interleukin II, or rll.sub.2), interferon alpha-2 a; interferon alpha-2 b; interferon alpha-n 1; interferon alpha-n 3; interferon beta-1 a; interferon gamma-1 b; iproplatin (iproplatin); irinotecan hydrochloride (irinotecan hydrochloride); lanreotide acetate (lanreotide acetate); letrozole; leuprolide acetate (leuprolide acetate); liarozole (liarozole hydrochloride); lometrexol sodium (lomerexol sodium); lomustine (lomustine); losoxantrone hydrochloride (losoxantrone hydrochloride); (ii) maxolone; maytansine (maytansine); mechlorethamine hydrochloride (mechlorethamine hydrochloride); megestrol acetate (megestrol acetate); melengestrol acetate (melengestrol acetate); melphalan; (ii) a melanoril; mercaptopurine (mercaptoprine); methotrexate; methotrexate sodium (methotrexate sodium); chlorpheniramine (metoprine); meturedepa; mitodomide (mitindoside); mitocarcin (mitocarcin); metronidazole (mitocromin); mitogillin (mitogillin); mitomalamycin (mitomalacin); mitomycin; mitosper (mitosper); mitotane (mitotane); mitoxantrone hydrochloride (mitoxantrone hydrochloride); mycophenolic acid (mycophenolic acid); nocodazole (nocodazole); nogalamycin (nogalamycin); ormaplatin; osxisulam (oxasuran); a pemetrexed; peuli et al Mycin (peliomycin); pentazocine (pentamustine); pelomomycin sulfate (peplomycin sulfate); cultivating phosphoramide; guanxueshuang (pipobroman); piposulfan; piroxantrone hydrochloride (piroxanthone hydrochloride); plicamycin (plicamycin); pramipexole (plomestane); porfimer sodium; methyl mitomycin; prednimustine (prednimustine); procarbazine hydrochloride (procarbazine hydrochloride); puromycin (puromycin); puromycin hydrochloride (puromycin hydrochloride); pyrazolomycin (pyrazofurin); lyboadenosine (ribopine); ludwimine; safrog; saffinge hydrochloride (safingol hydrochloride); semustine; citrazine (simtrazene;); sodium phosphonoaspartate (sparfosate sodium); sparamycin (sparnomycin); helical germanium hydrochloride (spirogyranium hydrochloride); spiromustine; spiroplatin (spirosplatin); streptonigrin (streptonigrin); streptozotocin (streptozocin); sulfochlorpheniramine (sulofenur); talithromycin (talisomycin); sodium tegafur; tegafur; tiaxantrone hydrochloride (teloxantrone hydrochloride); temoporphine; (ii) teniposide; tiroxilone (teroxirone); testolactone (testolactone); thiamiprine (thiamiprine); thioguanine (thioguanine); thiotepa; thiazolecarboxamide nucleosides (tiazofurin); tirapazamine; toremifene citrate (toremifene citrate); tritolone acetate; triciribine phosphate (triciribine phosphate); trimetrexate; tritrexate glucuronate; triptorelin; tobramzole hydrochloride (tubulozole hydrochloride); uramustine (uracil mustard); uretepa (uredepa); vapreotide; verteporfin; vinblastine sulfate (vinblastine sulfate); vincristine sulfate (vincristine sulfate); vindesine; vindesine sulfate; vinepidine sulfate (vinapidine sulfate); vinglycinate sulfate (vinglycinate sulfate); vincristine sulfate (vinleurosine sulfate); vinorelbine tartrate (vinorelbine tartrate); vinblastine sulfate (vinrosidine sulfate); vinzolidine sulfate (vinzolidine sulfate); (ii) vorozole; zeniplatin; neat stastatin (zinostatin); zorubicin hydrochloride (zorubicin hydrochloride), agents that block cells at the G2-M phase and/or modulate microtubule formation or stability (e.g., taxol TM, compounds comprising a taxane skeleton, Erbutoxazole (i.e., R-55104), Dekkera micrantin 10 (i.e., DLS-10 and NSC-376128), Milvobuzol isethionate (i.e., CI-980), vincristine, NSC-639829, Discodermolide (i.e., NVP-XX-A-296), ABT-751 (Abbott), E-7010), Altorhyretin (e.g., Altorysin A and Altoretin C), Spongistatin (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8 and Spongistatin 9), Spongistatin (e.g., Cedotropin 83, NSdolantin) and NSC-366335), Descholtin 83, and NSC-669356, Epothilone (Epothilone) (e.g., Epothilone A, Epothilone B, Epothilone C (i.e., desoxyepothilone A or dEpoA), Epothilone D (i.e., KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone BN-oxide, Epothilone AN-oxide, 16-aza-Epothilone B, 21-aminoepothilone B (i.e., BMS-310705), 21-hydroxyepothilone D (i.e., desoxyepothilone F and dEpoF), 26-fluoroepothilone, auristatin (Aurista) PE (i.e., NSC-654663), Soulidotin (i.e., TZT-1027), LS-4559-P (Pharmacia), LS-4577), LS-4578 (Pharmacia), LS-477-P), LS-4477 (Framex), LS-4559 (Framex), RPR-112378 (Annelis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Tengze (Fujisawa), i.e., WS-9885B), GS-164 (Wutian (Takeda)), GS-198 (Wutian), KAR-2 (Hungarian Academy of Sciences), BSF-223651 ((Pastev) BASF, i.e., ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (lilay/Nowa), AM-97 (Amador/Co-fermentation (Armad/yowa Kko)), AM-132 (Amador), AM-138 (Amador), and Sandea/Co-da (Ile), and Sandea/S-5005 (Indenda), and Sandea-5005 (Indenda), respectively, Nostoc 52 (i.e., LY-355703), AC-7739 (Ajinomoto, AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A), tretinoamide (Vitrevuamide) ) Tourbitusin A, Canadenson (Canadensol), cyanidin (Centaureidin) (i.e., NSC-106969), T-138067 (Tulark (Tularik), T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute), DDE-261 and WHI-261, H10 (Kansassi Li university), H16 (Kansassi Li university), Oncocidin (Oncocidin) A1 (BTO-956 and DIME), DDE-313 (Parker Husky Institute), Fijinosoluide (Fijienolide) B, Lyomycin (Laulimide), SPA-2 (Parker Institute), SPA-1 (Parker Huishi Institute), Sphaet-3 (Spinegun/Sitope.S.A), Spaethion (Skok Institute of Spaek et/Mtok et), MF-569), Narcosine (Narcosine) (also known as NSC-5366), Nascabine (Nascapine) D-24851 (AstaMedica), A-105972 (Yapei), Hamiltrin (Hemiasterlin), 3-BAABU (cytoskeleton/Western Nakayae Isaac institute of medicine, i.e., MF-191), TMPN (Hirisana. Nature. Canine.), Vanadocene (acetyl acetate), T-138026 (Duraleke), Monasol (Monsatrol), lina (lunaocin) (i.e., NSC-698666), 3-ABE (cytoskeleton/Western Nakayae Isaace.), A-204197 (Yapei), T-607 (Turiak), i.e., T-900607), RPR-115781 (Aminose), Elobine (Elobileyibin) (Deobetaine), Deroebin (Deroebin), such as Elobetaine (Deroebin) Isoiseuscobine (lsoeleutherobin) A and Z-iseulobin), carbobasde (Caribaeoside), Caribelalin (Caribaeolin), Halichondrin (Halichondrin) B, D-64131 (Amasda pharmaceuticals), D-68144 (Amasda pharmaceuticals), chlorocyclic peptides (Diazonamide) A, A-293620 (Yapeh), NPI-2350 (Nerous), Tacalanolide (TACCALOOLIDE) A, TUB-245 (AnNenit), A-259754 (Yapeb), Cissus chinensis (Diozostatin), (-) -phenylamustine (Phenylahistin) (i.e., NSCL-96F037), D-68838 (Amasda pharmaceuticals), D-68836 (Amasda pharmaceuticals), Mycosporin (muscle matrix) B, D-4328-Yataris (Zeoarsis), or SACK-110, P-493 23 (HTI), and E-23 (SPA I-23, P-493), trifluoroacetate (Whitman (Wyeth)), D-82317(Zentans corporation), D-82318(Zentans corporation), SC-12983(NCI), revastatin phosphate Sodium (Resverastatin phosphate sodium), BPR-OY-007 (national institute of Health (national Health Research Institutes)) and SSR-250411 (cinorfene (Sanofi))), steroids (e.g., dexamethasone), finasteride (finasteride), aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) such as goserelin (goserelin) or leuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate), megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol (diethylstilbestrol), ethinylestradiol (ethinylestradiol), antiestrogens (e.g., tamoxifen), androgenic hormones (e.g., testosterone), androgenic hormones (e.g., fluocinolone propionate), immunostimulants (e.g., fluocinolone propionate)), steroids (e.g., testosterone), steroids (e.g., fluocinolone propionate), BCG (Bacillus Calmette-Guerin, BCG), levamisole, interleukin-2, interferon-alpha, etc.), monoclonal antibodies (e.g., anti-CD 20, anti-HER 2, anti-CD 52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD 33 monoclonal antibody-calicheamicin conjugate, anti-CD 22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., with ¹¹¹In、⁹⁰Y is or¹³¹I-conjugated anti-CD 20 monoclonal antibodies and the like), triptolide (triptolide), homoharringtonine (homoharringtonine), dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole (itraconazole), vindesine, cerivastatin (cerivastatin), vincristine, deoxyadenosine (deoxyadenosine), sertraline, pitavastatin (pitavastatin), irinotecan, clofazimine (clofazimine), 5-nonyloxytryptamine, vemurafenib, dabrafenib (dabrafenib), erlotinib (erlotinib), gefitinib (gefitinib), EGFR inhibitors, Epidermal Growth Factor Receptor (EGFR) -targeted therapies or therapeutics (e.g., gefitinib (Iressa)^TM) Erlotinib (Tarceva)^TM) Cetuximab (Erbitux)^TM) Lapatinib (Tykerb)^TM) Panitumumab (Vectibix)^TM) Vandeta (vandeta)nib)(Caprelsa^TM) afatinib/BIBW 2992, CI-1033/canertinib, neratinib/HKI 272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF 299804, OSI-420/desmethyl erlotinib (desmethyl erlotinib), AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626, sorafenib (soranib), imatinib (imatinib), sunitinib (sunitinib), dasatinib (danitinib) and the like. A portion of the anticancer agents are monovalent anticancer agents (e.g., monovalent forms of the agents listed above).

In therapeutic use for treating diseases, the compounds used in the pharmaceutical compositions of the present invention may be administered at an initial dose of about 0.001mg/kg to about 1000mg/kg per day. The daily dose may range from about 0.01mg/kg to about 500mg/kg, or from about 0.1mg/kg to about 200mg/kg, or from about 1mg/kg to about 100mg/kg or from about 10mg/kg to about 50 mg/kg. However, the dosage may vary depending on the needs of the patient, the severity of the condition being treated, and the compound or drug employed. For example, the dosage may be determined empirically based on the type and stage of cancer diagnosed in a particular patient. In the context of the present invention, the dose administered to a patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also depend on the presence, nature and extent of any adverse side effects associated with administration of the compound in a particular patient. It is within the skill of the practitioner to determine the appropriate dosage for a particular situation. Typically, treatment begins with a smaller dose than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimum effect is achieved in multiple instances. For convenience, the total daily dose may be divided into several portions and administered in portions throughout the day as needed.

The compounds described herein may be used in combination with each other, with other active agents known to be useful in the treatment of cancer, or with adjuvants that may not be effective alone but may contribute to the efficacy of the active agent.

In the context of a substance or substance activity or function associated with a disease (e.g., a protein-related disease, a disease associated with a cellular component), the term "associated" or "associated with" means that the disease (e.g., neurodegenerative disease, cancer) is caused (in whole or in part) by the substance or substance activity or function, or that a symptom of the disease (in whole or in part) is caused by the substance or substance activity or function, or that the disease or symptom of the disease can be treated by modulating (e.g., inhibiting or activating) a substance (e.g., a cellular component). For example, a neurodegenerative disease associated with protein aggregates may be a neurodegenerative disease caused (in whole or in part) by abnormal protein aggregation or a neurodegenerative disease in which a particular symptom of the disease is caused (in whole or in part) by abnormal protein aggregation. As used herein, a pathogen is described as being associated with a disease if it can be the target for treatment of the disease. For example, neurodegenerative diseases associated with abnormal protein aggregation or neurodegenerative diseases associated with protein aggregation may be treated with protein aggregation modulators.

As used herein, the term "abnormal" refers to a difference from normal. When used to describe enzymatic activity, abnormal refers to an activity that is greater than or less than the average of a normal control or normal non-diseased control sample. Abnormal activity can refer to an amount of activity that causes a disease, wherein returning abnormal activity to normal or a non-disease associated amount (e.g., by administering a compound or using a method as described herein) results in a reduction in the disease or one or more symptoms of the disease.

As used herein, the term "electrophilic" refers to a chemical group capable of accepting an electron density. An "electrophilic substituent", "electrophilic chemical moiety" or "electrophilic moiety" refers to an electron-deficient chemical group, substituent or moiety (monovalent chemical group) that can form a bond by accepting an electron pair or electron density reacting with an electron donating group such as a nucleophile. In some embodiments, the electrophilic substituent of the compound is capable of reacting with a cysteine residue. In some embodiments, the electrophilic substituent is capable of forming a covalent bond with a cysteine residue and may be referred to as a "covalent cysteine modification moiety" or a "covalent cysteine modification substituent. The covalent bond formed between an "electrophilic substituent and the thiol group of a cysteine may be a reversible or irreversible bond. In some embodiments, the electrophilic substituent of the compound is capable of reacting with a lysine residue. In some embodiments, the electrophilic substituent of the compound is capable of reacting with a serine residue. In some embodiments, the electrophilic substituent of the compound is capable of reacting with a methionine residue.

As used herein, "nucleophilic" refers to a chemical group capable of providing electron density.

The term "isolated" when applied to a nucleic acid or protein means that the nucleic acid or protein is substantially free of other cellular components with which it is associated in its native state. It may, for example, be in a homogeneous state and may be in a dry state or in an aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. The major proteins present in the preparation are substantially purified.

The term "amino acid" refers to naturally occurring amino acids and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code and are later modified, such as hydroxyproline, γ -carboxyglutamic acid, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as a naturally occurring amino acid (i.e., an alpha carbon bound to a hydrogen, a carboxyl group, an amino group, and an R group), such as homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. The analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but the basic chemical structure remains the same as a naturally occurring amino acid. Amino acid mimetics refers to compounds that differ in structure from the general chemical structure of an amino acid, but that function in a manner similar to a naturally occurring amino acid. The terms "non-naturally occurring amino acid" and "unnatural amino acid" refer to amino acid analogs, synthetic amino acids, and amino acid mimetics that are not found in nature.

Amino acids are referred to herein by their commonly known three-letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission (IUPAC-IUB Biochemical Nomenclature Commission). Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

The terms "polypeptide", "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may be conjugated to a moiety that does not consist of an amino acid in an embodiment. The terms apply to amino acid polymers in which one or more amino acid residues is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

The "position" of an amino acid or nucleotide base is represented by a number that sequentially identifies each amino acid (or nucleotide base) in a reference sequence based on its position relative to the N-terminus (or 5' -end). Since deletions, insertions, truncations, fusions, etc. must be taken into account in determining the optimal alignment, typically the numbering of amino acid residues in the test sequence, as determined by counting from the N-terminus only, is not necessarily the same as the numbering of their corresponding positions in the reference sequence. For example, where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position at the site of the deletion in the reference sequence. In the case of an insertion in the aligned reference sequences, the insertion will not correspond to the numbered amino acid position in the reference sequence. In the case of truncation or fusion, there may be stretches of amino acids in the reference or aligned sequence that do not correspond to any amino acids in the corresponding sequence.

The term "numbering relative to" or "numbering corresponding to when used in the context of numbering a given amino acid or polynucleotide sequence refers to numbering the residues of a given reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

The term "protein complex" is used according to its plain ordinary meaning and refers to a protein associated with another substance (e.g., another protein, protein subunit, or compound). Protein complexes generally have a well-defined quaternary structure. The association between the protein and the additional substance may be a covalent bond. In embodiments, the association between a protein and another substance (e.g., a compound) is by non-covalent interaction. In embodiments, a protein complex refers to a set of two or more polypeptide chains. The proteins in the protein complex are linked by non-covalent protein-protein interactions. A non-limiting example of a protein complex is the proteasome.

The term "protein aggregate" is used according to its plain ordinary meaning and refers to the abnormal collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis). Generally, unfolded/misfolded proteins may aggregate when the protein is misfolded due to changes in the amino acid sequence or changes in the natural environment that disrupt normal non-covalent interactions, and the misfolded protein is not corrected or degraded. There are three main types of protein aggregates that can be formed: amorphous aggregates, oligomers and amyloid fibrils. In the examples, protein aggregates are referred to as aggregates (aggresomes).

The term "Nurr 1" or "NR 4a 2" refers to a protein encoded by the NR4a2 gene in humans. Nurr1 is a nuclear receptor and plays a key role in maintaining the brain dopaminergic system. The term "Nurr 1" may refer to the nucleotide sequence or protein sequence of human NR4a2 (e.g., Entrez 4929, Uniprot P43354, RefSeq NM _006186.3, or RefSeq NP _ 006177.1). In an example, Nurr1 has the following amino acid sequence:

the term "pituitary homeobox 3" or "Pitx 3" refers to genes encoding members of the RIEG/Pitx homeobox family, which belong to the dual class of homeodomain proteins and act as transcription factors. Pitx3 is involved in the maintenance of dopaminergic neurons. The term "Pitx 3" may refer to a nucleotide sequence or protein sequence of human Pitx3 (e.g., Entrez 5309, Uniprot O75364, RefSeq NM _005029.3, or RefSeq NP _ 005020.1). In an example, Pitx3 has the following amino acid sequence:

the term "tyrosine hydroxylase" or "tyrosine 3-monooxygenase" refers to an enzyme that negatively catalyzes the conversion of the amino acid L-tyrosine to L-3, 4-dihydroxyphenylalanine (L-DOPA). In humans, tyrosine hydroxylase is encoded by the TH gene. The term "TH" can refer to the nucleotide or protein sequence of human TH (e.g., Entrez 7054, Uniprot P07101, RefSeq NM-199292.2, or RefSeq NP-954986.2). In an embodiment, TH has the following amino acid sequence:

The term "vesicular monoamine transporter 2" or "VMAT 2" refers to an intact membrane protein that transports neurotransmitters such as dopamine, norepinephrine, serotonin and histamine from the cytosol to the synaptic vesicles. The term "VMAT 2" may refer to a nucleotide sequence or protein sequence of human VMAT2 (e.g., Entrez 6571, Uniprot Q05940, RefSeq NM _003054.4, or RefSeq NP _ 003045.2). In an embodiment, VMAT2 has the following amino acid sequence:

II. Compound

In one aspect, there is provided a compound having the formula:

ring a is aryl or heteroaryl.

L¹Is L¹⁰¹-L¹⁰²-L¹⁰³。

L¹⁰¹Is a bond, -S (O)₂-、-N(R¹⁰¹)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰¹)-、-N(R¹⁰¹)C(O)-、-N(R¹⁰¹)C(O)NH-、-NHC(O)N(R¹⁰¹) -, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, L¹⁰⁴-L¹⁰⁵、L¹⁰⁴-NH-L¹⁰⁵Or L¹⁰⁴-CH₂-L¹⁰⁵。

L¹⁰⁴Is a bond, -O-, -NH-, -S-, -S (O)₂-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

L¹⁰⁵Is a bond, -O-, -NH-、-S-、-S(O)₂-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene.

E is an electrophilic moiety.

R²Independently halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、 -N(O)_m2、 -N₃Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R bound to adjacent atoms²Substituents may be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

n1 and n2 are independently integers from 0 to 4.

m1, m2, v1 and v2 are independently 1 or 2.

X¹And X²Independently is-F, -Cl, -Br or-I.

z2 is an integer from 0 to 5.

In the examples, L¹⁰¹Is a bond, -S (O)₂-、-N(R¹⁰¹)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰¹)-、-N(R¹⁰¹)C(O)-、-N(R¹⁰¹)C(O)NH-、-NHC(O)N(R¹⁰¹) -, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

In the examples, L¹⁰¹Is a bond, -S (O)₂-、-N(R¹⁰¹)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰¹)-、-N(R¹⁰¹)C(O)-、-N(R¹⁰¹)C(O)NH-、-NHC(O)N(R¹⁰¹) -, -C (O) O-, -OC (O) -substituted or unsubstituted alkylene (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkylene (e.g., 2-to 10-membered, 2-to 6-membered, or 2-to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkylene (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted arylene (e.g., C)₆-C₁₀Or phenylene), substituted or unsubstituted heteroarylene (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered), L¹⁰⁴-L¹⁰⁵、L¹⁰⁴-NH-L¹⁰⁵Or L¹⁰⁴-CH₂-L¹⁰⁵。

In the examples, L¹⁰¹Is a bond, -S (O)₂-、-NH-、-O-、-S-、-C(O)-、-C(O)NH-、-NHC(O)-、-NHC(O)NH-、-NHC(O)NH-、-C(O)O-、-OC(O)-、R¹⁰¹Substituted or unsubstituted alkylene (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹⁰¹Substituted or unsubstituted heteroalkylene (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered), R¹⁰¹Substituted or unsubstituted cycloalkylene (e.g. C)₃-C₈、C₃-C₆Or C₅-C₆)、R¹⁰¹Substituted or unsubstituted heterocycloalkylene (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹⁰¹Substituted or unsubstituted arylene (e.g. C)₆-C₁₀Or phenylene), R¹⁰¹Substituted or unsubstituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered), L¹⁰⁴-L¹⁰⁵、L¹⁰⁴-NH-L¹⁰⁵Or L¹⁰⁴-CH₂-L¹⁰⁵。

In the examples, L¹⁰²Is a bond, -S (O)₂-、-N(R¹⁰²)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰²)-、-N(R¹⁰²)C(O)-、-N(R¹⁰²)C(O)NH-、-NHC(O)N(R¹⁰²) -, -C (O) O-, -OC (O) -substituted or unsubstituted alkylene (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkylene (e.g., 2-to 10-membered, 2-to 6-membered, or 2-to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkylene (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted arylene (e.g., C)₆-C₁₀Or phenylene) or substituted or unsubstituted heteroarylene (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, L¹⁰²Is a bond, -S (O)₂-、-NH-、-O-、-S-、-C(O)-、-C(O)NH-、-NHC(O)-、-NHC(O)NH-、-NHC(O)NH-、-C(O)O-、-OC(O)-、R¹⁰²Substituted or unsubstituted alkylene (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹⁰²Substituted or unsubstituted heteroalkylene (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered), R ¹⁰²Substituted or unsubstituted cycloalkylene (e.g. C)₃-C₈、C₃-C₆Or C₅-C₆)、R¹⁰²Substituted or unsubstituted heterocycloalkylene (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹⁰²Substituted or unsubstituted arylene (e.g. C)₆-C₁₀Or phenylene) or R¹⁰²Substituted or unsubstituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, L¹⁰³Is a bond, -S (O)₂-、-N(R¹⁰³)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰³)-、-N(R¹⁰³)C(O)-、-N(R¹⁰³)C(O)NH-、-NHC(O)N(R¹⁰³) -, -C (O) O-, -OC (O) -substituted or unsubstituted alkylene (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkylene (e.g., 2-to 10-membered, 2-to 6-membered, or 2-to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkylene (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted arylene (e.g., C)₆-C₁₀Or phenylene) or substituted or unsubstituted heteroarylene (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, L¹⁰³Is a bond, -S (O)₂-、-NH-、-O-、-S-、-C(O)-、-C(O)NH-、-NHC(O)-、-NHC(O)NH-、-NHC(O)NH-、-C(O)O-、-OC(O)-、R¹⁰³Substituted or unsubstituted alkylene (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹⁰³Substituted or unsubstituted heteroalkylene (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered), R¹⁰³Substituted or unsubstituted cycloalkylene (e.g. C) ₃-C₈、C₃-C₆Or C₅-C₆)、R¹⁰³Substituted or unsubstituted heterocycloalkylene (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹⁰³Substituted or unsubstituted arylene (e.g. C)₆-C₁₀Or phenylene) or R¹⁰³Substituted or unsubstituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In an embodiment of the present invention,andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkyl (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or substituted or unsubstitutedHeteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered); attached to the same nitrogen atomAndsubstituents may be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered) or a substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In an embodiment of the present invention,andindependently hydrogen, halogen, -CCl ₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹⁰Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹⁰Substituted or unsubstituted heteroalkyl (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered), R¹⁰Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R¹⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹⁰Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered); attached to the same nitrogen atomAndsubstituents may be linked to form R¹⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered) or R¹⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In an embodiment of the present invention,andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkyl (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C) ₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered); attached to the same nitrogen atomAndsubstituents may be linked to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered) or a substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In an embodiment of the present invention,andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R²⁰Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R²⁰Substituted or unsubstituted heteroalkyl (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered), R²⁰Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R²⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R²⁰Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R²⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered); attached to the same nitrogen atomAndsubstituents may be linked to form R²⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered) or R²⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, -L¹-R¹Is composed ofAnd R is¹As described herein, are included in the examples.

In embodiments, the compound has the formula

Ring A, R¹、R²、L¹⁰³、L¹⁰⁴、L¹⁰⁵And z2 are as described herein.

W is N or CH.

In the examples, L¹⁰³Is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

In the examples, L¹⁰⁴Is a bond, -S (O)₂-, -C (O) -, -NHC (O) -, -OC (O) -, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

In the examples, L¹⁰⁵Is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene.

In embodiments, ring A is aryl (e.g., C)₆-C₁₀Or phenyl) or heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered). In embodiments, ring A is C₆-C₁₀And (4) an aryl group. In embodiments, ring a is phenyl. In embodiments, ring a is a 5-to 10-membered heteroaryl. In embodiments, ring a is a 5-to 9-membered heteroaryl. In embodiments, ring a is a 5-to 6-membered heteroaryl.

In embodiments, ring a is phenyl or 5-to 10-membered heteroaryl. In embodiments, ring a is phenyl. In embodiments, ring a is naphthyl. In embodiments, ring a is quinolinyl. In embodiments, ring a is isoquinolinyl. In embodiments, ring a is benzoxazolyl. In the examples, ring A isWhereinIs represented by the formula¹-R¹Is connected toAnd (4) point. In the examples, ring A isWhereinIs represented by the formula¹-R¹The connection point of (a).

In embodiments, ring a is phenyl or 5-to 10-membered heteroaryl. In embodiments, ring a is phenyl. In embodiments, ring a is naphthyl. In embodiments, ring a is quinolinyl. In embodiments, ring A is 3-quinolinyl. In embodiments, ring a is isoquinolinyl. In embodiments, ring a is benzoxazolyl. In embodiments, ring a is 6-benzoxazolyl.

In embodiments, the compound has the formula

R¹、L¹⁰³、L¹⁰⁴、L¹⁰⁵And W is as described herein.

Andindependently hydrogen or R may be independently employed²Any values of (a) are included in the examples.

In an embodiment of the present invention,andindependently hydrogen, halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、-N(O)_m2、 -N₃Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C) ₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered);andsubstituents may be linked to form a substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered);andthe substituents may be linked to form a substituted or unsubstituted cycloalkaneRadical (e.g. C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In an embodiment of the present invention,andindependently hydrogen, halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、-N(O)_m2、 -N₃、R²⁰Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C ₁-C₄)、R²⁰Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R²⁰Substituted or unsubstituted cycloalkyl (e.g. C)₃-C₈、C₃-C₆Or C₅-C₆)、R²⁰Substituted or unsubstituted heterocycloalkyl (e.g. 3-to 8-, 3-to 6-or 5-to 6-membered), R²⁰Substituted or unsubstituted aryl (e.g. C)₆-C₁₀Or phenyl) or R²⁰Substituted or unsubstituted heteroaryl (e.g. 5-to 10-membered, 5-to 9-membered)Or 5 to 6);andsubstituents may be linked to form R²⁰Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R²⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R²⁰Substituted or unsubstituted aryl (e.g. C)₆-C₁₀Or phenyl), or R²⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered);andsubstituents may be linked to form R²⁰Substituted or unsubstituted cycloalkyl (e.g. C)₃-C₈、C₃-C₆Or C₅-C₆)、R²⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R²⁰Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl), or R²⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In an embodiment of the present invention,independently halogen or unsubstituted heteroalkyl;independently hydrogen or halogen; and isIndependently hydrogen, halogen, -CN,Unsubstituted heteroalkyl or substituted or unsubstituted heterocycloalkyl.

In an embodiment of the present invention,independently a halogen or an unsubstituted heteroalkyl. In an embodiment of the present invention,independently hydrogen or halogen. In an embodiment of the present invention,independently hydrogen, halogen, -CN,Unsubstituted heteroalkyl or substituted or unsubstituted heterocycloalkyl. In an embodiment of the present invention,independently a halogen. In an embodiment of the present invention,independently an unsubstituted heteroalkyl group. In an embodiment of the present invention,independently hydrogen. In an embodiment of the present invention,independently a halogen. In an embodiment of the present invention,independently hydrogen. In an embodiment of the present invention,independently a halogen. In an embodiment of the present invention,independently is-CN. In an embodiment of the present invention,independently isIn an embodiment of the present invention,independently an unsubstituted heteroalkyl group. In an embodiment, R2Z is independently substituted or unsubstituted heterocycloalkyl.

In an embodiment of the present invention,independently is halogen;independently is halogen; and isIndependently hydrogen.

In an embodiment of the present invention,independently a halogen. In an embodiment of the present invention, Independently a halogen. In an embodiment of the present invention,independently hydrogen.

In an embodiment of the present invention,independently halogen or unsubstituted 2-to 4-membered heteroAn alkyl group;independently is hydrogen;independently is halogen, -CN,Unsubstituted 2-to 4-membered heteroalkyl or substituted or unsubstituted 5-to 6-membered heterocycloalkyl;independently is hydrogen; and isIndependently is unsubstituted C₁-C₂An alkyl group.

In an embodiment of the present invention,independently halogen or unsubstituted 2-to 4-membered heteroalkyl. In an embodiment of the present invention,independently hydrogen. In an embodiment of the present invention,independently is halogen, -CN,Unsubstituted 2-to 4-membered heteroalkyl or substituted or unsubstituted 5-to 6-membered heterocycloalkyl. In an embodiment of the present invention,independently hydrogen. In an embodiment of the present invention,independently is unsubstitutedC of (A)₁-C₂An alkyl group. In an embodiment of the present invention,independently a halogen. In an embodiment of the present invention,independently an unsubstituted 2-to 4-membered heteroalkyl group. In an embodiment of the present invention,independently a halogen. In an embodiment of the present invention,independently is-CN. In an embodiment of the present invention,independently isIn an embodiment of the present invention,independently an unsubstituted 2-to 4-membered heteroalkyl group. In an embodiment of the present invention,independently a substituted or unsubstituted 5-to 6-membered heterocycloalkyl.

In an embodiment of the present invention,independently is halogen or-OCH₃；Independently is hydrogen;independently halogen, -CN, -NHC (O) CH₃、-OCH₃Or is substituted orUnsubstituted 5-to 6-membered heterocycloalkyl;independently is hydrogen; and isIndependently is unsubstituted C₁-C₂An alkyl group.

In an embodiment of the present invention,independently is halogen or-OCH₃. In an embodiment of the present invention,independently hydrogen. In an embodiment of the present invention,independently halogen, -CN, -NHC (O) CH₃、-OCH₃Or a substituted or unsubstituted 5-to 6-membered heterocycloalkyl group. In an embodiment of the present invention,independently hydrogen. In an embodiment of the present invention,independently is unsubstituted C₁-C₂An alkyl group. In an embodiment of the present invention,independently a halogen. In an embodiment of the present invention,independently is-OCH₃. In an embodiment of the present invention,independently a halogen. In an embodiment of the present invention,independently is-CN. In an embodiment of the present invention,independently is-NHC (O) CH₃. In an embodiment of the present invention,independently is-OCH₃. In an embodiment of the present invention,independently a substituted or unsubstituted 5-to 6-membered heterocycloalkyl.

In an embodiment of the present invention,independently is halogen or-OCH₃；Independently is hydrogen;independently halogen, -CN, -NHC (O) CH₃、-OCH₃Or a substituted or unsubstituted 5-to 6-membered heterocycloalkyl group. In an embodiment of the present invention,independently a substituted or unsubstituted 5-to 6-membered heterocycloalkyl. In an embodiment of the present invention, Independently a substituted 5-to 6-membered heterocycloalkyl. In an embodiment of the present invention,independently is

In the examples，L¹⁰³Is a bond, substituted or unsubstituted alkylene (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Or substituted or unsubstituted heteroalkylene (e.g., 2-to 8-membered, 2-to 6-membered, or 2-to 4-membered). In the examples, L¹⁰³Is a bond. In the examples, L¹⁰³Is substituted or unsubstituted C₁-C₈An alkylene group. In the examples, L¹⁰³Is substituted or unsubstituted C₁-C₆An alkylene group. In the examples, L¹⁰³Is substituted or unsubstituted C₁-C₄An alkylene group. In the examples, L¹⁰³Is a substituted or unsubstituted 2-to 8-membered heteroalkylene. In the examples, L¹⁰³Is a substituted or unsubstituted 2-to 6-membered heteroalkylene. In the examples, L¹⁰³Is a substituted or unsubstituted 2-to 4-membered heteroalkylene.

In the examples, L¹⁰³Is unsubstituted alkylene. In the examples, L¹⁰³Is unsubstituted C₁-C₄An alkylene group. In the examples, L¹⁰³Is unsubstituted ethylene.

In the examples, L¹⁰³Is a bond, R¹⁰³Substituted or unsubstituted alkylene (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Or R¹⁰³Substituted or unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered).

In the examples, R¹⁰¹、R¹⁰²And R¹⁰³Independently hydrogen, oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁰¹、R¹⁰²And R¹⁰³Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C ₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁰¹Independently hydrogen, oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹¹¹Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂)、R¹¹¹Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), R¹¹¹Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆)、R¹¹¹Substituted or unsubstitutedHeterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), R¹¹¹Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹¹¹Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R¹⁰¹Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹¹¹Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂)、R¹¹¹Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), R¹¹¹Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆)、R¹¹¹Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered), R ¹¹¹Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹¹¹Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

R¹¹¹Independently of one another, oxo, haloElement, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHC(NH)H、-NHC(NH)NH₂、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4) -unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁰¹Independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4) -unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁰²Independently hydrogen, oxo, halogen, -CCl ₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹¹²Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂)、R¹¹²Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), R¹¹²Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆)、R¹¹²Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered), R¹¹²Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹¹²Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R¹⁰²Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹¹²Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂)、R¹¹²Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), R¹¹²Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆)、R¹¹²Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered), R¹¹²Substituted or unsubstituted aryl (e.g., C)₆-C₁₆Or phenyl) or R¹¹²Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

R¹¹²Independently oxo, halogen, -CCl ₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHC(NH)H、-NHC(NH)NH₂、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4) -unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁰²Independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4) -unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁰³Independently hydrogen, oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHC(NH)H、-NHC(NH)NH₂、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹¹³Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹¹³Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R¹¹³Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C₈、C₃-C₆Or C₅-C₆)、R¹¹³Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹¹³Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹¹³Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R¹⁰³Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHC(NH)H、-NHC(NH)NH₂、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹¹³Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹¹³Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R¹¹³Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R¹¹³Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹¹³Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹¹³Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

R¹¹³Independently oxo, halogen、-CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHC(NH)H、-NHC(NH)NH₂、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4) -unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C) ₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁰³Independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4) -unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, L¹⁰⁴Is a bond, -S (O)₂-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

In the examples, L¹⁰⁴Is a bond, -O-, -NH-, -S-, -S (O)₂-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, substituted or unsubstituted alkylene (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Or substituted or unsubstituted heteroalkylene (e.g., 2-to 8-membered, 2-to 6-membered, or 2-to 4-membered). In the examples, L¹⁰⁴Is a bond. In the examples, L¹⁰⁴is-O-. In the examples, L¹⁰⁴is-NH-. In the examples, L ¹⁰⁴is-S-. In the examples, L¹⁰⁴is-S (O)₂-. In the examples, L¹⁰⁴is-C (O) -. In the examples, L¹⁰⁴is-NHC (O) -. In the examples, L¹⁰⁴is-C (O) NH-. In the examples, L¹⁰⁴is-OC (O) -. In the examples, L¹⁰⁴is-C (O) O-. In the examples, L¹⁰⁴Is substituted or unsubstituted C₁-C₈An alkylene group. In the examples, L¹⁰⁴Is substituted or unsubstituted C₁-C₆An alkylene group. In the examples, L¹⁰⁴Is substituted or unsubstituted C₁-C₄An alkylene group. In the examples, L¹⁰⁴Is a substituted or unsubstituted 2-to 8-membered heteroalkylene. In the examples, L¹⁰⁴Is a substituted or unsubstituted 2-to 6-membered heteroalkylene. In the examples, L¹⁰⁴Is a substituted or unsubstituted 2-to 4-membered heteroalkylene. In the examples, L¹⁰⁴Is unsubstituted C₁-C₈An alkylene group. In the examples, L¹⁰⁴Is unsubstituted 2-to 8-membered heteroalkylene.

In the examples, L¹⁰⁴Is a bond, -S (O)₂-, -C (O) -, -NHC (O) -, -OC (O) -, substituted or unsubstituted alkylene (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Or substituted or unsubstituted heteroalkylene (e.g., 2-to 8-membered, 2-to 6-membered, or 2-to 4-membered). In the examples, L¹⁰⁴Is a bond. In the examples, L¹⁰⁴is-S (O)₂-. In the examples, L ¹⁰⁴is-C (O) -. In the examples, L¹⁰⁴is-NHC (O) -. In the examples, L¹⁰⁴is-OC (O) -. In the examples, L¹⁰⁴Is substituted or unsubstituted C₁-C₈An alkylene group. In the examples, L¹⁰⁴Is substituted or unsubstituted C₁-C₆An alkylene group. In the examples, L¹⁰⁴Is substituted or unsubstituted C₁-C₄An alkylene group. In the examples, L¹⁰⁴Is a substituted or unsubstituted 2-to 8-membered heteroalkylene. In the examples, L¹⁰⁴Is a substituted or unsubstituted 2-to 6-membered heteroalkylene. In the examples, L¹⁰⁴Is a substituted or unsubstituted 2-to 4-membered heteroalkylene. In the examples, L¹⁰⁴Is unsubstituted C₁-C₈An alkylene group. In the examples, L¹⁰⁴Is unsubstituted 2-to 8-membered heteroalkylene.

In the examples, L¹⁰⁴Is a bond, -O-, -NH-, -S-, -S (O)₂-、-C(O)-、-NHC(O)-、-C(O)NH-、-OC(O)-、-C(O)O-、R¹⁰⁴Substituted or unsubstituted aryleneAlkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Or R¹⁰⁴Substituted or unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered).

In the examples, L¹⁰⁴Is a bond, -S (O)₂-、-C(O)-、-NHC(O)-、-OC(O)-、R¹⁰⁴Substituted or unsubstituted alkylene (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Or R¹⁰⁴Substituted or unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered).

R¹⁰⁴Independently oxo, halogen, -CCl ₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHC(NH)H、-NHC(NH)NH₂、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaromaticsA base (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁰⁴Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHC(NH)H、-NHC(NH)NH₂、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹¹⁴Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹¹⁴Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R¹¹⁴Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R¹¹⁴Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹¹⁴Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹¹⁴Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

R¹¹⁴Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHC(NH)H、-NHC(NH)NH₂、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4) -unsubstituted cycloalkyl (e.g., C) ₃-C₈、C₃-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, L¹⁰⁵Is a bond, -O-, -NH-, -S-, -S (O)₂-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, substituted or unsubstituted alkylene (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkylene (e.g., 2-to 8-membered)2-to 6-or 2-to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C₃-C₈、C₃-C₆Or C₅-C₆) Or substituted or unsubstituted heterocycloalkylene (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered). In the examples, L ¹⁰⁵Is a bond. In the examples, L¹⁰⁵is-O-. In the examples, L¹⁰⁵is-NH-. In the examples, L¹⁰⁵is-S-. In the examples, L¹⁰⁵is-S (O)₂-. In the examples, L¹⁰⁵is-C (O) -. In the examples, L¹⁰⁵is-NHC (O) -. In the examples, L¹⁰⁵is-C (O) NH-. In the examples, L¹⁰⁵is-OC (O) -. In the examples, L¹⁰⁵is-C (O) O-. In the examples, L¹⁰⁵Is substituted or unsubstituted C₁-C₈An alkylene group. In the examples, L¹⁰⁵Is substituted or unsubstituted C₁-C₆An alkylene group. In the examples, L¹⁰⁵Is substituted or unsubstituted C₁-C₄An alkylene group. In the examples, L¹⁰⁵Is a substituted or unsubstituted 2-to 8-membered heteroalkylene. In the examples, L¹⁰⁵Is a substituted or unsubstituted 2-to 6-membered heteroalkylene. In the examples, L¹⁰⁵Is a substituted or unsubstituted 2-to 4-membered heteroalkylene. In the examples, L¹⁰⁵Is substituted or unsubstituted C₃-C₈Cycloalkylene radicals. In the examples, L¹⁰⁵Is substituted or unsubstituted C₃-C₆Cycloalkylene radicals. In the examples, L¹⁰⁵Is substituted or unsubstituted C₅-C₆Cycloalkylene radicals. In the examples, L¹⁰⁵Is a substituted or unsubstituted 3-to 8-membered heterocycloalkylene group. In the examples, L¹⁰⁵Is a substituted or unsubstituted 3-to 6-membered heterocycloalkylene group. In the examples, L ¹⁰⁵Is a substituted or unsubstituted 5-to 6-membered heterocycloalkylene. In the examples, L¹⁰⁵Is unsubstituted C₁-C₈An alkylene group. In the examples, L¹⁰⁵Is unsubstituted 2-to 8-membered heteroalkanesAnd (4) a base. In the examples, L¹⁰⁵Is unsubstituted C₃-C₈Cycloalkylene radicals. In the examples, L¹⁰⁵Is unsubstituted 3-to 8-membered heterocycloalkylene.

In the examples, L¹⁰⁵Is a bond, substituted or unsubstituted alkylene (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), substituted or unsubstituted cycloalkylene (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Or substituted or unsubstituted heterocycloalkylene (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered). In the examples, L¹⁰⁵Is a bond. In the examples, L¹⁰⁵Is substituted or unsubstituted C₁-C₈An alkylene group. In the examples, L¹⁰⁵Is substituted or unsubstituted C₁-C₆An alkylene group. In the examples, L¹⁰⁵Is substituted or unsubstituted C₁-C₄An alkylene group. In the examples, L¹⁰⁵Is a substituted or unsubstituted 2-to 8-membered heteroalkylene. In the examples, L¹⁰⁵Is a substituted or unsubstituted 2-to 6-membered heteroalkylene. In the examples, L ¹⁰⁵Is a substituted or unsubstituted 2-to 4-membered heteroalkylene. In the examples, L¹⁰⁵Is substituted or unsubstituted C₃-C₈Cycloalkylene radicals. In the examples, L¹⁰⁵Is substituted or unsubstituted C₃-C₆Cycloalkylene radicals. In the examples, L¹⁰⁵Is substituted or unsubstituted C₅-C₆Cycloalkylene radicals. In the examples, L¹⁰⁵Is a substituted or unsubstituted 3-to 8-membered heterocycloalkylene group. In the examples, L¹⁰⁵Is a substituted or unsubstituted 3-to 6-membered heterocycloalkylene group. In the examples, L¹⁰⁵Is a substituted or unsubstituted 5-to 6-membered heterocycloalkylene. In the examples, L¹⁰⁵Is unsubstituted C₁-C₈An alkylene group. In the examples, L¹⁰⁵Is unsubstituted 2-to 8-membered heteroalkylene. In the examples, L¹⁰⁵Is unsubstituted C₃-C₈Cycloalkylene radicals. In the examples, L¹⁰⁵Is unsubstituted 3-to 8-membered heterocycloalkylene.

In the examples, L¹⁰⁵Is unsubstituted alkylene. In the examples, L¹⁰⁵Is unsubstituted C₁-C₄An alkylene group. In the examples, L¹⁰⁵Is composed ofIn the examples, L¹⁰⁵Is composed of

In the examples, L¹⁰⁵Is a bond, -O-, -NH-, -S-, -S (O)₂-、-C(O)-、-NHC(O)-、-C(O)NH-、-OC(O)-、-C(O)O-、R¹⁰⁵Substituted or unsubstituted alkylene (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹⁰⁵Substituted or unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R ¹⁰⁵Substituted or unsubstituted cycloalkylene (e.g. C)₃-C₈、C₃-C₆Or C₅-C₆) Or R¹⁰⁵Substituted or unsubstituted heterocycloalkylene (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered).

In the examples, L¹⁰⁵Is a bond, R¹⁰⁵Substituted or unsubstituted alkylene (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹⁰⁵Substituted or unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R¹⁰⁵Substituted or unsubstituted cycloalkylene (e.g. C)₃-C₈、C₃-C₆Or C₅-C₆) Or R¹⁰⁵Substituted or unsubstituted heterocycloalkylene (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered).

R¹⁰⁵Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHC(NH)H、-NHC(NH)NH₂、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁰⁵Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHC(NH)H、-NHC(NH)NH₂、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹¹⁵Substituted or unsubstituted alkyl (e.g. C) ₁-C₈、C₁-C₆Or C₁-C₄)、R¹¹⁵Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R¹¹⁵Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R¹¹⁵Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹¹⁵Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹¹⁵Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

R¹¹⁵Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHC(NH)H、-NHC(NH)NH₂、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) ASubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In an embodiment, W is N. In an embodiment, W is CH.

In an embodiment of the present invention,is composed of

In an embodiment of the present invention,is composed ofIn an embodiment of the present invention,is composed of In an embodiment of the present invention,is composed ofIn an embodiment of the present invention,is composed ofIn an embodiment of the present invention,is composed ofIn an embodiment of the present invention,is composed ofIn an embodiment of the present invention,is composed ofIn an embodiment of the present invention,is composed of

In the examples, R¹Is hydrogen, halogen, -CX¹ ₃、-CHX¹ ₂、-CH₂X¹、-OCX¹ ₃、-OCH₂X¹、-OCHX¹ ₂、-CN、 -N(O)_m1、 -N₃、E. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In the examples, R¹Is hydrogen, halogen, -CX¹ ₃、-CHX¹ ₂、-CH₂X¹、-OCX¹ ₃、-OCH₂X¹、-OCHX¹ ₂、-CN、 -N(O)_m1、 -N₃、-SP(O)(OH)₂E, substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkyl (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C) ₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹Is hydrogen, halogen, -CX¹ ₃、-CHX¹ ₂、-CH₂X¹、-OCX¹ ₃、-OCH₂X¹、-OCHX¹ ₂、-CN、 -N(O)_m1、 -N₃、-SP(O)(OH)₂、E、R¹⁰Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹⁰Substituted or unsubstituted heteroalkyl (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered), R¹⁰Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R¹⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹⁰Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R¹Independently is

In an embodiment of the present invention,independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkyl (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered), substituted or unsubstitutedSubstituted aryl radicals (e.g. C)₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In an embodiment of the present invention,independently hydrogen, halogen, -CCl ₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂、R¹⁰Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹⁰Substituted or unsubstituted heteroalkyl (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered), R¹⁰Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In an embodiment of the present invention,independently is substituted or unsubstituted C₁-C₄An alkyl group. In an embodiment of the present invention,independently is notSubstituted C₁-C₄An alkyl group. In an embodiment of the present invention,independently an unsubstituted methyl group. In an embodiment of the present invention,independently an unsubstituted ethyl group. In an embodiment of the present invention,independently an unsubstituted propyl group. In an embodiment of the present invention,independently an unsubstituted n-propyl group. In an embodiment of the present invention,independently unsubstituted isopropyl. In an embodiment of the present invention,independently an unsubstituted butyl group. In an embodiment of the present invention,independently unsubstituted n-butyl. In an embodiment of the present invention,independently an unsubstituted tert-butyl group.

In an embodiment of the present invention,independently a substituted or unsubstituted aryl group. In an embodiment of the present invention,independently is R¹⁰Substituted or unsubstituted aryl. In an embodiment of the present invention,independently is R ¹⁰Substituted or unsubstituted phenyl. In an embodiment of the present invention,independently an unsubstituted phenyl group.

In the examples, R¹Independently isAnd isAs described herein, are included in the examples. In the examples, R¹independently-C (O) OH. In the examples, R¹Independently is-C (O) NH₂。

In the examples, R¹Is composed of

In an embodiment of the present invention,independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Or substituted or unsubstituted heteroalkyl (e.g., 2-to 10-, 2-to 6-, or 2-to 4-membered).

In an embodiment of the present invention,independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂、R¹⁰Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Or R¹⁰Substituted or unsubstituted heteroalkyl (e.g., 2-to 10-membered, 2-to 6-membered, or 2-to 4-membered).

In an embodiment of the present invention,independently a substituted or unsubstituted alkyl group. In an embodiment of the present invention,independently is R¹⁰Substituted or unsubstituted alkyl. In an embodiment of the present invention,independently is R¹⁰Substituted or unsubstituted C₁-C₁₆An alkyl group. In an embodiment of the present invention,independently is unsubstituted C₁-C₁₆An alkyl group.

In the examples, R¹Is composed ofE. Unsubstituted alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl; Independently hydrogen or unsubstituted C₁-C₄An alkyl group;independently hydrogen or unsubstituted C₁-C₄An alkyl group; and isIndependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂Or substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄)。

In the examples, R¹Is composed ofE. Unsubstituted alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl. In an embodiment of the present invention,independently hydrogen or unsubstituted C₁-C₄An alkyl group. In an embodiment of the present invention,independently hydrogen or unsubstituted C₁-C₄An alkyl group. In an embodiment of the present invention,independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂Or substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄)。

In the examples, R¹Is composed ofE. Unsubstituted C₁-C₄Alkyl radical, R¹⁰Substituted or unsubstituted phenyl or R¹⁰A substituted or unsubstituted 5-to 6-membered heteroaryl;independently hydrogen or unsubstituted C₁-C₄An alkyl group;independently hydrogen or unsubstituted C₁-C₄An alkyl group; and isIndependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂、R¹⁰Substituted or unsubstituted C₁-C₄An alkyl group.

In the examples, R¹Is composed ofE. Unsubstituted C₁-C₄Alkyl radical, R¹⁰Substituted or unsubstituted phenyl or R¹⁰A substituted or unsubstituted 5-to 6-membered heteroaryl. In an embodiment of the present invention,independently hydrogen or unsubstituted C ₁-C₄An alkyl group. In an embodiment of the present invention,independently hydrogen or unsubstituted C₁-C₄An alkyl group. In an embodiment of the present invention,independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂、R¹⁰Substituted or unsubstituted C₁-C₄An alkyl group.

R¹⁰Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹Is composed ofOr R¹⁰Substituted phenyl;independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂、R¹⁰Substituted or unsubstituted C₁-C₄An alkyl group; and R is¹⁰Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃Unsubstituted C₁-C₄Alkyl, unsubstituted 2-to 4-membered heteroalkyl, unsubstituted C₅-C₆Cycloalkyl, unsubstituted 5-to 6-membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5-to 6-membered heteroaryl.

In the examples, R¹Is composed of Or R¹⁰A substituted phenyl group. In an embodiment of the present invention,independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂、R¹⁰Substituted or unsubstituted C₁-C₄An alkyl group. In the examples, R¹⁰Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃Unsubstituted C₁-C₄Alkyl, unsubstituted 2-to 4-membered heteroalkyl, unsubstituted C₅-C₆Cycloalkyl, unsubstituted 5-to 6-membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5-to 6-membered heteroaryl.

In the examples, R¹is-SH, -SC (O) CH₃or-SSCH₃. In the examples, R¹is-SH. In the examples, R¹is-SC (O) CH₃. In the examples, R¹is-SSCH₃。

In factIn the examples, R¹Independently halogen, -NO₂、-SH、-SeH、-SO₃H、-SC(O)CH₃、-SSCH₃、-SP(O)(OH)₂、R¹⁰Substituted or unsubstituted heteroalkyl or R¹⁰Substituted or unsubstituted heteroaryl; and R is¹⁰As described herein, are included in the examples. In the examples, R¹Independently is-F. In the examples, R¹Independently is-Cl. In the examples, R¹independently-Br. In the examples, R¹Independently is-I. In the examples, R¹Independently is-NO₂. In the examples, R¹Independently is-SH. In the examples, R¹Independently is-SeH. In the examples, R¹Independently is-SO₃H. In the examples, R¹Independently is-SC (O) CH ₃. In the examples, R¹Independently is-SSCH₃. In the examples, R¹Independently is-SP (O) (OH)₂. In the examples, R¹Independently is R¹⁰Substituted or unsubstituted heteroalkyl. In the examples, R¹Independently is R¹⁰Substituted or unsubstituted 2-to 20-membered heteroalkyl. In the examples, R¹Independently is R¹⁰Substituted 2-to 20-membered heteroalkyl. In the examples, R¹Independently an unsubstituted 2-to 20-membered heteroalkyl group. In the examples, R¹Independently is-S- (C)₁-C₂₀Alkyl groups). In the examples, R¹Independently is-SCH₃. In the examples, R¹Independently is-S (O)₂CH₃. In the examples, R¹Independently isWherein m is independently an integer from 0 to 4. In the examples, R¹Independently isIn the examples, R¹Independently is-Si (CH)₃)₃. In the examples, R¹Independently is-Si (CH₂CH₃)₃. In the examples, R¹Independently is-Si (CH)₂CH₂CH₃)₃. In the examples, R¹Independently is-Si (CH)₃)₂)₃. In the examples, R¹Independently is-Si (CH)₂CH₂CH₂CH₃)₃. In the examples, R¹Independently is-Si (C (CH)₃)₃)₃. In the examples, R¹Independently is R¹⁰Substituted or unsubstituted heteroaryl. In the examples, R¹Independently is R¹⁰Substituted or unsubstituted 5-to 10-membered heteroaryl. In the examples, R ¹Independently an unsubstituted 5-to 10-membered heteroaryl. In the examples, R¹Independently an unsubstituted phenylthio group. In the examples, R¹Independently an unsubstituted furyl group. In the examples, R¹Independently an unsubstituted pyrrolyl group. In the examples, R¹Independently an unsubstituted imidazolyl group. In the examples, R¹Independently an unsubstituted tetrazolyl group. In the examples, R¹Independently isIn the examples, R¹Independently isIn the examples, R¹Independently is

In the examples, R¹Is R¹⁰Substituted phenyl, and R¹⁰Independently a halogen. In the examples, R¹Is composed ofWherein R is^10.1And R^10.2May each independently be hydrogen or R as described herein¹⁰Any value of (1), includingIn the examples. In the examples, R^10.1And R^10.2Each independently is halogen. In the examples, R¹Is composed of

In the examples, R¹Independently is R¹⁰Substituted or unsubstituted 2-to 8-membered heteroalkyl, and R¹⁰As described herein, are included in the examples. In the examples, R¹Independently is R¹⁰Substituted 2-to 8-membered heteroalkyl, and R¹⁰Independently an oxo group. In the examples, R¹Independently is-NHC (O) - (R)¹⁰Substituted or unsubstituted C₁-C₄Alkyl groups). In the examples, R ¹Independently is-NHC (O) - (R)¹⁰Substituted C₁-C₄Alkyl groups). In the examples, R¹independently-NHC (O) - (unsubstituted C)₁-C₄Alkyl groups). In the examples, R¹Independently isIn the examples, R¹Independently isIn the examples, R¹Independently isIn the examples, R¹Independently isIn the examples, R¹Independently is-NHS (O)₂- (unsubstituted C)₁-C₄Alkyl groups). In the examples, R¹Independently is

In the examples, R¹Is E.

In the examples, E is

R¹⁶Independently hydrogen, halogen, -CX¹⁶ ₃、-CHX¹⁶ ₂、-CH₂X¹⁶、-CN、 -N(O)_m16、 -OCX¹⁶ ₃、-OCHX¹⁶ ₂、-OCH₂X¹⁶Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

R¹⁷Independently hydrogen, halogen, -CX¹⁷ ₃、-CHX¹⁷ ₂、-CH₂X¹⁷、-CN、 -N(O)_m17、 -OCX¹⁷ ₃、-OCHX¹⁷ ₂、-OCH₂X¹⁷Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C ₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

R¹⁸Independently hydrogen, halogen, -CX¹⁸ ₃、-CHX¹⁸ ₂、-CH₂X¹⁸、-CN、 -N(O)_m18、 -OCHX¹⁸ ₂、-OCH₂X¹⁸Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

R¹⁹Independently hydrogen, halogen, -CX¹⁹ ₃、-CHX¹⁹ ₂、-CH₂X¹⁹、-CN、 -N(O)_m19、 -OCX¹⁹ ₃、-OCHX¹⁹ ₂、-OCH₂X¹⁹Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C ₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

Andindependently hydrogen, -CX₃、-CHX₂、-CH₂X、-CN、-OH、-COOH、-CONH₂Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered); attached to the same nitrogen atomAndsubstituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; attached to the same nitrogen atom Andsubstituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may optionally be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.

X、X¹⁶、X¹⁷、X¹⁸And X¹⁹Independently is-F, -Cl, -Br or-I.

n16, n17, n18 and n19 are independently integers of 0 to 4.

m16, m17, m18, m19, v16, v17, v18 and v19 are independently 1 or 2.

In the examples, R¹⁶Independently hydrogen, halogen, -CX¹⁶ ₃、-CHX¹⁶ ₂、-CH₂X¹⁶、-CN、 -N(O)_m16、 -OCX¹⁶ ₃、-OCHX¹⁶ ₂、-OCH₂X¹⁶Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted aryl (e.g., C ₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, substituted R¹⁶(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent; wherein if substituted R¹⁶Substituted with a plurality of groups selected from the group consisting of substituents, size-limited substituents and lower substituents; each substituent, the size-limited substituent andand/or the lower substituents may optionally be different. In the examples, when R¹⁶When substituted, it is substituted with at least one substituent. In the examples, when R¹⁶When substituted, it is substituted with at least one size-limited substituent. In the examples, when R¹⁶When substituted, it is substituted with at least one lower substituent.

In the examples, R¹⁶Independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), unsubstituted cycloalkyl (e.g., C) ₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁷Independently hydrogen, halogen, -CX¹⁷ ₃、-CHX¹⁷ ₂、-CH₂X¹⁷、-CN、 -N(O)_m17、 -OCX¹⁷ ₃、-OCHX¹⁷ ₂、-OCH₂X¹⁷Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted aryl (e.g., C ₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, substituted R¹⁷(e.g., substituted alkyl, substituted heteroalkylSubstituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if substituted R¹⁷Substituted with a plurality of groups selected from the group consisting of substituents, size-limited substituents and lower substituents; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, when R¹⁷When substituted, it is substituted with at least one substituent. In the examples, when R¹⁷When substituted, it is substituted with at least one size-limited substituent. In the examples, when R¹⁷When substituted, it is substituted with at least one lower substituent.

In the examples, R¹⁷Independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), unsubstituted cycloalkyl (e.g., C) ₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered),Unsubstituted aryl (e.g. C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁸Independently hydrogen, halogen, -CX¹⁸ ₃、-CHX¹⁸ ₂、-CH₂X¹⁸、-CN、 -N(O)_m18、 -OCX¹⁸ ₉、-OCHX¹⁸ ₂、-OCH₂X¹⁸Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted aryl (e.g., C ₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, substituted R¹⁸(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent; wherein if substituted R¹⁸Substituted with a plurality of groups selected from the group consisting of substituents, size-limited substituents and lower substituents; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, when R¹⁸When substituted, it is substituted with at least one substituent. In the examples, when R¹⁸When substituted, it is substituted with at least one size-limited substituent. In the examples, when R¹⁸When substituted, it is substituted with at least one lower substituent.

In the examples, R¹⁸Independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Unsubstituted heteroalkyl group(e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), unsubstituted cycloalkyl (e.g., C) ₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R¹⁹Independently hydrogen, halogen, -CX¹⁹ ₃、-CHX¹⁹ ₂、-CH₂X¹⁹、-CN、 -N(O)_m19、 -OCX¹⁹ ₃、-OCHX¹⁹ ₂、-OCH₂X¹⁹Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Meridian ofSubstituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted aryl (e.g., C ₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, substituted R¹⁹(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent; wherein if substituted R¹⁹Substituted with a plurality of groups selected from the group consisting of substituents, size-limited substituents and lower substituents; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, when R¹⁹When substituted, it is substituted with at least one substituent. In the examples, when R¹⁹When substituted, it is substituted with at least one size-limited substituent. In the examples, when R¹⁹When substituted, it is substituted with at least one lower substituent.

In the examples, R¹⁹Independently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), unsubstituted cycloalkyl (e.g., C) ₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In an embodiment of the present invention,independently hydrogen, -CX₃、-CHX₂、-CH₂X、-CN、-OH、-COOH、-CONH₂Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered),Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted aryl (e.g., C ₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, substituted(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent; wherein if substitutedSubstituted with a plurality of groups selected from the group consisting of substituents, size-limited substituents and lower substituents; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, whenWhen substituted, it is substituted with at least one substituent. In the examples, whenWhen substituted, it is substituted with at least one size-limited substituent. In the examples, whenWhen substituted, it is substituted with at least one lower substituent.

In an embodiment of the present invention,independently hydrogen, -CX₃、-CHX₂、-CH₂X、-CN、-OH、-COOH、-CONH₂Substituted (example)E.g. substituted by at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g. C ₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, substituted(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent; wherein if substituted Substituted with a plurality of groups selected from the group consisting of substituents, size-limited substituents and lower substituents; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, whenWhen substituted, it is substituted with at least one substituent. In the examples, whenWhen substituted, it is substituted with at least one size-limited substituent. In the examples, whenWhen substituted, it is substituted with at least one lower substituent.

In the examples, attached to the same nitrogen atomAndsubstituents may be optionally linked to form a substituted (e.g., substituted with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroaryl.

In the examples, by linking to the same nitrogen atomAnda substituted moiety formed by the attachment of a substituent (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if by bonding to the same nitrogen atom Andthe substituted moiety formed by the connection of the substituents is substituted with a plurality of groups selected from the group consisting of a substituent, a size-limited substituent and a lower substituent; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, when the two are bonded to the same nitrogen atomAndwhen a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one substituent. In the examples, when the two are bonded to the same nitrogen atomAndwhen the moiety formed by the attachment of the substituents is substituted, the moiety is substituted with at least one size-limited substituent. In the examples, when the two are bonded to the same nitrogen atomAndwhen a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one lower substituent.

In an embodiment of the present invention,independently hydrogen, -CX₃、-CHX₂、-CH₂X、-CN、-OH、-COOH、-CONH₂Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C ₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, substituted(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent; wherein if substitutedSubstituted with a plurality of groups selected from the group consisting of substituents, size-limited substituents and lower substituents; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, whenWhen substituted, it is substituted with at least one substituent. In the examples, when When substituted, it is substituted with at least one size-limited substituent. In the examples, whenWhen substituted, it is substituted with at least one lower substituent.

In an embodiment of the present invention,independently hydrogen, -CX₃、-CHX₂、-CH₂X、-CN、-OH、-COOH、-CONH₂Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, by linking to the same nitrogen atomAnda substituted moiety formed by the attachment of a substituent (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if by bonding to the same nitrogen atomAndthe substituted moiety formed by the connection of the substituents is substituted with a plurality of groups selected from the group consisting of a substituent, a size-limited substituent and a lower substituent; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, when the two are bonded to the same nitrogen atomAndwhen a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one substituent. In the examples, when the two are bonded to the same nitrogen atomAndwhen the moiety formed by the attachment of the substituents is substituted, the moiety is substituted with at least one size-limited substituent. In the examples, when the two are bonded to the same nitrogen atomAndwhen a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one lower substituent.

In an embodiment of the present invention, Independently hydrogen, -CX₃、-CHX₂、-CH₂X、-CN、-OH、-COOH、-CONH₂Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, substituted(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, or substituted heterocycloalkyl,Substituted aryl and/or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if substitutedSubstituted with a plurality of groups selected from the group consisting of substituents, size-limited substituents and lower substituents; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, whenWhen substituted, it is substituted with at least one substituent. In the examples, whenWhen substituted, it is substituted with at least one size-limited substituent. In the examples, whenWhen substituted, it is substituted with at least one lower substituent.

In an embodiment of the present invention,independently hydrogen, -CX₃、-CHX₂、-CH₂X、-CN、-OH、-COOH、-CONH₂Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C ₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, substituted(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent; wherein if substitutedSubstituted with a plurality of groups selected from the group consisting of substituents, size-limited substituents and lower substituents; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, whenWhen substituted, it is substituted with at least one substituent. In the examples, when When substituted, it is substituted with at least one size-limited substituent. In the examples, whenWhen substituted, it is substituted with at least one lower substituent.

In the examplesAttached to the same nitrogen atomAndsubstituents may be optionally linked to form a substituted (e.g., substituted with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl or substituted (e.g., substituted with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroaryl.

In the examples, by linking to the same nitrogen atomAnda substituted moiety formed by the attachment of a substituent (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if by bonding to the same nitrogen atomAndthe substituted moiety formed by the connection of the substituents is substituted with a plurality of groups selected from the group consisting of a substituent, a size-limited substituent and a lower substituent; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, when the two are bonded to the same nitrogen atom Andwhen a moiety formed by connecting substituents is substituted, the moietyIs substituted with at least one substituent. In the examples, when the two are bonded to the same nitrogen atomAndwhen the moiety formed by the attachment of the substituents is substituted, the moiety is substituted with at least one size-limited substituent. In the examples, when the two are bonded to the same nitrogen atomAndwhen a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one lower substituent.

In an embodiment of the present invention,independently hydrogen, -CX₃、-CHX₂、-CH₂X、-CN、-OH、-COOH、-CONH₂Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-membered) To 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., with at least one substituent, size-limiting substituent, or lower substituent), or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In an embodiment of the present invention,independently hydrogen, -CX₃、-CHX₂、-CH₂X、-CN、-OH、-COOH、-CONH₂Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted cycloalkyl (e.g., C₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Substituted (e.g., with at least one substituent, size-limited substituent or lower substituent) or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., with at least one substituent, size-limited substituent or lower substituent), or unsubstituted aryl (e.g., C₆-C₁₀Or phenyl) or substituted (e.g., with at least one substituent, size-limited substituent, or lower substituent) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, substituted(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent, size-limiting substituent, or lower substituent; wherein if substitutedSubstituted with a plurality of groups selected from the group consisting of substituents, size-limited substituents and lower substituents; each substituent, size-limited substituent and/or lower substituent may optionally be substitutedDifferent. In the examples, whenWhen substituted, it is substituted with at least one substituent. In the examples, whenWhen substituted, it is substituted with at least one size-limited substituent. In the examples, whenWhen substituted, it is substituted with at least one lower substituent.

In the examples, by linking to the same nitrogen atomAnda substituted moiety formed by the attachment of a substituent (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent, or lower substituent; wherein if by bonding to the same nitrogen atomAndthe substituted moiety formed by the connection of the substituents is substituted with a plurality of groups selected from the group consisting of a substituent, a size-limited substituent and a lower substituent; each substituent, size-limited substituent and/or lower substituent may optionally be different. In the examples, when the two are bonded to the same nitrogen atomAndwhen a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one substituent. In the examples, when the two are bonded to the same nitrogen atomAndwhen the moiety formed by the attachment of the substituents is substituted, the moiety is substituted with at least one size-limited substituent. In the examples, when the two are bonded to the same nitrogen atomAndwhen a moiety formed by connecting substituents is substituted, the moiety is substituted with at least one lower substituent.

In an embodiment of the present invention, Andindependently of each other is hydrogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-COOH、-CONH₂Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆、C₁-C₄Or C₁-C₂) Unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆、C₄-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered); attached to the same nitrogen atomAndsubstituents may optionally be linked to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may optionally be linked to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may optionally be linked to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may optionally be linked to form an unsubstituted heterocycloalkyl or unsubstituted heteroaryl.

In the examples, E is

In the examples, E isIn the examples, E is In the examples, E isIn the examples, E isIn the examples, E isIn the examples, E isIn the examples, E is

In embodiments, the compound has the formulaRing A, R¹、R²、L¹⁰³、L¹⁰⁴、L¹⁰⁵And z2 are as described herein.

In the examples, L¹⁰³Is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

In the examples, L¹⁰⁴Is a bond, -O-, -NH-, -S-, or a substituted or unsubstituted alkylene.

In the examples, L¹⁰⁵is-S (O)₂-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, or-C (O) O-.

In the examples, L¹⁰⁵is-S (O)₂-, -C (O) -, -NHC (O) -, or-OC (O) -.

n is an integer of 0 to 4.

In embodiments, the compound has the formulaR¹、L¹⁰³、L¹⁰⁴、L¹⁰⁵N and z2 are as described herein. In the examples, L¹⁰³Is a bond, substituted or unsubstituted C₁-C₆Alkylene or substituted or unsubstituted 2-to 6-membered heteroalkylene; l is¹⁰⁴Is a bond, -O-, -NH-, -S-, or substituted or unsubstituted C₁-C₄An alkylene group; l is¹⁰⁵is-S (O)₂-, -C (O) -, -NHC (O) -, or-OC (O) -; n is an integer of 0 to 4; and isAndindependently hydrogen, halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、-N(O)_m2、 -N₃Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C) ₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered);andsubstituents may be linked to form a substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, L¹⁰³Is a bond, substituted or unsubstituted C₁-C₆Alkylene or substituted or unsubstituted 2-to 6-membered heteroalkylene; l is¹⁰⁴Is a bond, -O-, -NH-, -S-, or substituted or unsubstituted C₁-C₄An alkylene group; l is¹⁰⁵is-S (O)₂-, -C (O) -, -NHC (O) -, or-OC (O) -; n is an integer of 0 to 4; and isAndindependently hydrogen, halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、-N(O)_m2、 -N₃、R²⁰Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R²⁰Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R ²⁰Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R²⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R²⁰Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R²⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered);andsubstituents may be linked to form R²⁰Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R²⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R²⁰Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl), or R²⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4. In an embodiment, L is 0 when n¹⁰⁴And L¹⁰⁵Is not a bond.

In an embodiment of the present invention,andindependently a halogen. In an embodiment of the present invention,andindependently is-Cl.

In the examples, L¹⁰³Is unsubstituted alkylene. In the examples, L¹⁰³Is unsubstituted C₁-C₆An alkylene group. In the examples, L¹⁰³Is unsubstituted C₁-C₄An alkylene group. In the examples, L ¹⁰³Is a bond.

In the examples, L¹⁰⁴Is a bond, -O-, -NH-, -S-, or a substituted or unsubstituted alkylene (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄). In the examples, L¹⁰⁴Is a bond. In the examples, L¹⁰⁴is-O-. In the examples, L¹⁰⁴is-NH-. In the examples, L¹⁰⁴is-S-. In the examples, L¹⁰⁴Is substituted or notSubstituted C₁-C₈An alkylene group. In the examples, L¹⁰⁴Is substituted or unsubstituted C₁-C₆An alkylene group. In the examples, L¹⁰⁴Is substituted or unsubstituted C₁-C₄An alkylene group. In the examples, L¹⁰⁴Is unsubstituted C₁-C₈An alkylene group.

In the examples, L¹⁰⁴Is a bond, -O-, -NH-, -S-, or R¹⁰⁴Substituted or unsubstituted alkylene (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)。R¹⁰⁴As described herein, are included in the examples.

In the examples, L¹⁰⁵is-S (O)₂-, -C (O) -, -NHC (O) -, or-OC (O) -. In the examples, L¹⁰⁵is-S (O)₂-. In the examples, L¹⁰⁵is-C (O) -. In the examples, L¹⁰⁵is-NHC (O) -. In the examples, L¹⁰⁵is-OC (O) -.

In the examples, -L¹⁰⁴-CH₂-L¹⁰⁵NH-L¹⁰³-is of

In the examples, -L¹⁰⁴-CH₂-L¹⁰⁵NH-L¹⁰³-is ofIn the examples, -L¹⁰⁴-CH₂-L¹⁰⁵NH-L¹⁰³-is ofIn the examples, -L¹⁰⁴-CH₂-L¹⁰⁵NH-L¹⁰³-is ofIn the examples, -L¹⁰⁴-CH₂-L¹⁰⁵-NH-L¹⁰³-is ofIn the examples, -L¹⁰⁴-CH₂-L¹⁰⁵NH-L¹⁰³-is of

In the examples, -L¹⁰⁴-CH₂-L¹⁰⁵-NH-L¹⁰³-is of In the examples, -L ¹⁰⁴-CH₂-L¹⁰⁵-NH-L¹⁰³-is of

In the examples, R¹Is hydrogen,E. Substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted 2-to 10-membered heteroalkyl, substituted or unsubstituted C₅-C₆Cycloalkyl, substituted or unsubstituted 5-to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl; e is an electrophilic moiety;andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted 2-to 6-membered heteroalkyl, substituted or unsubstituted C₅-C₆Cycloalkyl, substituted or unsubstituted 5-to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl.

In the examples, R¹Is hydrogen,E、R¹⁰Substituted or unsubstituted C₁-C₆Alkyl radical, R¹⁰Substituted or unsubstituted 2-to 10-membered heteroalkyl, R¹⁰Substituted or unsubstituted C₅-C₆Cycloalkyl radical, R¹⁰Substituted or unsubstituted 5-to 6-membered heterocycloalkyl, R¹⁰Substituted or unsubstituted phenyl or R¹⁰Substituted or unsubstituted 5-to 6-membered heteroaryl. In an embodiment of the present invention,andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹⁰Substituted or unsubstituted C₁-C₆Alkyl radical, R¹⁰Substituted or unsubstituted 2-to 10-membered heteroalkyl, R ¹⁰Substituted or unsubstituted C₅-C₆Cycloalkyl radical, R¹⁰Substituted or unsubstituted 5-to 6-membered heterocycloalkyl, R¹⁰Substituted or unsubstituted phenyl or R¹⁰Substituted or unsubstituted 5-to 6-membered heteroaryl.

In the examples, R¹⁰Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃、R¹¹Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹¹Substituted or unsubstituted heteroalkyl (e.g., 2-membered)To 8-, 2-to 6-or 2-to 4-membered), R¹¹Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R¹¹Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹¹Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹¹Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

R¹¹Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃、R¹²Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹²Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R¹²Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R¹²Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹²Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R ¹²Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

R¹²Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃、R¹³Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R¹³Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R¹³Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R¹³Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R¹³Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R¹³Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

R¹³Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃Unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄) Unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4) -unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, R²Independently halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、 -N(O)_m2、 -N₃Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R bound to adjacent atoms ²Substituents may be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In the examples, R²Independently halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered); two R bound to adjacent atoms²Substituents may be linked to form a substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) orSubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R²Independently halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R²⁰Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R²⁰Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R²⁰Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R²⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R²⁰Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R²⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered); two R bound to adjacent atoms²Substituents may be linked to form R²⁰Substituted or unsubstituted cycloalkyl, R²⁰Substituted or unsubstituted heterocycloalkyl, R²⁰Substituted or unsubstituted aryl or R²⁰Substituted or unsubstituted heteroaryl.

R²⁰Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R²¹Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R²¹Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R²¹Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R²¹Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R²¹Substituted or unsubstituted aryl (e.g., C) ₆-C₁₀Or phenyl) or R²¹Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

R²¹Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R²²Substituted or unsubstituted alkyl (e.g. C)₁-C₈、C₁-C₆Or C₁-C₄)、R²²Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4-membered), R²²Substituted or unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆)、R²²Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, or 5-to 6-membered), R²²Substituted or unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or R²²Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

R²²Independently oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Unsubstituted aryl (e.g., C)₁-C₈、C₁-C₆Or C₁-C₄) Unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, or 2-to 4) -unsubstituted cycloalkyl (e.g., C)₃-C₈、C₃-C₆Or C₅-C₆) Unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, or 5-to 6-membered), unsubstituted aryl (e.g., C)₆-C₁₀Or phenyl) or unsubstituted heteroaryl) (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, the compounds are

In factIn the examples, the compounds are

In the examples, the compounds are

In embodiments, ring A is notIn embodiments, ring A is notIn embodiments, ring A is notX²Independently is-F, -Cl, -Br or-I. In the examples, X²Independently is-Cl.

In the examples, R¹Is not provided withAs described herein.

In the examples, E is not-SS- (unsubstituted C)₁-C₇Alkyl groups). In embodiments, E is not-SS- (3-to 7-membered unsubstituted heteroalkyl). In embodiments, E is not-SSCH₂CH₂N(CH₃)₂。

In the examples, the compounds are not In the examples, the compounds are notIn the examples, the compounds are not

In embodiments, the compound is covalently linked to Nurr1 (e.g., human Nurr 1). In embodiments, the compound is irreversibly covalently bound to Nurr1 (e.g., human Nurr 1). In embodiments, the compound is reversibly covalently bound to Nurr1 (e.g., human Nurr 1).

In an embodiment, the compound contacts the amino acid corresponding to Cys566 of human Nurr 1. In an embodiment, the compound contacts the amino acid corresponding to Cys475 of human Nurr 1. In an embodiment, the compound contacts the amino acid corresponding to Cys534 of human Nurr 1.

In an embodiment, the compound contacts the amino acid corresponding to Arg515 of human Nurr 1. In an embodiment, the compound contacts an amino acid corresponding to Arg563 of human Nurr 1. In embodiments, the compound contacts an amino acid corresponding to Glu445 of human Nurr 1.

In an embodiment, the compound is covalently linked to an amino acid corresponding to Cys566 of human Nurr 1. In an embodiment, the compound is irreversibly covalently bound to an amino acid corresponding to Cys566 of human Nurr 1. In an embodiment, the compound is reversibly covalently bound to an amino acid corresponding to Cys566 of human Nurr 1.

In an embodiment, the compound stabilizes Nurr1 homologous monomers. In an embodiment, the compound stabilizes the Nurr1 homodimer. In the examples, the compounds stabilized head-to-tail Nurr1 homodimers. In embodiments, the compounds stabilize a Nurr1 heterodimer. In an embodiment, the Nurr1 heterodimer is a heterodimer with RXR α.

In embodiments, the compound stabilizes the Nurr1 monomer relative to a control (e.g., in the absence of the compound). In embodiments, the compound stabilizes the Nurr1 homodimer relative to a control (e.g., in the absence of the compound). In embodiments, the compounds stabilize a head-to-tail Nurr1 homodimer relative to a control (e.g., in the absence of compound). In embodiments, the compound stabilizes the Nurr1 heterodimer relative to a control (e.g., in the absence of the compound). In an embodiment, the Nurr1 heterodimer is a heterodimer with RXR α.

In an embodiment, the compound contacts Nurr1 homomonomers. In an embodiment, the compound contacts Nurr1 homodimer. In embodiments, the compound is linked to a contact pair tail Nurr1 homodimer. In embodiments, the compound contacts a Nurr1 heterodimer. In an embodiment, the Nurr1 heterodimer is a heterodimer with RXR α.

In an embodiment, the compound is linked to a Nurr1 homomonomer. In an embodiment, the compound is linked to a Nurr1 homodimer. In the examples, the compounds were ligated head-to-tail Nurr1 homodimers. In embodiments, the compound is linked to a Nurr1 heterodimer. In an embodiment, the Nurr1 heterodimer is a heterodimer with RXR α.

In embodiments, the compound excludes Nurr 1: formation of RXR heterodimers. In embodiments, the compound inhibits Nurr 1: formation of RXR heterodimers. In the examples, compounds linked to Nurr1 inhibit the resulting compounds: the Nurr1 complex is linked to RXR.

In embodiments, the compounds stabilize a Nurr1 dimer conformation in which the distance between the N-termini is about(e.g., about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or ). In embodiments, the compounds stabilize a Nurr1 dimer conformation in which the distance between the N-termini is at least(e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or ). In embodiments, the compounds stabilize a Nurr1 dimer conformation in which the distance between the N-termini is less than(e.g., less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, or)。

In embodiments, the compound contacts a Nurr1 dimer conformation with a distance between the N-termini of about(e.g., about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 7)0. 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or). In embodiments, the compound contacts a Nurr1 dimer conformation in which the distance between the N-termini is at least(e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or). In embodiments, the compound contacts a Nurr1 dimer conformation in which the distance between the N-termini is less than(e.g., less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, or )。

In embodiments, the compounds are linked in a Nurr1 dimer conformation with a distance between the N-termini of about(e.g., about 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or). In embodiments, the compound is linked to a Nurr1 dimer conformation wherein the distance between the N-termini is at least(e.g., at least 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or). In embodiments, the compounds are linked to a Nurr1 dimer conformation in which the distance between the N-termini is less than(e.g., less than 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, or)。

In embodiments, the compounds stabilize a Nurr1 dimer conformation in which the distance between the N-termini is about(e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 or). In embodiments, the compounds stabilize a Nurr1 dimer conformation in which the distance between the N-termini is at least (e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or). In embodiments, the compounds stabilize a Nurr1 dimer conformation in which the distance between the N-termini is less than(e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or)。

In embodiments, the compound contacts a Nurr1 dimer conformation with a distance between the N-termini of about(e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 or). In embodiments, the compound contacts a Nurr1 dimer conformation in which the distance between the N-termini is at least(e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or). In embodiments, the compound contacts a Nurr1 dimer conformation in which the distance between the N-termini is less than(e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or)。

In embodiments, the compounds are linked in a Nurr1 dimer conformation with a distance between the N-termini of about (e.g., about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 or). In embodiments, the compound is linked to a Nurr1 dimer conformation wherein the distance between the N-termini is at least(e.g., at least 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or). In embodiments, the compounds are linked to a Nurr1 dimer conformation in which the distance between the N-termini is less than(e.g., less than 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, or)。

In embodiments, the compound is linked to Nurr1 and induces Nurr1 to link to NBRE, NuRE, or DR-5 responsive elements. In embodiments, the compound is linked to Nurr1 and induces Nurr1 to link to NBRE. In embodiments, the compound is linked to Nurr1 and induces Nurr1 to be linked to NuRE. In embodiments, the compound is linked to Nurr1 and induces Nurr1 to link to a DR-5 responsive element.

In embodiments, the compounds are as described herein, including in the examples. In embodiments, the compound is a compound described herein (e.g., in the examples section, figures, tables, claims, or appendix).

Pharmaceutical composition

In one aspect, a pharmaceutical composition is provided comprising a compound described herein and a pharmaceutically acceptable excipient.

In embodiments, the pharmaceutical composition comprises an effective amount of the compound. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound.

In an embodiment, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an agent for treating a neurodegenerative disease. In an embodiment, the neurodegenerative disease is parkinson's disease. In embodiments, the second agent is a parkinson's disease drug, e.g., levodopa, carbidopa, selegiline, amantadine, donepezil, galantamine, rivastigmine, tacrine, bromocriptine, pergolide, pramipexole, ropinirole, trihexyphenidyl, benztropine, biperiden, pridopidine, tolcapone, or entacapone. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent.

In embodiments, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an agent used to treat an inflammatory disorder, for example, acetaminophen, duloxetine, aspirin, ibuprofen, naproxen, diclofenac sodium, prednisone, betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, codeine, fentanyl, hydrocodone, hydromorphone, morphine, meperidine, or oxycodone. In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a second agent.

In an embodiment, the pharmaceutical composition comprises an effective amount of a second agent, wherein the second agent is an anti-cancer agent.

In one aspect, a pharmaceutical composition is provided comprising 5, 6-Dihydroxyindole (DHI) and a pharmaceutically acceptable excipient. In embodiments, the pharmaceutical composition comprises an effective amount of 5, 6-Dihydroxyindole (DHI). In embodiments, the pharmaceutical composition comprises a therapeutically effective amount of 5, 6-Dihydroxyindole (DHI). In embodiments, the pharmaceutical composition comprises an effective amount of a second agent described herein.

Method of use

In one aspect, a method for treating a disease associated with dopaminergic neuronal imbalance and/or degeneration in the central nervous system of a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of 5, 6-Dihydroxyindole (DHI).

In embodiments, the disease associated with dopaminergic neuronal disorder and/or degeneration is parkinson's disease, alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction. In an embodiment, the disease is parkinson's disease. In an embodiment, the disease is alzheimer's disease. In embodiments, the disease is multiple sclerosis. In embodiments, the disease is amyotrophic lateral sclerosis. In an embodiment, the disease is schizophrenia. In an embodiment, the disease is drug addiction.

In an embodiment, the disease associated with dopaminergic neuronal imbalance and/or degeneration is cancer.

In one aspect, there is provided a method for treating a disease in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

In one aspect, a method for treating a disease in a subject in need thereof is provided, the method comprising administering to the subject in need thereof a therapeutically effective amount of 5, 6-Dihydroxyindole (DHI).

In embodiments, the disease is parkinson's disease, alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction. In an embodiment, the disease is parkinson's disease. In an embodiment, the disease is alzheimer's disease. In embodiments, the disease is multiple sclerosis. In embodiments, the disease is amyotrophic lateral sclerosis. In an embodiment, the disease is schizophrenia. In an embodiment, the disease is drug addiction.

In embodiments, the disease is cancer.

In embodiments, the cancer is breast cancer, pancreatic cancer, bladder cancer, mucoepidermoid cancer, gastric cancer, prostate cancer, colorectal cancer, lung cancer, adrenocortical cancer, or cervical cancer.

In one aspect, there is provided a method for reducing inflammation in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

In embodiments, the method is for reducing inflammation of the central nervous system of a subject in need thereof.

In one aspect, there is provided a method for reducing oxidative stress in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein.

In embodiments, the method is for reducing oxidative stress of the central nervous system of a subject in need thereof.

In one aspect, there is provided a method of modulating the level of Nurr1 activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the subject has an increased level of Nurr1 activity by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the subject has an increased level of Nurr1 activity by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of increasing the level of Nurr1 activity of a cell, the method comprising contacting the cell with a compound described herein. In embodiments, the level of Nurr1 activity of a cell is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of Nurr1 activity of a cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of increasing the level of Pitx3 activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the subject has an increased Pitx3 activity level by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the subject has an increase in Pitx3 activity level of at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, a method of increasing the level of Pitx3 activity of a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the Pitx3 activity level of a cell is increased about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the Pitx3 activity level of the cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of increasing the level of TH activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the subject has an increased level of TH activity by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the subject has an increased level of TH activity by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, a method of increasing the level of TH activity of a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of TH activity of the cell is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of TH activity of the cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of increasing the level of VMAT2 activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of VMAT2 activity in the subject is increased about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of VMAT2 activity in the subject is increased at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, a method of increasing the level of VMAT2 activity of a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of VMAT2 activity of the cell is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of VMAT2 activity of the cell is increased at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of increasing the level of Dopa Decarboxylase (DDC) activity in a subject in need thereof, said method comprising administering to said subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of DDC activity in the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of DDC activity in the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, a method of increasing the level of Dopa Decarboxylase (DDC) activity in a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of DDC activity of a cell is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of DDC activity of a cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of increasing the level of dopamine transporter (DAT) activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the subject has an increased level of DAT activity by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the subject has an increased level of DAT activity by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, a method of increasing the level of dopamine transporter (DAT) activity of a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of DAT activity of the cell is increased about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of DAT activity of the cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of increasing the level of BDNF activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of BDNF activity of the subject is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of BDNF activity of the subject is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of increasing the level of BDNF activity of a cell, the method comprising contacting the cell with a compound described herein. In embodiments, the level of BDNF activity of the cell is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of BDNF activity of the cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of increasing the level of NGF activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the subject has an increased level of NGF activity by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the subject has an increase in NGF activity level of at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, a method of increasing the level of NGF activity of a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of NGF activity of the cell is increased about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of NGF activity of the cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of increasing the level of GDNF receptor c-Ret activity in a subject in need thereof, said method comprising administering to said subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the subject has an increase in the level of GDNF receptor c-Ret activity of about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the subject has an increase in the level of GDNF receptor c-Ret activity of at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, a method of increasing the level of GDNF receptor c-Ret activity of a cell is provided, said method comprising contacting said cell with a compound described herein. In embodiments, the level of GDNF receptor c-Ret activity of the cell is increased about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of GDNF receptor c-Ret activity of the cell is increased at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of increasing the level of SOD1 activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the subject has an increased level of SOD1 activity by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the subject has an increased level of SOD1 activity by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, a method of increasing the level of SOD1 activity of a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of SOD1 activity of the cell is increased about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of SOD1 activity of the cell is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of reducing the level of TNF α activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of TNF α activity in the subject is reduced by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of TNF α activity in the subject is reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, a method of reducing the level of TNF α activity of a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of TNF α activity of the cell is reduced by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of TNF α activity of the cell is reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of reducing the level of iNOS activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the level of iNOS activity of the subject is reduced by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of iNOS activity of the subject is reduced by at least 1.5 fold, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 35 fold, 40 fold, 45 fold, 50 fold, 60 fold, 70 fold, 80 fold, 90 fold, 100 fold, 150 fold, 200 fold, 250 fold, 300 fold, 350 fold, 400 fold, 450 fold, 500 fold, 600 fold, 700 fold, 800 fold, 900 fold, or 1000 fold.

In one aspect, a method of reducing the level of iNOS activity of a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of iNOS activity of the cell is reduced by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of iNOS activity of the cell is reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, there is provided a method of reducing the level of IL-1 β activity in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the subject has a decreased level of IL-1 β activity by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the subject has a decreased level of IL-1 β activity by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In one aspect, a method of reducing the level of IL-1 β activity of a cell is provided, the method comprising contacting the cell with a compound described herein. In embodiments, the level of IL-1 β activity of the cell is reduced by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of IL-1 β activity of the cell is reduced by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In embodiments, the method comprises a method of increasing dopamine levels in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound described herein. In embodiments, the dopamine level in the subject is increased about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the dopamine level in the subject is increased at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In embodiments, the method comprises a method of increasing dopamine levels in a cell, the method comprising contacting the cell with a compound described herein. In embodiments, the dopamine level of the cell is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the dopamine level of the cell is increased at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In embodiments, the methods comprise increasing dopamine synthesis in a cell using a compound described herein as compared to a control (e.g., in the absence of the compound). In embodiments, the level of dopamine synthesis is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of dopamine synthesis is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In embodiments, the methods comprise increasing dopamine packaging of a cell using a compound described herein as compared to a control (e.g., in the absence of the compound). In embodiments, the packaged level of dopamine is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the packaged level of dopamine is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In embodiments, the methods comprise increasing dopamine reuptake by a cell using a compound described herein as compared to a control (e.g., in the absence of the compound). In embodiments, the level of dopamine reuptake is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of dopamine reuptake is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In embodiments, the methods comprise increasing the development of a dopaminergic neuron using a compound described herein, as compared to a control (e.g., in the absence of the compound). In embodiments, the level of development of a dopaminergic neuron is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the level of development of a dopaminergic neuron is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In embodiments, the methods comprise increasing the maintenance of dopaminergic neurons using a compound described herein compared to a control (e.g., in the absence of the compound). In embodiments, the maintenance level of a dopaminergic neuron is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the maintenance level of a dopaminergic neuron is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In embodiments, the methods comprise increasing survival of a dopaminergic neuron using a compound described herein, as compared to a control (e.g., in the absence of the compound). In embodiments, the survival level of a dopaminergic neuron is increased by about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold. In embodiments, the survival level of a dopaminergic neuron is increased by at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350-fold, 400-fold, 450-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, or 1000-fold.

In embodiments, the method comprises covalently linking Nurr1 (e.g., human Nurr1) to a compound described herein. In embodiments, the method comprises irreversibly covalently linking Nurr1 (e.g., human Nurr1) to a compound described herein. In embodiments, the method comprises reversibly covalently linking Nurr1 (e.g., human Nurr1) to a compound described herein.

In an embodiment, the method comprises contacting an amino acid corresponding to Cys566 of human Nurr1 with a compound described herein. In embodiments, the method comprises contacting an amino acid corresponding to Cys475 of human Nurr1 with a compound described herein. In embodiments, the method comprises contacting an amino acid corresponding to Cys534 of human Nurr1 with a compound described herein.

In embodiments, the method comprises contacting an amino acid corresponding to Arg515 of human Nurr1 with a compound described herein. In embodiments, the method comprises contacting an amino acid corresponding to Arg563 of human Nurr1 with a compound described herein. In embodiments, the method comprises contacting an amino acid corresponding to Glu445 of human Nurr1 with a compound described herein.

In an embodiment, the method comprises covalently linking an amino acid corresponding to Cys566 of human Nurr1 to a compound described herein. In an embodiment, the method comprises irreversibly covalently linking an amino acid corresponding to Cys566 of human Nurr1 to a compound described herein. In embodiments, the method comprises reversibly covalently linking an amino acid corresponding to Cys566 of human Nurr1 to a compound described herein.

In an embodiment, the method comprises stabilizing a Nurr1 monomer with a compound described herein. In embodiments, the method comprises stabilizing a Nurr1 homodimer with a compound described herein. In an embodiment, the method comprises stabilizing a head-to-tail Nurr1 homodimer with a compound described herein. In embodiments, the method comprises stabilizing a Nurr1 heterodimer with a compound described herein. In an embodiment, the Nurr1 heterodimer is a heterodimer with RXR α.

In an embodiment, the method comprises contacting a Nurr1 monomer with a compound described herein. In an embodiment, the method comprises contacting a Nurr1 homodimer with a compound described herein. In embodiments, the method comprises contacting a contact pair tail Nurr1 homodimer with a compound described herein. In embodiments, the method comprises contacting a Nurr1 heterodimer with a compound described herein. In an embodiment, the Nurr1 heterodimer is a heterodimer with RXR α.

In embodiments, the method comprises linking a Nurr1 monomer with a compound described herein. In embodiments, the method comprises linking a Nurr1 homodimer with a compound described herein. In an embodiment, the method comprises ligating a head-to-tail Nurr1 homodimer with a compound described herein. In embodiments, the method comprises linking a Nurr1 heterodimer with a compound described herein. In an embodiment, the Nurr1 heterodimer is a heterodimer with RXR α.

In embodiments, the method comprises preventing the formation of a Nurr1: RXR heterodimer with a compound described herein.

In embodiments, the method comprises conformationally stabilizing Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is aboutIn embodiments, the method comprises conformationally stabilizing a Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is at leastIn embodiments, the method comprises conformationally stabilizing Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is less than

In embodiments, the method comprises contacting a conformation of Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is aboutIn embodiments, the method comprises contacting a conformation of Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is at leastIn embodiments, the method comprises contacting a conformation of Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is less than

In embodiments, the method comprises linking a conformation of Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is about In embodiments, the method comprises linking a conformation of Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is at leastIn embodiments, the method comprises linking a conformation of Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is less than

In embodiments, the method comprises contacting a conformation of Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is aboutIn embodiments, the method comprises contacting a Nurr1 dimer with a compound described hereinConformations in which the distance between the N-termini is at leastIn embodiments, the method comprises contacting a conformation of Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is less than

In embodiments, the method comprises linking a conformation of Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is aboutIn embodiments, the method comprises linking a conformation of Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is at leastIn embodiments, the method comprises linking a conformation of Nurr1 dimer with a compound described herein, wherein the distance between the N-termini is less than

In embodiments, the method comprises linking Nurr1 and inducing Nurr1 to link an NBRE, NuRE, or DR-5 responsive element. In embodiments, the method comprises linking Nurr1 and inducing Nurr1 to link to NBRE. In embodiments, the method comprises ligating Nurr1 and inducing Nurr1 to ligate with NuRE. In embodiments, the method comprises linking Nurr1 and inducing Nurr1 to link to a DR-5 responsive element.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that 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. All publications, patents, and patent applications cited herein are incorporated by reference in their entirety for all purposes.

V. examples

Example P1. A Compound of the formula

Wherein

Ring a is aryl or heteroaryl;

L¹is L¹⁰¹-L¹⁰²-L¹⁰³；

L¹⁰²is a bond, -S (O)₂-、-N(R¹⁰²)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰²)-、-N(R¹⁰²)C(O)-、-N(R¹⁰²)C(O)NH-、-NHC(O)N(R¹⁰²) -, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

R¹Is hydrogen, halogen, -CX¹ ₃、-CHX¹ ₂、-CH₂X¹、-OCX¹ ₃、-OCH₂X¹、-OCHX¹ ₂、-CN、 -N(O)_m1、 -N₃、E. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroAn alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

e is an electrophilic moiety;

R²independently halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、 -N(O)_m2、 -N₃Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R bound to adjacent atoms²Substituents may be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; attached to the same nitrogen atom Andsubstituents may be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstituents may be linked to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

n1 and n2 are independently integers from 0 to 4;

m1, m2, v1 and v2 are independently 1 or 2;

X¹and X²Independently is-F, -Cl, -Br or-I; and is

z2 is an integer from 0 to 5.

Embodiment P2. the compound of embodiment P1, wherein the compound has the formula

Wherein

L¹⁰⁴Is a bond, -S (O)₂-, -C (O) -, -NHC (O) -, -OC (O) -, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;

L¹⁰⁵is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene;

L¹⁰³is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and is

W is N or CH.

A compound according to embodiment P2, wherein ring a is phenyl or 5-to 10-membered heteroaryl.

A compound according to embodiment P2, wherein ring a is phenyl.

Embodiment P5. A compound of embodiment P2 wherein ring A is

Embodiment P6. the compound of one of embodiments P2 to P4, wherein the compound has the formula

And is

Embodiment P7. the compound of embodiment P6, wherein

Independently halogen or unsubstituted heteroalkyl;

independently hydrogen or halogen; and is

Independently hydrogen, halogen, -CN, Unsubstituted heteroalkyl or substituted or unsubstituted heterocycloalkyl.

Embodiment P8. the compound of embodiment P6, wherein

Independently is halogen;

independently is halogen; and is

Chongzhan is hydrogen.

Embodiment P9. the compound of embodiment P6, wherein

Civet is halogen or unsubstituted 2-to 4-membered heteroalkyl;

independently is hydrogen;

independently is halogen, -CN,Unsubstituted 2-to 4-membered heteroalkyl or substituted or unsubstituted 5-to 6-membered heterocycloalkyl;

independently is hydrogen; and is

Independently is unsubstituted C₁-C₂An alkyl group.

Embodiment P10. compounds according to one of embodiments P2 to P9, wherein L¹⁰⁴is-C (O) -.

Example P11. a compound according to one of embodiments P2 to P10, wherein L¹⁰⁵Is unsubstituted alkylene.

Example P12. a compound according to one of embodiments P2 to P10, wherein L¹⁰⁵Is unsubstituted C₁-C₄An alkylene group.

Embodiment P13. compounds according to one of embodiments P2 to P10, wherein L¹⁰⁵Is composed of

Example P14. a compound according to one of embodiments P2 to P13, wherein W is N.

Embodiment P15. compounds according to one of embodiments P2 to P14, wherein L ¹⁰³Is unsubstituted alkylene.

Example P16. a compound according to one of embodiments P2 to P14, wherein L¹⁰³Is unsubstituted C₁-C₄An alkylene group.

Example P17. a compound according to one of embodiments P2 to P14, wherein L¹⁰³Is unsubstituted ethylene.

Embodiment P18. compounds according to one of embodiments P2 to P9, whereinIs composed of

Example P19. a compound according to one of embodiments P1 to P18, wherein

R¹Is composed ofE. Unsubstituted alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl;

independently hydrogen or unsubstituted C₁-C₄An alkyl group;

independently hydrogen or unsubstituted C₁-C₄An alkyl group; and is

Example P20. a compound according to one of embodiments P1 to P18, wherein

R¹Is composed ofE. Unsubstituted C₁-C₄Alkyl radical, R¹⁰Substituted or unsubstituted phenyl or R¹⁰Substituted or unsubstituted 5-to 6-membered heteroaryl;

independently hydrogen or unsubstituted C₁-C₄An alkyl group;

R¹⁰Is oxo, halogen, -CCl ₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃Unsubstituted C₁-C₄Alkyl, unsubstituted 2-to 4-membered heteroalkyl, unsubstituted C₅-C₆Cycloalkyl, unsubstituted 5-to 6-membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5-to 6-membered heteroaryl.

Example P21. the compound according to one of embodiments P1 to P18, wherein R¹Is composed ofOr R¹⁰Substituted phenyl;

Embodiment P22. the compound of one of embodiments P1 to P18, wherein R¹is-SH, -SC (O) CH₃or-SSCH₃。

Embodiment P23. the compound of one of embodiments P1 to P18, wherein R¹Is E; and is

E is

Embodiment P24. the compound of embodiment P1, wherein the compound has the formula

L¹⁰⁴Is a bond; -O-, -NH-, -S-, or substituted or unsubstituted alkylene;

L¹⁰⁵is-S (O)₂-, -C (O) -, -NHC (O) -, or-OC (O) -; and is

L¹⁰³Is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

Embodiment P25. the compound of embodiment P24 wherein ring a is C₆-C₁₀Aryl or 5-to 10-membered heteroaryl.

A compound according to embodiment P24, wherein ring a is phenyl.

Embodiment P27. the compound of embodiment P24, wherein the compound has the formula

L¹⁰⁴Is a bond, -O-, -NH-, -S-, or substituted or unsubstituted C₁-C₄An alkylene group;

L¹⁰⁵is-S (O)₂-, -C (O) -, -NHC (O) -, or-OC (O) -;

L¹⁰³is a bond, substituted or unsubstituted C₁-C₆Alkylene oxideA substituted or unsubstituted 2-to 6-membered heteroalkylene; and is

Embodiment P28. the compound of embodiment P27, wherein Andindependently a halogen.

Embodiment P29. the compound of embodiment P27, whereinAndindependently is-Cl.

Embodiment P30. compounds according to one of embodiments P24 to P29, wherein L¹⁰⁴is-O-.

Embodiment P31. compounds according to one of embodiments P24 to P30, wherein L¹⁰⁵is-C (O) -.

Example P32. a compound according to one of embodiments P24 to P31, wherein L¹⁰³Is unsubstituted alkylene.

Example P33. a compound according to one of embodiments P24 to P31, wherein L¹⁰³Is unsubstituted C₁-C₆An alkylene group.

Example P34. a compound according to one of embodiments P24 to P31, wherein L¹⁰³Is unsubstituted C₁-C₄An alkylene group.

Embodiment P35. compounds according to one of embodiments P24 to P31, wherein L¹⁰³Is a bond.

Embodiment P36. the compound of one of embodiments P24 to P29, wherein-L¹⁰⁴-CH₂-L¹⁰⁵-NH-L¹⁰³-is of

Embodiment P37. the compound of one of embodiments P24 to P36, wherein R¹Is hydrogen, E. Substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted 2-to 6-membered heteroalkyl, substituted or unsubstituted C₅-C₆Cycloalkyl, substituted or unsubstituted 5-to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl;

E is an electrophilic moiety;

andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted 2-to 6-membered heteroalkyl, substituted or unsubstituted C₅-C₆Cycloalkyl, substituted or unsubstituted 5-to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl.

Example P38. a compound according to one of embodiments P24 to P36, wherein

e is an electrophilic moiety;

andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹⁰Substituted or unsubstituted C₁-C₆Alkyl radical, R¹⁰Substituted or unsubstituted 2-to 6-membered heteroalkyl, R¹⁰Substituted or unsubstituted C₅-C₆Cycloalkyl radical, R¹⁰Substituted or unsubstituted 5-to 6-membered heterocycloalkyl, R¹⁰Substituted or unsubstituted phenyl or R¹⁰Substituted or unsubstituted 5-to 6-membered heteroaryl;

R¹⁰is oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃、R¹¹Substituted or unsubstituted C ₁-C₄Alkyl radical, R¹¹Substituted or unsubstituted 2-to 4-membered heteroalkyl, R¹¹Substituted or unsubstituted C₅-C₆Cycloalkyl radical, R¹¹Substituted or unsubstituted 5-to 6-membered heterocycloalkyl, R¹¹Substituted or unsubstituted phenyl or R¹¹Substituted or unsubstituted 5-to 6-membered heteroaryl;

R¹¹is oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCI₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃、R¹²Substituted or unsubstituted C₁-C₄Alkyl radical, R¹²Substituted or unsubstituted 2-to 4-membered heteroalkyl, R¹²Substituted or unsubstituted C₅-C₆Cycloalkyl radical, R¹²Substituted or unsubstituted 5-to 6-membered heterocycloalkyl, R¹²Substituted or unsubstituted phenyl or R¹²Substituted or unsubstituted 5-to 6-membered heteroaryl; and is

Embodiment P39. the compound of one of embodiments P24 to P38, wherein R¹Is E; and is

E is

Embodiment P40. the compound of one of embodiments P1 to P39, wherein the compound is not

Embodiment P41. a pharmaceutical composition comprising a compound according to one of embodiments P1 to P40 and a pharmaceutically acceptable excipient.

Embodiment P42. a method for treating a disease of the central nervous system associated with dopaminergic neuronal imbalance and/or degeneration in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to one of embodiments P1 to P40.

The method of embodiment P43. according to embodiment P42, wherein the disease associated with dopaminergic neuronal dysfunction and/or degeneration is parkinson's disease, alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction.

Embodiment P44. the method according to one of embodiments P42 to P43, wherein the disease associated with dopaminergic neuronal dysfunction and/or degeneration is parkinson's disease.

Example P45. a method of modulating the level of Nurr1 activity in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound according to one of examples P1 to P40.

Example P46. a method of increasing the level of Nurr1 activity of a cell, the method comprising contacting the cell with a compound according to one of examples P1 to P40.

Example P47. a method of increasing dopamine levels in a cell, the method comprising contacting the cell with a compound according to one of examples P1 to P40.

Further examples

Example 1A Compound of formula

Wherein

Ring a is aryl or heteroaryl;

L¹is L¹⁰¹-L¹⁰²-L¹⁰³；

L¹⁰¹Is a bond, -S (O)₂-、-N(R¹⁰¹)-、-O-、-S-、-C(O)-、-C(O)N(R¹⁰¹)-、-N(R¹⁰¹)C(O)-、-N(R¹⁰¹)C(O)NH-、-NHC(O)N(R¹⁰¹) -, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, L¹⁰⁴-L¹⁰⁵、L¹⁰⁴-NH-L¹⁰⁵Or L¹⁰⁴-CH₂-L¹⁰⁵；

L¹⁰⁴Is a key、-O-、-NH-、-S-、-S(O)₂-, -C (O) -, -NHC (O) -, -C (O) NH-, -OC (O) -, -C (O) O-, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;

R¹is hydrogen, halogen, -CX¹ ₃、-CHX¹ ₂、-CH₂X¹、-OCX¹ ₃、-OCH₂X¹、-OCHX¹ ₂、-CN、 -N(O)_m1、 -N₃、-SP(O)(OH)₂E, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

e is an electrophilic moiety;

R²independently halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、 -N(O)_m2、 -N₃Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two R bound to adjacent atoms ²The substituents may be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstitutedA heteroaryl group;

andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; attached to the same nitrogen atomAndthe substituents may be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; attached to the same nitrogen atomAndsubstitutionGroups may be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;

n1 and n2 are independently integers from 0 to 4;

m1, m2, v1 and v2 are independently 1 or 2;

X¹and X²Independently is-F, -Cl, -Br or-I; and is

z2 is an integer from 0 to 5.

An embodiment 2. the compound of embodiment 1, wherein the compound has the formula

Wherein

L¹⁰⁴Is a bond, -S (O)₂-, -C (O) -, -NHC (O) -, -OC (O) -, substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;

L¹⁰³is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; and is

W is N or CH.

An embodiment 3. the compound of embodiment 2 wherein ring a is phenyl or 5-to 10-membered heteroaryl.

An embodiment 4 is the compound of embodiment 2, wherein ring a is phenyl.

An embodiment 5. the compound of embodiment 2 wherein ring a is 3-quinolinyl.

Embodiment 6. the compound of one of embodiments 2 to 4, wherein the compound has the formula

And is

Embodiment 7. the compound of embodiment 6, wherein

Independently halogen or unsubstituted heteroalkyl;

independently hydrogen or halogen; and is

The wormhole is hydrogen, halogen, -CN,Unsubstituted heteroalkyl or substituted or unsubstituted heterocycloalkyl.

Embodiment 8. the compound of embodiment 6, wherein

Independently is halogen;

independently is halogen; and is

Independently hydrogen.

Embodiment 9. the compound of embodiment 6, wherein

Independently is-OCH₃；

Independently is hydrogen; and is

Independently is-OCH₃。

Embodiment 10. the compound of embodiment 6, wherein

Independently halogen or unsubstituted 2-to 4-membered heteroalkyl;

independently is hydrogen;

independently is halogen, -CN,Unsubstituted 2-to 4-membered heteroalkyl or substituted or unsubstituted 5-to 6-membered heterocycloalkyl;

independently is hydrogen; and is

Independently is unsubstituted C₁-C₂An alkyl group.

Embodiment 11. the compound according to one of embodiments 2 to 10, wherein L ¹⁰⁴is-C (O) -.

Example 12. the compound according to one of examples 2 to 11, wherein L¹⁰⁵Is unsubstituted alkylene.

Example 13. A compound according to one of examples 2 to 11, wherein L¹⁰⁵Is unsubstituted C₁-C₄An alkylene group.

Embodiment 14. the compound according to one of embodiments 2 to 11, wherein L¹⁰⁵Is composed of

Example 15. a compound according to one of examples 2 to 14, wherein W is N.

Embodiment 16. the compound according to one of embodiments 2 to 15, wherein L¹⁰³Is unsubstituted alkylene.

Example 17. A compound according to one of examples 2 to 15, wherein L¹⁰³Is unsubstituted C₁-C₄An alkylene group.

Example 18. the compound according to one of examples 2 to 15, wherein L¹⁰³Is unsubstituted ethylene.

Embodiment 19. the compound according to one of embodiments 2 to 10, whereinIs composed of

Example 20. A compound according to one of examples 1 to 19, wherein R¹Is composed ofE. Unsubstituted alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl;

independently of each otherIs hydrogen or unsubstituted C₁-C₄An alkyl group;

independently hydrogen or unsubstituted C₁-C₄An alkyl group; and is

Independently hydrogen, halogen, -CCl ₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-N₃、-PO₃H₂Or substituted or unsubstituted alkyl.

Example 21. the compound according to one of examples 1 to 19, wherein

R¹Is composed ofE. Unsubstituted C₁-C₄Alkyl radical, R¹⁰Substituted or unsubstituted phenyl or R¹⁰Substituted or unsubstituted 5-to 6-membered heteroaryl;

independently hydrogen or unsubstituted C₁-C₄An alkyl group;

Example 22. A compound according to one of examples 1 to 19, wherein R¹Is composed ofOr R¹⁰Substituted phenyl;

Embodiment 23. the compound of one of embodiments 1 to 19, wherein R ¹is-SH, -SC (O) CH₃or-SSCH₃。

Embodiment 24. the compound according to one of embodiments 1 to 19, wherein R¹Is E; and is

E is

Embodiment 25. the compound of embodiment 1, wherein the compound has the formula

L¹⁰⁴Is a bond; -O-, -NH-, -S-, or substituted or unsubstituted alkylene;

L¹⁰⁵is-S (O)₂-, -C (O) -, -NHC (O) -, or-OC (O) -; and is

L¹⁰³Is a key, a meridian getsSubstituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

Embodiment 26. the compound of embodiment 25, wherein ring A is C₆-C₁₀Aryl or 5-to 10-membered heteroaryl.

An embodiment 27. the compound of embodiment 25 wherein ring a is phenyl.

Embodiment 28. the compound of embodiment 25, wherein the compound has the formula

L¹⁰⁴Is a bond, -O-, -NH-, -S-, or substituted or unsubstituted C₁-C₄An alkylene group;

L¹⁰⁵is-S (O)₂-, -C (O) -, -NHC (O) -, or-OC (O) -;

L¹⁰³is a bond, substituted or unsubstituted C₁-C₆Alkylene or substituted or unsubstituted 2-to 6-membered heteroalkylene; and is

Andindependently hydrogen, halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-OCX² ₃、-OCH₂X²、-OCHX² ₂、-CN、 -N(O)_m2、 -N₃Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; bound to adjacent atoms Andthe substituents may be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Embodiment 29. the compound of embodiment 28, whereinAndindependently a halogen.

Embodiment 30. the compound of embodiment 28, whereinAndindependently is-Cl.

Embodiment 31. the compound according to one of embodiments 25 to 30, wherein L¹⁰⁴is-O-.

Embodiment 32 the compound of one of embodiments 25 to 31 wherein L¹⁰⁵is-C (O) -.

Example 33. the compound of one of examples 25 to 32, wherein L¹⁰³Is unsubstituted alkylene.

Examples of the invention34. A compound according to one of embodiments 25 to 32, wherein L¹⁰³Is unsubstituted C₁-C₆An alkylene group.

Example 35. the compound according to one of examples 25 to 32, wherein L¹⁰³Is unsubstituted C₁-C₄An alkylene group.

Embodiment 36. the compound of one of embodiments 25 to 32, wherein L¹⁰³Is a bond.

Embodiment 37. the compound of one of embodiments 25 to 30, wherein

-L¹⁰⁴-CH₂-L¹⁰⁵-NH-L¹⁰³-is of

Embodiment 38. the compound of one of embodiments 25 to 37, wherein R ¹Is hydrogen, E. Substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted 2-to 6-membered heteroalkyl, substituted or unsubstituted C₅-C₆Cycloalkyl, substituted or unsubstituted 5-to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl;

e is an electrophilic moiety;

andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂Substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted 2-to 6-membered heteroalkyl, substituted or unsubstituted C₅-C₆Cycloalkyl, substituted or unsubstituted 5-to 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl.

Example 39. the compound of one of examples 25 to 37, wherein

e is an electrophilic moiety;

andindependently hydrogen, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、R¹⁰Substituted or unsubstituted C ₁-C₆Alkyl radical, R¹⁰Substituted or unsubstituted 2-to 6-membered heteroalkyl, R¹⁰Substituted or unsubstituted C₅-C₆Cycloalkyl radical, R¹⁰Substituted or unsubstituted 5-to 6-membered heterocycloalkyl, R¹⁰Substituted or unsubstituted phenyl or R¹⁰Substituted or unsubstituted 5-to 6-membered heteroaryl;

R¹⁰is oxo, halogen, -CCl₃、-CBr₃、-CF₃、-CI₃、-CH₂Cl、-CH₂Br、-CH₂F、-CH₂I、-CHCl₂、-CHBr₂、-CHF₂、-CHI₂、-OCCl₃、-OCBr₃、-OCF₃、-OCI₃、-OCH₂Cl、-OCH₂Br、-OCH₂F、-OCH₂I、-OCHCl₂、-OCHBr₂、-OCHF₂、-OCHI₂、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-N₃、R¹¹Substituted or unsubstituted C₁-C₄Alkyl radical, R¹¹Substituted or unsubstituted 2-to 4-membered heteroalkyl, R¹¹Substituted or unsubstituted C₅-C₆Cycloalkyl radical, R¹¹Substituted or unsubstituted 5-to 6-membered heterocycloalkyl, R¹¹Substituted or unsubstituted phenyl or R¹¹Substituted or unsubstituted 5-to 6-membered heteroaryl;

Embodiment 40. the compound of one of embodiments 25 to 39, wherein R¹Is E; and is

E is

Embodiment 41. the compound of one of embodiments 1 to 40, wherein the compound is not

Embodiment 42. a pharmaceutical composition comprising a compound according to one of embodiments 1 to 41 and a pharmaceutically acceptable excipient.

Example 43 a method for the treatment of a disease of the central nervous system associated with dopaminergic neuronal imbalance and/or degeneration in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to one of examples 1 to 41.

The method of embodiment 43, wherein the disease associated with dopaminergic neuronal imbalance and/or degeneration is parkinson's disease, alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction.

Embodiment 45. the method of one of embodiments 43 to 44, wherein the disease associated with dopaminergic neuron imbalance and/or degeneration is parkinson's disease.

Example 46. a method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to one of examples 1 to 41.

The method of embodiment 46, wherein the cancer is breast cancer, pancreatic cancer, bladder cancer, mucoepidermoid cancer, gastric cancer, prostate cancer, colorectal cancer, lung cancer, adrenocortical cancer, or cervical cancer.

Example 48 a method of modulating the level of Nurr1 activity in a subject in need thereof, the method comprising administering to the subject in need thereof an effective amount of a compound according to one of examples 1 to 41.

Example 49 a method of increasing the level of Nurr1 activity of a cell, the method comprising contacting the cell with a compound according to one of examples 1 to 41.

Example 50 a method of increasing dopamine levels in a cell, the method comprising contacting the cell with a compound according to one of examples 1 to 41.

Example 51A pharmaceutical composition comprising 5, 6-Dihydroxyindole (DHI) and a pharmaceutically acceptable excipient.

Example 52 a method for treating a disease of the central nervous system associated with dopaminergic neuronal imbalance and/or degeneration in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of 5, 6-Dihydroxyindole (DHI).

The method of embodiment 52, wherein the disease associated with dopaminergic neuronal imbalance and/or degeneration is parkinson's disease, alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, or drug addiction.

Example 54. a method of treating cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of 5, 6-Dihydroxyindole (DHI).

The method of embodiment 54, wherein the cancer is breast cancer, pancreatic cancer, bladder cancer, mucoepidermoid cancer, gastric cancer, prostate cancer, colorectal cancer, lung cancer, adrenocortical cancer, or cervical cancer.

Examples of the invention

Example 1: nurr1(NR4A2) receptor modulators

Currently, over one million americans suffer from parkinson's disease, and approximately 60,000 new cases are diagnosed each year (Wirdefeldt et al, 2011). In an estimated 90% of PD patients, the cause of the disease is unknown, with no clear genetic or environmental origin (de Lau and Breteler, 2006). The most prominent neuropathological feature of PD is progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta and the consequent reduction of dopamine levels in the striatum, which is manifested by impaired motor function (e.g. rigidity, tremor, bradykinesia) (Samii et al, 2004). Notably, this degeneration appears to be preceded by a loss of the dopaminergic phenotype; that is, at least some dopaminergic neurons first stop producing dopamine and signal before degeneration (Janezic et al, 2013). Although the molecular basis of idiopathic PD is not fully understood, it has been suggested to include oxidative stress, mitochondrial dysfunction and dopamine dyshomeostasis (Blesa et al, 2015; Hauser and Hastings, 2013; Hwang, 2013). Currently, there is no available therapeutic approach to prevent or even slow the progression of PD. Existing therapies alleviate PD symptoms by increasing dopaminergic signaling through one of three mechanisms: (1) increasing dopamine levels by increasing the amount of its biosynthetic precursor L-DOPA; (2) blocking dopamine decomposition by inhibiting dopamine metabolizing enzymes (monoamine oxidase (MAO), COMT); (3) dopamine activity is mimicked by direct agonism of dopamine receptors. However, these drugs only partially alleviate symptoms and can produce significant side effects, especially as the disease progresses. New therapies are urgently needed to combat the symptoms and progression of PD.

Modulators of the activity of the Nurr1 receptor have potential application in the treatment of diseases associated with the imbalance and/or degeneration of dopaminergic neurons in the central nervous system. These diseases include parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, and drug addiction. The focus of the current work is the development of Nurr1 modulators to treat the symptoms and progression of PD (Campos-Melo et al, 2013; Decrsac et al, 2013; Dong et al, 2016; Johnson et al, 2011; Kim et al, 2015). There is also increasing evidence that Nurr1 is a therapeutic target for alzheimer's disease (Moon et al, 2018).

Small molecule modulators of Nurr1 function may be useful for (1) stimulating stem cell development of dopaminergic neurons, (2) supporting the health of mature dopaminergic neurons, (3) preventing degeneration of mature dopaminergic neurons, and (4) stimulating dopamine synthesis in neurons. Diseases affected by these functions include parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, and drug addiction. For most indications, a Nurr1 agonist may be the desired activity. However, the biology of Nurr1 is not fully understood, and antagonists may prove valuable for some indications.

A few putative Nurr1 agonists have been reported in the patent and scientific literature (Dong et al, 2016). With the exception of amodiaquine (Kim et al, 2015), there was little evidence that any of these compounds was directly linked to Nurr 1. The invention identifies ligands that both directly link to Nurr1 and modulate the activity of Nurr1 of a cell.

Herein, small molecules are disclosed that are directly linked to and modulate the activity of the transcription factor nuclear receptor associated protein 1(Nurr1) (also known as NR4a 2). Nurr1 regulates the expression of genes essential for the development, maintenance and survival of dopaminergic neurons (Alavian et al, 2014; Jankovic et al, 2005; Johnson et al, 2011; Kadkhodaei et al, 2009; Luo, 2012; Zettertrom et al, 1997). In particular, Nurr1 plays an important role in maintaining dopamine homeostasis by regulating the transcription of genes controlling dopamine synthesis (TH, tyrosine hydroxylase; DDC, dopa decarboxylase), packaging (SLC18A2, vesicular monoamine transporter 2, VMAT2) and reuptake (DAT, dopamine transporter, also known as SLC6A3) (Hermanson et al, 2003; Iwawaki et al, 2000; Johnson et al, 2011; Sacchetti et al, 2001). Nurr1 also regulates the survival of dopaminergic neurons by stimulating the transcription of genes encoding neurotrophic factors (BDNF, NGF), anti-inflammatory responses (GDNF receptor c-Ret), and oxidative stress management (SOD1) and inhibiting the transcription of pro-inflammatory genes (TNF α, iNOS, IL-1 β) (Gallegullos et al, 2010; Johnson et al, 2011; Kadkhodaiei et al, 2013; Kim et al, 2003; Saijo et al, 2009; Sakurad et al, 1999; Volpicelli et al, 2007). Nurrl is a potential therapeutic target for several diseases associated with dopaminergic neuronal disorders and/or degeneration (e.g., multiple sclerosis, amyotrophic lateral sclerosis, schizophrenia, drug addiction), particularly Parkinson's disease (Campos-Melo et al, 2013; Decressac et al, 2013; Dong et al, 2016; Johnson et al, 2011; Kim et al, 2015). Some evidence also suggests that Nurr1 is a therapeutic target for alzheimer's disease (Moon et al, 2018).

Validation of Nurr1 as a PD therapeutic was primarily from mouse models and human data. Homozygote mice lacking Nurr1 fail to produce midbrain dopaminergic neurons and die shortly after birth, heterozygote mice have dyskinesias similar to Parkinson's disease deficits, and conditional ablation of Nurr1 in adult animals recapitulates the early features of PD with progressive dopaminergic neuropathology (Jiang et al, 2005; Kadhodaei et al, 2013; Kadhodaei et al, 2009; Zettertrom et al, 1997; Zhang et al, 2012). In PD patients, the expression of Nurr1 was reduced compared to age-matched controls (Chu et al, 2006; Le et al, 2008; Montarolo et al, 2016; Moran et al, 2007), although only a few rare polymorphisms in Nurr1 appear to be associated with the disease (Grimes et al, 2006; Le et al, 2003). Stimulation of Nurr1 activity may counteract the decrease in dopamine levels and increase in oxidative stress associated with PD.

Small molecule modulators of Nurr1 activity as described herein were developed as follows. First, the Nurr1 Ligand Binding Domain (LBD) and disulfide capture screen were used to identify 50 compounds that were directly conjugated to Nurr1, undergoing a disulfide exchange reaction with Cys 566. Next, the crystal structures of two (10.25 and 19.49) of the top screening hits covalently linked to Nurr1 were resolved (fig. 1A, fig. 1B), two different ligand binding pockets were defined within the Nurr1 ligand binding domain, and thereby provided a reasonable basis for improving ligand affinity and potency. The structure of Nurr1 linked to a dopamine metabolite was also resolved (Bruning et al, 2019); the metabolite was linked between the sites where the two screening hits were linked. Only another crystal structure of Nurr1 was published and there was no binding ligand (Wang et al, 2003).

Based on these data, analogs of two screening hits (10.25, 19.49) were synthesized and characterized according to their in vitro affinity and potency. Specifically, direct binding to Nurr1 LBD in vitro was measured using micro thermophoresis (MST) and Surface Plasmon Resonance (SPR), and the efficacy of the cells was measured using a luciferase reporter assay (fusion of Nurr1 LBD with Gal4 DBD, measuring the effect on luciferase activity) and a target gene transcription assay (full-length Nurr1, measuring the mRNA level of a particular Nurr1 target gene). These assays indicate a subset of compounds (Table 1, Table 2) that bind directly to Nurr1 LBD (by MST and/or SPR) and produce a ≧ 1.5-fold change in Nurr1 activity in the cell (by Luc and/or TGT assays).

Specifically, 15 compounds derived from screening hits 19.49 were identified that bound to Nurr1 LBD with micromolar affinity in a direct binding assay (MST, SPR) and modulated the activity of Nurr1 in a cellular assay (luciferase reporter assay, target gene transcription assay examining Nurr1, Pitx3, TH, VMAT2 transcripts). Of these 15 compounds, five are apparently agonists. Also identified were 11 compounds derived from screening hits 10.25 that bound to Nurr1 LBD with micromolar affinity in a direct binding assay (MST, SPR) and activated Nurr1 in a luciferase reporter assay. 10.25 analogs are being tested in a target gene transcription assay.

The continuing step of validating the invention (in relation to parkinson's disease) comprises: (1) quantifying the effect of the ligand on Nurr1 target gene transcription of other cells (e.g., SH-SY5Y, MND9 cells, acute dissociated dopaminergic neurons); (2) quantifying the effect of ligand on viable isolated cells in a PD model (e.g., rotenone-and 6-hydroxydopamine-treated cells); (3) quantifying ligand action in a mouse model for parkinson's disease, including blood brain barrier permeability; and (4) development of additional analogs with improved PK/PD properties and affinities as needed.

Example 2: development of Compounds that stabilize Nurr1 in a particular conformation

Efforts to Nurr1 drugs have been largely unsuccessful because of the significant gap in understanding receptor structure and regulation. Specifically, the only reported receptor crystal structure published more than 14 years ago (apo Nurr1) showed that the canonical NR ligand binding pocket was occupied by a bulky amino acid side chain (33). The endogenous ligand of Nurr1 has not been reported, further limiting the understanding of how this receptor is regulated. A small number of synthetic ligands for Nurr1 are described in the scientific and patent literature and reported to upregulate the transcription and protein levels of Nurr1 target genes in vivo; provide a degree of neuroprotection; and improve behavioral deficits in mouse models (7, 20, 38, 39-42). However, there is little evidence that any of these "Nurr 1 agonists" will directly activate the receptor, with the possible exception of recent studies on the antimalarial drug amodiaquine (20). Efforts to indirectly target the drug, Nurr1, RXR in the RXR heterodimer, Nurr1, produced some interesting but contradictory effects, and the exact mechanism of action of RXR agonists to enhance the expression of the Nurr1 target gene is unclear (41, 43, 44). For example, Perlmann showed that the transcriptional activity of Nurr1 itself is reduced when it forms a complex with RXR (45). In any case, strategies targeting the Nurr1: RXR heterodimer do not exclude methods aimed at direct activation of Nurr 1. In addition, it is also of great interest to address whether these two strategies may exhibit synergy. In this context, an orthogonal screening technique called disulfide capture (or tethering) was used in combination with biophysical and structural assays to identify Nurr1 ligands with a defined binding site.

There are five cysteine residues in Nurr1, but only three of them formed adducts in the disulfide capture screen. Specifically, about 50 compounds reacted with Cys566, five reacted with Cys475 (adjacent to Cys566 in LBD), and 10 reacted with Cys534 (on LBD surface). Based on these data, it is expected that the primary site of modification will be Cys566 within LBD.

Crystallographic evidence that disulfide-linked ligands stabilized different conformations of Nurr 1. The crystal structure of two screening hits (10.25 and 19.49) covalently linked to Nurr1 was resolved. While both ligands stabilized head-to-tail Nurr1 homodimers, the overall structure was significantly different. 10.25 homodimers were similar to those of Nur77 (a structurally related member of the NR4A nuclear receptor subfamily (NR)), but the 19.49 homodimer represents a new conformation not previously seen in NR (46, 47). The PISA score (48, 49) for each dimer (1.0 for 10.25, 0.93 for 19.49) indicates that both dimers represent biologically relevant assemblies of protein, rather than a reflection of crystal packing forces. Notably, both structures excluded the formation of Nurr1: RXR heterodimers (assuming that the interaction surface is similar to other RXR heterodimers observed). The spatial arrangement of the NRDNA binding domains (DBDs) linked to the Ligand Binding Domains (LBDs) (and other DNA-related factors) determines which DNA sequences are recognized by the NR complex. Specifically, NR distinguishes binding sites (DNA response elements) by recognizing the orientation and spacing of two DNA half-sites to direct sequence-specific gene activity (50). The full-length structure of the two different RXR: NR heterodimers complexed with DNA underscores this relationship (51, 52). The relative distance between DBDs was inferred from the structure and by measuring the distance between the N-termini, the two Nurr1 homodimers recognized different DNA response elements.

Identification of endogenous Nurr1 ligand. Dopamine is broken down within the neurons that produce it, producing oxygen radicals and other potentially damaging molecules (53). The reactive metabolite comprises 5, 6-Dihydroxyindole (DHI), a compound that spontaneously oxidizes to an active quinone, which is oligomeric in formBecomes a polymer with unknown function (neuromelanin). This polymer explains the black appearance of nigrostriatal neurons in the normal adult CNS (54, 55). Dopamine is also a core participant in stress and addiction (3). Clearly, there is a need to tightly regulate dopamine levels in the CNS. Nurr1 controls all genes required for dopamine synthesis, but its regulation is poorly understood due to the lack of a canonical NR ligand binding pocket and a classical NR co-regulator binding surface for the receptor (33). It is hypothesized that Nurr1 may be regulated by dopamine itself or one of its metabolites, and this possibility was investigated using a combination of biophysical and structural techniques. These data indicate that DHI binds to Nurr1 forming a reversible covalent adduct with Cys 566. Specifically, using Differential Scanning Fluorescence (DSF), DHI (but not dopamine or other metabolites) was found to stabilize Nurr1 LBD, increasing the melting temperature by one degree. Using surface plasmon resonance, DHI was observed to pass K at 5. mu.M _dBinds to Nurr1 and the off-rate is very slow. In addition, the x-ray structure of DHI covalently bound to Nurr1 was resolved. As in the apo structure, proteins crystallize as monomers. The position of Helix 12 is about displaced relative to the apo structureIndicating that the interaction has a physiological effect; helix 12 is a key regulator of classical NR function. The structure shows that DHI, which is likely to react as indoloquinone (DHIQ), forms a covalent adduct with Cys 566. Finally, DHI was shown to be active in cellular assays, stimulating Nurr1 activity and driving transcription of the Nurr1 target gene in live zebrafish in a classical reporter gene assay. DHI drives expression of VMAT (dopamine in packaging vesicles) after acute exposure (6 hours, data not shown) and TH (more dopamine produced) after prolonged exposure (24 hours). The identification of stable analogs of DHI would enable more detailed studies of this interesting biology.

Nurr1 binds to DNA as a monomer, homodimer or heterodimer via retinoid X receptor (RXR α) (11, 56-61). Based on extensive precedent in the NR field (37, 50), it was hypothesized that monomeric, homodimeric and heterodimeric Nurr1 complexes would modulate a discrete subset of the Nurr1 target genes. Nuclear receptors bind to specific DNA sequences (response elements) determined by the spatial relationship between their linked DNA Binding Domains (DBDs), or in the case of monomers, to half-sequences ("half-sites"). The deletion of the Nurr1 pharmacological probe precludes the elucidation of the specific biological functions and target genes regulated by each of its known conformations. Based on preliminary data, the following objective was to develop ligands that bind directly to Nurr1 to specifically modulate the transcription of target genes underlying the development and maintenance of dopaminergic neurons.

The effect of the ligand on the transcription of the Nurr1 target gene was determined. Focus was on developing covalent Nurr1 ligands that can be used to enhance a particular conformational state of Nurr1 within a cell, and then using these probes to identify the gene targets associated with each conformational state. In particular, screening hits have been synthesized in which disulfide electrophiles are substituted with electrophiles suitable for intracellular studies, and the role of these probes in cellular assays is then quantified. Notably, some Nurr1 target genes have a defined tandem NuRE binding element, suggesting that Nurr1 homodimer will increase transcription-but which? Ligands that enhance two distinct Nurr1 homodimer conformations were identified.

Example 3: details of the experiment

Micro thermophoresis (MST) assay. Data were collected using a Nanotemper Monolith nt.115 at a temperature of 25 ℃. The MST buffer used in each experiment was 25mM HEPES (Sigma Aldrich), pH 7.4, 150mM NaCl (Alfa Aesar) and 0.02% Pluronic (Sigma Aldrich). All samples were prepared using protein LoBind tubes or deep well plates (Eppendorf). His-tagged Nurr1 was labeled with RED-tris-NTA dye (NT-647) according to the protocol of the kit (Nanotemper). Dilutions of each ligand were made starting from a 10mM DMSO stock in DMSO. The analyte solution in DMSO was added to an aliquot of MST buffer to generate a DMSO concentration of 4%.

Two types of experiments were performed: endpoint and binding affinity assays. For endpoint determination, equal amounts of ligand solution and labeled Nurr1 were mixed to yield the final concentration: 50nM Nurr1, 25nM RED-tris-NTA dye, 2% DMSO and 25. mu.M, 50. mu.M or 100. mu.M of the desired ligand in MST buffer. The final concentrations used were: negative controls were prepared with 50nM Nurr1, 25nM RED-tris-NTA dye and 2% DMSO in MST buffer. After 5 minutes of incubation, the samples were loaded into Monolith NT.115 fine capillary tubes (nanotepper).

For binding affinity assays, a 1: 1 dilution titration series was prepared starting from an aliquot of 200 μ M ligand in MST buffer, 4% DMSO. These dilutions were made with 4% DMSO in MST buffer for a total of 16 dilutions. Equal amounts of label Nurr1 were added to each dilution of the titration series. After 20 minutes of incubation, the samples were loaded into Monolith NT.115 fine capillary tubes (nanotepper).

Monolith nt.115 was set at 40% excitation power and 40% MST power for all samples. Initial fluorescence was recorded for 3 seconds, and thermophoretic fluorescence response was recorded for 20 seconds. Screening analysis software (Nanotemper) was used to normalize the fluorescence response signal to the initial fluorescence of the sample. From this data, a plot of the fraction of Nurr1 bound to ligand versus ligand concentration. This plot is then used to determine the dissociation constant (K) using the following equation _d)。

Surface plasmon resonance measurement. Data were collected using a Biacore T200(GE) instrument at a flow rate of 30 μ l/min and a temperature of 25 ℃. The running buffer was 25mM HEPES, pH 7.4, 150mM NaCl, 0.05% surfactant Tween 20, and 2% DMSO. Biotinylated Nurr1 LBD was immobilized at sensor chip SA (GE Healthcare Life Sciences); product No. 29104992) or 6000-7000 RU or CAP chip (GE Healthcare Life Sciences; product No. 28920234)1500-2000 RU. Data collection was performed in a kinetic titration mode. Analyte dilutions were made starting from DMSO stock (10 mM). Analytes dissolved in DMSO were added to 1.02x running buffer without DMSO to generate a final DMSO concentration of 2%. When using CAP chips, surface regeneration was performed between each titration curve using 6M guanidine HCl +0.25M NaOH regeneration solution, followed by re-immobilization of Nurr1 (as described in the manufacturer's regeneration protocol). Data processing included double referencing (i.e., buffer injection using the appropriate contact time for a given injection minus the reference flow cell and buffer). Solvent calibration was performed using a standard curve in the range of 1.8-2.3% DMSO.

Luciferase reporter gene assay. pBIND-Nurr1 was generated by cloning Nurr1 LBD (a.a.328-598 of human Nurr 1) into pBIND vector (Promega) E2440. The pBIND vector also contains the renilla luciferase gene under the control of the SV40 promoter, which can be used to normalize transfection efficiency. The firefly luciferase reporter gene pG5-Luc vector (Promega E2440) contains 5 repeats of GAL4UAS (upstream activation sequence) upstream of the luciferase gene. SK-N-BE (2) C cells (ATCC CRL-2268) were transiently transfected with pBIND-Nurr1 and pG5-Luc in 96-well plates at a seeding density of 200,000 cells/ml by FuGENEHD (Promega, E2311). 24 hours after transfection, cells were incubated with the indicated concentration of Nurr1 agonist. After 18 hours, the luminescence of firefly and renilla luciferases was measured by the dual-luciferase reporter assay system (promega E1960).

MN 9D. MN9Dtet-on cells were treated with 10. mu.M of each compound or DMSO (vehicle control) for 6 to 24 hours. Total RNA was isolated using Quick-RNA miniprep Plus (ZYMO Research, Cat.: R1058) and then reverse transcribed using a high capacity cDNA reverse transcription kit (Applied Biosystems, Cat.: 4368814). SYBR Green quantitative real-time PCR analysis was performed using the CFX96 real-time system (BioRad). The following primer pairs were used for qPCR: nurr 1: 5'-CAACTACAGCACAGGCTACGA-3' (SEQ ID NO: 5) and 5'-GCATCTGAATGTCTTCTACCTTAATG-3' (SEQ ID NO: 6), Pitx 3; 5'-GCAACTGGCCGCCCAAGG-3' (SEQ ID NO: 7) and 5'-AGGCCCCACGTTGACCGA-3' (SEQ ID NO: 8), VMAT 2; 5'-GAAGTCCACCTGCTAAGGAAGAA-3' (SEQ ID NO: 9) and 5'-TCACTGGAGACACATGTACACAG-3' (SEQ ID NO: 10), TH; 5'-TCCAACCTTTCCTGGCCCAG-3' (SEQ ID NO: 11) and 5'-GCATGAAGGGCAGGAGGAAT-3' (SEQ ID NO: 12), HPRT; 5'-TGGGAGGCCATCACATTGT-3' (SEQ ID NO: 13) and 5'-AATCCAGCAGGTCAGCAAAGA-3' (SEQ ID NO: 14). Gene expression levels were normalized to housekeeping gene (HPRT) expression levels.

General information: all evaporation was performed in vacuo using a rotary evaporator. Samples were analyzed by vacuum drying (1-5mmHg) at room temperature. Thin Layer Chromatography (TLC) was performed on silica gel plates, and spots were visualized by UV light (214nm and 254 nm). Purification by column chromatography and flash chromatography was performed using silica gel (200-300 mesh). The solvent system is reported by volume as a mixture. All NMR spectra were recorded on a Bruker (Bruker)400(400MHz) spectrometer. Reported as delta values in ppm with deuterated solvents as internal standards¹And H chemical shift. The data are reported as follows: chemical shift, multiplicity (s ═ singlet, d ═ doublet, t ═ triplet, q ═ quartet, br ═ broad, m ═ multiplet), coupling constant (Hz), integral. LCMS spectra were obtained with electrospray ionization on an Agilent (Agilent)1200 series 6110 or 6120 mass spectrometer and the general LCMS conditions were as follows, unless otherwise noted: waterst X Bridge (Waters X Bridge) C18 column (50 mm. times.4.6 mm. times.3.5 um); flow rate: 2.0 ml/min, column temperature: at 40 ℃.

Unless otherwise indicated, all chemical reactions were similarly "worked up" and then purified as follows: the combined organic extracts were dried over anhydrous MgSO₄Dried, filtered, concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography.

General procedure for the synthesis of hydrazides from the corresponding phenoxyacetic acids, carboxylic acids and esters. A solution of phenoxyacetic acid (1mmol) and hydrazine hydrate (5mmol) in EtOH was refluxed for 18-24 hours. The solvent was removed under reduced pressure and the crude product was taken up with CH₂Cl₂Or EtOAc extraction.

General procedure for the synthesis of arylpyrazoles from the corresponding boronic acids and halopyrazoles. Commercially available heteroarylboronic acids (1.1 equiv), [ Pd [ ]₂(dba)₃](0.010 equivalent) and PCy_3n(0.024 eq) was added to a Schlenk flask equipped with a stir bar in air. The flask was evacuated and refilled five times with argon. Dioxane, (hetero) aryl halide (1.0 equivalent; if the halide is a solid, then on a pump-down/refill cycleAddition of the halide before the ring) and K₃PO₄Aqueous solution (1.27M, 1.70 eq). The schlank flask was sealed and heated by vigorous stirring in an oil bath at 100 ℃ for 18 hours. The mixture was then filtered through a pad of silica gel (washed with EtOAc), the filtrate was concentrated under reduced pressure, and the aqueous residue was extracted three times with EtOAc.

General procedure for the synthesis of acrylamide analogs from amines (hydrazine, pyrazole). To an ice-cold solution of amine (1.0 eq) in anhydrous EtOAc was added Et ₃N (1.5 equivalents), followed by addition of acryloyl chloride (1.2 equivalents). The resulting mixture was warmed to ambient temperature and stirred for about 2 hours. When the amine was completely consumed, the reaction mixture was diluted with water and then extracted with EtOAc.

General procedure for the synthesis of sulfonamide analogs from amines (hydrazine, pyrazole). To an amine (1.0 equivalent) and DMAP (0.1 equivalent) in CH₂Cl₂Et (1) to the solution₃N (3.0 equiv.). The mixture was stirred under argon for several minutes until the material dissolved and then cooled to 0 ℃. Next, 2-chloroethanesulfonyl chloride (1.4 equivalents) was added dropwise over several minutes. When the amine is completely consumed, the reaction mixture is diluted with water and then CH₂Cl₂And (4) extracting.

General procedure for the synthesis of alkyl chloride analogs from amines (hydrazine, pyrazole). To an amine (1.0 equivalent) in anhydrous CH₂Cl₂Adding Et to the ice-cooled solution of (1)₃N (1.5 equivalents), followed by addition of acryloyl chloride (1.2 equivalents). The mixture was warmed to ambient temperature and stirred for 2 hours. When the amine is completely consumed, the reaction mixture is diluted with water and then CH₂Cl₂And (4) extracting.

SU20666-0001

Route of SU20666-0001

Synthesis of N-phenyl-2, 2-diphenylpropanamide (SU 20666-0001).

To a stirred solution of 0001-1(200mg, 0.88mmol) in DCM (10ml) were added pentan-1-amine (92mg, 1.06mmol), DIEA (342mg, 2.66mmol) and HATU (504mg, 1.33 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product SU20666-0001(80mg, yield: 31%) as a white solid by preparative HPLC.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 2.220 minutes; MS calculated: 295.2; MS found: 296.3[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 11.484 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.83(3H，t，J＝6.8Hz)，1.12-1.25(4H，m)，1.37-1.41(2H，m)，1.84(3H，s)，3.07(2H，q，J＝6.8Hz)，7.15-7.17(4H，m)，7.21-7.32(7H，m)。

SU20666-0002

Routes of SU20666-0002

Synthesis of 2, 2-diphenyl N-propylpropionamide (SU 20666-0002-2).

To a stirred solution of 0002-1(500mg, 2.2mmol) in DCM (10ml) were added propan-1-amine (157mg, 2.6mmol), DIEA (851mg, 6.6mmol) and HATU (1250mg, 3.3 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative HPLC to yield the desired product SU20666-0002-2 as a white solid (415mg, yield: 70%).

Synthesis of 2, 2-diphenyl N-propylpropionamide (SU 20666-0002).

To a stirred solution of 0002-2(200mg, 0.75mmol) in THF (10mL) was added borane-tetrahydrofuran (1.0N, 4.5mL, 4.5 mmol). The resulting reaction mixture was heated to 50 ℃ and stirred for 16 hours. HCl (1.0N, 3mL) was then added and stirred at room temperature for 1 hour, the aqueous phase was neutralized and then extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0002 as a white solid (15mg, yield: 7.9%).

LC-MS (Agilent LCMS 1200-: 40 ℃; flow rate: 2.0 ml/min; mobile phase: 95% [ Water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 95.01%, and the retention time is 2.786 minutes; MS calculated: 253.2; MS found: 254.3[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2 ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 98.17%, retention time 11.992 minutes.

¹H NMR(400MHz，CDCl₃)δ0.83(3H，t，J＝7.2Hz)，1.39-1.42(3H，m)，1.74(3H，s)，2.54(2H，t，J＝6.8Hz)，3.20(2H，s)，7.16-7.22(6H，m)，7.27-7.30(4H，m)。

SU20666-0003

Routes of SU20666-0003

Synthesis of 2, 2, 2-triphenyl-N-propylacetamide (SU 20666-0003).

To a stirred solution of 0003-1(200mg, 0.7mmol) in DCM (10ml) were added propan-1-amine (49mg, 0.83mmol), DIEA (271mg, 2.1mmol) and HATU (400mg, 1.1 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative HPLC to yield the desired product SU20666-0003 as a white solid (160mg, yield: 70%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 2.245 minutes; MS calculated: 329.2; MS found: 330.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.71(3H，t，J＝7.2Hz)，1.34-1.40(2H，m)，3.08(2H，q，J＝6.8Hz)，7.08(1H，t，J＝5.6Hz)，7.19-7.31(15H，m)。

SU20666-0004

Routes of SU20666-0004

Synthesis of N- (3-hydroxypropyl) -2, 2-diphenylpropanamide (SU 20666-0004).

To a stirred solution of 0004-1(200mg, 0.88mmol) in DCM (10ml) were added 3-aminopropan-1-ol (80mg, 1.1mmol), DIEA (342mg, 2.7mmol) and HATU (504mg, 1.3 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative HPLC to yield the desired product SU20666-0004 as a colorless oil (110mg, yield: 44%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, and the retention time is 1.656 minutes; MS calculated: 283.2, respectively; MS found: 284.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.51-1.58(2H，m)，1.84(3H，s)，3.15(2H，q，J＝6.8Hz)，3.35-3.37(2H，m)，4.38(1H，t，J＝4.8Hz)，7.15-7.17(4H，m)，7.21-7.32(7H，m)。

SU20666-0005

The pathway of SU20666-0005

Synthesis of N-isopentyl-2, 2-diphenylpropanamide (SU 20666-0005).

To a stirred solution of 0005-1(200mg, 0.88mmol) in DCM (10ml) were added 3-methylbutan-1-amine (92mg, 1.1mmol), DIEA (342mg, 2.7mmol) and HATU (504mg, 1.3 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to give the desired product SU20666-0005 as a colorless oil (150mg, yield: 57%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 2.208 min; MS calculated: 295.2; MS found: 296.3[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 minutes), then continued under these conditions for 5 minutes, and finallyBecame 95% in 0.1 minute [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 11.413 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.83(6H，d，J＝6.4Hz)，1.28(2H，q，J＝7.2Hz)，1.43-1.50(1H，m)，1.84(3H，s)，3.10(2H，q，J＝6.4Hz)，7.14-7.16(4H，m)，7.21-7.31(7H，m)。

SU20666-0006

Routes of SU20666-0006

Synthesis of N- (2-cyclohexylethyl) -2, 2-diphenylpropanamide (SU 20666-0006).

To a stirred solution of 0006-1(200mg, 0.88mmol) in DCM (10ml) were added 2-cyclohexylethylamine (174mg, 1.1mmol), DIEA (342mg, 2.7mmol) and HATU (504mg, 1.3 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative HPLC to yield the desired product SU20666-0006 as a white solid (118mg, yield: 40%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 94.91%, and the retention time is 2.406 minutes; MS meterCalculating the value: 335.2; MS found: 336.3[ M + H ]]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.77-0.85(2H，m)，1.06-1.15(2H，m)，1.28(2H，q，J＝6.8Hz)，1.61-1.63(5H，m)，1.83(3H，s)，3.11(2H，q，J＝6.8Hz)，7.15-7.17(4H，m)，7.21-7.25(3H，m)，7.28-7.32(4H，m)。

SU20666-0015

0015-2 pathway

To a stirred solution of 0015-1(1.0g, 6.8mmol) in DMF (20ml) were added isopropyl bromide (878mg, 7.2mmol), Cs₂CO₃(3.3g, 10.2 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and further purified by c.c. to yield the desired product 0015-2 as a colorless oil (1.1g, yield: 85%).

Routes of SU20666-0015

Synthesis of N- (3-bromophenyl) acetamide (0015-4).

To a stirred solution of 0015-3(16.0g, 93.6mmol) in DCM (200ml) were added TEA (11.5g, 112mmol) and Ac₂O (11.5g, 112 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product 0015-4 as a yellow solid (10g, yield: 53%).

Synthesis of N- (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) acetamide (0015-5).

To a stirred solution of compound 3-bromo-5-chloro-1, 2, 4-thiadiazole (0015-4, 10.3g, 48.4mmol) in dioxane (200mL) was added bis (pinacolato) diboron (18.4g, 72.5mmol), KOAc (14.2g, 145.2mmol), pd (dppf) Cl₂(1.7g, 2.42 mmol). The resulting reaction mixture was heated to 85 ℃ and stirred for 16 h, and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to give the desired product 0015-5 as a yellow solid (5.0g, yield: 40%).

Synthesis of N- (3- (1-isopropyl-1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0015).

To a stirred solution of compound 0015-5(206mg, 1.1mmol) in dioxane/water (10mL/2mL) was added 0015-2(226mg,1.2mmol)、K₂CO₃(451mg，3.3mmol)、Pd(dppf)Cl₂(73mg, 0.10 mmol). The resulting reaction mixture was heated to 100 ℃ and stirred for 16 h and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0015 as a yellow solid (100ma, yield: 38%).

LC-MS (LC-MS (Agilent LCMS 1200-6120; column: Watt X bridge C18(30 mm. times.4.6 mm. times.2.7 μm), column temperature: 40 ℃; flow rate: 3.0 ml/min; mobile phase: 95% [ water + 0.05% TFA%]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](0.8 min) then continued under these conditions for 0.4 min, finally becoming 95% in 0.01 min [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％]) Purity: 100%, retention time 0.562 minutes; MS calculated: 243.1; MS found: 244.3[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA% ]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 94.40%, and the retention time was 7.188 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.44(6H，d，J＝6.8Hz)，2.05(3H，s)，4.48-4.55(1H，m)，7.22-7.28(2H，m)，7.38-7.40(1H，m)，7.74(2H，s)，8.10(1H，s)，9.92(1H，s)。

SU20666-0016

Routes of SU20666-0016

Synthesis of 1- (4-fluorophenyl) -1H-pyrazole (0016-2).

To a stirred solution of 0016-1(6.5g, 29mmol) in DMFA (50ml) was added 1H-pyrazole (2.0g, 29mmol), Cs₂CO₃(11.3g, 35mmol) and CuI (0.55g, 2.9 mmol). The resulting reaction mixture was heated to 120 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo whereupon it was further purified by c.c. to yield the desired product 0016-2 as a yellow oil (3.6g, yield: 75%).

Synthesis of 4-bromo-1- (4-fluorophenyl) -1H-pyrazole (0016-3).

To a stirred solution of 0016-2(0.50g, 3.1mmol) in HOAc (10ml) was slowly added Br₂(1.0g, 6.2 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product 0016-3 as a yellow solid (0.70g, yield: 94%).

Synthesis of N- (3- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0016).

To a stirred solution of compound 0016-3(200mg, 0.83mmol) in dioxane/water (10mL/2mL) was added 015-5(220mg, 0.83mmol), K₂CO₃(140mg，0.99mmol)、Pd(dppf)Cl₂(50 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0016 as a white solid (60mg, yield: 25%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, and the retention time is 1.973 minutes; MS calculated: 295.1, respectively; MS found: 296.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ2.06(3H，s)，7.31-7.45(5H，m)，7.85(1H，s)，7.92-7.96(2H，m)，8.08(1H，s)，8.89(1H，s)，9.97(1H，s)。

SU20666-0017 and SU20666-0057

Routes of SU20666-0017

Synthesis of 1-propyl-1H-pyrazol-3-ol (0017-2).

To the solution of 0017-1(1.5g, 17.9mmol) in CH₃CN (50ml) to a stirred solution was added 1-bromopropane (2.2g, 17.9mmol), K₂CO₃(2.7g, 19.6 mmol). The resulting reaction mixture was heated to 80 ℃ for 5 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by c.c. to yield the desired product 0017-2 as a yellow solid (0.40g, yield: 18%).

Synthesis of 4-bromo-1-propyl-1H-pyrazol-3 (2H) -one (0017-3).

To a stirred solution of 0017-2(0.30g, 2.4mmol) in DCM (20ml) was slowly added NaHCO₃(0.24g, 2.8mmol) and Br₂(0.42g, 2.6 mmol). The resulting reaction mixture was stirred at 0 ℃ for 3 hours. Then water was added, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product 0017-3 as a yellow solid (0.40g, yield: 82%).

Synthesis of 2-benzyl-4-bromo-1-propyl-1H-pyrazol-3 (2H) -one (0017-4).

To the solution of 0017-3(0.30g, 1.46mmol) in CH₃CN (20ml) in a stirred solution, K was added₂CO₃(0.22g, 1.6mmol) and BnBr (0.28g, 16 mmol). The resulting reaction mixture was heated to 80 ℃ for 3 hours. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product 0017-4 as a yellow solid (0.38g, yield: 88%).

Synthesis of N- (3- (2-benzyl-3-oxo-1-propyl-2, 3-dihydro-1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0057).

To a solution of compound 0017-4(115mg, 0.39mmol) in dioxane/water (5mL/1mL) was added 015-5(112mg, 0.43mmol), K₃PO₄(155mg，0.58mmol)、Pd(dppf)Cl₂(20 mg). The resulting reaction mixture was heated to 100 ℃ and stirred under microwave conditions for 0.5 h, then concentrated in vacuo to remove the solvent and water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative TLC to give the desired product SU20666-0057 as a white solid (30mg, yield: 22%).

LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.13%, retention time 2.060 minutes; MS calculated: 349.2, respectively; MS found: 350.2[ M + H]⁺。

¹H NMR(400MHz，CDCl₃)δ0.86(3H，t，J＝7.6Hz)，1.78-1.83(2H，m)，2.10(3H，s)，3.87(2H，t，J＝6.8Hz)，5.28(2H，s)，7.02(1H，s)，7.19-7.36(6H，m)，7.42-7.44(3H，m)，7.66(1H，s)。

Synthesis of N- (3- (3-oxo-1-propyl-2, 3-dihydro-1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0017).

To a stirred solution of compound SU20666-0057(30mg, 0.086mmol) in EA/methanol (10mL/2mL) was added Pd/C (10%, 10 mg). The resulting reaction mixture was stirred at room temperature for 2 hours and filtered, the filtrate was concentrated in vacuo to remove the solvent and further purified by preparative HPLC to yield the desired product SU20666-0017 as a white solid (5mg, yield: 23%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.24%, the retention time is 1.399 min; MS calculated: 259.1, respectively; MS found: 260.1[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 98.83%, retention time 6.745 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.84(3H，t，J＝7.2Hz)，1.73-1.78(2H，m)，2.02(3H，s)，3.85(2H，t，J＝6.8Hz)，7.17-7，21(1H，m)，7.25-7.27(1H，m)，7.40-7.42(1H，d，J＝9.2Hz)，7.78-7.82(2H，m)，9.86(1H，s)，10.24(1H，s)。

SU20666-0018

Routes of SU20666-0018

Synthesis of 4-bromo-1- (2-cyclohexylethyl) -1H-pyrazole (0018-2).

To a stirred solution of 0018-1(0.5g, 3.4mmol) in DMF (10ml) was added (2-bromoethyl) cyclohexane (0.78g, 4.1mmol) and K₂CO₃(0.94g, 6.8 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0018-2 as a colorless oil (0.80g, yield: 92%).

Synthesis of N- (3- (1- (2-cyclohexylethyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0018).

To a stirred solution of compound 0018-2(366mg, 1.4mmol) in dioxane/water (10mL/2mL) was added 0015-5(300mg, 1.2mmol), K₂CO₃(322mg，2.3mmol)、Pd(dppf)Cl₂(30 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 16 h, and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0018 as a yellow solid (25mg, yield: 7%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 95.43%, and the retention time is 2.462 minutes; MS calculated: 311.2; MS found: 312.3[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2 ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 99.82%, retention time 10.172 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.93-1.02(2H，q，J＝7.2Hz)，1.13-1.31(4H，m)，1.63-1.82(7H，m)，2.20(3H，s)，4.16(2H，t，J＝7.6Hz)，7.19-7，22(2H，m)，7.28-7.30(2H，m)，7.63(1H，s)，7.73-7.75(2H，m)。

SU20666-0019

Routes of SU20666-0019

Synthesis of 3- (4-bromo-1H-pyrazol-1-yl) propan-1-ol (0019-2).

To a stirred solution of 0019-1(2.7g, 18.2mmol) in DMF (50ml) was added 3-bromopropan-1-ol (2.8g, 20.0mmol) and K₂CO₃(3.8g, 27.3 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0019-2 as a colorless oil (1.7g, yield: 46%).

Synthesis of N- (3- (1- (3-hydroxypropyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0019).

To a stirred solution of compound 0019-2(240mg, 1.2mmol) in dioxane/water (10mL/2mL) was added 0015-5(305mg, 1.2mmol), K₂CO₃(484mg，3.5mmol)、Pd(dppf)Cl₂(80 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated by Preparative HPLC purified the crude product to give the desired product SU20666-0019(49mg, yield: 16%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 95.43%, the retention time is 1.389 minutes; MS calculated: 259.1, respectively; MS found: 260.2[ M + H ]]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.92-1.97(2H，m)，2.05(3H，s)，3.40-3.42(2H，m)，4.18(2H，t，J＝6.8Hz)，4.62(1H，t，J＝5.2Hz)，7.21-7.28(2H，m)，7.38(1H，d，J＝7.2Hz)，7.74-7.76(2H，m)，8.07(1H，s)，9.93(1H，s)。

SU20666-0020

The pathway of SU20666-0020

Synthesis of 3- (4-bromo-1H-pyrazol-1-yl) propionitrile (0020-2).

To a stirred solution of 0020-1(1.5g, 10.2mmol) in DMF (20ml) was added 3-bromopropionitrile (1.6g, 12.2mmol) and K ₂CO₃(2.8g, 20.4 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0020-2 as a yellow oil (1.9g, yield: 92%).

Synthesis of N- (3- (1- (2-cyanoethyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0020).

To a stirred solution of compound 0020-2(200mg, 1.0mmol) in dioxane/water (10mL/2mL) was added 0015-5(260mg, 1.0mmol), K₂CO₃(210mg，1.5mmol)、Pd(dppf)Cl₂(50 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0020 as a white solid (20mg, yield: 8%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.81%, retention time 1.382 minutes; MS calculated: 254.1; MS found: 255.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ2.05(3H，s)，3.20(2H，t，J＝6.4Hz)，4.42(2H，t，J＝6.4Hz)，7.22-7.30(2H，m)，7.38-7.40(1H，m)，7.77(1H，s)，7.85(1H，s)，8.17(1H，s)，9.94(1H，s)。

SU20666-0021

The pathway of SU20666-0021

Synthesis of tert-butyl 2- (((methylsulfonyl) oxy) methyl) morpholine-4-carboxylate (0021-2).

To a stirred solution of 0021-1(700mg, 3.2mmol) in DCM (20ml) at 0 deg.C were added DIEA (1.2g, 9.7mmol) and MsCl (443mg, 3.9 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0021-2 as a yellow oil (500mg, yield: 53%).

Synthesis of tert-butyl 2- ((3- (3-nitrophenyl) -5-propyl-1H-pyrazol-1-yl) methyl) morpholine-4-carboxylate (0021-4).

To a stirred solution of 0021-2(500mg, 1.7mmol) in THF (20ml) was added KI (188mg, 1.1mmol), t-BuOK (190mg, 1.7mmol), TBAI (417mg, 1.1mmol), and 0021-3(261mg, 1.1mmol) at room temperature. The resulting reaction mixture was stirred at 80 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to yield the desired product 0021-4 as a yellow oil (120mg, yield: 25%).

Synthesis of tert-butyl 2- ((3- (3-aminophenyl) -5-propyl-1H-pyrazol-1-yl) methyl) morpholine-4-carboxylate (0021-5).

0021-4(120mg, 0.28mmol) in EtOH/H at room temperature₂To a stirred solution of O (6mL/1mL) were added Fe powder (47mg, 0.84mmol) and NH₄Cl (30mg, 0.56 mmol). The resulting reaction mixture was stirred at 80 ℃ for 2 hours. Water was then added, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative TLC to give the desired product 0021-5 as a yellow oil (80mg, yield: 72%).

Synthesis of tert-butyl 2- ((3- (3-acetamidophenyl) -5-propyl-1H-pyrazol-1-yl) methyl) morpholine-4-carboxylate (0021-6).

To a stirred solution of 0021-5(80mg, 0.20mmol) in DCM (10mL) was added Ac at room temperature₂O (60mg, 0.60 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. Water was then added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative TLC to give the desired product 0021-6 as a yellow oil (50mg, yield: 57%).

Synthesis of N- (3- (1- (morpholin-2-ylmethyl) -5-propyl-1H-pyrazol-3-yl) phenyl) acetamide (SU 20666-0021).

To a stirred solution of compounds 0021-6(50mg, 0.11mmol) in DCM (10mL) was added TFA (1mL) at room temperature. The resulting reaction mixture was further stirred at room temperature for 2 hours, then concentrated in vacuo and purified by preparative HPLC to yield the desired product SU20666-0021(18mg, yield: 46%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.75%, retention time 1.544 minutes; MS calculated: 342.2; MS found: 343.4[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 minutes) and then under these conditions for 5 minutesFinally, it became 95% within 0.1 minute [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 7.564 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.98(3H，t，J＝7.2Hz)，1.63-1.68(2H，m)，2.04(3H，s)，2.62(2H，t，J＝7.6Hz)，2.68-2.71(1H，m)，2.77-2.80(1H，m)，3.06-3.08(1H，m)，3.15-3.20(1H，m)，3.36-3.40(1H，m)，3.61-3.64(2H，m)，3.96(2H，d，J＝6.4Hz)，6.41(1H，s)，7.28(1H，t，J＝8.0Hz)，7.38(1H，d，J＝7.6Hz)，7.56(1H，d，J＝8.0Hz)，7.95(1H，s)，9.97(1H，s)。

SU20666-0022

The pathway of SU20666-0022

Synthesis of 1- (3-nitrophenyl) hex-2-yn-1-one (0022-2).

To a stirred solution of 0022-1(9.2g, 50.0mmol) in THF (150ml) was added TEA (10.0g, 100.0mmol), pent-1-yne (3.4g, 50.0mmol), Pd (PPh)₃)₂Cl₂(0.90g) and CuI (0.50 g). The resulting reaction mixture was stirred at room temperature under an argon atmosphere for 16 hours. Then concentrated to remove the solvent and water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the crude product was purified by c.c. to yield the desired product 0022-2 as a yellow oil (6.8g, yield: 63%).

Synthesis of 3- (3-nitrophenyl) -5-propyl-1H-pyrazole (0022-3).

To a stirred solution of 0022-2(2.0g, 1.7mmol) in acetonitrile (20ml) was added N at room temperature₂H₄(98%, 1.3g, 27.6 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. Water was then added, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by c.c. to yield the desired product 0022-3 as a yellow solid (2.1g, yield: 99%).

Synthesis of 2- ((3- (3-nitrophenyl) -5-propyl-1H-pyrazol-1-yl) methyl) oxazole (0022-4) and 2- ((5- (3-nitrophenyl) -3-propyl-1H-pyrazol-1-yl) methyl) oxazole (0022-4A)

To a stirred solution of 0022-3(500mg, 2.1mmol) in acetonitrile (20mL) was added oxazol-2-ylmethyl methanesulfonate (R) at room temperature₁450mg, 2.6mmol) and K₂CO₃(360mg, 2.6 mmol). The resulting reaction mixture was stirred at 90 ℃ for 16 hours. Then water was added, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to yield the desired product 0022-4 as a yellow solid (200mg, yield: 30%) and product 0022-4A as a yellow solid (30mg, yield: 4.5%).

Synthesis of 3- (1- (oxazol-2-ylmethyl) -5-propyl-1H-pyrazol-3-yl) aniline (0022-5).

0022-4(200mg, 0.64mmol) in EtOH/H at room temperature₂To a stirred solution of O (10mL/2mL) were added Fe powder (180mg, 3.2mmol) and NH₄Cl (170mg, 3.2 mmol). The resulting reaction mixture was stirred at 80 ℃ for 2 hours. Water was then added, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield the desired product 0022-5(160mg, yield: 89%) as a yellow oil.

Synthesis of N- (3- (1- (oxazol-2-ylmethyl) -5-propyl-1H-pyrazol-3-yl) phenyl) acetamide (SU 20666-0022).

To a stirred solution of 0022-5(100mg, 0.35mmol) in DCM (10mL) was added Ac at room temperature₂O (72mg, 0.70 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. Water was then added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to give the desired product SU20666-0022 as a white solid (72mg, yield: 63%).

LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 96.24%, and the retention time is 1.659 minutes; MS calculated: 324.1, respectively; MS found: 325.1[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.96(3H，t，J＝7.2Hz)，1.61-1.67(2H，m)，2.03(3H，s)，2.67(2H，t，J＝7.6Hz)，5.51(2H，s)，6.49(1H，s)，7.22(1H，s)，7.28(1H，t，J＝8.0Hz)，7.38(1H，d，J＝8.0Hz)，7.56(1H，d，J＝8.8Hz)，7.95(1H，s)，8.10(1H，s)，9.96(1H，s)。

SU20666-0026

The pathway of SU20666-0026

Synthesis of methyl 4-bromo-1-propyl-1H-pyrazole-3-carboxylate (0026-2).

To a stirred solution of 0026-1(9.9g, 48.4mmol) in DMF (300ml) were added 1-bromopropane (6.2g, 50.8mmol), Cs₂CO₃(23.0g, 70.5 mmol). The resulting reaction mixture was heated to 60 ℃ for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0026-2(6,1g, yield: 51%) as a colorless oil.

Synthesis of (4-bromo-1-propyl-1H-pyrazol-3-yl) methanol (0026-3).

At room temperature to0026-2(1.2g, 4.88mmol) to a stirred solution of methanol (20mL) LiBH was added₄(153mg, 7.3 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by c.c. to yield the desired product 0026-3 as a colorless oil (1.0g, yield: 94%).

Synthesis of N- (3- (3- (hydroxymethyl) -1-propyl-1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0026-01).

To a solution of compound 0026-3(250mg, 1.2mmol) in dioxane/water (6mL/2mL) was added 015-5(328mg, 1.3mmol), K₂CO₃(476mg，3.4mmol)、Pd(dppf)Cl₂(90 mg). The resulting reaction mixture was heated to 90 ℃ and stirred for 3 hours, then concentrated in vacuo to remove the solvent and water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0026 as a yellow solid (40mg, yield: 13%).

LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 97.28%, the retention time is 1.377 minutes; MS calculated: 273.1; MS found: 274.7[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.86(3H，t，J＝7.6Hz)，1.78-1.84(2H，m)，2.04(3H，s)，4.04(2H，t，J＝6.8Hz)，4.47(2H，d，J＝5.2Hz)，5.04(1H，t，J＝5.2Hz)，7.27-7.29(2H，m)，7.45-7.47(2H，m)，7.69(1H，s)，7.90(1H，s)，9.91(1H，s)。

SU20666-0027 and SU20666-0029

Pathways of SU20666-0027 and SU20666-0029

Synthesis of 4- (3-acetamidophenyl) -1-propyl-1H-pyrazole-3-carboxylic acid methyl ester (0029-2).

To a solution of compound 0026-2(300mg, 1.2mmol) in dioxane/water (50mL/5mL) was added 015-5(317mg, 1.2mmol), K₂CO₃(200mg，1.5mmol)、Pd(dppf)Cl₂(30 mg). The resulting reaction mixture was heated to 90 ℃ and stirred for 3 hours, then concentrated in vacuo to remove the solvent and water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product 0029-2 as a yellow solid (200mg, yield: 54%).

Synthesis of 4- (3-acetamidophenyl) -1-propyl-1H-pyrazole-3-carboxylic acid (SU 20666-0029).

To a stirred solution of 0029-2(60mg, 0.20mmol) in methanol (10mL) was added LiOH (42mg, 1.0mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to yield the desired product SU20666-0029 as a white solid (20mg, yield: 35%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100 percent, and the retention time is 1.369 minutes; MS calculated: 287.1; MS found: 288.3[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2 ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 93.68%, and the retention time was 6.387 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.86(3H，t，J＝7.2Hz)，1.81-1.87(2H，m)，2.03(3H，s)，4.13(2H，t，J＝6.8Hz)，7.09(1H，d，J＝7.6Hz)，7.25(1H，t，J＝7.6Hz)，7.53(1H，d，J＝8.4Hz)，7.61(1H，s)，7.95(1H，s)，9.94(1H，s)。

Synthesis of 4- (3-acetamidophenyl) -1-propyl-1H-pyrazole-3-carboxamide (SU 20666-0027).

To a solution of compound SU20666-0029(60mg, 0.21mmol) in DMF (10mL) was added NH₄Cl (22mg, 0.42mmol), DIEA (134mg, 1.0mmol) and HATU (160mg, 0.42 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0029 as a white solid (25mg, yield: 42%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.70%, retention time 1.392 minutes; MS calculated: 286.1; MS found: 287.1[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.88(3H，t，J＝7.2Hz)，1.82-1.88(2H，m)，2.03(3H，s)，4.10(2H，t，J＝6.8Hz)，7.17-7.25(3H，m)，7.41(1H，s)，7.52(1H，d，J＝8.4Hz)，7.63(1H，s)，7.94(1H，s)，9.92(1H，s)。

SU20666-0033

The pathway of SU20666-0033

Synthesis of 7-bromo-1- (methylsulfonyl) -1, 2, 3, 4-tetrahydroquinoline (0033-2).

To a solution of compound 0033-2(1.0g, 4.7mmol) in DCM (15mL) at 0 deg.C were added DIEA (1.8g, 14.1mmol) and MsCl (0.65g, 5.7 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product 0033-2 as a yellow solid (700mg, yield: 52%).

Synthesis of 4- (3-acetamidophenyl) -1-propyl-1H-pyrazole-3-carboxylic acid (SU 20666-0033).

To a solution of compound 0033-2(200mg, 0.70mmol) in DME/water (5mL/1mL) were added 0033-3(128mg, 0.83mmol), K₂CO₃(193mg, 1.4mmol) and Pd (dppf) Cl₂(20 mg). Subjecting the obtained product toThe reaction mixture was heated to 90 ℃ and stirred under microwave conditions for 0.5 h, then concentrated in vacuo to remove the solvent and water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0033 as a white solid (18mg, yield: 8%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 97.44%, retention time 1.761 minutes; MS calculated: 319.1; MS found: 320.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2 ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 9.338 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.84(3H，t，J＝7.2Hz)，1.78-1.83(2H，m)，1.91-1.94(2H，m)，2.81(2H，t，J＝6.4Hz)，3.00(3H，s)，3.67-3.70(2H，m)，4.05(2H，t，J＝7.2Hz)，7.34-7.38(2H，m)，7.51(1H，d，J＝8.4Hz)，7.82(1H，s)，8.12(1H，s)。

SU20666-0034

The pathway of SU20666-0034

Synthesis of (1-propyl-1H-pyrazol-4-yl) boronic acid (0034-2).

To a solution of compound 0034-2(2.5g, 13.2mmol) in THF (30mL) at-78 deg.C was added n-BuLi (2.5M, 6.3mL, 15.9 mmol). The resulting reaction mixture was stirred at-78 ℃ for 1 hour, then triisopropyl borate (5.0g, 16.4mmol) was slowly added, and then the reaction mixture was stirred at room temperature for 3 hours. Water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product 0034-2(400mg, yield: 30%) as a yellow solid.

Synthesis of 7- (1-propyl-1H-pyrazol-4-yl) quinazoline (SU 20666-0034).

To a solution of compound 0034-2(266mg, 0.86mmol) in DME/water (5mL/1mL) was added 7-bromoquinazoline (300mg, 0.72mmol), K₂CO₃(400mg, 1.4mmol) and Pd (dppf) Cl₂(20 mg). The resulting reaction mixture was heated to 100 ℃ and stirred under microwave conditions for 1 hour, then concentrated in vacuo to remove the solvent and water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0034(12mg, yield: 7%) as a white solid.

LC-MS (Agilent LCMS 1200-Temperature: 40 ℃; flow rate: 2.0 ml/min; mobile phase: 95% [ Water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 97.89%, retention time 1.475 minutes; MS calculated: 238.1; MS found: 239.1[ M + H]⁺。

¹H NMR(400MHz，CDCl₃)δ0.99(3H，t，J＝7.2Hz)，1.95-2.00(2H，m)，4.17(2H，t，J＝7.2Hz)，7.80-7.85(2H，m)，7.91-7.93(1H，m)，7.97(1H，s)，8.10(1H，s)，9.29(1H，s)，9.32(1H，s)。

SU20666-0035

The pathway of SU20666-0035

Synthesis of N- (3-bromophenyl) isobutyramide (0035-2).

To a solution of compound 0035-2(1.0g, 5.8mmol) in DCM (10mL) at 0 deg.C was added TEA (648mg, 6.4mmol) and isobutyryl chloride (650mg, 6.1 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours. Water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product 0035-2 as a white solid (1.2g, yield: 85%).

Synthesis of N- (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) isobutyramide (0035-3).

To a stirred solution of compound 0035-2(240mg, 1.0mmol) in dioxane (5mL) was added bis (pinacolato) diboron (381mg, 1.5mmol), KOAc (294mg, 2.0mmol), pd (dppf) Cl₂(20 mg). The resulting reaction mixture was heated to 85 ℃ and stirred for 16 h and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product 0035-3 as a white solid (230mg, yield: 80%).

Synthesis of N- (3- (1-propyl-1H-pyrazol-4-yl) phenyl) isobutyramide (SU 20666-0035).

To a solution of compound 0035-3(153mg, 0.53mmol) in dioxane/water (3mL/1mL) was added 0035-4(100mg, 0.53mmol), K₂CO₃(146mg, 1.1mmol) and Pd (dppf) Cl₂(20 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 16 hours, then concentrated in vacuo to remove the solvent and water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered And concentrated, and the crude product was purified by preparative HPLC to give the desired product SU20666-0035(70mg, yield: 49%) as a pale yellow solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 97.15%, retention time 1.684 minutes; MS calculated: 271.2; MS found: 272.3[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 97.60%, retention time 8.419 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.85(3H，t，J＝7.2Hz)，1.11(6H，d，J＝6.8Hz)，1.79-1.84(2H，m)，2.59-2.62(1H，m)，4.08(2H，t，J＝6.8Hz)，7.21-7.28(2H，m)，7.40(1H，dt，J＝7.6，1.6Hz)，7.77(1H，s)，7.83(1H，s)，8.09(1H，s)，9.82(1H，s)。

SU20666-0036

Routes of SU20666-0036

Synthesis of 3-bromo-N-methylbenzamide (0036-2).

To a solution of compound 0036-1(4.0g, 19.9mmol) in DCM (10mL) at 0 deg.C were added DIEA (12.8g, 99.5mmol), HATU (11.3g, 29.8mmol), and methylamine hydrochloride (2.7g, 39.8 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product 0036-2 as a colorless oil (4.0g, yield: 94%).

Synthesis of N-methyl-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (0036-3).

To a stirred solution of compound 0036-2(2.0g, 9.3mmol) in dioxane (50mL) was added bis (pinacolato) diboron (4.7g, 18.6mmol), KOAc (1.8g, 18.6mmol), pd (dppf) Cl₂(200 mg). The resulting reaction mixture was heated to 85 ℃ and stirred for 8 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product 0036-3 as a yellow solid (1.4g, yield: 57%).

Synthesis of N-methyl-3- (1-propyl-1H-pyrazol-4-yl) benzamide (SU 20666-0036).

To a solution of compound 0036-3(330mg, 1.27mmol) in dioxane/water (20mL/2mL) was added 4-bromo-1-propyl-1H-pyrazole (200mg, 1.1mmol), K₂CO₃(290mg，21mmol) and Pd (dppf) Cl₂(20 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours, then concentrated in vacuo to remove the solvent and water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0036 as a yellow oil (70mg, yield: 37%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 1.455 min; MS calculated: 243.1; MS found: 244.3[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2 ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 95.41% and a retention time of 7.200 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.85(3H，t，J＝7.6Hz)，1.79-1.85(2H，m)，2.80(3H，d，J＝4.4Hz)，4.09(2H，t，J＝7.2Hz)，7.43(1H，t，J＝7.6Hz)，7.61-7.64(1H，m)，7.69-7.71(1H，m)，7.91(1H，s)，8.00-8.01(1H，m)，8.22(1H，s)，8.44(1H，d，J＝4.4Hz)。

SU20666-0037

The pathway of SU20666-0037

Synthesis of 2-phenyl N-propylpropionamide (SU 20666-0037).

To a solution of compound 0037-1(200mg, 1.3mmol) in DCM (10mL) at 0 deg.C were added DIEA (0.75mL, 4.0mmol), HATU (760mg, 2.0mmol) and propan-1-amine (94mg, 1.6 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product SU20666-0037(96mg, yield: 38%) as a colorless oil.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ] ₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 1.624 minutes; MS calculated: 191.1, respectively; MS found: 192.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.77(3H，t，J＝7.2Hz)，1.30-1.39(5H，m)，2.97(2H，q，J＝6.0Hz)，3.57(1H，q，J＝6.8Hz)，7.18-7.22(1H，m)，7.26-7.32(4H，m)，7.90(1H，s)。

SU20666-0038

The pathway of SU20666-0038

Synthesis of methyl 2- (isoquinolin-6-yl) -2-phenylpropionate (0038-3).

To a solution of compound 0038-1(590mg, 3.6mmol) in toluene (10mL) was added LDA (2.0M, 2.1mL, 4.3mmol) at-78 ℃ and stirred at this temperature for 10 min. Addition of Pd₂(dba)₃(50mg) and 0038-2(500mg, 2.4mmol) and stirred at this temperature for 10 minutes, then t-Bu-containing solution was added₃P (242mg, 1.2mmol) in toluene (10mL) and the resulting reaction mixture was stirred at room temperature for 16 h. Water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product 0038-3(130mg, yield: 18%) as a colorless oil.

Synthesis of 2- (isoquinolin-6-yl) -2-phenylpropionic acid (0038-4).

0038-3(130mg, 0.45mmol) in THF/H at room temperature₂To a stirred solution of O (10mL/2mL) was added LiOH (96mg, 2.2 mmol). Mixing the obtained reactionThe mixture was stirred at room temperature for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to yield the desired product 0038-4(85mg, yield: 69%) as a white solid.

Synthesis of 2- (isoquinolin-6-yl) -2-phenyl N-propylpropionamide (SU 20666-0038).

To a solution of compound 0038-4(85mg, 0.30mmol) in DCM (10mL) was added propan-1-amine (36mg, 0.60mmol), DIEA (190mg, 1.5mmol) and HATU (170mg, 0.45 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0038(41mg, yield: 42%) as a yellow oil.

LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 92.80%, and the retention time is 1.948 minutes; MS calculated: 318.2, respectively; MS found: 319.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.78(3H，t，J＝7.2Hz)，1.40-1.45(2H，m)，1.97(3H，s)，3.07(2H，q，J＝6.4Hz)，7.21-7.36(5H，m)，7.48-7.51(2H，m)，7.66(1H，s)，7.74(1H，d，J＝5.6Hz)，8.02(1H，d，J＝8.8Hz)，8.47(1H，d，J＝5.6Hz)，9.26(1H，s)。

SU20666-0040

The pathway of SU20666-0040

Synthesis of methyl 2- (4-methoxyphenyl-2-phenylpropionate (0040-2).

To a solution of compound 0040-1(600mg, 3.2mmol) in toluene (10mL) was added LDA (2.0M, 2.9mL, 5.8mmol) at-78 ℃ and stirred at this temperature for 10 min. Addition of Pd₂(dba)₃(50mg) and 0038-2(790mg, 4.8mmol) and stirred at this temperature for 10 minutes, then t-Bu-containing solution was added₃P (323mg, 1.6mmol) in toluene (10mL) and the resulting reaction mixture was stirred at room temperature for 16 h. Water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product 0040-2 as a yellow oil (400mg, yield: 46%).

Synthesis of 2- (4-methoxyphenyl-2-phenylpropionic acid (0040-3).

To a stirred solution of 0040-2(400mg, 1.5mmol) in methanol (10mL) was added LiOH (320mg, 7.5mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to yield the desired product 0040-3 as a yellow solid (320mg, yield: 84%).

Synthesis of 2- (4-methoxyphenyl) -2-phenyl N-propylpropionamide (SU 20666-0040).

To a solution of compound 0040-3(100mg, 0.39mmol) in DMF (10mL) was added propan-1-amine (34mg, 0.58mmol), DIEA (150mg, 1.2mmol) and HATU (220mg, 0.58 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0040 as a white solid (53mg, yield: 46%).

LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 2.131 minutes; MS calculated: 297.2, respectively; MS found: 298.4[ M + H ]]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.77(3H，t，J＝7.2Hz)，1.37-1.42(2H，m)，1.81(3H，s)，3.03(2H，q，J＝6.8Hz)，3.73(3H，s)，6.86(2H，d，J＝8.8Hz)，7.08(2H，d，J＝8.8Hz)，7.14(2H，d，J＝8.8Hz)，7.18-7.23(2H，m)，7.27-7.31(2H，m)。

SU20666-0042

The pathway of SU20666-0042

Synthesis of 2-methyl-2-phenyl N-propylpropionamide (SU 20666-0042).

To a solution of compound 0042-1(200mg, 1.2mmol) in DCM (10mL) was added propan-1-amine (86mg, 1.5mmol), DIEA (472mg, 3.7mmol) and HATU (695mg, 1.8 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0042 as a colorless oil (70mg, yield: 28%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 minutes), then under these conditionsThe reaction was continued for 1.4 minutes, and finally became 95% [ water +10mM NH ] in 0.1 minute₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, and the retention time is 1.754 minutes; MS calculated: 205.2; MS found: 206.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.74(3H，t，J＝7.6Hz)，1.33-1.38(2H，m)，1.43(6H，s)，2.98(2H，q，J＝6.8Hz)，7.18-7.22(1H，m)，7.28-7.32(5H，m)。

The designations SU20666-0043, SP 43 and 43 all refer to the same compound having the formula:

the pathway of SU20666-0043

Synthesis of ethyl 2- (3, 4-dichlorophenoxy) acetate (0043-2).

To a stirred solution of 0043-1(4.0g, 24.5mmol) in DMF (40ml) were added ethyl 2-bromoacetate (4.9g, 29.4mmol), Cs ₂CO₃(9.6g, 29.4 mmol). Will be provided withThe resulting reaction mixture was stirred at 100 ℃ for 12 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, further purified by c.c. to yield the desired product 0043-2 as a yellow solid (6.0g, yield: 98%).

Synthesis of 2- (3, 4-dichlorophenoxy) acetic acid (0043-3).

0043-2(6.0g, 24.1mmol) in MeOH/H at room temperature₂To a stirred solution of O (40mL/4mL) was added LiOH (4.6g, 120.5 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to yield the desired product 0043-3 as a yellow solid (4.5g, yield: 85%).

Synthesis of 2- (3, 4-dichlorophenoxy) -N-acetylethylamine (SU-20666-0043).

To a solution of compound 0043-3(200mg, 0.91mmol) in DCM (10mL) was added methylamine hydrochloride (89mg, 1.10mmol), DIEA (348mg, 2.7mmol), and HATU (518mg, 1.4 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0043 as a white solid (149mg, yield: 66%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](1.6 min)In minutes), then continued under these conditions for 1.4 minutes, finally became 95% in 0.1 minute [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 1.871 minutes; MS calculated: 247.0, respectively; MS found: 248.1[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.03(3H，t，J＝7.2Hz)，3.11-3.16(2H，m)，4.51(2H，s)，7.99(1H，dd，J＝9.2，3.2Hz)，7.26(1H，d，J＝3.2Hz)，7.55(1H，d，J＝8.8Hz)，8.13(1H，s)。

The designations SU20666-0044, SP 44 and 44 all refer to the same compound having the formula:

the pathway of SU20666-0044

Synthesis of 2- (3, 4-dichlorophenoxy) N- (2-hydroxyethyl) acetamide (SU-20666-0044).

To a solution of compound 0043-3(200mg, 0.91mmol) in DCM (10mL) was added 2-aminoethanol (67mg, 1.10mmol), DIEA (348mg, 2.7mmol), and HATU (518mg, 1.4 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0044 as a white solid (127mg, yield: 53%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 97.29 percent, and the retention time is 1.607 minutes; MS calculated: 263.0; MS found: 264.1[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ3.20(2H，q，J＝6.0Hz)，3.42(2H，q，J＝6.0Hz)，4.53(2H，s)，4.71(1H，t，J＝5.6Hz)，6.99(1H，dd，J＝8.8，2.8Hz)，7.26(1H，d，J＝2.8Hz)，7.50(1H，d，J＝9.2Hz)，8.07(1H，t，J＝4.8Hz)。

The designations SU20666-0045, SP 45 and 45 all refer to the same compound having the formula:

the pathway of SU20666-0045

Synthesis of N-butyl-2- (3, 4-dichlorophenoxy) acetamide (SU-20666-0045).

To a solution of compound 0043-3(200mg, 0.91mmol) in DCM (10mL) was added butane-1-amine (80mg, 1.10mmol), DIEA (348mg, 2.7mmol), and HATU (518mg, 1.4 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0045 as a white solid (121mg, yield: 48%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 2.073 min; MS calculated: 275.1, respectively; MS found: 276.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.86(2H，t，J＝7.2Hz)，1.22-1.27(2H，m)，1.36-1.42(2H，m)，3.11(2H，q，J＝6.8Hz)，4.52(2H，s)，6.98(1H，dd，J＝8.8，2.8Hz)，7.24(1H，d，J＝2.8Hz)，7.55(1H，d，J＝8.8Hz)，8.07(1H，t，J＝5.2Hz)。

The designations SU20666-0046, SP 46 and 46 all refer to the same compound having the formula:

the pathway of SU20666-0046

Synthesis of 2- (3, 4-dichlorophenoxy) N- (3-morpholinopropyl) acetamide (SU-20666-0046).

To a solution of compound 0043-3(150mg, 0.68mmol) in DCM (10mL) was added 3-morpholinopropan-1-amine (144mg, 0.82mmol), DIEA (258mg, 2.0mmol), and HATU (388mg, 1.0 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0046 as a white solid (94mg, yield: 40%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 1.734 minutes; MS calculated: 346.1, respectively; MS found: 347.1[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.53-1.61(2H，m)，2.22(2H，t，J＝7.2Hz)，2.29-2.33(4H，m)，3.15(2H，q，J＝6.8Hz)，3.55(4H，t，J＝4.8Hz)，4.52(2H，s)，6.98(1H，dd，J＝8.8，2.8Hz)，7.25(1H，d，J＝3.2Hz)，7.55(1H，d，J＝8.8Hz)，8.11(1H，t，J＝5.6Hz)。

The designations SU20666-0047, SP 47 and 47 all refer to the same compound having the formula:

the pathway of SU20666-0047

Synthesis of 1-chloro-N-ethylmethanesulfonamide (0047-2).

To compound 0047-1(1.5g, 1.0mmol) in Et at 0 deg.C₂To a solution in O (15mL) was added ethylamine (2.0M in THF, 12.5mL, 2.5 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product 0047-2 as a colorless oil (600mg, yield: 38%).

Synthesis of 1- (3, 4-dichlorophenoxy) -N-ethylmethanesulfonamide (SU-20666-0047).

To a stirred solution of 3, 4-dichlorophenol (200mg, 1.2mmol) in DMF (10ml) were added 0047-2(230mg, 1.5mmol) and K₂CO₃(339mg, 2.5mm0 l). The resulting reaction mixture was stirred at 60 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and further purified by preparative HPLC to yield the desired product SU-20666-0047 as a yellow solid (25mg, yield: 10%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 94.15%, retention time 1.932 minutes; MS calculated: 283.0; MS found: 282.0[ M-H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2 ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 9.636 min.

¹H NMR(400MHz，CDCl₃)δ1.22-1.27(3H，m)，3.24-3.27(2H，m)，4.44(1H，s)，4.97-4.99(2H，m)，6.92-6.95(1H，m)，7.17-7.18(1H，m)，7.37-7.42(1H，m)。

The designations SU20666-0051, SP 51 and 51 all refer to the same compound having the formula as shown below.

Routes of SU20666-0051 and SU20666-0076

Synthesis of 1-chloro-N-ethylmethanesulfonamide (0051-2).

To a stirred solution of 0051-1(1.0g, 5.7mmol) in DCM (20ml) at 0 deg.C were added TEA (1.2g, 11.4mmol) and MsCl (0.78g, 6.8 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Then water was added, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0051-2 as a yellow oil (1.3g, yield: 90%).

Synthesis of tert-butyl (3- (4-bromo-1H-pyrazol-1-yl) propyl) carbamate (0051-3).

To a stirred solution of 4-bromo-1H-pyrazole (0.74g, 5.1mmol) in acetonitrile (30ml) were added 0051-2(1.3g, 5.1mmol) and K₂CO₃(0.84g, 6.1 mmol). The resulting reaction mixture was stirred at 80 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and further purified by preparative HPLC to yield the desired product 0051-3(0.90g, yield: 58%) as a yellow solid.

Synthesis of tert-butyl (3- (4- (3-acetamidophenyl) -1H-pyrazol-1-yl) propyl) carbamate (0051-4).

To a stirred solution of compound 0051-3(300mg, 0.99mmol) in dioxane/water (10mL/2mL) was added 0015-5(260mg, 0.99mmol), K₂CO₃(164mg，1.2mmol)、Pd(dppf)Cl₂(30 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours, and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product 0051-4 as a yellow solid (150mg, yield: 36%).

Synthesis of N- (3- (1- (3-aminopropyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0076).

To a stirred solution of compound 0051-4(150mg, 0.41mmol) in DCM (10mL) was added TFA (3mL) at room temperature. The resulting reaction mixture was further stirred at room temperature for 2 hours, then concentrated in vacuo and further purified by preparative HPLC to give the desired product SU20666-0076(80mg, yield: 74%) as a yellow solid.

LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.69%, the retention time is 1.454 minutes; MS meterCalculating the value: 258.1; MS found: 259.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.83-1，90(2H，m)，2.04(3H，s)，3.32(2H，s)，4.13-4.19(2H，m)，4.54(2H，s)，7.21-7.28(2H，m)，7.37-7.38(1H，m)，7.74-7.76(2H，m)，8.08-8.11(1H，m)，9.92(1H，s)。

Synthesis of N- (3- (4- (3-acetamidophenyl) -1H-pyrazol-1-yl) propyl) -2- (3, 4-dichlorophenoxy) acetamide (SU 20666-0051).

To a solution of compound 0051-5(80mg, 0.31mmol) in DCM (10mL) was added 0043-3(68mg, 0.31mmol), DIEA (190mg, 1.5mmol), EDCI (88mg, 0.46mmol) and HOBT (62mg, 0.46 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0051 as a white solid (40mg, yield: 24%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 minutes), and then held under these conditionsFor 1.4 minutes, finally become 95% in 0.1 minute [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 96.47%, and the retention time is 1.883 minutes; MS calculated: 460.1; MS found: 461.2[ M + H ]]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.92-2.02(2H，m)，2.04(3H，s)，3.14(2H，q，J＝6.8Hz)，4.13(2H，t，J＝6.8Hz)，4.54(2H，s)，6.99(1H，dd，J＝9.2，3.2Hz)，7.20-7.28(3H，m)，7.37(1H，d，J＝8.0Hz)，7.55(1H，d，J＝8.8Hz)，7.74-7.77(2H，m)，8.08(1H，s)，8.20(1H，t，J＝5.6Hz)，9.92(1H，s)。

The designations SU20666-0052, SP 52 and 52 all refer to the same compound having the formula:

scheme 1: the route of SU20666-0052

Synthesis of 4- ((tert-butoxycarbonyl) amino) butyl methanesulfonate (0052-2).

To a stirred solution of 0052-1(1.0g, 5.3mmol) in DCM (30ml) at 0 deg.C were added TEA (1.0g, 10.6mmol) and MsCl (0.72g, 6.3 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Then water was added, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0052-2(1.2g, yield: 85%) as a yellow oil.

Synthesis of tert-butyl (4- (4-bromo-1H-pyrazol-1-yl) butyl) carbamate (0052-3).

To a stirred solution of 4-bromo-1H-pyrazole (0.65g, 4.5mmol) in acetonitrile (20ml) were added 0052-2(1.2g, 4.5mmol) and K₂CO₃(0.93g, 6.8 mmol). The resulting reaction mixture was stirred at 80 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and further purified by preparative HPLC to yield the desired product 0052-3 as a yellow solid (1.0g, yield: 70%).

Synthesis of tert-butyl (4- (4- (3-acetamidophenyl) -1H-pyrazol-1-yl) butyl) carbamate (0052-4).

To a stirred solution of compound 0052-3(300mg, 0.95mmol) in dioxane/water (20mL/2mL) was added 0015-5(250mg, 0.95mmol), K₂CO₃(200mg，1.4mmol)、Pd(dppf)Cl₂(30 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours, and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product 0052-4 as a yellow solid (160mg, yield: 45%).

Synthesis of N- (3- (1- (4-aminobutyl) -1H-pyrazol-4-yl) phenyl) acetamide (0052-5).

To a stirred solution of compound 0052-4(160mg, 0.43mmol) in DCM (10mL) was added TFA (3mL) at room temperature. The resulting reaction mixture was further stirred at room temperature for 2 hours, and then concentrated in vacuo to give the desired product 0052-5(120mg, yield: 100%) as a yellow solid.

Synthesis of N- (4- (4- (3-acetamidophenyl) -1H-pyrazol-1-yl) butyl) -2- (3, 4-dichlorophenoxy) acetamide (SU 20666-0052).

To a solution of compound 0052-5(110mg, 0.40mmol) in DCM (20mL) was added 0043-3(89mg, 0.40mmol), DIEA (260mg, 2.0mmol), EDCI (115mg, 0.60mmol) and HOBT (82mg, 0.60 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0052 as a white solid (48mg, yield: 25%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.62%, retention time 1.770 min; MS calculated: 474.1; MS found: 475.1[ M + H]⁺。

HPLC (an)Agilent HPLC 1200; column: vortesch X bridge C18(150mm 4.6mm 3.5 μm); column temperature: 40 ℃; flow rate: 1.0 ml/min; mobile phase: 95% [ Water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 9.045 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.38-1.42(2H，m)，1.74-1.79(2H，m)，2.04(3H，s)，3.15(2H，q，J＝8.8Hz)，4.12(2H，t，J＝6.8Hz)，4.52(2H，s)，6.97(1H，dd，J＝8.8，2.8Hz)，7.20-7.28(3H，m)，7.37(1H，d，J＝8.0Hz)，7.53(1H，d，J＝8.8Hz)，7.75(2H，s)，8.07(1H，s)，8.16(1H，t，J＝6.0Hz)，9.92(1H，s)。

The designations SU20666-0053, SP 53 and 53 all refer to the same compound having the formula as shown below. The designations SU20666-0054, SP 54 and 54 all refer to the same compound having the formula as shown below. The designations SU20666-0064, SP 64 and 64 all refer to the same compound having the formula as shown below.

Routes of SU20666-0053, SU20666-0054 and SU20666-0064

Synthesis of tert-butyl (4- (2- (3, 4-dichlorophenoxy) acetylamino) carbamate (SU 20666-0064).

To a solution of compound 0053-1(390mg, 1.8mmol) in DCM (20mL) was added 0043-3(400mg, 2.1mmol), DIEA (684mg, 5.3mmol), EDCI (510mg, 2.7mmol) and HOBT (362mg, 2.6 mmol). The resulting reaction mixture was stirred at room temperature for 16 h, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0064 as a colorless oil (500mg, yield: 58%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.49%, retention time 2.102 minutes; MS calculated: 390.1; MS found: 335.0[ M-56 ]]⁺And 291.0[ M-100 ]]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.32-1.34(2H，m)，1.37(9H，s)，1.37-1.39(2H，m)，2.87-2.91(2H，m)，3.10(1H，q，J＝6.4Hz)，4.51(2H，s)，6.78(1H，t，J＝5.6Hz)，6.98(1H，dd，J＝9.2，2.8Hz)，7.25(1H，d，J＝2.8Hz)，7.55(1H，d，J＝8.8Hz)，8.11(1H，t，J＝5.6Hz)。

Synthesis of N- (4-aminobutyl) -2- (3, 4-dichlorophenoxy) acetamide (SU 20666-0054).

To a stirred solution of compound 0053-2(400mg, 1.03mmol) in DCM (10mL) was added TFA (3mL) at room temperature. The resulting reaction mixture was further stirred at room temperature for 1 hour, then concentrated in vacuo and purified by preparative HPLC to give the desired product SU20666-0054(200mg, yield: 35%) as a colorless oil.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.49%, retention time 1.521 min; MS calculated: 290.1 of the total weight of the mixture; MS found: 291.1[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.23-1.47(6H，m)，3.10(2H，q，J＝6.4Hz)，4.52(2H，s)，6.98(1H，dd，J＝8.8，2.8Hz)，7.25(1H，d，J＝2.4Hz)，7.55(1H，d，J＝8.8Hz)，8.16(1H，t，J＝5.6Hz)。

Synthesis of N- (4- (2- (3, 4-dichlorophenoxy) acetylamino) butyl) -2, 2-diphenylpropanamide (SU 20666-0053).

To a solution of compound SU20666-0054(85mg, 0.29mmol) in DCM (20mL) was added 2, 2-diphenylpropionic acid (55mg, 0.24mmol), DIEA (155mg, 1.2mmol) and HATU (140mg, 0.37 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to give the desired product SU20666-0053 as a colorless oil (26mg, yield: 25%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 97.73 percent, and the retention time is 2.011 minutes; MS calculated: 498.1, respectively; MS found: 499.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.37(4H，brs.)，1.84(3H，s)，3.05-3.11(4H，m)，4.51(2H，s)，6.98(1H，dd，J＝8.8，2.8Hz)，7.14-7.16(4H，m)，7.20-7.31(8H，m)，7.54(1H，d，J＝8.8Hz)，8.11(1H，t，J＝5.6Hz)。

The designations SU20666-0055, SP 55 and 55 all refer to the same compound having the formula:

the route of SU20666-0055

Synthesis of 4-methylpentanamide (0055-2).

To a solution of compound 0055-1(500mg, 4.3mmol) in DCM (20mL) was added thionyl chloride (1.0g, 8.6 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo, then ammonium hydroxide (5mL) was added and stirred at room temperature for an additional 0.5 hours, the aqueous phase was extracted with EA, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product 0055-2 as a white solid (240mg, yield: 48%).

Synthesis of 4-methylpentane-1-amine (0055-3).

To a stirred solution of 0055-2(220mg, 1.9mmol) in THF (5mL) was added borane-tetrahydrofuran (1.0N, 11.5mL, 11.5 mmol). The resulting reaction mixture was heated to 50 ℃ and stirred for 16 hours. HCl (1.0N, 5mL) was then added and stirred at room temperature for 1 hour, the aqueous phase was neutralized and then extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0055-3 as a colorless oil (110mg, yield: 56%).

Synthesis of 2- (3, 4-dichlorophenoxy) N- (4-methylpentyl) acetamide (SU 20666-0055).

To a solution of compound 0055-3(200mg, 0.91mmol) in DCM (10mL) was added 0043-3(110mg, 1.1mmol), DIEA (348mg, 2.7mmol), EDCI (262mg, 1.4mmol) and HOBT (186mg, 1.4 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0055 as a white solid (26mg, yield: 9.5%).

LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mm NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 2.310 minutes; MS calculated: 303.1, and performing a grinding operation; MS found: 304.0[ M + H]⁺。

¹H NMR(400MHz，CDCl₃)δ0.87(6H，d，J＝6.8Hz)，1.17-1.21(2H，m)，1.51-1.57(3H，m)，3.33(2H，q，J＝6.8Hz)，4.46(2H，s)，6.45(1H，brs.)，6.79(1H，dd，J＝8.8，2.8Hz)，7.05(1H，d，J＝2.8Hz)，7.38(1H，d，J＝8.8Hz)。

The designations SU20666-0056, SP 56 and 56 all refer to the same compound having the formula:

the route of SU20666-0056

Synthesis of 2- (3, 4-dichlorophenoxy) N- (3-phenylpropyl) acetamide (SU 20666-0056).

To a solution of compound 0043-3(150mg, 0.68mmol) in DCM (5mL) was added 3-phenylpropan-1-amine (110mg, 0.82mmol), DIEA (258mg, 2.0mmol), and HATU (388mg, 1.0 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0056 as a white solid (42mg, yield: 18%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 2.194 min; MS calculated: 337.1; MS found: 338.1[ M + H]⁺。

HPLC (Agilent HPLC 1200; column:vortesch X bridge C18(150mm 4.6mm 3.5 μm); column temperature: 40 ℃; flow rate: 1.0 ml/min; mobile phase: 95% [ Water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 10.940 minutes.

¹H NMR(400MHz，CDCl₃)δ1.86-1,93(2H，m)，2.66(2H，t，J＝7.2Hz)，3.39(2H，q，J＝6.8Hz)，4.42(2H，s)，6.42(1H，brs.)，6.76(1H，dd，J＝8.8，2.8Hz)，7.03(1H，d，J＝2.8Hz)，7.15-7.20(3H，m)，7.28-7.30(2H，m)，7.37(1H，d，J＝8.8Hz)。

SU20666-0058 and SU20666-0063

Routes of SU20666-0058 and SU20666-0063

Synthesis of 3-propoxy-1H-pyrazole (0017-2A).

To the solution of 0017-1(1.5g, 17.9mmol) in CH₃CN (50ml) to a stirred solution was added 1-bromopropane (2.2g, 17.9mmol), K ₂CO₃(2.7g, 19.6 mmol). The resulting reaction mixture was heated to 80 ℃ for 5 hours. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by c.c. to yield the desired product 0017-2A as a yellow solid (1.0g, yield: 4)4％)。

Synthesis of 4-bromo-3-propoxy-1H-pyrazole (0017-3A).

To a stirred solution of 0017-2A (0.30g, 2.4mmol) in DCM (20ml) was slowly added NaHCO₃(0.24g, 2.8mmol) and Br₂(0.42g, 2.6 mmol). The resulting reaction mixture was stirred at 0 ℃ for 3 hours. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product 0017-3A as a yellow solid (0.42g, yield: 86%).

Synthesis of 1-benzyl-4-bromo-3-propoxy-1H-pyrazole (00174A).

To the solution of 0017-3A (0.30g, 1.46mmol) in CH₃CN (20ml) in a stirred solution, K was added₂CO₃(0.22g, 1.6mmol) and BnBr (0.28g, 1.6 mmol). The resulting reaction mixture was heated to 80 ℃ for 3 hours. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product 0017-4 as a yellow solid (0.40g, yield: 93%).

Synthesis of N- (3- (1-benzyl-3-propoxy-1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0058).

To a solution of compound 0017-4A (150mg, 0.51mmol) in dioxane/water (6mL/1mL) was added 015-5(146mg, 0.56mmol), K₃PO₄(200mg，0.76mmol)、Pd(dppf)Cl₂(30 mg). The resulting reaction mixture was heated to 100 ℃ and stirred under microwave conditions for 0.5 hour, then in vacuoConcentration to remove the solvent and water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative TLC to give the desired product SU20666-0058 as a white solid (20mg, yield: 11%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, and the retention time is 1.869 minutes; MS calculated: 349.2, respectively; MS found: 350.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2 ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 99.47%, retention time 10.083 minutes.

¹H NMR(400MHz，CDCl₃)δ0.98(3H，t，J＝7.6Hz)，1.76-1.81(2H，m)，2.09(3H，s)，4.18(2H，t，J＝6.8Hz)，5.07(2H，s)，7.15-7.33(9H，m)，7.37(1H，s)，7.66(1H，s)。

Synthesis of N- (3- (3-propoxy-1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0063).

To a solution of compound SU20666-0058(45mg, 0.13mmol) in methanolTo a stirred solution of/HOAc (10mL/2mL) was added Pd/C (10%, 20 mg). The reaction mixture obtained is reacted in H₂The mixture was stirred at room temperature under atmosphere (1.0Mpa) for 48 hours and then filtered, the filtrate was concentrated in vacuo to remove the solvent and further purified by preparative HPLC to give the desired product SU20666-0063 as a yellow solid (13mg, yield: 39%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, and the retention time is 1.577 minutes; MS calculated: 259.1, respectively; MS found: 260.2[ M + H ] ]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 100%, retention time 7.539 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.00(3H，t，J＝7.2Hz)，1.75-1.80(2H，m)，2.04(3H，s)，4.16(2H，t，J＝6.4Hz)，7.20-7,24(1H，m)，7.30-7.35(2H，m)，7.88(2H，d，J＝13.2Hz)，9.85(1H，s)，12.01(1H，s)。

The designations SU20666-0059, SP 59 and 59 all refer to the same compound having the formula:

the route of SU20666-0059

Synthesis of 2- (3, 4-dichlorophenoxy) N-phenethylacetamide (SU 20666-0059).

To a solution of compound 0043-3(150mg, 0.68mmol) in DCM (5mL) was added 2-phenylethylamine (100mg, 0.82mmol), DIEA (258mg, 2.0mmol), and HATU (388mg, 1.0 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0059 as a white solid (155mg, yield: 70%).

LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 2.193 min; MS calculated: 323.1; MS found: 324.0[ M + H]⁺。

¹H NMR(400MHz，CDCl₃)δ2.84(2H，t，J＝7.2Hz)，3.61(2H，q，J＝6.8Hz)，4.43(2H，s)，6.46(1H，brs.)，6.69(1H，dd，J＝8.8，2.8Hz)，6.96(1H，d，J＝2.4Hz)，7.14-7.16(2H，m)，7.22-7.24(1H，m)，7.31-7.36(3H，m)。

The designations SU20666-0060, SP 60 and 60 all refer to the same compound having the formula:

the pathway of SU20666-0060

Synthesis of 2- (3, 4-dichlorophenoxy) N- (3, 4-dihydroxyphenylethyl) acetamide (SU 20666-0060).

To a solution of compound 0060-1(86mg, 0.45mmol) in DCM (10mL) was added 0043-3(100mg, 0.45mmol), DIEA (174mg, 1.35mmol), EDCI (128mg, 0.67mmol) and HOBT (91mg, 0.67 mmol). The resulting reaction mixture was stirred at room temperature for 16 h, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to give the desired product SU20666-0060 as a yellow solid (60mg, yield: 32%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, retention time 1.674 min; MS calculated: 355.0, respectively; MS found: 356.0[ M + H ]]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2ODS (150mm 4.6mm 5.0 μm), column temperature 40 ℃ and flow rate 1.0 ml/minA clock; mobile phase: 95% [ Water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 96.78%, retention time 8.331 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.54-2.56(2H，m)，3.23-3.28(2H，m)，4.51(2H，s)，6.42(1H，d，J＝7.6Hz)，6.58-6.63(2H，m)，6.95(1H，dd，J＝8.8，2.8Hz)，7.25(1H，d，J＝2.8Hz)，7.54(1H，d，J＝8.8Hz)，8.14(1H，t，J＝5.2Hz)，8.65(1H，brs.)，8.76(1H，brs.)。

The designations SU20666-0061, SP 61 and 61 all refer to the same compound having the formula:

the pathway of SU20666-0061

Synthesis of 2- (3, 4-dichlorophenoxy) N- (4- (methylsulfonylamino) butyl) acetamide (SU 20666-0061).

To a solution of compound SU20666-0054(100mg, 0.35mmol) in DCM (5mL) at 0 deg.C was added methanesulfonyl chloride (59mg, 0.52mmol) and DIEA (89mg, 0.69 mmol). The resulting reaction mixture was stirred at room temperature for 0.5 h, then water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to give the desired product SU20666-0061 as a white solid (54mg, yield: 42%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 97.57%, retention time 1.785 minutes; MS calculated: 368.0, respectively; MS found: 369.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ] ₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 98.57%, and the retention time was 8.602 minutes.

¹H NMR(400MHz，CDCl₃)δ1.63-1.69(4H，m)，2.96(3H，s)，3.18(2H，q，J＝6.4Hz)，3.39(2H，q，J＝6.4Hz)，4.46(2H，s)，4.54(1H，t，J＝5.6Hz)，6.59(1H，s)，6.80(1H，dd，J＝8.8，2.8Hz)，7.05(1H，d，J＝3.2Hz)，7.38(1H，d，J＝9.2Hz)。

The designations SU20666-0062, SP 62 and 62 all refer to the same compound having the formula:

the pathway of SU20666-0062

Synthesis of methyl 5- (2- (3, 4-dichlorophenoxy) acetylamino) valerate (0062-2).

To a solution of compound 0043-3(250mg, 1.14mmol) in DCM (10mL) at 0 deg.C were added methyl 5-aminopentanoate (230mg, 1.36mmol), DIEA (732mg, 5.68mmol), EDCI (436mg, 2.27mmol), and HOBT (309mg, 2.27 mmol). The resulting reaction mixture was stirred at room temperature for 16 h, then water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to give the desired product 0062-2 as a yellow oil (250mg, yield: 76%).

Synthesis of 5- (2- (3, 4-dichlorophenoxy) acetylamino) pentanoic acid (SU 20666-0062).

To a stirred solution of 0062-2(250mg, 0.75mmol) in methanol (10mL) was added LiOH (210mg, 5.0mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to give the desired product SU20666-0062 as a white solid (33mg, yield: 14%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.07%, retention time 1.394 minutes; MS calculated: 319.0, respectively; MS found: 320.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watt X-bridge C18(150mm 4.6mm 3.5 μm), column temperature 40 ℃ and flow rate 1.0 ml/min(ii) a Mobile phase: 95% [ Water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 96.96%, retention time 6.593 minutes.

¹H NMR(400MHz，MeOD)δ1.60-1.61(4H，m)，2.72-2.30(2H，m)，3.30-3.31(2H，m)，4.53(2H，d，J＝1.2Hz)，6.96-6.99(1H，m)，7.21-7.22(1H，m)，7.45(1H，dd，J＝9.2，1.6Hz)。

The designations SU20666-0065, SP 65 and 65 all refer to the same compound having the formula:

the pathway of SU20666-0065

Synthesis of 2- (1-ethyl-1H-1, 2, 3-triazol-4-yl) propan-2-amine (0065-2).

To compound 0065-1(300mg, 3.60mmol) in THF/H at 0 deg.C ₂To a solution in O (20mL/4mL) were added copper sulfate pentahydrate (440mg, 1.80mmol), sodium L-ascorbate (350mg, 1.80mmol), and ethyl azide (300mg, 4.30 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours, then water was added, the aqueous phase was extracted with DCM, and then the aqueous phase was concentrated to give the desired product 0065-2 as a yellow oil (400mg, yield: 73%), which was used in the next step without further purification.

Synthesis of 3, 5-dichloro-N- (2- (1-ethyl-1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-0065).

To a solution of compound 0065-2(100mg, 0.65mmol) in DCM (10mL) was added 3, 5-dichlorobenzoic acid (124mg, 0.65mmol), DIEA (250mg, 1.95mmol) and HATU (380mg, 0.98 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to give the desired product SU20666-0065 as a white solid (41mg, yield: 19%).

LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.18%, retention time 1.970 min; MS calculated: 326.1, respectively; MS found: 327.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.41(3H，t，J＝7.2Hz)，1.69(6H，s)，4.32(2H，q，J＝7.2Hz)，7.79(1H，t，J＝2.0Hz)，7.85(2H，d，J＝2.0Hz)，7.94(1H，s)，8.59(1H，s)。

The designations SU20666-0066, SP 66 and 66 all refer to the same compound having the formula:

the pathway of SU20666-0066

Synthesis of 1-ethyl-1H-pyrazole-4-carbonitrile (0066-2).

To a solution of compound 0066-1(2.0g, 21.5mmol) in acetonitrile (20ml) were added iodoethane (4.0g, 25.8mmol), K₂CO₃(3.6g, 25.8 mmol). The resulting reaction mixture was stirred at 80 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the crude product was further purified by c.c. to yield the desired product 0066-2 as a yellow oil (2.4g, yield: 92%).

Synthesis of 1- (1-ethyl-1H-pyrazol-4-yl) cyclopropaneamine (0066-3).

To a solution of compound 0066-2(0.6g, 4.9mmol) in THF (10ml) was added Ti (O-iPr) at room temperature₄(1.7g, 5.9mmol), then the mixture was cooled to-78 ℃, ethyl magnesium bromide (1.0M, 12mL, 12.3mmol) was added dropwise and stirred at this temperature for 1 hour, then warmed to room temperature and stirred for an additional 1.5 hours. Adding BF to the reaction mixture₃OEt₂(1.0M，9.8mL，9.8mmol)And then stirred at room temperature for 16 hours. The reaction was then quenched with water, the aqueous phase was extracted with DCM/MeOH (10/1), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0066-3(600mg, yield: 80%, purity: 30%) as a white solid, which was used in the next step without further purification.

Synthesis of 3, 5-dichloro-N- (1- (1-ethyl-1H-pyrazol-4-yl) cyclopropyl) benzamide (SU 20666-0066).

To a solution of compound 0066-3(333mg, purity: 30%, 0.66mmol) in DMF (5mL) were added 3, 5-dichlorobenzoic acid (152mg, 0.79mmol), DIEA (170mg, 1.32mmol) and HATU (380mg, 0.98 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to give the desired product SU20666-0066 as a white solid (79mg, yield: 37%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 96.25%, retention time 1.954 minutes; MS calculated: 323.1; MS found: 324.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100%[CH₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 95.73%, retention time 9.266 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.02-1.05(2H，m)，1.11-1.14(2H，m)，1.31(3H，t，J＝7.2Hz)，4.02(2H，q，J＝7.2Hz)，7.22(1H，s)，7.53(1H，s)，7.80(1H，t，J＝2.0Hz)，7.86(2H，d，J＝2.0Hz)，9.27(1H，s)。

SU20666-0067

The pathway of SU20666-0067

Synthesis of N- (2-morpholinoethyl) -2, 2-diphenylpropanamide (SU 20666-0067).

To a solution of compound 0067-1(200mg, 0.88mmol) in DCM (5mL) was added 0067-2(140mg, 1.06mmol), DIEA (343mg, 2.66mmol) and HATU (504mg, 1.33 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to give the desired product SU20666-0067 as a white solid (188mg, yield: 63%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 1.936 min; MS calculated: 338.2; MS found: 339.1[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.85(3H，s)，2.29-2.35(6H，m)，3.21(2H，q，J＝6.0Hz)，3.48(4H，t，J＝4.4Hz)，6.98(1H，m)，7.19-7.26(6H，m)，7.29-7.33(4H，m)。

SU20666-0068

Scheme 1: the pathway of SU20666-0068

Synthesis of N-phenethyl-2, 2-diphenylpropanamide (SU 20666-0068).

To a stirred solution of compound 0068-1(100mg, 0.44mmol) in DCM (5ml) was added 0068-2(80mg, 0.66mmol), DIEA (170mg, 1.32mmol) and HATU (334mg, 0.88 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product SU20666-0068 as a white solid (20mg, yield: 15.9%).

LC-MS (Anjie)LomcMS 1200 and 6120; column: vortesch X bridge C18(50mm 4.6mm 3.5 μm); column temperature: 40 ℃; flow rate: 2.0 ml/min; mobile phase: 95% [ Water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 94.21 percent, and the retention time is 2.062 minutes; MS calculated: 329.2; MS found: 330.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.81(3H，s)，2.72(2H，t，J＝7.6Hz)，3.32(1H，s)，3.36(1H，d，J＝6.8Hz)，7.09-7.14(6H，m)，7.20-7.30(10H，m)。

SU20666-0069

The pathway of SU20666-0069

Synthesis of 4-bromo-1-phenylethyl-1H-pyrazole (0069-2).

To a solution of compound 0069-1(1.0g, 6.8mmol) in acetonitrile (15ml) was added (2-bromoethyl) benzene (1.5g, 8.2mmol), K₂CO₃(1.1g, 8.2 mmol). The resulting reaction mixture was stirred at 90 ℃ for 12 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the crude product was further purified by c.c. to yield the desired product 0069-2 as a yellow oil (1.2g, yield: 70%).

Synthesis of N- (2-morpholinoethyl) -2, 2-diphenylpropanamide (SU 20666-0069).

To a stirred solution of compound 0069-2(200mg, 0.80mmol) in dioxane/water (10mL/2mL) was added 0015-5(250mg, 0.96mmol), K₂CO₃(220mg，1.60mmol)、Pd(dppf)Cl₂(20 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0069 as a white solid (101mg, yield: 41%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.83%, retention time 1.753 minutes; MS calculated: 305.1; MS found: 306.1[ M + H]⁺。

HPLC (Agilent HPLC)1200; column: vortesch X bridge C18(150mm 4.6mm 3.5 μm); column temperature: 40 ℃; flow rate: 1.0 ml/min; mobile phase: 95% [ Water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 8.690 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.05(3H，s)，3.14(2H，t，J＝7.2Hz)，4.37(2H，t，J＝7.2Hz)，7.18-7.29(7H，m)，7.37(1H，d，J＝8.0Hz)，7.72(1H，s)，7.78(1H，s)，7.98(1H，s)，9.92(1H，s)。

SU20666-0070

Routes of SU20666-0070

Synthesis of 4- (2- (4-bromo-1H-pyrazol-1-yl) ethyl) morpholine (0070-2).

To a solution of compound 0070-1(445mg, 3.0mmol) in acetonitrile (15m1) was added 4- (2-bromoethyl) morpholine (1.0g, 3.6mmol), K₂CO₃(0.50g, 3.6 mmol). The resulting reaction mixture was stirred at 90 ℃ for 12 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the crude product was further purified by c.c. to yield the desired product 0070-2 as a yellow oil (0.50g, yield: 64%).

Synthesis of N- (2-morpholinoethyl) -2, 2-diphenylpropanamide (SU 20666-0070).

To a stirred solution of compound 0070-2(200mg, 0.77mmol) in dioxane/water (10mL/2mL) was added 0015-5(241mg, 0.92mmol), K₂CO₃(212mg，1.64mmol)、Pd(dppf)Cl₂(20 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0070 as a white solid (18mg, yield: 7.5%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 1.383 min; MS calculated: 314.2, respectively; MS found: 315.1[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ2.05(3H，s)，2.40-2.43(4H，m)，2.73(2H，t，J＝6.8Hz)，3.54-3.56(4H，m)，4.25(2H，t，J＝6.8Hz)，7.20-7.28(2H，m)，7.37(1H，d，J＝8.0Hz)，7.75(2H，s)，8.09(1H，s)，9.91(1H，s)。

SU20666-0071

Routes of SU20666-0071

Synthesis of N- (cyclohexylmethyl) -2, 2-diphenylpropanamide (SU 20666-0071).

To a solution of compound 0071-1(200mg, 0.88mmol) in DCM (5mL) were added cyclohexylmethylamine (120mg, 0.88mmol), DIEA (343mg, 2.66mmol) and HATU (504mg, 1.33 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0071 as a white solid (140mg, yield: 49%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.15%, retention time 2.197 min; MS calculated: 321.2, respectively; MS found: 322.2[ M + H]⁺。

¹HNMR(400MHz，DMSO-d₆)δ0.73-0.82(2H，m)，1.05-1.17(3H，m)，1.39-1.46(1H，m)，1.52-1.63(5H，m)，1.85(3H，s)，2.92(2H，t，J＝6.4Hz)，7.15-7.24(7H，m)，7.28-7.32(4H，m)。

SU20666-0072

Routes of SU20666-0072

Synthesis of N- (3, 3-dimethylbutyl) -2, 2-diphenylpropanamide (SU 20666-0072).

To a solution of compound 0072-1(200mg, 0.88mmol) in DCM (5mL) was added 3, 3-dimethylbutan-1-amine (107mg, 1.06mmol), DIEA (343mg, 2.66mmol) and HATU (504mg, 1.33 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to give the desired product SU20666-0072 as a white solid (212mg, yield: 78%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 minutes)) Then continued under these conditions for 1.4 minutes, finally becoming 95% in 0.1 minute [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 2.368 min; MS calculated: 309.2; MS found: 310.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.85(9H，s)，1.29-1.33(2H，m)，1.83(3H，s)，3.07-3.13(2H，m)，7.14-7.16(4H，m)，7.21-7.24(3H，m)，7.28-7.32(4H，m)。

SU20666-0074

Routes of SU20666-0074

Synthesis of ethyl 3- (3-nitrophenyl) -3-oxopropanoate (0074-2).

To a solution of compound LiHMDS (1.0M, 55mL, 63.5mmol) in THF (50mL) at-78 ℃ under an inert atmosphere was added ethyl acetate (2.7mL, 27.6mmol) dropwise, after stirring at this temperature for 0.5 h, 0074-1(5.0g, 27.6mmol) was added and stirring at-78 ℃ for an additional 1 h, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by c.c. to give the desired product 0074-2 as a white solid (5.4g, yield: 82%).

Synthesis of ethyl 3- (3-aminophenyl) -3-oxopropanoate (0074-3).

To compound 0074-2(3.0g, 12.7mmol) in THF/H₂To a solution in O (100mL/50mL) was added sodium dithionite (22.0g, 127.0mmol), the reaction mixture was stirred at 60 ℃ for 2 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to give the desired product 0074-3 as a yellow oil (1.2g, yield: 46%).

Synthesis of ethyl 3- (3-acetamidophenyl) -3-oxopropanoate (0074-4).

To a solution of compound 0074-3(1.2g, 5.8mmol) in DCM (20mL) was added acetic anhydride (0.88g, 8.7mmol) and DIEA (1.50g, 11.6mmol), the reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by c.c. to give the desired product 0074-4 as a yellow oil (0.80g, yield: 56%).

Synthesis of N- (3- (3-morpholino-3-oxopropanoyl) phenyl) acetamide (0074-5).

To a solution of compound 0074-4(0.80g, 3.2mmol) in toluene (5mL) was added morpholine (0.84g, 9.6mmol) and DMAP (0.12g, 0.96mmol), the reaction mixture was stirred at 110 ℃ for 48 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to give the desired product 0074-5 as a brown solid (0.40g, yield: 43%).

Synthesis of N- (3- (5-hydroxy-1-propyl-1H-pyrazol-3-yl) phenyl) acetamide (SU 20666-0074).

To a solution of compound 0074-5(100mg, 0.34mmol) in EtOH (5mL) was added propylhydrazine (77mg, 0.69mmol), the reaction mixture was stirred at room temperature for 16 h, then concentrated, and the crude product was purified by preparative HPLC to give the desired product SU20666-0074 as a white solid (1.2mg, yield: 1.3%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, retention time 1.313 min; MS calculated: 259.1, respectively; MS found: 260.3[ M + H ]]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA) ]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 99.02%, retention time 5.920 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.86(3H，t，J＝7.2Hz)，1.72(2H，q，J＝7.2Hz)，2.03(3H，s)，3.83(2H，t，J＝6.4Hz)，5.65(1H，s)，7.24(1H，t，J＝7.6Hz)，7.31(1H，d，J＝7.6Hz)，7.54(1H，d，J＝8.0Hz)，7.87(1H，s)，9.92(1H，s)。

SU20666-0075

Routes of SU20666-0075

Synthesis of N- (3- (5-hydroxy-1H-pyrazol-3-yl) phenyl) acetamide (SU 20666-0075).

To a solution of compound 0074-5(300mg, 1.0mmol) in piperidine/dioxane (1/19, 10mL) was added N₂H₄(62mg, 1.2mmol) and Lawessons Reagent (Lawessons Reagent) (460mg, 1.1mmol), the reaction mixture was heated to 50 ℃ and stirred for 5 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0075 as a white solid (42mg, yield: 19%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 90.29%, and the retention time is 1.135 minutes; MS calculated: 217.1, respectively; MS found: 218.1[ M + H ]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm); columnTemperature: 40 ℃; flow rate: 1.0 ml/min; mobile phase: 95% [ Water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 97.10%, and the retention time was 4.912 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.05(3H，s)，5.73(1H，s)，7.31-7.34(2H，m)，7.50-7.51(1H，m)，7.81(1H，s)，9.98(1H，s)。

SU20666-0077

Routes of SU20666-0077

Synthesis of 3- (1- (oxazol-2-ylmethyl) -3-propyl-1H-pyrazol-5-yl) aniline (0077-2).

0022-4A (30mg, 0.096mmol) in EtOH/H at room temperature₂To a stirred solution of O (10mL/2mL) were added Fe powder (28mg, 0.48mmol) and NH₄Cl (25mg, 0.48 mmol). The resulting reaction mixture was stirred at 80 ℃ for 2 hours. Then water was added, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product 0077-2(22mg, yield: 81%) as a yellow solid.

Synthesis of N- (3- (1- (oxazol-2-ylmethyl) -3-propyl-1H-pyrazol-5-yl) phenyl) acetamide (SU 20666-0077).

To a stirred solution of 0077-2(22mg, 0.078mmol) in DCM (10mL) was added Ac at room temperature ₂O (16mg, 0.15 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. Water was then added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to give the desired product SU20666-0077 as a white solid (10mg, yield: 40%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 94.96%, and the retention time is 1.757 minutes; MS calculated: 324.1, respectively; MS found: 325.1[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 7.805 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.92(3H，t，J＝6.8Hz)，1.57-1.63(2H，m)，2.05(3H，s)，2.47-2.49(2H，m)，5.37(2H，s)，6.21(1H，s)，7.17(1H，s)，7.21(1H，d，J＝7.6Hz)，7.39(1H，t，J＝8.0Hz)，7.58(1H，d，J＝8.0Hz)，7.75(1H，s)，8.05(1H，s)，10.04(1H，s)。

SU20666-0078

Routes of SU20666-0078

Synthesis of 5-bromo-1-propyl-1H-pyrazol-3-amine (0078-2).

To a solution of compound 0078-1(2.5g, 15.4mmol) in acetonitrile (25mL) was added 1-bromopropane (2.3g, 18.5mmol), K₂CO₃(2.6g, 18.5 mmol). The resulting reaction mixture was stirred at 80 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and further purified by c.c. to yield the desired product 0078-2 as a yellow solid (0.80g, yield: 48%).

Synthesis of 4- (5-bromo-1-propyl-1H-pyrazol-3-yl) morpholine (0078-3).

To a solution of compound 0078-2(500mg, 2.5mmol) in DMF (10mL) was added 1-chloro-2- (2-chloroethoxy) ethane (600mg, 4.2mmol), DIEA (645mg, 5.0 mmol). The resulting reaction mixture was stirred at 110 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and further purified by c.c. to give the desired product 0078-3 as a brown liquid (270mg, yield: 40%).

Synthesis of N- (3- (3-morpholin-1-propyl-1H-pyrazol-5-yl) phenyl) acetamide (SU 20666-0078).

To a stirred solution of compound 0078-3(130mg, 0.48mmol) in dioxane/water (10mL/2mL) was added 0015-5(150mg, 0.57mmol), K₂CO₃(132mg，0.96mmol)、Pd(dppf)Cl₂(20 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0078 as a white solid (78mg, yield: 50%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.33%, the retention time is 1.715 minutes; MS calculated: 328.2; MS found: 329.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2 ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 7.720 minutes.

¹H NMR(400MHz，DMSO-d₆)δ0.74(3H，t，J＝7.6Hz)，1.66-1.71(2H，m)，2.06(3H，s)，3.07-3.09(4H，m)，3.68-3.70(4H，m)，3.86(2H，t，J＝7.6Hz)，5.82(1H，s)，7.07(1H，d，J＝7.6Hz)，7.39(1H，t，J＝7.6Hz)，7.55(1H，d，J＝8.4Hz)，7.73(1H，s)，10.07(1H，s)。

SU20666-0083 and SU20666-0118

Routes of SU20666-0083 and SU20666-0118

Synthesis of N- (3- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) phenyl) acetamide (0083-2).

To a stirred solution of compound 0083-1(500mg, 2.6mmol) in dioxane/water (10mL/2mL) was added 0015-5(1.0g, 3.9mmol), K₂CO₃(1.1g，7.9mmol)、Pd(dppf)Cl₂(100 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to give the desired product 0083-2 as a brown solid (230mg, yield: 36%).

Synthesis of methanesulfonic acid 2- (4- (3-acetamidophenyl) -1H-pyrazol-1-yl) ethyl ester (0083-3).

To a stirred solution of 0083-2(230mg, 0.94mmol) in DCM (5ml) at 0 deg.C were added DIEA (364mg, 2.8mmol) and MsCl (161mg, 1.4 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0083-3(200mg, yield: 66%) as a brown solid.

Synthesis of S- (2- (4- (3-acetamidophenyl) -1H-pyrazol-1-yl) ethyl) acetylthio (0083-4).

To a stirred solution of compound 0083-3(200mg, 0.62mmol) in DMF (5mL) was added potassium thioacetate (106mg, 0.93 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours, and then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product 0083-4(100mg, yield: 54%) as a gray solid.

Synthesis of S- (2- (4- (3-acetamidophenyl) -1H-pyrazol-1-yl) ethyl) acetylthio (SU 20666-0083).

To a stirred solution of compound 0083-4(20mg, 0.066mmol) in methanol (1mL) was added sodium thiomethoxide (7mg, 0.10 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours, and then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0083 as a white solid (2mg, yield: 12%).

LC-MS (Agilent LCMS 1200- ]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](within 1.6 minutes), and then held under these conditionsFor 1.4 minutes, finally become 95% in 0.05 minutes [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 94.26%, and the retention time is 1.441 minutes; MS calculated: 261.1, respectively; MS found: 262.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 95.91% and a retention time of 6.998 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.05(3H，s)，2.38(1H，t，J＝8.4Hz)，2.94(2H，q，J＝7.2Hz)，4.28(2H，t，J＝7.2Hz)，7.22-7.29(2H，m)，7.48(1H，d，J＝7.6Hz)，7.75-7.79(2H，m)，8.11(1H，s)，9.92(1H，s)。

Synthesis of N, N '- ((1, 1' - (dithiodiylbis (ethane-2, 1-diyl)) bis (1H-pyrazole-4, 1-diyl)) bis (3, 1-phenylene)) diacetylamine (SU 20666-0118).

To a stirred solution of compound SU20666-0083(70mg, 0.27mmol) in acetonitrile (3mL) was added TEA (130mg, 1.3 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours, and then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0118 as a white solid (16mg, yield: 11%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ C ]H₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.50%, retention time 1.661 minutes; MS calculated: 520.2 of the basic material; MS found: 521.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ2.04(6H，s)，3.23(4H，t，J＝6.4Hz)，4.42(4H，t，J＝6.4Hz)，7.23-7.26(4H，m)，7.38(2H，d，J＝7.6Hz)，7.75-7.79(4H，m)，8.12(2H，s)，9.92(2H，s)。

The designations SU20666-0085, SU20666-0085-01, SP 85 and 85 all refer to the same compounds having the formula:

routes of SU20666-0085

Synthesis of 2- (3, 4-dichlorophenoxy) N- (2-mercaptoethyl) acetamide (SU 20666-0085).

To a stirred solution of 2- (3, 4-dichlorophenoxy) acetic acid (0085-1, 500mg, 2.3mmol) in dichloromethane (30mL) at 0 deg.C was added oxalyl chloride (1.4g, 11.4mmol) and DMF (0.1 mL). The resulting reaction mixture was stirred at 0 ℃ for 1 hour and concentrated in vacuo, the crude product was dissolved in dichloromethane (30mL), TEA (440mg, 4.4mmol) and 2-aminoethanethiol (340mg, 4.4mmol) were added at 0 ℃ and the reaction mixture was stirred at 0 ℃ for an additional 1 hour. Water (20mL) was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to give the desired product 2- (3, 4-dichlorophenoxy) N- (2-mercaptoethyl) acetamide as a yellow solid (130mg, yield: 22%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](0.8 min) then continued under these conditions for 0.4 min, finally becoming 95% in 0.01 min [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％]) Purity: 98.70%, R_t0.720 min; MS calculated: 279.0, respectively; MS found: 280.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 97.40%, and the retention time was 9.280 minutes.

¹H NMR(400MHz，CDCl₃)δ1.29(1H，t，J＝8.8Hz)，2.62-2.67(2H，m)，3.48(2H，q，J＝6.4Hz)，4.41(2H，s)，6.73(1H，dd，J＝3.2，9.2Hz)，6.82(1H，brs.)，6.99(1H，d，J＝2.8Hz)，7.31(1H，d，J＝8.8Hz)。

The designations SU20666-0087, SU20666-0087-01, SP 87 and 87 all refer to the same compounds having the formula:

the pathway of SU20666-0087

Synthesis of 2- (4- (2-aminopropyl-2-yl) -1H-1, 2, 3-triazol-1-yl) ethanol (0087-2).

To a stirred solution of compound 0087-1(1g, 11.5mmol) in THF/water (30ml/6ml) was added 2-methylbut-3-yn-2-amine (954mg, 11.5mmol), CuSO ₄(1.44g, 5.75mmol) and sodium L-ascorbate (1.14g, 5.75 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. The solvent was then removed, water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0087-2 as a green solid (1.9g, yield: 97.2%).

Synthesis of 3, 5-dichloro-N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (0087-3).

To a stirred solution of compound 0087-2(1.9g, 11.2mmol) in DCM (20ml) were added 3, 5-dichlorobenzoic acid (1.4g, 7.45mmol), DIEA (2.9g, 22.4mmol) and HATU (4.0g, 11.2 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative HPLC to yield the desired product 0087-3 as a white solid (1.5g, yield: 60%).

LC-MS (an)Jieren LCMS 1200-6120; column: vortesch X bridge C18(50mm 4.6mm 3.5 μm); column temperature: 40 ℃; flow rate: 2.0 ml/min; mobile phase: 95% [ Water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 88.81%, and the retention time is 1.700 minutes; MS calculated: 342.0; MS found: 343.2[ M + H]⁺。

Synthesis of 2- (4- (2- (3, 5-dichlorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl methanesulfonate (0087-4).

To a stirred solution of compound 0087-3(1.5g, 4.37mmol) in DCM (15ml) was added MsCl (0.75g, 6.56mmol) and DIEA (1.7g, 13mmol) under ice water. The resulting reaction mixture was stirred at 0 ℃ for 1 hour. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0087-4(1.0g, yield: 54.3%) as a yellow solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](0.8 min) then continued under these conditions for 0.4 min, finally becoming 95% in 0.01 min [ water + 0.05% TFA ]And 5% [ CH ]₃CN+0.05％]) Purity: 75.85%, and the retention time is 0.685 min; MS calculated: 420.0 of the total weight of the mixture; MS found: 421.2[ M + H]⁺。

Synthesis of S-2- (4- (2- (3, 5-dichlorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl thioacetate (0087-5).

To a stirred solution of compound 0087-4(1.0g, 2.4mmol) in DMF (10ml) was added potassium thioacetate (0.32g, 2.9 mmol). The resulting reaction mixture was stirred at room temperature overnight. Water was then added, the aqueous phase was extracted with EA, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0087-5(150mg, yield: 15.8%) as a yellow solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](0.8 min) then continued under these conditions for 0.4 min, finally becoming 95% in 0.01 min [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％]) Purity: 52.77 percent, and the retention time is 0.740 min; MS calculated: 400.0 of; MS found: 401.2[ M + H]⁺。

Synthesis of 3, 5-dichloro-N- (2- (1- (2-mercaptoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-0087).

To a stirred solution of compound 0087-5(150mg, 0.38mmol) in MeOH (5ml) was added NaSCH₃(41mg, 0.57 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. The solvent was then removed, water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative HPLC to give the desired product SU20666-0087 as a brown solid (70mg, yield: 52.2%).

LC-MS (Agilent LCMS 1200-TFA]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](0.8 min) then continued under these conditions for 0.4 min, finally becoming 95% in 0.01 min [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％]) Purity: 97.94%, retention time 1.770 min; MS calculated: 358.0, respectively; MS found: 357.8[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA) ]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 95.82%, retention time 9.038 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，2.43(1H，t，J＝8.0Hz)，2.95(2H，q，J＝7.6Hz)，4.46(2H，t，J＝7.2Hz)，7.78-7.84(3H，m)，7.98(1H，s)，8.60(1H，s)。

SU-20666-0089

Routes of SU20666-0089

Synthesis of ethyl 2- (3, 4-dimethoxyphenyl) acetate (0089-2).

To a solution of 0089-1(5.0g, 25.5mmol) in EtOH (30mL) was added SOCl₂(3.04g, 25.5 mmol). The mixture was stirred at room temperature for 16 hours. Then in vacuumConcentration gave 0089-2 as a yellow solid (4g, 70%).

Synthesis of ethyl 2- (4, 5-dimethoxy-2-nitrophenyl) acetate (0089-3).

To a solution of 0089-2(4, 0g, 14.9mmol) in CH₃HNO was added to a solution in COOH (15mL)₃(5 mL). The mixture was stirred at 0 ℃ to room temperature for 16 hours. Water was then added and the solid was collected to give compound 0089-3(2.5g, 63%) as a yellow solid.

Synthesis of 5, 6-dimethoxy indolin-2-one (0089-4).

To a solution of 0089-3(2.5g, 9.3mmol) in EtOH (15mL) was added Pd/C (10%, 250mg) and the mixture was taken up in H₂The mixture was stirred at room temperature under an atmosphere (1.0atm) overnight. The mixture was filtered and concentrated in vacuo to give a yellow oil. To the oil was added AcOH as solvent (30mL) and the mixture was stirred at 100 ℃ overnight. Then concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give compound 0089-4(950mg, 53%) as a yellow solid.

Synthesis of 5, 6-dimethoxy indoline-2-thioketone (0089-5).

To a solution of 0089-4(350mg, 1.8mmol) in THF (10mL) was added Lawson's reagent (1.4g, 3.6 mmol). The mixture was stirred at room temperature overnight. The solvent was then removed, water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0089-5(105mg, 28%) as a yellow solid.

Synthesis of 5, 6-dihydroxyindoline-2-thione (SU 20666-0089).

To a solution of 0089-5(80mg, 0.38mmol) in DCM (5mL) at-78 deg.C was added BBr₃(0.5mL), the mixture was warmed to room temperature and stirred for 3 hours. Water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the crude product was purified by preparative HPLC to give the desired product SU20666-0089(15mg, 22%) as a yellow solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA) ]And 5% [ CH ]₃CN+0.05％TFA]And under these conditions for 0.7 minutes), purity 100%, retention time 1.083 minutes; MS calculated: 181.0; MS found: 182.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ3.82(s，2H)，6.46(s，1H)，6.68(s，1H)，8.68(s，1H)，9.05(s，1H)，12.26(s，1H)。

SU20666-0090

Routes of SU20666-0090

Synthesis of 1- (2, 4-difluorophenyl) -1H-pyrazole (0090-2).

To a stirred solution of compound 0090-1(3.0g, 16.7mmol) in HCl/EtOH (5ml/20ml) was added 1, 1, 3, 3-tetramethoxypropane (4.1g, 25.0 mmol). The resulting reaction mixture was stirred at 90 ℃ for 24 hours. The solvent was then removed, water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0090-2 as a yellow liquid (2.3g, yield: 76.7%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](0.8 min) then continued under these conditions for 0.4 min, finally becoming 95% in 0.01 min [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％]) Purity: 94.19%, retention time 0.692 min; MS calculated: 180.1 of the total weight of the mixture; MS found: 181.4[ M + H ]⁺。

Synthesis of 4-bromo-1- (2, 4-difluorophenyl) -1H-pyrazole (0090-3).

To a stirred solution of compound 0090-2(500mg, 2.8mmol) in HOAc (8ml) was added Br₂(672mg, 4.2 mmol). The resulting reaction mixture was stirred at room temperature overnight. Then add NaHSO₃(aq.) and water, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0090-3 as a yellow liquid (340mg, yield: 78.5%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 95.86 percent, and the retention time is 1.929 minutes; MS calculated: 258.0; MS found: 259.1[ M + H]⁺。

Synthesis of N- (3- (1- (2, 4-difluorophenyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0090).

To 0090-3(300mg, 1.16mmol) in dioxane/H under an argon atmosphere₂0015-5(455mg, 1.74mmol) and K were added to a solution of O (8ml/2ml) ₂CO₃(480mg, 3.48mmol) and Pd (dppf) Cl₂(50 mg). The mixture was stirred at 100 ℃ for 5 hours. After cooling to room temperature, water was added. The aqueous phase was extracted with DCM (20mL × 3) and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give compound SU20666-0090(50mg, 13.7%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 1.889 minutes; MS calculated: 313.1; MS found: 314.3[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 8.920 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.07(3H，d，J＝6.0Hz)，7.29-7.38(3H，m)，7.48(1H，d，J＝7.6Hz)，7.60(1H，t，J＝2.4Hz)，7.82-7.89(2H，m)，8.14(1H，s)，8.52(1H，d，J＝1.6Hz)，9.98(1H，s)。

SU20666-0091

The pathway of SU20666-0091

Synthesis of 1- (4-fluoro-2-methylphenyl) -1H-pyrazole (0091-2).

1H-pyrazole (1.0g, 15.3mmol), CuI (0.30g), and K were added to a stirred solution of 0091-1(3.0g, 12.7mmol) in DMSO (30ml)₂CO₃(2.6g, 19.0mmol) and L-proline (0.90 g). The resulting reaction mixture was stirred at 90 ℃ for 16 hours. Water (30mL) was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by c.c. to give the desired product 0091-2 as a yellow oil (150mg, yield: 6.7%).

Synthesis of 4-bromo-1- (4-fluoro-2-methylphenyl) -1H-pyrazole (0091-3).

To a stirred solution of 0091-2(300mg, 1.7mmol) in HOAc (10ml) was slowly added Br2(820mg, 5.1 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product 0091-3 as a yellow oil (300mg, yield: 70%).

Synthesis of N- (3- (1- (4-fluoro-2-methylphenyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0091).

To a stirred solution of compound 0091-3(150mg, 0.59mmol) in dioxane/water (10mL/2mL) was added 015-5(231mg, 0.89mmol), K₂CO₃(244mg，1.77mmol)、Pd(dppf)Cl₂(20 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0091 as a white solid (25mg, yield: 14%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 1.894 minutes; MS calculated: 309.1, respectively; MS found: 310.4[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mm 4.6mm 3.5 μm) and column temperature 40DEG C; flow rate: 1.0 ml/min; mobile phase: 95% [ Water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 8.926 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.06(3H，s)，2.25(3H，s)，7.20(1H，dt，J＝8.8，2.8Hz)，7.28-7.35(3H，m)，7.44-7.49(2H，m)，7.81(1H，s)，8.04(1H，s)，8.40(1H，s)，9.96(1H，s)。

SU20666-0092

Routes of SU20666-0092

Synthesis of 1- (2-chloro-4-fluorophenyl) -1H-pyrazole (0092-2).

To a stirred solution of 0092-1(1.0g, 5.0mmol) in EtOH (20mL) was slowly added 1, 1, 3, 3-tetramethoxypropane (1.3g, 7.6mmol) and HCl (10.0N in water, 5 mL). The resulting reaction mixture was stirred at 90 ℃ for 16 hours, and then concentrated in vacuo, and the crude product was further purified by c.c. to yield the desired product 0092-2 as a yellow oil (960mg, yield: 98%).

Synthesis of 4-bromo-1- (2-chloro-4-fluorophenyl) -1H-pyrazole (0092-3).

To a stirred solution of 0092-2(960mg, 4.9mmol) in HOAc (10ml) was slowly added Br2(784mg, 4.9 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was further purified by c.c. to yield the desired product 0092-3 as a yellow solid (800mg, yield: 59%).

Synthesis of N- (3- (1- (4-fluoro-2-methylphenyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0092).

To a stirred solution of compound 0092-3(270mg, 1.0mmol) in dioxane/water (10mL/2mL) was added 015-5(311mg, 1.2mmol), K₂CO₃(206mg，1.5mmol)、Pd(dppf)Cl₂(70 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0092(58mg, yield: 18%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.32%, retention time 1.883 minutes; MS calculated: 329.1 of (a); MS found: 330.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watt-X bridge C18(150 mm. times.4.6) mm 3.5 μm); column temperature: 40 ℃; flow rate: 1.0 ml/min; mobile phase: 95% [ Water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 9.135 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.05(3H，s)，7.29-7.36(2H，m)，7.41-7.48(2H，m)，7.71-7.76(2H，m)，7.81(1H，s)，8.10(1H，s)，8.48(1H，s)，9.98(1H，s)。

SU20666-0093

The pathway of SU20666-0093

Synthesis of 3- (1H-pyrazol-1-yl) pyridine (0093-2).

To a stirred solution of 0093-1(2.0g, 12.7mmol) in acetonitrile (30ml) was added 1H-pyrazole (1.3g, 19.1mmol), Cs₂CO₃(6.5g, 20.0mmol), CuO (0.10g) and salicylaldehyde-oxime (0.35g, 2.5 mmol). The resulting reaction mixture was stirred at 80 ℃ for 24 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo whereupon it was further purified by c.c. to yield the desired product 0093-2 as a yellow oil (0.65g, yield: 35%).

Synthesis of 3- (4-bromo-1H-pyrazol-1-yl) pyridine (0093-3).

To a stirred solution of 0093-2(350mg, 2.4mmol) in acetonitrile (8ml) was added NBS (560mg, 3.1 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was further purified by c.c. to yield the desired product 0093-3(500mg, yield: 93%) as a yellow solid.

Synthesis of N- (3- (1- (pyridin-3-yl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0093).

To a stirred solution of compound 0093-3(350mg, 1.6mmol) in dioxane/water (10mL/2mL) was added 015-5(615mg, 2.4mmol), K₂CO₃(650mg，4.7mmol)、Pd(dppf)Cl₂(50 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 5 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0093 as a white solid (40mg, yield: 9.1%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, retention time 1.340 min; MS calculated: 278.1; MS found: 279.3[ M + H]⁺。

HPLC (an)Agilent HPLC 1200; column: l-column 2 ODS (150mm 4.6mm 5.0 μm); column temperature: 40 ℃; flow rate: 1.0 ml/min; mobile phase: 95% [ Water + 0.1% TFA% ]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 98.38% and a retention time of 6.634 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.07(3H，s)，7.33-7.40(2H，m)，7.45(1H，d，J＝7.6Hz)，7.58(1H，dd，J＝8.4，4.8Hz)，7.87(1H，s)，8.17(1H，s)，8.30(1H，d，J＝8.4Hz)，8.55(1H，d，J＝4.0Hz)，9.02(1H，s)，9.18(1H，d，J＝2.4Hz)，10.01(1H，s)。

The designations SU20666-0094, SP 94 and 94 all refer to the same compound having the formula:

the pathways of SU20666-0094

Synthesis of N-benzyl-2- (3, 4-dichlorophenoxy) acetamide (SU 20666-0094).

To a solution of compound 0094-1(100mg, 0.45mmol) in DCM (5mL) was added benzylamine (58mg, 0.54mmol), DIEA (176mg, 1.36mmol), and HATU (259mg, 0.68 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0094 as a white solid (20mg, yield: 14%).

LC-MS (Agilent LCMS 1200-Phase (1): 95% [ Water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ] ₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 2.139 minutes; MS calculated: 309.0, respectively; MS found: 310.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ4.32(2H，d，J＝6.4Hz)，4.61(2H，s)，6.99(1H，dd，J＝8.8，2.8Hz)，7.21-7.30(6H，m)，7.53(1H，d，J＝8.8Hz)，8.66(1H，t，J＝5.6Hz)。

The designations SU20666-0095, SP 95 and 95 all refer to the same compound having the formula:

routes of SU20666-0095

Synthesis of 2- (3, 4-dichlorophenoxy) N- (3, 4-dihydroxybenzyl) acetamide (SU 20666-0095).

To a solution of compound 0043-3(100mg, 0.45mmol) in DMF (5mL) was added 4- (aminomethyl) benzene-1, 2-diol (63mg, 0.45mmol), DIEA (174mg, 1.35mmol), EDCI (130mg, 0.67mmol) and HOBT (91mg, 0.67 mmol). The resulting reaction mixture was stirred at room temperature for 16 h, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0095 as a white solid (15mg, yield: 9.6%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, retention time 1.650 minutes; MS calculated: 341.0, and the other end is connected with the power supply; MS found: 342.1[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 100%, retention time 8.169 minutes.

¹H NMR(400MHz，DMSO-d₆)δ4.15(2H，d，J＝6.0Hz)，4.57(2H，s)，6.49(1H，dd，J＝8.0，2.0Hz)，6.63-6.66(2H，m)，6.99(1H，dd，J＝9.2，3.2Hz)，7.26(1H，d，J＝2.8Hz)，7.54(1H，d，J＝8.8Hz)，8.52(1H，t，J＝6.0Hz)，8.74(1H，s)，8.82(1H，s)。

The designations SU20666-0096, SP 96 and 96 all refer to the same compound having the formula:

routes of SU20666-0096

Synthesis of 2- (3, 4-dichlorophenoxy) N- (2, 3-dihydroxybenzyl) acetamide (SU 20666-0096).

To a solution of compound 0043-3(100mg, 0.45mmol) in DMF (5mL) was added 3- (aminomethyl) benzene-1, 2-diol (63mg, 0.45mmol), DIEA (174mg, 1.35mmol), EDCI (173mg, 0.90mmol) and HOBT (121mg, 0.90 mmol). The resulting reaction mixture was stirred at room temperature for 16 h, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0096 as a white solid (15mg, yield: 9.6%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, retention time 1.751 minutes; MS calculated: 341.0, and the other end is connected with the power supply; MS found: 342.1[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 100%, retention time 8.839 minutes.

¹H NMR(400MHz，DMSO-d₆)δ4.27(2H，d，J＝6.0Hz)，4.62(2H，s)，6.52-6.58(2H，m)，6.68(1H，dd，J＝7.6，2.0Hz)，7.01(1H，dd，J＝8.8，2.8Hz)，7.28(1H，d，J＝3.2Hz)，7.55(1H，d，J＝8.8Hz)，8.52(1H，t，J＝5.6Hz)，8.60(1H，s)，9.19(1H，s)。

The designations SU20666-0097, SP 97 and 97 all refer to the same compound having the formula:

the pathway of SU20666-0097

Synthesis of 1-azido-4-fluorobenzene (0097-2).

To 0097-1(500mg, 2.3mmol) in acetone/H₂To a stirred solution of O (20mL/3mL) were added sodium azide (176mg, 2.7mmol) and Na ₂CO₃(49mg, 0.45mmol) and L-proline (52mg, 0.45 mmol). The resulting reaction mixture was stirred at 60 ℃ for 8 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0097-2 as a colorless oil (290mg, yield: 94%).

Synthesis of 2- (1- (4-fluorophenyl) -1H-1, 2, 3-triazol-4-yl) propan-2-amine (0097-3).

To compound 0097-2(290mg, 2.1mmol) in THF/H at 0 deg.C₂To a solution of copper sulfate pentahydrate (523mg, 2.1mmol), sodium L-ascorbate (220mg, 1.1mmol) and 2-methylbut-3-yne in O (20mL/4mL) was added-2-amine (174mg, 2.1 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours, then water was added, the aqueous phase was extracted with DCM, and then the aqueous phase was concentrated to give the desired product 0097-2(160mg, yield: 34%) as a yellow oil, which was used in the next step without further purification.

Synthesis of 3, 5-dichloro-N- (2- (1- (4-fluorophenyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-0097).

To a solution of compound 0097-3(160mg, 0.73mmol) in DMF (5mL) was added 3, 5-dichlorobenzoic acid (63mg, 0.73mmol), DIEA (283mg, 2.20mmol) and HATU (466mg, 1.10 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0097 as a white solid (130mg, yield: 42%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 94.83%, retention time 2.364 minutes; MS calculated: 392.1, respectively; MS found: 393.2[ M + H ]]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 minutes) and then held under these conditionsFor 5 minutes, finally become 95% in 0.1 minute [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 98.30% and a retention time of 10.888 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.76(6H，s)，7.45(2H，t，J＝8.8Hz)，7.80(1H，d，J＝2.0Hz)，7.87(2H，d，J＝2.0Hz)，7.96(2H，dd，J＝9.2，4.8Hz)，8.68(1H，s)，8.72(1H，s)。

The designations SU20666-0098, SP 98 and 98 all refer to the same compound having the formula:

the pathway of SU20666-0098

Synthesis of 2- (1-benzyl-1H-1, 2, 3-triazol-4-yl) propan-2-amine (0098-2).

To compound 0098-2(500mg, 6.0mmol) in THF/H at 0 deg.C ₂To a solution of copper sulfate pentahydrate (750mg, 3.0mmol), sodium L-ascorbate (600mg, 3.0mmol) and (azidomethyl) benzene (800mg, 6.0mmol) in O (20mL/4mL) was added. The resulting reaction mixture was stirred at room temperature for 16 h, then water was added, the aqueous phase was extracted with DCM, then the aqueous phase was concentrated to give the desired product 0098-2(600mg, crude product) as a yellow oil, which was used in the next step without further purification.

Synthesis of N- (2- (1-benzyl-1H-1, 2, 3-triazol-4-yl) propan-2-yl) -3, 5-dichlorobenzamide (SU 20666-0098).

To a solution of compound 0098-2(500mg, 1.3mmol) in DMF (5mL) was added 3, 5-dichlorobenzoic acid (240mg, 1.3mmol), DIEA (484mg, 3.8mmol) and HATU (714mg, 1.9 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0098(110mg, yield: 19%) as a white solid.

LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.53%, retention time 2.140 minutes; MS calculated: 388.1, respectively; MS found: 389.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.69(6H，s)，5.54(2H，s)，7.29-7.37(5H，m)，7.78(1H，t，J＝2.0Hz)，7.83(2H，d，J＝2.0Hz)，8.01(1H，s)，8.60(1H，s)。

The designations SU20666-0099, SP 99 and 99 all refer to the same compound having the formula:

the pathway of SU20666-0099

Synthesis of (2-azidoethyl) benzene (0099-2).

To a stirred solution of 0099-1(0.60g, 3.3mmol) in DMF (10ml) was added sodium azide (0.43g, 6.6 mmol). The resulting reaction mixture was stirred at 80 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0099-2(0.40g, yield: 83%) as a yellow oil.

Synthesis of 2- (1-phenethyl-1H-1, 2, 3-triazol-4-yl) propan-2-amine (0099-3).

To compound 0099-2(0.40g, 2.7mmol) in THF/H at 0 deg.C₂To a solution of copper sulfate pentahydrate (0.67g, 2.7mmol), sodium L-ascorbate (0.27g, 1.3mmol) and 2-methylbut-3-yn-2-amine (0.23g, 2.7mmol) in O (20mL/4mL) was added. The resulting reaction mixture was stirred at room temperature for 16 hours, then water was added, the aqueous phase was extracted with DCM, and then the aqueous phase was concentrated to give the desired product 0099-3(0.12g, yield: 19%) as a yellow oil, which was used in the next step without further purification.

Synthesis of 3, 5-dichloro-N- (2- (1-phenethyl-1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-0099).

To a solution of compound 0099-3(120mg, 0.52mmol) in DMF (5mL) was added 3, 5-dichlorobenzoic acid (99mg, 0.52mmol), DIEA (200mg, 1.56mmol) and HATU (300mg, 0.78 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0099(56mg, yield: 27%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.29%, and the retention time is 2.164 minutes; MS calculated: 402.1; MS found: 403.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.67(6H，s)，3.12(2H，t，J＝7.6Hz)，4.53(2H，t，J＝7.6Hz)，7.16-7.25(5H，m)，7.79(1H，t，J＝2.0Hz)，7.83-7.85(3H，m)，8.01(1H，s)，8.58(1H，s)。

The designations SU20666-0100, SP 100 and 100 all refer to the same compound having the formula:

routes of SU20666-0100

Synthesis of 3, 4-dichlorophenethylmethanesulfonate (100-2).

To a stirred solution of 100-1(800mg, 4.2mmol) in DCM (10ml) at 0 deg.C were added TEA (850mg, 8.4mmol) and MsCl (720mg, 6.3 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 100-2 as a yellow oil (1.0g, yield: 89%).

Synthesis of 4- (2-azidoethyl) -1, 2-dichlorobenzene (100-3).

To a stirred solution of 100-2(1.0g, 3.7mmol) in DMF (10ml) was added sodium azide (0.49g, 7.4 mmol). The resulting reaction mixture was stirred at 80 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with EA, and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 100-3 as a yellow solid (0.70g, yield: 87%).

Synthesis of 2- (1- (3, 4-dichlorophenethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-amine (100-4).

To compound 100-3(0.40g, 1.9mmol) in THF/H at 0 deg.C₂To a solution of copper sulfate pentahydrate (0.24g, 0.95mmol), sodium L-ascorbate (0.19g, 0.95mmol) and 2-methylbut-3-yn-2-amine (0.15g, 1.9mmol) in O (20mL/4mL) was added. The resulting reaction mixture was stirred at room temperature for 16 hours, then water was added, the aqueous phase was extracted with DCM, and then the aqueous phase was concentrated to give the desired product 100-4 as a yellow oil (0.36g, yield: 65%), which was used in the next step without further purification.

Synthesis of 3, 5-dichloro-N- (2- (1- (3, 4-dichlorophenethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-0100).

To a solution of compound 100-4(200mg, 0.67mmol) in DMF (10mL) was added 3, 5-dichlorobenzoic acid (130mg, 0.67mmol), DIEA (260mg, 2.01mmol) and HATU (380mg, 1.0 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0100 as a white solid (100mg, yield: 32%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 97.26%, and the retention time is 2.325 minutes; MS calculated: 470.0, respectively; MS found: 471.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2 ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 11.486 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.67(6H，s)，3.13(2H，t，J＝7.2Hz)，4.54(2H，t，J＝7.2Hz)，7.11(1H，dd，J＝8.0，2.0Hz)，7.40(1H，d，J＝1.6Hz)，7.46(1H，d，J＝8.4Hz)，7.80(1H，d，J＝1.6Hz)，7.84-7.87(3H，m)，8.58(1H，s)。

The designations SU20666-0102, SP 102 and 102 all refer to the same compound having the formula:

routes of SU20666-0102

Synthesis of (2- (3, 4-dichlorophenoxy) acetylamino) methanesulfonic acid (SU 20666-0102).

To a solution of compound 0043-4(200mg, 0.91mmol) in DMF (6mL) was added aminomethane sulfonic acid (121mg, 1.10mmol), DIEA (350mg, 2.70mmol) and HATU (530mg, 1.4 mmol). The resulting reaction mixture was stirred at room temperature for 5 hours, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0102 as a yellow solid (110mg, yield: 38%).

LC-MS (Agilent LCMS 1200-World X bridge C18(50mm 4.6mm 3.5 μm); column temperature: 40 ℃; flow rate: 2.0 ml/min; mobile phase: 95% [ Water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ] ₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, and the retention time is 1.417 min; MS calculated: 313.0, respectively; MS found: 312.0[ M-H]⁺。

¹H NMR(400MHz，CD₃OD)δ4.39(2H，s)，4.59(2H，s)，6.97(1H，dd，J＝8.8，2.8Hz)，7.22(1H，d，J＝3.2Hz)，7.42(1H，d，J＝9.2Hz)。

SU20666-0103

Routes of SU20666-0103

Synthesis of 7- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -1, 2, 3, 4-tetrahydroquinoline (103-3).

To a stirred solution of compound 103-1(260mg, 1.23mmol) in dioxane/water (10mL/2mL) was added 103-2(530mg, 1.84mmol), K₂CO₃(508mg，3.68mmol)、Pd(dppf)Cl₂(50 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 2 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product 103-3 as a yellow oil (150mg, yield: 42%).

Synthesis of 7- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) -1- (methylsulfonyl) -1, 2, 3, 4-tetrahydroquinoline (SU 20666-0103).

To a stirred solution of 103-3(150mg, 0.50mmol) in DCM (3ml) at 0 deg.C were added DIEA (197mg, 1.53mmol) and MsCl (88mg, 0.77 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the crude product was further purified by preparative HPLC to yield the desired product SU20666-0103 as a white solid (12mg, yield: 6.4%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.04% and the retention time is 2.124 minutes; MS calculated: 371.1, respectively; MS found: 372.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2 ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 10.483 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.94(2H，t，J＝6.0Hz)，2.80(2H，t，J＝6.8Hz)，3.10(3H，s)，3，71(2H，t，J＝6.0Hz)，7.22(1H，d，J＝8.0Hz)，7.36-7.43(3H，m)，7.77(1H，s)，7.92-7.95(2H，m)，8.11(1H，s)，8.90(1H，s)。

SU20666-0104

Routes of SU20666-0104

Synthesis of 3- (1-propyl-1H-pyrazol-4-yl) aniline (104-2).

To a stirred solution of compound 104-1(300mg, 1.6mmol) in dioxane/water (20mL/2mL) was added SM2(420mg, 1.9mmol), K₂CO₃(442mg，3.2mmol)、Pd(dppf)Cl₂(50 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 2 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, purified by c.cThe crude product was purified to give the desired product 104-2 as a yellow solid (240mg, yield: 75%).

Synthesis of N- (3- (1-propyl-1H-pyrazol-4-yl) phenyl) methanesulfonamide (SU 20666-0104).

To a stirred solution of 104-2(200mg, 1.0mmol) in DCM (3ml) at 0 deg.C were added pyridine (240mg, 3.0mmol) and MsCl (115mg, 1.0 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the crude product was further purified by preparative HPLC to yield the desired product SU20666-0104 as a yellow solid (70mg, yield: 25%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.70%, retention time 1.590 minutes; MS calculated: 279.1; MS found: 280.1[ M + H]⁺。

¹H NMR(400MHz，CD₃OD)δ0.94(3H，t，J＝7.2Hz)，1.89-1.94(2H，m)，2.99(3H，s)，4.15(2H，t，J＝7.6Hz)，7.12-7.14(1H，m)，7.32-7.37(2H，m)，7.42(1H，s)，7.83(1H，s)，8.01(1H，s)。

SU20666-0105

Routes of SU20666-0105

Synthesis of 3- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) aniline (105-2).

To a stirred solution of compound 0016-3(500mg, 2.1mmol) in dioxane/water (20mL/2mL) was added SM2(547mg, 2.5mmol), K ₂CO₃(427mg，3.1mmol)、Pd(dppf)Cl₂(150 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 2 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product 105-2 as a yellow solid (450mg, yield: 86%).

Synthesis of N- (3- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) phenyl) methanesulfonamide (SU 20666-0105).

To a stirred solution of 105-2(100mg, 0.39mmol) in DCM (5ml) at 0 deg.C were added TEA (59mg, 0.59mmol) and MsCl (49mg, 0.43 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the crude product was further purified by preparative HPLC to yield the desired product SU20666-0105 as a white solid (23mg, yield: 18%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ] ₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, and the retention time is 1.877 minutes; MS calculated: 331.1, respectively; MS found: 332.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ3.04(3H，s)，7.11(1H，d，J＝7.6Hz)，7.36-7.41(3H，m)，7.45-7.47(2H，m)，7.92-7.96(2H，m)，8.13(1H，s)，8.94(1H，s)，9.77(1H，s)。

SU20666-0106

Routes of SU20666-0106

Synthesis of 1-methyl-3- (3- (1-propyl-1H-pyrazol-4-yl) phenyl) urea (SU 20666-0106).

To a stirred solution of compound 0104-2(200mg, 1.0mmol) in ethyl acetate (10mL) was added triphosgene (445mg, 1.5mmol), TEA (202mg, 2.0mmol) and methylamine hydrochloride (100mg, 1.5 mmol). The resulting reaction mixture was stirred for 3 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0106 as a white solid (100mg, yield: 39%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.15%, retention time 1.535 minutes; MS calculated: 258.1; MS found: 259.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)0.84(3H，t，J＝7.2Hz)，1.78-1.83(2H，m)，2.64(3H，d，J＝4.4Hz)，4.07(2H，t，J＝6.8Hz)，6.03(1H，d，J＝4.4Hz)，7.07-7.09(1H，m)，7.16-7.19(2H，m)，7.58(1H，s)，7.74(1H，s)，8.06(1H，s)，8.48(1H，s)。

SU20666-0107

Routes of SU20666-0107

Synthesis of 1- (3- (1- (4-fluorophenyl) -1H-pyrazol-4-yl) phenyl) -3-methylurea (SU 20666-0107).

To a stirred solution of compound 0105-2(100mg, 0.39mmol) in DCM (10mL) was added triphosgene (116mg, 0.39mmol), TEA (59mg, 0.59mmol), and methylamine hydrochloride (53mg, 0.78 mmol). The resulting reaction mixture was stirred for 2 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0107 as a white solid (56mg, yield: 46%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100 percent, and the retention time is 1.781 minutes; MS calculated: 310.1 of the total weight of the mixture; MS found: 311.3[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watt X-bridge C18(150mm 4.6mm 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ Water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 8.675 minutes.

¹H NMR(400MHz，DMSO-d₆)2.66(3H，d，J＝4.4Hz)，6.07(1H，d，J＝4.4Hz)，7.23-7.30(3H，m)，7.38(2H，t，J＝8.8Hz)，7.69(1H，s)，7.92-7.96(2H，m)，8.09(1H，s)，8.52(1H，s)，8.88(1H，s)。

The designations SU20666-0108, SP 108 and 108 all refer to the same compound having the formula as shown below. The designations SU20666-0120, SP120 and 120 all refer to the same compound having the formula as shown below.

Routes of SU20666-0108 and SU20666-0120

Synthesis of 2- (3, 4-dichlorophenoxy) acetamide (SU 20666-0120).

To a solution of compound 0043-3(1.0g, 4.5mmol) in DCM (30mL) was added NH₄Cl (294mg, 5.5mmol), DIEA (1.8g, 13.6mmol) and HATU (2.6g, 6.8 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours, then water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to give the desired product SU20666-0120 as a yellow solid (863mg, yield:87％)。

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, and the retention time is 1.582 minutes; MS calculated: 219.1; MS found: 220.1[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA% ]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 100%, retention time 7.783 minutes.

¹H NMR(400MHz，DMSO-d₆)4.48(2H，s)，6.98(1H，dd，J＝8.8，2.8Hz)，7.24(1H，d，J＝2.8Hz)，7.42(1H，s)，7.53-7.56(2H，m)。

Synthesis of N- (2- (3, 4-dichlorophenoxy) acetyl) acrylamide (SU 20666-0108).

To a solution of compound SU20666-0120(200mg, 0.91mmol) in THF (6mL) at-15 deg.C was added potassium tert-butoxide (205mg, 1.82mmol) and stirred at this temperature for 30 minutes, followed by addition of acryloyl chloride (123mg, 1.37 mmol). The resulting reaction mixture was stirred at-15 ℃ for 2 h, then water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0108 as a white solid (5.0mg, yield: 2%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 96.65%, retention time 1.942 minutes; MS calculated: 273.0, respectively; MS found: 274.2[ M + H]⁺。

¹H NMR(400MHz，CDCl₃)4.72(2H，s)，5.91(1H，d，J＝6.0Hz)，6.48-6.53(1H，m)，6.74-6.77(2H，m)，6.99(1H，d，J＝3.2Hz)，7.31(1H，d，J＝8.8Hz)，8.48(1H，s)。

The designations SU20666-0110, SP 110 and 110 all refer to the same compound having the formula:

the pathway of SU20666-0110

Synthesis of tert-butyl (2- (2- (3, 4-dichlorophenoxy) acetylamino) ethyl) carbamate (110-2).

To a solution of compound 0043-3(300mg, 1.4mmol) in DMF (10mL) was added tert-butyl (2-aminoethyl) carbamate (260mg, 1.6mmol), DIEA (350mg, 2.7mmol) and HATU (800mg, 2.1 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product 110-2 as a yellow solid (280mg, yield: 56%).

Synthesis of N- (2-aminoethyl) -2- (3, 4-dichlorophenoxy) acetamide (110-3).

To a stirred solution of compound 0110-2(280mg, 0.77mmol) in DCM (10mL) was added TFA (5mL) at room temperature. The resulting reaction mixture was further stirred at room temperature for 2 hours, and then concentrated in vacuo to give the desired product 110-3 as a yellow oil (220mg, yield: 99%).

Synthesis of N- (2-cyanoaminoethyl) -2- (3, 4-dichlorophenoxy) acetamide (SU 20666-0110).

To a stirred solution of compounds 0110-3(100mg, 0.38mmol) in THF (10mL) was added cyanogen bromide (80mg, 0.76mmol) at room temperature. The resulting reaction mixture was further stirred at room temperature for 2 hours, then concentrated in vacuo and purified by preparative HPLC to yield the desired product SU20666-0110 as a white solid (21mg, yield: 19%).

LC-MS (Agilent LCMS 1200-X-bridge C18(50mm 4.6mm 3.5 μm); column temperature: 40 ℃; flow rate: 2.0 ml/min; mobile phase: 95% [ Water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 95.72%, and the retention time is 1.709 minutes; MS calculated: 287.0, respectively; MS found: 288.1[ M + H ]⁺。

¹H NMR(400MHz，DMSO-d₆)3.01(2H，t，J＝6.0Hz)，3.23-3.27(2H，m)，4.54(2H，s)，7.00(1H，dd，J＝8.8，2.8Hz)，7.28(1H，d，J＝2.8Hz)，7.55(1H，d，J＝8.8Hz)，8.27(1H，s)。

SU-20666-0111

The pathway of SU20666-0111

Synthesis of 1- (3-nitrophenyl) -H-pyrazole (0111-2).

To a solution of 0111-1(4g, 19.9mmol) in DMF (30mL) was added 1H-pyrazole (1.35g, 19.9mmol), Cu₂O (285mg, 1.99mmol) and Cs₂CO₃(19.5g, 59.7 mmol). The mixture was stirred at 110 ℃ overnight, then concentrated in vacuo to give the crude compound, which was purified by preparative HPLC to give 0111-2(1.2g, 32%) as a yellow solid.

Synthesis of 4-bromo-1- (3-nitrophenyl) -1H-pyrazole (0111-3).

To a solution of 0111-2(1.2g, 6.3mmol) in HOAc (15mL) was added Br2(1.1g, 6.9 mmol). The mixture was stirred at room temperature for 3 hours, then concentrated in vacuo to yield compound 0111-3(450mg, 27%) as a yellow solid.

Synthesis of N- (3- (1- (3-nitrophenyl) -1H-pyrazol-4-yl) phenyl) acetamide (0111-4).

To 0111-3(450mg, 1.7mmol) in dioxane/H₂0115-5(443mg, 1.7mmol) and Pd (dppf) Cl were added to a solution of O (10/1mL)₂(125mg, 0.17mmol) and K₂CO₃(703mg, 5.1 mmol). The resulting reaction mixture was heated to 90 ℃ and stirred for 16 hours and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by c.c. to yield the desired product 0111-4(450mg, 82%) as a yellow solid.

Synthesis of N- (3- (1- (3-aminophenyl) -1H-pyrazol-4-yl) phenyl) acetamide (0111-5).

To 0111-4(450mg, 1.4mmol) in EtOH/H₂To a solution in O (10/2mL) were added Fe (7.8mg, 0.14mmol) and NH₄Cl (7.4mg, 0.14 mmol). The mixture was stirred at 70 ℃ for 2 hours. Water was then added, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative TLC to give the desired product 0111-5(250mg, 61%) as a yellow solid.

Synthesis of N- (3- (1- (3-cyanamidophenyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0111).

To a solution of 0111-5(250mg, 0.85mmol) in toluene (5mL) was added BrCN (90mg, 0.85mmol) and NaHCO₃(214mg, 2.55 mmol). The mixture was stirred at room temperature for 3 hours, then water was added, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to give the desired product SU20666-0111(41mg, 15%) as a yellow solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 98.28%, retention time 1.539 minutes; MS calculated: 317.1; MS found: 318.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1%％TFA]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA) ]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 97.98%, retention time 7.607 min.

¹H NMR(400MHz，DMSO-d₆)δ2.06(3H，s)，6.91(1H，dd，J＝7.9，1.6Hz)，7.33-7.60(m，6H)，7.85(1H，s)，8.10(1H，s)，8.92(1H，s)，9.98(1H，s)，10.46(1H，s)。

SU-20666-0112

The pathway of SU20666-0112

Synthesis of N- (3- (1- (2-cyanopyrimidin-4-yl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0112).

To 0112-1(50mg, 0.36mmol) in CH₃CN (5mL) solution was added SM2(73mg, 0.36mmol) and K₂CO₃(150mg, 1.08 mmol). The mixture was stirred at room temperature overnight, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to give SU20666-0112(48mg, 44%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 3.0 min), then continued under these conditions for 1.0 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under these conditions),purity: 99.35%, retention time 1.788 minutes; MS calculated: 304.1; MS found: 305.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Vortechno model X bridge C18(150 mM. times.4.6 mM. times.3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under these conditions), the purity was 98.63% and the retention time was 8.566 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.07(3H，s)，7.36(1H，t，J＝7.9Hz)，7.52(2H，t，J＝8.9Hz)，7.95(1H，s)，8.21(1H，d，J＝5.7Hz)，8.44(1H，s)，8.97-9.12(2H，m)，10.00(1H，s)。

SU20666-0113

The pathway of SU20666-0113

Synthesis of 4-bromo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (0113-2).

To a solution of compound 0113-1(1.0g, 6.8mmol) in THF (20mL) was added DTP (857mg, 10.2mmol) and TFA (catalytic amount). The resulting reaction mixture was heated to 80 ℃ and stirred for 16 h, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product 113-2 as a yellow oil (760mg, yield: 48%).

Synthesis of N- (3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) phenyl) acetamide (0113-3).

To a stirred solution of compound 0113-2(760mg, 3.3mmol) in dioxane/water (20mL/2mL) was added 0015-5(862mg, 3.3mmol), K₂CO₃(911mg，6.6mmol)、Pd(dppf)Cl₂(100 mg). The resulting reaction mixture was heated to 100 ℃ and stirred for 16 h, and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product 0113-3 as a yellow solid (510mg, yield: 54%).

Synthesis of N- (3- (1H-pyrazol-4-yl) phenyl) acetamide (0113-4).

To a stirred solution of compound 0113-3(510mg, 1.8mmol) in THF (10mL) at room temperature was added HCl (1.0N, 2 mL). The resulting reaction mixture was further stirred at room temperature for 1 hour, then concentrated in vacuo and purified by preparative HPLC to yield the desired product 0113-4(310mg, yield: 86%) as a white solid.

Synthesis of N- (3- (1-acryloyl-1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0113).

To a solution of compound 0113-4(100mg, 0.50mmol) in DCM (6mL) at 0 deg.C was added NaHCO₃(84mg, 1.0mmol) and acryloyl chloride (45mg, 0.50mmol) and stirred at this temperature for 2 minAfter this time, water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0113 as a white solid (31mg, yield: 24%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA) ]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, and the retention time is 1.579 minutes; MS calculated: 255.1; MS found: 256.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 100%, retention time 7.872 minutes.

¹H NMR(400MHz，CDCl₃)δ2，14(3H，s)，6.04(1H，dd，J＝10.8，2.0Hz)，6.70(1H，dd，J＝17.2，1.6Hz)，7.15(1H，s)，7.22-7.31(3H，m)，7.47-7.54(1H，m)，7.75(1H，s)，7.96(1H，s)，8.49(1H，s)。

SU20666-0116

The pathway of SU20666-0116

Synthesis of N, N' - (dithiodiylbis (ethane-2, 1-diyl)) bis (2, 2-diphenylpropanamide) (SU 20666-0116).

To a stirred solution of 0116-1(100mg, 0.44mmol) in dichloromethane (10mL) at 0 deg.C were added oxalyl chloride (280mg, 2.2mmol) and DMF (0.05 mL). The resulting reaction mixture was stirred at 0 ℃ for 1 hour and concentrated in vacuo, the crude product was dissolved in dichloromethane (10mL), TEA (220mg, 2.2mmol) and 2-aminoethanethiol (59mg, 0.88mmol) were added, and the reaction mixture was stirred at room temperature for an additional 16 hours. Water (10mL) was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to give the desired product SU20666-0116 as a yellow solid (30mg, yield: 24%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 95.84%, retention time 2.147 minutes; MS calculated: 568.2; MS found: 569.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 86.46%, and the retention time was 11.283 minutes.

¹H NMR(400MHz，CDCl₃)δ1.59(6H，s)，2.72(4H，t，J＝6.4Hz)，3.52(4H，q，J＝6.4Hz)，5.89(2H，t，J＝6.4Hz)，7.23-7.36(19H，m)。

The designations SU20666-0117, SP 117 and 117 all refer to the same compound having the formula:

the pathway of SU20666-0117

Synthesis of N, N' - (dithiodiylbis (ethane-2, 1-diyl)) bis (2- (3, 4-dichlorophenoxy) acetamide) (SU 20666-0117).

To a stirred solution of 0085-1(200mg, 0.92mmol) in dichloromethane (10mL) at 0 deg.C was added oxalyl chloride (0.56g, 4.6mmol) and DMF (0.05 mL). The resulting reaction mixture was stirred at 0 ℃ for 1 hour and concentrated in vacuo, the crude product was dissolved in dichloromethane (10mL), TEA (533mg, 5.28mmol) and 2-aminoethanethiol (136mg, 1.76mmol) were added, and the reaction mixture was stirred at room temperature for an additional 16 hours. Water (10mL) was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative HPLC to give the desired product SU20666-0117 as a yellow solid (30mg, yield: 12%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, retention time 2.035 minutes; MS calculated: 556.0, respectively; MS found: 557.0[ M + H ]⁺。

¹H NMR(400MHz，DMSO-d₆)δ2.82(4H，t，J＝6.8Hz)，3.42(4H，q，J＝6.4Hz)，4.54(4H，s)，6.99(2H，dd，J＝8.8，2.8Hz)，7.25(2H，d，J＝2.8Hz)，7.54(2H，d，J＝8.8Hz)，8.31(2H，t，J＝6.0Hz)。

The designations SU20666-0119, SP 119 and 119 all refer to the same compound having the formula:

the pathway of SU20666-0119

Synthesis of N, N '- (2, 2' - (1, 1 '- (2, 2' -dithiodiylbis (ethane-2, 1-diyl)) bis (1H-1, 2, 3-triazole-4, 1-diyl)) bis (propane-2, 2-diyl)) bis (3, 5-dichlorobenzamide) (SU 20666-0119).

To the compound SU20666-0987(40mg, 0.11mmol) in CH₃To a stirred solution in CN was added TEA (44mg, 0.33 mmol). The resulting reaction mixture was stirred at room temperature overnight. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative HPLC to yield the desired product SU20666-0119 as a white solid (16mg, yield: 20.0%).

LC-MS (Agilent LCMS 1200-[ Water +10mM NH₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 95.98%, and the retention time is 2.275 minutes; MS calculated: 714.0, respectively; MS found: 715.1[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.69(12H，s)，2.23(4H，t，J＝6.8Hz)，4.57(4H，t，J＝6.8Hz)，7.77-7.83(6H，m)，8.00(2H，s)，8.60(2H，s)。

The designations SU20666-0123, SU20666-0123-01, SP 123 and 123 all refer to the same compounds having the formula:

routes of SU20666-0123

Synthesis of 2-chloro-N- (2- (3, 4-dichlorophenoxy) acetyl) acetamide (SU 20666-0123).

To a stirred solution of compound SU20666-0120(200mg, 0.91mmol) in toluene (5ml) was added 2-chloroacetyl chloride (0.2ml, 1.36 mmol). The resulting reaction mixture was stirred at 60 ℃ overnight. Then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product SU20666-0123 as a white solid (20mg, yield: 7.5%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 95.02%, retention time 1.818 minutes; MS calculated: 295.0, respectively; MS found: 296.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ] ₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 93.57%, retention time 9.211 minutes.

¹H NMR(400MHz，DMSO-d₆)δ4.46(2H，s)，4.98(2H，s)，6.95(1H，dd，J＝8.8Hz，J＝2.8Hz)，7.23(1H，d，J＝2.8Hz)，7.49(1H，d，J＝8.8Hz)，11.27(1H，s)。

SU20666-0125

Routes of SU20666-0125

Synthesis of N- (3- (1-but-2-alkynoyl-1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0125).

To a solution of 0113-4(250mg, 1.24mmol) in DCM (10mL) was added but-2-ynoic acid (104mg, 1.24mmol) and DCC (30mg, 0.15 mmol). The mixture was stirred at 0 ℃ to room temperature for 5 hours. The mixture was concentrated in vacuo to give crude compound. The crude product was purified by preparative HPLC to give SU20666-0125(20mg, 6%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 3.0 min), then continued under these conditions for 1.0 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, and the retention time is 1.515 minutes; MS calculated: 267.1, respectively; MS found: 268.2[ M + H ]⁺。

HPLC (Agilent HPLC 1200; column: Vortechno model X bridge C18(150 mM. times.4.6 mM. times.3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 86.75%, retention time 7.448 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.06(3H，s)，2.24(3H，s)，7.30-7.53(3H，m)，7.88(1H，s)，8.34(1H，s)，8.79(1H，s)，10.00(1H，s)。

SU20666-0126

Routes of SU20666-0126

Synthesis of N- (3- (1- (2-chloroacetyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0126).

To a stirred solution of compound 0113-4(200mg, 1.09mmol) in DCM (5ml) was added 2-chloroacetyl chloride (0.25ml, 1.64 mmol). The resulting reaction mixture was stirred at room temperature for 8 hours. Then water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product SU20666-0126(50mg, yield: 18.1%) as a white solid by preparative HPLC.

LC-MS (Agilent LCMS 1200- ]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 89.23%, and the retention time is 1.593 minutes; MS calculated: 277.0; MS found: 278.1[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 89.78%, and the retention time was 7.921 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.06(3H，s)，5.21(2H，s)，7.35(1H，t，J＝8.0Hz)，7.45-7.52(2H，m)，7.88(1H，s)，8.33(1H，s)，8.80(1H，s)，10.0(1H，s)。

SU20666-0130

The SU20666-0130 pathway

Synthesis of 1- (3-nitrophenyl) -1H-pyrazole (0130-2).

To a solution of 1-bromo-3-nitrobenzene (4g, 19.8mmol) in DMF (15mL) was added 1H-pyrazole (898mg, 13.2mmol), Cu₂O (0.2g, 1.2mmol) and Cs₂CO₃(7.8g, 23.8 mmol). The mixture was stirred at 110 ℃ overnight, then concentrated in vacuo to give the crude compound, which was further purified by preparative HPLC to give compound 0130-2(1.2g, 32%) as a yellow solid.

Synthesis of 4-bromo-1- (3-nitrophenyl) -1H-pyrazole (0130-3).

To a solution of 0130-2(1.2g, 6.3mmol) in AcOH (10mL) was added Br₂(3mL, 6.9 mmol). The mixture was stirred at room temperature for 3 hours, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the desired product 0130-3 as a yellow solid (765mg, 45%).

Synthesis of N- (3- (1- (3-nitrophenyl) -1H-pyrazol-4-yl) phenyl) acetamide (0130-4).

To a stirred solution of compound 0130-3(765mg, 2.8mmol) in dioxane/water (10mL/2mL) was added 015-5(1.1g, 4.2mmol), K₂CO₃(1.2g，8.4mmol)、Pd(dppf)Cl₂(220mg, 0.3 mmol). The resulting reaction mixture was heated to 100 ℃ and stirred for 16 h and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product 0130-4(495mg, 55%) as a yellow solid.

Synthesis of N- (3- (1- (3-aminophenyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0130).

0130-4(400mg, 1.24mmol) in EtOH/H at room temperature₂To a stirred solution of O (10mL/1mL) were added Fe powder (69mg, 12.4mmol) and NH ₄Cl (66mg, 12.4 mmol). The resulting reaction mixture was stirred at 70 ℃ for 1 hour. Water was then added, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and purified by preparative HPLC to yield the desired product SU20666-0130(36mg, 10%) as a white solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, retention time 1.368 min; MS calculated: 292.1, respectively; MS found: 293.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA) ]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 100%, retention time 5.847 minutes.

¹H NMR(400MHz，DMSO-d₆)δ2.06(3H，s)，6.75(2H，d，J＝3.7Hz)，7.12-7.62(7H，m)，7.87(1H，s)，8.06(1H，s)，8.78(1H，s)，9.98(1H，s)。

The designations SU20666-0131, SP 131 and 131 all refer to the same compound having the formula as shown below.

Routes of SU20666-0131 and SU20666-0141

Synthesis of tert-butyl 3- (4- (3- (methylsulfonylamino) phenyl) -1H-pyrazol-1-yl) propylcarbamate (0131-2).

To a stirred solution of compound 0051-3(2.0g, 6.6mmol) in dioxane/water (20mL/2mL) was added 0131-1(1.87g, 6.6mmol), K₂CO₃(2.73g，19.8mmol)、Pd(dppf)Cl₂(483mg, 0.66 mmol). The resulting reaction mixture was heated to 120 ℃ and stirred under microwave conditions for 0.5 h, and concentrated in vacuo to remove the solvent, then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were extractedDried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product 0131-2(500mg, 19%) as a yellow solid.

Synthesis of N- (3- (1- (3-aminopropyl) -1H-pyrazol-4-yl) phenyl) methanesulfonamide (SU 20666-0141).

To a solution of 0131-2(500mg, 1.27mmol) in DCM (10mL) was added TFA (5 mL). The mixture was stirred at room temperature overnight, then concentrated in vacuo and purified by preparative HPLC to give compound SU20666-0141(360mg, 96.5%) as a yellow solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 3.0 min), then continued under these conditions for 1.0 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.47%, the retention time is 1.226 minutes; MS calculated: 496.1 of the total weight of the alloy; MS found: 497.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Vortechno model X bridge C18(150 mM. times.4.6 mM. times.3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 5.999 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.88(2H，t，J＝6.4Hz)，2.88-2.90(2H，m)，2，95(3H，s)，4.11(2H，t，J＝6.4Hz)，4.50(2H，brs)，6.05-6.79(1H，brs)，6.99(1H，d，J＝7.2Hz)，7.22-7.29(m，3H)，7.76(1H，s)，8.11(1H，s)。

Synthesis of 2- (3, 4-dichlorophenoxy) N- (3- (4- (3- (methylsulfonylamino) phenyl) -1H-pyrazol-1-yl) propyl) acetamide (SU 20666-0131).

To a solution of compound SU20666-0141(360mg, 1.22mmol) in DCM (10mL) was added 0043-3(268mg, 1.22mmol), DIEA (472mg, 3.66mmol), EDCI (234mg, 1.22mmol) and HOBT (165mg, 1.22 mmol). The resulting reaction mixture was stirred at room temperature for 16 h, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0131(32mg, 5%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 3.0 min), then continued under these conditions for 1.0 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.81%, retention time 1.838 minutes; MS calculated: 496.1 of the total weight of the alloy; MS found: 497.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Vortechno model X bridge C18(150 mM. times.4.6 mM. times.3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 97.06%, and the retention time was 9.172 minutes.

¹HNMR(400MHz，DMSO-d₆)δ1.93-2.00(2H，m)，3.00(3H，s)，3.14(2H，q，J＝6.8Hz)，4.13(2H，t，J＝6.8Hz)，4.55(2H，s)，6.98-7.05(2H，m)，7.26-7.34(m，4H)，7.55(1H，d，J＝8.8Hz)，7.80(1H，s)，8.12(1H，s)，8.22(1H，t，J＝5.6Hz)，9.72(s，1H)。

The designations SU20666-0133, SP 133 and 133 all refer to the same compound having the formula:

the pathway of SU20666-0133

Synthesis of 2- (3, 4-dichlorophenoxy) N- (3- (4- (3- (methylsulfonylamino) phenyl) -1H-pyrazol-1-yl) propyl) acetamide (SU 20666-0133).

To a solution of compound SU20666-0076(80mg, 0.31mmol) in DCM (10mL) was added 3- (3, 4-dichlorophenyl) propionic acid (68mg, 0.31mmol), DIEA (120mg, 0.93mmol), EDCI (59mg, 0.31mmol) and HOBT (42mg, 1.22 mmol). The resulting reaction mixture was stirred at room temperature for 16 h, then water was added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC to yield the desired product SU20666-0133(20mg, 14%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 3.0 min), then continued under these conditions for 1.0 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.38%, retention time 1.842 minutes; MS calculated: 458.1; MS found: 459.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.79-1.92(2H，m)，2.02(3H，s)，2.36(2H，t，J＝7.2Hz)，2.80(2H，t，J＝7.2Hz)，3.00(2H，q，J＝2.4Hz)，4.04(2H，t，J＝6.4Hz)，7.17-7.24(3H，m)，7.35(1H，d，J＝8.0Hz)，7.46-7.71(2H，m)，7.73-7.74(2H，m)，7.89(1H，t，J＝5.2Hz)，8.02(s，1H)，9.91(s，1H)。

The designations SU20666-0134, SP 134 and 134 all refer to the same compound having the formula as shown below.

Routes of SU20666-0134 and SU20666-0142

Synthesis of 2- (tert-butoxycarbonylamino) ethyl methanesulfonate (0134-2).

To a stirred solution of compound 0134-1(2g, 12.4mmol) in DCM (20ml) was added MsCl (2.13g, 18.6mmol) and TEA (4.8g, 37.2mmol) under ice water. The resulting reaction mixture was stirred at 0 ℃ for 1 hour. Water was then added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product 0134-2 as a yellow oil (2g, yield: 67.5%).

Synthesis of tert-butyl 2- (4-bromo-1H-pyrazol-1-yl) ethylcarbamate (0134-3).

To compound 0134-2(2.0g, 8.37mmol) in CH₃CN (18mL) solution was added 4-bromo-1H-pyrazole (0.95g, 6.44mmol) and K₂CO₃(1.33g, 9.66 mmol). The mixture was stirred at 80 ℃ for 5 hours. The solvent was removed, water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by silica gel to give the desired product 0134-3 as a yellow solid (1.0g, yield: 41.2%).

Synthesis of tert-butyl 2- (4- (3-acetamidophenyl) -1H-pyrazol-1-yl) ethylcarbamate (0134-4).

0134-3(1g, 3.46mmol) in dioxane/H under an argon atmosphere₂0015-5(1.08g, 4.2mmol) and K are added to a solution of O (15ml/3ml)₂CO₃(1.43g, 10.4mmol) and Pd (dppf) Cl₂(0.1 g). The mixture was stirred under microwave conditions at 130 ℃ for 2 hours. After cooling to room temperature, water was added. The aqueous phase was extracted with DCM (20mL × 3) and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified to give compound 01344(300mg, 22.6%) as a yellow solid.

Synthesis of N- (3- (1- (2-aminoethyl) -1H-pyrazol-4-yl) phenyl) acetamide (SU 20666-0142).

To a stirred solution of compound 0134-4(300mg, 0.87mmol) in DCM (5ml) was added TFA (1.0 ml). The resulting reaction mixture was stirred at room temperature for 1 hour. The solvent was removed, water (5mL) was added to the residue, and NaHCO was used₃(aqueous solution) the pH was adjusted to 6.0. The aqueous phase was extracted with dichloromethane and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and purified by preparative HPLC to give SU20666-0142 as a colorless oil (80mg, yield: 38%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.34%, retention time 1.186 minutes; MS calculated: 244.1; MS found: 245.3[ M + H]⁺。

¹HNMR(400MHz，DMSO-d₆)δ2.02(3H，s)，2.91(2H，t，J＝6.4Hz)，4.07(2H，t，J＝6.4Hz)，7.19-7.26(2H，m)，7.36(1H，dd，J＝6.0，2.0Hz)，7.72-7.75(2H，m)，8.02-8.04(1H，m)，9.91(1H，s)。

Synthesis of N- (2- (4- (3-acetamidophenyl) -1H-pyrazol-1-yl) ethyl) -2- (3, 4-dichlorophenoxy) acetamide (SU 20666-0134).

To a stirred solution of compound 0134-5(50mg, 0.2mmol) in DCM (3ml) were added 0043-3(38mg, 0.17mmol), EDCI (49mg, 0.26mmol), HOBt (35mg, 0.26mmol) and DIEA (0.2ml, 1.02 mmol). The resulting reaction mixture was stirred at room temperature overnight. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield SU20666-0134 as a white solid (20mg, yield: 37.7%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.40%, retention time 1.834 minutes; MS calculated: 446.1; MS found: 447.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ2.02(3H，s)，3.54(2H，t，J＝6.0Hz)，4.21(2H，t，J＝6.4Hz)，4.51(2H，s)，6.92(1H，dd，J＝8.8Hz，3.2Hz)，7.17-7.26(3H，m)，7.35(1H，d，J＝8.0Hz)，7.46(1H，d，J＝8.8Hz)，7.75(2H，d，J＝9.6Hz)，8.03(1H，s)，8.27(1H，t，J＝5.6Hz)，9.91(1H，s)。

The designations SU20666-0135, SP 135 and 135 all refer to the same compound as shown below. The designations SU20666-0143, SP 143 and 143 all refer to the same compounds as set forth below.

Routes of SU20666-0135 and SU20666-0143

Synthesis of 3, 4-Dimethoxybenzenethylmethanesulfonate (0143-2).

To a stirred solution of compound 0143-1(1g, 5.5mmol) in DCM (10ml) was added MsCl (0.7ml, 8.2mmol) and TEA (3.0ml, 16.5mmol) under ice water. The resulting reaction mixture was stirred at 0 ℃ for 1 hour. Water was then added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product 0143-2 as a yellow oil (1.0g, yield: 70%).

Synthesis of 4- (2-azidoethyl) -1, 2-dimethoxybenzene (0143-3).

Oriented foodTo a solution of compound 0143-2(1.0g, 3.85mmol) in DMF (10mL) was added NaN₃(0.50g, 7.70 mmol). The mixture was stirred at 80 ℃ for 12 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by silica gel to give the desired product 0143-3(0.5g, yield: 62.5%) as a yellow solid.

Synthesis of 2- (1- (3, 4-dimethoxyphenethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-amine (0143-4).

To 143-3(500mg, 2.4mmol) in THF/H₂To a solution of O (10ml/2ml) were added 2-methylbut-3-yn-2-amine (200mg, 2.4mmol) and CuSO₄(300mg, 1.2mmol) and sodium L-ascorbate (240mg, 1.2 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed, water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product 0143-4(300mg, yield: 42.9%) as a green solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 71.27%, retention time 0.463 min; MS calculated: 290.2 of the total weight of the mixture; MS found: 291.4[ M + H ]]⁺。

Synthesis of 3, 5-dichloro-N- (2- (1- (3, 4-dimethoxyphenethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-0143).

To a stirred solution of compound 0143-4(200mg, 0.69mmol) in DCM (8ml) was added 3, 5-dichlorobenzoic acid (110mg, 0.57mmol), EDCI (165mg, 0.86mmol), HOBt (116mg, 0.86mmol) and DIEA (0.3ml, 1.71 mmol). The resulting reaction mixture was stirred at room temperature overnight. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield SU20666-0143 as a white solid (80mg, yield: 30%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.10%, and the retention time is 2.098 minutes; MS calculated: 462.1 of the first group; MS found: 463.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.68(6H，s)，3.04(2H，t，J＝7.2Hz)，3.69(6H，s)，4.49(2H，t，J＝7.2Hz)，6.66-6.81(3H，m)，7.79-7.88(4H，m)，8.60(1H，s)。

Synthesis of 3, 5-dichloro-N- (2- (1- (3, 4-dihydroxyphenethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-0135).

To a stirred solution of compound SU20666-0143(300mg, 0.65mmol) in DCM (10ml) at-78 deg.C was added BBr ₃(0.68M, 2mL, 1.30 mmol). The resulting reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield SU20666-0135 as a white solid (120mg, yield: 43%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 98.69%, retention time 1.700 min; MS calculated: 434.1; MS found: 435.1[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA) ]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 100%, retention time 8.515 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.68(6H，s)，2.93(2H，t，J＝7.2Hz)，4.14(2H，t，J＝7.2Hz)，6.40(1H，dd，J＝8.0，2.0Hz)，6.56-6.61(2H，m)，7.79-7.89(4H，m)，8.61(1H，s)，8.75(2H，d，J＝9.2Hz)。

The designations SU20666-0136, SP 136 and 136 all refer to the same compound having the formula:

the pathways of SU20666-0136

Synthesis of 2- (1- (3, 4-dichlorophenethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-amine (136-2).

To the solution was added 137-3(250mg, 3.0mmol) in THF/H₂To a solution of O (10ml/2ml) were added 2-methylbut-3-yn-2-amine (650mg, 3.0mmol) and CuSO₄(374mg, 1.5mmol) and sodium L-ascorbate (297mg, 1.5 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed, water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product 0136-2 as a green solid (400mg, yield: 45%).

Synthesis of N- (3, 5-dichlorobenzyl) -2- (1- (3, 4-dichlorophenethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-amine (SU 20666-0136).

To a solution of 136-2(200mg, 1.0mmol) in MeOH/HOAc (10ml/0.5ml) were added 3, 5-dichlorobenzaldehyde (175mg, 1.0mmol) and NaBH₃CN (190mg, 3.0 mmol). The mixture was stirred at room temperature for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product SU20666-0136 as a white solid (35mg, yield) ：7.7％)。

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 96.45%, retention time 2.515 minutes; MS calculated: 456.0; MS found: 457.1[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.35(6H，s)，3.13(2H，t，J＝7.2Hz)，3.33(2H，s)，4.56(2H，t，J＝6.8Hz)，7.11(1H，dd，J＝8.4，2.0Hz)，7.28(2H，d，J＝3.2Hz)，7.35-7.44(3H，m)，7.80(1H，s)。

The designations SU20666-0137, SP 137 and 137 all refer to the same compound having the formula:

the pathway of SU20666-0137

Synthesis of 3, 4-dichlorophenethylmethanesulfonate (137-2).

To a stirred solution of compound 137-1(2g, 10.5mmol) in DCM (20ml) was added MsCl (1.8g, 15.7mmol) and TEA (5.6ml, 31.5mmol) under ice water. The resulting reaction mixture was stirred at 0 ℃ for 1 hour. Water was then added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 137-2 as a yellow oil (1.5g, yield: 53.6%).

Synthesis of 4- (2-azidoethyl) -1, 2-dichlorobenzene (137-3).

To a solution of compound 137-2(1.5g, 5.6mmol) in DMF (15mL) was added NaN₃(0.73g, 11.2 mmol). The mixture was stirred at 80 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by silica gel to yield the desired product 137-3(0.9g, yield: 75%) as a yellow solid.

Synthesis of (1- (3, 4-dichlorophenethyl) -1H-1, 2, 3-triazol-4-yl) methylamine (137-4).

To a solution of 137-3(500mg, 2.3mmol) in THF/H₂To a solution of O (10ml/2ml) were added prop-2-yn-1-amine (128mg, 2.3mmol) and CuSO₄(288mg, 1.16mmol) and sodium L-ascorbate (230mg, 1.16 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed, water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product 137-4(400mg, product) as a green solidRate: 63.7%).

Synthesis of 3, 5-dichloro-N- ((1- (3, 4-dichlorophenethyl) -1H-1, 2, 3-triazol-4-yl) methyl) benzamide (SU 20666-0137).

To a stirred solution of compound 137-4(200mg, 0.74mmol) in DCM (8ml) were added 3, 5-dichlorobenzoic acid (118mg, 0.62mmol), EDCI (180mg, 0.93mmol), HOBt (126mg, 0.93mmol) and DIEA (0.33ml, 1.86 mmol). The resulting reaction mixture was stirred at room temperature overnight. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield SU20666-0137 as a white solid (10mg, yield: 3.7%) which was purified by preparative HPLC.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 95.80%, retention time 2.230 minutes; MS calculated: 442.0, respectively; MS found: 443.0[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ3.12(2H，t，J＝7.2Hz)，4.44(2H，d，J＝5.2Hz)，4.57(2H，t，J＝7.2Hz)，7.12(1H，d，J＝8.0Hz)，7.46(2H，d，J＝8.4Hz)，7.81-7.91(4H，m)，9.24(1H，s)。

The designations SU20666-0138, SP 138 and 138 all refer to the same compound having the formula:

the pathways of SU20666-0138

Synthesis of N- (2- (1- (3, 4-dichlorophenethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-0138).

To a stirred solution of compound 0136-2(300mg, 1.0mmol) in DCM (8ml) were added benzoic acid (146mg, 1.2mmol), HATU (570mg, 1.5mmol) and DIEA (387mg, 3.0 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield SU20666-0138 as a white solid (20mg, yield: 5%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.38%, retention time 2.089 min; MS calculated: 402.1; MS found: 403.1[ M + H]⁺。

HPLC (Agilent)HPLC 1200; column: l-column 2 ODS (150mm 4.6mm 5.0 μm); column temperature: 40 ℃; flow rate: 1.0 ml/min; mobile phase: 95% [ Water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA% ]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 95.42%, and the retention time was 9.561 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.66(6H，s)，3.11(2H，t，J＝7.2Hz)，4.53(2H，t，J＝7.2Hz)，7.09(1H，dd，J＝8.4，2.0Hz)，7.40-7.49(5H，m)，7.78(2H，d，J＝8.4Hz)，7.82(1H，s)，8.27(1H，s)。

The designations SU20666-0139, SP 139 and 139 all refer to the same compound having the formula:

the pathway of SU20666-0139

Synthesis of 3- (3, 4-dichlorophenyl) propan-1-ol (139-2).

To a stirred solution of 0139-1(2.0g, 9.2mmol) in THF (20mL) was added borane-tetrahydrofuran (1.0N, 55mL, 55 mmol). The resulting reaction mixture was stirred for 12 hours. HCl (1.0N, 3mL) was then added and stirred at room temperature for 1 hour, the aqueous phase was neutralized and then extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 139-2 as a white solid (15mg, yield: 7.9%).

Synthesis of 3- (3, 4-dichlorophenyl) propyl methanesulfonate (139-3).

To a stirred solution of compound 139-2(2g, 10.0mmol) in DCM (20ml) was added MsCl (1.7g, 15.0mmol) and TEA (3.0g, 30.0mmol) under ice water. The resulting reaction mixture was stirred at 0 ℃ for 1 hour. Water was then added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 139-3 as a yellow oil (2.5g, yield: 91%).

Synthesis of 4- (3-azidopropyl) -1, 2-dichlorobenzene (139-4).

To a solution of 0139-3(3.0g, 10.6mmol) in DMF (10mL) was added NaN₃(1.4g, 21.3 mmol). The mixture was stirred at 80 ℃ for 12 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by silica gel to give the desired product 0139-4 as a yellow solid (2.5g, yield: 100%).

Synthesis of 2- (1- (3- (3, 4-dichlorophenyl) propyl) -1H-1, 2, 3-triazol-4-yl) propan-2-amine (0139-5).

To a solution of 139-4(2.5g, 10.9mmol) in THF/H₂To a solution of O (25ml/5ml) were added 2-methylbut-3-yn-2-amine (0.90g, 10.9mmol) and CuSO₄(1.4g, 5.4mmol) and sodium L-ascorbate (1.1g, 5.4 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed, water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product 0139-5(2.0g,yield: 59%).

Synthesis of 3, 5-dichloro N- (2- (1- (3- (3, 4-dichlorophenyl) propyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-0139).

To a stirred solution of compound 0139-5(197mg, 0.63mmol) in DCM (5ml) were added 3, 5-dichlorobenzoic acid (100mg, 0.52mmol), HATU (298mg, 0.79mmol) and DIEA (202mg, 1.57 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield SU20666-0139 as a white solid (77mg, yield: 30%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 97.78%, retention time 2.451 minutes; MS calculated: 484.0, respectively; MS found: 485.1[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2 ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 12.015 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.69(6H，s)，2.10-2.14(2H，m)，2.52-2.56(2H，m)，4.30(2H，t，J＝7.2Hz)，7.21(1H，dd，J＝8.4，2.0Hz)，7.48-7.53(2H，m)，7.79(1H，s)，7.85(2H，d，J＝2.0Hz)，7.96(1H，s)，8.61(1H，s)。

SU-20666-0141

The pathway SU-20666-0141

Synthesis of 3- (tert-butoxycarbonylamino) propyl methanesulfonate (0141-2).

To a solution of tert-butyl 3-hydroxypropyl carbamate (5g, 28.6mmol) in DCM (20mL) was added MsCl (4.92mg, 42.9mmol) and TEA (8.7g, 85.8 mmol). The mixture was stirred at room temperature for 3 hours. And then concentrated in vacuo to yield the crude compound. The crude product was purified by preparative HPLC to give 3- (tert-butoxycarbonylamino) propyl methanesulfonate (7.6g, 100%) as a yellow solid.

Synthesis of tert-butyl 3- (4-bromo-1H-pyrazol-1-yl) propylcarbamate (0141-3).

To 3- (tert-Butoxycarbonylamino) propyl methanesulfonate (7.6g, 30mmol) in CH₃CN (30mL) solution was added 4-bromo-1H-pyrazole (2.94g, 20mmol) and K₂CO₃(5.52g, 40 mmol). The mixture was stirred at 85 ℃ overnight. Then concentrated in vacuo to give 3- (4-bromo-1H-pyrazole-1) as a yellow solid-yl) propyl carbamic acid tert-butyl ester (2g, 20%).

Synthesis of tert-butyl 3- (4- (3- (methylsulfonylamino) phenyl) -1H-pyrazol-1-yl) propylcarbamate (0141-4).

In N₂To 3- (4-bromo-1H-pyrazol-1-yl) propylcarbamic acid tert-butyl ester (1.8g, 5.94mmol) in dioxane/H with protection₂To a solution in O (20/2mL) were added N- (3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanesulfonamide (2.2g, 7.2mmol), Pd (dppf) Cl₂(180mg) and K₂CO₃(2.46g, 17.8 mmol). The mixture was stirred at 100 ℃ overnight. And then concentrated in vacuo to yield the crude compound. The crude product was purified by preparative HPLC to give tert-butyl 3- (4- (3- (methylsulfonylamino) phenyl) -1H-pyrazol-1-yl) propylcarbamate as a yellow solid (600mg, 26%).

Synthesis of N- (3- (1- (3-aminopropyl) -1H-pyrazol-4-yl) phenyl) methanesulfonamide (SU 20666-0130).

To a solution of tert-butyl 3- (4- (3- (methylsulfonylamino) phenyl) -1H-pyrazol-1-yl) propylcarbamate (500mg, 1.3mmol) in DCM (10mL) was added TFA (5 mL). The mixture was stirred at room temperature overnight. And then concentrated in vacuo to yield the compound. N- (3- (1- (3-aminopropyl) -1H-pyrazol-4-yl) phenyl) methanesulfonamide (260mg, 68%) as a white solid. LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 3.0 min), then continued under these conditions for 1.0 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under these conditions), purity 98.47%, retention time 1.226 minutes; MS calculated: 294.1; MS found: 295.1[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Vortechno model X bridge C18(150 mM. times.4.6 mM. times.3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And under these conditions for 5 minutes), the purity was 100%, and the retention time was 5.999 minutes.

¹H NMR(400MHz，DMSO)δ8.11(s，1H)，7.76(s，1H)，7.26(dd，J＝17.4，10.1Hz，3H)，6.99(d，J＝7.1Hz，1H)，6.42(d，J＝300.2Hz，1H)，4.28(s，2H)，4.11(t，J＝6.7Hz，2H)，2.95(s，3H)，2.90(d，J＝6.3Hz，2H)，1.95-1.75(m，2H)。

The designations SU20666-0146, SP 146 and 146 all refer to the same compound having the formula:

the pathway of SU20666-0146

Synthesis of 3, 4-dichloro-N- (2- (1- (3, 4-dichlorophenethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-0146).

To a stirred solution of compound 0136-2(100mg, 0.33mmol) in DMF (5ml) were added 3, 4-dichlorobenzoic acid (54mg, 0.28mmol), EDCI (80mg, 0.42mmol), HOBT (57mg, 0.42mmol) and DIEA (108mg, 0.84 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield SU20666-0146 as a white solid (30mg, yield: 23%) which was purified by preparative HPLC.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 96.90%, and the retention time is 2.321 minutes; MS calculated: 470.0, respectively; MS found: 471.0[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.67(6H，s)，3.13(2H，t，J＝7.2Hz)，4.54(2H，t，J＝7.2Hz)，7.11(1H，d，J＝8.4Hz)，7.41(1H，s)，7.46(1H，d，J＝8.4Hz)，7.72-7.80(2H，m)，7.86(1H，s)，8.09(1H，s)，8.54(1H，s)。

The designations SU20666-0147, SP 147 and 147 all refer to the same compound having the formula:

the pathway of SU20666-0147

Synthesis of 1- (2-azidoethyl) -4-bromobenzene (0147-2).

To a solution of compound 0147-1(5g, 18.9mmol) in DMF (20mL) was added NaN ₃(2.46g, 37.9 mmol). The mixture was stirred at 80 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0147-2(4g, yield: 94%) as a yellow solid.

Synthesis of 2- (1- (4-bromophenylethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-amine (0147-3).

To 0147-2(4g, 17.8mmol) in THF/H₂To a solution of O (20ml/4ml) were added 2-methylbut-3-yn-2-amine (1.48g, 17.8mmol) and CuSO₄(2.2g, 8.9mmol) and sodium L-ascorbate (1.76g, 8.9 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed, water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product 0147-3(2g, yield: 36.5%) as a green solid.

Synthesis of N- (2- (1- (4-bromophenylethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) -3, 5-dichlorobenzamide (SU 20666-0147).

To a stirred solution of compound 0147-3(200mg, 0.65mmol) in DMF (5ml) were added 3, 5-dichlorobenzoic acid (100mg, 0.54mmol), HATU (300mg, 0.81mmol) and DIEA (0.3ml, 1.62 mmol). The resulting reaction mixture was stirred at room temperature overnight. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield SU20666-0147 as a white solid (70mg, yield: 28%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.23%, retention time 2.312 minutes; MS calculated: 480.0 of the total weight of the mixture; MS found: 481.0[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.67(6H，s)，3.10(2H，t，J＝6.8Hz)，4.52(2H，t，J＝7.2Hz)，7.08(2H，d，J＝8.4Hz)，7.40(2H，d，J＝8.4Hz)，7.79-7.86(4H，m)，8.59(1H，s)。

SU20666-0148

The pathway of SU20666-0148

Synthesis of 2- (azidomethyl) naphthalene (0148-2).

To a solution of compound 0148-1(5g, 22.6mmol) in DMF (20mL) was added NaN₃(2.9g, 45.2 mmol). The mixture was stirred at 80 ℃ for 16 hours. Water was then added, the aqueous phase was extracted with EA, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0148-2(3g, yield: 72.5%) as a yellow solid.

Synthesis of 2- (1- (naphthalen-2-ylmethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-amine (0148-3).

To 0148-2(3g, 16.4mmol) in THF/H₂To a solution of O (20ml/4ml) were added 2-methylbut-3-yn-2-amine (1.36g, 16.4mmol) and CuSO₄(2.0g, 8.2mmol) and sodium L-ascorbate (1.6g, 8.2 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed, water was added, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the desired product 0148-3 as a green solid (1.5g, yield: 34%).

Synthesis of 3, 4-dichloro-N- (2- (1- (naphthalen-2-ylmethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-0148).

To a stirred solution of compound 0148-3(200mg, 0.75mmol) in DMF (5ml) were added 3, 4-dichlorobenzoic acid (119mg, 0.63mmol), HATU (357mg, 0.94mmol) and DIEA (0.4ml, 1.88 mmol). The resulting reaction mixture was stirred at room temperature overnight. Then water was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield SU20666-0148 as a white solid (40mg, yield: 14.5%) which was purified by preparative HPLC.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.27%, retention time 2.263 minutes; MS calculated: 438.1, respectively; MS found: 439.1[ M + H]⁺。

¹H NMR(400MHz，CDCl₃)δ1.75(6H，s)，5.62(2H，s)，6.99(1H，s)，7.33(1H，d，J＝1.6Hz)，7.39-7.52(5H，m)，7.72(1H，s)，7.78-7.81(4H，m)。

The designations SU20666-150, SP 150 and 150 all refer to the same compound having the formula:

routes of SU20666-150

Synthesis of 2- (4- (2-aminopropyl-2-yl) -1H-1, 2, 3-triazol-1-yl) ethanol (0087-2).

Synthesis of 3, 5-dichloro-N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-150).

To a stirred solution of compound 0087-2(1.9g, 11.2mmol) in DCM (20ml) were added 3, 5-dichlorobenzoic acid (1.4g, 7.45mmol), DIEA (2.9g, 22.4mmol) and HATU (4.0g, 11.2 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product SU20666-150 as a white solid (1.5g, yield: 60%).

LCMS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 1.636 minutes; MS calculated: 342; MS found: 343.0[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，3.77(2H，q，J＝5.2Hz)，4.34(2H，t，J＝5.2Hz)，5.01(1H，t，J＝5.2Hz)，7.79(1H，t，J＝2.0Hz)，7.84(2H，d，J＝2.0Hz)，7.89(1H，s)，8.58(1H，s)。

The designations SU20666-151, SP 151 and 151 all refer to the same compound having the formula:

the pathways of SU20666-151

Synthesis of 2- (4- (2- (3, 5-dichlorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl 4-methylbenzenesulfonate (0087-4).

To a stirred solution of 150-01(100mg, 0.29mmol) in DCM (15ml) at 0 deg.C were added DIEA (113.1mg, 0.875mmol) and TsCl (82.94mg, 0.435 mmol). The resulting reaction mixture was stirred at 0 ℃ for 3 hours. Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield the desired product 0087-4 as a white solid (100mg, yield: 68%).

Synthesis of S-2- (4- (2- (3, 5-dichlorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl thioacetate (SU 20666-151).

To a solution of compound 087-4(50mg, 0.1mmol) in DMF (15mL) was added potassium thioacetate (13.78mg, 0.12 mmol). The mixture was stirred at room temperature for 16 h, after consumption of the starting material (by LCMS), the mixture was purified by preparative HPLC to give SU20666-151 as a brown solid (19.22mg, yield: 47%).

LCMS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 1.985 min; MS calculated: 400, respectively; MS found: 401.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ] ₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 94.49 percent, and the retention time is 9.513 minutes; MS calculated: 400, respectively; MS found: 401.0[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.69(6H，s)，2.23(3H，s)，3.32(2H，t，J＝6.8Hz)，4.46(2H，t，J＝6.8Hz)，7.79(1H，t，J＝1.6Hz)，7.84(2H，d，J＝2.4Hz)，7.95(1H，s)，8.6(1H，s)。

The designations SU20666-152, SP 152 and 152 all refer to the same compound having the formula:

pathways of su20666-152

Synthesis of N- (2- (1- (2-aminoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) -3, 5-dichlorobenzamide (SU 20666-152).

To a solution of compound SU20666-181(100mg, 0.272mmol) in THF (15ml) was added Ph₃P (92.33mg, 0.352mmol) and ammonium hydroxide (19.03mg, 0.543 mmol). The mixture was heated to reflux for 16 hours. After consumption of the starting material (by LCMS), the mixture was concentrated in vacuo and purified by preparative HPLC to give SU20666-152 as a white solid (42mg, yield: 45%).

LCMS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](1In 6 min) and then under these conditions for 1.4 min, finally becomes 95% in 0.1 min [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 98.92%, retention time 1.551 minutes; MS calculated: 341; MS found: 342.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，2.94(2H，t，J＝6.0Hz)，4.26(2H，t，J＝6.0Hz)，7.79(1H，t，J＝2.0Hz)，7.83(2H，d，J＝1.6Hz)，7.93(1H，s)，8.58(1H，s)。

The designations SU20666-153, SP 153 and 153 all refer to the same compound having the formula as shown below. The designations SU20666-174, SP 174 and 174 all refer to the same compound having the formula as shown below. The designations SU20666-175, SP 175 and 175 all refer to the same compound having the formula as shown below. The designations SU20666-184, SP 184 and 184 all refer to the same compound having the formula as shown below.

Routes of SU20666-153, SU20666-174, SU20666-175 and SU20666-184

Synthesis of ethyl 1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-4-carboxylate (153-2).

To a solution of compound 153-1(7.0g, 50.0mmol) in dry N, N-dimethylformamide (30mL) was added sodium hydride (60%, 3.0g, 75.0mmol) in portions, the mixture was stirred at 0 ℃ for 15 minutes, then 2- (trimethylsilyl) ethoxymethyl chloride (13.3mL, 75.0mmol) was slowly added dropwise, and the reaction mixture was allowed to warm to room temperature overnight. After consumption of the starting material (by LCMS), the mixture was quenched with 150mL water and extracted with EtOAc (50 × 3mL), the organic layers were combined and extracted over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to yield the desired product 153-2 as a colorless oil (13.4g, yield: 99.3%).

Synthesis of 2- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) propan-2-ol (153-3).

Then in N₂To a solution of compound 153-2(13.4g, 49.6mmol) in THF (130mL) at-78 deg.C under protection was slowly added CH₃MgBr(Et₂3M in O, 19.9 mL). The mixture was warmed to room temperature to stir overnight. After consumption of the starting material (by LCMS), the mixture was taken up with 150mL NH₄Aqueous Cl was quenched and extracted with EtOAc (100X 3mL), and the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to yield the desired product 153-3 as a colorless oil (10.2g, yield: 80%).

Synthesis of 4- (2-azidopropan-2-yl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole (153-4).

To compound 153-3(2.9g, 11.6mmol) in CH₂Cl₂(50mL) to the solution was added TMSN₃(1.8mL, 13.9mmol) and (CF)₃SO₂)₃Bi (764.0mg, 1.2 mmol). The mixture was stirred at room temperature for 2 hours. After consumption of the starting material (by LCMS), the mixture was filtered and the filtrate was concentrated in vacuo to yield the desired product 153-4 as a yellow oil (2.4g, yield: 94.1%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 0.8 min), then continued under these conditions for 0.4 min, finally became 0% [ water + 0.05% TFA ] in 0.01 min]And 100% [ CH ]₃CN+0.05％TFA]To 95% [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％TFA]Purity: 84.54%, and the retention time is 0.867 min; MS calculated: 281.0; MS found: 282.2[ M + H]⁺。

Synthesis of 2- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) propan-2-amine (153-5).

To a solution of compound 1534(2.8g, 10.0mmol) in MeOH (30mL) was added Pd/C (10%, 618 mg). At H ₂The mixture was stirred at room temperature under an atmosphere (1.0atm) for 16 hours, the mixture was filtered and concentrated in vacuo to yield the desired product 153-5(2.8g, yield: 85.9%) as a colorless oil.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 0.8 min), then continued under these conditions for 0.4 min, finally became 0% [ water + 0.05% TFA ] in 0.01 min]And 100％[CH₃CN+0.05％TFA]To 95% [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％TFA]Purity: 97.80 percent, and the retention time is 0.560 minutes; MS calculated: 255.0; MS found: 256.1[ M + H]⁺。

Synthesis of 3, 5-dichloro-N- (2- (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazol-4-yl) propan-2-yl) benzamide (SU 20666-174).

To the compound 3, 5-dichlorobenzoic acid (950mg, 5.0mmol) in CH₂Cl₂To a solution in (25mL) were added HATU (2.85g, 7.5mmol), DIEA (3.31mL, 20.0mmol) and 153-5(1.28g, 5.0 mmol). The mixture was stirred at room temperature for 1 hour. After consumption of the starting material (by LCMS), the mixture was quenched with 30mL water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na ₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to yield the desired product 174(1.6g, yield: 78.7%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% NH ]₄HCO₃]And 95% [ water + 0.05% NH ]₄HCO₃](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally becoming 95% in 0.05 minutes [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 0.7 minutes under this condition), purity: 97.70%, and the retention time is 2.460 minutes; MS calculated: 427.0, respectively; MS found: 428.3[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% NH ]₄HCO₃]And 95% [ water + 0.05% NH ]₄HCO₃](within 10 minutes) and then under these conditions for 5 minutes, finally becoming 95% in 0.1 minute [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 5 minutes under this condition), purity: 97.93%, and the retention time was 11.472 minutes.

¹H NMR(400MHz，CDCl₃)δ0.03(9H，s)，0.92-0.96(2H，m)，1.85(6H，s)，3.59-3.64(2H，m)，5.42(2H，s)，6.14(1H，s)，7.48(1H，t，J＝2.0Hz)，7.57-7.59(3H，m)，7.64(1H，s)。

Synthesis of N- (2- (1H-pyrazol-4-yl) propan-2-yl) -3, 5-dichlorobenzamide (SU 20666-175).

To compound 174(2.17g, 5.0mmol) in CH₂Cl₂To a solution in (20mL) was added TFA (8 mL). The mixture was stirred at room temperature for 5 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 30mL water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo. The crude product was dissolved in CH₃To OH (20mL) was added ethylenediamine (1mL, 15.0 mmol). The mixture was stirred at room temperature for 16 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 30mL water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, the crude product was purified by flash chromatography to yield the desired product 175(1.2g, yield: 80.0%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% NH ]₄HCO₃]And 95% [ water + 0.05% NH ]₄HCO₃](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally becoming 95% in 0.05 minutes [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 0.7 minutes under this condition), purity: 97.87%, retention time 1.908 minutes; MS calculated: 297.0, respectively; MS found: 298.0[ M + H ]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.67(6H，s)，7.43(1H，s)，7.61(1H，s)，7.76-7.77(1H，m)，7.82(2H，d，J＝2.0Hz)，8.36(1H，s)，12.54(1H，s)。

Synthesis of 3, 5-dichloro-N- (2- (1- (2-chloroethyl) -1H-pyrazol-4-yl) propan-2-yl) benzamide (153-8).

To compound 175(290.0mg, 1.0mmol) in CH₃CN (5mL) solution was added 1-bromo-2-chloroethane (215.0mg, 1.5mmol) and K₂CO₃(652mg, 2.0 mmol). The mixture was stirred at 80 ℃ for 16 hours. After consumption of the starting material (by LCMS), the solvent was removed in vacuo, the crude product quenched with 30mL of water and quenched withCH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 153-8 as a white solid (312.0mg, yield: 87.0%).

LC-MS (Agilent LCMS 1200- ]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 0.8 min), then continued under these conditions for 0.4 min, finally became 0% [ water + 0.05% TFA ] in 0.01 min]And 100% [ CH ]₃CN+0.05％TFA]To 95% [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％TFA]) Purity: 69.96%, and the retention time is 0.767 min; MS calculated: 359.0; MS found: 360.0[ M + H ]]⁺。

Synthesis of S-2- (4- (2- (3, 5-dichlorobenzamide) propan-2-yl) -1H-pyrazol-1-yl) ethyl thioacetate (SU 20666-184).

To a solution of compound 153-8(312mg, 0.87mmol) in DMF (5mL) were added potassium iodide (29mg, 0.20mmol) and potassium thioacetate (150mg, 1.30 mmol). The mixture was stirred at room temperature for 16 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 50mL water and extracted with EtOAc (30 × 3mL), the organic layers were combined and extracted over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 184(192.0mg, yield: 48.0%) as a white solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA% ]And 95% [ water + 0.05% TFA](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally at 0.0Became 95% in 5 minutes [ water + 0.05% TFA ]]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 96.86%, retention time 1.900 minutes; MS calculated: 399.0, respectively; MS found: 399.9[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% TFA%]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 5 minutes under this condition), purity: 98.49%, retention time 9.685 minutes.

¹H NMR(400MHz，CDCl₃)δ1.83(6H，s)，2.37(3H，s)，3.33(2H，t，J＝6.8Hz)，4.27(2H，t，J＝6.4Hz)，6.15(1H，s)，7.47-7.50(2H，m)，7.55(1H，s)，7.58(2H，d，J＝2.0Hz)。

Synthesis of 3, 5-dichloro-N- (2- (1- (2- (methyldithio) ethyl) -1H-pyrazol-4-yl) propan-2-yl) benzamide (SU 20666-153-A).

To compound 184(120.0mg, 0.3mmol) in CH₃To a solution in OH (5mL) was added sodium thiomethoxide (32.0mg, 0.5 mmol). The mixture was stirred at room temperature for 3 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 20mL water and with CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na ₂SO₄Dried, filtered and concentrated in vacuo to yield the product 153-A as a white solid (46.0mg, yield: 38.0%).

Synthesis of 3, 5-dichloro-N- (2- (1- (2-mercaptoethyl) -1H-pyrazol-4-yl) propan-2-yl) benzamide (SU 20666-153).

To a solution of compound 153-A (46.0mg, 0.11mmol) in glacial acetic acid (2mL) was added zinc powder (23.0mg, 0.34 mmol). The mixture was stirred at 90 ℃ for 1 hour. After consumption of the starting material (by LCMS), the solvent was removed in vacuo, the crude product quenched with 20mL of water and CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by preparative HPLC to give product 153(12.0mg, yield: 27.2%) as a yellow solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 76.40%, retention time 1.874 minutes; MS calculated: 357.0; MS found: 357.9[ M + H ]⁺。

¹H NMR(400MHz，CDCl₃)61.30(1H，t，J＝8.8Hz)，1.74(6H，s)，2.89-2.94(2H，m)，4.20(2H，t，J＝6.4Hz)，6.06(1H，s)，7.39(1H，t，J＝1.6Hz)，7.45(1H，s)，7.48(3H，t，J＝1.6Hz)。

The designations SU20666-154, SP 154 and 154 all refer to the same compound having the formula:

routes of SU20666-154

Synthesis of 3, 5-dichloro-N- (2- (1- (2-hydroxyethyl) -1H-pyrazol-4-yl) propan-2-yl) benzamide (SU 20666-154).

To a solution of compound 175(595.0mg, 2.0mmol) in DMF (10mL) was added 2-bromoethanol (500.0mg, 4.0mmol) and K₂CO₃(830.0mg, 6.0 mmol). The mixture was stirred at 80 ℃ for 24 hours. After the reaction was complete (by LCMS), the reaction was quenched with 100mL water and extracted with EtOAc (30X 3mL), the organic layers were combined and extracted with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to yield the desired product 154 as a white solid (250mg, yield: 37%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 99.76%, retention time 1.645 minutes; MS calculated: 341.0, and the other end is connected with the power supply; MS found: 342.0[ M + H ]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.65(6H，s)，3.68-3.73(2H，s)，4.06(2H，t，J＝6.0Hz)，4.86(1H，t，J＝5.2Hz)，7.37(1H，s)，7.60(1H，s)，7.77-7.78(1H，m)，7.82(2H，d，J＝1.6Hz)，8.37(1H，s)。

The designations SU20666-155, SP 155 and 155 all refer to the same compound having the formula: s

Pathways of SU20666-155

Synthesis of tert-butyl 2- (4- (2- (3, 5-dichlorobenzamide) propan-2-yl) -1H-pyrazol-1-yl) ethylcarbamate (155-1).

To compound 153-5(208mg, 0.7mmol) in acetone (10mL) was added tert-butyl N- (2-bromoethyl) carbamate (235mg, 1.1mmol) and cesium carbonate (685mg, 2.1 mmol). The mixture was stirred at 60 ℃ for 24 hours. After the reaction was complete (by LCMS), the reaction was quenched with 30mL water and CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 155-1 as a white solid (221.0mg, yield: 72.0%).

Synthesis of N- (2- (1- (2-aminoethyl) -1H-pyrazol-4-yl) propan-2-yl) -3, 5-dichlorobenzamide (SU 20666-155).

To compound 155-1(221mg, 0.5mmol) in CH₂Cl₂To the solution in (5mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 3 hours. After consumption of the starting material (by LCMS), the solvent was removed in vacuo, the crude product was dissolved in 20mL of water, and potassium carbonate was added to adjust the pH to 9-10. Then the aqueous phase is treated with CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Drying, filtering and vacuum dryingWas concentrated, the crude product was dissolved with DMF and purified by preparative HPLC to give the desired product 155 as a white solid (54mg, yield: 23%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% NH ]₄HCO₃]And 95% [ water + 0.05% NH ]₄HCO₃](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally becoming 95% in 0.05 minutes [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 0.7 minutes under this condition), purity: 99.74 percent, and the retention time is 1.475 minutes; MS calculated: 340.0 of the total weight of the mixture; MS found: 341.0[ M + H ]⁺。

¹H NMR(400MHz，DMSO-d₆+D₂O)δ1.66(6H，s)，2.85(1H，t，J＝6.4Hz)，3.29(1H，t，J＝6.4Hz)，3.99-4.07(2H，m)，7.39(1H，d，J＝2.4Hz)，7.61(1H，s)，7.77(1H，s)，7.81(2H，d，J＝1.6Hz)。

The designations SU20666-156, SP 156, and 156 all refer to the same compound having the formula as shown below. The designations SU20666-169, SP 169 and 169 all refer to the same compound having the formula as shown below. The designations SU20666-173, SP 173 and 173 all refer to the same compound having the formula as shown below.

Pathways of SU20666-156, SU20666-169 and SU20666-173

Synthesis of 2- (4- (2-aminopropyl-2-yl) -1H-1, 2, 3-triazol-1-yl) ethanol (156-2).

To a solution of compound 156-1(5.0g, 57.4mmol) in THF (150mL) were added copper sulfate pentahydrate (14.3g, 57.4mmol), sodium L-ascorbate (11.4g, 57.4mmol), and 2-methyl-3-butyn-2-amine (5.7g, 68.9mmol), and the mixture was stirred at room temperature overnight. After consumption of the starting material (by LCMS), the mixture was filtered and the filtrate was concentrated to yield the desired product 156-2 as a brown oil (5.3g, yield: 54.2%).

Synthesis of 3, 5-dibromo N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-169).

To the compound 3, 5-dibromobenzoic acid (500mg, 1.8mmol) in CH₂Cl₂To the solution in (25mL) were added HATU (1.0g, 2.7mmol), DIEA (1.1mL, 7.2mmol) and 156-2(307mg, 1.8 mmol). The mixture was stirred at room temperature for 1 hour. After consumption of the starting material (by LCMS), the mixture was quenched with 30mL water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Drying, filtering and concentrating in vacuo, purifying the crude product by flash chromatography to obtainDesired product 169 was produced as a white solid (650.0mg, yield: 84.0%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% NH ]₄HCO₃]And 95% [ water + 0.05% NH ]₄HCO₃](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally becoming 95% in 0.05 minutes [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 0.7 minutes under this condition), purity: 97.20%, retention time 1.722 minutes; MS calculated: 430.0; MS found: 431.0[ M + H ]⁺。

¹H NMR(400MHz，CDCl₃)δ1.87(6H，s)，2.82(1H，s)，4.08(2H，t，J＝4.8Hz)，4.50(2H，t，J＝4.8Hz)，7.00(1H，s)，7.69(1H，s)，7.78(1H，t，J＝2.0Hz)，7.82(2H，d，J＝2.0Hz)。

Synthesis of 4-methylbenzenesulfonic acid 2- (4- (2- (3, 5-dibromobenzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl ester (156-4).

To compound 169(430.0mg, 1.0mmol) in CH₂Cl₂To a solution in (20mL) were added DIEA (258.5mg, 2.0mmol) and TsCl (286.0mg, 1.5 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete (by LCMS), the mixture was quenched with 30mL of water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 156-4 as a white solid (300.0mg, yield: 51.0%).

Synthesis of S-2- (4- (2- (3, 5-dibromobenzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl thioacetate (SU 20666-173).

To a mixture of compound 156-4(300.0mg, 0.54mmol) in DMF (5mL) was added potassium thioacetate (89.0mg, 0.78 mmol). The mixture was stirred at room temperature for 5 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 50mL water and extracted with EtOAc (30 × 3mL), the organic layers were combined and extracted over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, the crude product was purified by flash chromatography to yield the desired product 173 as a white solid (250.0mg, yield: 95.0%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% NH ]₄HCO₃]And 95% [ water + 0.05% NH ]₄HCO₃](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally becoming 95% in 0.05 minutes [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 0.7 minutes under this condition), purity: 100.00%, retention time 2.044 min; MS calculated: 488.0(ii) a MS found: 489.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% TFA% ]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 5 minutes under this condition), purity: 91.33%, and the retention time was 9.547 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.68(6H，s)，2.33(3H，s)，3.32(2H，t，J＝1.6Hz)，4.46(2H，t，J＝1.6Hz)，7.95(1H，s)，8.00-8.01(3H，m)，8.60(1H，s)。

Synthesis of 3, 5-dibromo N- (2- (1- (2-mercaptoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-156).

To compound 173(150.0mg, 0.31mmol) in CH₃To a solution in OH (5mL) was added sodium thiomethoxide (33.0mg, 0.46 mmol). The mixture was stirred at room temperature for 3 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 20mL water and with CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, the crude product was purified by preparative HPLC to yield the desired product 156 as a white solid (55.0mg, yield: 40.0%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA) ]And 5% [ CH ]₃CN+0.05％TFA]And continues under these conditions0.7 min), purity: 100.00%, retention time 1.832 minutes; MS calculated: 446.0; MS found: 446.8[ M + H ]]⁺。

¹H NMR(400MHz，CDCl₃)δ1.41(1H，t，J＝8.8Hz)，1.82(6H，s)，2.98(2H，t，J＝6.4Hz)，4.48(2H，t，J＝6.0Hz)，6.86(1H，s)，7.58(1H，s)，7.70(1H，s)，7.75(2H，d，J＝1.2Hz)。

The designations SU20666-157, SP 157 and 157 all refer to the same compound having the formula as shown below. The designations SU20666-170, SP 170 and 170 all refer to the same compound having the formula as shown below. The designations SU20666-171, SP 171 and 171 all refer to the same compound having the formula as shown below.

Pathways of SU20666-157, SU20666-170 and SU20666-171

Synthesis of 3, 4-dichloro-N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-170).

To the compound 3, 4-Dichlorobenzoic acid (570.0mg, 3.0 mm)ol) to CH ₂Cl₂To a solution in (25mL) were added HATU (1.7g, 4.5mmol), DIEA (2.0mL, 12.0mmol) and 156-2(511mg, 3.0 mmol). The mixture was stirred at room temperature for 1 hour. After consumption of the starting material (by LCMS), the mixture was quenched with 30mL water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to yield the desired product 170 as a white solid (650.0mg, yield: 64.0%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% NH ]₄HCO₃]And 95% [ water + 0.05% NH ]₄HCO₃](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally becoming 95% in 0.05 minutes [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 0.7 minutes under this condition), purity: 97.53%, and the retention time is 1.595 minutes; MS calculated: 342.0; MS found: 343.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% TFA%]And 5% [ CH ] ₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 5 minutes under this condition), purity: 99.15%, retention time 7.524 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，3.77(2H，q，J＝5.2Hz)，4.34(2H，t，J＝5.6Hz)，5.01(1H，t，J＝5.6Hz)，7.71-7.74(1H，m)，7.77-7.80(1H，m)，7.89(1H，s)，8.08(1H，d，J＝2.0Hz)，8.53(1H，s)。

Synthesis of methanesulfonic acid 2- (4- (2- (3, 4-dichlorobenzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl ester (157-2).

To compound 170(457.0mg, 1.3mmol) in CH₂Cl₂To a solution in (20mL) were added DIEA (345.0mg, 2.7mmol) and Ms₂O (349.0mg, 2.0 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete (by LCMS), the mixture was quenched with 30mL of water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 157-2 as a white solid (520.0mg, yield: 92.4%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 0.8 min), then continued under these conditions for 0.4 min, finally became 0% [ water + 0.05% TFA ] in 0.01 min ]And 100% [ CH ]₃CN+0.05％TFA]To 95% [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％TFA]Purity: 57.88%, the retention time is 0.666 minutes; MS calculated: 420.0 of the total weight of the mixture; MS found: 420.9[ M + H]⁺。

Synthesis of S-2- (4- (2- (3, 4-dichlorobenzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl thioacetate (SU 20666-171).

To a mixture of compound 157-2(572.0mg, 1.34mmol) in DMF (5mL) was added potassium thioacetate (230.0mg, 2.01 mmol). The mixture was stirred at room temperature for 5 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 50mL of water and EtOAc (30X 3mL) extraction, the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, the crude product was purified by preparative HPLC to yield the desired product 171(218.0mg, yield: 38.8%) as a white solid.

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% NH ]₄HCO₃]And 95% [ water + 0.05% NH ]₄HCO₃](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally becoming 95% in 0.05 minutes [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 0.7 minutes under this condition), purity: 100.00 percent, and the retention time is 1.925 minutes; MS calculated: 400.0 of; MS found: 401.0[ M + H ]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.69(6H，s)，2.33(3H，s)，3.33(2H，t，J＝6.8Hz)，4.46(2H，t，J＝6.8Hz)，7.72-7.74(1H，m)，7.77-7.80(1H，m)，7.95(1H，s)，8.09(1H，d，J＝2.0Hz)，8.55(1H，s)。

Synthesis of 3, 4-dichloro-N- (2- (1- (2-mercaptoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-157).

To compound 171(150.0mg, 0.38mmol) in CH₃To a solution in OH (5mL) was added sodium thiomethoxide (40.0mg, 0.46 mmol). The mixture was stirred at room temperature for 3 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 20mL water and with CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by preparative HPLC to yield the desired product 157(60.0mg, yield: 44.0%) as a white solid.

LC-MS (Agilent LCMS 1200- ]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100.00 percent, and the retention time is 1.748 minutes; MS calculated: 358.0, respectively; MS found: 359.0[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，2.43(1H，s)，2.94(2H，t，J＝6.8Hz)，4.46(2H，t，J＝6.8Hz)，7.72-7.74(1H，m)，7.77-7.80(1H，m)，7.97(1H，s)，8.08(1H，d，J＝2.0Hz)，8.55(1H，s)。

The designations SU20666-158, SP 158 and 158 all refer to the same compound having the formula as shown below. The designations SU20666-176, SP 176 and 176 all refer to the same compound having the formula as shown below. The designations SU20666-177, SP 177 and 177 all refer to the same compound having the formula as shown below.

Pathways of SU20666-158, SU20666-176 and SU20666-177

Synthesis of 3, 5-difluoro N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-176).

To the compound 3, 5-difluorobenzoic acid (237.0mg, 1.5mmol) in CH₂Cl₂To a solution in (15mL) were added HATU (856mg, 2.3mmol), DIEA (1.0mL, 6.0mmol) and 156-2(256.0mg, 1.5 mmol). The mixture was stirred at room temperature for 1 hour. After consumption of the starting material (by LCMS), the mixture was quenched with 30mL water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 176 as a white solid (400.0mg, yield: 86.0%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% NH ]₄HCO₃]And 95% [ water + 0.05% NH ]₄HCO₃](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally becoming 95% in 0.05 minutes [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 0.7 minutes under this condition), purity: 100.00%, retention time 1.410 min; MS calculated: 310.0, respectively; MS found: 311.1[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% TFA% ]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 5 minutes under this condition), purity: 98.69%, retention time 6.539 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，3.78(2H，q，J＝5.2Hz)，4.34(2H，t，J＝5.6Hz)，5.01(1H，t，J＝5.2Hz)，7.41-7.47(1H，m)，7.52-7.57(2H，m)，7.89(1H，s)，8.49(1H，s)。

Synthesis of methanesulfonic acid 2- (4- (2- (3, 5-difluorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl ester (158-2).

To compound 176(310.0mg, 1.0mmol) in CH₂Cl₂To a solution (10mL) were added DIEA (259.0mg, 2.0mmol) and Ms₂O (262.0mg, 1.5 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete (by LCMS), the mixture was quenched with 30mL of water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 158-2 as a white solid (369.0mg, yield: 95.0%).

Synthesis of S-2- (4- (2- (3, 5-difluorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl thioacetate (SU 20666-177).

To a mixture of compound 158-2(388.0mg, 1.0mmol) in DMF (5mL) was added potassium thioacetate (114.0mg, 1.5 mmol). The mixture was stirred at room temperature for 5 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 50mL water and extracted with EtOAc (30 × 3mL), the organic layers were combined and extracted over anhydrous Na ₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by preparative HPLC to give the desired product 177 as a white solid (226.0mg, yield: 61.4%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100.00%, retention time 1.653 minutes; MS calculated: 368.0, respectively; MS found: 369.0[ M + H]⁺。

¹H NMR(400MHz，CDCl₃)δ1.90(6H，s)，2.40(3H，s)，3.39(2H，t，J＝6.8Hz)，5.40(2H，t，J＝6.8Hz)，6.92-6.97(1H，m)，7.04(1H，s)，7.29-7.33(2H，m)，7.62(1H，s)。

Synthesis of 3, 5-difluoro N- (2- (1- (2- (methyldithio) ethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-158-A).

To compound 177(200.0mg, 0.54mmol) in CH₃To a solution in OH (5mL) was added sodium thiomethoxide (57.0mg, 0.81 mmol). The mixture was stirred at room temperature for 3 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 20mL water and with CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to yield the product 158-A as a white solid (200.0mg, yield: 99.0%).

Synthesis of 3, 5-difluoro N- (2- (1- (2-mercaptoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-158).

To a solution of compound 158-A (200.0mg, 0.54mmol) in glacial acetic acid (5mL) was added zinc powder (53.0mg, 0.81 mmol). The mixture was stirred at 90 ℃ for 1 hour. After consumption of the starting material (by LCMS), the solvent was removed in vacuo, the crude product quenched with 20mL of water and CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by preparative HPLC to yield product 158 as a white solid (60.0mg, yield: 34.1%).

LC-MS (Agilent LCMS 1200- ]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100.00 percent, and the retention time is 1.619 minutes; MS calculated: 326.0, respectively; MS found: 327.0[ M +H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，2.44(1H，t，J＝8.0Hz)，2.95(2H，q，J＝6.8Hz)，4.46(2H，t，J＝6.8Hz)，7.41-7.47(1H，m)，7.52-7.56(2H，m)，7.98(1H，s)，8.51(1H，s)。

The designations SU20666-159, SP 159 and 159 all refer to the same compound having the formula:

routes of SU20666-159

Synthesis of N- (2- (1-acryloyl-1H-1, 2, 3-triazol-4-yl) endo-2-yl) -3, 5-dichlorobenzamide (SU 20666-159).

To compound 159-4(209.0mg, 0.7mmol) in dry CH₂Cl₂(5mL) to the solution was added K₂CO₃(291.0mg, 2.1mmol) and acryloyl chloride (95.0mg, 1.1 mmol). The mixture was stirred at room temperature for 16 hours. After consumption of the starting material (by LCMS), the reaction mixture was quenched with 20mL of water and with CH ₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Drying, filtration and concentration in vacuo, purification of the crude product by flash chromatography and recrystallization from petroleum ether/ethyl acetate (1: 1) to yield the desired product as a white solid159(150.0mg, yield: 61.0%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 97.64 percent, and the retention time is 1.940 minutes; MS calculated: 352.0; MS found: 352.9[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% TFA%]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.05% TFA)]And 5% [ CH ] ₃CN+0.05％TFA]And for 5 minutes under this condition), purity: 93.78%, and the retention time was 9.533 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.74(6H，s)，6.36-6.39(1H，m)，6.75-6.79(1H，m)，7.48-7.55(1H，m)，7.80-7.88(3H，m)，8.65(1H，s)，8.78(1H，s)。

The designations SU20666-162, SP 162, and 162 all refer to the same compound having the formula:

routes of SU20666-162

Synthesis of N- (2- (1-acryloyl-1H-pyrazol-4-yl) propan-2-yl) -3, 5-dichlorobenzamide (SU 20666-162).

To compound 153-5(80.0mg, 0.3 m)mol) to dry CH₂Cl₂(5mL) to the solution was added K₂CO₃(112.0mg, 0.8mmol) and acryloyl chloride (36.0mg, 0.4 mmol). The mixture was stirred at room temperature for 16 hours. After consumption of the starting material (by LCMS), the reaction mixture was quenched with 20mL of water and with CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄The crude product was purified by flash chromatography and recrystallization from petroleum ether/ethyl acetate (1: 1) to yield the desired product 162 as a white solid (36.0mg, yield: 38.0%).

LC-MS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% NH ]₄HCO₃]And 95% [ water + 0.05% NH ]₄HCO₃](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally becoming 95% in 0.05 minutes [ water + 0.05% NH ] ₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 0.7 minutes under this condition), purity: 98.42%, retention time 2.206 minutes; MS calculated: 351.0; MS found: 352.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% NH ]₄HCO₃](within 10 minutes) and then under these conditions for 5 minutes, finally becoming 95% in 0.1 minute [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 5 minutes under this condition), purity: 97.18%, and the retention time was 10.249 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.68(6H，s)，6.18-6.21(1H，m)，6.61-6.65(1H，m)，7.44-7.51(1H，m)，7.79(1H，t，J＝2.0Hz)，7.85(2H，d，J＝2.0Hz)，7.94(1H，s)，8.33(1H，s)，8.58(1H，s)。

The designations SU20666-163, SP 163, and 163 all refer to the same compound having the formula:

the pathways of SU 20666-163-

Synthesis of S-2- (4- (2- (3, 5-dichlorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl 2-methylthiopropionate (SU 20666-163).

To a solution of compound SU20666-087(100mg, 0.278mmol) in DCM (20ml) was added TEA (71.95mg, 0.557mmol) and acryloyl chloride (37.75mg, 0.417 mmol). The mixture was stirred at-78 ℃ for 1 hour. After consumption of the starting material (by LCMS), the mixture was concentrated in vacuo and purified by preparative HPLC to give SU20666-163 as a white solid (70mg, yield: 58%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, retention time 1.981 minutes; MS calculated: 428; MS found: 428.9[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 97.12%, retention time 9.780 minutes; MS calculated: 428; MS found: 428.9[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.08(6H，d，J＝6.8Hz)，1.69(6H，s)，2.70-2.75(1H，m)，3.31(2H，d，J＝6.4Hz)，4.46(2H，t，J＝6.8Hz)，7.79(1H，t，J＝2.0Hz)，7.84(2H，d，J＝1.6Hz)，7.94(1H，s)，8.60(1H，s)。

The designations SU20666-164, SP 164 and 164 all refer to the same compound having the formula:

routes of SU20666-164

Synthesis of S-2- (4- (2- (3, 5-dichlorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl thiobenzoate (SU 20666-164).

To a solution of compound SU20666-087(100mg, 0.278mmol) in DCM (20ml) was added TEA (71.95mg, 0.557mmol) and benzoyl chloride (58.62mg, 0.417 mmol). The mixture was stirred at-78 ℃ for 1 hour. After consumption of the starting material (by LCMS), the mixture was concentrated in vacuo and purified by preparative HPLC to give SU20666-164 as a white solid (75mg, yield: 58.1%).

LCMS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally changed within 0.1 minuteIs 95% [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 96.93%, retention time 2.228 minutes; MS calculated: 462; MS found: 463.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 97.65%, retention time 10.013 minutes; MS calculated: 462; MS found: 463.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.67(6H，s)，3.55(2H，t，J＝6.8Hz)，4.58(2H，t，J＝6.8Hz)，7.55(2H，t，J＝7.6Hz)，7.79(1H，t，J＝2.0Hz)，7.83(2H，d，J＝1.6Hz)，7.88-7.90(2H，m)，8.00(1H，s)，8.60(1H，s)。

The designations SU20666-166, SP 166 and 166 all refer to the same compound having the formula as shown below. The designations SU20666-182, SP 182 and 182 all refer to the same compound having the formula as shown below. The designations SU20666-183, SP 183 and 183 all refer to the same compound having the formula as shown below.

Routes of SU20666-166, SU20666-182 and SU20666-183

Synthesis of 3, 5-difluoro N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (166-2).

To a solution of compound 3-amino-5-chlorobenzoic acid (342.0mg, 2.0mmol) in THF (15mL) at 0 deg.C was added Et3N (606mg, 6.0mmol) and acetyl chloride (157.0mg, 2.0 mmol). The mixture was then warmed to room temperature for 5 hours. After consumption of the starting material (by LCMS), the reaction solvent was removed in vacuo, the crude product was dissolved with 30mL of water and 1N HCl was added to adjust the pH 2-3, filtered and the filter cake was collected, lyophilized to yield the desired product 166-2 as a white solid (410.0mg, yield: 96.2%).

Synthesis of 3-acetamido-5-chloro N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-182).

To the compound 3-acetamido-5-chlorobenzoic acid (410.0mg, 1.9mmol) in CH₂Cl₂To a solution in (30mL) were added HATU (1.1g, 2.9mmol), DIEA (1.3mL, 7.6mmol) and 156-2(325.0mg, 1.9 mmol). The mixture was stirred at room temperature for 1 hour. After consumption of the starting material (by LCMS), the mixture was quenched with 30mL water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to yield the desired product 182 as a white solid (500.0mg, yield: 72.0%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under these conditions),purity: 100.00%, retention time 1.320 minutes; MS calculated: 365.0, respectively; MS found: 366.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% TFA% ]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 5 minutes under this condition), purity: 100.00% and a retention time of 6.109 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.69(6H，s)，2.06(3H，s)，3.75-3.79(2H，m)，4.34(2H，t，J＝5.6Hz)，5.02(1H，t，J＝5.2Hz)，7.56(1H，t，J＝1.6Hz)，7.75(1H，t，J＝1.6Hz)，7.87(1H，s)，7.97(1H，t，J＝1.6Hz)，10.29(1H，s)。

Synthesis of methanesulfonic acid 2- (4- (2- (3-acetamido-5-chlorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl ester (166-4).

To compound 166-3(300.0mg, 0.8mmol) in CH₂Cl₂To a solution in (10mL) were added DIEA (212.0mg, 1.6mmol) and Ms₂O (215.0mg, 1.2 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete (by LCMS), the mixture was quenched with 30mL of water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 166-4(325.0mg, yield: 89.5%) as a white solid.

Synthesis of Thioacetic acid S-2- (4- (2- (3-acetamido-5-chlorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl ester (166-5).

To a mixture of compound 1664(220.0mg, 0.50mmol) in DMF (5mL) was added potassium thioacetate (86.0mg, 0.75 mmol). The mixture was stirred at room temperature for 5 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 50mL water and extracted with EtOAc (30 × 3mL), the organic layers were combined and extracted over anhydrous Na ₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by preparative HPLC to yield the desired product 166-5(180.0mg, yield: 85.3%) as a white solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 0.8 min), then continued under these conditions for 0.4 min, finally became 0% [ water + 0.05% TFA ] in 0.01 min]And 100% [ CH ]₃CN+0.05％TFA]To 95% [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％TFA]) Purity: 66.22 percent, and the retention time is 0.596 minutes; MS calculated: 423.0, respectively; MS found: 424.0[ M + H]⁺。

Synthesis of 3-acetamido-5-chloro N- (2- (1- (2- (methyldithio) ethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-183).

To compound 166-5(180.0mg, 0.43mmol) in CH₃To a solution in OH (5mL) was added sodium thiomethoxide (45.0mg, 0.64 mmol). The mixture was stirred at room temperature for 3 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 20mL water and with CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to yield product 183 as a white solid (175.0mg, yield: 95.3%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100.00%, retention time 1.772 min; MS calculated: 372.0, respectively; MS found: 373.0[ M + H ]]⁺。

HPLC (Agilent HPLC 1200; column: L. column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% TFA%]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 5 minutes under this condition), purity: 99.38%, retention time 8.912 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，2.41(3H，s)，3.24(2H，t，J＝6.8Hz)，4.60(2H，t，J＝6.8Hz)，7.41-7.47(1H，m)，7.52-7.57(2H，m)，8.01(1H，m)，8.51(1H，s)。

Synthesis of 3-acetamido-5-chloro N- (2- (1- (2-mercaptoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-166).

To a solution of compound 166-A (175.0mg, 0.41mmol) in glacial acetic acid (5mL) was added zinc powder (81.0mg, 1.23 mmol). The mixture was stirred at 90 ℃ for 1 hour. After consumption of the starting material (by LCMS), the solvent was removed in vacuo, the crude product quenched with 20mL of water and CH ₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to yieldThe crude product was purified by preparative HPLC to give product 166 as a white solid (19.0mg, yield: 10.0%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 97.47%, and the retention time is 1.496 minutes; MS calculated: 381.0, respectively; MS found: 382.0[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.69(6H，s)，2.05(3H，s)，2.41(1H，d，J＝6.0Hz)，2.92-2.96(2H，m)，4.46(2H，t，J＝6.8Hz)，7.56(1H，s)，7.73(1H，s)，7.96-7.99(2H，m)，8.46(1H，s)，10.25(1H，s)。

The designations SU20666-168, SP 168 and 168 all refer to the same compound having the formula:

the pathways of SU20666-168

Synthesis of 3, 5-dichloro-N- (2- (1- (2-chloroethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-168).

To compound SU20666-150(50mg, 0.146mmol) in SOCl₂(25 ml). The mixture was heated to reflux for 16 hours. The mixture was concentrated in vacuo and purified by preparative HPLC to give SU20666-168(18.54mg, yield: 35.25%) as a white solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, retention time 1.799 minutes; MS calculated: 360; MS found: 361.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA% ]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 98.37%, the retention time is 9.144 minutes; MS calculated: 360; MS found: 361.0[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，4.06(2H，t，J＝6.0Hz)，4.66(2H，t，J＝5.6Hz)，7.79(1H，t，J＝2.0Hz)，7.84(2H，d，J＝2.0Hz)，8.01(1H，s)，8.62(1H，s)。

The designations SU20666-172, SP 172 and 172 all refer to the same compound having the formula:

routes of SU20666-172

Synthesis of 3, 5-dibromo N- (2- (1- (2-chloroethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-172).

To compound 169(107.0mg, 0.25mmol) in thionyl chloride (5mL) at 0 ℃ then the mixture was warmed to 60 ℃ for 5 hours. After consumption of the starting material (by LCMS), the solvent was removed in vacuo, the crude product was dissolved in 20mL of water, and the aqueous phase was taken up with CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, the crude product was dissolved by DMF and purified by preparative HPLC to yield the desired product 172 as a white solid (37.0mg, yield: 33.0%).

LC-MS (Agilent LCMS 1200- ₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]To 5% [ water + 0.05% NH ]₄HCO₃]And 95% [ water + 0.05% NH ]₄HCO₃](within 1.6 minutes), then continued under these conditions for 1.4 minutes, finally becoming 95% in 0.05 minutes [ water + 0.05% NH ]₄HCO₃]And 5% [ CH ]₃CN+0.05％NH₄HCO₃]And for 0.7 minutes under this condition), purity: 95.32%, retention time 2.038 minutes; MS calculated: 448.0, respectively; MS found: 449.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% TFA%]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And under such conditionsFor 5 minutes), purity: 94.47%, retention time 9.430 minutes.

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，4.05(2H，t，J＝5.6Hz)，4.66(2H，t，J＝5.6)，8.00-8.01(4H，m)，8.62(1H，s)。

The designations SU20666-178, SP 178 and 178 all refer to the same compound having the formula:

routes of SU20666-178

Synthesis of 2- (1- (4-methoxybenzyl) -1H-1, 2, 3-triazol-4-yl) propan-2-amine (159-2).

To a solution of compound 159-1(2.5g, 15.32mmol) in THF (150ml) was added copper sulfate pentahydrate (3.83g, 15.32mmol), 2-methylbut-3-yn-2-amine (1.28g, 15.32mmol) and sodium L-ascorbate (3.03g, 15.32 mmol). The mixture was heated to 40 ℃ for 16 hours. After consumption of the starting material (by LCMS), the mixture was concentrated under vacuum and water (20mL) was added. The mixture was freeze-dried under vacuum to give 159-2(10.94g, crude product) which was used in the next step without further purification.

Synthesis of 3, 5-dichloro N- (2- (1- (4-methoxybenzyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-178).

To a solution of compound 159-2(10.94g, 15.32mmol) in DMF (250mL) were added DIEA (2.58g, 19.92mmol), HATU (11.65g, 30.64mmol) and 3, 5-dichlorobenzoic acid (2.93g, 15.32 mmol). The mixture was stirred at 40 ℃ for 3 hours. After consumption of the starting material (by LCMS), water was added and the mixture was extracted by DCM. The combined organic phases were concentrated in vacuo and purified by preparative HPLC to give SU20666-178 as a white solid (3.5g, yield: 53.85%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100%, retention time 1.913 minutes; MS calculated: 418; MS found: 419.0[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA% ]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 100%, retention time 9.826 min; MS calculated: 418; MS found: 419.0[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.67(6H，s)，3.73(3H，s)，5.44(2H，s)，6.92(2H，d，J＝8.8Hz)，7.28(2H，d，J＝8.8Hz)，7.78(1H，t，J＝1.6Hz)，7.82(2H，d，J＝2.0Hz)，7.96(1H，s)，8.59(1H，s)。

The designations SU20666-179, SP 179 and 179 all refer to the same compound having the formula:

the pathway of SU20666-179

Synthesis of 3, 5-dichloro-N- (2- (1- (4-methoxybenzyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-179).

To a mixture of SU20666-178-01(3.0g, 7.15mmol) in acetonitrile (300ml) and H₂CAN (43.12g, 7.86mmol) was added to a solution in O (100 ml). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and purified by preparative HPLC to give SU20666-179 as a yellow solid (1.83g, yield: 85.5%).

LCMS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ] ₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 97.25%, retention time 1.716 minutes; MS calculated: 298; MS found: 299.0[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.69(6H，s)，7.58-7.68(1H，m)，7.79(1H，t，J＝2.0Hz)，7.84(2H，d，J＝2.0Hz)，8.62(1H，s)。

The designations SU20666-180, SP 180 and 180 all refer to the same compound having the formula:

the pathways of SU20666-168

Synthesis of 1-azidopropane (180-2).

To compound 150-1(200mg, 1.63mmol) in THF (10ml) and H₂NaN was added to a solution of O (10ml)₃(126.84mg, 1.95 mmol). The mixture was heated to 80 ℃ for 16 hours. The mixture was concentrated in vacuo and extracted three times with DCM. The combined organic phases were concentrated under vacuum to give 180-2 as a white solid (100mg, yield: 72%).

Synthesis of 2- (1-propyl-1H-pyrazol-4-yl) propan-2-amine (180-3).

To a solution of compound 180-2(100mg, 1.18mmol) in THF (50ml) were added copper sulfate pentahydrate (22.7mg, 1.29mmol), 2-methylbut-3-yn-2-amine (107.5mg, 1.29mmol) and sodium L-ascorbate (256mg, 1.29 mmol). The mixture was heated to 40 ℃ for 16 hours. After consumption of the starting material (by LCMS), the mixture was concentrated under vacuum and water (20mL) was added. The mixture was freeze-dried under vacuum to give 180-3(450mg, crude product) which was used in the next step without further purification.

Synthesis of 3, 5-dichloro-N- (2- (1-propyl-1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-180).

To a solution of compound 180-3(450mg (crude), 1.18mmol) in DMF (25mL) was added DIEA (305mg, 2.36mmol), HATU (538.4mg, 1.42mmol) and 3, 5-dichlorobenzoic acid (225.4mg, 1.178 mmol). The mixture was stirred at 40 ℃ for 16 hours. After consumption of the starting material (by LCMS). Water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative HPLC to yield the desired product SU20666-180 as a white solid (20mg, yield: 5%).

LCMS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 99.67%, retention time 2.138 minutes; MS calculated: 340, respectively; MS found: 341.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.1% TFA%]And 5% [ CH ]₃CN+0.1％TFA]To 0% [ water + 0.1% TFA%]And 100% [ CH ]₃CN+0.1％TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.1% TFA)]And 5% [ CH ]₃CN+0.1％TFA]And for 5 minutes under this condition), purity: 98.96%, retention time 9.320 minutes; MS calculated: 340, respectively; MS found: 341.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ0.83(3H，t，J＝7.6Hz)，1.69(6H，s)，1.76-1.85(2H，m)，4.25(2H，t，J＝6.4Hz)，7.78(1H，t，J＝2.0Hz)，7.84(2H，d，J＝1.6Hz)，7.93(1H，s)，8.59(1H，s)。

The designations SU20666-181, SP 181 and 181 all refer to the same compound having the formula:

routes of SU20666-181

Synthesis of N- (2- (1- (2-azidoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) -3, 5-dichlorobenzamide (SU 20666-181).

To a solution of compound 150-01(1.0g, 2.91mmol) in THF (30ml) were added DPPA (1.04g, 3.79mmol) and DBU (577mg, 3.79 mmol). The mixture was stirred at 0 ℃ for 2 hours. After consumption of the starting material (by LCMS), water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative HPLC to yield the desired product SU20666-181 as a white solid (600mg, yield: 56%).

LCMS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 100%, retention time 1.935 min; MS calculated: 367; MS found: 368.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ] ₄HCO₃]And 100% [ CH ]₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 100%, retention time 9.256 minutes; MS calculated: 367; MS found: 368.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，3.80(2H，t，J＝6.0Hz)，4.5(2H，t，J＝5.6Hz)，7.78(1H，t，J＝2.0Hz)，7.84(2H，d，J＝2.0Hz)，8.00(1H，s)，8.62(1H，s)

The designations SU20666-186, SP 186 and 186 all refer to the same compound having the formula:

routes of SU20666-186

Synthesis of 3-chloro-5- (4-methylpiperazin-1-yl) benzonitrile (167-2).

To a solution of compound 167-1(623.0mg, 4.0mmol) in DMSO (10mL) was added K₂CO₃(1.1_g8.0mmol) and 1-methylpiperazine (601.0mg, 6.0 mmol). The mixture was warmed to 80 ℃ for 24 hours. After consumption of the starting material (by LCMS), the reaction solvent was quenched with 100mL water and extracted with EtOAc (30X 3mL), and the organic layer was washed with saturated aqueous NaClWashing, collecting the organic layer and passing through anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was used directly in the next step without further purification to give the crude product 167-2 as a white solid (910.0mg, yield: 96.8%).

Synthesis of 3-chloro-5- (4-methylpiperazin-1-yl) benzoic acid (167-3).

To a solution of compound 167-2(910.0mg, 3.9mmol) in 95% EtOH (15mL) was added NaOH (165.0mg, 11.6 mmol). The mixture was refluxed for 16 hours. After consumption of the starting material (by LCMS), the solvent was removed in vacuo, the crude product was dissolved with 30mL of water and 1N aqueous HCl was added to adjust PH 2-3, the aqueous phase was taken up with CH ₂Cl₂∶CH₃OH 10: 1(30 × 5mL), combined organic layers and extracted over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was used directly in the next step without further purification to give 167-3(800.0mg, yield: 81.3%) as a white solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 0% [ water + 0.05% TFA%]And 100% [ CH ]₃CN+0.05％TFA](in 0.8 min), then continued under these conditions for 0.4 min, finally became 0% [ water + 0.05% TFA ] in 0.01 min]And 100% [ CH ]₃CN+0.05％TFA]To 95% [ water + 0.05% TFA]And 5% [ CH ]₃CN+0.05％TFA]Purity: 100.00%, retention time 0.443 min; MS calculated: 254.0; MS found: 255.2[ M + H]⁺。

Synthesis of 3-chloro-N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) -5- (4-methylpiperazin-1-yl) benzamide (167-4).

To the mixture of 167-3(508.0mg, 2.0mmol) in CH₂Cl₂To a solution in (20mL) were added HATU (1.2g, 6.0mmol), DIEA (1.3mL, 8.0mmol) and 156-2(340.0mg, 2.0 mmol). The mixture was stirred at room temperature for 1 hour. After consumption of the starting material (by LCMS), the mixture was quenched with 30mL water and with CH ₂Cl₂:CH₃OH (30X 4mL) extraction, organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, the crude product was purified by flash chromatography to yield the desired product 167-4 as a white solid (500.0mg, yield: 61.6%).

Synthesis of 2- (4- (2- (3-chloro-5- (4-methylpiperazin-1-yl) benzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl 4-methylbenzenesulfonate (167-5).

To compound 1674(812.0mg, 2.0mmol) in CH₂Cl₂(20mL) to a solution of DIEA (517.0mg, 4.0mmol) and Ms₂O (523.0mg, 3.0 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete (by LCMS), the mixture was quenched with 30mL of water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 167-5 as a white solid (850.0mg, yield: 87.8%).

Synthesis of S-2- (4- (2- (3-chloro-5- (4-methylpiperazin-1-yl) benzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl thioacetate (SU 20666-186).

To compound 167-5(968.0mg, 2.0mmol) in DMF (5mL)To the mixture of (3) was added potassium thioacetate (343.0mg, 3.0 mmol). The mixture was stirred at room temperature for 5 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 50mL water and extracted with EtOAc (30 × 4mL), the organic layers were combined and extracted with anhydrous Na ₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by preparative HPLC and preparative TLC to give the desired product 186(510.0mg, yield: 55.0%) as a yellow solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 97.62%, retention time 1.714 minutes; MS calculated: 464.0; MS found: 465.2[ M + H]⁺。

¹H NMR(400MHz，CDCl₃)δ1.80(6H，s)，2.31(6H，d，J＝2.4Hz)，2.52(4H，t，J＝4.4Hz)，3.21(4H，t，J＝4.8Hz)，3.30(2H，t，J＝6.8Hz)，4.44(2H，t，J＝6.8Hz)，6.78(1H，s)，6.88(1H，t，J＝2.0Hz)，7.01(1H，t，J＝1.2Hz)，7.15(1H，t，J＝2.0Hz)，7.53(1H，s)。

The designations SU20666-191, SP 191 and 191 all refer to the same compound having the formula as shown below. The designations SU20666-193, SP 193 and 193 all refer to the same compound having the formula as shown below.

Pathways of SU20666-191 and SU20666-193

Synthesis of N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) -3, 5-dimethoxybenzamide (191-1).

To the compound 3, 5-dimethoxybenzoic acid (365.0mg, 2.0mmol) in CH₂Cl₂To a solution in (25mL) were added EDCI (460.0mg, 2.4mmol), HOBT (325.0mg, 2.4mmol), DIEA (517.0mg, 4.0mmol), the mixture was stirred at room temperature for 10 minutes, and 156-2(340.0mg, 2.0mmol) was dissolved in 5mL CH₂Cl₂To be added to the reaction mixture. The mixture was stirred at room temperature for 24 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 30mL water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 191-1(453.0mg, yield: 67.8%) as a white solid.

Synthesis of methanesulfonic acid 2- (4- (2- (3, 5-dimethoxybenzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl ester (191-2).

To compound 191-1(400.0mg, 1.2mmol) in CH₂Cl₂(10mL) to a solution of DIEA (310.0mg, 2.4mmol) and Ms₂O (314.0mg, 1.8 mmol). Will be provided withThe mixture was stirred at room temperature for 16 hours. After the reaction was complete (by LCMS), the mixture was quenched with 30mL of water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 191-2 as a white solid (480.0mg, yield: 97.0%).

Synthesis of S-2- (4- (2- (3, 5-dimethoxybenzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl thioacetate (SU 20666-193).

To a mixture of compound 191-2(555.0mg, 1.4mmol) in DMF (5mL) was added potassium thioacetate (231.0mg, 2.0 mmol). The mixture was stirred at room temperature for 5 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 50mL water and extracted with EtOAc (30 × 3mL), the organic layers were combined and extracted over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, the crude product was purified by preparative HPLC to yield the desired product 193 as a white solid (398.0mg, yield: 75.0%).

LC-MS (Agilent LCMS 1200- ]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 93.48%, retention time 1.625 minutes; MS calculated: 392.0, respectively; MS found: 393.0[ M + H ]]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% TFA%]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](within 10 minutes), thenUnder these conditions for 5 minutes, finally 95% in 0.1 minute [ water + 0.05% TFA ]]And 5% [ CH ]₃CN+0.05％TFA]And for 5 minutes under this condition), purity: 95.44%, retention time 7.486 minutes.

¹H NMR(400MHz，CDCl₃)δ1.81(6H，s)，3.29(2H，t，J＝6.8Hz)，3.74(6H，s)，4.43(2H，t，J＝6.8Hz)，6.49(1H，t，J＝2.4Hz)，6.81(3H，t，J＝2.8Hz)，7.54(1H，s)。

Synthesis of 3, 5-dimethoxy N- (2- (1- (2- (methyldithio) ethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-191-A).

To compound 193(286.0mg, 0.73mmol) in CH₃To a solution in OH (10mL) was added sodium thiomethoxide (77.0mg, 1.09 mmol). The mixture was stirred at room temperature for 3 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 20mL water and with CH ₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to yield the product 191-A (150.0mg, yield: 51.9%) as a white solid.

Synthesis of N- (2- (1- (2-mercaptoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) -3, 5-dimethoxybenzamide (SU 20666-191).

To a bath of compound 191-A (150.0mg, 0.38mmol) in glacial acetic acid (5mL) was added zinc powder (75.0mg, 1.14 mmol). The mixture was stirred at 90 ℃ for 1 hour. After consumption of the starting material (by LCMS), the solvent was removed in vacuo, the crude product quenched with 20mL of water and CH₂Cl₂(20X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo to yieldThe crude product was purified by preparative HPLC to give product 191(33.0mg, yield: 24.8%) as a white solid.

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA) ]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 98.74 percent, and the retention time is 1.579 minutes; MS calculated: 350.0 of the total weight of the mixture; MS found: 351.0[ M + H ]]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.70(6H，s)，2.50(1H，t，J＝1.6Hz)，2.95(2H，t，J＝6.8Hz)，3.78(6H，d，J＝3.2Hz)，4.46(2H，t，J＝6.8Hz)，6.63(1H，t，J＝2.0Hz)，6.96(2H，d，J＝2.4Hz)，7.94(1H，s)，8.29(1H，s)。

The designations SU20666-194, SP 194 and 194 all refer to the same compound having the formula:

the pathway of SU20666-194

Synthesis of N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) endo-2-yl) quinoline-3-carboxamide (192-1).

To the compound quinoline-3-carboxylic acid (346.0mg, 2.0mmol) in CH₂Cl₂To a solution in (25mL) were added EDCI (460.0mg, 2.4mmol), HOBT (325.0mg, 2.4mmol), DIEA (517.0mg, 4.0mmol), the mixture was stirred at room temperature for 10 minutes, and 156-2(340.0mg, 2.0mmol) was dissolved in 5mL CH₂Cl₂To be added to the reaction mixture. The mixture was stirred at room temperature for 24 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 30mL water and with CH ₂Cl₂:CH₃OH (30X 5mL) extraction, organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, the crude product was purified by flash chromatography to give the desired product 192-1 as a white solid (446.0mg, yield: 68.6%).

Synthesis of methanesulfonic acid 2- (4- (2- (quinoline-3-carboxamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl ester (192-2).

To the reaction mixture 192-1(390.0mg, 1.2mmol) in CH₂Cl₂(10mL) to a solution of DIEA (310.0mg, 2.4mmol) and Ms₂O (314.0mg, 1.8 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete (by LCMS), the mixture was quenched with 30mL of water and with CH₂Cl₂(30X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by flash chromatography to give the desired product 192-2 as a white solid (475.0mg, yield: 98.1%).

Synthesis of S-2- (4- (2- (quinoline-3-carboxamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl thioacetate (SU 20666-194).

To a mixture of compound 192-2(490.0mg, 1.2mmol) in DMF (5mL) was added potassium thioacetate (209.0mg, 1.8 mmol). The mixture was stirred at room temperature for 5 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 50mL water and extracted with EtOAc (30 × 3mL), the organic layers were combined and extracted over anhydrous Na ₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by recrystallization from petroleum ether/ethyl acetate to yield the desired product 194 as a white solid (350.0mg, yield: 76.1%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100.00%, retention time 1.387 minutes; MS calculated: 383.0; MS found: 384.0[ M + H]⁺。

¹H NMR(400MHz，CDCl₃)δ1.88(6H，s)，2.32(3H，s)，3.32(2H，t，J＝6.8Hz)，4.47(2H，t，J＝6.8Hz)，7.17(1H，s)，7.53-7.58(2H，m)，7.72-7.76(1H，s)，7.84(1H，d，J＝8.0Hz)，8.09(1H，d，J＝8.4Hz)，8.49(1H，d，J＝2.0Hz)，9.23(1H，d，J＝2.0Hz)。

The designations SU20666-195, SP 195 and 195 all refer to the same compound having the formula:

routes of SU20666-195

Synthesis of N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzo [ d ] oxazole-5-carboxamide (195-3).

To a solution of compound 156-2(200mg, 1.18mmol) in DCM (15mL) was added DIEA (303.72mg, 2.36mmol), HATU (583.28mg, 1.54mmol) and benzo [ d ] oxazole-5-carboxylic acid (192.5mg, 1.18 mmol). The mixture was stirred at room temperature for 1 hour. After consumption of the starting material (by LCMS), water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and purified by preparative TLC to give the desired product 195-3 as a brown solid (250mg, yield: 67%).

Synthesis of methanesulfonic acid 2- (4- (2- (benzo [ d ] oxazole-5-carboxamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl ester (195-4).

To a solution of compound 195-3(250mg, 0.793mmol) in DCM (15mL) was added DIEA (303.72mg, 2.36mmol) and Ms₂O (179.58mg, 1.03 mmol). The mixture was stirred at room temperature for 16 hours. After consumption of the starting material (by LCMS), water was then added and the aqueous phase was washed with dichloro-benzeneMethane extraction, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative TLC to yield the desired product 1954 as a brown solid (224mg, yield: 67%).

Synthesis of S-2- (4- (2- (benzo [ d ] oxazole-5-carboxamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl thioacetate (SU20666-195)

To a solution of compound 195-4(224mg, 0.57mmol) in DMF (15mL) was added potassium thioacetate (65.03mg, 0.57 mmol). The mixture was stirred at room temperature for 3 hours and after consumption of the starting material (by LCMS), the mixture was purified by preparative TLC to give SU20666-195(50mg, yield: 23.5%) as a brown solid.

LCMS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 0.7 minutes under this condition), purity: 95.21%, and the retention time is 1.432 minutes; MS calculated: 373; MS found: 374.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ] ₃CN](within 10 min), then continued under these conditions for 5 min, finally became 95% within 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 96.35%, retention time 7.081 minutes; MS calculated: 373; MS found:374.2[M+H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ1.73(6H，s)，2.34(3H，s)，3.34(2H，t，J＝6.8Hz)，4.48(2H，t，J＝6.8Hz)，7.83(1H，d，J＝8.8Hz)，7.93(1H，dd，J＝8.4，1.6Hz)，7.97(1H，s)，8.33(1H，d，J＝1.6Hz)，8.45(1H，s)，8.85(1H，s)。

the designations SU20666-196, SP 196 and 196 all refer to the same compound having the formula:

routes of SU20666-196

Synthesis of 3-cyano-N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (196-3).

To a solution of compound 156-2(200mg, 1.18mmol) in DCM (15mL) were added DIEA (303.72mg, 2.36mmol), HATU (583.28mg, 1.54mmol), and 3-cyanobenzoic acid (173.7mg, 1.18 mmol). The mixture was stirred at room temperature for 1 hour. After consumption of the starting material (by LCMS), water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, purified by preparative TLC to give the desired product 196-3 as a brown solid (170mg, yield: 48%).

Synthesis of methanesulfonic acid 2- (4- (2- (3-cyanobenzoylamino) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl ester (196-4).

To a solution of compound 196-3(170mg, 0.568mmol) in DCM (15mL) was added DIEA (303.72mg, 2.36mmol) and Ms ₂O (128.62mg, 0.739 mmol). The mixture was stirred at room temperature for 16 hours. After consumption of the starting material (by LCMS), water was then added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and purified by preparative TLC to give the desired product 196-4 as a brown solid (150mg, yield: 70%).

Synthesis of S-2- (4- (2- (3-cyanobenzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl thioacetate (SU20666-196)

To a solution of compound 196-4(150mg, 0.397mmol) in DMF (15mL) was added potassium thioacetate (50mg, 0.437 mmol). The mixture was stirred at room temperature for 3 hours and after consumption of the starting material (by LCMS), the mixture was purified by preparative TLC to give SU20666-196 as a brown oil (50mg, yield: 35%).

LCMS (Agilent LCMS 1200-₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.1 min [ water +10mM NH ]₄HCO₃]And 5% [ CH ] ₃CN]And for 0.7 minutes under this condition), purity: 97.64 percent, and the retention time is 1.780 minutes; MS calculated: 357; MS found: 358.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: Watts X-bridge C18(150mM 4.6mM 3.5 μm), column temperature 40 deg.C, flow rate 1.0 ml/min, mobile phase 95% [ water +10mM NH 2₄HCO₃]And 5% [ CH ]₃CN]To 0% [ water +10mM NH ]₄HCO₃]And 100% [ CH ]₃CN](within 10 minutes)) Then continued under these conditions for 5 minutes, finally becoming 95% in 0.1 minute [ water +10mM NH ]₄HCO₃]And 5% [ CH ]₃CN]And for 5 minutes under this condition), purity: 96.88%, and the retention time is 7.818 minutes; MS calculated: 357; MS found: 358.2[ M + H]⁺。

¹H NMR(400MHz，CDCl₃)δ1.82(6H，s)，2.32(3H，s)，3.30(2H，t，J＝6.8Hz)，4.46(2H，t，J＝6.8Hz)，7.06(1H，s)，7.48(1H，t，J＝8.0Hz)，7.54(1H，s)，7.68-7.71(1H，m)，7.91-7.94(1H，m)，8.01(1H，t，J＝1.2Hz)。

The designations SU20666-197-01, SP 197 and 197 all refer to the same compound having the formula:

the pathway of SU20666-197-01

Synthesis of 2- (4- (2-aminopropyl-2-yl) -1H-1, 2, 3-triazol-1-yl) ethanol (197-2).

To a solution of compound 197-1(5.0g, 57.4mmol) in THF (150mL) were added copper (II) sulfate (4.6g, 29.0mmol), sodium L-ascorbate (5.7g, 29.0mmol) and 2-methyl-3-butyn-2-amine (5.7g, 68.9mmol), and the mixture was stirred at room temperature overnight. After consumption of the starting material (by LCMS), the mixture was filtered and the filtrate was concentrated to yield the desired product 197-2 as a brown oil (6.0g, yield: 61.7%).

Synthesis of 3, 5-dibromo N- (2- (1- (2-hydroxyethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (197-3).

To the compound 3, 5-dibromobenzoic acid (9.8g, 35.3mmol) in CH₂Cl₂To a solution in (150mL) were added HATU (20.0g, 52.9mmol), DIEA (11.7mL, 70.5mmol) and 197-2(6.0g, 35.3 mmol). The mixture was stirred at room temperature for 1 hour. After consumption of the starting material (detected by LCMS), the mixture was quenched with 30mL of water and with CH₂Cl₂(60 mL. times.3), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and purified by flash chromatography (MeOH/CH)₂Cl₂5%) to yield the desired product 197-3 as a white solid (13.0g, yield: 85.7%).

Synthesis of 2- (4- (2- (3, 5-dibromobenzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl methanesulfonate (1974).

197-3(6.5g, 30.4mmol) to CH at 0 deg.C₂Cl₂To a solution in (100mL) were added DIEA (5.0mL, 60.8mmol) and Ms₂O (4.0g, 45.6 mmol). The mixture was stirred at room temperature for 16 hours. After the reaction was complete (by LCMS), the mixture was quenched with 30mL of water and with CH₂Cl₂(50X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and purified by flash chromatography (MeOH/CH) ₂Cl₂5%) to yield the desired product 197-4 as a white solid (5.0g, yield: 65.1%).

Synthesis of Thioacetic acid S-2- (4- (2- (3, 5-dibromobenzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl ester (197-5).

To a mixture of compound 197-4(4.9g, 9.8mmol) in DMF (50mL) was added potassium thioacetate (1.7g, 14.7 mmol). The mixture was stirred at room temperature for 5 hours. After consumption of the starting material (by LCMS), the mixture was quenched with 150mL water and extracted with EtOAc (50 × 3mL), the organic layers were combined and extracted over anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, the crude product was purified by flash chromatography (EtOAc/PE ═ 55%) to yield the desired product 197-5 as a white solid (3.3g, yield: 68.4%).

Synthesis of 3, 5-dibromo N- (2- (1- (2-mercaptoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (197-6).

To compound 197-5(3.3g, 6.7mmol) in CH₃To a solution in OH (50mL) was added NaOH (535.0mg, H)₂2M in O). In N₂The reaction mixture was stirred at room temperature for 3 hours under protection. After consumption of the starting material (by LCMS), the mixture was quenched with 50mL of water, the pH of the mixture was adjusted to-4.0 by HCl (1.0N), and CH was used ₂Cl₂(50X 3mL), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, and the crude product was purified by preparative HPLC (0.05% HCOOH in water) to yield the desired product 197-6 as a white solid (3.0g, yield: 99.5%).

Synthesis of thiobenzoic acid S-2- (4- (2- (3, 5-dibromobenzamido) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) ethyl ester (SU 20666-197-01).

To a solution of compound 197-6(535.0mg, 1.2mmol) in DCM (20mL) was added DIEA (310.0mg, 2.4mmol) and benzoyl chloride (253.0mg, 1.8 mmol). The mixture was stirred at-78 ℃ for 2 hours. After consumption of the starting material (by LCMS), the mixture was concentrated in vacuo and the crude product was purified by preparative HPLC (0.05% HCOOH in water) to yield the desired product SU20666-197-01 as a white solid (470mg, yield: 71.2%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA) ]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 100.00%, retention time 2.031 minutes; MS calculated: 550.0 of the total weight of the mixture; MS found: 551.0[ M + H]⁺。

¹H NMR(400MHz，CDCl₃)δ7.93-7.96(m，2H)，7.81(d，J＝2.0Hz，2H)，7.76(d，J＝1.8Hz，1H)，7.59-7.63(m，2H)，7.47(t，J＝7.8Hz，2H)，6.98(s，1H)，4.62(t，J＝6.8Hz，2H)，3.56(t，J＝6.8Hz，2H)，1.85(s，6H)。

The designations SU20666-198-01, SP 198 and 198 all refer to the same compound having the formula:

the pathway of SU20666-198-01

Synthesis of 3, 5-dibromo N- (2- (1- (2- ((2E, 6E) -3, 7, 11-trimethyldodecane-2, 6, 10-trienylthio) ethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SU 20666-198-01).

To a solution of compound 197-6(535.0mg, 1.2mmol) in DCM (20mL) was added K₂CO₃(332.0mg, 2.4mmol), SM2(409.0mg, 1.4mmol), and the mixture was stirred at room temperature for 18 hours. After consumption of the starting material (by LCMS), the mixture was taken up with H ₂O (30mL) and with CH₂Cl₂(25 mL. times.3), the organic layers were combined and washed with anhydrous Na₂SO₄Dried, filtered and concentrated in vacuo, by preparative HPLC (H)₂0.05% HCCOH in O) to yield the desired product SU20666-0198-01 as a white semi-solid (426.0mg, yield: 54.6%).

LC-MS (Agilent LCMS 1200-]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](in 1.6 min), then continued under these conditions for 1.4 min, finally becoming 95% in 0.05 min [ water + 0.05% TFA)]And 5% [ CH ]₃CN+0.05％TFA]And for 0.7 minutes under this condition), purity: 98.59%, retention time 2.481 minutes; MS calculated: 650.0; MS found: 651.2[ M + H]⁺。

HPLC (Agilent HPLC 1200; column: L-column 2 ODS (150mm 4.6mm 5.0 μm), column temperature: 40 deg.C, flow rate: 1.0 ml/min, mobile phase: 95% [ water + 0.05% TFA%]And 5% [ CH ]₃CN+0.05％TFA]To 5% [ water + 0.05% TFA%]And 95% [ water + 0.05% TFA](over 10 min), then continued under these conditions for 5 min, finally becoming 95% in 0.1 min [ water + 0.05% TFA) ]And 5% [ CH ]₃CN+0.05％TFA]And for 5 minutes under this condition), purity: 93.48%, retention time 8.712 minutes.

¹H NMR(400MHz，DMSO-d₆)δ8.61(s，1H)，8.00(s，3H)，7.94(s，1H)，5.14(t，J＝7.2Hz，1H)，5.05(t，J＝6.4Hz，2H)，4.47(t，J＝6.8Hz，2H)，3.10(d，J＝7.6Hz，2H)，2.85-2.91(m，2H)，1.87-2.04(m，8H)，1.69(s，6H)，1.61(d，J＝8.8Hz，6H)，1.53(d，J＝8.8Hz，6H)。

¹H NMR(400MHz，CDCl₃)δ7.82(d，J＝1.6Hz，2H)，7.77(t，J＝1.6Hz，1H)，7.62(s，1H)，7.00(s，1H)，5.21(t，J＝7.6Hz，1H)，5.08(t，J＝5.6Hz，2H)，4.52(t，J＝6.8Hz，2H)，3.14(d，J＝7.6Hz，2H)，2.95(t，J＝6.8Hz，2H)，1.94-2.11(m，8H)，1.87(s，6H)，1.67(d，J＝6.4Hz，6H)，1.59(d，J＝3.2Hz，6H)。

3, 5-dichloro-N- (2-methylbut-3-yn-2-yl) benzamide (Pronamide, intermediate #1)

In a round bottom flask, 3, 5-dichlorobenzoyl chloride (3g, 14.32mmol, 1.0 eq.) was dissolved in dichloromethane (100mM) in an ice bath under nitrogen. Then 2-methyl-3-butyn-2-amine (1.31g, 15.70mmol, 1.66ml, 1.1 equiv.) followed by diisopropylethylamine (5.55g, 42.96mmol, 7.48ml, 3.0 equiv.) by syringe. The reaction flask was removed from the ice bath and allowed to stir for 4.5 hours. The reaction was monitored by TLC using 30% ethyl acetate in hexane (3: 7 EtOAc/Hex). Upon completion, the reaction mixture was diluted with DCM, washed with 1M HCl, brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporation. The crude material was purified by column chromatography 3: 7 EtOAc and Hex. At large scale, the product was recrystallized using 10% EtOAc in hexanes. The product was a white solid. 90% (2.29 g).¹H NMR(400mHz，CDCl₃，TMS)δ7.76(d，J＝1.88，2H)，7.48(t，J＝1.88，1H)，6.09(s，1H)，2.41(s，1H)，1.76(s，6H)。

GWL3.008

(B) N- (2- (1- (2-amino-2-oxoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) -3, 5-dichlorobenzamide (GWL3.008, intermediate #2)

In a round bottom flask, pronamide (intermediate #1) (371mg, 1.450mmol, 1.0 equiv.), 2-bromoacetamide (200mg, 1.450mmol, 1.0 equiv.), copper (I) iodide (28mg, 0.145mmol, 0.1 equiv.), sodium L-ascorbate (29mg, 0.145mmol, 0.1 equiv.), and sodium azide (189mg, 2.900mmol, 0.1 equiv.) were dissolved in 15ml of 7: 3 ethanol and deionized water. Then, N' -dimethylethylenediamine (26mg, 0.03m1, 0.290mmol, 0.2 eq) was added via syringe. The reaction mixture was placed in an oil bath at 50 ℃ and allowed to mix overnight. The reaction was monitored by TLC in 10% methanol in dichloromethane. Upon completion, the reaction mixture was diluted with deionized water and extracted four times with ethyl acetate. The organic extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. The crude material was purified by column chromatography with ethyl acetate containing 5% methanol. The product was a white solid. 65% (336 mg).¹H NMR(400mHz，DMSO-d₆，TMS)δ8.60(s，1H)，7.88(s，1H)，7.84(d，J＝1.92，2H)，7.79(t，J＝1.88，1H)，7.64(s，1H)，7.36(s，1H)，4.99(s，2H)，1.71(s，6H)。

SP 150

Naproxen (intermediate #1) (1.40g, 5.420mmol, 1.0 equiv.), copper (II) sulfate pentahydrate (136mg, 0.542mmol, 0.1 equiv.), and sodium L-ascorbate (215mg, 1.084mmol, 0.2 equiv.) were dissolved in dimethylformamide (27.1ml, 200mM) in a round bottom flask under nitrogen. Then, 2-azidoethanol (472mg, 5.420mmol, 0.4ml, 1.0 equiv.) was added via syringe. The reaction was monitored by TLC with 7: 3 EtOAc/Hex. After completion, the reaction solution was diluted with deionized water and extracted three times with ethyl acetate. Will be provided with The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography. The starting material was washed off using a 7: 3 EtOAc/Hex solvent system, then the product was eluted through 10% methanol in dichloromethane. The product was a white solid. 93% (1.74 g).¹H NMR(400mHz，CDCl₃，TMS)δ7.66(s，1H)，7.62(d，J＝1.72，2H)，7.46(t，J＝1.68，1H)，6.97(s，1H)，4.49(t，J＝4.80，2H)，4.08(t，J＝4.24，2H)，2.50(s，1H)，1.87(s，6H)。

GWL2.131

(D)2- (4- (2- (3, 5-Dichlorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) acetic acid (GWL2.131, intermediate #7)

Preparation of 6.67mM CrO in acetonitrile (9mL)₃(6mg, 0.06mmol) and 243mM periodic acid (500mg, 2.194 mmol). In a round bottom flask, intermediate #6(100mg, 0.2914mmol) was dissolved in acetonitrile (2.3 mL). The reaction mixture was placed in ice bath nitrogen under nitrogen, and 3mL CrO was added by syringe₃/H₅IO₆And (3) solution. The reaction mixture was stirred at 0 ℃ for 1 hour, then allowed to stir at room temperature for 1 hour. The reaction was monitored by TLC (100% EtOAc). When completed, with Na₂HPO₄A solution of (87mg) in water (3mL) quenched the reaction. The pH of the solution was adjusted to between 3 and 4. The solution was transferred to a separatory funnel and extracted five times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography using 3% acetic acid, 5% methanol in dichloromethane. The purified product was a white solid. 15.3% (16 mg). ¹H NMR(400mHz，DMSO-d₆，TMS)δ8.59(s，1H)，7.86(s，1H)，7.84(d，J＝1.84)2H，7.78(t，J＝1.84，1H)，4.98(s，2H)，1.71(s，6H)。

4-Methylbenzenesulfonic acid (E) ethyl 2- (4- (2- (3, 5-dichlorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) (intermediate #8)

In a round-bottom flask, intermediate #6(400mg, 1.166mmol, 1.0 equiv.) and p-toluenesulfonyl chloride (444mg, 2.331mmol, 2.0 equiv.) were dissolved in dichloromethane (12ml, 100mM) in an ice bath under nitrogen. Diisopropylethylamine (753mg, 5.828mmol, 1ml, 5.0 equiv.) was then added via syringe. The ice bath was removed and the reaction was allowed to proceed for 5 hours. The reaction was monitored by TLC with 1: 1 EtOAc/Hex. Upon completion, the reaction mixture was diluted with dichloromethane, washed with 1m hcl, washed with brine, dried over anhydrous sodium sulfate and concentrated by rotary evaporator. The crude material was purified by column chromatography with 1: 1 EtOAc/Hex. The product was a white solid. 73% (422 mg).¹H NMR(400mHz，CDCl₃，TMS)δ7.72(d，J＝8.36，1H)，7.62(d，J＝1.88，1H)，7.60(s，1H)，7.46(t，J＝1.88，1H)，7.33(d，J＝8.04，2H)，6.90(s，1H)，4.64(t，J＝5.00，2H)，4.41(t，J＝5.4，2H)，2.44(s，3H)，1.86(s，6H)。

SP 87

(F)3, 5-dichloro-N- (2- (1- (2-mercaptoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (SP 87, intermediate #9)

Intermediate #8(600mg, 1.206mmol, 1.0 equiv.) and potassium thioacetate (350mg, 2.016mmol, 2.5 equiv.) were dissolved in DMF (12ml, 100mM) under nitrogen in a round bottom flask. The reaction was monitored by TLC with 1: 1 EtOAc/Hex. After completion, the reaction mixture was saturated with 1: 1 NaHCO ₃/H₂Diluted O and extracted three times with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated. The recovered material was used for the next step and assumed quantitative yield. The recovered material was dissolved in methanol (12ml, 100)mM). A solution of 1M sodium methionate in methanol was prepared. Sodium thiomethoxide (250mg, 3.618mmol, 3.6ml, 3.0 equiv) was added via syringe. The progress of the reaction was monitored by TLC at 1: 1 EtOAc/Hex. After completion, the reaction mixture was concentrated. The crude material was purified by flash chromatography using 5% ethyl acetate in dichloromethane. The product was a white solid. 88% (383 mg).¹H NMR(400mHz，DMSO-d6，TMS)δ8.60(s，1H)，7.97(s，1H)，7.83(d，J＝1.92，2H)，7.89(t，J＝1.92，1H)，4.45(t，J＝6.96，2H)，2.94(q，J＝7.44，2H)，2.43(t，J＝8.12，1H)，1.70(s，6H)。

GWL2.97

(G)3, 5-dichloro-N- (2- (1- (2- (methylthio) ethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (GWL2.97, intermediate #10)

Intermediate #8(150mg, 0.3016mmol, 1.0 eq) and sodium thiomethoxide (23mg, 0.3317mmol, 1.1 eq, sigma aldrich) were placed in a round bottom flask by a stir bar. Dimethylformamide (6.0mL, 50mM, Acros Organic) was added by syringe under a nitrogen balloon. The reaction mixture was stirred at room temperature. Completion of the reaction was confirmed by TLC (7: 3 EtOAc/Hex). The reaction mixture was diluted with deionized water and extracted three times with ethyl acetate. The organic extracts were combined, washed with brine and dried over anhydrous sodium sulfate. The crude material was purified by column chromatography (1: 1 EA/Hex). The product was a white solid. 75.4%, 85 mg. ¹H NMR(400mHz，CDCl₃，TMS)δ7.62(d，J＝1.28，2H)7.61(s，1H)，7.46(t，J＝1.64，1H)，6.97(s，1H)，4.55(t，J＝6.92，2H)，3.00(t，J＝6.96，2H)，2.08(s，3H)，1.88(s，6H)。

GWL2.143

(H)3, 5-dichloro-N- (2- (1- (2- (methylthio) ethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (GWL2.143, intermediate #11)

A solution of 350mM Oxone (212mg, 1.4032mmol) in methanol (4mL) was prepared. In a round bottom flask, #87(SMe) (87.3mg, 0.2339mmol, 1.0 equiv.) was dissolved in 2.7mL of methanol. Under nitrogen, 2mL of Oxone solution was added to the intermediate #10 solution by syringe. The reaction mixture was allowed to stir at room temperature overnight (20 hours). The progress of the reaction was monitored by TLC (7: 3 EtOAc/Hex). The reaction mixture was concentrated and then diluted with deionized water. The aqueous layer was extracted four times with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by column chromatography with 1: 1 EtOAc/Hex and 7: 3 EtOAc/Hex. The product was a white solid. 77%, 73.6 mg.¹H NMR(400mHz，DMSO-d₆，TMS)δ8.63(s，1H)，8.04(s，1H)，7.83(d，J＝1.92，2H)，7.79(t，J＝1.92，1H)，4.74(t，J＝6.92，2H)，3.78(t，J＝7.12，2H)，2.88(s，3H)，1.69(s，6H)。

GWL2.137

(J)3, 5-dichloro-N- (2- (1- (3-hydroxypropyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (GWL2.137, intermediate #3)

Intermediate #3 was prepared using the same procedure as #87(OH), but using 3-azidopropanol instead of 2-azidoethanol. The product was a white solid. 88% (610 mg).¹H NMR(400mHz，CDCl₃，TMS)δ6.62(d，J＝1.88，2H)，7.57(s，1H)，7.46(t，J＝1.88，1H)，6.97(s，1H)，4.52(t，J＝6.80，2H)，3.67(t，J＝5.80，2H)，2.16(m，J＝6.60，5.98，2H)，1.87(s，6H)，1.77(s，1H)。

GWL2.129

(J)3- (4- (2- (3, 5-Dichlorobenzamide) propan-2-yl) -1H-1, 2, 3-triazol-1-yl) propanoic acid (GWL2.129, intermediate #4)

This compound was prepared using the same procedure as #87 (COOH). The purified product was a white solid. 21% (66.8 mg).¹H NMR(400mHz，DMSO-d₆，TMS)δ8.58(s，1H)，7.92(s，1H)，7.83(d，J＝1.88，2H)，7.78(t，J＝1.84，1H)，7.49(t，J＝6.92，2H)，2.85(t，J＝6.88，2H)，1.68(s，6H)。

GWL2.154

(K) N- (2- (1- (3-amino-3-oxopropyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) -3, 5-dichlorobenzamide (GWL2.154, intermediate #5)

Intermediate #4(100mg, 0.269mmol, 1.0 equiv.), HATU (307mg, 0.808mmol, 3.0 equiv.), and ammonium chloride (29mg, 0.539mmol, 2.0 equiv.) were dissolved in dimethylformamide (2.7ml, 100mM) in a round bottom flask under nitrogen. Diisopropylethylamine (139mg, 0.2ml, 1.078mmol, 4.0 equiv.) was added by syringe. The reaction mixture was stirred at room temperature overnight. The progress of the reaction was monitored by TLC in dichloromethane containing 5% methanol. After completion, the reaction solution was diluted with ethyl acetate and washed with 1M HCl, 1: 1 sodium bicarbonate, deionized water and brine. The crude organic mixture was dried over anhydrous sodium sulfate and concentrated by rotary evaporator. The crude material was purified by column chromatography with dichloromethane and 5% methanol in dichloromethane. The product was a white solid. 47% (48 mg).¹H NMR(400mHz，DMSO-d6，TMS)δ8.58(s，1H)，7.87(s，1H)，7.84(d，J＝1.88，2H)，7.78(t，J＝1.88，1H)，7.41(s，1H)，6.95(s，1H)，4.47(t，J＝7.08，2H)，2.67(t，J＝7.08，2H)，1.68(s，6H)。

GWL2.171

N- (2- (1- (2-bromoethyl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) -3, 5-dichlorobenzamide (GWL2.171)

Intermediate #8(200mg, 0.402mmol, 1.0 equiv.) and lithium bromide (175mg, 2.010mmol, 5.0 equiv.) were dissolved in acetonitrile in a round bottom flask. A reflux condenser was assembled and the reaction was placed in an oil bath. The reaction was stirred under nitrogen for 2 hours. The progress of the reaction was monitored by TLC with 1: 1 EtOAc/Hex. After completion of the reaction, the solvent was removed by a rotary evaporator. The crude material was purified by column chromatography with 3: 7 EtOAc/Hex. The product was a white solid. 91% (149 mg).¹H NMR(400mHz，DMSO-d₆，TMS)δ8.61(s，1H)，8.00(s，1H)，7.84(d，J＝1.92，2H)，7.89(t，J＝1.92，2H)，4.73(t，J＝6.12，2H)，3.90(t，J＝6.12，2H)，1.70(s，6H)。

GWL3.001

3, 5-dichloro-N- (2- (1- (furan-3-yl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (GWL3.001)

In a round bottom flask, pronamide (intermediate #1) (174mg, 0.680mmol, 1.0 equiv.), 3-bromofuran (100mg, 0.680mmol, 1.0 equiv.), copper (I) iodide (13mg, 0.068mmol, 0.1 equiv.), sodium L-ascorbate (14mg, 0.068mmol, 0.1 equiv.), and sodium azide (88mg, 1.361mmol, 2.0 equiv.) were dissolved in 6.8ml of 7: 3 ethanol and deionized water. Then, N' -dimethylethylenediamine (12mg, 0.01ml, 0.136mmol, 0.2 equiv) was added via syringe. The reaction mixture was placed in an oil bath at 50 ℃ and allowed to mix for 20 hours. The reaction was monitored by TLC with 3: 7 EtOAc/Hex. Upon completion, the reaction mixture was diluted with deionized water and extracted three times with ethyl acetate. The organic extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. The crude material was purified by column chromatography with 1: 1 EtOAc/Hex. The product was a white solid. 10% (36 mg). ¹H NMR(400mHz，DMSO-d₆，TMS)δ8.71(s，1H)，8.46(s，1H)，8.39(s，1H)，7.87(d，J＝1.84，3H)，7.79(t，J＝1.76，1H)，7.11(d，J＝1.44，1H)，1.74(s，6H)。

GWL2.190

3, 5-dichloro-N- (2- (1- (thiophen-3-yl) -1H-1, 2, 3-triazol-4-yl) propan-2-yl) benzamide (GWL2.190)

In a round bottom flask, pronamide (intermediate #1) (122mg, 0.476mmol, 1.0 equiv.), 3-iodothiophene (100mg, 0.476mmol, 1.0 equiv.), copper (I) iodide (9mg, 0.048mmol, 0.1 equiv.), sodium L-ascorbate (10mg, 0.048mmol, 0.1 equiv.), and sodium azide (62mg, 0.952mmol, 2.0 equiv.) were dissolved in 4.7ml of 7: 3 ethanol and deionized water. Then, N' -dimethylethylenediamine (12mg, 0.01ml, 0.136mmol, 0.2 equiv) was added via syringe. The reaction mixture was placed in an oil bath at 50 ℃ and allowed to mix for 20 hours. The reaction was monitored by TLC with 1: 1 EtOAc/Hex. Upon completion, the reaction mixture was diluted with deionized water and extracted three times with ethyl acetate. The organic extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. The crude material was purified by column chromatography with 3: 7 EtOAc/Hex. The product was a white solid. 86% (157 mg).¹H NMR(400mHz，DMSO-d₆，TMS)δ8.71(s，1H)，8.59(s，1H)，8.00(dd，J＝1.36，1.80，1.40，1H)，7.87(d，J＝1.88，2H)，7.79(t，J＝1.88，1H)，7.78(m，J＝2.00，5.28，1H)，(dd，J＝1.36，5.24，1.36，1H)1.75(s，6H)。

UNI6-001

Pathway of UNI6-001

Step-1: synthesis of N' - (2- (3, 4-dichlorophenoxy) acetyl) acrylhydrazide

To a solution of Stent-1 (0.20g, 0.00085mol) in THF (2mL) at 0 deg.C was added TEA (0.17mL, 0.00128 mol). Acryloyl chloride (0.06mL, 0.000854mol) was added dropwise to the reaction mixture at 0 ℃. The reaction mixture was stirred at 0 ℃ for 4 hours, and further at room temperature for 14 hours. The reaction was monitored by TLC (5% methanol in chloroform). The resulting reaction mixture was poured into water (20mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with brine solution (15mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material obtained was purified by flash chromatography (product eluted using 35% ethyl acetate in hexanes) to yield the title compound (0.022g, 000076mol, 9%).

¹H NMR(400MHz，DMSO-d6)δppm：10.29(s，1H)，10.20(s，1H)，7.56(d，J＝8.8Hz，1H)，7.28(d，J＝2.8Hz，1H)，7.01(dd，J＝8.8，2.8Hz，1H)，6.32-6.17(m，2H)，5.73(dd，J＝9.6，2.4Hz，1H)4.73(s，2H)。

LCMS method: UPLC _2A, O2H method _ A _0, Retention time-1.914 minutes. MS: 288.96(M + 1).

Stent-1

Approach to Stent-1

Step-1: synthesis of ethyl 2- (3, 4-dichlorophenoxy) acetate

To a solution of 3, 4-dichlorophenol (15.0g, 0.0920mol) in acetone (150mL) was added K at room temperature₂CO₃(17.8g, 0.128 mol). Ethyl chloroacetate (10.6mL, 0.101mol) was added dropwise to the reaction mixture at room temperatureIn (1). The reaction mixture was heated at 80 ℃ for 18 hours. The reaction was monitored by TLC (10% ethyl acetate in hexane). The resulting reaction mixture was cooled to room temperature, poured into water (300mL), and extracted with ethyl acetate (4 × 100 mL). The combined organic phases were washed with brine solution (50mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield ethyl 2- (3, 4-dichlorophenoxy) acetate (23g, 0.0927mol, 100%). This material was used directly in the next step without any further purification.

¹H NMR(400MHz，DMSO-d6)δppm：7.52(d，J＝9.2Hz，1H)，7.26(d，J＝2.8Hz，1H)，6.97(dd，J＝8.8，2.8Hz，1H)，4.85(s，2H)，4.19-4.13(m，2H)，1.20(t，J＝8.4Hz，3H)。

Step-2: synthesis of 2- (3, 4-dichlorophenoxy) acethydrazide

To a solution of ethyl 2- (3, 4-dichlorophenoxy) acetate (1.0g, 0.00403mol) in ethanol (10mL) was added a hydrazine hydrate solution (1mL, 0.0201mol) at room temperature. The reaction mixture was heated at 80 ℃ for 4 hours. The reaction was monitored by TLC (5% methanol in chloroform). Another 14 batches of the same size were made and processed together. The resulting reaction mixture was poured into water (450mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with brine solution (100mL), dried over sodium sulfate, filtered and concentrated in vacuo. The solid material obtained was purified by trituration with ether (2 × 25mL) to give 2- (3, 4-dichlorophenoxy) acetohydrazide (8.4g, 0.0358mol, 59%).

¹H NMR(400MHz，DMSO-d6)δppm：9.38(s，1H)，7.52(d，J＝9.2Hz，1H)，7.25(d，J＝2.8Hz，1H)，6.98(dd，J＝8.8，2.8Hz，1H)，4.54(s，2H)，4.35(s，2H)。

LCMS method: UPLC _2A, O2H method _ A _3, retention time-1.850 minutes. MS: 235.04(M + 1).

UNI6-002

The pathway of UNI6-002

Step-1: (E) synthesis of (E) -N' - (2- (3, 4-dichlorophenoxy) acetyl) but-2-enohydrazide

To a solution of Stent-1 (0.50g, 0.0021mol) in THF (5mL) at 0 deg.C was added TEA (0.44mL, 0.00320 mol). Crotonyl chloride (0.2mL, 0.00213mol) was added dropwise to the reaction mixture at 0 ℃. The reaction mixture was stirred at 0 ℃ for 4 hours, and further at room temperature for 14 hours. The reaction was monitored by TLC (5% methanol in chloroform). The resulting reaction mixture was poured into water (30mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with brine solution (10mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material obtained was purified by flash chromatography (product eluted using 57% ethyl acetate in hexanes) to yield the title compound (0.052g, 000172mol, 8%).

¹H NMR(400MHz，DMSO-d6)δppm：10.19(s，1H)，9.96(s，1H)，7.55(d，J＝8.8Hz，1H)，7.26(d，J＝2.8Hz，1H)，7.01(dd，J＝8.8，2.8Hz，1H)，6.78-6.69(m，1H)，5.96(dd，J＝15.2，1.6Hz，1H)，4.68(s，2H)，1.82(dd，J＝6.8，1.6Hz，3H)。

LCMS method: UPLC _2A, O2H method _ a _1, retention time-2.009 minutes. MS: 303.01(M + 1).

UNI6-003

The pathway of UNI6-003

Synthesis of N' - (2- (3, 4-dichlorophenoxy) acetyl) vinyl sulfonyl hydrazide

To a solution of scaffold-1 (0.5g, 0.00213mol) in DCM (6.5mL) was added N, N-diisopropylethylamine (0.28mL, 0.00341mol) at 0 ℃. 2-Chloroethanesulfonyl chloride (0.56mL, 0.00256mol) was added dropwise to the reaction mixture at 0 ℃. The reaction mixture was stirred at 0 ℃ for 3 hours, and further stirred at room temperature for 15 hours. The reaction was monitored by TLC (5% methanol in chloroform). The resulting reaction mixture was poured into water (40mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with brine solution (10mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material obtained was purified by flash chromatography (product eluted using 82% ethyl acetate in hexanes) to yield the title compound (0.33g, 0.00101 mol). Purification by preparative HPLC using ACN containing 10mm ammonium bicarbonate: water (0.030g, 0.000092mol) further purified the compound. The isolated solid material was further purified by trituration with methanol (1mL) to give the title compound (0.019g, 0.000058mol, 3%).

¹H NMR(400MHz，DMSO-d6)δppm：10.47(s，1H)，9.67(s，1H)，7.54(d，J＝8.8Hz，1H)，7.20(d，J＝2.8Hz，1H)，6.95(dd，J＝8.8，1.6Hz，1H)，6.65-6.59(m，1H)，6.08-5.99(m，2H)，4.65(s，2H)。

LCMS method: UPLC _3AA, O2H method _ A _2, retention time-2.632 minutes. MS: 323.12 (M-1).

UNI6-005

The pathway of UNI6-005

Step-1: synthesis of 2-chloro-N' - (2- (3, 4-dichlorophenoxy) acetyl) acethydrazide

To a solution of Stent-1 (0.15g, 0.000641mol) in THF (1.5mL) at 0 deg.C was added TEA (0.13mL, 0.000961 mol). Chloroacetyl chloride (0.05mL, 0.000641mol) was added dropwise to the reaction mixture at 0 ℃. The reaction mixture was stirred at 0 ℃ for 4 hours, and further at room temperature for 14 hours. The reaction was monitored by TLC (5% methanol in chloroform). The resulting reaction mixture was poured into water (30mL) and extracted with ethyl acetate (2 × 40 mL). The combined organic phases were washed with brine solution (20mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material obtained was purified by flash chromatography (product eluted using 45% ethyl acetate in hexanes) to yield the title compound (0.089g, 000287mol, 45%).

¹H NMR(400MHz，DMSO-d6)δppm：10.34(s，2H)，7.56(d，J＝8.8Hz，1H)，7.27(d，J＝2.8Hz，1H)，7.01(dd，J＝9.2，3.2Hz，1H)，4.69(s，2H)，4.15(s，2H)。

LCMS method: UPLC _2A, O2H method _ A _1, retention time-1.986 minutes. MS: 311.1(M + 1).

UNI6-006

The pathway of UNI6-006

Step-1: synthesis of 2-chloro-N' - (2- (3, 4-dichlorophenoxy) acetyl) propionylhydrazide

To a solution of Stent-1 (0.20g, 0.000854mol) in THF (2.0mL) at 0 deg.C was added TEA (0.17mL, 0.00128 mol). 2-Chloropropylchloride (0.08mL, 0.000854mol) was added dropwise to the reaction mixture at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 4 hours, and further at room temperature for 14 hours. The reaction was monitored by TLC (5% methanol in chloroform). The resulting reaction mixture was poured into water (30mL) and extracted with ethyl acetate (2 × 25 mL). The combined organic phases were washed with brine solution (10mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material obtained was purified by flash chromatography (product eluted using 50% ethyl acetate in hexanes) to yield the title compound (0.047g, 000145mol, 17%).

¹H NMR(400MHz，DMSO-d6)δppm：10.37(s，1H)，10.35(s，1H)，7.56(d，J＝8.8Hz，1H)，7.26(d，J＝3.2Hz，1H)，7.01(dd，J＝8.8，2.8Hz，1H)，4.69(s，2H)，4.56-4.55(m，1H)，1.55(d，J＝6.8Hz，3H)。

LCMS method: UPLC _2A, O2H method _ a _3, retention time-2.133 minutes. MS: 323.31 (M-1).

Example 4: binding and Activity data

TABLE 1 binding and Activity data for analogs of Compound 87

The key points are as follows: binding assay: binding ++++, low, medium to high nanomolar. Cell assay (cpds tested at 10 μ M): ++++ > 10 times, ++++ > 4 times, +++ > 3 times, and +++ > 1.5 times. All measurements were: and nt is not tested.

TABLE 2 binding and Activity data for analogs of Compound 85

Example 5: additional compounds

TABLE 3 additional Compounds

Example 6: nurr1 cancer indications

Nurr1 is involved in a variety of biological processes important in tumorigenesis, such as cell proliferation, apoptosis, differentiation, and glucose utilization. Nurr1 is a potential cancer therapeutic (Komiya et al, 2017). Specific cancers in which Nurr1(NR4a2) expression and/or activity plays a role include: breast (Llopis et al, 2013), pancreatic (Li et al, 2012), bladder (Inamoto et al, 2010; Inamoto et al, 2008), Mucoepidermoid (MEC), gastric (Guo et al, 2015), prostate (Wang et al, 2013), colorectal (Han et al, 2013; Vijaykumar et al, 2005), lung (Bai et al, 2015), adrenocortical (Li et al, 2018) and cervical (Li et al, 2006).

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Lou, X, Torresson, G, Benod, C, Suh, J.H., Philips, K.J., Webb, P, and Gustafsson, J.A (2014) "Structure of retinoid X receptor alpha-liver X receptor beta (RXRalpha-LXRbeta) heterodimer on DNA (Structure of the receptor alpha-liver X receptor beta (RXRalpha-LXRbeta) heterodimer" Nature-Structure and molecular biology (Nat Structure Mol Biol) 21, 277) 281. 53.Meiser, J., Weindl, D., and Hiller, K. (2013) "Complexity of dopamine metabolism," Cell communication and signaling (Cell Commun Signal) 11, 34. D' Ischia, M., Napolitano, A., Pezzella, A., Land, E.J., Ramsden, C.A., and Riley, P.A. (2005) "5, 6-dihydroxyindole and Indole-5, 6-diones (5, 6-dihydroindoles and indices-5, 6-diones)", "Advances in Heterocyclic Chemistry (Advances in Heterocyclic Chemistry) 89, 1-55. Pezzella, a., Iadonisi, a., Valerio, s., Panzella, l., Napolitano, a., Adinolfi, m., and d' Ischia, M. 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Walleh-Mackenzie, A., Mata de Urquinza, A., Petersson, S., Rodriguez, F.J., Friling, S., Wagner, J., Ordentlich, P., Lengqvist, J., Heyman, R.A., Arenas, E., and Perlmann, T. (2003) "Nurr 1-RXR heterodimer mediates RXR ligand-induced signaling in neuronal cells (Nurr1-RXR heterodimers R ligand-induced signaling in neuronal cells)", "Gene and development" 17, 3036-3047. 58.Lammi, J., Huppunen, J, and Aarnisalo, P. (2004) "Regulation of osteopontin gene by orphan nuclear receptor NURR1 in osteoblasts" molecular Endocrinol (Mol Endocrinol) 18, 1546-1557. Castro, D.S., Hermanson, E., Joseph, B., Wallen, A., Aarnisalo, P., Heller, A. and Perlmann, T. (2001) "Nurr 1 and retinoids induce cell cycle arrest and morphological differentiation in dopamine MN9D cells (Induction of cell arrest and morphological differentiation by Nurr1 and retinoids in dopamin MN9D cells)," J. Biochem. 276, 43277-43284. Maira, M., Martens, C., Batsche, E., Gauthier, Y, and Drouin, J. 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Komiya, t., Yamamoto, s., Roy, a., McDonald, p., Perez, R.P (2017) "Drug screening targeting nuclear orphan receptor NR4a2 for Cancer therapy" (Drug screening to target nuclear receptor NR4a2 for Cancer therapeutics) ", transformed Lung Cancer study (trans Lung Cancer Res) 6 (5): 600-610. 63.Llopis et al, "BMC Cancer (BMC Cancer)" 2013, 13: 139. li, x, Lee, s.o., Safe, S. (2012) "Structure-dependent activation of NR4a2(Nurr1) by 1, 1-bis (3 '-indolyl) -1- (aromatic) methane analogs in pancreatic cancer cells (Structure-dependent activity of NR4a2(Nurr1) by 1, 1-bis (3' -indolyl) -1- (aromatic) methane analogs in pancreatic cancer cells" [ biochemical pharmacology (Biochem Pharmacol.) 83(10) ]: 1445-55. 65.Inamoto, T, Czerniak, B.A., Dinney, C.P., Kamat, A.M (2010) "Cytoplasmic mislocalization of orphan nuclear receptor Nurr1 as a prognostic factor for bladder Cancer (Cytoplasmic mislocalization of the organ nuclear receptor Nurr1 is a viral factor in the vane Cancer)", Cancer (Cancer) 116: 340-6. 66.Inamoto, T., Papineni, S., Chinthalaclli, S. et al (2008) "1, 1-Bis (3 '-indolyl) -1- (p-chlorophenyl) methane activates orphan nuclear receptor Nurr1 and inhibits bladder Cancer growth (1, 1-Bis (3' -indolyl) -1- (p-chlorophenyl) methane activators the orphan nuclear receptor Nurr1 and inhibit bladder Cancer growth)", molecular Cancer therapeutics (Mol Cancer Ther) 7: 3825-33. Guo, j., Zu, g., Zhou, t. et al (2015) "clinical pathological significance of orphan nuclear receptor nuclear 1 expression in gastric cancer" (clinical diagnostic of organ nuclear receptor nuclear 1 expression) "clinical and transforming oncology (clinn trans Oncol) 17: 788-94. 68.Wang, J., Yang, J., Zou, Y, et al (2013) "Orphan nuclear receptor nuclear 1 as a potential novel marker of human prostate Cancer progression (Orphan nuclear receptor nuclear 1 as a potential novel marker for progression in human prostate Cancer)", J.Atai Cancer prevention and treatment (Asian Pac J Cancer Prev) 14: 2023-8. Han, y, Cai, h, Ma, l, et al (2013) "orphan Nuclear receptor NR4a2 confers resistance to chemotherapy and predicts poor prognosis in colorectal Cancer patients receiving post-operative chemotherapy (Nuclear receptor NR4a2 responses and predictions of colorectal Cancer patients receiving post-operative chemotherapy)", "european journal of Cancer (Eur J Cancer) 49: 3420-30. Holla, V.R., Mann, J.R., Shi, O, and DuBois, R.N. (2005) J.Biol.Chem.281, 2676-. 71.Bai, R., Weng, C., Dong, H., Li, S., Chen, G., Xu, Z. (2015) "MicroRNA-409-3 p inhibits colorectal Cancer invasion and metastasis in part by targeting GAB1 expression (MicroRNA-409-3p consensus Cancer invasion and metastasis by targeting GAB1 expression)", International journal of Cancer (Int J Cancer). 137(10): 2310-22. Li, X, Wang, b, Tang, l, Zhang, y, Chen, l, Gu, l, Zhang, f, Ouyang, J, Zhang, X, (2018) "GSTA 1 Expression Correlated With Aldosterone levels in an Adrenal Aldosterone Adenoma With KCNJ5 mutation (GSTA1 Expression Correlated With wavelength Aldosterone Level in KCNJ5 mutant adrenosterone Level in KCNJ5-Mutated additional Aldosterone-Producing adoma)" (J clinin endocrine metabolism metane metab. 103 (3): 813-823. 73.Li, Q. - -X., Ke, N., Sundaram, R., Wong-Staal, F. (2006) "NR 4A1, 2, 3-family of orphan nuclear hormone receptors involved in apoptosis and carcinogenesis (NR4A1, 2, 3-an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis)", histology and histopathology (Histol histopatho.) (21 (5)): 533-40. "Covalent modification and modulation of nuclear receptor Nurr1 by dopamine metabolites" (Coval modification and modulation of the nuclear receptor Nurr1 by a polypeptide metabolite) "" cytochemistry. biol 26 (Cell. biol. 26) (5): 674-685.

Sequence listing

<110> board of University of California (The Regents of The University of California)

Shanghai Innovation Inc (ShangPharma Innovation Inc.)

England, Pamela M.

Jacobson, Matthew P.

Beresis, Richard

<120> NURR1 receptor modulators

<130> 048536-637001WO

<150> US 62/807,642

<151> 2019-02-19

<160> 14

<170> PatentIn version 3.5

<210> 1

<211> 598

<212> PRT

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polypeptide

<400> 1

Met Pro Cys Val Gln Ala Gln Tyr Gly Ser Ser Pro Gln Gly Ala Ser

1 5 10 15

Pro Ala Ser Gln Ser Tyr Ser Tyr His Ser Ser Gly Glu Tyr Ser Ser

20 25 30

Asp Phe Leu Thr Pro Glu Phe Val Lys Phe Ser Met Asp Leu Thr Asn

35 40 45

Thr Glu Ile Thr Ala Thr Thr Ser Leu Pro Ser Phe Ser Thr Phe Met

50 55 60

Asp Asn Tyr Ser Thr Gly Tyr Asp Val Lys Pro Pro Cys Leu Tyr Gln

65 70 75 80

Met Pro Leu Ser Gly Gln Gln Ser Ser Ile Lys Val Glu Asp Ile Gln

85 90 95

Met His Asn Tyr Gln Gln His Ser His Leu Pro Pro Gln Ser Glu Glu

100 105 110

Met Met Pro His Ser Gly Ser Val Tyr Tyr Lys Pro Ser Ser Pro Pro

115 120 125

Thr Pro Thr Thr Pro Gly Phe Gln Val Gln His Ser Pro Met Trp Asp

130 135 140

Asp Pro Gly Ser Leu His Asn Phe His Gln Asn Tyr Val Ala Thr Thr

145 150 155 160

His Met Ile Glu Gln Arg Lys Thr Pro Val Ser Arg Leu Ser Leu Phe

165 170 175

Ser Phe Lys Gln Ser Pro Pro Gly Thr Pro Val Ser Ser Cys Gln Met

180 185 190

Arg Phe Asp Gly Pro Leu His Val Pro Met Asn Pro Glu Pro Ala Gly

195 200 205

Ser His His Val Val Asp Gly Gln Thr Phe Ala Val Pro Asn Pro Ile

210 215 220

Arg Lys Pro Ala Ser Met Gly Phe Pro Gly Leu Gln Ile Gly His Ala

225 230 235 240

Ser Gln Leu Leu Asp Thr Gln Val Pro Ser Pro Pro Ser Arg Gly Ser

245 250 255

Pro Ser Asn Glu Gly Leu Cys Ala Val Cys Gly Asp Asn Ala Ala Cys

260 265 270

Gln His Tyr Gly Val Arg Thr Cys Glu Gly Cys Lys Gly Phe Phe Lys

275 280 285

Arg Thr Val Gln Lys Asn Ala Lys Tyr Val Cys Leu Ala Asn Lys Asn

290 295 300

Cys Pro Val Asp Lys Arg Arg Arg Asn Arg Cys Gln Tyr Cys Arg Phe

305 310 315 320

Gln Lys Cys Leu Ala Val Gly Met Val Lys Glu Val Val Arg Thr Asp

325 330 335

Ser Leu Lys Gly Arg Arg Gly Arg Leu Pro Ser Lys Pro Lys Ser Pro

340 345 350

Gln Glu Pro Ser Pro Pro Ser Pro Pro Val Ser Leu Ile Ser Ala Leu

355 360 365

Val Arg Ala His Val Asp Ser Asn Pro Ala Met Thr Ser Leu Asp Tyr

370 375 380

Ser Arg Phe Gln Ala Asn Pro Asp Tyr Gln Met Ser Gly Asp Asp Thr

385 390 395 400

Gln His Ile Gln Gln Phe Tyr Asp Leu Leu Thr Gly Ser Met Glu Ile

405 410 415

Ile Arg Gly Trp Ala Glu Lys Ile Pro Gly Phe Ala Asp Leu Pro Lys

420 425 430

Ala Asp Gln Asp Leu Leu Phe Glu Ser Ala Phe Leu Glu Leu Phe Val

435 440 445

Leu Arg Leu Ala Tyr Arg Ser Asn Pro Val Glu Gly Lys Leu Ile Phe

450 455 460

Cys Asn Gly Val Val Leu His Arg Leu Gln Cys Val Arg Gly Phe Gly

465 470 475 480

Glu Trp Ile Asp Ser Ile Val Glu Phe Ser Ser Asn Leu Gln Asn Met

485 490 495

Asn Ile Asp Ile Ser Ala Phe Ser Cys Ile Ala Ala Leu Ala Met Val

500 505 510

Thr Glu Arg His Gly Leu Lys Glu Pro Lys Arg Val Glu Glu Leu Gln

515 520 525

Asn Lys Ile Val Asn Cys Leu Lys Asp His Val Thr Phe Asn Asn Gly

530 535 540

Gly Leu Asn Arg Pro Asn Tyr Leu Ser Lys Leu Leu Gly Lys Leu Pro

545 550 555 560

Glu Leu Arg Thr Leu Cys Thr Gln Gly Leu Gln Arg Ile Phe Tyr Leu

565 570 575

Lys Leu Glu Asp Leu Val Pro Pro Pro Ala Ile Ile Asp Lys Leu Phe

580 585 590

Leu Asp Thr Leu Pro Phe

595

<210> 2

<211> 302

<212> PRT

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polypeptide

<400> 2

Met Glu Phe Gly Leu Leu Ser Glu Ala Glu Ala Arg Ser Pro Ala Leu

1 5 10 15

Ser Leu Ser Asp Ala Gly Thr Pro His Pro Gln Leu Pro Glu His Gly

20 25 30

Cys Lys Gly Gln Glu His Ser Asp Ser Glu Lys Ala Ser Ala Ser Leu

35 40 45

Pro Gly Gly Ser Pro Glu Asp Gly Ser Leu Lys Lys Lys Gln Arg Arg

50 55 60

Gln Arg Thr His Phe Thr Ser Gln Gln Leu Gln Glu Leu Glu Ala Thr

65 70 75 80

Phe Gln Arg Asn Arg Tyr Pro Asp Met Ser Thr Arg Glu Glu Ile Ala

85 90 95

Val Trp Thr Asn Leu Thr Glu Ala Arg Val Arg Val Trp Phe Lys Asn

100 105 110

Arg Arg Ala Lys Trp Arg Lys Arg Glu Arg Ser Gln Gln Ala Glu Leu

115 120 125

Cys Lys Gly Ser Phe Ala Ala Pro Leu Gly Gly Leu Val Pro Pro Tyr

130 135 140

Glu Glu Val Tyr Pro Gly Tyr Ser Tyr Gly Asn Trp Pro Pro Lys Ala

145 150 155 160

Leu Ala Pro Pro Leu Ala Ala Lys Thr Phe Pro Phe Ala Phe Asn Ser

165 170 175

Val Asn Val Gly Pro Leu Ala Ser Gln Pro Val Phe Ser Pro Pro Ser

180 185 190

Ser Ile Ala Ala Ser Met Val Pro Ser Ala Ala Ala Ala Pro Gly Thr

195 200 205

Val Pro Gly Pro Gly Ala Leu Gln Gly Leu Gly Gly Gly Pro Pro Gly

210 215 220

Leu Ala Pro Ala Ala Val Ser Ser Gly Ala Val Ser Cys Pro Tyr Ala

225 230 235 240

Ser Ala Ala Ala Ala Ala Ala Ala Ala Ala Ser Ser Pro Tyr Val Tyr

245 250 255

Arg Asp Pro Cys Asn Ser Ser Leu Ala Ser Leu Arg Leu Lys Ala Lys

260 265 270

Gln His Ala Ser Phe Ser Tyr Pro Ala Val His Gly Pro Pro Pro Ala

275 280 285

Ala Asn Leu Ser Pro Cys Gln Tyr Ala Val Glu Arg Pro Val

290 295 300

<210> 3

<211> 528

<212> PRT

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polypeptide

<400> 3

Met Pro Thr Pro Asp Ala Thr Thr Pro Gln Ala Lys Gly Phe Arg Arg

1 5 10 15

Ala Val Ser Glu Leu Asp Ala Lys Gln Ala Glu Ala Ile Met Val Arg

20 25 30

Gly Gln Gly Ala Pro Gly Pro Ser Leu Thr Gly Ser Pro Trp Pro Gly

35 40 45

Thr Ala Ala Pro Ala Ala Ser Tyr Thr Pro Thr Pro Arg Ser Pro Arg

50 55 60

Phe Ile Gly Arg Arg Gln Ser Leu Ile Glu Asp Ala Arg Lys Glu Arg

65 70 75 80

Glu Ala Ala Val Ala Ala Ala Ala Ala Ala Val Pro Ser Glu Pro Gly

85 90 95

Asp Pro Leu Glu Ala Val Ala Phe Glu Glu Lys Glu Gly Lys Ala Val

100 105 110

Leu Asn Leu Leu Phe Ser Pro Arg Ala Thr Lys Pro Ser Ala Leu Ser

115 120 125

Arg Ala Val Lys Val Phe Glu Thr Phe Glu Ala Lys Ile His His Leu

130 135 140

Glu Thr Arg Pro Ala Gln Arg Pro Arg Ala Gly Gly Pro His Leu Glu

145 150 155 160

Tyr Phe Val Arg Leu Glu Val Arg Arg Gly Asp Leu Ala Ala Leu Leu

165 170 175

Ser Gly Val Arg Gln Val Ser Glu Asp Val Arg Ser Pro Ala Gly Pro

180 185 190

Lys Val Pro Trp Phe Pro Arg Lys Val Ser Glu Leu Asp Lys Cys His

195 200 205

His Leu Val Thr Lys Phe Asp Pro Asp Leu Asp Leu Asp His Pro Gly

210 215 220

Phe Ser Asp Gln Val Tyr Arg Gln Arg Arg Lys Leu Ile Ala Glu Ile

225 230 235 240

Ala Phe Gln Tyr Arg His Gly Asp Pro Ile Pro Arg Val Glu Tyr Thr

245 250 255

Ala Glu Glu Ile Ala Thr Trp Lys Glu Val Tyr Thr Thr Leu Lys Gly

260 265 270

Leu Tyr Ala Thr His Ala Cys Gly Glu His Leu Glu Ala Phe Ala Leu

275 280 285

Leu Glu Arg Phe Ser Gly Tyr Arg Glu Asp Asn Ile Pro Gln Leu Glu

290 295 300

Asp Val Ser Arg Phe Leu Lys Glu Arg Thr Gly Phe Gln Leu Arg Pro

305 310 315 320

Val Ala Gly Leu Leu Ser Ala Arg Asp Phe Leu Ala Ser Leu Ala Phe

325 330 335

Arg Val Phe Gln Cys Thr Gln Tyr Ile Arg His Ala Ser Ser Pro Met

340 345 350

His Ser Pro Glu Pro Asp Cys Cys His Glu Leu Leu Gly His Val Pro

355 360 365

Met Leu Ala Asp Arg Thr Phe Ala Gln Phe Ser Gln Asp Ile Gly Leu

370 375 380

Ala Ser Leu Gly Ala Ser Asp Glu Glu Ile Glu Lys Leu Ser Thr Leu

385 390 395 400

Tyr Trp Phe Thr Val Glu Phe Gly Leu Cys Lys Gln Asn Gly Glu Val

405 410 415

Lys Ala Tyr Gly Ala Gly Leu Leu Ser Ser Tyr Gly Glu Leu Leu His

420 425 430

Cys Leu Ser Glu Glu Pro Glu Ile Arg Ala Phe Asp Pro Glu Ala Ala

435 440 445

Ala Val Gln Pro Tyr Gln Asp Gln Thr Tyr Gln Ser Val Tyr Phe Val

450 455 460

Ser Glu Ser Phe Ser Asp Ala Lys Asp Lys Leu Arg Ser Tyr Ala Ser

465 470 475 480

Arg Ile Gln Arg Pro Phe Ser Val Lys Phe Asp Pro Tyr Thr Leu Ala

485 490 495

Ile Asp Val Leu Asp Ser Pro Gln Ala Val Arg Arg Ser Leu Glu Gly

500 505 510

Val Gln Asp Glu Leu Asp Thr Leu Ala His Ala Leu Ser Ala Ile Gly

515 520 525

<210> 4

<211> 514

<212> PRT

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polypeptide

<400> 4

Met Ala Leu Ser Glu Leu Ala Leu Val Arg Trp Leu Gln Glu Ser Arg

1 5 10 15

Arg Ser Arg Lys Leu Ile Leu Phe Ile Val Phe Leu Ala Leu Leu Leu

20 25 30

Asp Asn Met Leu Leu Thr Val Val Val Pro Ile Ile Pro Ser Tyr Leu

35 40 45

Tyr Ser Ile Lys His Glu Lys Asn Ala Thr Glu Ile Gln Thr Ala Arg

50 55 60

Pro Val His Thr Ala Ser Ile Ser Asp Ser Phe Gln Ser Ile Phe Ser

65 70 75 80

Tyr Tyr Asp Asn Ser Thr Met Val Thr Gly Asn Ala Thr Arg Asp Leu

85 90 95

Thr Leu His Gln Thr Ala Thr Gln His Met Val Thr Asn Ala Ser Ala

100 105 110

Val Pro Ser Asp Cys Pro Ser Glu Asp Lys Asp Leu Leu Asn Glu Asn

115 120 125

Val Gln Val Gly Leu Leu Phe Ala Ser Lys Ala Thr Val Gln Leu Ile

130 135 140

Thr Asn Pro Phe Ile Gly Leu Leu Thr Asn Arg Ile Gly Tyr Pro Ile

145 150 155 160

Pro Ile Phe Ala Gly Phe Cys Ile Met Phe Val Ser Thr Ile Met Phe

165 170 175

Ala Phe Ser Ser Ser Tyr Ala Phe Leu Leu Ile Ala Arg Ser Leu Gln

180 185 190

Gly Ile Gly Ser Ser Cys Ser Ser Val Ala Gly Met Gly Met Leu Ala

195 200 205

Ser Val Tyr Thr Asp Asp Glu Glu Arg Gly Asn Val Met Gly Ile Ala

210 215 220

Leu Gly Gly Leu Ala Met Gly Val Leu Val Gly Pro Pro Phe Gly Ser

225 230 235 240

Val Leu Tyr Glu Phe Val Gly Lys Thr Ala Pro Phe Leu Val Leu Ala

245 250 255

Ala Leu Val Leu Leu Asp Gly Ala Ile Gln Leu Phe Val Leu Gln Pro

260 265 270

Ser Arg Val Gln Pro Glu Ser Gln Lys Gly Thr Pro Leu Thr Thr Leu

275 280 285

Leu Lys Asp Pro Tyr Ile Leu Ile Ala Ala Gly Ser Ile Cys Phe Ala

290 295 300

Asn Met Gly Ile Ala Met Leu Glu Pro Ala Leu Pro Ile Trp Met Met

305 310 315 320

Glu Thr Met Cys Ser Arg Lys Trp Gln Leu Gly Val Ala Phe Leu Pro

325 330 335

Ala Ser Ile Ser Tyr Leu Ile Gly Thr Asn Ile Phe Gly Ile Leu Ala

340 345 350

His Lys Met Gly Arg Trp Leu Cys Ala Leu Leu Gly Met Ile Ile Val

355 360 365

Gly Val Ser Ile Leu Cys Ile Pro Phe Ala Lys Asn Ile Tyr Gly Leu

370 375 380

Ile Ala Pro Asn Phe Gly Val Gly Phe Ala Ile Gly Met Val Asp Ser

385 390 395 400

Ser Met Met Pro Ile Met Gly Tyr Leu Val Asp Leu Arg His Val Ser

405 410 415

Val Tyr Gly Ser Val Tyr Ala Ile Ala Asp Val Ala Phe Cys Met Gly

420 425 430

Tyr Ala Ile Gly Pro Ser Ala Gly Gly Ala Ile Ala Lys Ala Ile Gly

435 440 445

Phe Pro Trp Leu Met Thr Ile Ile Gly Ile Ile Asp Ile Leu Phe Ala

450 455 460

Pro Leu Cys Phe Phe Leu Arg Ser Pro Pro Ala Lys Glu Glu Lys Met

465 470 475 480

Ala Ile Leu Met Asp His Asn Cys Pro Ile Lys Thr Lys Met Tyr Thr

485 490 495

Gln Asn Asn Ile Gln Ser Tyr Pro Ile Gly Glu Asp Glu Glu Ser Glu

500 505 510

Ser Asp

<210> 5

<211> 21

<212> DNA

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polynucleotides

<400> 5

caactacagc acaggctacg a 21

<210> 6

<211> 26

<212> DNA

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polynucleotides

<400> 6

gcatctgaat gtcttctacc ttaatg 26

<210> 7

<211> 18

<212> DNA

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polynucleotides

<400> 7

gcaactggcc gcccaagg 18

<210> 8

<211> 18

<212> DNA

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polynucleotides

<400> 8

aggccccacg ttgaccga 18

<210> 9

<211> 23

<212> DNA

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polynucleotides

<400> 9

gaagtccacc tgctaaggaa gaa 23

<210> 10

<211> 23

<212> DNA

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polynucleotides

<400> 10

tcactggaga cacatgtaca cag 23

<210> 11

<211> 20

<212> DNA

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polynucleotides

<400> 11

tccaaccttt cctggcccag 20

<210> 12

<211> 20

<212> DNA

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polynucleotides

<400> 12

gcatgaaggg caggaggaat 20

<210> 13

<211> 19

<212> DNA

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polynucleotides

<400> 13

tgggaggcca tcacattgt 19

<210> 14

<211> 21

<212> DNA

<213> Artificial sequence (Artificial sequence)

<220>

<223> Synthesis of polynucleotides

<400> 14

aatccagcag gtcagcaaag a 21

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