Compositions and methods for modulating PPP2R1A

文档序号：1525046 发布日期：2020-02-11 浏览：38次中文

阅读说明：本技术 用于调节ppp2r1a的组合物和方法 (Compositions and methods for modulating PPP2R1A ) 是由 D·K·野村 E·A·格罗斯曼 C·C·沃德 L·A·贝特曼 T·R·赫夫曼 D·K·宫本于 2018-02-02 设计创作，主要内容包括：本文尤其公开适用于调节PPP2R1 A并且适用于治疗癌症的组合物和方法。(Disclosed herein, inter alia, are compositions and methods useful for modulating PPP2R1a and for treating cancer.)

1. A method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of a compound having the formula:

wherein the content of the first and second substances,

z1 is an integer from 0 to 7;

L ¹is a bond, -S (O) ₂-、-NR ⁴-、-O-、-S-、-C(O)-、-C(O)NR ⁴-、-NR ⁴C(O)-、-NR ⁴C(O)NH-、-NHC(O)NR ⁴-, -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;

R ⁴is hydrogen, -CX ⁴ ₃、-CHX ⁴ ₂、-CH ₂X ⁴、-OCX ⁴ ₃、-OCH ₂X ⁴、-OCHX ⁴ ₂、-CN、-C(O)R ^4A、-C(O)-OR ^4A、-C(O)NR ^4AR ^4B、-OR ^4ASubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L ²is a bond, -S (O) ₂-、-NR ⁵-、-O-、-S-、-C(O)-、-C(O)NR ⁵-、-NR ⁵C(O)-、-NR ⁵C(O)NH-、-NHC(O)NR ⁵-, -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;

R ⁵is hydrogen, -CX ⁵ ₃、-CHX ⁵ ₂、-CH ₂X ⁵、-OCX ⁵ ₃、-OCH ₂X ⁵、-OCHX ⁵ ₂、-CN、-C(O)R ^5A、-C(O)-OR ^5A、-C(O)NR ^5AR ^5B、-OR ^5ASubstituted 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;

each R ^1A、R ^1B、R ^1C、R ^1D、R ^4A、R ^4B、R ^5AAnd R ^5BIndependently hydrogen, -CX ₃、-CN、-COOH、-CONH ₂、-CHX ₂、-CH ₂X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstitutedA substituted heteroaryl group; r bound to the same nitrogen atom ^1AAnd R ^1BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^4AAnd R ^4BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^5AAnd R ^5BCan optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;

each X, X ¹、X ⁴And X ⁵Independently is-F, -Cl, -Br or-I;

n1, n4, and n5 are independently integers from 0 to 4; and is

m1, m4, m5, v1, v4 and v5 are independently integers of 1 to 2.

2. The method of claim 1, having the formula:

3. the method of claim 1, having the formula:

4. the method of claim 2, having the formula:

5. the method of claim 1, having the formula:

6. the method of claim 1, having the formula:

7. the method of claim 5, having the formula:

8. the method of claim 1, wherein R ¹Independently halogen, -CX ¹ ₃、-CHX ¹ ₂、-CH ₂X ¹、-OCX ¹ ₃、-OCH ₂X ¹、-OCHX ¹ ₂、-CN、-SR ^1D、-NR ^1AR ^1B、-C(O)R ^1C、-C(O)OR ^1C、-C(O)NR ^1AR ^1B、-OR ^1DSubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

9. The method of claim 1, wherein R ¹Independently halogen, -CX ¹ ₃、-CHX ¹ ₂、-CH ₂X ¹、-OCX ¹ ₃、-OCH ₂X ¹、-OCHX ¹ ₂、-CN、-SH、-NH ₂、-C(O)OH、-C(O)NH ₂-OH, substituted or unsubstituted C ₁-C ₈Alkyl or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C ₃-C ₈Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl, substituted or unsubstituted C ₆-C ₁₂Cycloalkyl or substituted or unsubstituted 5 to 12 membered heteroaryl.

10. The method of claim 1, wherein R ¹Independently halogen, -CX ¹ ₃、-CHX ¹ ₂、-CH ₂X ¹、-OCX ¹ ₃、-OCH ₂X ¹、-OCHX ¹ ₂、-CN、-SH、-NH ₂、-C(O)OH、-C(O)NH ₂-OH, substituted or unsubstituted C ₁-C ₈Alkyl or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C ₃-C ₈Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroaryl.

11. The method of claim 1, wherein two adjacent R' s ¹The substituents join to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

12. The method of claim 1, wherein L ¹Is a bond, substituted or unsubstituted C ₁-C ₈Alkylene, substituted or unsubstituted 2-to 8-membered heteroalkylene, substituted or unsubstituted C ₃-C ₈Cycloalkylene, substituted or unsubstituted 3-to 8-membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5-to 6-membered heteroarylene.

13. The method of claim 1, wherein L ¹Is a bond.

14. The method of claim 1, wherein L ²is-NR ⁵-orA substituted or unsubstituted heterocycloalkylene group containing the ring nitrogen directly bonded to E.

15. The method of claim 1, wherein L ²is-NR ⁵-。

16. The method of claim 15, wherein R ⁵Is hydrogen, substituted or unsubstituted C ₁-C ₆Alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl.

17. The method of claim 15, wherein R ⁵Is hydrogen or unsubstituted C ₁-C ₃An alkyl group.

18. The method of claim 15, wherein R ⁵Is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl or unsubstituted benzyl.

19. The method of claim 15, wherein R ⁵Is hydrogen.

20. The method of claim 1, wherein E is a covalent cysteine modification moiety.

21. The method of claim 1, wherein E is:

R ¹⁶independently hydrogen, halogen, CX ¹⁶ ₃、-CHX ¹⁶ ₂、-CH ₂X ¹⁶、-CN、-SO _n16R ^16D、-SO _v16NR ^16AR ^16B、-NHNR ^16AR ^16B、-ONR ^16AR ^16B、-NHC＝(O)NHNR ^16AR ^16B、-NHC(O)NR ^16AR ^16B、-N(O) _m16、-NR ^16AR ^16B、-C(O)R ^16C、-C(O)-OR ^16C、-C(O)NR ^16AR ^16B、-OR ^16D、-NR ^16ASO ₂R ^16D、-NR ^16AC(O)R ^16C、-NR ^16AC(O)OR ^16C、-NR ^16AOR ^16C、-OCX ¹⁶ ₃、-OCHX ¹⁶ ₂Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁷independently hydrogen, halogen, CX ¹⁷ ₃、-CHX ¹⁷ ₂、-CH ₂X ¹⁷、-CN、-SO _n17R ^17D、-SO _v17NR ^17AR ^17B、-NHNR ^17AR ^17B、--ONR ^17AR ^17B、--NHC＝(O)NHNR ^17AR ^17B、--NHC(O)NR ^17AR ^17B、-N(O) _m17、-NR ^17AR ^17B、-C(O)R ^17C、-C(O)-OR ^17C、-C(O)NR ^17AR ^17B、-OR ^17D、-NR ^17ASO ₂R ^17D、-NR ^17AC(O)R ^17C、-NR ^17AC(O)OR ^17C、-NR ^17AOR ^17C、-OCX ¹⁷ ₃、-OCHX ¹⁷ ₂Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ¹⁸independently hydrogen, -CX ¹⁸ ₃、-CHX ¹⁸ ₂、-CH ₂X ¹⁸、-C(O)R ^18C、-C(O)OR ^18C、-C(O)NR ^18AR ^18BSubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R ^15A、R ^15B、R ^15C、R ^15D、R ^16A、R ^16B、R ^16C、R ^16D、R ^17A、R ^17B、R ^17C、R ^17D、R ^18A、R ^18B、R ^18C、R ^18Dindependently hydrogen, -CX ₃、-CN、-COOH、-CONH ₂、-CHX ₂、-CH ₂X, 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; r bound to the same nitrogen atom ^15AAnd R ^15BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^16AAnd R ^16BThe substituent can beOptionally joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^17AAnd R ^17BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^18AAnd R ^18BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;

each X, X ¹⁵、X ¹⁶、X ¹⁷And X ¹⁸Independently is-F, -Cl, -Br or-I;

n15, n16, n17, v15, v16 and v17 are independently integers from 0 to 4; and is

m15, m16, and m17 are independently integers of 1 to 2.

22. The method of claim 21, wherein R ¹⁵、R ¹⁶、R ¹⁷And R ¹⁸Is hydrogen.

23. The method of claim 21, wherein E is:

24. the method of claim 21, wherein E is:

25. the method of claim 1, wherein the compound has the formula:

26. the method of claim 1, wherein the compound has the formula:

27. the method of claim 1, wherein the cancer is breast cancer.

28. The method of claim 1, wherein the cancer is triple negative breast cancer.

29. Use of a compound for the manufacture of a medicament for the treatment of cancer, wherein the compound has the formula:

wherein the content of the first and second substances,

z1 is an integer from 0 to 7;

e is an electrophilic moiety;

each R ^1A、R ^1B、R ^1C、R ^1D、R ^4A、R ^4B、R ^5AAnd R ^5BIndependently hydrogen, -CX ₃、-CN、-COOH、-CONH ₂、-CHX ₂、-CH ₂X, 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; r bound to the same nitrogen atom ^1AAnd R ^1BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^4AAnd R ^4BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^5AAnd R ^5BCan optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;

each X, X ¹、X ⁴And X ⁵Independently is-F, -Cl, -Br or-I;

n1, n4, and n5 are independently integers from 0 to 4; and is

m1, m4, m5, v1, v4 and v5 are independently integers of 1 to 2.

30. A pharmaceutical composition comprising a modulator of the serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isomer (PPP2R1A) and a pharmaceutically acceptable excipient.

31. The pharmaceutical composition of claim 30, wherein the serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isomer (PPP2R1A) modulator is a compound having the formula:

wherein the content of the first and second substances,

z1 is an integer from 0 to 7;

e is an electrophilic moiety;

each R ^1A、R ^1B、R ^1C、R ^1D、R ^4A、R ^4B、R ^5AAnd R ^5BIndependently hydrogen, -CX ₃、-CN、-COOH、-CONH ₂、-CHX ₂、-CH ₂X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkylSubstituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^1AAnd R ^1BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^4AAnd R ^4BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^5AAnd R ^5BCan optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;

each X, X ¹、X ⁴And X ⁵Independently is-F, -Cl, -Br or-I;

n1, n4, and n5 are independently integers from 0 to 4; and is

m1, m4, m5, v1, v4 and v5 are independently integers of 1 to 2.

32. A method of modulating a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein, the method comprising contacting the PPP2R1A protein with an effective amount of a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) modulator.

33. A method of activating tumor suppressor protein phosphatase 2A (PP2A), the method comprising contacting a serine/threonine-protein phosphatase 2A65kDa regulatory subunit a α isomer (PPP2R1A) protein with an effective amount of a serine/threonine-protein phosphatase 2A65kDa regulatory subunit a α isomer (PPP2R1A) modulator.

34. The method of claim 32, wherein the serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) modulator is an antisense nucleic acid, antibody, or compound.

35. The method of claim 32, wherein the serine/threonine-protein phosphatase 2A65kDa regulatory subunit A α isoform (PPP2R1A) modulator is contacted with one or more amino acids corresponding to Q339, S343, E379, K416, H340 of SEQ ID NO:4, N264, Q272, M245, and D290 of SEQ ID NO:6, or E117 and P113 and F118 of human SEQ ID NO: 5.

36. The method of claim 32, wherein the serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) modulator is a compound having the formula:

wherein the content of the first and second substances,

z1 is an integer from 0 to 7;

e is an electrophilic moiety;

each R ^1A、R ^1B、R ^1C、R ^1D、R ^4A、R ^4B、R ^5AAnd R ^5BIndependently hydrogen, -CX ₃、-CN、-COOH、-CONH ₂、-CHX ₂、-CH ₂X, 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; r bound to the same nitrogen atom ^1AAnd R ^1BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^4AAnd R ^4BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^5AAnd R ^5BCan optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;

each X, X ¹、X ⁴And X ⁵Independently is-F, -Cl, -Br or-I;

n1, n4, and n5 are independently integers from 0 to 4; and is

m1, m4, m5, v1, v4 and v5 are independently integers of 1 to 2.

37. The method of claim 36, wherein the compound is covalently bonded to an amino acid corresponding to C377 of SEQ ID No. 4.

38. The method of claim 36, wherein the compound is contacted with one or more amino acids corresponding to Q339, S343, E379, K416, H340 of SEQ ID No. 4.

39. A serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein covalently bonded to a compound having the formula:

wherein the content of the first and second substances,

z1 is an integer from 0 to 7;

e is an electrophilic moiety;

each R ^1A、R ^1B、R ^1C、R ^1D、R ^4A、R ^4B、R ^5AAnd R ^5BIndependently hydrogen, -CX ₃、-CN、-COOH、-CONH ₂、-CHX ₂、-CH ₂X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstitutedSubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^1AAnd R ^1BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^4AAnd R ^4BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^5AAnd R ^5BCan optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;

each X, X ¹、X ⁴And X ⁵Independently is-F, -Cl, -Br or-I;

n1, n4, and n5 are independently integers from 0 to 4; and is

m1, m4, m5, v1, v4 and v5 are independently integers of 1 to 2;

wherein the PPP2R1A protein is covalently bonded through a reactive residue of the electrophilic moiety.

40. The serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein according to claim 39, wherein said compound is bound to a cysteine residue of said protein.

41. The serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein according to claim 39, irreversibly covalently bonded to the compound.

42. The serine/threonine-protein phosphatase 2A65kDa regulatory subunit A α isoform (PPP2R1A) protein according to claim 39, wherein said compound or a portion of said compound is covalently bonded to an amino acid corresponding to C377 of SEQ ID NO 4.

43. A method of increasing the activity of a protein phosphatase 2A (PP2A), the method comprising contacting a PP2A protein complex with an effective amount of a serine/threonine-protein phosphatase 2A65kDa regulatory subunit a α isomer (PPP2R1A) modulator.

44. The method of claim 43, wherein the serine/threonine-protein phosphatase 2A65kDa regulatory subunit A α isoform (PPP2R1A) modulator is an antisense nucleic acid, antibody, or compound.

45. The method of claim 43, wherein the serine/threonine-protein phosphatase 2A65kDa regulatory subunit A α isoform (PPP2R1A) modulator is contacted with one or more amino acids corresponding to Q339, S343, E379, K416, H340 of SEQ ID NO:4, N264, Q272, M245, and D290 of SEQ ID NO:6, or E117 and P113 and F118 of SEQ ID NO: 5.

46. The method of claim 43, wherein the serine/threonine-protein phosphatase 2A65kDa regulatory subunit A α isoform (PPP2R1A) modulator is a compound having the formula:

wherein the content of the first and second substances,

z1 is an integer from 0 to 7;

e is an electrophilic moiety;

each R ^1A、R ^1B、R ^1C、R ^1D、R ^4A、R ^4B、R ^5AAnd R ^5BIndependently hydrogen, -CX ₃、-CN、-COOH、-CONH ₂、-CHX ₂、-CH ₂X, 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; r bound to the same nitrogen atom ^1AAnd R ^1BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^4AAnd R ^4BSubstituents can optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^5AAnd R ^5BCan optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl;

each X, X ¹、X ⁴And X ⁵Independently is-F, -Cl, -Br or-I;

n1, n4, and n5 are independently integers from 0 to 4; and is

m1, m4, m5, v1, v4 and v5 are independently integers of 1 to 2.

47. The method of claim 46, wherein the compound is covalently bonded to an amino acid corresponding to C377 of human SEQ ID NO 4.

48. The method of claim 46, wherein the compound is contacted with one or more amino acids corresponding to Q339, S343, E379, K416, H340 of SEQ ID NO 4.

Background

Breast cancer in women is the fourth leading cause of cancer death in the united states. It is estimated that about 1 (about 12%) of 8 american women will suffer invasive breast cancer during their lifetime and that the number of deaths per 100,000 women per year is 21.5 according to the 2009 and 2013 data. In 2017, it was expected that american women would have an estimated 255,180 new cases of invasive breast cancer diagnosed, and 63,410 new cases of non-invasive (in situ) breast cancer. Current treatment strategies for breast cancer include resection and non-specific therapies, such as radiation or chemotherapy. Unfortunately, these therapeutic strategies are insufficient for highly aggressive Triple Negative Breast Cancer (TNBC), and thus better strategies are needed to find new anticancer agents and targets against triple negative breast cancer. To achieve this goal, the identification of new anti-cancer targets, druggable nodes and major small molecules is crucial to combat respiratory cancers. Solutions to these and other problems in the art are disclosed, inter alia, herein.

Disclosure of Invention

Provided herein, inter alia, are compounds and methods of use thereof that are capable of modulating the level of activity of the subunit PPP2R1A of the tumor suppressor protein phosphatase 2A (PP2A) complex.

In one aspect, compounds are provided having the formula:

R ¹independently halogen, -CX ¹ ₃、-CHX ¹ ₂、-CH ₂X ¹、-OCX ¹ ₃、-OCH ₂X ¹、-OCHX ¹ ₂、-CN、-SO _n1R ^1D、-SO _v1NR ^1AR ^1B、-NHC(O)NR ^1AR ^1B、-N(O) _m1、-NR ^1AR ^1B、-C(O)R ^1C、-C(O)-OR ^1C、-C(O)NR ^1AR ^1B、-OR ^1D、-NR ^1ASO ₂R ^1D、-NR ^1AC(O)R ^1C、-NR ^1AC(O)OR ^1C、-NR ^1AOR ^1C、-N ₃Substituted 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 adjacent R ¹The substituents may optionally join to form a substituted or unsubstituted ringAn alkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. The notation z1 is an integer from 0 to 7. L is ¹Is a bond, -S (O) ₂-、-NR ⁴-、-O-、-S-、-C(O)-、-C(O)NR ⁴-、-NR ⁴C(O)-、-NR ⁴C(O)NH-、-NHC(O)NR ⁴-, -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. R ⁴Is hydrogen, -CX ⁴ ₃、-CHX ⁴ ₂、-CH ₂X ⁴、-OCX ⁴ ₃、-OCH ₂X ⁴、-OCHX ⁴ ₂、-CN、-C(O)R ^4A、-C(O)-OR ^4A、-C(O)NR ^4AR ^4B、-OR ^4ASubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L is ²Is a bond, -S (O) ₂-、-NR ⁵-、-O-、-S-、-C(O)-、-C(O)NR ⁵-、-NR ⁵C(O)-、-NR ⁵C(O)NH-、-NHC(O)NR ⁵-, -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. R ⁵Is hydrogen, -CX ⁵ ₃、-CHX ⁵ ₂、-CH ₂X ⁵、-OCX ⁵ ₃、-OCH ₂X ⁵、-OCHX ⁵ ₂、-CN、-C(O)R ^5A、-C(O)-OR ^5A、-C(O)NR ^5AR ^5B、-OR ^5ASubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstitutedSubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. E is an electrophilic moiety. Each R ^1A、R ^1B、R ^1C、R ^1D、R ^4A、R ^4B、R ^5AAnd R ^5BIndependently hydrogen, -CX ₃、-CN、-COOH、-CONH ₂、-CHX ₂、-CH ₂X, 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. R bound to the same nitrogen atom ^1AAnd R ^1BThe substituents may optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. R bound to the same nitrogen atom ^4AAnd R ^4BThe substituents may optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. R bound to the same nitrogen atom ^5AAnd R ^5BThe substituents may optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. Each X, X ¹、X ⁴And X ⁵Independently is-F, -Cl, -Br or-I. The symbols n1, n4, and n5 are independently integers from 0 to 4. The symbols m1, m4, m5, v1, v4 and v5 are independently integers of 1 to 2.

In one aspect, a pharmaceutical composition is provided that includes a modulator of the serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isomer (PPP2R1A) and a pharmaceutically acceptable excipient.

In one aspect, a pharmaceutical composition is provided that includes a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In one aspect, a method of modulating a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein is provided, the method comprising contacting the serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein with an effective amount of a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) modulator.

In one aspect, there is provided a method of modulating a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein, the method comprising contacting the serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein with an effective amount of a compound described herein.

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

In one aspect, a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein covalently bound to a PPP2R1A modulator is provided.

In one aspect, a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein covalently bound to a compound described herein is provided.

Drawings

FIGS. 1A-1D: theafenidin a (withaferin a) impairs the pathogenicity of breast cancer cells. (FIG. 1A) Structure of theafenicol A. (FIG. 1B) Theaflavin A (10. mu.M) impaired cell proliferation and serum-free cell survival after 48 hours in MCF7, 231MFP and HCC38 cells.

Figures 2A-2f mapping of the proteomic range of theafenidin a targets in breast cancer cells using the isoTOP-ABPP platform. (FIG. 2A) competitive IsoTOP-ABPP method. We mapped the cysteine reactivity of theafenidin a by pre-incubation of theafenidin a (10 μ M) in the 231MFP breast cancer cell proteome for 30 minutes before labeling with a cysteine reactive iodoacetamide-alkyne (IAyne) probe (100 μ M, 30 minutes). The probe-labeled protein was then labeled by CuAAC with either an isotopically light (for control) or heavy (for theafennin a-treated) biotin-azide label carrying a TEV protease recognition site. The control and treated proteomes were then mixed at a 1:1 ratio, probe-labeled protein enriched in avidin and trypsinized, probe-labeled tryptic peptide again enriched in avidin and released by TEV protease and analyzed by quantitative proteomics methods and the light to heavy peptide ratio was quantified. FIG. 2B: competitive isoTOP-ABPP analysis of theafenfenin a cysteine reactivity in 231MFP breast cancer cell proteome in vitro. A light to weight ratio of about 1 indicates a peptide labeled with IAyne but not bound to theafenidin a. We expressed the light to weight ratio >5 as the target for binding to theafenninol a. The modification sites for the peptide sequence recognized for PPP2R1A and the probe-modified peptide and the light to weight ratio of C377 to C390 on PPP2R1A are also shown. The sequence in the figure is C377: DNTIEHLLPLFLAQLKDEC PEVR corresponding to SEQ ID NO: 2; and C390: LNIISNLDC VNEVIGIR, corresponding to SEQ ID NO: 3. FIG. 2C: PPP2R1A was verified as a target for theafenninol a. Theafenidin a was pre-incubated with pure human PPP2R1A protein, then with IAyne. The probe-labeled protein was conjugated to rhodamine (rhodamine) -azide by CuAAC and analyzed by SDS/PAGE and fluorescence in gel. FIG. 2D: the crystal structure of the PP2A complex shows C377 (shown in white) of PPP2R1A, the catalytic subunit, and another regulatory subunit. The PDB structure used is 2 IAE. FIG. 2E: assays for PP2A activity were performed with PP2A complex proteins PPP2R1A wild-type (WT) or C377A mutant and PPP2R2A and PPP2CA subunits that measure phosphate release from the phosphopeptide of the PP2A substrate. This PP2A complex was treated with DMSO or theafennel a (10 μ M) in vitro for 30 minutes prior to starting the assay. FIG. 2F: theafenidin a (10 μ M, 4 hr) treatment significantly reduced phosphorylated AKT content in 231MFP breast cancer cells, and this reduction was rescued by co-treatment with cantharidin (10 μ M, 4 hr). The data in fig. 2B is the average scale from n-3. The gel in fig. 2C is a representative gel from n-3. The data in fig. 2E-2F are presented as mean ± sem, n ═ 3. Significance was expressed as p <0.05 compared to vehicle treated control and # p <0.05 compared to control treated with theafenidin a. NS means no significance compared to vehicle treated C377A PPP2R1A group. Additional data (e.g., theafenidin A in situ) and the isoTOP-ABPP analysis can be found in FIGS. 7A-7G.

FIGS. 3A-3C: screening a library of covalent ligands in breast cancer cells. (FIG. 3A): cysteine-reactive covalent ligand libraries in 231MFP breast cancer cells were screened using a competitive isoTOP-ABPP platform coupling to identify anticancer lead compounds, targets, and coordinatable hot spots within these targets. (FIG. 3B): a library of cysteine-reactive fragments consisting of acrylamide and chloroacetamide was screened in 231MFP breast cancer cells (100 μ M) to identify any leads that significantly impaired proliferation of 231MFP breast cancer cells. Cell viability was assessed 48 hours after Hoescht staining treatment. From the left side to the right side of FIG. 3B, the compounds tested were DKM 2-91, DKM 2-90, DKM 2-101, TRH 1-53, DKM 2-52, DKM2-76, DKM 2-79, DKM 2-71, DKM 3-30, DKM 3-22, TRH 1-17, TRH 1-51, DKM 2-72, DKM 3-70, TRH 1-50, DKM2-76, TRH 1-23, DKM 3-42, DKM 2-94, DKM 2-93, DKM 2-114, TRH 1-DKM 12, DKM 3-3, DKM 2-59, DKM 2-107, DKM 2-98, DKM 2-85, DKM 2-119, DKM 2-83, TRH 1-55, DKM 2-101, DKM 2-97, DKM 2-117, DKM 2-80, DKM 3-10, DKM 3-43, DKM 3-31, DKM 2-40, DKM 3-41, DKM 2-87, TRH 1-32, DKM2-47, DKM 2-43, DKM 3-7, DKM 2-116, DKM 2-106, DKM 2-120, DKM 2-102, DKM 3-29, DKM 3-16, DKM 2-111, DKM 1-19, DKM 3-36, DKM 2-109, DKM 3-4, DKM 3-13, DKM 2-32, TRH 1-54, DKM 2-113, DKM 3-5, DKM 2-110, DKM 2-37, DKM 2-84, DKM 2-60, DKM 2-13, DKM 2-32, DKM 2-13, DKM 48, TRH 1-20, DKM 2-67, DKM 2-31, DKM 2-103, TRH 1-13, DKM 2-49, DKM 2-62, DKM 2-42, TRH 1-27, DKM 2-100, DKM 3-32, DKM 3-11, DKM 3-8, DKM 3-15, DKM 2-95, DKM 2-50, DKM 2-108, DKM 2-58, DKM2-86, DKM 3-12, DKM 2-34, DKM 3-9, DKM 2-33 and DKM 2-39. (FIG. 3C): PPP2R1A was verified as a target for theafenninol a. The theafenidin A is pre-incubated with pure human PPP2R1A protein and then with IAyne. The probe-labeled protein was conjugated to rhodamine-azide by CuAAC and analyzed by SDS/PAGE and fluorescence in gel. The data in (fig. 3B) are expressed as mean ± sem, n being 3. Significance was expressed as p <0.05 compared to vehicle treated controls.

FIGS. 4A-4E: DKM 2-90 was target-identified using a competitive isoTOP-ABPP platform. (FIG. 4A): dose-responsive effects of DKM 2-90 and DKM 2-91 on cell proliferation in 231MFP breast cancer cells. 231MFP cells were treated with DMSO or DKM 2-90 or DKM 2-91 and proliferation was assessed 48 hours after Hoescht staining treatment. (FIG. 4B): the effect of DKM 2-90 and DKM 2-91 on cell proliferation in MCF10A mammary epithelial cells was assessed by 48 hours after Hoescht staining treatment. (FIG. 4C): Isotop-ABPP assay of DKM 2-90 in the 231MFP cell proteome. 231MFP proteomes were pretreated with DMSO or DKM 2-90(100 μ M) for 30 minutes, followed by IAyne (100 μ M) labeling of the proteomes, followed by attachment of biotin-azide labels carrying isotopic light (control) or heavy (treatment) control points and TEV protease recognition sites. The control and treated proteomes were mixed in a 1:1 ratio and the probe-labeled protein tryptic peptides were subsequently enriched and analyzed by quantitative proteomic methods. A light to heavy ratio of 1 indicates that the peptide bearing the probe-labeled cysteine does not bind to the covalent ligand, while a ratio >10 indicates the binding site. (FIG. 4D): DKM 2-90 competes with IAyne, which marks the pure human PPP2R1A protein. DKM 2-90 was preincubated with pure PPP2R1A protein for 30 min, followed by labeling with IAyne (100. mu.M) for 30 min. The attachment to rhodamine-azide was by copper-catalyzed azide-alkyne cycloaddition, and the proteins were separated by SDS/PAGE and analyzed by fluorescence in the gel. (FIG. 4E): total AKT and levels of phosphorylated AKT (p-AKT) and vinculin (vinculin) as internal references in 231MFP breast cancer cells. 231MFP cells were treated with vehicle, DKM 2-90 (100. mu.M), cantharidin or (10. mu.M) and DKM 2-90 (100. mu.M) for 5 hours. Western blots were performed for p-AKT, total AKT and Nebulin reference. All data shown represent n-3-5/group.

FIGS. 5A-5C: theafenfenidin a and DKM 2-90 mediate alterations in cellular metabolism in breast cancer cells. (FIG. 5A): metabolomics profiling of theafenicol a and DKM 2-90 in 231MFP breast cancer cells. 231MFP breast cancer cells were treated with vehicle DMSO or theafenfenidin A (10 μ M) or DKM 2-90(100 μ M) for 5 hours and metabolites were assayed using SRM-based LC-MS/MS. (FIG. 5B): representative metabolite content showing the common metabolic changes conferred by theafennins a and DKM 2-90 on glycolysis and phospholipid metabolism. (FIG. 5C): models of the proposed effects of theafennins a and DKM 2-90 in combination with C377 at PPP2R1A to activate PP2A activity, impair AKT signaling, impair PFK1 activity, and inhibit glycolysis and lipid metabolism and ATP levels. Theafennins a and DKM 2-90 activate PP2A to inhibit AKT signaling and glycolysis and lipid metabolism in breast cancer cells. The data in (fig. 5B) are presented as mean ± sem, n being 5/group. Compared to vehicle treated controls, significance was shown as p < 0.05.

FIG. 6 residues of protein phosphatase 2A regulatory subunit A α isoform (PPP2R1A), protein phosphatase 2A catalytic subunit α isoform (PPP2CA), and protein phosphatase 2A (PP2A) protein phosphatase 2A regulatory subunit gamma isoform (PPP2R5C) in complex.

FIGS. 7A-7G: the interaction of theafenninol A and DKM 2-90 was studied. (FIG. 7A) anti-proliferative dose response of theafenidin A in 231MFP cells. Cells were treated with DMSO or theafennel a in serum-containing medium for 48 hours, and cell viability was assessed by Hoechst staining. (FIG. 7B) IsoTOP-ABPP analysis of theafenfenidin A treatment in 231MFP cells. 231MFP cells were treated with DMSO or theafennel A (10. mu.M) for 4 hours. The proteome was then labeled ex situ with IAyne for 1 hour and subjected to the isoTOP-ABPP method. The light to weight ratio of the probe modified peptides is shown. (FIG. 7C) gel-based ABPP assay in competition with pure human KEAP1 and anti-IAyne-labeled theafenidin A of vimentin. The purified protein was pretreated with DMSO or theafennel A (10. mu.M) for 30 min at 37 ℃ before IAyne labeling (10. mu.M) for 30 min. The probe-labeled protein was then attached to rhodamine-azide by CuAAC and analyzed by SDS/PAGE and fluorescence in gel. (FIG. 7D) PPP2R1A expression assessed by qPCR. 231MFP cells were transfected with siControl or siPPP2R1A oligonucleotide and the cells were harvested 48 hours later for qPCR analysis. (FIG. 7E)231MFP cells proliferated. 231MFP cells were transfected with siControl or siPPP2R1A oligonucleotide for 48 hours, and then the cells were seeded and treated with DMSO or theafennel A (10. mu.M) for an additional 48 hours, and cell viability was assessed by Hoechst staining. (FIG. 7F) analysis of DKM 2-90 treated IsoTOP-ABPP in 231MFP cells. 231MFP cells were treated with DMSO or DKM 2-90 (100. mu.M) for 4 hours. The proteome was then labeled ex situ with IAyne for 1 hour and subjected to the isoTOP-ABPP method. The light to weight ratio of the probe modified peptides is shown. (FIG. 7G)231MFP cells proliferated. 231MFP cells were transfected with siControl or siPPP2R1A oligonucleotide for 48 hours and then the cells were seeded and treated with DMSO or DKM 2-90 (100. mu.M) for an additional 48 hours and cell viability was assessed by Hoechst staining. The data in (fig. 7A, 7D, 7E and 7G) are presented as mean ± sem, n ═ 3-5/group. Significance in (fig. 7D, 7E and 7G) compared to vehicle-treated siControl cells was expressed as p <0.05, compared to theafennin a or DKM 2-90 treated siControl cells, # p < 0.05.

Characteristics of the DKM 2-90 analogs JNS 1-37 and JNS 1-40. (FIG. 8A) gel-based ABPP analysis of JNS 1-37 structure and its potency for PPP2R 1A. Pure human PPP2R1A was pretreated with DMSO or JNS 1-37 for 30 min at 37 ℃ followed by IAyne labeling for 30 min at room temperature. The probe-labeled protein was then attached to rhodamine-azide by CuAAC and analyzed by SDS/PAGE and fluorescence in gel. (FIG. 8B) IsoTOP-ABPP assay of JNS1-40 treatment in 231MFP cells. 231MFP cells were treated with DMSO or JNS1-40 (100. mu.M) for 4 hours. The proteome was then labeled ex situ with IAyne for 1 hour and subjected to the isoTOP-ABPP method. The light to weight ratio of the probe modified peptides is shown. (FIG. 8C)231MFP cells proliferated. 231MFP cells were transfected with siControl or siPPP2R1A oligonucleotide for 48 hours and then the cells were seeded and treated with DMSO or JNS1-40 (100. mu.M) for an additional 48 hours and cell viability was assessed by Hoechst staining. The data in (fig. 8C) are presented as mean ± sem, n being 5/group. Significance in (fig. 8C) was expressed as p <0.05 compared to vector treated siControl cells and p <0.05 compared to JNS1-40 treated siControl cells.

Fig. 9A-9g. covalent ligand JNS1-40 selectively targets C377 of PPP2R1A to activate PP2A activity and impair breast cancer pathogenicity. Structure of JNS1-40 and its gel-based ABPP analysis of the potency of PPP2R 1A. Pure human PPP2R1A was pretreated with DMSO or JNS1-40 for 30 min at 37 ℃ followed by IAyne labeling for 30 min at room temperature. The probe-labeled protein was then attached to rhodamine-azide by CuAAC and analyzed by SDS/PAGE and fluorescence in gel. (FIG. 9B) IsoTOP-ABPP assay of JNS1-40 treatment in 231MFP cells. 231MFP proteomes were treated in vitro with DMSO or JNS1-40 (100. mu.M) for 30 minutes, followed by IAyne labeling for 1 hour, and subjected to the IsoTOP-ABPP method. The light to weight ratio of the probe modified peptides is shown. (FIG. 9C) assay of PP2A activity, in which PP2A complex protein PPP2R1A Wild Type (WT) or C377A mutant and PPP2R2A and PPP2CA subunits measure phosphate release from PP2A substrate phosphopeptides. This PP2A complex was treated in vitro with DMSO or JNS1-40 (100. mu.M) for 30 min before the assay was started. (FIG. 9D) total AKT and phosphorylated AKT (p-AKT) and Neulin levels as internal reference in 231MFP breast cancer cells. 231MFP cells were treated with vehicle or JNS1-40 (100. mu.M) for 5 hours. (FIGS. 9E, 9F) JS1-40 (100. mu.M) impaired cell proliferation and serum-free cell survival after 48 hours in 231MFP cells. (FIG. 9G) 231MFP tumor xenograft growth in immunodeficient SCID mice. 231MFP cells were injected subcutaneously into mice. Treatment with vehicle or JNS1-40 (50mg/kg ip) once daily began 15 days after tumor implantation. Data in (fig. 9C-9G) are presented as mean ± sem, n-3-7/group. The data in (fig. 9B) is the average ratio of n to 3. Compared to vehicle treated controls, significance was shown as p < 0.05. The NS indication was not significant (p >0.05) compared to the carrier-treated C377APPP2R1A group.

Detailed Description

I. Definition of

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

When substituents are illustrated by conventional formulas written from left to right, the substituents likewise encompass chemically identical substituents resulting from writing the structure from right to left, e.g., -CH ₂O-equivalent to-OCH ₂-。

Unless otherwise stated, the term "alkyl", by itself or as one of another substituentMoiety, means a straight (i.e., unbranched) or branched carbon chain (or carbon), or a combination thereof, which may be fully saturated, mono-unsaturated, or polyunsaturated, and may include monovalent, divalent, and multivalent groups. The alkyl group can include a specified number of carbons (e.g., C) ₁-C ₁₀Meaning one to ten carbons). Alkyl is an acyclic chain. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, methyl, homologs 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 (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 linking group (-O-). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. In addition to one or more double bonds, an alkenyl group may include more than one double bond and/or one or more triple bonds. In addition to one or more triple bonds, an alkynyl group may include more than one triple bond and/or one or more double bonds.

Unless otherwise stated, the term "alkylene", by itself or as part of another substituent, means a divalent group derived from an alkyl group, such as, but not limited to, -CH ₂CH ₂CH ₂CH ₂-. Generally, 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 shorter alkyl or alkylene group typically having 8 or fewer carbon atoms. Unless otherwise stated, the term "alkenylene", by itself or as part of another substituent, means a divalent group derived from an alkene.

Unless otherwise stated, the term "heteroalkyl", by itself or in combination with another term, means a stable, straight chainOr a branched chain or combination thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si or S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom (e.g., O, N, P, S, B, As or Si) can be located at any internal position of the heteroalkyl group or position where the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an acyclic chain. Examples include, but are not limited to: -CH ₂-CH ₂-O-CH ₃、-CH ₂-CH ₂-NH-CH ₃、-CH ₂-CH ₂-N(CH ₃)-CH ₃、-CH ₂-S-CH ₂-CH ₃、-CH ₂-CH ₂、-S(O)-CH ₃、-CH ₂-CH ₂-S(O) ₂-CH ₃、-CH＝CH-O-CH ₃、-Si(CH ₃) ₃、-CH ₂-CH＝N-OCH ₃、-CH＝CH-N(CH ₃)-CH ₃、-O-CH ₃、-O-CH ₂-CH ₃and-CN. Up to two or three heteroatoms may be consecutive, e.g. -CH ₂-NH-OCH ₃and-CH ₂-O-Si(CH ₃) ₃. The heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si or P). The heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si or P).

Similarly, unless otherwise stated, the term "heteroalkylene", by itself or as part of another substituent, means a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH ₂-CH ₂-S-CH ₂-CH ₂-and-CH ₂-S-CH ₂-CH ₂-NH-CH ₂-. 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 written direction of the formula for the linking group does not imply orientation of the linking group. For example, of the formula-C (O) ₂R' -represents-C (O) ₂R '-and-R' C (O) ₂-both. As noted above, heteroalkyl groups as used herein include 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-SO ₂R' is provided. When "heteroalkyl" is recited, followed by a particular heteroalkyl, such as-NR 'R "or the like, it is understood that the terms heteroalkyl and-NR' R" are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are recited for added clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude a particular heteroalkyl, such as — NR' R "or the like.

Unless otherwise stated, 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. In addition, for heterocycloalkyl, a heteroatom may occupy the position at which the heterocycle 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, mean divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively.

Unless otherwise stated, the term "halo" or "halogen", by itself or as part of another substituent, means a fluorine, chlorine, bromine or iodine atom. Additionally, terms such as "haloalkyl" are meant to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo (C) ₁-C ₄) Alkane (I) and its preparation method"group" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

Unless otherwise stated, 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 stated, 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, such as N, O or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atoms are optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A5, 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, a6, 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, 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, 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-quinolyl, 5-quinolyl, 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. "arylene" and "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from aryl and heteroaryl, respectively. The heteroaryl substituent may be-O-bonded to the nitrogen of the ring heteroatom.

A spiro ring is two or more rings in which adjacent rings are connected by a single atom. The individual rings within a spiro ring may be the same or different. Individual rings in the spiro ring may be substituted or unsubstituted, and may have different substituents than other individual rings in the spiro ring group. Possible substituents for individual rings within a spiro ring are possible substituents for the same ring when not part of a spiro ring (e.g., substituents for cycloalkyl 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 individual rings within the spirocyclic group can be any of the immediately preceding list, including all rings having one type (e.g., all rings of a 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 spirocyclic 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 "pendant oxy group" means an oxygen that is double bonded to a carbon atom.

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

the alkylarylene moiety may be substituted (e.g., by a substituent) on the alkylene moiety or the arylene linking group (e.g., at carbon atoms 2,3, 4, or 6) by: halogen, oxo, -N ₃、-CF ₃、-CCl ₃、-CBr ₃、-CI ₃、-CN、-CHO、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₂CH ₃、-SO ₃H、-OSO ₃H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC(O)NHNH ₂C substituted or unsubstituted ₁-C ₅Alkyl 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") includes the indicated groups in both substituted and unsubstituted forms. Preferred substituents for each type of group are provided below.

Substituents for alkyl and heteroalkyl (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be selected from one or more of the following various groups:-OR ', - (O), (NR', - (N-OR ', - (NR' R '), - (SR'), - (halogen), -SiR 'R' ″, - (oc) (O) R ', - (c) (O) R', - (CO) 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”、-NRSO ₂R'、-NR'NR”R”'、-ONR'R”、-NR'C(O)NR”NR”'R””、-CN、-NO ₂、-NR'SO ₂R ", -NR 'C (O) -OR", -NR' OR ", in a number ranging from zero to (2m '+1), where m' is the total number of carbon atoms in such a group. R, R ', R ", R'" and R "" each preferably independently mean 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 the compounds described herein include more than one R group, for example, each of the R groups is independently selected as are each R ', R ", R'" and R "" groups 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 include groups containing carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF) ₃and-CH ₂CF ₃) And acyl (e.g., -C (O) CH) ₃、-C(O)CF ₃、-C(O)CH ₂OCH ₃And the like).

Similar to the substituents described for alkyl, the substituents for aryl and heteroaryl are different and are selected, for example, from the following: -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”、-NRSO ₂R'、-NR'NR”R”'、-ONR'R”、-NR'C(O)NR”NR”'R””、-CN、-NO ₂、-R'、-N ₃、-CH(Ph) ₂Fluorine (C) ₁-C ₄) Alkoxy and fluorine (C) ₁-C ₄) Alkyl, -NR' SO ₂R ", -NR 'C (O) -OR", -NR' OR ", in an amount 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 the compounds described herein include more than one R group, for example, each of the R groups is independently selected as are each R ', R ", R'" and R "" groups when more than one of these groups is present.

Substituents on a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be described as substituents on the ring (often referred to as floating substituents) other than on a particular atom of 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 described as being associated with one member of the fused ring or spiro ring (a floating substituent on a single ring) may be any substituent on 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. When the point of attachment of a 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 or spiro ring, any atom of the fused or spiro ring, while complying with the rules of chemical valency. When the ring, fused ring or spiro ring contains one or more ring heteroatoms and the ring, fused ring or spiro ring is displayed with one or more floating substituents (including but not limited to the point of attachment to the rest of the molecule), the floating substituent may be bonded to the heteroatom. When a ring heteroatom is shown with one or more hydrogens in a structure or formula with a floating substituent (e.g., a ring nitrogen with two bonds to the ring atom and a third bond to a hydrogen), when the heteroatom is bonded to a floating substituent, the substituent will be understood to replace the hydrogen while adhering to the rules of chemical valency.

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

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a compound 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 be optionally substituted by a group of formula-A- (CH) ₂) _rSubstitution of substituents of-B-, wherein A and B are independently-CRR' -, -O-, -NR-, -S-, -S (O) -, -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 by a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by a group of 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 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) pendant oxy, halogen, -CCl ₃、-CBr ₃、-CF ₃、-CI ₃、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC(O)NHNH ₂、-NHC(O)NH ₂、-NHSO ₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl ₃、-OCF ₃、-OCBr ₃、-OCI ₃,-OCHCl ₂、-OCHBr ₂、-OCHI ₂、-OCHF ₂Unsubstituted alkyl (e.g. C) ₁-C ₈Alkyl radical, C ₁-C ₆Alkyl or C ₁-C ₄Alkyl), 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-C ₈Cycloalkyl radical, C ₃-C ₆Cycloalkyl or C ₅-C ₆Cycloalkyl), 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-C ₁₀Aryl radical, C ₁₀Aryl 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, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, said groups substituted with at least one substituent selected from the group consisting of:

(i) lateral oxygen radicalHalogen, -CCl ₃、-CBr ₃、-CF ₃、-CI ₃、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC(O)NHNH ₂、-NHC(O)NH ₂、-NHSO ₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl ₃、-OCF ₃、-OCBr ₃、-OCI ₃、-OCHCl ₂、-OCHBr ₂、-OCHI ₂、-OCHF ₂Unsubstituted alkyl (e.g. C) ₁-C ₈Alkyl radical, C ₁-C ₆Alkyl or C ₁-C ₄Alkyl), 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-C ₈Cycloalkyl radical, C ₃-C ₆Cycloalkyl or C ₅-C ₆Cycloalkyl), 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-C ₁₀Aryl radical, C ₁₀Aryl 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, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, said groups substituted with at least one substituent selected from the group consisting of:

(a) pendant oxy, halogen, -CCl ₃、-CBr ₃、-CF ₃、-CI ₃、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC(O)NHNH ₂、-NHC(O)NH ₂、-NHSO ₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl ₃、-OCF ₃、-OCBr ₃、-OCI ₃、-OCHCl ₂、-OCHBr ₂、-OCHI ₂、-OCHF ₂Unsubstituted alkyl (e.g. C) ₁-C ₈Alkyl radical, C ₁-C ₆Alkyl or C ₁-C ₄Alkyl), 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-C ₈Cycloalkyl radical, C ₃-C ₆Cycloalkyl or C ₅-C ₆Cycloalkyl), 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-C ₁₀Aryl radical, C ₁₀Aryl 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, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, said groups substituted with at least one substituent selected from the group consisting of: pendant oxy, halogen, -CCl ₃、-CBr ₃、-CF ₃、-CI ₃、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC(O)NHNH ₂、-NHC(O)NH ₂、-NHSO ₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl ₃、-OCF ₃、-OCBr ₃、-OCI ₃、-OCHCl ₂、-OCHBr ₂、-OCHI ₂、-OCHF ₂Unsubstituted alkyl (e.g. C) ₁-C ₈Alkyl radical, C ₁-C ₆Alkyl or C ₁-C ₄Alkyl), 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-C ₈Cycloalkyl radical, C ₃-C ₆Cycloalkyl or C ₅-C ₆Cycloalkyl), 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-C ₁₀Aryl radical, C ₁₀Aryl 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, "largeBy small limited substituents (size-limited substituents/size-limited substituents group) "is meant a group selected from all substituents described above for" substituent ", wherein each substituted or unsubstituted alkyl group is a substituted or unsubstituted C ₁-C ₂₀Alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C ₃-C ₈Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C ₆-C ₁₀Aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5-to 10-membered heteroaryl.

As used herein, "lower number substituent (lower substituent group)" means a group selected from all substituents described above for "substituent", wherein each substituted or unsubstituted alkyl group is substituted or unsubstituted C ₁-C ₈Alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C ₃-C ₇Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C ₆-C ₁₀Aryl, 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 size limiting substituents. In other embodiments, at least one or all of these groups are substituted with at least one lower number substituent.

In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be substituted or unsubstituted C ₁-C ₂₀Alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C ₃-C ₈Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C ₆-C ₁₀Aryl, 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 C ₁-C ₂₀Alkylene, each substituted or unsubstituted heteroalkylene being substituted or unsubstituted 2-to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene being substituted or unsubstituted C ₃-C ₈Cycloalkylene, each substituted or unsubstituted heterocycloalkylene is substituted or unsubstituted 3-to 8-membered heterocycloalkylene, each substituted or unsubstituted arylene is substituted or unsubstituted C ₆-C ₁₀The 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 C ₁-C ₈Alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 8 membered heteroalkyl, each substitutedSubstituted or unsubstituted cycloalkyl is substituted or unsubstituted C ₃-C ₇Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted C ₆-C ₁₀Aryl, 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 C ₁-C ₈Alkylene, each substituted or unsubstituted heteroalkylene being substituted or unsubstituted 2-to 8-membered heteroalkylene, each substituted or unsubstituted cycloalkylene being substituted or unsubstituted C ₃-C ₇Cycloalkylene, each substituted or unsubstituted heterocycloalkylene is substituted or unsubstituted 3-to 7-membered heterocycloalkylene, each substituted or unsubstituted arylene is substituted or unsubstituted C ₆-C ₁₀The 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 set forth in the examples section, figures, or tables below.

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-limiting substituent, wherein each size-limiting substituent may optionally be different if the substituted moiety is substituted with multiple size-limiting substituents. In embodiments, if a substituted moiety is substituted with multiple size-limited substituents, then 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 lower carbon number substituent, wherein if the substituted moiety is substituted with multiple lower carbon number substituents, each lower carbon number substituent may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower carbon number substituents, then each lower carbon number 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-limiting substituent, or lower number substituent; wherein if the substituted moiety is substituted with a plurality of groups selected from substituents, size-limiting substituents and lower-number substituents, each substituent, size-limiting substituent and/or lower-number substituent may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituents, size-limiting substituents, and lower-number substituents, then each substituent, size-limiting substituent, and/or lower-number substituent is different.

Certain compounds of the present invention possess asymmetric carbon atoms (optical or chiral centers) or double bonds; within the scope of the present invention, enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, as well as individual isomers, are encompassed which can be defined in absolute stereochemistry as (R) -or (S) -or for amino acids as (D) -or (L) -. The compounds of the present invention do not include those compounds known in the art to be too unstable to synthesize and/or isolate. The present invention is meant to include 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 specified, it is intended that the compounds include 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 with respect to structural arrangement or atomic configuration.

As used herein, the term "tautomer" refers to one of the structural isomers that exist in equilibrium in two or more species 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 invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.

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

Unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except that hydrogen is replaced by deuterium or tritium or carbon is replaced by ¹³C or ¹⁴Compounds having the structure of the invention outside the carbon substitution of C-rich are within the scope of the invention.

The compounds of the present invention 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 radiolabeled with a radioisotope, such as tritium (A) ³H) Iodine-125 ( ¹²⁵I) Or carbon-14 ( ¹⁴C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

It should be noted that throughout the application, substitutes are written in the Markush group, e.g., 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 separately to encompass another embodiment, and that the Markush group should not be read as a single unit.

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

The terms "a" and "an," as used herein, mean one or more. Further, as used herein, the phrase "being a [ n ]]… substituted means that the indicated group can be substituted with any or all of one or more of the substituents set forthAnd (4) generation. For example, when a group, such as alkyl or heteroaryl, is "unsubstituted C ₁-C ₂₀When alkyl or unsubstituted 2-to 20-membered heteroalkyl is substituted ", the group may contain one or more unsubstituted C ₁-C ₂₀Alkyl, and/or one or more unsubstituted 2-to 20-membered heteroalkyl.

Further, when a moiety is substituted with an R substituent, the group may be referred to as "substituted with R". When 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 species, such as formula (I), a roman alphabet symbol may be used to distinguish each occurrence of the particular R group. For example, when multiple R' s ¹³When a substituent is present, each R ¹³The substituent may be R ^13A、R ^13B、R ^13C、R ^13DAre distinguished wherein R ^13A、R ^13B、R ^13C、R ^13DEach of which is defined in R ¹³Within the scope of the definition, and optionally different.

As used herein, a "covalent cysteine modification moiety" refers to a substituent capable of reacting with the thio functional group of a cysteine amino acid (e.g., cysteine corresponding to C377 of human PPP2R1A) to form a covalent bond. Thus, the covalent cysteine-modifying moiety is typically electrophilic.

The description of the compounds of the present invention is limited by the chemical bonding principles known to those skilled in the art. Thus, when a group can be substituted with one or more of a number of substituents, such substitutions are selected so as to comply with the principles of chemical bonding and to yield compounds that are not inherently unstable and/or that would be known to one of ordinary skill in the art to be potentially unstable under environmental conditions (e.g., aqueous, neutral, and several known physiological conditions). For example, a heterocycloalkyl or heteroaryl group is attached to the rest of the molecule through a ring heteroatom, according to chemical bonding principles known to those skilled in the art, thereby avoiding compounds that are inherently unstable.

The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include acid addition salts derived from 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 and the like; and salts derived from relatively nontoxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are Salts of amino acids, such as arginine Salts and similar Salts thereof, as well as Salts of organic acids, such as glucuronic acid or galacturonic acid and similar acids thereof (see, e.g., Berge et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977,66, 1-19). Certain specific compounds of the invention contain both basic and acidic functional groups that convert the compounds to base addition salts or acid addition salts.

Thus, the compounds of the invention may be present in the form of a salt, for example with a pharmaceutically acceptable acid. The present invention includes 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 including a racemic mixture), succinate, benzoate, and salts with amino acids (e.g., glutamic acid) and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). 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 by certain physical characteristics, such as solubility in polar solvents.

In addition to salt forms, the present invention 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 invention. Prodrugs of the compounds described herein may be converted in vivo following administration. In addition, prodrugs can be converted to compounds of the present invention in an ex vivo environment by chemical or biochemical means, for example, when contacted with a suitable enzyme or chemical reagent.

Certain compounds of the present invention 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 intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

"pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that facilitate administration of an active agent to and absorption by an individual, and 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, standard saline solution, lactated Ringer's solution, common sucrose, common glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavor, salt solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates (e.g., lactose, amylose, or starch), fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and 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 and the like. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use in the present invention.

The term "preparing" is intended to include formulating the active compound as an encapsulating material with a carrier to give capsules in which the active component, with or without other carriers, is surrounded by a carrier and is thus associated therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

A "PPP 2R1A modulator" and "serine/threonine-protein phosphatase 2A65kDa regulatory subunit a α isoform modulator" is a substance (e.g., an oligonucleotide, protein, composition or compound) that alters the physical state of PPP2R1A relative to the physical state of PPP2R1A in the absence of a modulator (e.g., where PPP2R1A modulator binds to PPP2R1A, covalently modifies PPP2R1A, covalently modifies cysteine of PPP2R 1A.) in an embodiment, a PPP2R A modulator binds to PPP2R1A protein in a protein phosphatase 2A complex (PP2A) a protein phosphatase 2A complex (PP2A) is a trimeric phosphotase complex comprising a catalytic protein (e.g., PPP2CA) and a regulatory a or structural a protein (e.g., PPP2R1 CA) and optionally a regulatory B protein (e.g., PPP2R5 CA) which has a heterologous protein phosphatase activity that increases the level of the activity of the PPP2R1 phosphatase modulator in the absence of the PPP2R1, the PPP2 phosphatase modulator, and/threonine-ligand binding to PPP2 receptor activity of the PPP2 receptor CA, a known polypeptide, e.g., a compound, a covalently modified compound CA, a compound that increases the level of the PPP2 receptor activity of the PPP2 receptor CA, the PPP2 receptor modulator in an embodiment, the PPP2 receptor CA modulator, the PPP2 receptor CA, and the PPP2 receptor CA modulator in the PPP2 receptor CA, the PPP2 receptor activity of a ligand.

The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may optionally be conjugated to a moiety that does not consist of an amino acid. 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.

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

An amino acid residue in a protein "corresponds" to a given residue when it occupies the same basic structural and/or spatial position within the protein as the given residue in a reference sequence. For example, a selected residue in a selected protein corresponds to Cys377 when the selected residue occupies the same basic structural and/or spatial position as Cys377 in SEQ ID NO 4. In some embodiments in which the selected protein is aligned for maximum homology to the human PPP2R1A protein, the position in the aligned selected protein aligned with Cys377 is referred to as corresponding to Cys 377. Instead of a primary sequence alignment, a three-dimensional structural alignment may also be used, for example, in which the three-dimensional structure of the selected protein is aligned for maximum correspondence with the human PPP2R1A protein (reference sequence) and the overall structure is compared. In this case, the amino acid occupying the same basic structural position as Cys377 in the structural model relative to the reference sequence is referred to as corresponding to the Cys377 residue.

"contacting" is used according to its ordinary conventional meaning and refers to the process of bringing at least two different species (e.g., chemical compounds including biomolecules or cells) into sufficient proximity to react, interact, or physically touch. It will be appreciated, however, that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate from one or more of the added reagents, which may be produced in the reaction mixture.

The term "contacting" may include reacting, interacting, or physically touching two species, wherein the two species may be a compound and a protein or enzyme as described herein. In some embodiments, contacting comprises interacting a compound described herein with a protein or enzyme involved in the signaling pathway.

As defined herein, the term "activate/activating and like terms" with respect to a protein-inhibitor interaction means that the activity or function of a protein is positively affected (e.g., increased) relative to the activity or function of the protein in the absence of an activating agent. In embodiments, activation means positively affecting (e.g., increasing) the concentration or amount of protein relative to the concentration or amount of protein in the absence of an activating agent. The term may refer to reduced activation of the protein, sensitization or upregulation of signal transduction or enzyme activity or the amount of protein in a disease.

As defined herein, the term "inhibit (inhibition/inhibition and like terms) with respect to protein-inhibitor interactions means to negatively affect (e.g., reduce) protein activity or function relative to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibiting means negatively affecting (e.g., reducing) the concentration or amount of protein relative to the concentration or amount of protein in the absence of inhibitor. In embodiments, inhibition refers to a reduction in a disease or symptom of a disease. In embodiments, inhibition refers to a decrease in the activity of a particular protein target. Thus, inhibiting at least partially includes partially or completely blocking stimulation, reducing, preventing, or delaying an agent or, or inactivating, desensitizing, or down-regulating signal transduction or enzyme activity or the amount of protein. In embodiments, inhibition refers to a decrease in the activity of a target protein caused by a direct interaction (e.g., binding of an inhibitor to the target protein). In embodiments, inhibition refers to a decrease in the activity of a target protein due to an indirect interaction (e.g., binding of an inhibitor to a protein that activates the target protein, thereby preventing activation of the target protein).

The terms "serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform" and "PPP 2R 1A" refer to proteins (including homologs, isoforms and functional fragments thereof) having PPP2R1A activity the terms include any recombinant or naturally occurring form of PPP2R1A or variants thereof that maintain PPP2R1A activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% activity compared to wild-type PPP2R 1A.) in embodiments, the PPP2R1A protein encoded by the PPP2R1A gene has an amino acid sequence set forth in or corresponding to Entrez 5518, UniProt P30153 or RefSeq (protein) NP _055040.

The terms "serine/threonine-protein phosphatase 2a56kDa regulatory subunit gamma isomer" and "PPP 2R 5C" refer to proteins (including homologs, isomers, and functional fragments thereof) having PPP2R5C activity. The term includes any recombinant or naturally occurring form of PPP2R5C or variant thereof that maintains PPP2R5C activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of the activity compared to wild-type PPP2R 5C). In an example, the PPP2R5C protein encoded by the PPP2R5C gene has an amino acid sequence that is set forth in or corresponds to Entrez 5527, UniProt Q13362 or RefSeq (protein) NP _002710. In embodiments, the PPP2R5C gene has the nucleic acid sequence set forth in refseq (mrna) NM _002719. In embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing the present application. In an embodiment, the sequence corresponds to NP _ 002710.2. In an embodiment, the sequence corresponds to NM _ 002719.3. In embodiments, the PPP2R5C is human PPP2R5C, e.g., PPP2R5C causing human cancer. In an embodiment, PPP2R5C has the following sequence:

the terms "serine/threonine-protein phosphatase 2A catalytic subunit α isoform" and "PPP 2 CA" refer to proteins (including homologs, isoforms, and functional fragments thereof) having PPP2CA activity, including any recombinant or naturally occurring form of PPP2CA or variants thereof that maintain PPP2CA activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity as compared to wild-type PPP2 CA.) in embodiments, the PPP2CA protein encoded by the PPP2CA gene has a nucleic acid sequence set forth in or corresponding to Entrez 5515, UniProt P67775, or RefSeq (protein) NP _002706 in embodiments, PPP CA gene has a nucleic acid sequence set forth in RefSeq (mrna) (NM _ 002715) in embodiments, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing of the present application.

The terms "protein phosphatase 2" and "PP 2" and "PP 2A", "PP 2A protein complex" refer to a protein encoded by the PPP2CA gene (including homologues, isomers and functional fragments thereof). PP2A is a heterotrimeric protein phosphatase composed of structural, catalytic and regulatory subunits. subunits comprising PP2A include the PP2a65kDa regulatory subunit a α isomer (PPP2R1A), the PP2a65kDa regulatory subunit a A isomer (PPP2R1A), the PP2A 55kDa regulatory subunit B A isomer (PPP2R 2A), the PP2A 55kDa regulatory subunit B γ isomer (PPP2R 2A), the PP2A kDa regulatory subunit B δ isomer (PPP2R 2A), the PP2A kDa regulatory subunit B (PPP2R3A), the PP2 3648 kDa regulatory subunit B (PPP2R3A), the PP2A B "γ subunit (PP 2R 3), the PP2A regulatory subunit B" (PPP2R 3), the PP2A regulatory subunit B A, the PP2A protein having a regulatory sequence corresponding to the PPP2 e.g. PPP2R A, the PPP2 e.g. the PP2R 72, the PP 2A:

the term "expression" includes 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 blotting), flow cytometry, immunofluorescence, immunohistochemistry, and the like).

The term "disease" or "condition" refers to a state or health condition of a patient or individual that can be treated with a compound or method provided herein. The disease may be cancer. The disease may be stroke. The disease may be an inflammatory disease. In some other instances, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, and the like, including solid and lymphoid cancers, renal cancers, breast cancers, lung cancers, bladder cancers, colon cancers, ovarian cancers, prostate cancers, pancreatic cancers, stomach cancers, brain cancers, head and neck cancers, skin cancers, uterine cancers, testicular cancers, gliomas, esophageal cancers, and liver cancers (including liver cancers (hepatorcinoma)); lymphomas, including B acute lymphoblastic lymphomas, non-Hodgkin's lymphoma (e.g., Burkitt's, small cell and large cell lymphomas), Hodgkin's lymphoma; leukemia (including AML, ALL, and CML) or multiple myeloma.

As used herein, the term "cancer" refers to all types of cancers, neoplasms or malignancies found in mammals (e.g., humans), including leukemias, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer, and head cancer. 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, pancreatic cancer. Additional examples include hodgkin's disease, non-hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic cancer, malignant carcinoid cancer, bladder cancer, precancerous skin lesion, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortex cancer, endocrine or exocrine pancreatic neoplasm, medullary thyroid cancer, medullary thyroid tumor, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

The term "leukemia" broadly refers to a progressive malignant disease of the blood-forming organs and is generally characterized by the distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias are generally clinically classified based on: (1) duration and character of acute or chronic disease; (2) the cell type involved; myeloid (myelogenous), lymphoid (lymphoid) or monocytic; and (3) an increase or no increase in the number of abnormal cells in the blood of leukemia or leukopenia (sub-leukemia). 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, leukemia deficient in cells, leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, skin leukemia, embryonic leukemia, eosinophilic leukemia, murine leukemia (Gross' leukamia), hairy cell leukemia, hemablastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphoblastic leukemia, basophilic leukemia, lymphosarcoma cellular leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Negerli leukemia (Naegeli leukemia), plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Reed's (Rieder) cell leukemia, Hill's leukemia, stem cell leukemia, sub-leukemia or undifferentiated cell leukemia.

The term "sarcoma" generally refers to a tumor that is composed of a substance such as embryonic connective tissue and generally comprises 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, melanoma, myxosarcoma, osteosarcoma, Abelmei meisshcian sarcoma (Abemethy's sarcoma), adipose tissue sarcoma, liposarcoma, alveolar soft tissue sarcoma, amelogenic sarcoma, botryoid sarcoma, chloroma, choriocarcinoma, embryonal sarcoma, Wilms ' sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fasciosarcoma, fibrosarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic polychrome hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's sarcoma (Kupffer cell sarcoma), Kaposi's sarcoma, and Kaposi's sarcoma, Angiosarcoma, white sarcoma, malignant metaplastic sarcoma, epiphysis sarcoma, reticulosarcoma, Rous sarcoma (Rous sarcoma), serous sarcoma, synovial sarcoma, or capillary-expansive sarcoma.

The term "melanoma" is considered to mean tumors produced by the melanocytic system of the skin and other organs. Melanoma that may be treated with a compound or method provided herein includes, for example, acral freckle melanoma, leucoma, benign juvenile melanoma, cloudlan' S melanoma, S91 melanoma, hadrine-pasque melanoma (Harding-Passey melanoma), juvenile melanoma, lentigo melanoma, malignant nodular melanoma, scrotal melanoma, or superficial spreading melanoma.

The term "carcinoma" refers to a malignant new growth consisting of epithelial cells that tends to infiltrate the surrounding tissues and cause metastasis of the cancer. Exemplary carcinomas that can be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, alveolar carcinoma, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar cell carcinoma, basal-like cytoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchial carcinoma, brain carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, acne carcinoma, uterine corpus carcinoma, ethmoid carcinoma, thyroid carcinoma, skin carcinoma, columnar cell carcinoma, ductal carcinoma, hard carcinoma, embryonic carcinoma, medullary carcinoma, epidermoid carcinoma, adenoid epithelial cell carcinoma, explanted carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatin carcinoma, glioma, giant cell carcinoma, adenocarcinoma, lamellar cell carcinoma, seminal granuloma, leukemia, and other cancers, Hepatocellular carcinoma, schlieren's cell adenocarcinoma (Hurthle cell carcinoma), hyaluronan carcinoma, adrenocarcinoid carcinoma, juvenile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, cromopercher's carcinoma, Kulchitzky cell carcinoma (Kulchitzky-cell carcinoma), large cell carcinoma, lenticular carcinoma (lenticular carcinoma), lenticular carcinoma (lenticular lenticulate), lipomatoid carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous epidermoid carcinoma, mucinous neoplasia carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossified carcinoma, osteoid carcinoma, acanthomatoid carcinoma, schchenoderm carcinoma, infiltrating precancerous carcinoma, cervical carcinoma, amatic carcinoma, kidney cell carcinoma, renal carcinoma (nephritic cell carcinoma), renal carcinoma, cystic carcinoma, renal carcinoma, and esophageal carcinoma, Signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato-like carcinoma, globular cell carcinoma, spindle cell carcinoma, medullary carcinoma, squamous cell carcinoma, tethered carcinoma, vasodilatory carcinoma, transitional cell carcinoma, nodular skin carcinoma, warty cancer, or choriocarcinoma.

The term "treatment" refers to any indicia of successful treatment or amelioration of an injury, disease, pathology, or condition, including any objective or subjective parameter, such as elimination; (iii) alleviating; reduce symptoms or make injuries, pathologies, or conditions more tolerable to the patient; slowing the rate of degeneration or decline; the final point of degeneration is less debilitating; or improving the physical and 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 mental assessment. The term "treating" and word variants thereof may include preventing injury, pathology, condition, or disease. In an embodiment, the treatment is prophylaxis. In embodiments, treatment does not include prophylaxis. In embodiments, the treatment (treating/treatment) is not a prophylactic treatment

"patient" or "subject in need thereof" refers to a living organism suffering from or predisposed to a disease or condition treatable 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.

An "effective amount" is an amount of a compound sufficient to achieve the stated purpose relative to the absence of the compound (e.g., to achieve the effect of its administration, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce a signaling pathway, or to reduce one or more symptoms of a disease or condition). An example of an "effective amount" is an amount sufficient to facilitate the treatment, prevention, or reduction of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount". "reducing" one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of the symptoms, or eliminating the symptoms. A "prophylactically effective amount" of a drug is an amount that, when the drug is administered to an individual, will have an expected prophylactic effect, e.g., preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A completely prophylactic effect need not 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 enzymatic activity relative to the absence of the antagonist. As used herein, "functionally disrupting amount" refers to the amount of antagonist required to disrupt enzyme function relative to the absence of antagonist. The precise amount will depend on The purpose of treatment and will be determinable by those skilled in The Art using known techniques (see, e.g., Lieberman, "Pharmaceutical Dosage Forms (Pharmaceutical Dosage Forms) (Vol.1-3, 1992); Lloyd," Art, Science and Technology of Pharmaceutical Compounding (The Art, Science and Technology of Pharmaceutical Compounding) (1999); Pickar, Dosage calculation (Pharmaceutical Calculations) (1999); and Remington: The Science and Practice of medicine (20 th Ed., 2003, Gennaro eds., Lippincott, Williams & Wilkins).

For any of the compounds described herein, a therapeutically effective amount can be initially determined according to a cell culture assay. The target concentrations will be those concentrations of the active compound that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

As is well known in the art, a therapeutically effective amount for use in humans can also be determined from animal models. For example, a dose for use in humans may be formulated to achieve a concentration found to be effective in animals. As described above, the dosage in humans can be adjusted by monitoring the effectiveness of the compound and up-or down-regulating the dosage. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the ability of one of ordinary skill in the art.

The dosage may vary depending on the needs of the patient and the compound employed. In the context of the present invention, the dose administered to a patient should be sufficient to achieve a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the presence, nature and extent of any adverse side effects. The determination of the appropriate dosage for a particular situation is within the skill of the physician. Generally, treatment is initiated at a dose that is less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimum effect under circumstances is reached. The dosage and interval may be independently adjusted to provide an amount of the compound administered effective for the particular clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

As used herein, the term "administering" refers to oral administration to an individual, administration in the form of a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a slow release device (e.g., a mini osmotic pump). Administration is by any route compatible with the formulation, including parenterally and transmucosally (e.g., buccally, sublingually, palatantly, gingiva, nasally, vaginally, rectally, or transdermally). Parenteral administration includes, for example, intravenous, intramuscular, internal arteriole, intradermal, subcutaneous, intraperitoneal, intracerebroventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. In embodiments, administering does not include administering any active agent other than the recited active agent.

By "co-administration," it is meant that the compositions described herein are administered simultaneously with, just prior to, or just after the administration of one or more additional therapies. The compounds of the invention may be administered to the patient individually or may be co-administered. Co-administration is meant to include simultaneous or sequential administration of a compound (more than one compound), either alone or in combination. Thus, the formulation 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, or formulated as application sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

As used herein, "cell" refers to a cell that performs a metabolic or other function sufficient to maintain or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with a particular dye, being able to produce progeny, or in the case of a gamete being able to combine with a second gamete to produce live progeny. Cells may include 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 cells derived from plants and animals, such as mammalian, insect (e.g., spodoptera) and human cells. Cells may be suitable when they are naturally non-adherent or have been treated (e.g., by trypsinization) so as not to adhere to a surface.

"control" or "control experiment" is used in accordance with its ordinary conventional meaning and refers to an experiment in which an individual or reagent of the experiment is treated as in a parallel experiment except for omission of procedures, reagents or variables from the experiment. In some cases, a control is used as a standard for comparison in assessing the effect of an experiment. In some embodiments, the control is measuring the activity of the protein in the absence of a compound as described herein (including examples and examples).

The term "modulator" refers to a substance (e.g., an oligonucleotide, a protein, a composition, or a compound) that changes the physical state of a target molecule (e.g., PPP2R1A or PP2A) relative to the physical state of the target molecule in the absence of a modulator (e.g., cysteine wherein the modulator binds to, covalently modifies, or covalently modifies the target molecule). In some embodiments, the PPP2R 1A-associated disease modulator is a compound that reduces the severity of one or more symptoms of a disease (e.g., cancer) associated with PPP2R 1A. In embodiments, the PPP2R1A modulator is a compound that changes the physical state of PPP2R1A by covalently modifying the cysteine of PPP2R 1A. In embodiments, a PPP2R1A modulator is a compound that alters the physical state of PPP2R1A by covalently modifying the cysteine of PPP2R1A, which compound causes activation of PP2A (e.g., increases PP2A activity) as a result of being a subunit of PP 2A. In embodiments, the modulator is an inhibitor of PPP2R 1A. In an embodiment, the modulator is an activator of PPP2R 1A.

The term "modulate" is used in accordance with its ordinary conventional meaning and refers to the act of altering or changing one or more characteristics. "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 or the physical state of the molecule. In an embodiment, the modulation is active. In embodiments, modulation is inhibitory.

In the case where a substance or substance activity or function is associated with a disease (e.g., a protein-related disease, a cancer associated with PPP2R1A activity, a PPP2R 1A-related cancer, a PPP2R 1A-related disease), the term "associated with" or "associated with …" means that the disease (e.g., cancer) is caused (in whole or in part) by the substance or substance activity or function, or that a symptom of the disease is caused (in whole or in part) by the substance or substance activity or function. For example, a cancer having PPP2R1A activity or function associated therewith may be the result of (in whole or in part) aberrant PPP2R1A function (e.g., enzymatic activity, protein-protein interactions, signaling pathways) or cancer, wherein a particular symptom of the disease results (in whole or in part) from aberrant PPP2R1A activity or function. 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, where PPP2R1A activity or function (e.g., signaling pathway activity) causes cancer, a cancer associated with PPP2R1A activity or function or a PPP2R 1A-related cancer may be treated with a PPP2R1A modulator.

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

The term "signaling pathway" as used herein refers to the interaction between a series of cells and optionally extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that conveys a change from one component to one or more other components, which in turn can convey a change to additional components, which is optionally transferred to other signaling pathway components. For example, binding of a PPP2R1A protein to a compound as described herein can reduce the interaction between the PPP2R1A protein and a downstream effector (e.g., PPP2CA) or signaling pathway component, resulting in a change in cell growth, proliferation, or survival.

The term "electrophilic chemical moiety" is used according to its ordinary conventional chemical meaning and refers to an electrophilic chemical group (e.g., a monovalent chemical group).

The term "nucleophilic chemical moiety" is used according to its ordinary conventional chemical meaning and refers to a nucleophilic chemical group (e.g., a monovalent chemical group).

"nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in single-, double-, or multistrand form or their complements. The terms "polynucleotide," "oligonucleotide core," or similar terms refer to a linear sequence of nucleotides in the usual and customary sense. The term "nucleotide" refers in a general and customary sense to a single unit of a polynucleotide, i.e., a monomer. The nucleotide may be a ribonucleotide, a deoxyribonucleotide or a modified form thereof. Examples of polynucleotides encompassed herein include single-and double-stranded DNA, single-and double-stranded RNA, and hybrid molecules having a mixture of single-and double-stranded DNA and RNA. Examples of nucleic acids, such as polynucleotides encompassed herein, include any type of RNA (e.g., mRNA, siRNA, miRNA, and guide RNA) and any type of DNA, genomic DNA, plastid DNA, and minicircle DNA, and any fragments thereof. In the case of polynucleotides, the term "double helix" refers in the usual and customary sense to the double stranded form. The nucleic acid may be linear or branched. For example, a nucleic acid may be a linear chain of nucleotides or a nucleic acid may be branched, e.g., such that the nucleic acid comprises an arm or branch of one or more nucleotides. Optionally, the branched-chain nucleic acids are repeatedly branched to form higher order structures, such as dendrimers and the like.

Nucleic acids, including, for example, those having a phosphorothioate backbone, may include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule (e.g., a nucleic acid or polypeptide) by covalent, non-covalent, or other interaction. By way of example, a nucleic acid may include an amino acid reactive moiety that reacts with an amino acid on a protein or polypeptide by covalent, non-covalent, or other interactions.

The term also includes the inclusion of known nucleotide analogs or modificationsNucleic acids that decorate backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as a reference nucleic acid, and which are metabolized in a manner similar to a reference nucleotide. Examples of such analogs include, but are not limited to, phosphodiester derivatives including, for example, phosphoramidates, phosphorodiamidates, phosphorothioates (also known as phosphates, having double bonds sulfur substituted for oxygen in phosphorus), phosphorodithioates, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acids, phosphonoformic acids. Methylphosphonate, boronate, or O-methylphosphonoamidate linkages (see Exostat, oligonucleotides and analogs: Utility methods, Oxford university Press), and modified nucleotide bases such as 5-methylcytidine or pseudouridine; and peptide nucleic acid backbones and linkages. Other analog nucleic acids include nucleic acids having a positive backbone; nonionic backbones, modified sugar and non-ribose backbones (e.g., phosphorodiamidate morpholino oligonucleotides or Locked Nucleic Acids (LNAs) known in the art), including those described in U.S. patent nos. 5,235,033 and 5,034,506 and chapters 6 and 7, ASC Symposium Series 580, a _NTCarbohydrate modification in antisense studies, Sanghui&Cook, edit. Nucleic acids containing one or more carbocyclic sugars are also included within the definition of nucleic acid. Modifications of the ribose-phosphate backbone can be made for a variety of reasons, for example, to increase the stability and half-life of these molecules in physiological environments, or as probes on biochips. Mixtures of naturally occurring nucleic acids and analogs can be prepared; alternatively, mixtures of different nucleic acid analogs can be prepared, as well as mixtures of naturally occurring nucleic acids and analogs. In embodiments, the internucleotide linkage in the DNA is a phosphodiester, phosphodiester derivative, or a combination of both.

The nucleic acid may include a non-specific sequence. As used herein, the term "non-specific sequence" refers to a nucleic acid sequence comprising a series of any other nucleic acid sequence residues that are not designed to be complementary or are only partially complementary. For example, a non-specific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when in contact with a cell or organism.

"antisense nucleic acid" as referred to herein is a nucleic acid (e.g., a DNA or RNA molecule) that is at least a portion of a particular target nucleic acid that is complementary (e.g., encoding a nucleic acid for one or more amino acids: 4 of H340ID NO corresponding to Q339, S343, E379, K416, SEQ ID NO: 4; N264, Q272, M245, and D290 SEQ ID NO: 6; or E117, and F118: 5 of P113 and SEQ ID NO) and is capable of reducing transcription of the target nucleic acid (e.g., mRNA), reducing translation of the target nucleic acid (e.g., mRNA), altering transcript splicing (e.g., single-stranded morpholino oligonucleotides, or interfering with endogenous activity of the target nucleic acid see, e.g., Weintraub, scientific americans, 262:40(1990), typically synthetic antisense nucleic acids (e.g., oligonucleotides) are typically 15 to 25 bases in length. Nucleic acid encoding one or more amino acids corresponding to Q339, S343, E379, K416, H340 of SEQ ID NO: 4). (ii) a N264, Q272, M245 and D290 of SEQ ID NO 6; or E117 and P113 and F118 of SEQ ID NO. 5. In embodiments, the antisense nucleic acid hybridizes to a target nucleic acid (e.g., a nucleic acid encoding one or more amino acids corresponding to Q339, S343, E379, K416, H340 of SEQ ID NO: 4; N264, Q272, M245, and D290: 6 of SEQ ID NO; or E117, and P113 and F118: 5 of SEQ ID NO) in vitro. In embodiments, the antisense nucleic acid hybridizes to a cell in a target nucleic acid (e.g., a nucleic acid encoding one or more amino acids corresponding to Q339, S343, E379, K416, H340 of SEQ ID NO: 4; N264, Q272, M245, and D290: 6 of SEQ ID NO; or E117, and P113 and F118: 5 of SEQ ID NO). In embodiments, the antisense nucleic acid hybridizes to a target nucleic acid (e.g., a nucleic acid encoding one or more amino acids corresponding to Q339, S343, E379, K416, H340 of SEQ ID NO: 4; N264, Q272, M245, and D290: 6 of SEQ ID NO; or E117, and P113 and F118: 5 of SEQ ID NO) in an organism. In embodiments, the antisense nucleic acid hybridizes to a target nucleic acid (e.g., a nucleic acid encoding one or more amino acids corresponding to Q339, S343, E379, K416, H340 of SEQ ID NO: 4; N264, Q272, M245, and D290: 6 of SEQ ID NO; or E117, and P113 and F118: 51 of SEQ ID NO) under physiological conditions. Antisense nucleic acids can comprise naturally occurring nucleotides or modified nucleotides, such as phosphorothioate, methylphosphonate and anomeric sugar-phosphate, backbone modified nucleotides.

In cells, antisense nucleic acids hybridize to the corresponding RNA (e.g., nucleic acids encoding one or more amino acids corresponding to Q339, S343, E379, K416, H340 of SEQ ID NO: 4; N264, Q272, M245 and D290 of SEQ ID NO: 6; or E117 and P113 and F118 of SEQ ID NO: 5) to form double-stranded β molecules the antisense nucleic acids interfere with the endogenous behavior of the RNA (e.g., nucleic acids encoding one or more amino acids corresponding to Q339, S343, E379, K416, H340 of SEQ ID NO: 4; N264, Q272, M245, and D290 of SEQ ID NO: 6; or E117 and P113 and F118 of SEQ ID NO:5, and inhibit the function thereof relative to the absence of the antisense nucleic acids.) furthermore, double-stranded molecules can be degraded by RNAi pathways.

The term "complement," as used herein, refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides or sequences complementary to nucleotides that are capable of base pairing. As described herein and well known in the art, the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanidine is cytosine. Thus, a complement can include a nucleotide sequence that base pairs with a corresponding complementary nucleotide of the second nucleic acid sequence. The nucleotides of the complement may partially or completely match the nucleotides of the second nucleic acid sequence. When the nucleotides of the complement are perfectly matched to each nucleotide of the second nucleic acid sequence, the complement forms a base pair with each nucleotide of the second nucleic acid sequence. When the nucleotides of the complement match the nucleotide portion of the second nucleic acid sequence, only some of the nucleotides of the complement form base pairs with the nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and non-coding sequences, wherein a non-coding sequence contains nucleotides complementary to a coding sequence, thereby forming a complementary sequence to a coding sequence. Another example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains the nucleotides complementary to the antisense sequence, thereby forming the complement of the antisense sequence.

The complementarity of sequences as described herein may be partial, where only some nucleic acid matches are according to base pairing, or complete, where all nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other can have a particular percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91% within a specified region, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity).

The term "antibody" refers to polypeptides encoded by immunoglobulin genes or functional fragments that specifically bind and recognize antigens.

An exemplary immunoglobulin (antibody) building block comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" (about 25kDa) and one "heavy" chain (about 50-70 kDa). The N-terminus of each chain defines a variable region of about 100-110 or more amino acids, primarily responsible for antigen recognition. The terms "variable heavy chain", "V _H"or" VH "refers to an immunoglobulin heavy chain, including Fv, the variable region of dsFv or Fab in scFv; and the terms "variable light chain", "V _L"or" VL "refers to the variable region of an immunoglobulin light chain, including Fv, dsFv in scFv, or Fab.

Examples of functional fragments of antibodies include, but are not limited to, intact antibody molecules, antibody fragments such as Fv, single chain Fv (scfv), Complementarity Determining Regions (CDRs), VL (light chain variable region), VH (heavy chain variable region), Fab, f (ab)2', and any combination of those or any other functional portions of immunoglobulin peptides capable of binding a target antigen (see, e.g., Paul ed., 4th ed.2001). As understood by those skilled in the art, various antibody fragments can be obtained by a variety of methods, such as digestion of intact antibodies with enzymes (e.g., pepsin); or synthesized de novo. Antibody fragments are generally synthesized de novo either chemically or by using recombinant DNA methods. Thus, as used herein, the term antibody includes antibody fragments produced by modification of intact antibodies, or antibody fragments synthesized de novo using recombinant DNA methods (e.g., single chain Fv) or identified using phage display libraries (see, e.g., McCafferty et al, (1990) Nature 348: 552). The term "antibody" also includes bivalent or bispecific molecules, diabodies, triabodies and tetrabodies. Bivalent and bispecific molecules are described, for example, in Kostelny et al. (1992) Immunol. 148: 1547, Pack and Pluckthun (1992) Biochemistry 31:1579, Hollinger et al (1993), PNAS. U.S. Pat. No. 90: 6444, Gruber et al. (1994) J Immunol. 152: 5368 Zhu et al. (1997) Protein Sci. 6: 781, Hu et al. (1996) The Cancer Res. 56: 3055, Adams et al. (1993) And (4) cancer research. 53: 4026, mecartnib et al. (1995) Protein Eng. 8: 301.

"percent sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (determining the optimal alignment for the two sequences as compared to the reference sequence (which does not comprise additions or deletions), i.e., gaps). The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, and dividing the number of matched positions by the total number of positions in the window of comparison. And multiplying the result by 100 to yield the percentage of sequence identity.

The term "identical" or percent "identity," in the context of two or more nucleic acid or polypeptide sequences, refers to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, when compared and aligned over a comparison window or designated region for maximum correspondence as measured using BLAST or BLAST 2.0 sequence comparison, the% identity over the designated region, 95%, 96%, 97%, 98%, 99% or more, has the default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI website http:///www.ncbi.nlm.nih.gov/BLAST/etc.) And/or added sequences, as well as sequences with substitutions. As described below, the preferred algorithm can account for gaps and the like. Preferably, the identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.

"anti-cancer agent" and "anti-cancer agent" are used in their ordinary conventional sense and refer to a compound (e.g., 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 that is useful 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. Examples of anticancer agents include, but are not limited to, MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973, ARRY). -162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, nitrogen mustard, uramustine, thiotepa, nitrosourea, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meikhalan), ethyleneimine and methylmelamine (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozotocin)), triazenes (decazi)ne)), antimetabolites (e.g., 5-azathioprine, formyltetrahydronaphthalene, capecitabine flu, fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil), fluorouracil, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, pullulan, etc.), platinum compounds (e.g., cisplatin, oxaliplatin, carboplatin)), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoacetamides), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin). Bleomycin), enzymes (e.g. L-asparaginase), inhibitors of mitogen-activated protein kinase signalling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY43-9006, wortmannin or LY294002, Syk INHIBI thTOR, mTOR inhibitors, antibodies (e.g. rituximab), gossypol, genasense, polyphenol E, 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), 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), flavopirol, bortezomib 292, Zygosamide 7082, Zygosarta-7082, PKC412, PD184352,20-epi-1,25 dihydroxy vitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecyenol; (ii) Alexanox; aldesleukin drug; ALL-TK antagonist; altretamine; ambamustine; (ii) amidox; amifostine; (ii) aminolevulinic acid; aminorubicinAmphetamine, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G, antarelix, antiretromorphogenetic protein-1, antiandrogen, prostatic cancer, antiestrogen, antineomone, antisense oligonucleotides, aphrodiclin glycinate, apoptosis gene modulators, apoptosis modulators, depurination acid, ARA-CDP-DL-PTBA, arginine deaminase, asucrosine, atamestane, atrimustine, axinostatin 1, axinostatin 2, axinattatin 3, azasetron, azatoxixin, azatyrosine, baccatin III derivatives, balanol, BCR/ABL antagonists, benzocystatins, betazocine, quinoxalinone derivatives, β -lactam derivatives, β -zeaceticine, betahistidin B, cystatin-beta-isoxadiol, diazepine-N-isovaleramide, diazepine-N-isovalerolactone, diazirin-isovalerolactone, penicillin-N-diazirin-penicillin-N-penicillin B, penicillin-diazirin, penicillin-N-penicillin, penicillin-N;exemestane, fadrozole, fazarabine, fenretin A, filgrastim, finasteride, flavonoid antineoplastic, flezelastine, flusterone, fludarabine, fluorouracil hydrochloride, forfenimex, formestane, fosstricin, fotemustine, gadifolin, gadoteridazine, gallium nitrate, galocitabine, ganirelix, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, nerve growth factor, hexamethylene diacetylamide, hypericin, ibandronic acid, idarubicin, fenirantone, imosidenafoxidine, imosidectastatin, imidazosoridomycin, imipramipeline, 4-gonadolastatin, insulin-like growth factor-1 receptor inhibitors, interferon agonists, monophosphointerferon, interleukine, pennyxolone, idorubicin, mitomycin-N-ketolide, mitomycin-N-beta-interferon, mitomycin-beta-interferon, mitomycin, beta-interferon, beta-interferon, beta-interferon, beta-interferon, beta-interferon, beta-interferon, beta-betaAn ogastrim; nedaplatin; nemo; neridronic acid; a neutral endopeptidase; nilutamide; nisamycin; a nitric oxide modulator; a nitrogen oxide antioxidant; nitrulyn; o6-benzyl; octreotide; okicenone; an oligonucleotide; onapristone; ondansetron; ondansetron; oracin; an oral cytokine inducer; ormaplatin; an oxateclone; oxaliplatin; oxanonomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; pancmifene; a parabencin; pazelliptine; asparaginase enzyme; peldesine; sodium pentosan polysulfate; pentostatin; (ii) pentazole; perfluorobromoalkane; perfosfamide; perilla alcohol; phenazinomomycin; phenylacetic acid; a phosphatase inhibitor; hemolytic streptococcus; pilocarpine hydrochloride; pirarubicin; pirtroxine; placetin A; placetin B; a plasminogen activator inhibitor; a platinum complex; a platinum compound; a platinum-triamine complex; sodium porphine; poise and Po are not; prednisone; propyl bisacridone; 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; purple; pyrazoloradine; pyridinyloxy hemoglobin polyoxyethylene conjugates; a raf antagonist; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; (ii) a ras inhibitor; ras-GAP inhibitors; retelliptine methylated; rhenium Re186 etronate; rhizomycin; a ribozyme; RII retinoamide; rogletimide; rohitukine; a romurtide; loquimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophylol A; sargrastim; sdi1 emulation; semustine; senescence-derived inhibitor 1; a sense oligonucleotide; a signal transduction inhibitor; a signal transduction modulator; a single-chain antigen-binding protein; sizofuran; sobuconazole; sodium borocholate; sodium phenylacetate; solverol; a growth regulator binding protein; sonermemin; punicic acid; spicamycin D; spiromustine; spleenetin; spongistatin 1; squalamine; a stem cell inhibitor; inhibitors of stem cell division; stiiamide; a stromelysin inhibitor; sulfinosine; a superactive vasoactive intestinal peptide antagonist; (ii) surfasta; suramin; swainsonine; synthesis of glycosaminoglycans(ii) a tallimustine; tamoxifen methyl iodide; tauromustine; tazarotene; a tecogalan sodium; tegafur; telluropyrylium; a telomerase inhibitor; temoporfin; temozolomide; (ii) teniposide; tetrachloro; tetrazomine; (ii) a thioablistatin; thiocoraline; thrombopoietin; a thrombopoietin mimetic; thymalfasin (Thymalfasin); a thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; d, pulling and pricking; titanocene dichloride; topstein; toremifene; a totipotent stem cell factor; a translation inhibitor; tretinoin; triacetyl; (iii) triciribine; a third part; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrosine phosphorylation; an UBC inhibitor; ubenimex; urogenital sinus derived growth inhibitory factor; a urokinase receptor antagonist; vapreotide; variolin B; vector systems, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaline; vitaxin; (ii) chlorazol; zanoterone; zeniplatin; zilascorb; zinostatin stimomer, Adriamycin, Dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; axicon hydrochloride; acronine; (ii) Alexanox; aldesleukin drug; altretamine; ambomamycin; amitriptyline acetate; luminal; amsacrine; anastrozole; fennel; an asparaginase enzyme; asperlin; azacitidine; azetepa; azotomycin; bara; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; briprimine; busulfan; a cactinomycin; (ii) carpoterone; caracemide; a carbbeimer; carboplatin; carmustine; carrabine hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziqutone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; a duazomycin; edatrexae; eflornithine hydrochloride; sand-based; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; female dieSestine, estramustine sodium phosphate, itraconazole, etoposide phosphate, etoposine, fadrozole hydrochloride, fazabine, fenretin, floxuridine, fludarabine phosphate, fluorouracil, fluorocitabine, fosquidone, fosstricinonide, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, imifosfestosin, interleukin I1 (including recombinant interleukin II or rIL2), interferon α -2a, interferon α -2b, interferon α -n1, interferon α -n3, interferon β -1a, interferon gamma-1 b, ipratropium, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, linazole hydrochloride, lomefloxacin sodium, lomustine hydrochloride, loxapine hydrochloride, flutriafol hydrochloride, fluxofenacetrin hydrochloride, flunomine hydrochloride, flunominated adenine, flunomine hydrochloride, flunominated adenine hydrochloride, flunomine hydrochloride, flunominated adenine hydrochloride, flunomine hydrochloride(iii) retigabine tartrate; vinrosidine sulfate; thiazolidine sulfate; (ii) chlorazol; zeniplatin; 1, neat setastine; zollin hydrochloride, agents that prevent cell growth at the G2-M phase and/or modulate microtubule formation or stability (e.g., Taxol. TM. (i.e., paclitaxel), Taxotere. TM. (i.e., a compound comprising a taxane backbone), Erbutoxazole (i.e., R-55104)), Dolastatin 10 (i.e., DLS-10 and NSC-376128), Mivobulin isethionate (i.e., CI-980), vincristine, NSC-639829, Discodermolide (i.e., NVP-XX-A-296), ABT-LU (Abbott, i.e., E-7010), Altorhyrtins (e.g., Altorhyrtin A and Altorhyrtin C), Spongistatin (e.g., Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin5, Spongistatin 6, Spongistatin 7, Spongistatin B, Spongistat A4, Spongistat C (e.g., epothilone A-369, Spongistat C), epothilone D (i.e., KOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-Epothilone B, 21-amino Epothilone B (i.e., BMS-310705), 21-hydroxymethylpiperidone D (i.e., desoxyyep Epothilone F and dEpoF), 26-fluoroepothilone, Auristatin PE (i.e., NSC-654663), Soblidotin (i.e., TZT-1027), LS-4559-P (Pharmacia, LS-4577), LS-4578(Pharmacia, LS-477-P), LS-4477(Pharmacia), LS-4559(Pharmacia), RPR-112378(Aventis), vincristine sulfate, DZ-3358 (Daijhi), Fuseavida-877 (Fusawa-18285), and Tawa B-31085), GS-198(Takeda), KAR-2 (Hungary academy of sciences), BSF-223651(BASF, i.e., ILX-651 and LU-223651), SAH-49960(Lilly/Novartis), SDZ-268970(Lilly/Novartis), AM-97(Armad/Kyowa Hakko), AM-132(Armad), AM-138(Armad/Kyowa Hakko), IDN-5005(Indena), Cryptophycin 52 (i.e., LY-355703), AC-7739(Ajinomoto, i.e., AVE-8063A and CS-39.HCl), AC-7700(Ajinomoto, i.e., AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A), Tuilemion, Tubuisin, Tubutein 261, Hungary-138067, Hungary-3967, Ab-5929 (Ab-34, Ab-35, Ab-34, Ab-Ab), h10 (university of Kansassi Li), H16 (university of Kansassi Li),oncocidin A1 (i.e., BTO-956 and DIME), DDE-313(Parker Hughes Institute), Fijianolide B, Laulimallide, SPA-2(Parker Hughes Institute), SPA-1(Parker Hughes Institute, i.e., SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Wenyi Institute, i.e., MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851(Asta medical), A-105972(Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. sina Schnooi School of Medicine), MF-191), TMPN (Areata verysisin), Abies-5, Abies-5, Abies-Abies, Abies-5-Abies, Abies-5, such as anti-Abies, Abies-5, Abies-5-Abies, Abies-5-D, Abies, such as anti-2, Abies-2, such as anti-2, Abies, such as anti-5, Abiesnas exotoxin conjugate, etc.), radioimmunotherapy (e.g., anti-CD 20+ monoclonal antibody and ^111In， ⁹⁰y is or ¹³¹I.e. coupling), triptolide, homoharringtonine, actinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, Epidermal Growth Factor Receptor (EGFR) targeted therapies or treatments (e.g. gefitinib (Iressa) ^TM) Erlotinib (Tarceva) ^TM) Cetuximab (Erbitux) ^TM) Lapatinib (Tykerb) ^TM) Panitumumab (Vectibix) ^TM) Vandetanib (Caprolsa) ^TM) afatinib/BIBW 2992, CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306, ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/norerlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, and the like.

The term "i irreversible covalent bond" is used according to its ordinary conventional meaning in the art and means that the probability of dissociation into atoms or (e.g., the resulting cognate and nucleophilic moieties between molecules of electrophilic chemistry) therein is low. In embodiments, the irreversible covalent bond is not readily dissociated under normal biological conditions. In embodiments, an irreversible covalent bond is formed by a chemical reaction between two species (e.g., an electrophilic chemical moiety and a nucleophilic moiety).

The term "activity of protein phosphatase 2A (PP 2A)" as used herein refers to the biological activity of the protein. The activity of Protein phosphatase 2A (PP2A) can be quantified by measuring the amount of PP2A (e.g., PPP2CA) bound to another Protein (e.g., AKT), dephosphorylation of a Protein of PP2A (e.g., PPP2CA) (e.g., AKT), measurement of cell division rate, cell viability, cell mobility, actin cell backbone polymerization, actin cell backbone stability, or epithelial-mesenchymal transition rate.

The term "PPP 2R1A protein PPP2R1A modulator complex," as used herein, refers to a PPP2R1A protein that is linked (e.g., covalently linked) to a PPP2R1A modulator (e.g., a compound described herein).

II. Compound

In one aspect, compounds are provided having the formula:

Two adjacent R ¹Substituents may optionally join to form substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

The notation z1 is an integer from 0 to 7.

L ¹Is a bond, -S (O) ₂-、-NR ⁴-、-O-、-S-、-C(O)-、-C(O)NR ⁴-、-NR ⁴C(O)-、-NR ⁴C(O)NH-、-NHC(O)NR ⁴-, -C (O) O-, -OC (O) -substituted or unsubstitutedAn alkylene group, a substituted or unsubstituted heteroalkylene group, a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted heterocycloalkylene group, a substituted or unsubstituted arylene group, or a substituted or unsubstituted heteroarylene group.

R ⁴Is hydrogen, -CX ⁴ ₃、-CHX ⁴ ₂、-CH ₂X ⁴、-OCX ⁴ ₃、-OCH ₂X ⁴、-OCHX ⁴ ₂、-CN、-C(O)R ^4A、-C(O)-OR ^4A、-C(O)NR ^4AR ^4B、-OR ^4ASubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

L ²Is a bond, -S (O) ₂-、-NR ⁵-、-O-、-S-、-C(O)-、-C(O)NR ⁵-、-NR ⁵C(O)-、-NR ⁵C(O)NH-、-NHC(O)NR ⁵-, -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.

R ⁵Is hydrogen, -CX ⁵ ₃、-CHX ⁵ ₂、-CH ₂X ⁵、-OCX ⁵ ₃、-OCH ₂X ⁵、-OCHX ⁵ ₂、-CN、-C(O)R ^5A、-C(O)-OR ^5A、-C(O)NR ^5AR ^5B、-OR ^5ASubstituted 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.

Each R ^1A、R ^1B、R ^1C、R ^1D、R ^4A、R ^4B、R ^5AAnd R ^5BIndependently hydrogen, -CX ₃、-CN、-COOH、-CONH ₂、-CHX ₂、-CH ₂X, 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.

R bound to the same nitrogen atom ^1AAnd R ^1BThe substituents may optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. R bound to the same nitrogen atom ^4AAnd R ^4BThe substituents may optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. R bound to the same nitrogen atom ^5AAnd R ^5BThe substituents may optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl.

Each X, X ¹、X ⁴And X ⁵Independently is-F, -Cl, -Br or-I.

The symbols n1, n4, and n5 are independently integers from 0 to 4.

The symbols m1, m4, m5, v1, v4 and v5 are independently integers of 1 to 2.

In embodiments, the compound has the formula:

R ¹、L ¹、z1、L ²and E is as described herein.

In embodiments, the compound has the formula:

R ¹、L ¹、z1、L ²and E is as described herein.

In embodiments, the compound has the formula:

R ¹、z1、R ⁴、L ²and E is as described herein.

In embodiments, the compound has the formula:

R ¹、z1、R ⁵、L ¹and E is as described herein.

In embodiments, the compound has the formula:

R ¹、L ¹、z1、L ²and E is as described herein.

In embodiments, the compound has the formula:

R ¹、L ¹、z1、L ²and E is as described herein.

In embodiments, the compound has the formula:

R ¹、R ⁴、z1、L ²and E is as described herein.

In embodiments, the compound has the formula:

R ¹、L ¹、z1、R ⁵and E is as described herein.

In embodiments, the compound has the formula:

R ¹、L ¹、z1、L ²and E is as described herein.

In embodiments, the compound has the formula:

R ¹、L ¹、z1、L ²and E is as described herein.

In embodiments, the compound has the formula:

R ¹、R ⁴、z1、L ²and E is as described herein.

In embodiments, the compound has the formula:

R ¹、R ⁵、z1、L ¹and E is as described herein.

It is to be understood that R ¹Are floating substituents and can be connected to any of the fused rings in the formulae shown herein above. For example, the following two equations are equivalent:

the two formulae shown below are equivalent:

it will be further understood that multiple floating substituents may be bonded to any of the fused rings shown above, or one or more substituents may be bonded to one ring and one or more othersThe substituents may be bonded to different rings.

In the examples, R ¹Independently halogen, -CX ¹ ₃、-CHX ¹ ₂、-CH ₂X ¹、-OCX ¹ ₃、-OCH ₂X ¹、-OCHX ¹ ₂、-CN、-SR ^1D、-NR ^1AR ^1B、-C(O)R ^1C、-C(O)OR ^1C、-C(O)NR ^1AR ^1B、-OR ^1D、-N ₃Substituted 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, R ¹Independently halogen, -CX ¹ ₃、-CHX ¹ ₂、-CH ₂X ¹、-OCX ¹ ₃、-OCH ₂X ¹、-OCHX ¹ ₂、-CN、-SH、-NH ₂、-C(O)OH、-C(O)NH ₂-OH, substituted or unsubstituted C ₁-C ₈Alkyl or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C ₃-C ₈Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl, substituted or unsubstituted C ₆-C ₁₂Aryl or substituted or unsubstituted 5 to 12 membered heteroaryl.

In the examples, R ¹Independently halogen, -CX ¹ ₃、-CHX ¹ ₂、-CH ₂X ¹、-OCX ¹ ₃、-OCH ₂X ¹、-OCHX ¹ ₂、-CN、-SH、-NH ₂、-C(O)OH、-C(O)NH ₂-OH, substituted or unsubstituted C ₁-C ₈Alkyl or substituted or unsubstituted 2 to 8 membered heteroalkyl; substituted or unsubstituted C ₃-C ₈Cycloalkyl, substituted or unsubstituted 3-to 8-membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-to 6-membered heteroarylAnd (4) a base.

In an embodiment, two adjacent R ¹The substituents join to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In an embodiment, two adjacent R ¹The substituents join to form a substituted cycloalkyl group. In an embodiment, two adjacent R ¹The substituents being joined to form unsubstituted C ₃-C ₆A cycloalkyl group.

In the examples, R ¹Independently an unsubstituted methyl group. In the examples, R ¹Independently an unsubstituted ethyl group. In the examples, R ¹Independently unsubstituted propyl. In the examples, R ¹Independently unsubstituted isopropyl. In the examples, R ¹Independently unsubstituted n-propyl. In the examples, R ¹Independently an unsubstituted butyl group. In the examples, R ¹Independently unsubstituted n-butyl. In the examples, R ¹Independently an unsubstituted tert-butyl group. In the examples, R ¹Independently an unsubstituted pentyl group. In the examples, R ¹Independently an unsubstituted n-pentyl group. In the examples, R ¹Independently an unsubstituted hexyl group. In the examples, R ¹Independently, unsubstituted n-hexyl. In the examples, R ¹Independently an unsubstituted heptyl group. In the examples, R ¹Independently an unsubstituted n-heptyl group. In the examples, R ¹Independently an unsubstituted octyl group. In the examples, R ¹Independently an unsubstituted n-octyl group. In the examples, R ¹Independently an unsubstituted benzyl group. In the examples, R ¹Independently is unsubstituted C ₁-C ₈An alkyl group. In the examples, R ¹Independently a methyl group substituted with a halogen. In the examples, R ¹Independently an ethyl group substituted with a halogen. In the examples, R ¹Independently isopropyl substituted with halogen. In the examples, R ¹Independently is halogen-substituted nAnd (4) propyl. In the examples, R ¹Independently n-butyl substituted with halogen. In the examples, R ¹Independently a tert-butyl group substituted with a halogen. In the examples, R ¹Independently n-pentyl substituted by halogen. In the examples, R ¹Independently a benzyl group substituted with a halogen. In the examples, R ¹Independently halogen substituted C ₁-C ₈An alkyl group. In the examples, R ¹Independently an unsubstituted 2-to 6-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 2-to 7-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 2-to 8-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 2-to 9-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 2-to 10-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 3-to 10-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 4-to 10-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 5-to 10-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 6-to 10-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 7-to 10-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 8-to 10-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 6-to 10-membered heteroalkyl group. In the examples, R ¹Independently an unsubstituted 7-to 9-membered heteroalkyl group.

In an embodiment, two adjacent R ¹The substituents being joined to form unsubstituted C ₃-C ₆A cycloalkyl group. In an embodiment, two adjacent R ¹The substituents being joined to form unsubstituted C ₄-C ₆A cycloalkyl group. In an embodiment, two adjacent R ¹The substituents being joined to form unsubstituted C ₃-C ₅A cycloalkyl group. In an embodiment, two adjacent R ¹The substituents being joined to form unsubstituted C ₅-C ₆A cycloalkyl group. In an embodiment, two adjacent R ¹The substituents being joined to form unsubstituted C ₄A cycloalkyl group.

In the examples, R ¹Independently an unsubstituted 5-membered heteroaryl. In the examples, R ¹Independently an unsubstituted 6-membered heteroaryl. In the examples, R ¹Independently an unsubstituted pyridyl group. In the examples, R ¹Independently an unsubstituted 2-pyridyl group. In the examples, R ¹Independently an unsubstituted 3-pyridyl group. In the examples, R ¹Independently an unsubstituted 4-pyridyl group. In the examples, R ¹Independently an unsubstituted pyridazinyl group. In the examples, R ¹Independently an unsubstituted pyrimidinyl group. In the examples, R ¹Independently an unsubstituted pyrazinyl group. In the examples, R ¹Independently an unsubstituted triazinyl group. In the examples, R ¹Independently an unsubstituted pyrrolyl group. In the examples, R ¹Independently an unsubstituted 2-pyrrolyl group. In the examples, R ¹Independently an unsubstituted 3-pyrrolyl group. In the examples, R ¹Independently an unsubstituted furyl group. In the examples, R ¹Independently an unsubstituted 2-furyl group. In the examples, R ¹Independently an unsubstituted 3-furyl group. In the examples, R ¹Independently an unsubstituted thienyl group. In the examples, R ¹Independently an unsubstituted 2-thienyl group. In the examples, R ¹Independently an unsubstituted 3-thienyl group. In the examples, R ¹Independently unsubstituted pyrazolyl. In the examples, R ¹Independently an unsubstituted isoxazolyl. In the examples, R ¹Independently an unsubstituted isothiazolyl group. In the examples, R ¹Independently an unsubstituted imidazolyl group. In the examples, R ¹Independently an unsubstituted oxazolyl group. In the examples, R ¹Independently an unsubstituted thiazolyl group. In the examples, R ¹Independently unsubstituted phenyl. In the examples, R ¹Independently unsubstituted biphenyl. In the examples, R ¹Independently unsubstituted 2-biphenyl. In the examples, R ¹Independently unsubstituted 3-biphenyl. In the examples, R ¹Independently unsubstituted 4-biphenyl.

In the examples, R ¹Independently is-CX ¹ ₃. In the examples, R ¹Independently is-CHX ¹ ₂. In the examples, R ¹Independently is-CH ₂X ¹. In the examples, R ¹Independently is-OCX ¹ ₃. In the examples, R ¹Independently is-OCH ₂X ¹. In the examples, R ¹Independently is-OCHX ¹ ₂. In the examples, R ¹Independently is-CN. In the examples, R ¹Independently is-SO _n1R ^1D. In the examples, R ¹Independently is-SO _v1NR ^1AR ^1B. In the examples, R ¹Independently is-NHC (O) NR ^1AR ^1B. In the examples, R ¹Independently is-N (O) _m1. In the examples, R ¹Independently is-NR ^1AR ^1B. In the examples, R ¹Independently is-C (O) R ^1C. In the examples, R ¹Independently is-C (O) -OR ^1C. In the examples, R ¹Independently is-C (O) NR ^1AR ^1B. In the examples, R ¹Independently is-OR ^1D. In the examples, R ¹Independently is-NR ^1ASO ₂R ^1D. In the examples, R ¹Independently is-NR ^1AC(O)R ^1C. In the examples, R ¹Independently is-NR ^1AC(O)OR ^1C. In the examples, R ¹Independently is-NR ^1AOR ^1C. In the examples, R ¹Independently is-OH. In the examples, R ¹Independently is-NH ₂. In the examples, R ¹independently-COOH. In the examples, R ¹Independently is-CONH ₂. In the examples, R ¹Independently is-NO ₂. In the examples, R ¹Independently is-SH. In the examples, R ¹Independently a halogen. In the examples, R ¹Independently is-F. In the examples, R ¹Independently is-Cl. In the examples, R ¹independently-Br. In the examples, R ¹Independently is-I. In the examples, R ¹Independently is-CF ₃. In the examples, R ¹Independently is-CHF ₂. In the examples, R ¹Independently is-CH ₂F. In the examples, R ¹Independently is-OCF ₃. In the examples, R ¹Independently is-OCH ₂F. In the examples, R ¹Independently of one another is-OCHF ₂. In the examples, R ¹Independently is-OCH ₃. In the examples, R ¹Independently is-OCH ₂CH ₃. In the examples, R ¹Independently is-OCH ₂CH ₂CH ₃. In the examples, R ¹Independently is-OCH (CH) ₃) ₂. In the examples, R ¹Independently is-OC (CH) ₃) ₃. In the examples, R ¹Independently is-SCH ₃. In the examples, R ¹Independently is-SCH ₂CH ₃. In the examples, R ¹Independently is-SCH ₂CH ₂CH ₃. In the examples, R ¹Independently is-SCH (CH) ₃) ₂. In the examples, R ¹Independently is-SC (CH) ₃) ₃。

In the examples, R ¹Independently halogen, -CX ¹ ₃、-CHX ¹ ₂、-CH ₂X ¹、-OCX ¹ ₃、-OCH ₂X ¹、-OCHX ¹ ₂、-CN、-SO _n1R ^1D、-SO _v1NR ^1AR ^1B、-NHC(O)NR ^1AR ^1B、-N(O) _m1、-NR ^1AR ^1B、-C(O)R ^1C、-C(O)-OR ^1C、-C(O)NR ^1AR ^1B、-OR ^1D、-NR ^1ASO ₂R ^1D、-NR ^1AC(O)R ^1C、-NR ^1AC(O)OR ^1C、-NR ^1AOR ^1CSubstituted or unsubstituted alkylRadical (e.g. C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6,4 to 6, 2 to 3, or 4 to 5), substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6 membered).

In the examples, R ¹Independently is substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ¹Independently substituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ¹Independently unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ¹Independently an unsubstituted methyl group. In the examples, R ¹Independently an unsubstituted ethyl group. In the examples, R ¹Independently unsubstituted propyl. In the examples, R ¹Independently unsubstituted isopropyl. In the examples, R ¹Independently an unsubstituted tert-butyl group. In the examples, R ¹Independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6,4 to 6, 2 to 3, or 4 to 5). In the examples, R ¹Independently a substituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ¹Independently is unsubstituted heteroalkyl (e.g., 2-to 8-membered, 2)To 6,4 to 6, 2 to 3, or 4 to 5) members. In the examples, R ¹Independently is substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ¹Independently is substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ¹Independently unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ¹Independently a substituted or unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ¹Independently a substituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ¹Independently an unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ¹Independently is substituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ¹Independently is substituted aryl (e.g. C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ¹Independently unsubstituted aryl (e.g. C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ¹Independently substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). In the examples, R ¹Independently a substituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ¹Independently unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered).

In an embodiment, two adjacent R ¹The substituents may optionally join to form a substituted or unsubstituted ring (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In an embodiment, two adjacent R ¹Substituents may optionally join to form substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In an embodiment, two adjacent R ¹Substituents may optionally join to form unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In an embodiment, two adjacent R ¹Substituents may optionally join to form a substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered). In an embodiment, two adjacent R ¹Substituents may optionally join to form substituted heterocycloalkyl groups (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered). In an embodiment, two adjacent R ¹Substituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered). In an embodiment, two adjacent R ¹The substituents may optionally join to form a substituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In an embodiment, two adjacent R ¹Substituents may optionally join to form substituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In an embodiment, two adjacent R ¹Substituents may optionally join to form unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In an embodiment, two adjacent R ¹Substituents may optionally join to form substituted or unsubstituted heteroaryl (e.g., 5-12, 5-10, 5-9, or 5-6 membered). In an embodiment, two adjacent R ¹Substituents may optionally join to form substituted heteroaryl groups (e.g., 5-12, 5-10, 5-9, or 5-6). In an embodiment, two adjacent R ¹The substituents may beOptionally joined to form an unsubstituted heteroaryl (e.g., 5-12, 5-10, 5-9, or 5-6 membered).

In the examples, R ^1AIndependently hydrogen. In the examples, R ^1AIndependently is-CX ^1A ₃. In the examples, R ^1AIndependently is-CHX ^1A ₂. In the examples, R ^1AIndependently is-CH ₂X ^1A. In the examples, R ^1AIndependently is-CN. In the examples, R ^1Aindependently-COOH. In the examples, R ^1AIndependently is-CONH ₂. In the examples, X ^1AIndependently is-F, -Cl, -Br or-I.

In the examples, R ^1AIndependently is substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1AIndependently substituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1AIndependently unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1AIndependently an unsubstituted methyl group. In the examples, R ^1AIndependently an unsubstituted ethyl group. In the examples, R ^1AIndependently unsubstituted propyl. In the examples, R ^1AIndependently unsubstituted isopropyl. In the examples, R ^1AIndependently an unsubstituted tert-butyl group. In the examples, R ^1AIndependently substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6,4 to 6, 2 to 3, or 4 to 5). In the examples, R ^1AIndependently a substituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^1AIndependently an unsubstituted heteroalkyl group (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the implementation ofIn the examples, R ^1AIndependently is substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1AIndependently is substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1AIndependently unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1AIndependently a substituted or unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1AIndependently a substituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1AIndependently an unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1AIndependently is substituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1AIndependently is substituted aryl (e.g. C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1AIndependently unsubstituted aryl (e.g. C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1AIndependently substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). In the examples, R ^1AIndependently a substituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^1AIndependently unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R ^1BIndependently hydrogen. In the examples, R ^1BIndependently is-CX ^1B ₃. In the examples, R ^1BIndependent of each otheris-CHX ^1B ₂. In the examples, R ^1BIndependently is-CH ₂X ^1B. In the examples, R ^1BIndependently is-CN. In the examples, R ^1Bindependently-COOH. In the examples, R ^1BIndependently is-CONH ₂. In the examples, X ^1BIndependently is-F, -Cl, -Br or-I.

In the examples, R ^1bIndependently is substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1BIndependently substituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1BIndependently unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1BIndependently an unsubstituted methyl group. In the examples, R ^1BIndependently an unsubstituted ethyl group. In the examples, R ^1BIndependently unsubstituted propyl. In the examples, R ^1BIndependently unsubstituted isopropyl. In the examples, R ^1BIndependently an unsubstituted tert-butyl group. In the examples, R ^1BIndependently substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6,4 to 6, 2 to 3, or 4 to 5). In the examples, R ^1BIndependently a substituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^1BIndependently an unsubstituted heteroalkyl group (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^1BIndependently is substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1BIndependently is substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1BIndependently unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1BIndependently a substituted or unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1BIndependently a substituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1BIndependently an unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1BIndependently is substituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1BIndependently is substituted aryl (e.g. C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1BIndependently unsubstituted aryl (e.g. C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1BIndependently substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). In the examples, R ^1BIndependently a substituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^1BIndependently unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered).

In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BThe substituents may join to form a substituted or unsubstituted heterocycloalkyl group (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BThe substituents may join to form a substituted heterocycloalkyl group (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BThe substituents may join to form an unsubstituted heterocycloalkyl group (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered).

In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BThe substituents may join to form a substituted or unsubstituted heteroaryl (e.g., 5-12, 5-10, 5-9, or 5-6 membered). In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BThe substituents may join to form substituted heteroaryl groups (e.g., 5-12, 5-10, 5-9, or 5-6). In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BThe substituents may join to form unsubstituted heteroaryl (e.g., 5-12, 5-10, 5-9, or 5-6 membered).

In the examples, R ^1CIndependently hydrogen. In the examples, R ^1CIndependently is-CX ^1C ₃. In the examples, R ^1CIndependently is-CHX ^1C ₂. In the examples, R ^1CIndependently is-CH ₂X ^1C. In the examples, R ^1CIndependently is-CN. In the examples, R ^1Cindependently-COOH. In the examples, R ^1CIndependently is-CONH ₂. In the examples, X ^1CIndependently is-F, -Cl, -Br or-I.

In the examples, R ^1CIndependently is substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1CIndependently substituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1CIndependently unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1CIndependently an unsubstituted methyl group. In the examples, R ^1CIndependently an unsubstituted ethyl group. In factIn the examples, R ^1CIndependently unsubstituted propyl. In the examples, R ^1CIndependently unsubstituted isopropyl. In the examples, R ^1CIndependently an unsubstituted tert-butyl group. In the examples, R ^1CIndependently substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6,4 to 6, 2 to 3, or 4 to 5). In the examples, R ^1CIndependently a substituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^1CIndependently an unsubstituted heteroalkyl group (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^1CIndependently is substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1CIndependently is substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1CIndependently unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1CIndependently a substituted or unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1CIndependently a substituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1CIndependently an unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1CIndependently is substituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1CIndependently is substituted aryl (e.g. C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1CIndependently unsubstituted aryl (e.g. C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1CIndependently substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). In the examples, R ^1CIndependently a substituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^1CIndependently unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R ^1DIndependently hydrogen. In the examples, R ^1DIndependently is-CX ^1D ₃. In the examples, R ^1DIndependently is-CHX ^1D ₂. In the examples, R ^1DIndependently is-CH ₂X ^1D. In the examples, R ^1DIndependently is-CN. In the examples, R ^1Dindependently-COOH. In the examples, R ^1DIndependently is-CONH ₂. In the examples, X ^1DIndependently is-F, -Cl, -Br or-I.

In the examples, R ^1DIndependently is substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1DIndependently substituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1DIndependently unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^1DIndependently an unsubstituted methyl group. In the examples, R ^1DIndependently an unsubstituted ethyl group. In the examples, R ^1DIndependently unsubstituted propyl. In the examples, R ^1DIndependently unsubstituted isopropyl. In the examples, R ^1DIndependently an unsubstituted tert-butyl group. In the examples, R ^1DIndependently is a substituted or unsubstituted heteroalkyl group (e.g., 2 to 8 membered)2-to-6, 4-to-6, 2-to-3, or 4-to-5). In the examples, R ^1DIndependently a substituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^1DIndependently an unsubstituted heteroalkyl group (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^1DIndependently is substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1DIndependently is substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1DIndependently unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^1DIndependently a substituted or unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1DIndependently a substituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1DIndependently an unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6). In the examples, R ^1DIndependently is substituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1DIndependently is substituted aryl (e.g. C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1DIndependently unsubstituted aryl (e.g. C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In the examples, R ^1DIndependently substituted or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). In the examples, R ^1DIndependently a substituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered).In the examples, R ^1DIndependently unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R ¹Independently halogen, -CX ¹ ₃、-CHX ¹ ₂、-CH ₂X ¹、-OCX ¹ ₃、-OCH ₂X ¹、-OCHX ¹ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ²⁰Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ²⁰Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ²⁰Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ²⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ²⁰Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ²⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ¹Independently halogen, -CX ¹ ₃、-CHX ¹ ₂、-CH ₂X ¹、-OCX ¹ ₃、-OCH ₂X ¹、-OCHX ¹ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ¹Independently is-F, -Cl, -Br or-I. In the examples, R ¹Independently an unsubstituted methyl group. In the examples, R ¹Independently an unsubstituted ethyl group.

In an embodiment, two adjacent R ¹The substituents may optionally be joined to form a group represented by R ²⁰Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In an embodiment, two adjacent R ¹The substituents may optionally be joined to form a group represented by R ²⁰Substituted cycloalkyl (e.g. C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In an embodiment, two adjacent R ¹Substituents may optionally join to form unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In an embodiment, two adjacent R ¹The substituents may optionally be joined to form a group represented by R ²⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6 membered). In an embodiment, two adjacent R ¹The substituents may optionally be joined to form a group represented by R ²⁰Substituted heterocycloalkyl (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6 membered). In the examplesIn two adjacent R ¹Substituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered). In an embodiment, two adjacent R ¹The substituents may optionally be joined to form a group represented by R ²⁰Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In an embodiment, two adjacent R ¹The substituents may optionally be joined to form a group represented by R ²⁰Substituted aryl radicals (e.g. C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In an embodiment, two adjacent R ¹Substituents may optionally join to form unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl). In an embodiment, two adjacent R ¹The substituents may optionally be joined to form a group represented by R ²⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In an embodiment, two adjacent R ¹The substituents may optionally be joined to form a group represented by R ²⁰Substituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6 membered). In an embodiment, two adjacent R ¹Substituents may optionally join to form unsubstituted heteroaryl (e.g., 5-12, 5-10, 5-9, or 5-6 membered).

R ²⁰Independently is a pendant oxy group, a halogen, -CX ²⁰ ₃、-CHX ²⁰ ₂、-CH ₂X ²⁰、-OCX ²⁰ ₃、-OCH ₂X ²⁰、-OCHX ²⁰ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ²¹Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ²¹Substituted or unsubstitutedSubstituted heteroalkyl (e.g., 2 to 8, 2 to 6,4 to 6, 2 to 3, or 4 to 5) with R ²¹Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ²¹Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ²¹Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ²¹Substituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ²⁰Independently is a pendant oxy group, a halogen, -CX ²⁰ ₃、-CHX ²⁰ ₂、-CH ₂X ²⁰、-OCX ²⁰ ₃、-OCH ₂X ²⁰、-OCHX ²⁰ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ²⁰Independently is-F, -Cl, -Br or-I. In the examples, R ²⁰Independently an unsubstituted methyl group. In the examples, R ²⁰Independently an unsubstituted ethyl group.

R ²¹Independently is a pendant oxy group, a halogen, -CX ²¹ ₃、-CHX ²¹ ₂、-CH ₂X ²¹、-OCX ²¹ ₃、-OCH ₂X ²¹、-OCHX ²¹ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ²²Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ²²Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ²²Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ²²Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ²²Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ²²Substituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ²¹Independently is a pendant oxy group, a halogen, -CX ²¹ ₃、-CHX ²¹ ₂、-CH ₂X ²¹、-OCX ²¹ ₃、-OCH ₂X ²¹、-OCHX ²¹ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ²¹Independently is-F, -Cl, -Br or-I. In the examples, R ²¹Independently an unsubstituted methyl group. In the examples, R ²¹Independently an unsubstituted ethyl group.

R ²²Independently is a pendant oxy group, a halogen, -CX ²² ₃、-CHX ²² ₂、-CH ₂X ²²、-OCX ²² ₃、-OCH ₂X ²²、-OCHX ²² ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ²²Independently is-F, -Cl, -Br or-I. In the examples, R ²²Independently an unsubstituted methyl group. In the examples, R ²²Independently an unsubstituted ethyl group.

In the examples, R ^1AIndependently hydrogen, -CX ^1A ₃、-CHX ^1A ₂、-CH ₂X ^1A、-CN、-COOH、-CONH ₂Quilt R ^20ASubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^20ASubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^20ASubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^20ASubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^20ASubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^20ASubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^1AIndependently hydrogen, -CX ^1A ₃、-CHX ^1A ₂、-CH ₂X ^1A、-CN、-COOH、-CONH ₂Unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5 to 12, 5 to 10, 5 to 9, or5 to 6 membered). X ^1AIndependently is-F, -Cl, -Br or-I. In the examples, R ^1AIndependently hydrogen. In the examples, R ^1AIndependently an unsubstituted methyl group. In the examples, R ^1AIndependently an unsubstituted ethyl group.

In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BThe substituents may optionally be joined to form a group represented by R ^20ASubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6) or by R ^20ASubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered) or unsubstituted heteroaryl (e.g., 5-to 12-membered, 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BThe substituents may optionally be joined to form a group represented by R ^20ASubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6 membered). In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered).

R ^20AIndependently is a pendant oxy group, a halogen, -CX ^20A ₃、-CHX ^20A ₂、-CH ₂X ^20A、-OCX ^20A ₃、-OCH ₂X ^20A、-OCHX ^20A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^21ASubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^21ASubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^21ASubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^21ASubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^21ASubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^21ASubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^20AIndependently is a pendant oxy group, a halogen, -CX ^20A ₃、-CHX ^20A ₂、-CH ₂X ^20A、-OCX ^20A ₃、-OCH ₂X ^20A、-OCHX ^20A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^20AIndependently is-F, -Cl, -Br or-I. In the examples, R ^20AIndependent of each otherOr is unsubstituted methyl. In the examples, R ^20AIndependently an unsubstituted ethyl group.

R ^21AIndependently is a pendant oxy group, a halogen, -CX ^21A ₃、-CHX ^21A ₂、-CH ₂X ^21A、-OCX ^21A ₃、-OCH ₂X ^21A、-OCHX ^21A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^22ASubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^22ASubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^22ASubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^22ASubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^22ASubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^22ASubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^21AIndependently is a pendant oxy group, a halogen, -CX ^21A ₃、-CHX ^21A ₂、-CH ₂X ^21A、-OCX ^21A ₃、-OCH ₂X ^21A、-OCHX ^21A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^21AIndependently is-F, -Cl, -Br or-I. In the examples, R ^21AIndependently an unsubstituted methyl group. In the examples, R ^21AIndependently an unsubstituted ethyl group.

R ^22AIndependently is a pendant oxy group, a halogen, -CX ^22A ₃、-CHX ^22A ₂、-CH ₂X ^22A、-OCX ^22A ₃、-OCH ₂X ^22A、-OCHX ^22A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^22AIndependently is-F, -Cl, -Br or-I. In the examples, R ^22AIndependently an unsubstituted methyl group. In the examples, R ^22AIndependently an unsubstituted ethyl group.

In the examples, R ^1BIndependently hydrogen, -CX ^1B ₃、-CHX ^1B ₂、-CH ₂X ^1B、-CN、-COOH、-CONH ₂Quilt R ^20BSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^20BSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^20BSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^20BSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^20BSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^20BSubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^1BIndependently hydrogen, -CX ^1B ₃、-CHX ^1B ₂、-CH ₂X ^1B、-CN、-COOH、-CONH ₂Unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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.E.g. C ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^1BIndependently is-F, -Cl, -Br or-I. In the examples, R ^1BIndependently hydrogen. In the examples, R ^1BIndependently an unsubstituted methyl group. In the examples, R ^1BIndependently an unsubstituted ethyl group.

In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BThe substituents may optionally be joined to form a group represented by R ^20BSubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6) or by R ^20BSubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered) or unsubstituted heteroaryl (e.g., 5-to 12-membered, 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BThe substituents may optionally be joined to form a group represented by R ^20BSubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6,4 to 5, or 5 to 6 membered). In embodiments, R is bonded to the same nitrogen atom ^1AAnd R ^1BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered).

R ^20BIndependently is a pendant oxy group, a halogen, -CX ^20B ₃、-CHX ^20B ₂、-CH ₂X ^20B、-OCX ^20B ₃、-OCH ₂X ^20B、-OCHX ^20B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O) H, -NHC (O) -OH, -NHOH, by R ^21BSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^21BSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^21BSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^21BSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^21BSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^21BSubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^20BIndependently is a pendant oxy group, a halogen, -CX ^20B ₃、-CHX ^20B ₂、-CH ₂X ^20B、-OCX ^20B ₃、-OCH ₂X ^20B、-OCHX ^20B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl(e.g., 5 to 12, 5 to 10, 5 to 9, or 5 to 6). X ^20BIndependently is-F, -Cl, -Br or-I. In the examples, R ^20BIndependently an unsubstituted methyl group. In the examples, R ^20BIndependently an unsubstituted ethyl group.

R ^21BIndependently is a pendant oxy group, a halogen, -CX ^21B ₃、-CHX ^21B ₂、-CH ₂X ^21B、-OCX ^21B ₃、-OCH ₂X ^21B、-OCHX ^21B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^22BSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^22BSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^22BSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^22BSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^22BSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^22BSubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^21BIndependently is a pendant oxy group, a halogen, -CX ^21B ₃、-CHX ^21B ₂、-CH ₂X ^21B、-OCX ^21B ₃、-OCH ₂X ^21B、-OCHX ^21B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^21BIndependently is-F, -Cl, -Br or-I. In the examples, R ^21BIndependently an unsubstituted methyl group. In the examples, R ^21BIndependently an unsubstituted ethyl group.

R ^22BIndependently is a pendant oxy group, a halogen, -CX ^22B ₃、-CHX ^22B ₂、-CH ₂X ^22B、-OCX ^22B ₃、-OCH ₂X ^22B、-OCHX ^22B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^22BIndependently is-F, -Cl, -Br or-I. In the examples, R ^22BIndependently an unsubstituted methyl group. In the examples, R ^22BIndependently an unsubstituted ethyl group.

In the examples, R ^1CIndependently hydrogen, -CX ^1C ₃、-CHX ^1C ₂、-CH ₂X ^1C、-CN、-COOH、-CONH ₂Quilt R ^20CSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^20CSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^20CSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^20CSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^20CSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^20CSubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^1CIndependently hydrogen, -CX ^1C ₃、-CHX ^1C ₂、-CH ₂X ^1C、-CN、-COOH、-CONH ₂Unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^1CIndependently is-F, -Cl, -Br or-I. In the examples, R ^1CIndependently hydrogen. In the examples, R ^1CIndependently an unsubstituted methyl group. In the examples, R ^1CIndependently an unsubstituted ethyl group.

R ^20CIndependently is a pendant oxy group, a halogen, -CX ^20C ₃、-CHX ^20C ₂、-CH ₂X ^20C、-OCX ^20C ₃、-OCH ₂X ^20C、-OCHX ^20C ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^21CSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^21CSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^21CSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^21CSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^21CSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^21CSubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^20CIndependently is a pendant oxy group, a halogen, -CX ^20C ₃、-CHX ^20C ₂、-CH ₂X ^20C、-OCX ^20C ₃、-OCH ₂X ^20C、-OCHX ^20C ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^20CIndependently is-F, -Cl, -Br or-I. In the examples, R ^20CIndependently an unsubstituted methyl group. In the examples, R ^20CIndependently an unsubstituted ethyl group.

R ^21CIndependently is a pendant oxy group, a halogen, -CX ^21C ₃、-CHX ^21C ₂、-CH ₂X ^21C、-OCX ^21C ₃、-OCH ₂X ^21C、-OCHX ^21C ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^22CSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^22CSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^22CSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^22CSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^22CSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^22CSubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^21CIndependently is a pendant oxy group, a halogen, -CX ^21C ₃、-CHX ^21C ₂、-CH ₂X ^21C、-OCX ^21C ₃、-OCH ₂X ^21C、-OCHX ^21C ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^21CIndependently is-F, -Cl, -Br or-I. In the examples, R ^21CIndependently of each otherIs unsubstituted methyl. In the examples, R ^21CIndependently an unsubstituted ethyl group.

R ^22CIndependently is a pendant oxy group, a halogen, -CX ^22C ₃、-CHX ^22C ₂、-CH ₂X ^22C、-OCX ^22C ₃、-OCH ₂X ^22C、-OCHX ^22C ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^22CIndependently is-F, -Cl, -Br or-I. In the examples, R ^22CIndependently an unsubstituted methyl group. In the examples, R ^22CIndependently an unsubstituted ethyl group.

In the examples, R ^1DIndependently hydrogen, -CX ^1D ₃、-CHX ^1D ₂、-CH ₂X ^1D、-CN、-COOH、-CONH ₂Quilt R ^20DSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^20DSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered)) Quilt R ^20DSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^20DSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^20DSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^20DSubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^1DIndependently hydrogen, -CX ^1D ₃、-CHX ^1D ₂、-CH ₂X ^1D、-CN、-COOH、-CONH ₂Unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^1DIndependently is-F, -Cl, -Br or-I. In the examples, R ^1DIndependently hydrogen. In the examples, R ^1DIndependently an unsubstituted methyl group. In the examples, R ^1DIndependently an unsubstituted ethyl group.

R ^20DIndependently is a pendant oxy group, a halogen, -CX ^20D ₃、-CHX ^20D ₂、-CH ₂X ^20D、-OCX ^20D ₃、-OCH ₂X ^20D、-OCHX ^20D ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^21DSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^21DSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^21DSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^21DSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^21DSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^21DSubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^20DIndependently is a pendant oxy group, a halogen, -CX ^20D ₃、-CHX ^20D ₂、-CH ₂X ^20D、-OCX ^20D ₃、-OCH ₂X ^20D、-OCHX ^20D ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^20DIndependently is-F, -Cl, -Br or-I. In the examples, R ^20DIndependently an unsubstituted methyl group. In the examples, R ^20DIndependently an unsubstituted ethyl group.

R ^21DIndependently is a pendant oxy group, a halogen, -CX ^21D ₃、-CHX ^21D ₂、-CH ₂X ^21D、-OCX ^21D ₃、-OCH ₂X ^21D、-OCHX ^21D ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^22DSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^22DSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^22DSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^22DSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^22DSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₂、C ₆-C ₁₀Or phenyl) or by R ^22DSubstituted or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^21DIndependently is a pendant oxy group, a halogen, -CX ^21D ₃、-CHX ^21D ₂、-CH ₂X ^21D、-OCX ^21D ₃、-OCH ₂X ^21D、-OCHX ^21D ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^21DIndependently is-F, -Cl, -Br or-I. In the examples, R ^21DIndependently an unsubstituted methyl group. In the examples, R ^21DIndependently an unsubstituted ethyl group.

R ^22DIndependently is a pendant oxy group, a halogen, -CX ^22D ₃、-CHX ^22D ₂、-CH ₂X ^22D、-OCX ^22D ₃、-OCH ₂X ^22D、-OCHX ^22D ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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.E.g. C ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₂、C ₆-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 12-, 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^22DIndependently is-F, -Cl, -Br or-I. In the examples, R ^22DIndependently an unsubstituted methyl group. In the examples, R ^22DIndependently an unsubstituted ethyl group.

In an embodiment, z1 is 0. In an embodiment, z1 is 0 and the compound has formula (la) In an embodiment, z1 is 0 and the compound has formula (la) In an embodiment, z1 is 0 and the compound has formula (la)

In an embodiment, z1 is 0 and the compound has formula (la) In an embodiment, z1 is 0 and the compound has formula (la)

In an embodiment, z1 is 0 and the compound has formula (la)

In an embodiment, z1 is 0 and the compound has formula (la) In an embodiment, z1 is 0 and the compound has formula (la)

In an embodiment, z1 is 0 and the compound has formula (la)

In an embodiment, z1 is 1. In an embodiment, z1 is 2. In an embodiment, z1 is 3. In an embodiment, z1 is 4. In an embodiment, z1 is 5.

In embodiments, the compound has the formula:

wherein R is ⁴Is substituted or unsubstituted C ₁-C ₈An alkyl group. In the examples, R ⁴Independently is unsubstituted C ₁-C ₈An alkyl group. In the examples, R ⁴Is methyl substituted by phenyl. In the examples, R ⁴Is unsubstituted benzyl. In embodiments, the compound has the formula:

wherein R is ⁴Is substituted or unsubstituted C ₁-C ₈An alkyl group. In embodiments, the compounds haveHaving the formula:

wherein R is ⁵Is substituted or unsubstituted C ₁-C ₈An alkyl group. In embodiments, the compound has the formula:

wherein ring a is independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z30 and z33 are independently integers from 0 to 10. In an embodiment, z30 is 0. In an embodiment, z30 is 1. In an embodiment, z30 is 2. In an embodiment, z30 is 3. In an embodiment, z30 is 4. In an embodiment, z30 is 5. In an embodiment, z30 is 6. In an embodiment, z30 is 7. In an embodiment, z30 is 8. In an embodiment, z30 is 9. In an embodiment, z30 is 10. In an embodiment, z33 is 0. In an embodiment, z33 is 1. In an embodiment, z33 is 2. In an embodiment, z33 is 3. In an embodiment, z33 is 4. In an embodiment, z33 is 5. In an embodiment, z33 is 6. In an embodiment, z33 is 7. In an embodiment, z33 is 8. In an embodiment, z33 is 9. In an embodiment, z33 is 10.

In embodiments, the compound has the formula:

in embodiments, the compound has the formula:

in embodiments, ring a is substituted or unsubstituted cycloalkyl. In embodiments, ring a is a substituted or unsubstituted heterocycloalkyl. In embodiments, ring a is substituted or unsubstituted aryl. In embodiments, ring a is substituted or unsubstituted heteroaryl. In embodiments, ring a is substituted or unsubstituted (C) ₃-C ₁₀) Cycloalkyl, substituted or unsubstituted 3-to 10-membered heterocycloalkyl, substituted or unsubstituted (C) ₆-C ₁₀) Aryl or substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments, ring a is substituted or unsubstituted (C) ₃-C ₁₀) A cycloalkyl group. In embodiments, ring a is a substituted or unsubstituted 3-to 10-membered heterocycloalkyl. In embodiments, ring a is substituted or unsubstituted (C) ₆-C ₁₀) And (4) an aryl group. In embodiments, ring a is a substituted or unsubstituted 5-to 10-membered heteroaryl. In embodiments, ring a is substituted or unsubstituted (C) ₃-C ₆) A cycloalkyl group. In embodiments, ring a is a substituted or unsubstituted 3-to 6-membered heterocycloalkyl. In embodiments, ring a is substituted or unsubstituted phenyl. In embodiments, ring a is substituted or unsubstituted naphthyl. In embodiments, ring a is a substituted or unsubstituted 5-to 9-membered heteroaryl. In embodiments, ring a is a substituted or unsubstituted 5-to 6-membered heteroaryl. In embodiments, ring a is an unsubstituted 5-to 6-membered heteroaryl. In embodiments, ring a is a substituted or unsubstituted 5-membered heteroaryl. In embodiments, ring a is a substituted 5-membered heteroaryl. In the examplesRing a is unsubstituted 5-membered heteroaryl.

In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted (C) ₃-C ₁₀) Cycloalkyl radicals, by R ³⁰Substituted or unsubstituted 5-to 10-membered heterocyclic ring, substituted or unsubstituted ³⁰Substituted or unsubstituted (C) ₆-C ₁₀) Aryl or by R ³⁰Substituted or unsubstituted 5-to 10-membered heteroaryl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted (C) ₃-C ₁₀) Cycloalkyl radicals or by R ³⁰Substituted or unsubstituted 5-to 10-membered heterocycloalkyl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted (C) ₃-C ₁₀) A cycloalkyl group. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted 3 to 10 membered heterocycloalkyl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted (C) ₆-C ₁₀) And (4) an aryl group. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted 5-to 10-membered heteroaryl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted (C) ₃-C ₆) A cycloalkyl group. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted 3-to 6-membered heterocycloalkyl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted phenyl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted naphthyl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted 5-to 9-membered heteroaryl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted 5-to 6-membered heteroaryl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted thienyl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted phenyl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted benzothienyl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted naphthyl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted benzofuranyl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted furyl. In embodiments, ring A is substituted with R ³⁰Substituted or unsubstituted pyrrolyl.

In embodiments, ring a is substituted cycloalkyl. In embodiments, ring a is a substituted heterocycloalkyl. In embodiments, ring a is substituted aryl. In embodiments, ring a is substituted heteroaryl. In embodiments, ring a is substituted (C) ₃-C ₁₀) Cycloalkyl, substituted 3-to 10-membered heterocycloalkyl, substituted (C) ₆-C ₁₀) Aryl or substituted 5-to 10-membered heteroaryl. In embodiments, ring a is substituted (C) ₃-C ₁₀) A cycloalkyl group. In embodiments, ring a is a substituted 3-to 10-membered heterocycloalkyl. In embodiments, ring a is substituted (C) ₆-C ₁₀) And (4) an aryl group. In embodiments, ring a is a substituted 5-to 10-membered heteroaryl. In embodiments, ring a is substituted (C) ₃-C ₆) A cycloalkyl group. In embodiments, ring a is a substituted 3-to 6-membered heterocycloalkyl. In embodiments, ring a is substituted phenyl. In embodiments, ring a is substituted naphthyl. In embodiments, ring a is a substituted 5-to 9-membered heteroaryl. In embodiments, ring a is a substituted 5-to 6-membered heteroaryl. In embodiments, ring A is substituted with R ³⁰Substituted (C) ₃-C ₁₀) Cycloalkyl radicals, by R ³⁰Substituted 5-to 10-membered heterocycloalkyl, by R ³⁰Substituted (C) ₆-C ₁₀) Aryl or by R ³⁰Substituted 5 to 10 membered heteroaryl. In embodiments, ring A is substituted with R ³⁰Substituted (C) ₃-C ₁₀) Cycloalkyl radicals or by R ³⁰Substituted 5 to 10 membered heterocycloalkyl. In embodiments, ring A is substituted with R ³⁰Substituted (C) ₃-C ₁₀) A cycloalkyl group. In embodiments, ring A is substituted with R ³⁰Substituted 3 to 10 membered heterocycloalkyl. In embodiments, ring A is substituted with R ³⁰Substituted (C) ₆-C ₁₀) And (4) an aryl group. In embodiments, ring A is substituted with R ³⁰Substituted 5 to 10 membered heteroaryl. In embodiments, ring A is substituted with R ³⁰Substituted (C) ₃-C ₆) A cycloalkyl group. In embodiments, ring A is substituted with R ³⁰Substituted 3 to 6 membered heterocycloalkyl. In embodiments, ring A is substituted with R ³⁰A substituted phenyl group. In embodiments, ring A is substituted with R ³⁰Substituted naphthyl. In the examplesRing A is by R ³⁰Substituted 5 to 9 membered heteroaryl. In embodiments, ring A is substituted with R ³⁰Substituted 5 to 6 membered heteroaryl. In embodiments, ring A is substituted with R ³⁰Substituted thienyl. In embodiments, ring A is substituted with R ³⁰A substituted phenyl group. In embodiments, ring A is substituted with R ³⁰Substituted benzothienyl. In embodiments, ring A is substituted with R ³⁰Substituted naphthyl. In embodiments, ring A is substituted with R ³⁰Substituted benzofuranyl. In embodiments, ring A is substituted with R ³⁰A substituted furyl group. In embodiments, ring A is substituted with R ³⁰A substituted pyrrolyl group. In embodiments, ring A is substituted with R ³⁰Substituted 2, 3-dihydro-1H-indenyl.

In embodiments, ring a is unsubstituted cycloalkyl. In embodiments, ring a is unsubstituted heterocycloalkyl. In embodiments, ring a is unsubstituted aryl. In embodiments, ring a is unsubstituted heteroaryl. In embodiments, ring a is unsubstituted (C) ₃-C ₁₀) Cycloalkyl, unsubstituted 3-to 10-membered heterocycloalkyl, unsubstituted (C) ₆-C ₁₀) Aryl or unsubstituted 5-to 10-membered heteroaryl. In embodiments, ring a is unsubstituted (C) ₃-C ₁₀) A cycloalkyl group. In embodiments, ring a is unsubstituted 3-to 10-membered heterocycloalkyl. In embodiments, ring a is unsubstituted (C) ₆-C ₁₀) And (4) an aryl group. In embodiments, ring a is an unsubstituted 5-to 10-membered heteroaryl. In embodiments, ring a is unsubstituted (C) ₃-C ₆) A cycloalkyl group. In embodiments, ring a is unsubstituted 3-to 6-membered heterocycloalkyl. In embodiments, ring a is unsubstituted phenyl. In embodiments, ring a is unsubstituted naphthyl. In embodiments, ring a is an unsubstituted 5-to 9-membered heteroaryl. In embodiments, ring a is an unsubstituted 5-to 6-membered heteroaryl. In embodiments, ring a is unsubstituted (C) ₃-C ₁₀) Cycloalkyl, unsubstituted 5-to 10-membered heterocycloalkyl, unsubstituted (C) ₆-C ₁₀) Aryl or unsubstituted 5-to 10-membered heteroaryl. In embodiments, ring a is unsubstituted (C) ₃-C ₁₀) Cycloalkyl radicals or not substituted bySubstituted 5 to 10 membered heterocycloalkyl. In embodiments, ring a is unsubstituted (C) ₃-C ₁₀) A cycloalkyl group. In embodiments, ring a is unsubstituted 3-to 10-membered heterocycloalkyl. In embodiments, ring a is unsubstituted (C) ₆-C ₁₀) And (4) an aryl group. In embodiments, ring a is an unsubstituted 5-to 10-membered heteroaryl. In embodiments, ring a is unsubstituted (C) ₃-C ₆) A cycloalkyl group. In embodiments, ring a is unsubstituted 3-to 6-membered heterocycloalkyl. In embodiments, ring a is unsubstituted phenyl. In embodiments, ring a is unsubstituted naphthyl. In embodiments, ring a is an unsubstituted 5-to 9-membered heteroaryl. In embodiments, ring a is an unsubstituted 5-to 6-membered heteroaryl. In embodiments, ring a is unsubstituted thienyl. In embodiments, ring a is unsubstituted phenyl. In embodiments, ring a is unsubstituted benzothienyl. In embodiments, ring a is unsubstituted naphthyl. In embodiments, ring a is unsubstituted benzofuranyl. In embodiments, ring a is unsubstituted furanyl. In embodiments, ring a is unsubstituted pyrrolyl.

Ring A may be substituted by one R ³⁰And (4) substitution. Ring A may be substituted by two optionally different R ³⁰And (4) substituent substitution. Ring A may be substituted by three optionally different R ³⁰And (4) substituent substitution. Ring A may be substituted by four optionally different R ³⁰And (4) substituent substitution. Ring A may be substituted by five optionally different R ³⁰And (4) substituent substitution. Ring A may be substituted by six optionally different R ³⁰And (4) substituent substitution. Ring A may be substituted with seven optionally different R ³⁰And (4) substituent substitution. The ring A may be substituted by eight optionally different R ³⁰And (4) substituent substitution. Ring A may be substituted by nine optionally different R ³⁰And (4) substituent substitution. Ring A may be substituted by ten optionally different R ³⁰And (4) substituent substitution.

In the examples, L ¹Is a bond, substituted or unsubstituted C ₁-C ₈Alkylene, substituted or unsubstituted 2-to 8-membered heteroalkyl, substituted or unsubstituted C ₃-C ₈Cycloalkylene, substituted or unsubstituted 3-to 8-membered heterocycloalkylene, substituted or unsubstitutedSubstituted phenylene or substituted or unsubstituted 5-to 6-membered heteroarylene. In the examples, L ¹Is a bond.

In the examples, L ¹Is a bond. In the examples, L ¹is-S (O) ₂-. In the examples, L ¹is-NR ⁶-. In the examples, L ¹is-O-. In the examples, L ¹is-S-. In the examples, L ¹is-C (O) -. In the examples, L ¹is-C (O) NR ⁶-. In the examples, L ¹is-NR ⁶C (O) -. In the examples, L ¹is-NR ⁶C (O) NH-. In the examples, L ¹is-NHC (O) NR ⁶-. In the examples, L ¹is-C (O) O-. In the examples, L ¹is-OC (O) -. In the examples, L ¹is-NH-. In the examples, L ¹is-C (O) NH-. In the examples, L ¹is-NHC (O) -. In the examples, L ¹is-NHC (O) NH-. In the examples, L ¹is-CH ₂-. In the examples, L ¹is-OCH ₂-. In the examples, L ¹is-CH ₂O-is formed. In the examples, L ¹is-CH ₂CH ₂-. In the examples, L ¹is-NHCH ₂-. In the examples, L ¹is-CH ₂NH-. In the examples, L ¹Is a bond.

In the examples, L ¹Is a bond, -S (O) ₂-、-NR ⁴-、-O-、-S-、-C(O)-、-C(O)NR ⁴-、-NR ⁴C(O)-、-NR ⁴C(O)NH-、-NHC(O)NR ⁴-, -C (O) O-, -OC (O) -substituted or unsubstituted alkylene (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Substituted or unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), substituted or unsubstituted cycloalkylene (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Substituted or unsubstituted heterocycloalkylene (e.g., 3 to8-, 3-to 6-, 4-to 5-or 5-to 6-membered), substituted or unsubstituted arylene (e.g., C ₆-C ₁₀Or phenyl) or substituted or unsubstituted heteroarylene (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, L ¹Independently substituted or unsubstituted alkylene (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, L ¹Independently substituted alkylene (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, L ¹Independently unsubstituted alkylene (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, L ¹Independently an unsubstituted methylene group. In the examples, L ¹Independently an unsubstituted ethylene group. In the examples, L ¹Independently an unsubstituted propylene group. In the examples, L ¹Independently unsubstituted isopropylidene. In the examples, L ¹Independently an unsubstituted tert-butylidene group. In the examples, L ¹Independently substituted or unsubstituted heteroalkylene (e.g., 2 to 8, 2 to 6,4 to 6, 2 to 3, or 4 to 5 membered). In the examples, L ¹Independently a substituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, L ¹Independently an unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, L ¹Independently is a substituted or unsubstituted cycloalkylene group (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, L ¹Independently is a substituted cycloalkylene group (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In thatIn the examples, L ¹Independently unsubstituted cycloalkylene (e.g. C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, L ¹Independently a substituted or unsubstituted heterocycloalkylene group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, L ¹Independently a substituted heterocycloalkylene group (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered). In the examples, L ¹Independently an unsubstituted heterocycloalkylene group (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered). In the examples, L ¹Independently is a substituted or unsubstituted arylene group (e.g., C) ₆-C ₁₀Or phenyl). In the examples, L ¹Independently substituted arylene (e.g. C) ₆-C ₁₀Or phenyl). In the examples, L ¹Independently unsubstituted arylene (e.g., C) ₆-C ₁₀Or phenyl). In the examples, L ¹Independently a substituted or unsubstituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, L ¹Independently a substituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, L ¹Independently an unsubstituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, L ¹Independently a bond, -S (O) ₂-、-N(R ⁴)-、-O-、-S-、-C(O)-、-C(O)N(R ⁴)-、-N(R ⁴)C(O)-、-N(R ⁴)C(O)NH-、-NHC(O)N(R ⁴) -, -C (O) O-, -OC (O) -or R ³⁵Substituted or unsubstituted alkylene (e.g. C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ³⁵Substituted or unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ³⁵Substituted or unsubstituted cycloalkylene (e.g. C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ³⁵Substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6), with R ³⁵Substituted or unsubstituted arylene (e.g., C) ₆-C ₁₀Or phenylene) or by R ³⁵Substituted or unsubstituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, L ¹Independently a bond, -S (O) ₂-、-N(R ⁴)-、-O-、-S-、-C(O)-、-C(O)N(R ⁴)-、-N(R ⁴)C(O)-、-N(R ⁴)C(O)NH-、-NHC(O)N(R ⁴) -, -C (O) O-, -OC (O) -unsubstituted alkylene (e.g. C ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Unsubstituted heteroalkylene (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), unsubstituted cycloalkylene (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Unsubstituted heterocycloalkylene (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), unsubstituted arylene (e.g., C) ₆-C ₁₀Or phenylene) or unsubstituted heteroarylene (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered). In the examples, L ¹Independently an unsubstituted methylene group. In the examples, L ¹Independently an unsubstituted ethylene group. In the examples, L ¹Independently a methylene group substituted with a methyl group.

R ³⁵Independently is a pendant oxy group, a halogen, -CX ³⁵ ₃、-CHX ³⁵ ₂、-CH ₂X ³⁵、-OCX ³⁵ ₃、-OCH ₂X ³⁵、-OCHX ³⁵ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH, by R ³⁶Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ³⁶Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ³⁶Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ³⁶Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ³⁶Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ³⁶Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ³⁵Independently is a pendant oxy group, a halogen, -CX ³⁵ ₃、-CHX ³⁵ ₂、-CH ₂X ³⁵、-OCX ³⁵ ₃、-OCH ₂X ³⁵、-OCHX ³⁵ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ³⁵Independently is-F, -Cl, -Br or-I. In an embodiment of the present invention,R ³⁵independently an unsubstituted methyl group. In the examples, R ³⁵Independently an unsubstituted ethyl group.

R ³⁶Independently is a pendant oxy group, a halogen, -CX ³⁶ ₃、-CHX ³⁶ ₂、-CH ₂X ³⁶、-OCX ³⁶ ₃、-OCH ₂X ³⁶、-OCHX ³⁶ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、－NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ³⁷Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ³⁷Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ³⁷Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ³⁷Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ³⁷Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ³⁷Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ³⁶Independently is a pendant oxy group, a halogen, -CX ³⁶ ₃、-CHX ³⁶ ₂、-CH ₂X ³⁶、-OCX ³⁶ ₃、-OCH ₂X ³⁶、-OCHX ³⁶ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, notSubstituted alkyl (e.g. C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ³⁶Independently is-F, -Cl, -Br or-I. In the examples, R ³⁶Independently an unsubstituted methyl group. In the examples, R ³⁶Independently an unsubstituted ethyl group.

R ³⁷Independently is a pendant oxy group, a halogen, -CX ³⁷ ₃、-CHX ³⁷ ₂、-CH ₂X ³⁷、-OCX ³⁷ ₃、-OCH ₂X ³⁷、-OCHX ³⁷ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ³⁷Independently is-F, -Cl, -Br or-I. In the examples, R ³⁷Independently an unsubstituted methyl group. In the examples, R ³⁷Independently an unsubstituted ethyl group.

In the examples, R ⁴Independently hydrogen, -CX ⁴ ₃、-CHX ⁴ ₂、-CH ₂X ⁴、-OCX ⁴ ₃、-OCH ₂X ⁴、-OCHX ⁴ ₂、-CN、-C(O)R ^4A、-C(O)OR ^4A、-C(O)NR ^4AR ^4B、-OR ^4ASubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5), substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6 membered).

In the examples, R ⁴Independently hydrogen. In the examples, R ⁴Independently is-CX ⁴ ₃. In the examples, R ⁴Independently is-CHX ⁴ ₂. In the examples, R ⁴Independently is-CH ₂X ⁴. In the examples, R ⁴Independently is-CN. In the examples, R ⁴Independently is-C (O) R ^4A. In the examples, R ⁴Independently is-C (O) -OR ^4A. In the examples, R ⁴Independently is-C (O) NR ^4AR ^4B. In the examples, R ⁴independently-COOH. In the examples, R ⁴Independently is-CONH ₂. In the examples, R ⁴Independently is-CF ₃. In the examples, R ⁴Independently is-CHF ₂. In factIn the examples, R ⁴Independently is-CH ₂F. In the examples, R ⁴Independently is-CH ₃. In the examples, R ⁴Independently is-CH ₂CH ₃. In the examples, R ⁴Independently is-CH ₂CH ₂CH ₃. In the examples, R ⁴Independently is-CH (CH) ₃) ₂. In the examples, R ⁴Independently is-C (CH) ₃) ₃。

In the examples, R ⁴Independently an unsubstituted methyl group. In the examples, R ⁴Independently an unsubstituted ethyl group. In the examples, R ⁴Independently unsubstituted propyl. In the examples, R ⁴Independently unsubstituted isopropyl. In the examples, R ⁴Independently unsubstituted n-propyl. In the examples, R ⁴Independently an unsubstituted butyl group. In the examples, R ⁴Independently unsubstituted n-butyl. In the examples, R ⁴Independently an unsubstituted tert-butyl group. In the examples, R ⁴Independently an unsubstituted pentyl group. In the examples, R ⁴Independently an unsubstituted n-pentyl group. In the examples, R ⁴Independently an unsubstituted hexyl group. In the examples, R ⁴Independently, unsubstituted n-hexyl. In the examples, R ⁴Independently an unsubstituted heptyl group. In the examples, R ⁴Independently an unsubstituted n-heptyl group. In the examples, R ⁴Independently an unsubstituted octyl group. In the examples, R ⁴Independently an unsubstituted n-octyl group. In the examples, R ⁴Independently an unsubstituted benzyl group. In the examples, R ⁴Independently is unsubstituted C ₁-C ₈An alkyl group. In the examples, R ⁴Independently a methyl group substituted with a halogen. In the examples, R ⁴Independently an ethyl group substituted with a halogen. In the examples, R ⁴Independently isopropyl substituted with halogen. In the examples, R ⁴Independently n-propyl substituted with halogen. In the examples, R ⁴Independently n-butyl substituted with halogen. In the examples, R ⁴Independently a tert-butyl group substituted with a halogen. In the examples, R ¹Independently n-pentyl substituted by halogen. In the examples, R ⁴Independently a benzyl group substituted with a halogen. In the examples, R ⁴Independently halogen substituted C ₁-C ₈An alkyl group. In the examples, R ⁴Independently an unsubstituted 2-to 6-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 2-to 7-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 2-to 8-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 2-to 9-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 2-to 10-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 3-to 10-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 4-to 10-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 5-to 10-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 6-to 10-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 7-to 10-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 8-to 10-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 6-to 10-membered heteroalkyl group. In the examples, R ⁴Independently an unsubstituted 7-to 9-membered heteroalkyl group.

In the examples, R ⁴Independently is substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ⁴Independently substituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ⁴Independently unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ⁴Independently is notA substituted methyl group. In the examples, R ⁴Independently an unsubstituted ethyl group. In the examples, R ⁴Independently unsubstituted propyl. In the examples, R ⁴Independently unsubstituted isopropyl. In the examples, R ⁴Independently an unsubstituted tert-butyl group. In the examples, R ⁴Independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5). In the examples, R ⁴Independently a substituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ⁴Independently an unsubstituted heteroalkyl group (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ⁴Independently is substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ⁴Independently is substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ⁴Independently unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ⁴Independently a substituted or unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ⁴Independently a substituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ⁴Independently an unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ⁴Independently is substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl). In the examples, R ⁴Independently is substituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ⁴Independently unsubstituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ⁴Independently substituted or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6). In the examples, R ⁴Independently a substituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ⁴Independently unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R ^4AIndependently hydrogen. In the examples, R ^4AIndependently is-CX ^4A ₃. In the examples, R ^4AIndependently is-CHX ^4A ₂. In the examples, R ^4AIndependently is-CH ₂X ^4A. In the examples, R ^4AIndependently is-CN. In the examples, R ^4Aindependently-COOH. In the examples, R ^4AIndependently is-CONH ₂. In the examples, X ^4AIndependently is-F, -Cl, -Br or-I.

In the examples, R ^4AIndependently is substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^4AIndependently substituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^4AIndependently unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^4AIndependently an unsubstituted methyl group. In the examples, R ^4AIndependently an unsubstituted ethyl group. In the examples, R ^4AIndependently unsubstituted propyl. In the examples, R ^4AIndependently unsubstituted isopropyl. In the examples, R ^4AIndependently an unsubstituted tert-butyl group. In the examples, R ^4AIndependently substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5). In factIn the examples, R ^4AIndependently a substituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^4AIndependently an unsubstituted heteroalkyl group (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^4AIndependently is substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^4AIndependently is substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^4AIndependently unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^4AIndependently a substituted or unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^4AIndependently a substituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^4AIndependently an unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^4AIndependently is substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl). In the examples, R ^4AIndependently is substituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ^4AIndependently unsubstituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ^4AIndependently substituted or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6). In the examples, R ^4AIndependently a substituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^4AIndependently unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R ^4BIndependently hydrogen. In the examples, R ^4BIndependently is-CX ^4B ₃. In the examples, R ^4BIndependently is-CHX ^4B ₂. In the examples, R ^4BIndependently is-CH ₂X ^4B. In the examples, R ^4BIndependently is-CN. In the examples, R ^4Bindependently-COOH. In the examples, R ^4BIndependently is-CONH ₂. In the examples, X ^4BIndependently is-F, -Cl, -Br or-I.

In the examples, R ^4BIndependently is substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^4BIndependently substituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^4BIndependently unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^4BIndependently an unsubstituted methyl group. In the examples, R ^4BIndependently an unsubstituted ethyl group. In the examples, R ^4BIndependently unsubstituted propyl. In the examples, R ^4BIndependently unsubstituted isopropyl. In the examples, R ^4BIndependently an unsubstituted tert-butyl group. In the examples, R ^4BIndependently substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5). In the examples, R ^4BIndependently a substituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^4BIndependently an unsubstituted heteroalkyl group (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^4BIndependently is substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^4BIndependently is substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^4BIndependently unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^4BIndependently a substituted or unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^4BIndependently a substituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^4BIndependently an unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^4BIndependently is substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl). In the examples, R ^4BIndependently is substituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ^4BIndependently unsubstituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ^4BIndependently substituted or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6). In the examples, R ^4BIndependently a substituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^4BIndependently unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BThe substituents may join to form a substituted or unsubstituted heterocycloalkyl group (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BThe substituents may join to form a substituted heterocycloalkyl group (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BThe substituents may join to form an unsubstituted heterocycloalkyl group (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered).

In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BThe substituents may join to form a substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BThe substituents may join to form substituted heteroaryl groups (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BThe substituents may join to form unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R ⁴Independently hydrogen, -CX ⁴ ₃、-CHX ⁴ ₂、-CH ₂X ⁴、-CN、-COOH、-CONH ₂Quilt R ²⁹Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ²⁹Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ²⁹Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ²⁹Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ²⁹Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ²⁹Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ⁴Independently hydrogen, -CX ⁴ ₃、-CHX ⁴ ₂、-CH ₂X ⁴、-CN、-COOH、-CONH ₂Unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Is unsubstituted, is not substitutedHeteroalkyl (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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ⁴Independently is-F, -Cl, -Br or-I. In the examples, R ⁴Independently hydrogen. In the examples, R ⁴Independently an unsubstituted methyl group. In the examples, R ⁴Independently an unsubstituted ethyl group.

R ²⁹Independently is a pendant oxy group, a halogen, -CX ²⁹ ₃、-CHX ²⁹ ₂、-CH ₂X ²⁹、-OCX ²⁹ ₃、-OCH ₂X ²⁹、-OCHX ²⁹ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ³⁰Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ³⁰Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ³⁰Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ³⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ³⁰Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ³⁰Substituted or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9 membered)Or 5 to 6 members). In the examples, R ²⁹Independently is a pendant oxy group, a halogen, -CX ²⁹ ₃、-CHX ²⁹ ₂、-CH ₂X ²⁹、-OCX ²⁹ ₃、-OCH ₂X ²⁹、-OCHX ²⁹ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ²⁹Independently is-F, -Cl, -Br or-I. In the examples, R ²⁹Independently an unsubstituted methyl group. In the examples, R ²⁹Independently an unsubstituted ethyl group. In the examples, R ²⁹Independently unsubstituted phenyl.

R ³⁰Independently is a pendant oxy group, a halogen, -CX ³⁰ ₃、-CHX ³⁰ ₂、-CH ₂X ³⁰、-OCX ³⁰ ₃、-OCH ₂X ³⁰、-OCHX ³⁰ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ³¹Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ³¹Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ³¹Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ³¹Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ³¹Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ³¹Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ³⁰Independently is a pendant oxy group, a halogen, -CX ³⁰ ₃、-CHX ³⁰ ₂、-CH ₂X ³⁰、-OCX ³⁰ ₃、-OCH ₂X ³⁰、-OCHX ³⁰ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ³⁰Independently is-F, -Cl, -Br or-I. In the examples, R ³⁰Independently an unsubstituted methyl group. In the examples, R ³⁰Independently an unsubstituted ethyl group.

R ³¹Independently is a pendant oxy group, a halogen, -CX ³¹ ₃、-CHX ³¹ ₂、-CH ₂X ³¹、-OCX ³¹ ₃、-OCH ₂X ³¹、-OCHX ³¹ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ³¹Independently is-F, -Cl, -Br or-I. In the examples, R ³¹Independently an unsubstituted methyl group. In the examples, R ³¹Independently an unsubstituted ethyl group.

In the examples, R ^4AIndependently hydrogen, -CX ^4A ₃、-CHX ^4A ₂、-CH ₂X ^4A、-CN、-COOH、-CONH ₂Quilt R ^29ASubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^29ASubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^29ASubstituted or not substitutedSubstituted cycloalkyl (e.g. C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^29ASubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^29ASubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^29ASubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^4AIndependently hydrogen, -CX ^4A ₃、-CHX ^4A ₂、-CH ₂X ^4A、-CN、-COOH、-CONH ₂Unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^4AIndependently is-F, -Cl, -Br or-I. In the examples, R ^4AIndependently hydrogen. In the examples, R ^4AIndependently an unsubstituted methyl group. In the examples, R ^4AIndependently an unsubstituted ethyl group.

In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BThe substituents may optionally be joined to form a group represented by R ^29ASubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6) or by R ^29ASubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 6-membered)4-to 5-or 5-to 6-membered) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BThe substituents may optionally be joined to form a group represented by R ^29ASubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6 membered). In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered).

R ^29AIndependently is a pendant oxy group, a halogen, -CX ^29A ₃、-CHX ^29A ₂、-CH ₂X ^29A、-OCX ^29A ₃、-OCH ₂X ^29A、-OCHX ^29A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^30ASubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^30ASubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^30ASubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^30ASubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^30ASubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^30ASubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^29AIndependently is a pendant oxy group, a halogen, -CX ^29A ₃、-CHX ^29A ₂、-CH ₂X ^29A、-OCX ^29A ₃、-OCH ₂X ^29A、-OCHX ^29A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^29AIndependently is-F, -Cl, -Br or-I. In the examples, R ^29AIndependently an unsubstituted methyl group. In the examples, R ^29AIndependently an unsubstituted ethyl group.

R ^30AIndependently is a pendant oxy group, a halogen, -CX ^30A ₃、-CHX ^30A ₂、-CH ₂X ^30A、-OCX ^30A ₃、-OCH ₂X ^30A、-OCHX ^30A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^31ASubstituted or unsubstituted alkyl (e.g. C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^31ASubstituted or unsubstitutedSubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5) with R ^31ASubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^31ASubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^31ASubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^31ASubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^30AIndependently is a pendant oxy group, a halogen, -CX ^30A ₃、-CHX ^30A ₂、-CH ₂X ^30A、-OCX ^30A ₃、-OCH ₂X ^30A、-OCHX ^30A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^30AIndependently is-F, -Cl, -Br or-I. In the examples, R ^30AIndependently an unsubstituted methyl group. In the examples, R ^30AIndependently an unsubstituted ethyl group.

R ^31AIndependently is a pendant oxy group, halogen、-CX ^31A ₃、-CHX ^31A ₂、-CH ₂X ^31A、-OCX ^31A ₃、-OCH ₂X ^31A、-OCHX ^31A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^31AIndependently is-F, -Cl, -Br or-I. In the examples, R ^31AIndependently an unsubstituted methyl group. In the examples, R ^31AIndependently an unsubstituted ethyl group.

In the examples, R ^4BIndependently hydrogen, -CX ^4B ₃、-CHX ^4B ₂、-CH ₂X ^4B、-CN、-COOH、-CONH ₂Quilt R ^29BSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^29BSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^29BSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^29BSubstituted or unsubstitutedSubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6 membered), with R ^29BSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^29BSubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^4BIndependently hydrogen, -CX ^4B ₃、-CHX ^4B ₂、-CH ₂X ^4B、-CN、-COOH、-CONH ₂Unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^4BIndependently is-F, -Cl, -Br or-I. In the examples, R ^4BIndependently hydrogen. In the examples, R ^4BIndependently an unsubstituted methyl group. In the examples, R ^4BIndependently an unsubstituted ethyl group.

In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BThe substituents may optionally be joined to form a group represented by R ^29BSubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6) or by R ^29BSubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BSubstituent groupOptionally joined to form a quilt R ^29BSubstituted or substituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6 membered). In embodiments, R is bonded to the same nitrogen atom ^4AAnd R ^4BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered).

R ^29BIndependently is a pendant oxy group, a halogen, -CX ^29B ₃、-CHX ^29B ₂、-CH ₂X ^29B、-OCX ^29B ₃、-OCH ₂X ^29B、-OCHX ^29B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^30BSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^30BSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^30BSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^30BSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^30BSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^30BSubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^29BIndependently is a pendant oxy group, a halogen, -CX ^29B ₃、-CHX ^29B ₂、-CH ₂X ^29B、-OCX ^29B ₃、-OCH ₂X ^29B、-OCHX ^29B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^29BIndependently is-F, -Cl, -Br or-I. In the examples, R ^29BIndependently an unsubstituted methyl group. In the examples, R ^29BIndependently an unsubstituted ethyl group.

R ^30BIndependently is a pendant oxy group, a halogen, -CX ^30B ₃、-CHX ^30B ₂、-CH ₂X ^30B、-OCX ^30B ₃、-OCH ₂X ^30B、-OCHX ^30B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^31BSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^31BSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^31BSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^31BSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^31BSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^31BSubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^30BIndependently is a pendant oxy group, a halogen, -CX ^30B ₃、-CHX ^30B ₂、-CH ₂X ^30B、-OCX ^30B ₃、-OCH ₂X ^30B、-OCHX ^30B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^30BIndependently is-F, -Cl, -Br or-I. In the examples, R ^30BIndependently an unsubstituted methyl group. In the examples, R ^30BIndependently an unsubstituted ethyl group.

R ^31BIndependently is a pendant oxy group, a halogen, -CX ^31B ₃、-CHX ^31B ₂、-CH ₂X ^31B、-OCX ^31B ₃、-OCH ₂X ^31B、-OCHX ^31B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^31BIndependently is-F, -Cl, -Br or-I. In the examples, R ^31BIndependently an unsubstituted methyl group. In the examples, R ^31BIndependently an unsubstituted ethyl group.

In the examples, L ²is-NR ⁵-or substituted or unsubstituted heterocycloalkyl, including the ring nitrogen bonded directly to E. In the examples, L ²is-NR ⁵-。

In the examples, L ²Is a bond. In the examples, L ²is-S (O) ₂-. In the examples, L ²is-NR ⁵-. In the examples, L ²is-O-. In the examples, L ²is-S-. In the examples, L ²is-C (O) -. In the examples, L ²is-C (O) NR ⁵-. In the examples, L ²is-NR ⁵C (O) -. In the examples, L ²is-NR ⁵C (O) NH-. In the examples, L ²is-NHC (O) NR ⁵-. In the examples, L ²is-C (O) O-. In the examples, L ²is-OC (O) -. In the examples, L ²is-NH-. In the examples, L ²is-C (O) NH-. In the examples, L ²is-NHC (O) -. In the examples, L ²is-NHC (O) NH-. In the examples, L ²is-CH ₂-. In the examples, L ²is-OCH ₂-. In the examples, L ²is-CH ₂O-is formed. In the examples, L ²is-NHCH ₂-. In the examples, L ²is-CH ₂NH-。

In the examples, L ²Is a bond, -S (O) ₂-、-NR ⁵-、-O-、-S-、-C(O)-、-C(O)NR ⁵-、-NR ⁴C(O)-、-NR ⁵C(O)NH-、-NHC(O)NR ⁵-, -C (O) O-, -OC (O) -substituted or unsubstituted alkylene (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Substituted or unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), substituted or unsubstituted cycloalkylene (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Substituted or unsubstituted heterocycloalkylene (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted or unsubstituted arylene (e.g., C) ₆-C ₁₀Or phenyl) or substituted or unsubstituted heteroarylene (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered).

In the examples, L ²Independently substituted or unsubstituted alkylene (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, L ²Independently substituted alkylene (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, L ²Independently substituted alkylene (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, L ²Independently not takenA substituted methylene group. In the examples, L ²Independently an unsubstituted ethylene group. In the examples, L ²Independently an unsubstituted propylene group. In the examples, L ²Independently unsubstituted isopropylidene. In the examples, L ²Independently an unsubstituted tert-butylidene group. In the examples, L ²Independently substituted or unsubstituted heteroalkylene (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5 membered). In the examples, L ²Independently a substituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, L ²Independently an unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, L ²Independently is a substituted or unsubstituted cycloalkylene group (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, L ²Independently is a substituted cycloalkylene group (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, L ²Independently unsubstituted cycloalkylene (e.g. C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, L ²Independently a substituted or unsubstituted heterocycloalkylene group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, L ²Independently a substituted heterocycloalkylene group (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered). In the examples, L ²Independently an unsubstituted heterocycloalkylene group (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered). In the examples, L ²Independently is a substituted or unsubstituted arylene group (e.g., C) ₆-C ₁₀Or phenyl). In the examples, L ²Independently substituted arylene (e.g. C) ₆-C ₁₀Or phenyl). In the examples, L ²Independently is notSubstituted arylene radicals (e.g. C) ₆-C ₁₀Or phenyl). In the examples, L ²Independently a substituted or unsubstituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, L ²Independently a substituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, L ²Independently an unsubstituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, L ²Independently a bond, -S (O) ₂-、-N(R ⁵)-、-O-、-S-、-C(O)-、-C(O)N(R ⁵)-、-N(R ⁵)C(O)-、-N(R ⁵)C(O)NH-、-NHC(O)N(R ⁵) -, -C (O) O-, -OC (O) -or R ³⁸Substituted or unsubstituted alkylene (e.g. C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ³⁸Substituted or unsubstituted heteroalkylene (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ³⁸Substituted or unsubstituted cycloalkylene (e.g. C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ³⁸Substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6), with R ³⁸Substituted or unsubstituted arylene (e.g., C) ₆-C ₁₀Or phenylene) or by R ³⁸Substituted or unsubstituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, L ²Independently a bond, -S (O) ₂-、-N(R ⁵)-、-O-、-S-、-C(O)-、-C(O)N(R ⁵)-、-N(R ⁵)C(O)-、-N(R ⁵)C(O)NH-、-NHC(O)N(R ⁵) -, -C (O) O-, -OC (O) -unsubstituted alkylene (e.g. C ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Unsubstituted heteroalkylene (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), unsubstituted cycloalkylene (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Unsubstituted heterocycloalkylene (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), unsubstituted arylene (e.g., C) ₆-C ₁₀Or phenylene) or unsubstituted heteroarylene (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered). In the examples, L ²Independently an unsubstituted methylene group. In the examples, L ²Independently an unsubstituted ethylene group. In the examples, L ²Independently a methylene group substituted with a methyl group.

R ³⁸Independently is a pendant oxy group, a halogen, -CX ³⁸ ₃、-CHX ³⁸ ₂、-CH ₂X ³⁸、-OCX ³⁸ ₃、-OCH ₂X ³⁸、-OCHX ³⁸ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ³⁹Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ³⁹Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ³⁹Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ³⁹Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ³⁹Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ³⁹Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ³⁸Independently is a pendant oxy group, a halogen, -CX ³⁸ ₃、-CHX ³⁸ ₂、-CH ₂X ³⁸、-OCX ³⁸ ₃、-OCH ₂X ³⁸、-OCHX ³⁸ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ³⁸Independently is-F, -Cl, -Br or-I. In the examples, R ³⁸Independently an unsubstituted methyl group. In the examples, R ³⁸Independently an unsubstituted ethyl group.

R ³⁹Independently is a pendant oxy group, a halogen, -CX ³⁹ ₃、-CHX ³⁹ ₂、-CH ₂X ³⁹、-OCX ³⁹ ₃、-OCH ₂X ³⁹、-OCHX ³⁹ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ⁴⁰Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ⁴⁰Substituted or unsubstitutedIs (e.g., 2-to 8-membered, 2-to 6-membered, 4-to 6-membered, 2-to 3-membered, or 4-to 5-membered), is R ⁴⁰Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ⁴⁰Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ⁴⁰Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ⁴⁰Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ³⁹Independently is a pendant oxy group, a halogen, -CX ³⁹ ₃、-CHX ³⁹ ₂、-CH ₂X ³⁹、-OCX ³⁹ ₃、-OCH ₂X ³⁹、-OCHX ³⁹ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ³⁹Independently is-F, -Cl, -Br or-I. In the examples, R ³⁹Independently an unsubstituted methyl group. In the examples, R ³⁹Independently an unsubstituted ethyl group.

R ⁴⁰Independently is a pendant oxy group, a halogen, -CX ⁴⁰ ₃、-CHX ⁴⁰ ₂、-CH ₂X ⁴⁰、-OCX ⁴⁰ ₃、-OCH ₂X ⁴⁰、-OCHX ⁴⁰ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ⁴⁰Independently is-F, -Cl, -Br or-I. In the examples, R ⁴⁰Independently an unsubstituted methyl group. In the examples, R ⁴⁰Independently an unsubstituted ethyl group.

In the examples, R ⁵Is hydrogen, substituted or unsubstituted C ₁-C ₆Alkyl or substituted or unsubstituted 2 to 6 membered heteroalkyl. In the examples, R ⁵Is hydrogen or unsubstituted C ₁-C ₃An alkyl group. In the examples, R ⁵Is hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted hexyl or unsubstituted benzyl. In the examples, R ⁵Is hydrogen.

In the examples, R ⁵Independently an unsubstituted methyl group. In the examples, R ⁵Independently an unsubstituted ethyl group. In the examples, R ⁵Independently unsubstituted propyl. In the examples, R ⁵Independently is unsubstituted heteroAnd (4) propyl. In the examples, R ⁵Independently unsubstituted n-propyl. In the examples, R ⁵Independently an unsubstituted butyl group. In the examples, R ⁵Independently unsubstituted n-butyl. In the examples, R ⁵Independently an unsubstituted tert-butyl group. In the examples, R ⁵Independently an unsubstituted pentyl group. In the examples, R ⁵Independently an unsubstituted n-pentyl group. In the examples, R ⁵Independently an unsubstituted hexyl group. In the examples, R ⁵Independently, unsubstituted n-hexyl. In the examples, R ⁵Independently an unsubstituted heptyl group. In the examples, R ⁵Independently an unsubstituted n-heptyl group. In the examples, R ⁵Independently an unsubstituted octyl group. In the examples, R ⁵Independently an unsubstituted n-octyl group. In the examples, R ⁵Independently an unsubstituted benzyl group. In the examples, R ⁵Independently is unsubstituted C ₁-C ₈An alkyl group. In the examples, R ⁵Independently a methyl group substituted with a halogen. In the examples, R ⁵Independently an ethyl group substituted with a halogen. In the examples, R ⁵Independently isopropyl substituted with halogen. In the examples, R ⁵Independently n-propyl substituted with halogen. In the examples, R ⁵Independently n-butyl substituted with halogen. In the examples, R ⁵Independently a tert-butyl group substituted with a halogen. In the examples, R ¹Independently n-pentyl substituted by halogen. In the examples, R ⁵Independently a benzyl group substituted with a halogen. In the examples, R ⁵Independently C substituted by halogen ₁-C ₈An alkyl group. In the examples, R ⁵Independently an unsubstituted 2-to 6-membered heteroalkyl group. In the examples, R ⁵Independently an unsubstituted 2-to 7-membered heteroalkyl group. In the examples, R ⁵Independently an unsubstituted 2-to 8-membered heteroalkyl group. In the examples, R ⁵Independently an unsubstituted 2-to 9-membered heteroalkyl group. In the examples, R ⁵Independently is unsubstituted 2 to 1A 0 membered heteroalkyl group. In the examples, R ⁵Independently an unsubstituted 3-to 10-membered heteroalkyl group. In the examples, R ⁵Independently an unsubstituted 4-to 10-membered heteroalkyl group. In the examples, R ⁵Independently an unsubstituted 5-to 10-membered heteroalkyl group. In the examples, R ⁵Independently an unsubstituted 6-to 10-membered heteroalkyl group. In the examples, R ⁵Independently an unsubstituted 7-to 10-membered heteroalkyl group. In the examples, R ⁵Independently an unsubstituted 8-to 10-membered heteroalkyl group. In the examples, R ⁵Independently an unsubstituted 6-to 10-membered heteroalkyl group. In the examples, R ⁵Independently an unsubstituted 7-to 9-membered heteroalkyl group.

In the examples, R ⁵Independently hydrogen, -CX ⁵ ₃、-CHX ⁵ ₂、-CH ₂X ⁵、-OCX ⁵ ₃、-OCH ₂X ⁵、-OCHX ⁵ ₂、-CN、-C(O)R ^5A、-C(O)OR ^5A、-C(O)NR ^5AR ^5B、-OR ^5ASubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5), substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6 membered).

In the examples, R ⁵Independently hydrogen. In the examples, R ⁵Independently is-CX ⁵ ₃. In the examples, R ⁵Independently is-CHX ⁵ ₂. In the examples, R ⁵Independently is-CH ₂X ⁵. In the examples，R ⁵Independently is-CN. In the examples, R ⁵Independently is-C (O) R ^5A. In the examples, R ⁵Independently is-C (O) -OR ^5A. In the examples, R ⁵Independently is-C (O) NR ^5AR ^5B. In the examples, R ⁵independently-COOH. In the examples, R ⁵Independently is-CONH ₂. In the examples, R ⁵Independently is-CF ₃. In the examples, R ⁵Independently is-CHF ₂. In the examples, R ⁵Independently is-CH ₂F. In the examples, R ⁵Independently is-CH ₃. In the examples, R ⁵Independently is-CH ₂CH ₃. In the examples, R ⁵Independently is-CH ₂CH ₂CH ₃. In the examples, R ⁵Independently is-CH (CH) ₃) ₂. In the examples, R ⁵Independently is-C (CH) ₃) ₃。

In the examples, R ⁵Independently is substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ⁵Independently substituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ⁵Independently unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ⁵Independently an unsubstituted methyl group. In the examples, R ⁵Independently an unsubstituted ethyl group. In the examples, R ⁵Independently unsubstituted propyl. In the examples, R ⁵Independently unsubstituted isopropyl. In the examples, R ⁵Independently an unsubstituted tert-butyl group. In the examples, R ⁵Independently substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5). In the implementation ofIn the examples, R ⁵Independently a substituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ⁵Independently an unsubstituted heteroalkyl group (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ⁵Independently is substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ⁵Independently is substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ⁵Independently unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ⁵Independently a substituted or unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ⁵Independently a substituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ⁵Independently an unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ⁵Independently is substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl). In the examples, R ⁵Independently is substituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ⁵Independently unsubstituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ⁵Independently substituted or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6). In the examples, R ⁵Independently a substituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ⁵Independently unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R ^5AIndependently of each otherIs hydrogen. In the examples, R ^5AIndependently is-CX ^5A ₃. In the examples, R ^5AIndependently is-CHX ^5A ₂. In the examples, R ^5AIndependently is-CH ₂X ^5A. In the examples, R ^5AIndependently is-CN. In the examples, R ^5Aindependently-COOH. In the examples, R ^5AIndependently is-CONH ₂. In the examples, X ^5AIndependently is-F, -Cl, -Br or-I.

In the examples, R ^5AIndependently is substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^5AIndependently substituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^5AIndependently unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^5AIndependently an unsubstituted methyl group. In the examples, R ^5AIndependently an unsubstituted ethyl group. In the examples, R ^5AIndependently unsubstituted propyl. In the examples, R ^5AIndependently unsubstituted isopropyl. In the examples, R ^5AIndependently an unsubstituted tert-butyl group. In the examples, R ^5AIndependently substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5). In the examples, R ^5AIndependently a substituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^5AIndependently an unsubstituted heteroalkyl group (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^5AIndependently is substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^5AIndependently is substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^5AIndependently unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^5AIndependently a substituted or unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^5AIndependently a substituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^5AIndependently an unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^5AIndependently is substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl). In the examples, R ^5AIndependently is substituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ^5AIndependently unsubstituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ^5AIndependently substituted or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6). In the examples, R ^5AIndependently a substituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^5AIndependently unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R ^5BIndependently hydrogen. In the examples, R ^5BIndependently is-CX ^5B ₃. In the examples, R ^5BIndependently is-CHX ^5B ₂. In the examples, R ^5BIndependently is-CH ₂X ^5B. In the examples, R ^5BIndependently is-CN. In the examples, R ^5Bindependently-COOH. In the examples, R ^5BIndependently is-CONH ₂. In the examples, X ^5BIndependently is-F, -Cl, -Br or-I.

In the examples, R ^5BIndependently is substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^5BIndependently substituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^5BIndependently unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂). In the examples, R ^5BIndependently an unsubstituted methyl group. In the examples, R ^5BIndependently an unsubstituted ethyl group. In the examples, R ^5BIndependently unsubstituted propyl. In the examples, R ^5BIndependently unsubstituted isopropyl. In the examples, R ^5BIndependently an unsubstituted tert-butyl group. In the examples, R ^5BIndependently substituted or unsubstituted heteroalkyl (e.g., 2 to 8, 2 to 6, 4 to 6, 2 to 3, or 4 to 5). In the examples, R ^5BIndependently a substituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^5BIndependently an unsubstituted heteroalkyl group (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered). In the examples, R ^5BIndependently is substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^5BIndependently is substituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples, R ^5BIndependently unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆). In the examples，R ^5BIndependently a substituted or unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^5BIndependently a substituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^5BIndependently an unsubstituted heterocycloalkyl group (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6). In the examples, R ^5BIndependently is substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl). In the examples, R ^5BIndependently is substituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ^5BIndependently unsubstituted aryl (e.g. C) ₆-C ₁₀Or phenyl). In the examples, R ^5BIndependently substituted or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6). In the examples, R ^5BIndependently a substituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^5BIndependently unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BThe substituents may join to form a substituted or unsubstituted heterocycloalkyl group (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BThe substituents may join to form a substituted heterocycloalkyl group (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BThe substituents may join to form an unsubstituted heterocycloalkyl group (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered).

In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BThe substituents may join to form a substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BSubstituent groupMay join to form substituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^5AAnd R ^5BThe substituents bonded to the same nitrogen atom may join to form an unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered).

In the examples, R ⁵Independently hydrogen, -CX ⁵ ₃、-CHX ⁵ ₂、-CH ₂X ⁵、-CN、-COOH、-CONH ₂Quilt R ³²Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ³²Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ³²Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ³²Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ³²Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ³²Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ⁵Independently hydrogen, -CX ⁵ ₃、-CHX ⁵ ₂、-CH ₂X ⁵、-CN、-COOH、-CONH ₂Unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 96-membered). X ⁵Independently is-F, -Cl, -Br or-I. In the examples, R ⁵Independently hydrogen. In the examples, R ⁵Independently an unsubstituted methyl group. In the examples, R ⁵Independently an unsubstituted ethyl group.

R ³²Independently is a pendant oxy group, a halogen, -CX ³² ₃、-CHX ³² ₂、-CH ₂X ³²、-OCX ³² ₃、-OCH ₂X ³²、-OCHX ³² ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ³³Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ³³Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ³³Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ³³Substituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ³³Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ³³Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ³²Independently is a pendant oxy group, a halogen, -CX ³² ₃、-CHX ³² ₂、-CH ₂X ³²、-OCX ³² ₃、-OCH ₂X ³²、-OCHX ³² ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ³²Independently is-F, -Cl, -Br or-I. In the examples, R ³²Independently an unsubstituted methyl group. In the examples, R ³²Independently an unsubstituted ethyl group.

R ³³Independently is a pendant oxy group, a halogen, -CX ³³ ₃、-CHX ³³ ₂、-CH ₂X ³³、-OCX ³³ ₃、-OCH ₂X ³³、-OCHX ³³ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ³⁴Substituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ³⁴Substituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ³⁴Substituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ³⁴Substituted or unsubstituted heterocycloalkyl (e.g. substituted or unsubstituted3 to 8, 3 to 6, 4 to 5, or 5 to 6), by R ³⁴Substituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ³⁴Substituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ³³Independently is a pendant oxy group, a halogen, -CX ³³ ₃、-CHX ³³ ₂、-CH ₂X ³³、-OCX ³³ ₃、-OCH ₂X ³³、-OCHX ³³ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ³³Independently is-F, -Cl, -Br or-I. In the examples, R ³³Independently an unsubstituted methyl group. In the examples, R ³³Independently an unsubstituted ethyl group.

R ³⁴Independently is a pendant oxy group, a halogen, -CX ³⁴ ₃、-CHX ³⁴ ₂、-CH ₂X ³⁴、-OCX ³⁴ ₃、-OCH ₂X ³⁴、-OCHX ³⁴ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、－NHNH ₂、－ONH ₂、－NHC＝(O)NHNH ₂、－NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ³⁴Independently is-F, -Cl, -Br or-I. In the examples, R ³⁴Independently an unsubstituted methyl group. In the examples, R ³⁴Independently an unsubstituted ethyl group.

In the examples, R ^5AIndependently hydrogen, -CX ^5A ₃、-CHX ^5A ₂、-CH ₂X ^5A、-CN、-COOH、-CONH ₂Quilt R ^32ASubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^32ASubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^32ASubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^32ASubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^32ASubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^32ASubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^5AIndependently hydrogen, -CX ^5A ₃、-CHX ^5A ₂、-CH ₂X ^5A、-CN、-COOH、-CONH ₂Unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^5AIndependently is-F, -Cl, -Br or-I. In the examples, R ^5AIndependently hydrogen. In the examples, R ^5AIndependently an unsubstituted methyl group. In the examples, R ^5AIndependently an unsubstituted ethyl group.

In the examples, R ^5Aand R ^5BThe substituents being bonded to the same nitrogen atom optionally joined to form R ^32ASubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6) or by R ^32ASubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BThe substituents may optionally be joined to form a group represented by R ^32ASubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6 membered). In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-membered)To 6-membered).

R ^32AIndependently is a pendant oxy group, a halogen, -CX ^32A ₃、-CHX ^32A ₂、-CH ₂X ^32A、-OCX ^32A ₃、-OCH ₂X ^32A、-OCHX ^32A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^33ASubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^33ASubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^33ASubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^33ASubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^33ASubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^33ASubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^32AIndependently is a pendant oxy group, a halogen, -CX ^32A ₃、-CHX ^32A ₂、-CH ₂X ^32A、-OCX ^32A ₃、-OCH ₂X ^32A、-OCHX ^32A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^32AIndependently is-F, -Cl, -Br or-I. In the examples, R ^32AIndependently an unsubstituted methyl group. In the examples, R ^32AIndependently an unsubstituted ethyl group.

R ^33AIndependently is a pendant oxy group, a halogen, -CX ^33A ₃、-CHX ^33A ₂、-CH ₂X ^33A、-OCX ^33A ₃、-OCH ₂X ^33A、-OCHX ^33A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^34ASubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^34ASubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^34ASubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^34ASubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^34ASubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^34ASubstituted or unsubstituted(ii) heteroaryl (e.g., 5 to 10, 5 to 9, or 5 to 6). In the examples, R ^33AIndependently is a pendant oxy group, a halogen, -CX ^33A ₃、-CHX ^33A ₂、-CH ₂X ^33A、-OCX ^33A ₃、-OCH ₂X ^33A、-OCHX ^33A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^33AIndependently is-F, -Cl, -Br or-I. In the examples, R ^33AIndependently an unsubstituted methyl group. In the examples, R ^33AIndependently an unsubstituted ethyl group.

R ^34AIndependently is a pendant oxy group, a halogen, -CX ^34A ₃、-CHX ^34A ₂、-CH ₂X ^34A、-OCX ^34A ₃、-OCH ₂X ^34A、-OCHX ^34A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl(e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^34AIndependently is-F, -Cl, -Br or-I. In the examples, R ^34AIndependently an unsubstituted methyl group. In the examples, R ^34AIndependently an unsubstituted ethyl group.

In the examples, R ^5BIndependently hydrogen, -CX ^5B ₃、-CHX ^5B ₂、-CH ₂X ^5B、-CN、-COOH、-CONH ₂Quilt R ^32BSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^32BSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^32BSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^32BSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^32BSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^32BSubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^5BIndependently hydrogen, -CX ^5B ₃、-CHX ^5B ₂、-CH ₂X ^5B、-CN、-COOH、-CONH ₂Unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^5BIndependently is-F, -Cl, -Br or-I. In the examples, R ^5BIndependently hydrogen. In the examples, R ^5BIndependently an unsubstituted methyl group. In the examples, R ^5BIndependently an unsubstituted ethyl group.

In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BThe substituents may optionally be joined to form a group represented by R ^32BSubstituted or unsubstituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6) or by R ^32BSubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered) or unsubstituted heteroaryl (e.g., 5-to 10-membered, 5-to 9-membered, or 5-to 6-membered). In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BThe substituents may optionally be joined to form a group represented by R ^32BSubstituted or substituted heterocycloalkyl (e.g., 3 to 8, 3 to 6, 4 to 5, or 5 to 6 membered). In embodiments, R is bonded to the same nitrogen atom ^5AAnd R ^5BSubstituents may optionally join to form unsubstituted heterocycloalkyl (e.g., 3-to 8-, 3-to 6-, 4-to 5-, or 5-to 6-membered).

R ^32BIndependently is a pendant oxy group, a halogen, -CX ^32B ₃、-CHX ^32B ₂、-CH ₂X ^32B、-OCX ^32B ₃、-OCH ₂X ^32B、-OCHX ^32B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、－NHC＝(O)NHNH ₂、－NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^33BSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^33BSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^33BSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^33BSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^33BSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^33BSubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^32BIndependently is a pendant oxy group, a halogen, -CX ^32B ₃、-CHX ^32B ₂、-CH ₂X ^32B、-OCX ^32B ₃、-OCH ₂X ^32B、-OCHX ^32B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、－NHNH ₂、－ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^32BIndependently is-F, -Cl, -Br or-I. In the examples, R ^32BIndependently an unsubstituted methyl group. In the examples, R ^32BIndependently an unsubstituted ethyl group.

R ^33BIndependently is a pendant oxy group, a halogen, -CX ^33B ₃、-CHX ^33B ₂、-CH ₂X ^33B、-OCX ^33B ₃、-OCH ₂X ^33B、-OCHX ^33B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, by R ^34BSubstituted or unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Quilt R ^34BSubstituted or unsubstituted heteroalkyl (e.g., 2-to 8-, 2-to 6-, 4-to 6-, 2-to 3-, or 4-to 5-membered), with R ^34BSubstituted or unsubstituted cycloalkyl (e.g., C) ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Quilt R ^34BSubstituted or unsubstituted heterocycloalkyl (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), with R ^34BSubstituted or unsubstituted aryl (e.g., C) ₆-C ₁₀Or phenyl) or by R ^34BSubstituted or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). In the examples, R ^33BIndependently is a pendant oxy group, a halogen, -CX ^33B ₃、-CHX ^33B ₂、-CH ₂X ^33B、-OCX ^33B ₃、-OCH ₂X ^33B、-OCHX ^33B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^33BIndependently is-F, -Cl, -Br or-I. In the examples, R ^33BIndependently an unsubstituted methyl group. In the examples, R ^33BIndependently an unsubstituted ethyl group.

R ^34BIndependently is a pendant oxy group, a halogen, -CX ^34B ₃、-CHX ^34B ₂、-CH ₂X ^34B、-OCX ^34B ₃、-OCH ₂X ^34B、-OCHX ^34B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H. -NHC ═ (O) H, -NHC (O) -OH, -NHOH, unsubstituted alkyl (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) 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-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) 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-C ₁₀Or phenyl) or unsubstituted heteroaryl (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). X ^34BIndependently is-F, -Cl, -Br or-I. In the examples, R ^34BIndependently an unsubstituted methyl group. In the examples, R ^34BIndependently an unsubstituted ethyl group.

In an embodiment, X is-F. In embodiments, X is-Cl. In the examples, X is-Br. In an embodiment, X is-I. In the examples, X ¹is-F. In the examples, X ¹is-Cl. In the examples, X ¹is-Br. In the examples, X ¹is-I. In the examples, X ²is-F. In the examples, X ²is-Cl. In the examples, X ²is-Br. In the examples, X ²is-I. In the examples, X ⁴is-F. In the examples, X ⁴is-Cl. In the examples, X ⁴is-Br. In the examples, X ⁴is-I. In the examples, X ⁵is-F. In the examples, X ⁵is-Cl. In the examples, X ⁵is-Br. In the examples, X ⁵is-I.

In an embodiment, n1 is 0. In an embodiment, n1 is 1. In an embodiment, n1 is 2. In an embodiment, n1 is 3. In an embodiment, n1 is 4. In an embodiment, n2 is 0. In an embodiment, n2 is 1. In an embodiment, n2 is 2. In an embodiment, n2 is 3. In an embodiment, n2 is 4. In an embodiment, n4 is 0. In an embodiment, n4 is 1. In an embodiment, n4 is 2. In an embodiment, n4 is 3. In an embodiment, n4 is 4. In an embodiment, n5 is 0. In an embodiment, n5 is 1. In an embodiment, n5 is 2. In an embodiment, n5 is 3. In an embodiment, n5 is 4.

In an embodiment, m1 is 1. In an embodiment, m1 is 2. In an embodiment, m2 is 1. In an embodiment, m2 is 2. In an embodiment, m4 is 1. In an embodiment, m4 is 2. In an embodiment, m5 is 1. In an embodiment, m5 is 2.

In an embodiment, v1 is 1. In an embodiment, v1 is 2. In an embodiment, v2 is 1. In an embodiment, v2 is 2. In an embodiment, v4 is 1. In an embodiment, v4 is 2. In an embodiment, v5 is 1. In an embodiment, v5 is 2.

In embodiments, E is a covalent cysteine modification moiety.

In an embodiment, E is:

R ¹⁵independently hydrogen, halogen, CX ¹⁵ ₃、-CHX ¹⁵ ₂、-CH ₂X ¹⁵、-CN、-SO _n15R ^15D、-SO _v15NR ^15AR ^15B、-NHNR ^15AR ^15B、-ONR ^15AR ^15B、-NHC＝(O)NHNR ^15AR ^15B、-NHC(O)NR ^15AR ^15B、-N(O) _m15、-NR ^15AR ^15B、-C(O)R ^15C、-C(O)-OR ^15C、-C(O)NR ^15AR ^15B、-OR ^15D、-NR ^15ASO ₂R ^15D、-NR ^15AC(O)R ^15C、-NR ^15AC(O)OR ^15C、-NR ^15AOR ^15C、-OCX ¹⁵ ₃、-OCHX ¹⁵ ₂Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. R ¹⁶Independently hydrogen, halogen, CX ¹⁶ ₃、-CHX ¹⁶ ₂、-CH ₂X ¹⁶、-CN、-SO _n16R ^16D、-SO _v16NR ^16AR ^16B、-NHNR ^16AR ^16B、-ONR ^16AR ^16B、-NHC＝(O)NHNR ^16AR ^16B、-NHC(O)NR ^16AR ^16B、-N(O) _m16、-NR ^16AR ^16B、-C(O)R ^16C、-C(O)-OR ^16C、-C(O)NR ^16AR ^16B、-OR ^16D、-NR ^16ASO ₂R ^16D、-NR ^16AC(O)R ^16C、-NR ^16AC(O)OR ^16C、-NR ^16AOR ^16C、-OCX ¹⁶ ₃、-OCHX ¹⁶ ₂Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. R ¹⁷Independently hydrogen, halogen, CX ¹⁷ ₃、-CHX ¹⁷ ₂、-CH ₂X ¹⁷、-CN、-SO _n17R ^17D、-SO _v17NR ^17AR ^17B、-NHNR ^17AR ^17B、－ONR ^17AR ^17B、－NHC＝(O)NHNR ^17AR ^17B、-NHC(O)NR ^17AR ^17B、-N(O) _m17、-NR ^17AR ^17B、-C(O)R ^17C、-C(O)-OR ^17C、-C(O)NR ^17AR ^17B、-OR ^17D、-NR ^17ASO ₂R ^17D、-NR ^17AC(O)R ^17C、-NR ^17AC(O)OR ^17C、-NR ^17AOR ^17C、-OCX ¹⁷ ₃、-OCHX ¹⁷ ₂Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. R ¹⁸Independently hydrogen, -CX ¹⁸ ₃、-CHX ¹⁸ ₂、-CH ₂X ¹⁸、-C(O)R ^18C、-C(O)OR ^18C、-C(O)NR ^18AR ^18BSubstituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

Each R ^15A、R ^15B、R ^15C、R ^15D、R ^16A、R ^16B、R ^16C、R ^16D、R ^17A、R ^17B、R ^17C、R ^17D、R ^18A、R ^18B、R ^18C、R ^18DIndependently hydrogen, -CX ₃、-CN、-COOH、-CONH ₂、-CHX ₂、-CH ₂X, 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; r bound to the same nitrogen atom ^15AAnd R ^15BThe substituents may optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^16AAnd R ^16BThe substituents may optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^17AAnd R ^17BThe substituents may optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; r bound to the same nitrogen atom ^18AAnd R ^18BThe substituents may optionally join to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl. Each X, X ¹⁵、X ¹⁶、X ¹⁷And X ¹⁸Independently is-F, -Cl, -Br or-I. The symbols n15, n16, n17, v15, v16 and v17 are independently integers from 0 to 4. The symbols m15, m16 and m17 are independently integers between 1 and 2.

In an embodiment, E is:

and X ¹⁷is-Cl. In an embodiment, E is:

in the examples, X ¹⁷is-Cl.

In an embodiment, E is:

and R is ¹⁵、R ¹⁶And R ¹⁷Independently hydrogen. In an embodiment, E is:

in the examples, R ¹⁵、R ¹⁶And R ¹⁷Independently hydrogen.

In an embodiment, E is: R ¹⁵independently is hydrogen; r ¹⁶Independently is hydrogen or-CH ₂NR ^16AR ^16B；R ¹⁷Independently is hydrogen; and R is ^16AAnd R ^16BIndependently hydrogen or unsubstituted alkyl. In an embodiment, E is:

in the examples, R ¹⁵Independently hydrogen. In the examples, R ¹⁶Independently is hydrogen or-CH ₂NR ^16AR ^16B. In the examples, R ¹⁷Independently hydrogen. In the examples, R ^16AAnd R ^16BIndependently hydrogen or unsubstituted alkyl. In the examples, R ^16AAnd R ^16BIndependently an unsubstituted methyl group.

In an embodiment, E is: in an embodiment, E is: in an embodiment, E is:

in an embodiment, E is:

in an embodiment, E is: in an embodiment, E is:

in an embodiment, E is:

x may independently be-F. X may independently be-Cl. X may independently be-Br. X may independently be-I. X ¹⁵May independently be-F. X ¹⁵May independently be-Cl. X ¹⁵May independently be-Br. X ¹⁵May independently be-I. X ¹⁶May independently be-F. X ¹⁶May independently be-Cl. X ¹⁶May independently be-Br. X ¹⁶May independently be-I. X ¹⁷May independently be-F. X ¹⁷May independently be-Cl. X ¹⁷May independently be-Br. X ¹⁷May independently be-I. X ¹⁸May independently be-F. X ¹⁸May independently be-Cl. X ¹⁸May independently be-Br. X ¹⁸May independently be-I. n15 can independently be 0. n15 may independently be 1. n15 may independently be 2. n15 may independently be 3. n15 may independently be 4. n16 can independently be 0. n16 may independently be 1. n16 may independently be 2. n16 may independently be 3. n16 may independently be 4. n17 can independently be 0. n17 may independently be 1. n17 may independently be 2. n17 may independently be 3. n17 may independently be 4. v15 may independently be 0. v15 may independently be 1. v15 may independently be 2. v15 may independently be 3. v15 may independently be 4. v16 may independently be 0. v16 may independently be 1. v16 may independently be 2. v16 may independently be 3. v16 may independently be 4. v17 may independently be 0. v17 may independently be 1. v17 may independently be 2. v17 may independently be 3. v17 may independently be 4. m15 may independently be 1. m15 may independently be 2. m16 may independently be 1. m16 may independently be 2. m17 may independently be 1. m17 may independently be 2.

In the examples, R ¹⁵Is hydrogen. In the examples, R ¹⁵Is halogen. In the examples, R ¹⁵Is CX ¹⁵ ₃. In the examples, R ¹⁵is-CHX ¹⁵ ₂. In the examples, R ¹⁵is-CH ₂X ¹⁵. In the examples, R ¹⁵is-CN. In the examples, R ¹⁵is-SO _n15R ^15D. In the examples, R ¹⁵is-SO _v15NR ^15AR ^15B. In the examples, R ¹⁵is-NHNR ^15AR ^15B. In the examples, R ¹⁵is-ONR ^15AR ^15B. In the examples, R ¹⁵is-NHC ═ O-NHNR ^15AR ^15B. In the examples, R ¹⁵is-NHC (O) NR ^15AR ^15B. In the examples, R ¹⁵is-N (O) _m15. In the examples, R ¹⁵is-NR ^15AR ^15B. In the examples, R ¹⁵is-C (O) R ^15C. In the examples, R ¹⁵is-C (O) -OR ^15C. In the examples, R ¹⁵is-C (O) NR ^15AR ^15B. In the examples, R ¹⁵is-OR ^15D. In the examples, R ¹⁵is-NR ^15ASO ₂R ^15D. In the examples, R ¹⁵is-NR ^15AC(O)R ^15C. In the examples, R ¹⁵is-NR ^15AC(O)OR ^15C. In the examples, R ¹⁵is-NR ^15AOR ^15C. In the examples, R ¹⁵is-OCX ¹⁵ ₃. In the examples, R ¹⁵is-OCHX ¹⁵ ₂. In the examples, R ¹⁵Is a substituted or unsubstituted alkyl group. In the examples, R ¹⁵Is a substituted or unsubstituted heteroalkyl group. In the examples, R ¹⁵Is a substituted or unsubstituted cycloalkyl. In the examples, R ¹⁵Is a substituted or unsubstituted heterocycloalkyl. In the examples, R ¹⁵Is substituted or unsubstituted aryl. In the examples, R ¹⁵Is a substituted or unsubstituted heteroaryl. In the examples, R ¹⁵Is a substituted alkyl group. In the examples, R ¹⁵Is a substituted heteroalkyl group. In the examples, R ¹⁵Is a substituted cycloalkyl group. In the examples, R ¹⁵Is a substituted heterocycloalkyl group. In the examples, R ¹⁵Is a substituted aryl group. In the examples, R ¹⁵Is a substituted heteroaryl group. In the examples, R ¹⁵Is unsubstituted alkyl. In the examples, R ¹⁵Is unsubstituted heteroalkyl. In the examples, R ¹⁵Is unsubstituted cycloalkyl. In the examples, R ¹⁵Is unsubstituted heterocycloalkyl. In the examples, R ¹⁵Is unsubstituted aryl. In the examples, R ¹⁵Is unsubstituted heteroaryl. In the examples, R ¹⁵Is unsubstituted methyl. In the examples, R ¹⁵Is unsubstituted ethyl. In the examples, R ¹⁵Is unsubstituted propyl. In the examples, R ¹⁵Is unsubstituted isopropyl. In the examples, R ¹⁵Is unsubstituted butyl. In the examples, R ¹⁵Is unsubstituted tert-butyl.

In the examples, R ^15AIs hydrogen. In the examples, R ^15Ais-CX ₃. In the examples, R ^15Ais-CN. In the examples, R ^15Ais-COOH. In the examples, R ^15Ais-CONH ₂. In the examples, R ^15Ais-CHX ₂. In the examples, R ^15Ais-CH ₂And (4) X. In the implementation ofIn the examples, R ^15AIs unsubstituted methyl. In the examples, R ^15AIs unsubstituted ethyl. In the examples, R ^15AIs unsubstituted propyl. In the examples, R ^15AIs unsubstituted isopropyl. In the examples, R ^15AIs unsubstituted butyl. In the examples, R ^15AIs unsubstituted tert-butyl.

In the examples, R ^15BIs hydrogen. In the examples, R ^15Bis-CX ₃. In the examples, R ^15Bis-CN. In the examples, R ^15Bis-COOH. In the examples, R ^15Bis-CONH ₂. In the examples, R ^15Bis-CHX ₂. In the examples, R ^15Bis-CH ₂And (4) X. In the examples, R ^15BIs unsubstituted methyl. In the examples, R ^15BIs unsubstituted ethyl. In the examples, R ^15BIs unsubstituted propyl. In the examples, R ^15BIs unsubstituted isopropyl. In the examples, R ^15BIs unsubstituted butyl. In the examples, R ^15BIs unsubstituted tert-butyl.

In the examples, R ^15CIs hydrogen. In the examples, R ^15Cis-CX ₃. In the examples, R ^15Cis-CN. In the examples, R ^15Cis-COOH. In the examples, R ^15Cis-CONH ₂. In the examples, R ^15Cis-CHX ₂. In the examples, R ^15Cis-CH ₂And (4) X. In the examples, R ^15CIs unsubstituted methyl. In the examples, R ^15CIs unsubstituted ethyl. In the examples, R ^15CIs unsubstituted propyl. In the examples, R ^15CIs unsubstituted isopropyl. In the examples, R ^15CIs unsubstituted butyl. In the examples, R ^15CIs unsubstituted tert-butyl.

In the examples, R ^15DIs hydrogen. In the examples, R ^15Dis-CX ₃. In the examples, R ^15Dis-CN. In an embodiment of the present invention,R ^15Dis-COOH. In the examples, R ^15Dis-CONH ₂. In the examples, R ^15Dis-CHX ₂. In the examples, R ^15Dis-CH ₂And (4) X. In the examples, R ^15DIs unsubstituted methyl. In the examples, R ^15DIs unsubstituted ethyl. In the examples, R ^15DIs unsubstituted propyl. In the examples, R ^15DIs unsubstituted isopropyl. In the examples, R ^15DIs unsubstituted butyl. In the examples, R ^15DIs unsubstituted tert-butyl.

In the examples, R ¹⁵Independently hydrogen, pendant oxy, halogen, -CX ¹⁵ ₃、-CHX ¹⁵ ₂、-OCH ₂X ¹⁵、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ¹⁵ ₃、-OCHX ¹⁵ ₂Quilt R ⁷²Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁷²Substituted or unsubstituted heteroalkyl by R ⁷²Substituted or unsubstituted cycloalkyl, by R ⁷²Substituted or unsubstituted heterocycloalkyl, by R ⁷²Substituted or unsubstituted aryl or by R ⁷²Substituted or unsubstituted heteroaryl. X ¹⁵Is a halogen. In the examples, X ¹⁵Is F.

R ⁷²Independently is a pendant oxy group, a halogen, -CX ⁷² ₃、-CHX ⁷² ₂、-OCH ₂X ⁷²、-OCHX ⁷² ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ⁷² ₃、-OCHX ⁷² ₂Quilt R ⁷³Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁷³Substituted or unsubstituted heteroalkyl by R ⁷³Substituted or unsubstituted cycloalkyl, by R ⁷³Substituted or unsubstituted heterocycloalkyl, by R ⁷³Substituted or unsubstituted aryl or by R ⁷³Substituted or unsubstituted heteroaryl. X ⁷²Is a halogen. In the examples, X ⁷²Is F.

R ⁷³Independently is a pendant oxy group, a halogen, -CX ⁷³ ₃、-CHX ⁷³ ₂、-OCH ₂X ⁷³、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ⁷³ ₃、-OCHX ⁷³ ₂Quilt R ⁷⁴Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁷⁴Substituted or unsubstituted heteroalkyl by R ⁷⁴Substituted or unsubstituted cycloalkyl, by R ⁷⁴Substituted or unsubstituted heterocycloalkyl, by R ⁷⁴Substituted or unsubstituted aryl or by R ⁷⁴Substituted or unsubstituted heteroaryl. X ⁷³Is a halogen. In the examples, X ⁷³Is F.

In the examples, R ^15AIndependently hydrogen, pendant oxy, halogen, -CX ^15A ₃、-CHX ^15A ₂、-OCH ₂X ^15A、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^15A ₃、-OCHX ^15A ₂Quilt R ^72ASubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^72ASubstituted or unsubstituted heteroalkyl by R ^72ASubstituted or unsubstituted cycloalkyl, by R ^72ASubstituted or unsubstituted heterocycloalkyl, by R ^72ASubstituted or unsubstituted aryl or by R ^72ASubstituted or unsubstituted heteroaryl. X ^15AIs a halogen. In the examples, X ^15AIs F.

R ^72AIndependently is a pendant oxy group, a halogen, -CX ^72A ₃、-CHX ^72A ₂、-OCH ₂X ^72A、-OCHX ^72A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^72A ₃、-OCHX ^72A ₂Quilt R ^73ASubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^73ASubstituted or unsubstituted heteroalkyl by R ^73ASubstituted or unsubstituted cycloalkyl, by R ^73ASubstituted or unsubstituted heterocycloalkyl, by R ^73ASubstituted or unsubstituted aryl or by R ^73ASubstituted or unsubstituted heteroaryl. X ^72AIs a halogen. In the examples, X ^72AIs F.

R ^73AIndependently is a pendant oxy group, a halogen, -CX ^73A ₃、-CHX ^73A ₂、-OCH ₂X ^73A、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^73A ₃、-OCHX ^73A ₂Quilt R ^74ASubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^74ASubstituted or unsubstituted heteroalkyl by R ^74ASubstituted or unsubstituted cycloalkyl, by R ^74ASubstituted or unsubstituted heterocycloalkyl, by R ^74ASubstituted or unsubstitutedAryl or by R ^74ASubstituted or unsubstituted heteroaryl. X ^73AIs a halogen. In the examples, X ^73AIs F.

In the examples, R ^15BIndependently hydrogen, pendant oxy, halogen, -CX ^15B ₃、-CHX ^15B ₂、-OCH ₂X ^15B、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^15B ₃、-OCHX ^15B ₂Quilt R ^72BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^72BSubstituted or unsubstituted heteroalkyl by R ^72BSubstituted or unsubstituted cycloalkyl, by R ^72BSubstituted or unsubstituted heterocycloalkyl, by R ^72BSubstituted or unsubstituted aryl or by R ^72BSubstituted or unsubstituted heteroaryl. X ^15BIs a halogen. In the examples, X ^15BIs F.

R ^72BIndependently is a pendant oxy group, a halogen, -CX ^72B ₃、-CHX ^72B ₂、-OCH ₂X ^72B、-OCHX ^72B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^72B ₃、-OCHX ^72B ₂Quilt R ^73BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^73BSubstituted or unsubstituted heteroalkyl by R ^73BSubstituted or unsubstituted cycloalkyl, by R ^73BSubstituted or unsubstituted heterocycloalkyl, by R ^73BSubstituted or unsubstituted aryl or by R ^73BSubstituted or unsubstituted heteroaryl. X ^72BIs a halogen. In the examples，X ^72BIs F.

R ^73BIndependently is a pendant oxy group, a halogen, -CX ^73B ₃、-CHX ^73B ₂、-OCH ₂X ^73B、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^73B ₃、-OCHX ^73B ₂Quilt R ^74BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^74BSubstituted or unsubstituted heteroalkyl by R ^74BSubstituted or unsubstituted cycloalkyl, by R ^74BSubstituted or unsubstituted heterocycloalkyl, by R ^74BSubstituted or unsubstituted aryl or by R ^74BSubstituted or unsubstituted heteroaryl. X ^73BIs a halogen. In the examples, X ^73BIs F.

In the examples, R ^15CIndependently hydrogen, pendant oxy, halogen, -CX ^15C ₃、-CHX ^15C ₂、-OCH ₂X ^15C、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^15C ₃、-OCHX ^15C ₂Quilt R ^72CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^72CSubstituted or unsubstituted heteroalkyl by R ^72CSubstituted or unsubstituted cycloalkyl, by R ^72CSubstituted or unsubstituted heterocycloalkyl, by R ^72CSubstituted or unsubstituted aryl or by R ^72CSubstituted or unsubstituted heteroaryl. X ^15CIs a halogen. In the examples, X ^15CIs F.

R ^72CIndependently is a pendant oxy group, a halogen, -CX ^72C ₃、-CHX ^72C ₂、-OCH ₂X ^72C、-OCHX ^72C ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^72C ₃、-OCHX ^72C ₂Quilt R ^73CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^73CSubstituted or unsubstituted heteroalkyl by R ^73CSubstituted or unsubstituted cycloalkyl, by R ^73CSubstituted or unsubstituted heterocycloalkyl, by R ^73CSubstituted or unsubstituted aryl or by R ^73CSubstituted or unsubstituted heteroaryl. X ^72CIs a halogen. In the examples, X ^72CIs F.

R ^73CIndependently is a pendant oxy group, a halogen, -CX ^73C ₃、-CHX ^73C ₂、-OCH ₂X ^73C、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^73C ₃、-OCHX ^73C ₂Quilt R ^74CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^74CSubstituted or unsubstituted heteroalkyl by R ^74CSubstituted or unsubstituted cycloalkyl, by R ^74CSubstituted or unsubstituted heterocycloalkyl, by R ^74CSubstituted or unsubstituted aryl or by R ^74CSubstituted or unsubstituted heteroaryl. X ^73CIs a halogen. In the examples, X ^73CIs F.

In the examples, R ^15DIndependently hydrogen, pendant oxy, halogen, -CX ^15D ₃、-CHX ^15D ₂、-OCH ₂X ^15D、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^15D ₃、-OCHX ^15D ₂Quilt R ^72DSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^72DSubstituted or unsubstituted heteroalkyl by R ^72DSubstituted or unsubstituted cycloalkyl, by R ^72DSubstituted or unsubstituted heterocycloalkyl, by R ^72DSubstituted or unsubstituted aryl or by R ^72DSubstituted or unsubstituted heteroaryl. X ^15DIs a halogen. In the examples, X ^15DIs F.

R ^72DIndependently is a pendant oxy group, a halogen, -CX ^72D ₃、-CHX ^72D ₂、-OCH ₂X ^72D、-OCHX ^72D ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^72D ₃、-OCHX ^72D ₂Quilt R ^73DSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^73DSubstituted or unsubstituted heteroalkyl by R ^73DSubstituted or unsubstituted cycloalkyl, by R ^73DSubstituted or unsubstituted heterocycloalkyl, by R ^73DSubstituted or unsubstituted aryl or by R ^73DSubstituted or unsubstituted heteroaryl. X ^72DIs a halogen. In the examples, X ^72DIs F.

R ^73DIndependently is a pendant oxy group, a halogen, -CX ^73D ₃、-CHX ^73D ₂、-OCH ₂X ^73D、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^73D ₃、-OCHX ^73D ₂Quilt R ^74DSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^74DSubstituted or unsubstituted heteroalkyl by R ^74DSubstituted or unsubstituted cycloalkyl, by R ^74DSubstituted or unsubstituted heterocycloalkyl, by R ^74DSubstituted or unsubstituted aryl or by R ^74DSubstituted or unsubstituted heteroaryl. X ^73DIs a halogen. In the examples, X ^73DIs F.

In the examples, R ¹⁶Is hydrogen. In the examples, R ¹⁶Is halogen. In the examples, R ¹⁶Is CX ¹⁶ ₃. In the examples, R ¹⁶is-CHX ¹⁶ ₂. In the examples, R ¹⁶is-CH ₂X ¹⁶. In the examples, R ¹⁶is-CN. In the examples, R ¹⁶is-SO _n16R ^16D. In the examples, R ¹⁶is-SO _v16NR ^16AR ^16B. In the examples, R ¹⁶is-NHNR ^16AR ^16B. In the examples, R ¹⁶is-ONR ^16AR ^16B. In the examples, R ¹⁶is-NHC ═ O-NHNR ^16AR ^16B. In the examples, R ¹⁶is-NHC (O) NR ^16AR ^16B. In the examples, R ¹⁶is-N (O) _m16. In the examples, R ¹⁶is-NR ^16AR ^16B. In the examples, R ¹⁶is-C (O) R ^16C. In the examples, R ¹⁶is-C (O) -OR ^16C. In the examples, R ¹⁶is-C (O) NR ^16AR ^16B. In the examples, R ¹⁶is-OR ^16D. In the examples, R ¹⁶is-NR ^16ASO ₂R ^16D. In the examples, R ¹⁶is-NR ^16AC(O)R ^16C. In the examples, R ¹⁶is-NR ^16AC(O)OR ^16C. In the examples, R ¹⁶is-NR ^16AOR ^16C. In the examples, R ¹⁶is-OCX ¹⁶ ₃. In the examples, R ¹⁶is-OCHX ¹⁶ ₂. In the examples, R ¹⁶Is a substituted or unsubstituted alkyl group. In the examples, R ¹⁶Is a substituted or unsubstituted heteroalkyl group. In the examples, R ¹⁶Is a substituted or unsubstituted cycloalkyl. In the examples, R ¹⁶Is a substituted or unsubstituted heterocycloalkyl. In the examples, R ¹⁶Is substituted or unsubstituted aryl. In the examples, R ¹⁶Is a substituted or unsubstituted heteroaryl. In the examples, R ¹⁶Is a substituted alkyl group. In the examples, R ¹⁶Is a substituted heteroalkyl group. In the examples, R ¹⁶Is a substituted cycloalkyl group. In the examples, R ¹⁶Is a substituted heterocycloalkyl group. In the examples, R ¹⁶Is a substituted aryl group. In the examples, R ¹⁶Is a substituted heteroaryl group. In the examples, R ¹⁶Is unsubstituted alkyl. In the examples, R ¹⁶Is unsubstituted heteroalkyl. In the examples, R ¹⁶Is unsubstituted cycloalkyl. In the examples, R ¹⁶Is unsubstituted heterocycloalkyl. In the examples, R ¹⁶Is unsubstituted aryl. In the examples, R ¹⁶Is unsubstituted heteroaryl. In the examples, R ¹⁶Is unsubstituted methyl. In the examples, R ¹⁶Is unsubstituted ethyl. In the examples, R ¹⁶Is unsubstituted propyl. In the examples, R ¹⁶Is unsubstituted isopropyl. In the examples, R ¹⁶Is unsubstituted butyl. In the examples, R ¹⁶Is unsubstituted tert-butyl.

In the examples, R ^16AIs hydrogen. In the examples, R ^16Ais-CX ₃. In the examples, R ^16Ais-CN. In the examples, R ^16Ais-COOH. In the examples, R ^16Ais-CONH ₂. In the examples, R ^16Ais-CHX ₂. In the examples, R ^16Ais-CH ₂And (4) X. In the examples, R ^16AIs unsubstituted methyl. In the examples, R ^16AIs unsubstituted ethyl. In the examples, R ^16AIs unsubstituted propyl. In the examples, R ^16AIs unsubstituted isopropyl. In the examples, R ^16AIs unsubstituted butyl. In the examples, R ^16AIs unsubstituted tert-butyl.

In the examples, R ^16BIs hydrogen. In the examples, R ^16Bis-CX ₃. In the examples, R ^16Bis-CN. In the examples, R ^16Bis-COOH. In the examples, R ^16Bis-CONH ₂. In the examples, R ^16Bis-CHX ₂. In the examples, R ^16Bis-CH ₂And (4) X. In the examples, R ^16BIs unsubstituted methyl. In the examples, R ^16BIs unsubstituted ethyl. In the examples, R ^16BIs unsubstituted propyl. In the examples, R ^16BIs unsubstituted isopropyl. In the examples, R ^16BIs unsubstituted butyl. In the examples, R ^16BIs unsubstituted tert-butyl.

In the examples, R ^16CIs hydrogen. In the examples, R ^16Cis-CX ₃. In the examples, R ^16Cis-CN. In the examples, R ^16Cis-COOH. In the examples, R ^16Cis-CONH ₂. In the examples, R ^16Cis-CHX ₂. In the examples, R ^16Cis-CH ₂And (4) X. In the examples, R ^16CIs unsubstituted methyl. In the examples, R ^16CIs unsubstituted ethyl. In the examples, R ^16CIs unsubstituted propyl. In the examples, R ^16CIs unsubstituted isopropyl. In the examples, R ^16CIs unsubstituted butyl. In the examples, R ^16CIs unsubstituted tert-butyl.

In the examples, R ^16DIs hydrogen. In the examples, R ^16Dis-CX ₃. In the examples, R ^16Dis-CN. In the examples, R ^16Dis-COOH. In the examples, R ^16Dis-CONH ₂. In the examples, R ^16Dis-CHX ₂. In the examples, R ^16Dis-CH ₂And (4) X. In the examples, R ^16DIs unsubstituted methyl. In the examples, R ^16DIs unsubstituted ethyl. In the examples, R ^16DIs a substituted propyl group. In the examples, R ^16DIs unsubstituted isopropyl. In the examples, R ^16DIs unsubstituted butyl. In the examples, R ^16DIs unsubstituted tert-butyl.

In the examples, R ¹⁶Independently hydrogen, pendant oxy, halogen, -CX ¹⁶ ₃、-CHX ¹⁶ ₂、-OCH ₂X ¹⁶、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ¹⁶ ₃、-OCHX ¹⁶ ₂Quilt R ⁷⁵Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁷⁵Substituted or unsubstituted heteroalkyl by R ⁷⁵Substituted or unsubstituted cycloalkyl, by R ⁷⁵Substituted or unsubstituted heterocycloalkyl, by R ⁷⁵Substituted or unsubstituted aryl or by R ⁷⁵Substituted or unsubstituted heteroaryl. X ¹⁶Is a halogen. In the examples, X ¹⁶Is F.

R ⁷⁵Independently is a pendant oxy group, a halogen, -CX ⁷⁵ ₃、-CHX ⁷⁵ ₂、-OCH ₂X ⁷⁵、-OCHX ⁷⁵ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ⁷⁵ ₃、-OCHX ⁷⁵ ₂Quilt R ⁷⁶Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁷⁶Substituted or unsubstituted heteroalkyl by R ⁷⁶Substituted or unsubstituted cycloalkyl, by R ⁷⁶Substituted or unsubstituted heterocycloalkyl, by R ⁷⁶Substituted or unsubstituted aryl or by R ⁷⁶Substituted or unsubstituted heteroaryl. X ⁷⁵Is a halogen. In the examples, X ⁷⁵Is F.

R ⁷⁶Independently is a pendant oxy group, a halogen, -CX ⁷⁶ ₃、-CHX ⁷⁶ ₂、-OCH ₂X ⁷⁶、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ⁷⁶ ₃、-OCHX ⁷⁶ ₂Quilt R ⁷⁷Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁷⁷Substituted or unsubstituted heteroalkyl by R ⁷⁷Substituted or unsubstituted cycloalkyl, by R ⁷⁷Substituted or unsubstituted heterocycloalkyl, by R ⁷⁷Substituted or unsubstituted aryl or by R ⁷⁷Substituted or unsubstituted heteroaryl. X ⁷⁶Is a halogen. In the examples, X ⁷⁶Is F.

In the examples, R ^16AIndependently hydrogen, pendant oxy, halogen, -CX ^16A ₃、-CHX ^16A ₂、-OCH ₂X ^16A、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^16A ₃、-OCHX ^16A ₂Quilt R ^75ASubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^75ASubstituted or unsubstitutedHeteroalkyl group, by R ^75ASubstituted or unsubstituted cycloalkyl, by R ^75ASubstituted or unsubstituted heterocycloalkyl, by R ^75ASubstituted or unsubstituted aryl or by R ^75ASubstituted or unsubstituted heteroaryl. X ^16AIs a halogen. In the examples, X ^16AIs F.

R ^75AIndependently is a pendant oxy group, a halogen, -CX ^75A ₃、-CHX ^75A ₂、-OCH ₂X ^75A、-OCHX ^75A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^75A ₃、-OCHX ^75A ₂Quilt R ^76ASubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^76ASubstituted or unsubstituted heteroalkyl by R ^76ASubstituted or unsubstituted cycloalkyl, by R ^76ASubstituted or unsubstituted heterocycloalkyl, by R ^76ASubstituted or unsubstituted aryl or by R ^76ASubstituted or unsubstituted heteroaryl. X ^75AIs a halogen. In the examples, X ^75AIs F.

R ^76AIndependently is a pendant oxy group, a halogen, -CX ^76A ₃、-CHX ^76A ₂、-OCH ₂X ^76A、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^76A ₃、-OCHX ^76A ₂Quilt R ^77ASubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^77ASubstituted or unsubstituted heteroalkyl by R ^77ASubstituted or unsubstituted cycloalkyl, by R ^77ASubstituted or unsubstituted heterocycloalkyl, by R ^77ASubstituted or unsubstituted aryl or by R ^77ASubstituted or unsubstituted heteroaryl. X ^76AIs a halogen. In the examples, X ^76AIs F.

In the examples, R ^16BIndependently hydrogen, pendant oxy, halogen, -CX ^16B ₃、-CHX ^16B ₂、-OCH ₂X ^16B、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^16B ₃、-OCHX ^16B ₂Quilt R ^75BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^75BSubstituted or unsubstituted heteroalkyl by R ^75BSubstituted or unsubstituted cycloalkyl, by R ^75BSubstituted or unsubstituted heterocycloalkyl, by R ^75BSubstituted or unsubstituted aryl or by R ^75BSubstituted or unsubstituted heteroaryl. X ^16BIs a halogen. In the examples, X ^16BIs F.

R ^75BIndependently is a pendant oxy group, a halogen, -CX ^75B ₃、-CHX ^75B ₂、-OCH ₂X ^75B、-OCHX ^75B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^75B ₃、-OCHX ^75B ₂Quilt R ^76BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^76BSubstituted or unsubstituted heteroalkyl by R ^76BSubstituted or unsubstituted cycloalkyl, by R ^76BSubstituted or unsubstituted heterocycloalkyl, by R ^76BSubstituted or unsubstituted aryl or by R ^76BSubstituted or unsubstituted heteroaryl. X ^75BIs a halogen. In the examples, X ^75BIs F.

R ^76BIndependently is a pendant oxy group, a halogen, -CX ^76B ₃、-CHX ^76B ₂、-OCH ₂X ^76B、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^76B ₃、-OCHX ^76B ₂Quilt R ^77BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^77BSubstituted or unsubstituted heteroalkyl by R ^77BSubstituted or unsubstituted cycloalkyl, by R ^77BSubstituted or unsubstituted heterocycloalkyl, by R ^77BSubstituted or unsubstituted aryl or by R ^77BSubstituted or unsubstituted heteroaryl. X ^76BIs a halogen. In the examples, X ^76BIs F.

In the examples, R ^16CIndependently hydrogen, pendant oxy, halogen, -CX ^16C ₃、-CHX ^16C ₂、-OCH ₂X ^16C、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^16C ₃、-OCHX ^16C ₂Quilt R ^75CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^75CSubstituted or unsubstituted heteroalkyl by R ^75CSubstituted or unsubstituted cycloalkyl, by R ^75CSubstituted or unsubstituted heterocycloalkyl, by R ^75CSubstituted or unsubstituted aryl or by R ^75CSubstituted or unsubstituted heteroaryl. X ^16CIs a halogen. In the examples, X ^16CIs F.

R ^75CIndependently is a pendant oxy group, halogen, -CX ^75C ₃、-CHX ^75C ₂、-OCH ₂X ^75C、-OCHX ^75C ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^75C ₃、-OCHX ^75C ₂Quilt R ^76CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^76CSubstituted or unsubstituted heteroalkyl by R ^76CSubstituted or unsubstituted cycloalkyl, by R ^76CSubstituted or unsubstituted heterocycloalkyl, by R ^76CSubstituted or unsubstituted aryl or by R ^76CSubstituted or unsubstituted heteroaryl. X ^75CIs a halogen. In the examples, X ^75CIs F.

R ^76CIndependently is a pendant oxy group, a halogen, -CX ^76C ₃、-CHX ^76C ₂、-OCH ₂X ^76C、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^76C ₃、-OCHX ^76C ₂Quilt R ^77CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^77CSubstituted or unsubstituted heteroalkyl by R ^77CSubstituted or unsubstituted cycloalkyl, by R ^77CSubstituted or unsubstituted heterocycloalkyl, by R ^77CSubstituted or unsubstituted aryl or by R ^77CSubstituted or unsubstituted heteroaryl. X ^76CIs a halogen. In the examples, X ^76CIs F.

In the examples, R ^16DIndependently hydrogen, pendant oxy, halogen, -CX ^16D ₃、-CHX ^16D ₂、-OCH ₂X ^16D、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^16D ₃、-OCHX ^16D ₂Quilt R ^75DSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^75DSubstituted or unsubstituted heteroalkyl by R ^75DSubstituted or unsubstituted cycloalkyl, by R ^75DSubstituted or unsubstituted heterocycloalkyl, by R ^75DSubstituted or unsubstituted aryl or by R ^75DSubstituted or unsubstituted heteroaryl. X ^16DIs a halogen. In the examples, X ^16DIs F.

R ^75DIndependently is a pendant oxy group, a halogen, -CX ^75D ₃、-CHX ^75D ₂、-OCH ₂X ^75D、-OCHX ^75D ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^75D ₃、-OCHX ^75D ₂Quilt R ^76DSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^76DSubstituted or unsubstituted heteroalkyl by R ^76DSubstituted or unsubstituted cycloalkyl, by R ^76DSubstituted or unsubstituted heterocycloalkyl, by R ^76DSubstituted or unsubstituted aryl or by R ^76DSubstituted or unsubstituted heteroaryl. X ^75DIs a halogen. In the examples, X ^75DIs F.

R ^76DIndependently is a pendant oxy group, a halogen, -CX ^76D ₃、-CHX ^76D ₂、-OCH ₂X ^76D、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^76D ₃、-OCHX ^76D ₂Quilt R ^77DSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^77DSubstituted or unsubstituted heteroalkyl by R ^77DSubstituted or unsubstituted cycloalkyl, by R ^77DSubstituted or unsubstituted heterocycloalkyl, by R ^77DSubstituted or unsubstituted aryl or by R ^77DSubstituted or unsubstituted heteroaryl. X ^76DIs a halogen. In the examples, X ^76DIs F.

In the examples, R ¹⁷Is hydrogen. In the examples, R ¹⁷Is halogen. In the examples, R ¹⁷Is CX ¹⁷ ₃. In the examples, R ¹⁷is-CHX ¹⁷ ₂. In the examples, R ¹⁷is-CH ₂X ¹⁷. In the examples, R ¹⁷is-CN. In the examples, R ¹⁷is-SO _n17R ^17D. In the examples, R ¹⁷is-SO _v17NR ^17AR ^17B. In the examples, R ¹⁷is-NHNR ^17AR ^17B. In the examples, R ¹⁷is-ONR ^17AR ^17B. In the examples, R ¹⁷is-NHC ═ O-NHNR ^17AR ^17B. In the examples, R ¹⁷is-NHC (O) NR ^17AR ^17B. In the examples, R ¹⁷is-N (O) _m17. In the examples, R ¹⁷is-NR ^17AR ^17B. In the examples, R ¹⁷is-C (O) R ^17C. In the examples, R ¹⁷is-C (O) -OR ^17C. In the examples, R ¹⁷is-C (O) NR ^17AR ^17B. In the examples, R ¹⁷is-OR ^17D. In the examples, R ¹⁷is-NR ^17ASO ₂R ^17D. In the examples, R ¹⁷is-NR ^17AC(O)R ^17C. In the examples, R ¹⁷is-NR ^17AC(O)OR ^17C. In the examplesIn, R ¹⁷is-NR ^17AOR ^17C. In the examples, R ¹⁷is-OCX ¹⁷ ₃. In the examples, R ¹⁷is-OCHX ¹⁷ ₂. In the examples, R ¹⁷Is a substituted or unsubstituted alkyl group. In the examples, R ¹⁷Is a substituted or unsubstituted heteroalkyl group. In the examples, R ¹⁷Is a substituted or unsubstituted cycloalkyl. In the examples, R ¹⁷Is a substituted or unsubstituted heterocycloalkyl. In the examples, R ¹⁷Is substituted or unsubstituted aryl. In the examples, R ¹⁷Is a substituted or unsubstituted heteroaryl. In the examples, R ¹⁷Is a substituted alkyl group. In the examples, R ¹⁷Is a substituted heteroalkyl group. In the examples, R ¹⁷Is a substituted cycloalkyl group. In the examples, R ¹⁷Is a substituted heterocycloalkyl group. In the examples, R ¹⁷Is a substituted aryl group. In the examples, R ¹⁷Is a substituted heteroaryl group. In the examples, R ¹⁷Is unsubstituted alkyl. In the examples, R ¹⁷Is unsubstituted heteroalkyl. In the examples, R ¹⁷Is unsubstituted cycloalkyl. In the examples, R ¹⁷Is unsubstituted heterocycloalkyl. In the examples, R ¹⁷Is unsubstituted aryl. In the examples, R ¹⁷Is unsubstituted heteroaryl. In the examples, R ¹⁷Is unsubstituted methyl. In the examples, R ¹⁷Is unsubstituted ethyl. In the examples, R ¹⁷Is unsubstituted propyl. In the examples, R ¹⁷Is unsubstituted isopropyl. In the examples, R ¹⁷Is unsubstituted butyl. In the examples, R ¹⁷Is unsubstituted tert-butyl.

In the examples, R ^17AIs hydrogen. In the examples, R ^17Ais-CX ₃. In the examples, R ^17Ais-CN. In the examples, R ^17Ais-COOH. In the examples, R ^17Ais-CONH ₂. In the examples, R ^17Ais-CHX ₂. In factIn the examples, R ^17Ais-CH ₂And (4) X. In the examples, R ^17AIs unsubstituted methyl. In the examples, R ^17AIs unsubstituted ethyl. In the examples, R ^17AIs unsubstituted propyl. In the examples, R ^17AIs unsubstituted isopropyl. In the examples, R ^17AIs unsubstituted butyl. In the examples, R ^17AIs unsubstituted tert-butyl.

In the examples, R ^17BIs hydrogen. In the examples, R ^17Bis-CX ₃. In the examples, R ^17Bis-CN. In the examples, R ^17Bis-COOH. In the examples, R ^17Bis-CONH ₂. In the examples, R ^17Bis-CHX ₂. In the examples, R ^17Bis-CH ₂And (4) X. In the examples, R ^17BIs unsubstituted methyl. In the examples, R ^17BIs unsubstituted ethyl. In the examples, R ^17BIs unsubstituted propyl. In the examples, R ^17BIs unsubstituted isopropyl. In the examples, R ^17BIs unsubstituted butyl. In the examples, R ^17BIs unsubstituted tert-butyl.

In the examples, R ^17CIs hydrogen. In the examples, R ^17Cis-CX ₃. In the examples, R ^17Cis-CN. In the examples, R ^17Cis-COOH. In the examples, R ^17Cis-CONH ₂. In the examples, R ^17Cis-CHX ₂. In the examples, R ^17Cis-CH ₂And (4) X. In the examples, R ^17CIs unsubstituted methyl. In the examples, R ^17CIs unsubstituted ethyl. In the examples, R ^17CIs unsubstituted propyl. In the examples, R ^17CIs unsubstituted isopropyl. In the examples, R ^17CIs unsubstituted butyl. In the examples, R ^17CIs unsubstituted tert-butyl.

In the examples, R ^17DIs hydrogen. In the examples, R ^17Dis-CX ₃. In thatIn the examples, R ^17Dis-CN. In the examples, R ^17Dis-COOH. In the examples, R ^17Dis-CONH ₂. In the examples, R ^17Dis-CHX ₂. In the examples, R ^17Dis-CH ₂And (4) X. In the examples, R ^17DIs unsubstituted methyl. In the examples, R ^17DIs unsubstituted ethyl. In the examples, R ^17DIs unsubstituted propyl. In the examples, R ^17DIs unsubstituted isopropyl. In the examples, R ^17DIs unsubstituted butyl. In the examples, R ^17DIs unsubstituted tert-butyl.

In the examples, R ¹⁷Independently hydrogen, pendant oxy, halogen, -CX ¹⁷ ₃、-CHX ¹⁷ ₂、-OCH ₂X ¹⁷、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ¹⁷ ₃、-OCHX ¹⁷ ₂Quilt R ⁷⁸Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁷⁸Substituted or unsubstituted heteroalkyl by R ⁷⁸Substituted or unsubstituted cycloalkyl, by R ⁷⁸Substituted or unsubstituted heterocycloalkyl, by R ⁷⁸Substituted or unsubstituted aryl or by R ⁷⁸Substituted or unsubstituted heteroaryl. X ¹⁷Is a halogen. In the examples, X ¹⁷Is F.

R ⁷⁸Independently is a pendant oxy group, a halogen, -CX ⁷⁸ ₃、-CHX ⁷⁸ ₂、-OCH ₂X ⁷⁸、-OCHX ⁷⁸ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ⁷⁸ ₃、-OCHX ⁷⁸ ₂Quilt R ⁷⁹Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁷⁹Substituted or unsubstituted heteroalkyl by R ⁷⁹Substituted or unsubstituted cycloalkyl, by R ⁷⁹Substituted or unsubstituted heterocycloalkyl, by R ⁷⁹Substituted or unsubstituted aryl or by R ⁷⁹Substituted or unsubstituted heteroaryl. X ⁷⁸Is a halogen. In the examples, X ⁷⁸Is F.

R ⁷⁹Independently is a pendant oxy group, a halogen, -CX ⁷⁹ ₃、-CHX ⁷⁹ ₂、-OCH ₂X ⁷⁹、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ⁷⁹ ₃、-OCHX ⁷⁹ ₂Quilt R ⁸⁰Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁸⁰Substituted or unsubstituted heteroalkyl by R ⁸⁰Substituted or unsubstituted cycloalkyl, by R ⁸⁰Substituted or unsubstituted heterocycloalkyl, by R ⁸⁰Substituted or unsubstituted aryl or by R ⁸⁰Substituted or unsubstituted heteroaryl. X ⁷⁹Is a halogen. In the examples, X ⁷⁹Is F.

In the examples, R ^17AIndependently hydrogen, pendant oxy, halogen, -CX ^17A ₃、-CHX ^17A ₂、-OCH ₂X ^17A、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^17A ₃、-OCHX ^17A ₂Quilt R ^78ASubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^78ASubstituted or unsubstituted heteroalkyl by R ^78ASubstituted or unsubstituted cycloalkyl, by R ^78ASubstituted or unsubstituted heterocycloalkyl, by R ^78ASubstituted or unsubstituted aryl or by R ^78ASubstituted or unsubstituted heteroaryl. X ^17AIs a halogen. In the examples, X ^17AIs F.

R ^78AIndependently is a pendant oxy group, a halogen, -CX ^78A ₃、-CHX ^78A ₂、-OCH ₂X ^78A、-OCHX ^78A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^78A ₃、-OCHX ^78A ₂Quilt R ^79ASubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^79ASubstituted or unsubstituted heteroalkyl by R ^79ASubstituted or unsubstituted cycloalkyl, by R ^79ASubstituted or unsubstituted heterocycloalkyl, by R ^79ASubstituted or unsubstituted aryl or by R ^79ASubstituted or unsubstituted heteroaryl. X ^78AIs a halogen. In the examples, X ^78AIs F.

R ^79AIndependently is a pendant oxy group, a halogen, -CX ^79A ₃、-CHX ^79A ₂、-OCH ₂X ^79A、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^79A ₃、-OCHX ^79A ₂Quilt R ^80ASubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^80ASubstituted or unsubstituted heteroalkyl by R ^80ASubstituted or unsubstituted cycloalkyl, by R ^80ASubstituted or unsubstitutedIs substituted with R ^80ASubstituted or unsubstituted aryl or by R ^80ASubstituted or unsubstituted heteroaryl. X ^79AIs a halogen. In the examples, X ^79AIs F.

In the examples, R ^17BIndependently hydrogen, pendant oxy, halogen, -CX ^17B ₃、-CHX ^17B ₂、-OCH ₂X ^17B、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^17B ₃、-OCHX ^17B ₂Quilt R ^78BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^78BSubstituted or unsubstituted heteroalkyl by R ^78BSubstituted or unsubstituted cycloalkyl, by R ^78BSubstituted or unsubstituted heterocycloalkyl, by R ^78BSubstituted or unsubstituted aryl or by R ^78BSubstituted or unsubstituted heteroaryl. X ^17BIs a halogen. In the examples, X ^17BIs F.

R ^78BIndependently is a pendant oxy group, a halogen, -CX ^78B ₃、-CHX ^78B ₂、-OCH ₂X ^78B、-OCHX ^78B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^78B ₃、-OCHX ^78B ₂Quilt R ^79BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^79BSubstituted or unsubstituted heteroalkyl by R ^79BSubstituted or unsubstituted cycloalkyl, by R ^79BSubstituted or unsubstituted heterocycloalkyl, by R ^79BSubstituted or unsubstituted aryl or by R ^79BSubstituted or unsubstitutedThe heteroaryl group of (a). X ^78BIs a halogen. In the examples, X ^78BIs F.

R ^79BIndependently is a pendant oxy group, a halogen, -CX ^79B ₃、-CHX ^79B ₂、-OCH ₂X ^79B、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^79B ₃、-OCHX ^79B ₂Quilt R ^80BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^80BSubstituted or unsubstituted heteroalkyl by R ^80BSubstituted or unsubstituted cycloalkyl, by R ^80BSubstituted or unsubstituted heterocycloalkyl, by R ^80BSubstituted or unsubstituted aryl or by R ^80BSubstituted or unsubstituted heteroaryl. X ^79BIs a halogen. In the examples, X ^79BIs F.

In the examples, R ^17CIndependently hydrogen, pendant oxy, halogen, -CX ^17C ₃、-CHX ^17C ₂、-OCH ₂X ^17C、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^17C ₃、-OCHX ^17C ₂Quilt R ^78CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^78CSubstituted or unsubstituted heteroalkyl by R ^78CSubstituted or unsubstituted cycloalkyl, by R ^78CSubstituted or unsubstituted heterocycloalkyl, by R ^78CSubstituted or unsubstituted aryl or by R ^78CSubstituted or unsubstituted heteroaryl. X ^17CIs a halogen. In the examples, X ^17CIs F.

R ^78CIndependently of each otherIs a pendant oxy group, a halogen, -CX ^78C ₃、-CHX ^78C ₂、-OCH ₂X ^78C、-OCHX ^78C ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^78C ₃、-OCHX ^78C ₂Quilt R ^79CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^79CSubstituted or unsubstituted heteroalkyl by R ^79CSubstituted or unsubstituted cycloalkyl, by R ^79CSubstituted or unsubstituted heterocycloalkyl, by R ^79CSubstituted or unsubstituted aryl or by R ^79CSubstituted or unsubstituted heteroaryl. X ^78CIs a halogen. In the examples, X ^78CIs F.

R ^79CIndependently is a pendant oxy group, a halogen, -CX ^79C ₃、-CHX ^79C ₂、-OCH ₂X ^79C、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^79C ₃、-OCHX ^79C ₂Quilt R ^80CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^80CSubstituted or unsubstituted heteroalkyl by R ^80CSubstituted or unsubstituted cycloalkyl, by R ^80CSubstituted or unsubstituted heterocycloalkyl, by R ^80CSubstituted or unsubstituted aryl or by R ^80CSubstituted or unsubstituted heteroaryl. X ^79CIs a halogen. In the examples, X ^79CIs F.

In the examples, R ^17DIndependently hydrogen, pendant oxy, halogen, -CX ^17D ₃、-CHX ^17D ₂、-OCH ₂X ^17D、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^17D ₃、-OCHX ^17D ₂Quilt R ^78DSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^78DSubstituted or unsubstituted heteroalkyl by R ^78DSubstituted or unsubstituted cycloalkyl, by R ^78DSubstituted or unsubstituted heterocycloalkyl, by R ^78DSubstituted or unsubstituted aryl or by R ^78DSubstituted or unsubstituted heteroaryl. X ^17DIs a halogen. In the examples, X ^17DIs F.

R ^78DIndependently is a pendant oxy group, a halogen, -CX ^78D ₃、-CHX ^78D ₂、-OCH ₂X ^78D、-OCHX ^78D ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^78D ₃、-OCHX ^78D ₂、R ^79D-substituted or unsubstituted alkyl, R ^79D-substituted or unsubstituted heteroalkyl, R ^79D-substituted or unsubstituted cycloalkyl, R ^79D-substituted or unsubstituted heterocycloalkyl, R ^79D-substituted or unsubstituted aryl or R ^79D-substituted or unsubstituted heteroaryl. X ^78DIs a halogen. In the examples, X ^78DIs F.

R ^79DIndependently is a pendant oxy group, a halogen, -CX ^79D ₃、-CHX ^79D ₂、-OCH ₂X ^79D、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^79D ₃、-OCHX ^79D ₂Quilt R ^80DSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^80DSubstituted or unsubstituted heteroalkyl by R ^80DSubstituted or unsubstituted cycloalkyl, by R ^80DSubstituted or unsubstituted heterocycloalkyl, by R ^80DSubstituted or unsubstituted aryl or by R ^80DSubstituted or unsubstituted heteroaryl. X ^79DIs a halogen. In the examples, X ^79DIs F.

In the examples, R ¹⁸Is hydrogen. In the examples, R ¹⁸Is halogen. In the examples, R ¹⁸Is CX ¹⁸ ₃. In the examples, R ¹⁸is-CHX ¹⁸ ₂. In the examples, R ¹⁸is-CH ₂X ¹⁸. In the examples, R ¹⁸is-CN. In the examples, R ¹⁸is-SO _n18R ^18D. In the examples, R ¹⁸is-SO _v18NR ^18AR ^18B. In the examples, R ¹⁸is-NHNR ^18AR ^18B. In the examples, R ¹⁸is-ONR ^18AR ^18B. In the examples, R ¹⁸is-NHC ═ O-NHNR ^18AR ^18B. In the examples, R ¹⁸is-NHC (O) NR ^18AR ^18B. In the examples, R ¹⁸is-N (O) _m18. In the examples, R ¹⁸is-NR ^18AR ^18B. In the examples, R ¹⁸is-C (O) R ^18C. In the examples, R ¹⁸is-C (O) -OR ^18C. In the examples, R ¹⁸is-C (O) NR ^18AR ^18B. In the examples, R ¹⁸is-OR ^18D. In the examples, R ¹⁸is-NR ^18ASO ₂R ^18D. In the examples, R ¹⁸is-NR ^18AC(O)R ^18C. In the examples, R ¹⁸is-NR ^18AC(O)OR ^18C. In the examples, R ¹⁸is-NR ^18AOR ^18C. In the examples, R ¹⁸is-OCX ¹⁸ ₃. In the examples, R ¹⁸is-OCHX ¹⁸ ₂. In the examples, R ¹⁸Is a substituted or unsubstituted alkyl group. In the examples, R ¹⁸Is a substituted or unsubstituted heteroalkyl group. In the examples, R ¹⁸Is a substituted or unsubstituted cycloalkyl. In the examples, R ¹⁸Is a substituted or unsubstituted heterocycloalkyl. In the examples, R ¹⁸Is substituted or unsubstituted aryl. In the examples, R ¹⁸Is a substituted or unsubstituted heteroaryl. In the examples, R ¹⁸Is a substituted alkyl group. In the examples, R ¹⁸Is a substituted heteroalkyl group. In the examples, R ¹⁸Is a substituted cycloalkyl group. In the examples, R ¹⁸Is a substituted heterocycloalkyl group. In the examples, R ¹⁸Is a substituted aryl group. In the examples, R ¹⁸Is a substituted heteroaryl group. In the examples, R ¹⁸Is unsubstituted alkyl. In the examples, R ¹⁸Is unsubstituted heteroalkyl. In the examples, R ¹⁸Is unsubstituted cycloalkyl. In the examples, R ¹⁸Is unsubstituted heterocycloalkyl. In the examples, R ¹⁸Is unsubstituted aryl. In the examples, R ¹⁸Is unsubstituted heteroaryl. In the examples, R ¹⁸Is unsubstituted methyl. In the examples, R ¹⁸Is unsubstituted ethyl. In the examples, R ¹⁸Is unsubstituted propyl. In the examples, R ¹⁸Is unsubstituted isopropyl. In the examples, R ¹⁸Is unsubstituted butyl. In the examples, R ¹⁸Is unsubstituted tert-butyl.

In the examples, R ^18AIs hydrogen. In the examples, R ^18Ais-CX ₃. In the examples, R ^18Ais-CN. In the examples, R ^18Ais-COOH. In the examples, R ^18Ais-CONH ₂. In the examples, R ^18Ais-CHX ₂. In the examples, R ^18Ais-CH ₂And (4) X. In the examples, R ^18AIs unsubstituted methyl. In the examples, R ^18AIs unsubstituted ethyl. In the examples, R ^18AIs unsubstituted propyl. In the examples, R ^18AIs unsubstituted isopropyl. In the examples, R ^18AIs unsubstituted butyl. In the examples, R ^18AIs unsubstituted tert-butyl.

In the examples, R ^18BIs hydrogen. In the examples, R ^18Bis-CX ₃. In the examples, R ^18Bis-CN. In the examples, R ^18Bis-COOH. In the examples, R ^18Bis-CONH ₂. In the examples, R ^18Bis-CHX ₂. In the examples, R ^18Bis-CH ₂And (4) X. In the examples, R ^18BIs unsubstituted methyl. In the examples, R ^18BIs unsubstituted ethyl. In the examples, R ^18BIs unsubstituted propyl. In the examples, R ^18BIs unsubstituted isopropyl. In the examples, R ^18BIs unsubstituted butyl. In the examples, R ^18BIs unsubstituted tert-butyl.

In the examples, R ^18CIs hydrogen. In the examples, R ^18Cis-CX ₃. In the examples, R ^18Cis-CN. In the examples, R ^18Cis-COOH. In the examples, R ^18Cis-CONH ₂. In the examples, R ^18Cis-CHX ₂. In the examples, R ^18Cis-CH ₂And (4) X. In the examples, R ^18CIs unsubstituted methyl. In the examples, R ^18CIs unsubstituted ethyl. In the examples, R ^18CIs unsubstituted propyl. In the examples, R ^18CIs unsubstituted isopropyl. In the examples, R ^18CIs unsubstituted butyl. In the examples, R ^18CIs unsubstituted tert-butyl.

In the examples, R ^18DIs hydrogen. In the examples，R ^18Dis-CX ₃. In the examples, R ^18Dis-CN. In the examples, R ^18Dis-COOH. In the examples, R ^18Dis-CONH ₂. In the examples, R ^18Dis-CHX ₂. In the examples, R ^18Dis-CH ₂And (4) X. In the examples, R ^18DIs unsubstituted methyl. In the examples, R ^18DIs unsubstituted ethyl. In the examples, R ^18DIs unsubstituted propyl. In the examples, R ^18DIs unsubstituted isopropyl. In the examples, R ^18DIs unsubstituted butyl. In the examples, R ^18DIs unsubstituted tert-butyl.

In the examples, R ¹⁸Independently hydrogen, pendant oxy, halogen, -CX ¹⁸ ₃、-CHX ¹⁸ ₂、-OCH ₂X ¹⁸、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ¹⁸ ₃、-OCHX ¹⁸ ₂Quilt R ⁸¹Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁸¹Substituted or unsubstituted heteroalkyl by R ⁸¹Substituted or unsubstituted cycloalkyl, by R ⁸¹Substituted or unsubstituted heterocycloalkyl, by R ⁸¹Substituted or unsubstituted aryl or by R ⁸¹Substituted or unsubstituted heteroaryl. X ¹⁸Is a halogen. In the examples, X ¹⁸Is F.

R ⁸¹Independently is a pendant oxy group, a halogen, -CX ⁸¹ ₃、-CHX ⁸¹ ₂、-OCH ₂X ⁸¹、-OCHX ⁸¹ ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ⁸¹ ₃、-OCHX ⁸¹ ₂Quilt R ⁸²Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁸²Substituted or unsubstituted heteroalkyl by R ⁸²Substituted or unsubstituted cycloalkyl, by R ⁸²Substituted or unsubstituted heterocycloalkyl, by R ⁸²Substituted or unsubstituted aryl or by R ⁸²Substituted or unsubstituted heteroaryl. X ⁸¹Is a halogen. In the examples, X ⁸¹Is F.

R ⁸²Independently is a pendant oxy group, a halogen, -CX ⁸² ₃、-CHX ⁸² ₂、-OCH ₂X ⁸²、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ⁸² ₃、-OCHX ⁸² ₂Quilt R ⁸³Substituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ⁸³Substituted or unsubstituted heteroalkyl by R ⁸³Substituted or unsubstituted cycloalkyl, by R ⁸³Substituted or unsubstituted heterocycloalkyl, by R ⁸³Substituted or unsubstituted aryl or by R ⁸³Substituted or unsubstituted heteroaryl. X ⁸²Is a halogen. In the examples, X ⁸²Is F.

In the examples, R ^18AIndependently hydrogen, pendant oxy, halogen, -CX ^18A ₃、-CHX ^18A ₂、-OCH ₂X ^18A、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^18A ₃、-OCHX ^18A ₂Quilt R ^81ASubstitutionOr unsubstituted alkyl, by R ^81ASubstituted or unsubstituted heteroalkyl by R ^81ASubstituted or unsubstituted cycloalkyl, by R ^81ASubstituted or unsubstituted heterocycloalkyl, by R ^81ASubstituted or unsubstituted aryl or by R ^81ASubstituted or unsubstituted heteroaryl. X ^18AIs a halogen. In the examples, X ^18AIs F.

R ^81AIndependently is a pendant oxy group, a halogen, -CX ^81A ₃、-CHX ^81A ₂、-OCH ₂X ^81A、-OCHX ^81A ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^81A ₃、-OCHX ^81A ₂Quilt R ^82ASubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^82ASubstituted or unsubstituted heteroalkyl by R ^82ASubstituted or unsubstituted cycloalkyl, by R ^82ASubstituted or unsubstituted heterocycloalkyl, by R ^82ASubstituted or unsubstituted aryl or by R ^82ASubstituted or unsubstituted heteroaryl. X ^81AIs a halogen. In the examples, X ^81AIs F.

R ^82AIndependently is a pendant oxy group, a halogen, -CX ^82A ₃、-CHX ^82A ₂、-OCH ₂X ^82A、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^82A ₃、-OCHX ^82A ₂Quilt R ^83ASubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^83ASubstituted or unsubstituted heteroalkyl by R ^83ASubstituted or unsubstituted cycloalkylQuilt R ^83ASubstituted or unsubstituted heterocycloalkyl, by R ^83ASubstituted or unsubstituted aryl or by R ^83ASubstituted or unsubstituted heteroaryl. X ^82AIs a halogen. In the examples, X ^82AIs F.

In the examples, R ^18BIndependently hydrogen, pendant oxy, halogen, -CX ^18B ₃、-CHX ^18B ₂、-OCH ₂X ^18B、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^18B ₃、-OCHX ^18B ₂Quilt R ^81BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^81BSubstituted or unsubstituted heteroalkyl by R ^81BSubstituted or unsubstituted cycloalkyl, by R ^81BSubstituted or unsubstituted heterocycloalkyl, by R ^81BSubstituted or unsubstituted aryl or by R ^81BSubstituted or unsubstituted heteroaryl. X ^18BIs a halogen. In the examples, X ^18BIs F.

R ^81BIndependently is a pendant oxy group, a halogen, -CX ^81B ₃、-CHX ^81B ₂、-OCH ₂X ^81B、-OCHX ^81B ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^81B ₃、-OCHX ^81B ₂Quilt R ^82BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^82BSubstituted or unsubstituted heteroalkyl by R ^82BSubstituted or unsubstituted cycloalkyl, by R ^82BSubstituted or unsubstituted heterocycloalkyl, by R ^82BSubstituted or unsubstituted arylOr by R ^82BSubstituted or unsubstituted heteroaryl. X ^81BIs a halogen. In the examples, X ^81BIs F.

R ^82BIndependently is a pendant oxy group, a halogen, -CX ^82B ₃、-CHX ^82B ₂、-OCH ₂X ^82B、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^82B ₃、-OCHX ^82B ₂Quilt R ^83BSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^83BSubstituted or unsubstituted heteroalkyl by R ^83BSubstituted or unsubstituted cycloalkyl, by R ^83BSubstituted or unsubstituted heterocycloalkyl, by R ^83BSubstituted or unsubstituted aryl or by R ^83BSubstituted or unsubstituted heteroaryl. X ^82BIs a halogen. In the examples, X ^82BIs F.

In the examples, R ^18CIndependently hydrogen, pendant oxy, halogen, -CX ^18C ₃、-CHX ^18C ₂、-OCH ₂X ^18C、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^18C ₃、-OCHX ^18C ₂Quilt R ^81CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^81CSubstituted or unsubstituted heteroalkyl by R ^81CSubstituted or unsubstituted cycloalkyl, by R ^81CSubstituted or unsubstituted heterocycloalkyl, by R ^81CSubstituted or unsubstituted aryl or by R ^81CSubstituted or unsubstituted heteroaryl. X ^18CIs a halogen. In the examples, X ^18CIs F.

R ^81CIndependently is a pendant oxy group, a halogen, -CX ^81C ₃、-CHX ^81C ₂、-OCH ₂X ^81C、-OCHX ^81C ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^81C ₃、-OCHX ^81C ₂Quilt R ^82CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^82CSubstituted or unsubstituted heteroalkyl by R ^82CSubstituted or unsubstituted cycloalkyl, by R ^82CSubstituted or unsubstituted heterocycloalkyl, by R ^82CSubstituted or unsubstituted aryl or by R ^82CSubstituted or unsubstituted heteroaryl. X ^81CIs a halogen. In the examples, X ^81CIs F.

R ^82CIndependently is a pendant oxy group, a halogen, -CX ^82C ₃、-CHX ^82C ₂、-OCH ₂X ^82C、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^82C ₃、-OCHX ^82C ₂Quilt R ^83CSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^83CSubstituted or unsubstituted heteroalkyl by R ^83CSubstituted or unsubstituted cycloalkyl, by R ^83CSubstituted or unsubstituted heterocycloalkyl, by R ^83CSubstituted or unsubstituted aryl or by R ^83CSubstituted or unsubstituted heteroaryl. X ^82CIs a halogen. In the examples, X ^82CIs F.

In the examples, R ^18DIndependently hydrogen, pendant oxy, halogen, -CX ^18D ₃、-CHX ^18D ₂、-OCH ₂X ^18D、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^18D ₃、-OCHX ^18D ₂Quilt R ^81DSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^81DSubstituted or unsubstituted heteroalkyl by R ^81DSubstituted or unsubstituted cycloalkyl, by R ^81DSubstituted or unsubstituted heterocycloalkyl, by R ^81DSubstituted or unsubstituted aryl or by R ^81DSubstituted or unsubstituted heteroaryl. X ^18DIs a halogen. In the examples, X ^18DIs F.

R ^81DIndependently is a pendant oxy group, a halogen, -CX ^81D ₃、-CHX ^81D ₂、-OCH ₂X ^81D、-OCHX ^81D ₂、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^81D ₃、-OCHX ^81D ₂Quilt R ^82DSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^82DSubstituted or unsubstituted heteroalkyl by R ^82DSubstituted or unsubstituted cycloalkyl, by R ^82DSubstituted or unsubstituted heterocycloalkyl, by R ^82DSubstituted or unsubstituted aryl or by R ^82DSubstituted or unsubstituted heteroaryl. X ^81DIs a halogen. In the examples, X ^81DIs F.

R ^82DIndependently is a pendant oxy group, a halogen, -CX ^82D ₃、-CHX ^82D ₂、-OCH ₂X ^82D、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC＝(O)NHNH ₂、-NHC＝(O)NH ₂、-NHSO ₂H、-NHC＝(O)H、-NHC(O)-OH、-NHOH、-OCX ^82D ₃、-OCHX ^82D ₂Quilt R ^83DSubstituted or unsubstituted alkyl, or substituted or unsubstituted alkyl ^83DSubstituted or unsubstituted heteroalkyl by R ^83DSubstituted or unsubstituted cycloalkyl, by R ^83DSubstituted or unsubstituted heterocycloalkyl, by R ^83DSubstituted or unsubstituted aryl or by R ^83DSubstituted or unsubstituted heteroaryl. X ^82DIs a halogen. In the examples, X ^82DIs F.

R ⁷⁴、R ⁷⁷、R ⁸⁰、R ⁸³、R ^74A、R ^77A、R ^80A、R ^83A、R ^74B、R ^77B、R ^80B、R ^83B、R ^74C、R ^77C、R ^80C、R ^83C、R ^74D、R ^77D、R ^80D、R ^83D、R ⁸⁶、R ⁸⁹、R ⁹²And R ⁹⁸Independently hydrogen, pendant oxy, halogen, -CF ₃、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC(O)NHNH ₂、-NHC(O)NH ₂、-NHSO ₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF ₃、-OCHF ₂Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In the examples, R ⁷⁴、R ⁷⁷、R ⁸⁰、R ⁸³、R ^74A、R ^77A、R ^80A、R ^83A、R ^74B、R ^77B、R ^80B、R ^83B、R ^74C、R ^77C、R ^80C、R ^83C、R ^74D、R ^77D、R ^80D、R ^83D、R ⁸⁶、R ⁸⁹、R ⁹²And R ⁹⁸Independently is a pendant oxy group, halogen, -CF ₃、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC(O)NHNH ₂、-NHC(O)NH ₂、-NHSO ₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF ₃、-OCHF ₂Unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In the examples, R ⁷⁴、R ⁷⁷、R ⁸⁰、R ⁸³、R ^74A、R ^77A、R ^80A、R ^83A、R ^74B、R ^77B、R ^80B、R ^83B、R ^74C、R ^77C、R ^80C、R ^83C、R ^74D、R ^77D、R ^80D、R ^83D、R ⁸⁶、R ⁸⁹、R ⁹²And R ⁹⁸Independently is a pendant oxy group, halogen, -CF ₃、-CN、-OH、-NH ₂、-COOH、-CONH ₂、-NO ₂、-SH、-SO ₃H、-SO ₄H、-SO ₂NH ₂、-NHNH ₂、-ONH ₂、-NHC(O)NHNH ₂、-NHC(O)NH ₂、-NHSO ₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCF ₃、-OCHF ₂Unsubstituted C ₁-C ₈Alkyl, unsubstituted 2-to 8-membered heteroalkyl, unsubstituted C ₃-C ₈Cycloalkyl, unsubstituted 3-to 6-membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5-to 6-membered heteroaryl.

In the examples, R ¹⁵、R ¹⁶、R ¹⁷And R ¹⁸Is hydrogen.

In an embodiment, E is:

in an embodiment, E is:

in an embodiment, E is: in an embodiment, E is:

in an embodiment, E is:

in some embodiments, a compound as described herein may include R ¹Or R ²And/or multiple instances of other variables. In such embodiments, each variable may optionally be different, and for higher clarity, appropriately labeled to distinguish each group. For example, at each R ¹And/or R ²In different cases, they may be referred to as, for example, R, respectively ^1.1、R ^1.2、R ^1.3、R ^1.4、R ^1.5、R ^2.1、R ^2.2、R ^2.3Or R ^2.4Wherein R is ¹Is defined by R ^1.1、R ^1.2、R ^1.3、R ^1.4、R ^1.5Adopting; and/or R ²From R ^2.1、R ^2.2、R ^2.3、R ^2.4The method is adopted. At R ¹And/or R ²And/or other variables that occur at multiple instances and that are different may be similarly labeled as appropriate for higher clarity to distinguish groups. In some embodiments, the compound is as described hereinThe compound (e.g., in an aspect, embodiment, example, claim, table, scheme, figure, or figure).

In the examples, unless otherwise indicated, the compounds described herein are racemic mixtures of all stereoisomers. In the examples, unless otherwise indicated, the compounds described herein are racemic mixtures of all enantiomers. In the examples, unless otherwise indicated, the compounds described herein are racemic mixtures of two relative stereoisomers. In the examples, unless otherwise indicated, the compounds described herein are racemic mixtures of two relative enantiomers. In the examples, unless otherwise indicated, the compounds described herein are single stereoisomers. In the examples, unless otherwise indicated, the compounds described herein are single enantiomers. In embodiments, the compound is a compound described herein (e.g., in an aspect, embodiment, example, figure, table, scheme, or claim).

In one aspect, serine/threonine-protein phosphatase 2A regulatory subunit a α isoform (PPP2R1A) modulators (i.e., PPP2R1A modulators) are provided in embodiments, serine/threonine-protein phosphatase 2A regulatory subunit a α isoform (PPP2R1A) modulators (i.e., PPP2R1A modulators) increase protein phosphatase 2A activity (e.g., can additionally optionally inhibit AKT/protein kinase B signaling by increasing PP2A activity) in embodiments, PPP2R1A modulators are compounds described herein in embodiments, PPP2R1A modulators are oligonucleotides (e.g., DNA, RNA, shRNA or siRNA), proteins (e.g., antibodies, anti-PPP 2R1A antibodies, anti-PPP 2R1A antibody fragments), theafennetin a or compounds (e.g., compounds described herein) in embodiments, PPP2R1A modulators are contacted with the human phosphatase 2A regulatory subunit a 264, the protein a phosphatase 2R 1R 2R1A antibody fragment, the human phtennin a or a compound corresponding to one of human phosphatase 2 e.g., human protein kinase e.g., P2R1, P6326, P2R 2H, P2R 1B, P2H, P2R 1B, P2H, P1B, P2R 1B, P2H, P1B, P1, P2H, P1, P2.

In one embodiment, PPP2R1A modulator covalently binds to an amino acid corresponding to C377 SEQ ID NO:4 in one embodiment, PPP2R1A modulator contacts an amino acid corresponding to H340 SEQ ID NO:4 in one embodiment, PPP2R1A modulator contacts an amino acid corresponding to S343 SEQ ID NO:4 in one embodiment, PPP2R1 modulator contacts an amino acid corresponding to E379SEQ ID NO:4 in one embodiment, PPP2R1 modulator contacts an amino acid corresponding to Q339 SEQ ID NO:4 in one embodiment, PPP2R1A modulator contacts an amino acid corresponding to K416 SEQ ID NO:4 in one embodiment, PPP2R1A modulator contacts an amino acid corresponding to N264, Q272, D290 and M245 SEQ ID NO:6 in one or more amino acids corresponding to human amino acid modulators of PPP2R1, PPP2R1A, contact with an amino acid corresponding to N264, Q272, D290, human amino acid A, 366, A, 366, A, 366, or 366, A, 366, A, 366, A, 366, A, 366, A, 366, A, 366, A, 366.

In embodiments, the compound has the formula: R ¹z1 and R ⁴As described herein.

In embodiments, the compound has the formula: L ²and E is as described herein.

In embodiments, the compound has the formula:

R ¹and z1 are as described herein.

In embodiments, the compound has the formula:

R ¹、R ⁴and z1 are as described herein.

In embodiments, the compound has the formula:

in embodiments, the compound has the formula:

in embodiments, the compound has the formula: in embodiments, the compound is theafenfenitin a.

Pharmaceutical compositions

In one aspect, a pharmaceutical composition is provided that includes a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isomer (PPP2R1A) modulator and a pharmaceutically acceptable excipient in embodiments, the PPP2R1A modulator is a compound described herein in embodiments, the PPP2R1A modulator is an oligonucleotide (e.g., DNA, RNA, or siRNA), an antisense nucleic acid, a protein (e.g., an antibody, an anti-PPP 2R1A antibody, an anti-PPP 2R1A binding antibody fragment), theafenidin a, or a compound (e.g., a compound described herein) in embodiments, a PPP2R1A modulator is included in a therapeutically effective amount.

In one aspect, a pharmaceutical composition is provided that includes a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In an embodiment of the pharmaceutical composition, the compound or pharmaceutically acceptable salt is included in a therapeutically effective amount.

In an embodiment of the pharmaceutical composition, the pharmaceutical composition includes a second agent (e.g., a therapeutic agent). In an embodiment of the pharmaceutical composition, the pharmaceutical composition includes a therapeutically effective amount of a second agent (e.g., a therapeutic agent). In an embodiment of the pharmaceutical composition, the second agent is an agent for treating cancer. In embodiments, the second agent is an anti-cancer agent. In an embodiment, the second agent is a chemotherapeutic agent.

Methods of treatment

In one aspect, a method of treating cancer is provided, the method comprising administering to an individual in need thereof an effective amount of a modulator of the serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isomer (PPP2R1A) in embodiments, the PPP2R1A modulator is a compound described herein in embodiments, the PPP2R1A modulator is an oligonucleotide (e.g., DNA, RNA, or siRNA), an antisense nucleic acid, a protein (e.g., an antibody, an anti-PPP 2R1A antibody, an anti-PPP 2R1A antibody fragment), theafenidin a, or a compound (e.g., a compound described herein) in embodiments, a PPP2R1A modulator is included in a therapeutically effective amount.

In one aspect, there is provided a method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of a compound described herein. In an embodiment, the cancer is a gynecological cancer. In an embodiment, the cancer is uterine cancer. In an embodiment, the cancer is ovarian cancer. In embodiments, the cancer is endometrial cancer. In an embodiment, the cancer is vulvar cancer. In an embodiment, the cancer is colon cancer. In an embodiment, the cancer is breast cancer. In an embodiment, the cancer is estrogen receptor positive breast cancer. In an embodiment, the cancer is Estrogen Receptor (ER) negative breast cancer. In an embodiment, the cancer is tamoxifen resistant breast cancer. In an embodiment, the cancer is HER2 negative breast cancer. In an embodiment, the cancer is HER2 positive breast cancer. In an embodiment, the cancer is low-grade (well-differentiated) breast cancer. In an embodiment, the cancer is moderate grade (mesodifferentiated) breast cancer. In an embodiment, the cancer is high-grade (poorly differentiated) breast cancer. In an embodiment, the cancer is stage 0 breast cancer. In an embodiment, the cancer is stage I breast cancer. In an embodiment, the cancer is stage II breast cancer. In an embodiment, the cancer is stage III breast cancer. In an embodiment, the cancer is stage IV breast cancer. In an embodiment, the cancer is triple negative breast cancer. In an embodiment, the cancer is glioblastoma. In an embodiment, the cancer is pancreatic cancer. In an embodiment, the cancer is prostate cancer. In embodiments, the cancer is a metastatic cancer.

In embodiments, the cancer is associated with a cysteine-containing protein. In embodiments, the cancer expresses a cysteine-containing protein. In embodiments, the compound is contacted with (e.g., covalently bound to) a cysteine-containing protein. In embodiments, the compound is contacted with (e.g., covalently bound to) a cysteine-containing protein. In the examples, the compounds are covalently reacted with cysteine-containing proteins.

In one aspect, a method of treating cancer is provided, the method comprising administering to an individual in need thereof an effective amount of a cysteine modulator (e.g., a compound described herein). As used herein, a cysteine modulator is a compound that modulates (e.g., increases or decreases) the content activity of a protein relative to the content or activity of the protein in the absence of the modulator. In an embodiment, the cancer is associated with a cysteine-containing protein. In embodiments, the cancer expresses a cysteine-containing protein. In embodiments, the compound is contacted with (e.g., covalently bound to) a cysteine-containing protein. In embodiments, the compound is contacted with (e.g., covalently bound to) a cysteine-containing protein. In the examples, the compounds are covalently reacted with cysteine-containing proteins.

In one aspect, a method of treating a cancer associated with an AKT/protein kinase B signaling pathway (e.g., AKT protein activity) is provided, the method comprising administering to an individual in need thereof an effective amount of a serine/threonine-protein phosphatase 2A regulatory subunit a α isomer (PPP2R1A) modulator, in embodiments, the PPP2R1A modulator is a compound described herein, in embodiments, the PPP2R1A modulator is an oligonucleotide (e.g., DNA, RNA, or siRNA), a protein (e.g., an antibody, an anti-PPP 2R1A antibody, an anti-PPP 2R1A antibody fragment), theafenidin a, or a compound (e.g., a compound described herein), in embodiments, a PPP2R1A modulator is included in a therapeutically effective amount.

In one aspect, a method is provided for treating a disease associated with protein phosphatase 2A (PP2A) activity (e.g., increasing or activating PP2A phosphatase activity), the method comprising administering to an individual in need thereof an effective amount of a serine/threonine-protein phosphatase 2A regulatory subunit a α isomer (PPP2R1A) modulator, in an embodiment, the PPP2R1A modulator is a compound described herein, in an embodiment, the PPP2R1A modulator is an oligonucleotide (e.g., DNA, RNA, or siRNA), a protein (e.g., an antibody, an anti-PPP 2R1A antibody, an anti-PPP 2R1A antibody fragment), theafenidin a, or a compound (e.g., a compound described herein), in an embodiment, a PPP2R1A modulator is included in a therapeutically effective amount.

In one aspect, a method of treating a disease, including an activator protein phosphatase 2A (PP2A) complex, by administering to an individual in need thereof an effective amount of a serine/threonine-protein phosphatase 2A regulatory subunit a α isoform (PPP2R1A) modulator in embodiments, the PPP2R1A modulator is a compound described herein, in embodiments, the PPP2R1A modulator is an oligonucleotide (e.g., DNA, RNA, or siRNA), a protein (e.g., an antibody, an anti-PPP 2R1A antibody, an anti-PPP 2R1A antibody fragment), theafenidin a, or a compound (e.g., a compound described herein), in embodiments, a PPP2R1A modulator is included in a therapeutically effective amount.

In embodiments, the method comprises administering a second agent (e.g., a therapeutic agent). In embodiments, the method comprises administering a second agent (e.g., a therapeutic agent) in a therapeutically effective amount. In an embodiment, the second agent is an agent for treating cancer. In embodiments, the second agent is an anti-cancer agent. In an embodiment, the second agent is a chemotherapeutic agent.

V. regulating method

In one aspect, a method of modulating a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isomer (PPP2R1A) protein is provided, the method comprising contacting the serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isomer (PPP2R1A) protein with an effective amount of a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isomer (PPP2R1A) modulator (e.g., a compound described herein). in embodiments, the modulation alters a physical state of the PPP2R1A protein (e.g., covalently modifies the protein). in embodiments, the modulation alters a physical state of the PPP2R1A protein (e.g., covalently modifies the protein), which activates the pp2a. in embodiments, the modulation comprises activating PP2A (e.g., and inhibiting AKT signaling).

In one aspect, a method of activating tumor suppressor protein phosphatase 2A (PP2A) is provided, the method comprising contacting a serine/threonine-protein phosphatase 2A65kDa regulatory subunit a α isomer (PPP2R1A) protein with an effective amount of a serine/threonine-protein phosphatase 2A65kDa regulatory subunit a α isomer (PPP2R1A) modulator (e.g., a compound described herein).

In one aspect, a method of modulating PPP2R1A is provided, the method comprising contacting PPP2R1A with a PPP2R1A modulator. In embodiments, PPP2R1A is human PPP2R 1A. In embodiments, the PPP2R1A modulator is a compound described herein. In embodiments, the PPP2R1A modulator is an oligonucleotide (e.g., DNA, RNA, or siRNA), a protein (e.g., an antibody, an anti-PPP 2R1A antibody, an anti-PPP 2R1A binding antibody fragment), or a compound (e.g., a compound described herein). In embodiments, the PPP2R1A modulator is provided in a therapeutically effective amount.

In embodiments, the PPP2R1A modulator is contacted with one or more amino acids corresponding to E379, H340, S343, C377, C198, Q339, and K416 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is covalently bound to an amino acid corresponding to C377 in human PPP2R 1A. In embodiments, the PPP2R1A modulator is covalently bound to an amino acid corresponding to C198 in human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with amino acids corresponding to E379, H340, S343, C377, Q339, K416, and H340 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to E379 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to H340 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to S343 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to C377 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to Q339 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to K416 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to H340 of human PPP2R 1A.

In embodiments, the PPP2R1A modulator is contacted with one or more amino acids corresponding to E379, H340, S343, C377, C198, Q339, and K416 of SEQ ID No. 4. In an example, a PPP2R1A modulator is covalently bound to an amino acid corresponding to C377 in SEQ ID NO. 4. In an example, the PPP2R1A modulator is covalently bound to the amino acid corresponding to C198 in SEQ ID No. 4. In embodiments, the PPP2R1A modulator is contacted with amino acids corresponding to E379, H340, S343, C377, Q339, K416 and H340 of SEQ ID No. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to E379 of SEQ ID No. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to H340 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with the amino acid corresponding to S343 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to C377 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to Q339 of SEQ ID No. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to K416 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to H340 of SEQ ID NO. 4.

When the compound is covalently bound to PPP2R1A, a PPP2R1A protein (e.g., human PPP2R1A) (also referred to herein as a "PPP 2R 1A-compound adduct") covalently bound to a PPP2R1A modulator is formed, as described below. In embodiments, the resulting covalent bonds are reversible. Where the resulting covalent bond is reversible, the bond is reversed upon denaturation of the protein. Thus, in embodiments, the reversibility (relative to irreversibility) of the covalent bond between the compound and PPP2R1A after denaturation of PPP2R1A avoids or reduces an autoimmune response in the individual after administration of the compound. Furthermore, in the examples, the reversibility (relative to irreversibility) of the covalent bond between the compound and PPP2R1A following denaturation of PPP2R1A avoids or reduces toxicity (e.g., hepatotoxicity) of the compound in the subject.

In one aspect, a method of modulating the activity of protein phosphatase 2A (PP2A) is provided, the method comprising contacting a serine/threonine-protein phosphatase 2A65kDa regulatory subunit a α isoform (PPP2R1A) protein included in PP2CA with an effective amount of a serine/threonine-protein phosphatase 2A65kDa regulatory subunit a α isoform (PPP2R1A) modulator.

In one aspect, there is provided a method of modulating the activity of PP2CA, the method comprising contacting the serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isomer (PPP2R1A) protein of PP2CA with an effective amount of a compound described herein.

In one aspect, a method of modulating the activity of PP2CA is provided, the method comprising contacting PPP2R1A comprised in PP2CA with a PPP2R1A modulator. In embodiments, the PPP2R1A modulator is contacted with the PPP2R1A protein when it is not associated with the PP2CA complex (e.g., after formation of the PP2CA complex using the PPP2R1A protein). In embodiments, the PPP2R1A modulator is contacted with the PPP2R1A protein when associated with the PP2CA complex (e.g., after formation of the PP2CA complex using the PPP2R1A protein). In embodiments, PPP2R1A is human PPP2R 1A. In embodiments, the PPP2R1A modulator is a compound described herein. In embodiments, the PPP2R1A modulator is an oligonucleotide (e.g., DNA, RNA, or siRNA), a protein (e.g., an antibody, an anti-PPP 2R1A antibody, an anti-PPP 2R1A binding antibody fragment), or a compound (e.g., a compound described herein). In embodiments, the PPP2R1A modulator is provided in a therapeutically effective amount.

In embodiments, the PPP2R1A modulator is contacted with one or more amino acids corresponding to E379, H340, S343, C377, C198, Q339, and K416 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is covalently bound to an amino acid corresponding to C377 in human PPP2R 1A. In embodiments, the PPP2R1A modulator is covalently bound to an amino acid corresponding to C198 in human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with amino acids corresponding to E379, H340, S343, C377, C198, Q339, and K416 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to E379 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to H340 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to S343 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to C377 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to C198 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to Q339 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to K416 of human PPP2R 1A. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to H340 of human PPP2R 1A.

In embodiments, the PPP2R1A modulator is contacted with one or more amino acids corresponding to E379, H340, S343, C377, C198, Q339, and K416 of SEQ ID No. 4. In an example, a PPP2R1A modulator is covalently bound to an amino acid corresponding to C377 in SEQ ID NO. 4. In an example, the PPP2R1A modulator is covalently bound to the amino acid corresponding to C198 in SEQ ID No. 4. In embodiments, the PPP2R1A modulator is contacted with amino acids corresponding to E379, H340, S343, C377, C198, Q339, and K416 of SEQ ID No. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to E379 of SEQ ID No. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to H340 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with the amino acid corresponding to S343 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to C377 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with the amino acid corresponding to C198 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to Q339 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to K416 of SEQ ID No. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to H340 of SEQ ID NO. 4.

In an embodiment, the modulation is irreversible. In an embodiment, the modulation is reversible. In embodiments, the compound is covalently bound to PPP2R1A protein.

In the examples, a PPP2R1A modulator in combination with PPP2R1A increases the activity of PP2A (e.g., PPP2CA) activity. In the examples, a PPP2R1A modulator bound to PPP2R1A increases the activity of PP2A (e.g., PPP2CA) phosphatase activity. In embodiments, a PPP2R1A modulator that binds to PPP2R1A increases PP2A (e.g., PPP2CA) binding to another protein. In embodiments, a PPP2R1A modulator bound to PPP2R1A increases the dephosphorylation of PP2A (e.g., PPP2CA) of a protein. In embodiments, a PPP2R1A modulator that binds PPP2R1A increases PP2A (e.g., PPP2CA) dephosphorylation of Akt. In embodiments, a PPP2R1A modulator that binds PPP2R1A increases Akt dephosphorylation. In embodiments, a PPP2R1A modulator that binds to PPP2R1A increases PPP2R1A binding to PP2A (e.g., PPP2 CA). In embodiments, a PPP2R1A modulator that binds to PPP2R1A reduces cell division. In embodiments, a PPP2R1A modulator bound to PPP2R1A reduces the rate of cell division. In embodiments, a PPP2R1A modulator that binds to PPP2R1A reduces cell survival. In embodiments, a PPP2R1A modulator that binds to PPP2R1A reduces cell migration. In embodiments, a PPP2R1A modulator bound to PPP2R1A reduces actin cell backbone polymerization. In embodiments, a PPP2R1A modulator that binds PPP2R1A reduces actin cell backbone stability. In embodiments, a PPP2R1A modulator that binds to PPP2R1A reduces epithelial-mesenchymal transition. In embodiments, a PPP2R1A modulator that binds to PPP2R1A reduces the promotion of epithelial-mesenchymal transition. In embodiments, a PPP2R1A modulator that binds to PPP2R1A reduces angiogenesis.

PPP2R1A protein

In one aspect, a PPP2R1A protein (PPP2R1A protein PPP2R1A modulator complex) covalently bonded to a PPP2R1A modulator is provided. In embodiments, PPP2R1A is human PPP2R 1A. In embodiments, the PPP2R1A modulator is a compound described herein. In embodiments, the PPP2R1A modulator is an oligonucleotide (e.g., DNA, RNA, or siRNA), a protein (e.g., an antibody, an anti-PPP 2R1A antibody, an anti-PPP 2R1A binding antibody fragment), or a compound (e.g., a compound described herein). In embodiments, the PPP2R1A modulator is provided in a therapeutically effective amount.

In embodiments, the PPP2R1A modulator is contacted with one or more amino acids corresponding to E379, H340, S343, C377, C198, Q339, and K416 of SEQ ID No. 4. In an example, a PPP2R1A modulator is covalently bound to an amino acid corresponding to C377 in SEQ ID NO. 4. In embodiments, the PPP2R1A modulator is contacted with amino acids corresponding to E379, H340, S343, C377, C198, Q339, and K416 of SEQ ID No. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to E379 of SEQ ID No. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to H340 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with the amino acid corresponding to S343 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to C377 of SEQ ID NO. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to Q339 of SEQ ID No. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to K416 of SEQ ID No. 4. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to H340 of SEQ ID NO. 4.

In embodiments, the PPP2R1A modulator contacts one or more amino acids corresponding to M245; n264, Q272 and D290 of human PPP2 CA. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to M245 of human PPP2 CA. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to N264 of human PPP2 CA. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to Q272 of human PPP2 CA. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to D290 of human PPP2 CA.

In embodiments, the PPP2R1A modulator is contacted with one or more amino acids corresponding to M245, N264, Q272, and D290 of SEQ ID No. 6. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to M245 of SEQ ID No. 6. In an example, a PPP2R1A modulator is contacted with the amino acid corresponding to N264 of SEQ ID No. 6. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to Q272 of SEQ ID No. 6. In an example, a PPP2R1A modulator is contacted with the amino acid corresponding to D290 of SEQ ID No. 6.

In embodiments, the PPP2R1A modulator is contacted with one or more amino acids corresponding to E117, F118, and P113 of human PPP2R 5C. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to E117 of human PPP2R 5C. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to F118 of human PPP2R 5C. In embodiments, the PPP2R1A modulator is contacted with an amino acid corresponding to P113 of human PPP2R 5C.

In embodiments, the PPP2R1A modulator is contacted with one or more amino acids corresponding to E117, F118, and P113 of SEQ ID No. 5. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to E117 of SEQ ID No. 5. In an example, a PPP2R1A modulator is contacted with an amino acid corresponding to F118 of SEQ ID No. 5. In an example, a PPP2R1A modulator is contacted with the amino acid corresponding to P113 of SEQ ID No. 5.

In one aspect, there is provided a PPP2R1A protein covalently bound to a compound described herein. In embodiments, the compound is covalently bonded to an amino acid corresponding to C377 of human PPP2R1A (e.g., SEQ ID NO: 4). In embodiments, the compound is covalently bonded to an amino acid corresponding to C198 of human PPP2R1A (e.g., SEQ ID NO: 4). In embodiments, the compound is bound to a cysteine residue of PPP2R1A protein. In embodiments, the compound is covalently bonded to a cysteine residue of the PPP2R1A protein. In embodiments, the compound is reversibly covalently bound to a cysteine residue of the PPP2R1A protein. In embodiments, the compound is irreversibly covalently bound to a cysteine residue of the PPP2R1A protein. In an example, the cysteine residue corresponds to C377 of human PPP2R1A (e.g., SEQ ID NO: 4).

In one embodiment, the PPP2R1A protein is covalently bound (e.g., reversibly or irreversibly) to a portion of a compound described herein (e.g., a portion of a PPP2R1A modulator or a portion of a compound described herein). In one embodiment, the PPP2R1A protein is covalently bonded (e.g., reversibly or irreversibly) to a monovalent variant of a compound described herein (e.g., a monovalent variant of a PPP2R1A compound described herein). In embodiments, a monovalent variant of a compound (e.g., a compound described herein) is formed by reaction with an electrophilic moiety and a cysteine. As a non-limiting example, a monovalent variant of a compound described herein can be represented as:

in one aspect, a PPP2R1A protein (e.g., human PPP2R1A) covalently bonded to a PPP2R1A modulator (e.g., a PPP2R1A modulator, a compound described herein, or a portion of a compound described herein) is provided.

In embodiments, a PPP2R1A protein (e.g., human PPP2R1A) is covalently bonded to a PPP2R1A modulator (e.g., a compound described herein or a portion of a compound described herein). In embodiments, a PPP2R1A protein (e.g., human PPP2R1A) is irreversibly covalently bound to a PPP2R1A modulator (e.g., a compound described herein or a portion of a compound described herein). In embodiments, a PPP2R1A protein (e.g., human PPP2R1A) is reversibly covalently bound to a PPP2R1A modulator (e.g., a compound described herein or a portion of a compound described herein). In embodiments, a PPP2R1A protein (e.g., human PPP2R1A) is covalently bonded to a portion of a PPP2R1A modulator (e.g., a compound described herein). In embodiments, a PPP2R1A protein (e.g., human PPP2R1A) is irreversibly covalently bonded to a portion of a PPP2R1A modulator (e.g., a compound described herein). In embodiments, a PPP2R1A protein (e.g., human PPP2R1A) is reversibly covalently bound to a portion of a PPP2R1A modulator (e.g., a compound described herein). In embodiments, a PPP2R1A modulator (e.g., a compound described herein) binds to a protein of PPP2R1A (e.g., human PPP2R1A) with one cysteine residue (e.g., SEQ, Cys377ID NO:4 or cysteine corresponding to Cys 377: 4 of SEQ ID NO). In embodiments, a portion of a PPP2R1A modulator (e.g., a compound described herein) binds to a PPP2R1A protein (e.g., human PPP2R1A) of a cysteine residue (e.g., SEQ, Cys377ID NO:4 or cysteine corresponding to Cys 377: 4 of SEQ ID NO).

In embodiments, the PPP2R1A protein covalently bonded to a PPP2R1A modulator or a compound described herein is the product of a reaction between a PPP2R1A protein and a PPP2R1A modulator or a compound described herein. It is understood that the covalently bonded PPP2R1A protein and PPP2R1A modulator (e.g., the compounds described herein) are the remaining portions of the reactants PPP2R1A protein and PPP2R1A modulator or compound, wherein each reactant now participates in the covalent bond between PPP2R1A protein and PPP2R1A modulator or compound. In embodiments in which the PPP2R1A protein and the compounds described herein are covalently bonded, the remainder of the E substituentAre linking groups that comprise covalent bonds between the PPP2R1A protein and the remainder of the compounds described herein. It will be understood by one of ordinary skill in the art that when the PPP2R1A protein is covalently bonded to the PPP2R1A modulator (e.g., a compound described herein), the PPP2R1A modulator (e.g., a compound described herein) forms a residual portion of the pre-reacted PPP2R1A modulator (e.g., a compound described herein), wherein the bond links the residual portion of the PPP2R1A modulator (e.g., a compound described herein) to the residual portion of the PPP2R1A protein (e.g., a cysteine sulfur, a sulfur corresponding to the amino acid C377 of human PPP2R1A, a sulfur corresponding to C377 of human PPP2R1A (e.g., SEQ ID NO: 354)). The remainder of the PPP2R1A modulator (the compounds described herein) may also be referred to as part of the PPP2R1A modulator. In embodiments, the remainder of the E substituent is a linking group selected from: 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)-、-CH ₂NH-, substituted (e.g., substituted with a substituent, a size-limiting substituent or a lower number substituent) or unsubstituted alkylene (e.g., C) ₁-C ₈、C ₁-C ₆、C ₁-C ₄Or C ₁-C ₂) Substituted (e.g., substituted with a substituent, a size-limiting substituent or a lower carbon number substituent) or unsubstituted heteroalkylene (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., substituted with a substituent, a size-limiting substituent or a lower carbon number substituent), or unsubstituted cycloalkylene (e.g., C ₃-C ₈、C ₃-C ₆、C ₄-C ₆Or C ₅-C ₆) Substituted (e.g., substituted with a substituent, a size-limiting substituent or a lower carbon number substituent) or unsubstituted heterocycloalkylene (e.g., 3-to 8-membered, 3-to 6-membered, 4-to 5-membered, or 5-to 6-membered), substituted (e.g., substituted with a substituent, a size-limiting substituent or a lower carbon number substituent), or unsubstituted arylene (e.g., C ₆-C ₁₀Or phenyl) or substituted (e.g., substituted with a substituent, a size-limiting substituent or a lower number substituent) orUnsubstituted heteroarylene (e.g., 5-to 10-, 5-to 9-, or 5-to 6-membered). As a non-limiting example, the PPP2R1A protein is covalently bound to a PPP2R1A modulator that may have the formula:

wherein S is the sulfur of a cysteine of the PPP2R1A protein (e.g., C377 or C198 corresponding to human PPP2R1A (e.g., SEQ ID NO: 4)), which is bonded to the remainder of the PPP2R1A protein, and wherein R is ¹、L ¹、L ²And z1 are as described herein. As a non-limiting example, the PPP2R1A protein is covalently bound to a PPP2R1A modulator that may have the formula:

wherein S is the sulfur of a cysteine of the PPP2R1A protein (e.g., C377 or C198 corresponding to human PPP2R1A (e.g., SEQ ID NO: 4)), which is bonded to the remainder of the PPP2R1A protein, and wherein R is ¹、R ¹⁵、R ¹⁶、R ¹⁷、L ¹、L ²And z1 are as described herein.

As a non-limiting example, the PPP2R1A protein is covalently bound to a PPP2R1A modulator that may have the formula:

wherein S is the sulfur of a cysteine of the PPP2R1A protein (e.g., C377 or C198 corresponding to human PPP2R1A (e.g., SEQ ID NO: 4)), which is bonded to the remainder of the PPP2R1A protein, and wherein R is ¹、R ¹⁵、R ¹⁶、R ¹⁷、L ¹、L ²And z1 are as described herein.

As a non-limiting example, the PPP2R1A protein is covalently bound to a PPP2R1A modulator that may have the formula:

wherein S is the sulfur of a cysteine of the PPP2R1A protein (e.g., C377 or C198 corresponding to human PPP2R1A (e.g., SEQ ID NO: 4)), which is bonded to the remainder of the PPP2R1A protein, and wherein R is ¹、R ¹⁵、R ¹⁶、R ¹⁷、L ¹、L ²And z1 are as described herein.

In one aspect, a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein covalently bound to a PPP2R1A modulator is provided.

In one aspect, a serine/threonine-protein phosphatase 2a65kDa regulatory subunit a α isoform (PPP2R1A) protein covalently bound to a compound described herein is provided.

VII. examples

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Compositions and methods for modulating PPP2R1A

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