Novel medicine of target apoptosis inhibiting protein

文档序号：1246529 发布日期：2020-08-18 浏览：21次中文

阅读说明：本技术 靶向凋亡抑制蛋白的新型药物 (Novel medicine of target apoptosis inhibiting protein ) 是由 M·佩莱齐亚 C·巴吉奥 L·甘比尼 P·尤多福尔库尔于 2018-11-01 设计创作，主要内容包括：本文特别公开了靶向含有Bir结构域的多种凋亡抑制蛋白的Smac结合位点的新型抑制剂的使用方法和组成,所述凋亡抑制蛋白包括XIAP、cIAP1、cIAP2或其他IAP蛋白。(Specifically disclosed herein are methods of use and compositions of novel inhibitors that target the Smac binding site of various inhibitor of apoptosis proteins, including XIAP, cIAP1, cIAP2 or other IAP proteins, that contain Bir domains.)

1. A compound having the formula:

wherein the content of the first and second substances,

R¹is-CX¹ ₃、-CHX¹ ₂、-CH₂X¹Substituted or unsubstituted C₁-C₄An alkyl group;

L²is a bond, -NH-, -O-, -S-, -C (O) NH-, -NHC (O) NH-, -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;

R²independently is unsubstituted or substituted by R⁷SubstitutionOr unsubstituted or substituted by R⁷Substituted heteroaryl;

L³is a bond, -NH-, -O-, -S-, -C (O) NH-, -NHC (O) NH-, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted alkylenearyl, substituted or unsubstituted alkyleneheteroaryl;

ring a is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R³independently of one another is halogen, -CX³ ₃、-CHX³ ₂、-CH₂X³、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX³ ₃、-OCHX³ ₂、-OCH₂X³、-SO₂X³、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X³、-NHSO₂X³、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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; two adjacent R³Substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁴independently hydrogen, halogen, -CX⁴ ₃、-CHX⁴ ₂、-CH₂X⁴、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX⁴ ₃、-OCHX⁴ ₂、-OCH₂X⁴、-NHC(NH)NH₂、-SO₂X⁴、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X⁴、-NHSO₂X⁴、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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;

R⁵independently hydrogen, halogen, -CX⁵ ₃、-CHX⁵ ₂、-CH₂X⁵、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX⁵ ₃、-OCHX⁵ ₂、-OCH₂X⁵、-NHC(NH)NH₂、-SO₂X⁵、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X⁵、-NHSO₂X⁵、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstitutedThe heteroaryl group of (a);

L⁶is a bond or unsubstituted methylene;

R⁶independently is hydrogen, 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;

R⁷independently of one another is halogen, -CX⁷ ₃、-CHX⁷ ₂、-CH₂X⁷、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX⁷ ₃、-OCHX⁷ ₂、-OCH₂X⁷、-NHC(NH)NH₂、-N＝C(NH₂)₂、-CH₂SO₃ ^-、-PO₃ ^-2、-SO₃ ^-、-SO₂NH₂、-CH₂PO₃ ^-2、-CH₂SO₂NH₂、-NHC(O)CHCH₂、-NHC(O)CH₂Cl、-B(OH)₂、-SO₂X⁷、-OSO₂X⁷、-NHSO₂X⁷、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, unsubstituted or substituted by R⁸Substituted alkyl, unsubstituted or substituted by R⁸Substituted heteroalkyl, unsubstituted or substituted by R⁸Substituted cycloalkyl, unsubstituted or substituted by R⁸Substituted heterocycloalkyl, unsubstituted or substituted by R⁸Substituted aryl, or unsubstituted or substituted by R⁸Substituted heteroaryl;

R⁸independently of one another is halogen, -CX⁸ ₃、-CHX⁸ ₂、-CH₂X⁸、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX⁸ ₃、-OCHX⁸ ₂、-OCH₂X⁸、-NHC(NH)NH₂、-N＝C(NH₂)₂、-CH₂SO₃ ^-、-PO₃ ^-2、-SO₃ ^-、-SO₂NH₂、-CH₂PO₃ ^-2、-CH₂SO₂NH₂、-NHC(O)CHCH₂、-NHC(O)CH₂Cl、-B(OH)₂、-SO₂X⁸、-OSO₂X⁸、-NHSO₂X⁸、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, unsubstituted or substituted by R⁹Substituted alkyl, unsubstituted or substituted by R⁹Substituted heteroalkyl, unsubstituted or substituted by R⁹Substituted cycloalkyl, unsubstituted or substituted by R⁹Substituted heterocycloalkyl, unsubstituted or substituted by R⁹Substituted aryl, or unsubstituted or substituted by R⁹Substituted heteroaryl;

R⁹independently of one another is halogen, -CX⁹ ₃、-CHX⁹ ₂、-CH₂X⁹、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX⁹ ₃、-OCHX⁹ ₂、-OCH₂X⁹、-NHC(NH)NH₂、-N＝C(NH₂)₂、-CH₂SO₃ ^-、-PO₃ ^-2、-SO₃ ^-、-SO₂NH₂、-CH₂PO₃ ^-2、-CH₂SO₂NH₂、-NHC(O)CHCH₂、-NHC(O)CH₂Cl、-B(OH)₂、-SO₂X⁹、-OSO₂X⁹、-NHSO₂X⁹、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;

X¹、X²、X³、X⁴、X⁵、X⁷、X⁸and X⁹Each independently is-F, -Cl, -Br or-I; and is

z3 is independently an integer from 0 to 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R⁸Is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

3. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R¹is-CH₃、-C₂H₅、-CF₃、-CH₂F、-CHF₂、-CH₂CF₃、-CF₂CH₃、-CH₂OH、-CF₂OH or-CHFOH.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof, wherein L²Is a bond, -NH-, -O-, -S-, -C (O) -, -C (O) NH-, -NHC (O) -, -NHC (O) NH-, -C (O) O-, -OC (O) -, - (CH)₂)_1-5-、-(CH₂)_1-5O-、-(CH₂)_1-5NHC(O)-、-(CH₂)_1-5S-、-(CH₂)_1-5C(O)NH-、-O(CH₂)_1-5-、-(CH₂)_1-5NH-、-(CH₂)_1-5NHCH₂-or- (CH)₂)_1-5C(O)-。

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof, wherein L²Is a bond, -NH-, -O-, -S-, -C (O) -, -C (O) NH-, -NHC (O) -, -NHC (O) NH-, -C (O) O-, -OC (O) -, - (CH)₂)_1-3-、-(CH₂)_1-3O-、-(CH₂)_1-3NHC(O)-、-(CH₂)_1-3S-、-(CH₂)_1-3C(O)NH-、-O(CH₂)_1-3-、-(CH₂)_1-3NH-、-(CH₂)_1-3NHCH₂-or- (CH)₂)_1-3C(O)-。

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof, wherein L²Is a bond.

7. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R²Independently is unsubstituted tetrazolyl, unsubstituted aziridinyl, unsubstituted oxiranyl, unsubstituted or substituted by R⁷Substituted 2-pyridyl, unsubstituted or substituted by R⁷Substituted 3-pyridyl, unsubstituted or substituted by R⁷Substituted 4-pyridyl group, And is

z7 is an integer from 0 to 3.

8. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R²Independent of each otherIs unsubstituted or substituted by R⁷Substituted 2-pyridyl, unsubstituted or substituted by R⁷Substituted 3-pyridyl, or unsubstituted or substituted by R⁷Substituted 4-pyridyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R²Independently is

R⁷Independently is-CH₂F、-CH₂SO₃-、-PO₃-²、-SO₃-、-SO₂NH₂、-CH₂PO₃-²、-CH₂SO₂NH₂、-CF₃、-Cl、-F、-CH₃、-NO₂、-C₂H₅、-OCH₃、-OCF₃Guanidino, acrylamide, -2-chloroacetamide, -B (OH)₂、-SO₂F、-OSO₂F、-NHSO₂F、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂-COH, -CO-epoxide, -CO-aziridine, epoxide, oxaziridine, aziridine, or-OCH₂C ≡ CH; and is

z7 is an integer from 0 to 3.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof, wherein L³Is a bond, -C (O) NH-, or unsubstituted alkyleneheteroaryl.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof, wherein L³Is a bond, -C (O) NH-, -CH₂-、

12. The compound of claim 1, wherein- (ring A) - (R) is³)_z3Is that

13. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R³Independently of one another is halogen, -CX³ ₃、-CHX³ ₂、-CH₂X³、-OH、-OCX³ ₃、-OCHX³ ₂、-OCH₂X³Unsubstituted C₁-C₄Alkyl, or unsubstituted 2 to 3 membered heteroalkyl.

14. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R³Independently is-F, -Cl, -CH₃、-C₂H₅、-OH、-OCH₃or-OCF₃。

15. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R⁴Independently hydrogen, -F, -OH, -OCF₃、-OCH₃、-OCH₂CH₃or-NHC (NH) NH₂。

16. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R⁵Independently hydrogen, -F, -OH, -OCF₃、-OCH₃、-OCH₂CH₃or-NHC (NH) NH₂。

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof, wherein L⁶Is a bond.

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof, wherein L⁶Is an unsubstituted methylene group.

19. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R⁶Independently hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted isopropyl, substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted pentyl, substituted or unsubstituted hexyl, or substituted or unsubstituted phenyl.

20. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R⁶Independently hydrogen, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted cyclohexyl, unsubstituted n-butyl, unsubstituted isobutyl, unsubstituted sec-butyl, unsubstituted pentyl, unsubstituted hexyl, or unsubstituted phenyl.

21. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R⁶Independently of each other is hydrogen, -CH₃、-C₂H₅、-CH(CH₃)₂Cyclopropyl, cyclopropyl-CH₂-, cyclobutyl-CH₂-, cyclopentyl-CH₂-, cyclohexyl-CH₂-, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, phenyl, or substituted or unsubstituted benzyl.

22. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, having the formula:

wherein, W¹、W²And W³Independently is-CH or-N; and is

z7 is an integer from 0 to 3.

23. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, having the formula:

wherein, W¹And W²Independently is-CH or-N; and is

z7 is an integer from 0 to 3.

24. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, having the formula:

wherein, W¹And W²Independently is-CH or-N; and is

z7 is an integer from 0 to 3.

25. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, having the formula:

wherein, W¹And W²Independently is-CH or-N; and is

z7 is an integer from 0 to 3.

26. The compound of claim 1, or a pharmaceutically acceptable salt or prodrug thereof, wherein R²、R³、R⁴Or R⁵At least one of which comprises a gas selected from-SO₂CH＝CH₂、-SO₂X、-NHSO₂CH＝CH₂、-OSO₂X、-B(OH)₂、-NHSO₂X, or CH₂A covalent modifying group moiety of X; and is

X is independently-F, -Cl, -Br or-I.

27. A compound having the formula:

wherein the content of the first and second substances,

R¹is-CX¹ ₃、-CHX¹ ₂、-CH₂X¹Substituted or unsubstituted C₁-C₄An alkyl group;

R²independently hydrogen, halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX² ₃、-OCHX² ₂、-OCH₂X²、-SO₂CH₃、-SO₂CX² ₃、-SO₂CH₃、-SO₂X²、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X²、-NHSO₂X²、-B(OH)₂-CO-Oxiranyl, -CO-aziridinyl, oxiranyl, oxaziridinylAziridinyl, and-OCH₂C ≡ CH, 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;

ring a is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

R³independently of one another is halogen, -CX³ ₃、-CHX³ ₂、-CH₂X³、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX³ ₃、-OCHX³ ₂、-OCH₂X³、-SO₂CH₃、-SO₂CX³ ₃、-SO₂CH₃、-SO₂X³、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X³、-NHSO₂X³、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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; two adjacent R³The substituents may optionally be linked to form substituted or unsubstitutedA substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

R⁴independently hydrogen, halogen, -CX⁴ ₃、-CHX⁴ ₂、-CH₂X⁴、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX⁴ ₃、-OCHX⁴ ₂、-OCH₂X⁴、NHC(NH)NH₂、-SO₂CH₃、-SO₂CX⁴ ₃、-SO₂CH₃、-SO₂X⁴、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X⁴、-NHSO₂X⁴、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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;

R⁵independently hydrogen, halogen, -CX⁵ ₃、-CHX⁵ ₂、-CH₂X⁵、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX⁵ ₃、-OCHX⁵ ₂、-OCH₂X⁵、-NHC(NH)NH₂、-SO₂CH₃、-SO₂CX⁵ ₃、-SO₂CH₃、-SO₂X⁵、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X⁵、-NHSO₂X⁵、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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;

R²、R³、R⁴or R⁵At least one of which comprises a gas selected from-SO₂CH＝CH₂、-SO₂X、-NHSO₂CH＝CH₂、-OSO₂X、-B(OH)₂、-NHSO₂X or CH₂A covalent modifying group moiety of X;

L⁶is a bond or unsubstituted methylene;

X¹、X²、X³、X⁴、X⁵and X are each independently-F, -Cl, -Br, or-I; and is

z3 is independently an integer from 0 to 3.

28. A compound having the formula or a pharmaceutically acceptable salt or prodrug thereof, comprising a first moiety which is a compound according to any one of claims 1 to 27 and optionally a second, different moiety which is a compound according to any one of claims 1 to 27, wherein the first and second moieties are linked by a covalent linker:

wherein the content of the first and second substances,

L¹⁰⁰is a covalent linking group.

29. The compound of claim 28, or a pharmaceutically acceptable salt or prodrug thereof, wherein L¹⁰⁰Is a bond, -NH-, -O-, -S-, -C (O) NH-, -NHC (O) NH-, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted alkylenearyl, substituted or unsubstituted alkyleneheteroaryl.

30. The compound of claim 28, or a pharmaceutically acceptable salt or prodrug thereof, wherein L¹⁰⁰Is a substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene.

31. The compound of claim 28, or a pharmaceutically acceptable salt or prodrug thereof, wherein L¹⁰⁰Is substituted or unsubstituted C₄-C₁₂Alkylene, or substituted or unsubstituted 4 to 12 membered heteroalkylene.

32. A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt or prodrug of any one of claims 1 to 27 and a pharmaceutically acceptable excipient.

33. A method of reducing the level of activity of an XIAP, cIAP1 and/or cIAP2, the method comprising contacting the XIAP, cIAP1 and/or cIAP2 with a compound, pharmaceutically acceptable salt or prodrug of any one of claims 1 to 27.

34. A method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt or prodrug of any one of claims 1 to 27.

35. The method of claim 34, wherein the cancer is pancreatic cancer, Acute Lymphocytic Leukemia (ALL), or multiple myeloma.

36. A method of increasing apoptosis of cancer cells in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 27, a pharmaceutically acceptable salt or prodrug of a compound according to any one of claims 1 to 27.

37. The method of claim 34, further comprising administering to the subject a therapeutically effective amount of a second medicament.

38. The method of claim 37, wherein the second drug is an apoptosis-increasing drug.

39. The method of claim 37, wherein the second drug is a Bcl-2 family antagonist.

40. The method of claim 39, wherein the Bcl-2 family antagonist is Venetocrix or navitoclax.

41. The method of claim 37, wherein the second drug is abraxane or gemcitabine.

42. The method of claim 37, wherein the second drug is gemcitabine.

43. The method of claim 34, further comprising applying a therapeutically effective amount of radiation to the individual.

44. A method of inducing apoptosis of cancer cells in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 27, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

45. The method of claim 44, further comprising administering to the subject a therapeutically effective amount of a second medicament.

46. The method of claim 45, wherein the second drug is an apoptosis-inducing drug.

47. The method of claim 46, wherein the second drug is a Bcl-2 family antagonist.

48. The method of claim 47, wherein the Bcl-2 family antagonist is Venetocrix or navitoclax.

49. The method of claim 44, further comprising applying a therapeutically effective amount of radiation to the individual.

50. A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt or prodrug of claim 28 and a pharmaceutically acceptable excipient.

51. A method of reducing the level of XIAP, cIAP1, and/or cIAP2 activity, the method comprising contacting an XIAP, cIAP1, and/or cIAP2 with a compound, pharmaceutically acceptable salt, or prodrug of claim 28.

52. A method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt or prodrug of claim 28.

53. The method of claim 52, wherein the cancer is pancreatic cancer, Acute Lymphocytic Leukemia (ALL), or multiple myeloma.

54.A method of inducing apoptosis of cancer cells in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of claim 28, a pharmaceutically acceptable salt or prodrug of a compound of claim 28.

55. The method of claim 52, further comprising administering to the subject a therapeutically effective amount of a second medicament.

56. The method of claim 55, wherein the second drug is an apoptosis-increasing drug.

57. The method of claim 55, wherein the second drug is a Bcl-2 family antagonist.

58. The method of claim 57, wherein the Bcl-2 family antagonist is Venetocrix or navitoclax.

59. The method of claim 55, wherein the second drug is abraxane or gemcitabine.

60. The method of claim 55, wherein the second drug is gemcitabine.

61. The method of claim 52, further comprising applying a therapeutically effective amount of radiation to the individual.

62.A method of inducing apoptosis of cancer cells in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of claim 28, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

63. The method of claim 62, further comprising administering to the subject a therapeutically effective amount of a second medicament.

64. The method of claim 63, wherein the second drug is an apoptosis-inducing drug.

65. The method of claim 64, wherein the second drug is a Bcl-2 family antagonist.

66. The method of claim 65, wherein the Bcl-2 family antagonist is Venetocrix or navitoclax.

67. The method of claim 62, further comprising applying a therapeutically effective amount of radiation to the individual.

Background

Inhibitor of Apoptosis Proteins (IAPs) are an important class of apoptosis regulators characterized by the presence of 1 to 3 Baculovirus IAP Repeat (BIR) domains. Inhibitor of apoptosis proteins (cellularity inhibitors of apoptosis proteins) 1(cIAP1) and inhibitor of apoptosis proteins 2(cIAP2) are involved in tumor necrosis factor receptor-mediated apoptosis. The X-linked inhibitor of apoptosis protein (XIAP) antagonizes three caspases: caspase-3, caspase-7 and caspase-9. The third BIR domain of XIAP (BIR3) binds to and inhibits caspase-9, while the second BIR domain (BIR2) binds to and inhibits caspase-3 and caspase-7. These IAPs are often overexpressed in many tumor cell lines and human tumor tissues and therefore play an important role in the resistance of cancer cells to various anti-cancer treatments. The broad and selective inhibition of BIR3 or BIR2 domains of proteins XIAP, cIAP1 or cIAP2 remains an elusive challenge. In particular, disclosed herein are approaches to solving these and other problems of the prior art.

Summary of The Invention

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

R¹is CX¹ ₃、-CHX¹ ₂、-CH₂X¹Substituted or unsubstituted C₁-C₄An alkyl group. L is²Is a bond, -NH-, -O-, -S-, -C (O) NH-, -NHC (O) NH-, -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. R²Independently hydrogen, halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX² ₃、-OCHX² ₂、-OCH₂X²、-SO₂CH₃、-SO₂CX² ₃、-SO₂CH₃、-SO₂X²、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X²、-NHSO₂X²、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxazidinyl, aziridinyl, -OCH₂C ≡ CH, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstitutedThe heteroaryl group of (a). L is³Is a bond, -NH-, -O-, -S-, -C (O) NH-, -NHC (O) NH-, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted alkylenearyl (alkylheteroarylene), or substituted or unsubstituted alkyleneheteroaryl (alkylheterocyclylene)). Ring a is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. R³Independently of one another is halogen, -CX³ ₃、-CHX³ ₂、-CH₂X³、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX³ ₃、-OCHX³ ₂、-OCH₂X³、-SO₂X³、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X³、-B(OH)₂、-NHSO₂X³-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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. Two adjacent R³Substituents may optionally be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁴Independently hydrogen, halogen, -CX⁴ ₃、-CHX⁴ ₂、-CH₂X⁴、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、、-NHOH、-OCX⁴ ₃、-OCHX⁴ ₂、-OCH₂X⁴、-NHC(NH)NH₂、-SO₂X⁴、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X⁴、-NHSO₂X⁴、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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. R⁵Independently hydrogen, halogen, -CX⁵ ₃、-CHX⁵ ₂、-CH₂X⁵、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX⁵ ₃、-OCHX⁵ ₂、-OCH₂X⁵、-NHC(NH)NH₂、-SO₂X⁵、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X⁵、-NHSO₂X⁵、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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. L is⁶Is a bond or unsubstituted methylene. R⁶Independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, and heterocyclyl,A substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. X¹、X²、X³、X⁴And X⁵Each independently is-F, -Cl, -Br or-I. The symbols z3 are independently integers from 0 to 3.

In another aspect, is a compound comprising a first moiety of a compound described herein and a second moiety of a compound described herein, wherein the first and second moieties are linked by a covalent linker.

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

In one aspect, there is provided a method of reducing the level of XIAP, cIAP1, and/or cIAP2 activity relative to a control, the method comprising contacting an XIAP, cIAP1, and/or cIAP2 with a compound, pharmaceutically acceptable salt, or prodrug (including embodiments) described herein.

In another aspect, there is provided a method of increasing cancer cell apoptosis in an individual in need thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt or prodrug (including embodiments) described herein.

In one aspect, there is provided a method of inducing apoptosis of cancer cells in an individual in need thereof, comprising administering to the individual in need thereof a therapeutically effective amount of a compound, pharmaceutically acceptable salt or prodrug (including embodiments) described herein.

Drawings

Figure 1 compounds 139H3 and 139H2 have XIAP Bir3 selectivity. The pan-active compound GDG-0152 is shown as a reference compound.

Figure 2 compounds 139H8 and 139H7 targeted Bir2 domain of XIAP. The chemical structures of compounds 139H7 (top left) and 139H8 (top right) are reported,and DELFIA displacement values for XIAP Bir2 domain. As a reference compound, data relating to Nowaw compound LCL-161 is reported. IC of all 3 Compounds₅₀The value was about 1. mu.M. 138H7-P3 is the enantiomer of 139H7(P1), and it appears as a negative control. However, unlike LCL-161, these drugs are not active against Bir3 domain. IC of LCL-161 for the Bir3 domain of XIAP, cIAP1 and cIAP2₅₀Values were 53nM, 10nM and 13nM, respectively. IC for these Bir3 domains for 139H8 and 139H8₅₀The values are usually respectively>5000nM and>10000nM。

fig. 3A-3d. HTS schematic by Δ H method. FIG. 3A: a position-scanning (POS) library of compounds needs to be assembled by first selecting the anchor (triangle). This may be any preferred scaffold essential for binding and recognition of a given target, e.g. the best fragment hits identified by screening methods and/or by defragmentation of known endogenous or synthetic inhibitors etc. In this example, a four-bit synthetic combinatorial library was then prepared, with the first position fixed by an anchor segment (triangle). Using a library with n elements, there will be 3x n mixtures, each containing n x n compounds. Thus, rather than resulting in the synthesis and testing of n x n x n individual compounds, the method results in the testing of 3x n mixtures. For example, a library of 50 fragments assembled at three different locations can be sampled by synthesizing and screening 150 mixtures (50x 3) rather than synthesizing and testing 125,000 drugs (503) as a single compound. FIG. 3B: the 3x n mixtures can be screened for enthalpy (Δ H) by injecting the mixture solution 1 or more times with the protein of interest. FIG. 3C: the Δ H of each mixture was measured and plotted as a function of the immobilized fragment at each position, thereby potentially identifying the element with the highest enthalpy of binding for a given target at each position. FIG. 3D: therefore, preferred fragments for each position were selected and the final independent test compound was synthesized. The dissociation constant (Kd) and the relative thermodynamics of binding of the resulting compounds were determined by Isothermal Titration Calorimetry (ITC) analysis, while selectivity can be achieved by a series of displacement biochemical assays of the relevant anti-targets.

Fig. 4A-4d. HTS was used to identify the BIR3 consensus binding motif by the Δ H method. FIG. 4A: the BIR3 domain of XIAP complexes with the N-terminal amino acid residue of SMAC of the amino acid sequence AVPI. FIG. 4B: data from a Δ H screen of AVPI peptide and the known inhibitor GDC-0152. Measurements were made by injecting 4 times 2.5. mu.L of a 200. mu.M solution of XIAP BIR3 domain into cells containing the test inhibitor at a concentration of 50. mu.M. Δ H values were calculated as the average of injections 2 to 4. FIG. 4C: HTS based on Δ H data from three positive mixtures (one at each position) determined that BIR3 of the known sequence AVPI (or AVPF) binds to the consensus motif. Δ H was calculated using the first point obtained by injecting 2.5 μ L of 200 μ M XIAP BIR3 domain into cells containing 1mM of each mixture consisting of 2,116 peptoids. FIG. 4D: Δ H data HTS for three negative mixtures per position. Measurements were made as shown in fig. 4C. Due to the focusing nature of the libraries containing anchoring elements, it is generally observed that the minimum Δ H value for most mixtures is about-2 kcal/mol.

FIGS. 5A-5℃ library deconvolution and characterization of novel XIAP-BIR3 binding drug Ala (pY) Pro (4F-Phe). FIG. 5A: the Δ H values for the highest ranked blend and the selected low ranked blends for each location are summarized. Mixtures with the fixed residues phosphotyrosine (pY) and 4-fluorophenylalanine (4F-Phe) at positions P2 and P4, respectively, are ranked higher than mixtures containing valine and isoleucine at positions P2 and P4, respectively. For position P3, the highest ranking was confirmed for the mixture with proline as the fixed amino acid. FIG. 5B: HTS of Δ H data for two mixtures, Ala-pY-XX and Ala-XX-4FPhe, respectively. Δ H was calculated using the first point obtained by injecting 2.5 μ L of 200 μ M XIAP BIR3 domain into cells containing 1mM each mixture. FIG. 5C: isothermal Titration Calorimetry (ITC) data for binding of the BIR3 domain of XIAP to the tetrapeptide of the sequence AVPI and to the novel peptide of the sequence a (py) P (4F-Phe). The measurement is performed as described in the method section.

FIGS. 6A-6D.A (pY) thermodynamic analyses of P (4F-Phe), GDC-0152, and AVPI followed by a selectivity study of the BIR3 domain of XIAP, cIAP1, and cIAP 2. FIG. 6A: isothermal Titration Calorimetry (ITC) data for BIR3 domain of XIAP in combination with the known inhibitor GDC-0152 (reported structure). Measured thermodynamic parameters of GDC-0152(Δ H ═ 5.16kcal/mol, T Δ S ═ 4.44kcal/mol, Δ G ═ 9.58kcal/mol), AVPI (Δ H ═ 4.30kcal/mol, T Δ S ═ 4.00kcal/mol, Δ G ═ 8.30kcal/mol) and a (py) P (4F-Phe) (Δ H ═ 12.17kcal/mol, T Δ S ═ 3.04kcal/mol, Δ G ═ 9.13kcal/mol) are also reported. FIG. 6B: DELFIA substitution curves for BIR3 domain of XIAP, cIAP1 or cIAP2 tested against the binding drugs GDC-0152, AVPI and A (pY) P (4F-Phe). FIG. 6C: the top panel reports the docking position (docking position) of A (pY) P (4F-Phe) into the binding site of the XIAP-BIR3 domain; the following figure reports the overlap of the structure of GDC-0152 (Flygare, J.A.et. al.,2012, J.Med.chem.55,4101-4113) with the XIAP-BIR3 domain (PDB 1G73) in conjunction with the cIAP1-BIR3 domain (PDB 3UW4) (Wu, G.et. al.,2000, Nature, 1008-1012). According to these models, pY residues interact directly with Lys311 of the binding surface of XIAP-BIR 3. Such interaction is not present in GDC-0152. FIG. 6D: sequence alignment of the BIR3 domains of XIAP, cIAP1 and cIAP2, which shows that cIAP1 and cIAP2 contain a glutamic acid residue instead of Lys311, thus identifying this amino acid as a potential residue for designing selective binding drugs. Similarly, Lys299 and/or Lys297 in XIAP-BIR3 (or the equivalent Lys residue in BIR2 or BIR3 domains in XIAP-BIR2 or other IAPs) may be targeted by the same electrophile introduced here.

Fig. 7A-7 I.N-molecular docking and thermodynamic analysis of Me-AVPF-NH2, LCL161, and compound 1, followed by selective studies of BIR3 domains of XIAP, cIAP1, and cIAP 2. FIG. 7A: N-Me-AVPF-NH₂Into a docking position within the binding pocket of BIR3 domain of XIAP (PDB ID2 OPZ). FIG. 7B: BIR3 domain of XIAP with N-Me-AVPF-NH₂Combined Isothermal Titration Calorimetry (ITC) curves. FIG. 7C: DELFIA displacement curves relative to compound N-Me-AVPF-NH2 detected for BIR3 domains of XIAP, cIAP1 and cIAP2, respectively (IC of XIAP, cIAP1 and cIAP2₅₀Values were 108.2nM, 48.2nM and 209nM, respectively). FIG. 7D: the clinical compound LCL161 entered the docking position within the binding pocket of XIAP (PDB ID2OPZ) BIR3 domain. FIG. 7E: isothermal Titration Calorimetry (ITC) profile of the interaction between BIR3 domain of XIAP and LCL 161. FIG. 7F: targeting BIR3 domains of XIAP, cIAP1 and cIAP2DELFIA displacement curves (IC of XIAP, cIAP1 and cIAP2) detected relative to compound LCL161₅₀Values were 52.7nM, 10.4nM and 12.9nM, respectively). FIG. 7G: compound 1 entered the docking position within the binding pocket of BIR3 domain of XIAP (PDB ID2 OPZ). Residues Lys311 of XIAPBIR3 interacting with the phosphonate group are highlighted. FIG. 7H: isothermal Titration Calorimetry (ITC) curve between BIR3 domain of XIAP and compound 1. FIG. 7I: DELFIA displacement curves detected for BIR3 domains of XIAP, cIAP1 and cIAP2 relative to Compound 1 (IC of XIAP, cIAP1 and cIAP2)₅₀Values were 35nM, 197.6nM and 364.3nM, respectively).

Fig. 8A-8e Craig plots of thermodynamic parameters guide the design of selective inhibitors and pan-inhibitors against the BIR3 domain of XIAP, cIAP1 and cIAP 2. FIG. 8A: craig plot of (-T. DELTA.S) as a function of (. DELTA.H) showing N-Me-AVPF-NH relative to the reference compound₂The difference in thermodynamic parameters of (a). Compounds on or near the diagonal (solid line) are expected to have similar affinities for the reference peptide; compounds below the diagonal will show increased activity, while drugs above the diagonal will have less potency than N-Me-AVPF-NH₂. Position P2 and N-Me-AVPF-NH₂The different compounds are shown as circles, while those compounds differing in the P3/P4 position are shown as triangles; the combination of different P2 and P3/P4 substituents produced compounds that are shown as squares. FIG. 8B: schematic representation of combinations of selected compounds with P2 and P3/P4 substituents based on thermodynamic Craig diagram analysis. On the left, the combination of the P2 element of compound 2 with the P3/P4 element of compound 19 produced compound 22, which was designed to be more selective for XIAP than cIAP 1/2. On the right, the combination of element P2 of compound 14 with element P3/P4 of compound 17 produced compound 31, which is designed as a pan-drug to IAPs. FIG. 8C: correlation between predictions (based on thermodynamic Craig plots) and experimental thermodynamic values for the synthesized compounds. FIG. 8D: isothermal Titration Calorimetry (ITC) curves of BIR3 domain of XIAP binding to compound 22 (left panel) or compound 31 (right panel). FIG. 8E: DELFIA displacement curves versus compound 22 (left panel) and compound 31 (right panel) tested against the BIR3 domain of XIAP, cIAP1 and cIAP 2. Compound 22 is directed against XIAP, cIAP1 and B of cIAP2IC of IR3 Domain₅₀Values were 191nM,>1000nM and>1000 nM. IC of compound 31 against BIR3 domain of XIAP, cIAP1 and cIAP2₅₀Values were 37.1nM, 4.5nM and 15nM, respectively.

FIGS. 9A-9K. design and characterization of covalent XIAP BIR inhibitors. FIG. 9A: compound 32 enters the covalent docking position within the binding pocket of BIR3 domain of XIAP (PDB ID2 OPZ). Lysine 311, which forms a covalent bond with compound 32, is highlighted. FIG. 9B: after incubation for 10 min at RT and protein-ligand ratio of 1:2, SDS-PAGE gels were run in the absence and presence of compound 32, followed by Coomassie blue staining of BIR3 domain of XIAP. FIG. 9C: LC-MS spectra of BIR3 domain of XIAP in the absence (upper panel) and presence (lower panel) of compound 32 at a protein-to-ligand ratio of 1: 2. FIG. 9D: DELFIA displacement curves relative to compound 32 tested against the BIR3 domain of XIAP, cIAP1 and cIAP 2. IC of compound 32 against BIR3 domain of XIAP, cIAP1 and cIAP2₅₀Values were 11.3nM, 180.4nM and 306.7nM, respectively. FIG. 9E: compound 34 entered the covalent docking position within the binding pocket of BIR3 domain of XIAP (PDB ID2 OPZ). Lysine 311, which forms a covalent bond with compound 34, is highlighted. FIG. 9F: after 10 min incubation at RT and protein-ligand ratio 1:2, SDS-PAGE gels were run in the absence and presence of compound 34 and diastereomer 34 followed by coomassie brilliant blue staining of BIR3 domain of XIAP. FIG. 9G: LC-MS spectra of BIR3 domain of XIAP in the absence (upper panel) and presence (lower panel) of compound 34 in protein-ligand ratio 1: 2. FIG. 9H: DELFIA displacement curves versus compound 34 tested against the BIR3 domains of XIAP, cIAP1 and cIAP 2. IC of compound 34 against BIR3 domains of XIAP, cIAP1 and cIAP2₅₀Values of 16.6nM,>200nM and 353.3 nM. FIG. 9I: after 10 min incubation at RT and protein-ligand ratio of 1:2, BIR3 domains of XIAP, XIAP-BIR 3K311E and XIAP-BIR 3K322A were subjected to SDS-PAGE gel electrophoresis in the absence and presence of compound 34, followed by Coomassie brilliant blue staining. FIG. 9J: after incubation for 10 min at RT and a protein-ligand ratio of 1:2, atThe BIR3 domains of XIAP, cIAP1 and cIAP2 were subjected to SDS-PAGE gel electrophoresis in the absence and presence of compound 34 followed by coomassie brilliant blue staining. FIG. 9K: dose response curves for Compound 34 against XIAP-BIR3, XIAP-BIR 3K311E, and XIAP-BIR 3K322A in the DELFIA replacement assay (XIAP-BIR3, XIAP-BIR 3K311E, and IC of XIAP-BIR 3K322A₅₀Values were 16.6nM, 1039nM and 19.7nM, respectively).

FIGS. 10A-10E.LCL161, Compound 31 and Compound 34 comparative cellular activities in ALL, MM and pancreatic cancer cell lines FIG. 10A: treatment of ALL cell line MOLT-4 cells with indicated compounds for 48 hours, assessment of cell viability thereof. error bars are triplicate reads SD. B: IAP inhibitor induces degradation of IAP protein levels FIG. 10B: treatment of MOLT-4 cells with 1. mu.M for 3 hours and support of XIAP, cIAP1 or cIAP 2. detection of β -actin blots to ensure equal amounts of the upper sample FIG. 10C: treatment of multiple cell lines with 20. mu.M concentration of indicated compounds for 48 hours. error bars are triplicate reads SD. D: XIAP, cIAP1 and cIAP2 in pancreatic cancer cell lines BxPC3, PANC-1 and MIAPaCa-2 for Western blot analysis to ensure equal amounts of basal expression levels of the upper sample E, compound 31 and compound 34 are treated with the upper sample of pancreatic cancer cell lines either a GEMCNA, or a GEMCIA-12 bar supplemented with the upper sample of GESD β -12C 34, 9-12-DMSO-supplemented with the upper sample compounds for 24 hours<0.05；**，P<0.005，***，P<0.0005, and<10^-5。

FIGS. 11A-11B chemical structures of 32 compounds were synthesized for detecting the P3/P4 substituents in NMe-Ala-Val-P3/P4. Each compound was synthesized and tested against BIR3 domain of XIAP using an enthalpy screening method.

FIG. 12 dose response curves for Compound 31 in DELFIA replacement assays against XIAP BIR3, XIAP BIR 3K311E, and XIAP BIR 3K322A, respectively.

FIG. 13 ITC curves for compounds AT-406 (K1.9 nM, 5.1nM and 66.4nM for BIR3 domain of cIAP1, cIAP2 and XIAP, respectively) and GDC-0152 (K17 nM, 43nM and 28nM for BIR3 domain of cIAP1, cIAP2 and XIAP, respectively).

FIG. 14 LC-MS spectra of XIAP BIR3 domain in the absence (upper panel) and presence (lower panel) of compound 33 at a protein-to-ligand ratio of 1: 2.

Detailed Description

In particular, provided herein are novel compositions and methods of using these compounds for anticancer therapy that broadly and/or selectively targets Bir3 or Bir2 domains of the proteins XIAP, cIAP1 or cIAP 2. The compounds described herein target the Smac binding site of a variety of inhibitor of apoptosis proteins, including XIAP, cIAP1 and cIAP2, that contain a Bir domain. These agents inhibit these proteins with various selectivities and potencies, including, for example, the Bir2 and Bir3 domains of XIAP, and the Bir3 domain of cIAP1 and cIAP 2. These compounds differ from previously reported molecules in chemistry and selectivity for these targets.

I. Definition of

Abbreviations used herein have their ordinary meaning in the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to standard rules for chemical potency known in the chemical art.

When substituent groups are designated by their conventional formula written from left to right, they likewise contain the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH₂O-is equivalent to-OCH₂-。

Unless otherwise specified, the term "alkyl" by itself or as part of another substituent refers to a straight (i.e., unbranched) or branched carbon chain (or carbon) or combination thereof, which may be fully saturated, monounsaturated, or polyunsaturated, and may include monovalent, divalent, and multivalent radicals. The alkyl group can contain a specified number of carbons (e.g., C)₁-C₁₀Representing 1 to 10 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, t-butyl, isobutyl, sec-butyl, methyl, e.g., homologs and isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl radicalExamples of (b) include, but are not limited to, ethenyl, 2-propenyl, butenyl, 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 linkage (-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 also 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 indicated, the term "alkylene" by itself or as part of another substituent refers to a divalent radical derived from an alkyl group, e.g., -CH₂CH₂CH₂CH₂-, but not limited thereto. Typically, the alkyl (or alkylene) group will have 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. "lower alkyl" or "lower alkylene" is a short chain alkyl or alkylene group, typically having 8 or fewer carbon atoms. Unless otherwise indicated, the term "alkenylene" by itself or as part of another substituent refers to a divalent group derived from an alkene.

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

Similarly, unless otherwise specified, the term "heteroalkylene" by itself or as part of another substituent refers to a divalent radical derived from a heteroalkyl radical, such as-CH₂-CH₂-S-CH₂-CH₂-and-CH₂-S-CH₂-CH₂-NH-CH₂-is shown, but not limited thereto. For heteroalkylene groups, heteroatoms can also occupy one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Furthermore, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not affected by the direction in which the linking group is written. For example, of the formula-C (O)₂R' -represents-C (O)₂R '-and-R' C (O)₂-. As mentioned above, heteroalkyl as used herein includes groups attached to the remainder of the molecule through a heteroatom, such as-C (O) R ', -C (O) NR ', -NR ' R ", -OR ', -SR ', and/OR-SO₂R' is provided. Where reference to "heteroalkyl" is followed by reference to a particular heteroalkyl group such as-NR 'R ", and the like, it is understood that the terms heteroalkyl and-NR' R" are not intended to be repeated, nor mutually exclusive. Rather, specific heteroalkyl groups are mentioned to increase clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude a particular heteroalkyl, such as-NR 'R' and the like.

Unless otherwise indicated, the terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms refer to 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 where 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-tetrahydropyridinyl), 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 refer to divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively.

Unless otherwise indicated, 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 monohaloalkyl and polyhaloalkyl. For example, the term "halo (C)₁-C₄) Alkyl "includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

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

Unless otherwise indicated, the term "aryl" refers to polyunsaturated aromatic hydrocarbon substituents that may be fused together (i.e., fused ring aryl) or covalently linked monocyclic or polycyclic rings (preferably 1 to 3 rings). Fused ring aryl refers to multiple rings that are fused together, wherein at least one fused ring is an aryl ring. The term "heteroaryl" refers to an aryl (or ring) containing at least one heteroatom (e.g., N, O or S), wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atom may optionally be quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl (i.e., multiple rings fused together, wherein at least one fused ring is a heteroaromatic ring). A 5, 6-fused ring heteroarylene refers to two rings fused together, wherein one ring is 5-membered and the other ring is 6-membered, and wherein at least one ring is a heteroaryl ring. Likewise, a 6, 6-fused ring heteroarylene refers to two rings fused together, wherein one ring is 6-membered and the other ring is 6-membered, 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 is 6-membered and the other ring is 5-membered, and wherein at least one ring is a heteroaryl ring. The heteroaryl group may be attached to the remainder of the molecule through a carbon or heteroatom.

Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, benzocyclopentyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuryl, indolyl, isoindolyl, benzothienyl, isoquinolyl, quinoxalinyl, 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-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. The substituents for each of the above 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, refer to divalent radicals derived from aryl and heteroaryl, respectively. The heteroaryl substituent may be-O-bonded to the nitrogen of the ring heteroatom.

Spiro 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 a spiro ring may be substituted or unsubstituted, and individual rings in a group of spiro rings may have different substituents from other individual rings. When not part of a spiro ring (e.g., a substituent for a cycloalkyl or heterocycloalkyl ring), possible substituents for each ring in the spiro ring are possible substituents for the same ring. The spirocyclic ring can be a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and an individual ring within the spirocyclic group can be any of the above list, including all rings of one type (e.g., all rings are substituted heterocycloalkylene, where each ring can be the same or different substituted heterocycloalkylene). When referring to a spiro ring system, heterocyclic spiro ring refers to a spiro ring in which at least one ring is heterocyclic and in which each ring may be a different ring. When referring to a spiro ring system, substituted spiro means that at least one ring is substituted, and each substituent may optionally be different.

SymbolDenotes the point of attachment of a chemical moiety to the rest of the molecule or formula.

The term "oxo" as used herein refers to an oxygen double bonded to a carbon atom.

The term "alkylenearyl" refers to an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In some embodiments, the alkylene aryl has the formula:

the alkylene aryl moiety may be substituted (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at the 2,3, 4, or 6 carbon position), for example with: halogen, oxo, -N₃、-CF₃、-CCl₃、-CBr₃、-CI₃、-CN、-CHO、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₂CH₃、-SO₃H、-OSO₃H、-SO₂NH₂、-NHNH₂、-ONH₂、NHC(O)NHNH₂、-SO₂F、SO₂Cl、-SO₂Br、-SO₂I. Substituted or unsubstituted C₁-C₅Alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl. In some embodiments, an alkylene aryl group is unsubstituted.

The term "alkylidene heteroaryl" refers to a heteroarylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In some embodiments, the alkylene heteroaryl has the formula:

the alkylidene heteroaryl moiety may be substituted (e.g., a substituent group) on the alkylene moiety or heteroarylene linker, for example, halogen, oxo, -N₃、-CF₃、-CCl₃、-CBr₃、-CI₃、-CN、-CHO、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₂CH₃、-SO₃H、-OSO₃H、-SO₂NH₂、NHNH₂、ONH₂、NHC(O)NHNH₂、-SO₂F、SO₂Cl、-SO₂Br、-SO₂I. Substituted or unsubstituted C₁-C₅Alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl). In some embodiments, the alkylene heteroaryl is unsubstituted.

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

Substituents for alkyl and heteroalkyl groups (including those groups commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more groups selected from the following, but are not limited to: -OR ', - (O), (NR ', - (N-OR ', - (NR ' R), - (SR ',), - (halgen, -SiR ' R ' ", - (oc) (O) R ', - (c) (O) R ', - (CO)₂R'、-CONR'R”、-OC(O)NR'R”、-NR”C(O)R'、-NR'-C(O)NR”R”'、-NR”C(O)₂R'、-NR-C(NR'R”R”')＝NR””、-NR-C(NR'R”)＝NR”'、-S(O)R'、-S(O)₂R'、-S(O)₂NR'R”、-NRSO₂R'、NR'NR”R”'、-ONR'R”、-NR'C(O)NR”NR”'R””、-CN、-NO₂、-NR'SO₂R ", -NR 'C (O) -OR", -NR' OR ", the number of which ranges from 0 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 refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy, or arylalkyl. When the compounds described herein include more than one R group, for example, when more than one R group is present, each R group is independently selected as a group for each R ', R ", R'" and R "". 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, one of skill in the art will understand that the term "alkyl" refers to a group that includes a carbon atom bonded to a group other than a hydrogen radical, such as haloalkyl (e.g., -CF)₃and-CH₂CF₃) And acyl (e.g., -C (O) CH)₃、-C(O)CF₃、-C(O)CH₂OCH₃Etc.).

Similar to the substituents described for the alkyl groups, the substituents for the aryl and heteroaryl groups are different and are selected, for example, from: -OR ', -NR ' R ", -SR ', halogen, -SiR ' R" R ' ", -OC (O) R ', -C (O) R ', -CO₂R'、-CONR'R”、-OC(O)NR'R”、-NR”C(O)R'、-NR'-C(O)NR”R”'、-NR”C(O)₂R'、-NR-C(NR'R”R”')＝NR””、-NR-C(NR'R”)＝NR”'、-S(O)R'、-S(O)₂R'、-S(O)₂NR'R”、-NRSO₂R'、NR'NR”R”'、ONR'R”、-NR'C(O)NR”NR”'R””、-CN、-NO₂、-R'、-N₃、-CH(Ph)₂Fluorine (C)₁-C₄) Alkoxy, and fluorine (C)₁-C₄) Alkyl, -NR' SO₂R ", -NR 'C (O) -OR", -NR' OR ", the number ranging from 0 to the total number of open rings 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, when more than one R group is present, each R group is independently selected as each R ', R ", R'" and R "" group.

Ring substituents (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) can be described as substituents on the ring, rather than substituents at specific atoms of the ring (often referred to as non-fixed substituents). In such cases, the substituent may be attached to any ring atom (following the rules of chemical valency), while in the case of fused or spiro rings, it is described as a substituent associated with one member of the fused or spiro ring (a non-fixed substituent on a single ring), and may be a substituent on any fused or spiro ring (a non-fixed substituent on a multi-ring).

When a substituent is attached to a ring other than a particular atom (a non-fixed substituent), and the subscript of the substituent is an integer greater than one, multiple substituents can be on the same atom, on the same ring, on different atoms, on different fused rings, on different spirorings, and each substituent can optionally be different. If the point of attachment of a ring to the rest of the molecule is not limited to a single atom (no fixed 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. If a ring, fused ring, or spiro ring contains one or more ring heteroatoms and the ring, fused ring, or spiro ring exhibits more than one labile substituent (including but not limited to a point of attachment to the rest of the molecule), the labile substituent may be bonded to a heteroatom. In structures or formulae containing a labile substituent, if a ring heteroatom exhibits a bond to one or more hydrogens (e.g., a ring nitrogen having two bonds to the ring atom and a third bond to a hydrogen), when the heteroatom is bonded to a labile substituent, the substituent will be understood to be a substitution for a hydrogen while following the rules of chemical valency. Two or more substituents may be optionally joined to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically (although not necessarily) attached to a cyclic base structure. In one embodiment, the ring-forming substituent is attached to an adjacent member of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure result in a fused ring structure. In another embodiment, the ring-forming substituent is attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure result in a spiro ring structure. In another embodiment, the ring-forming substituent is attached to a non-adjacent member of the base structure.

Two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a compound of the formula-T-C (O) - (CRR')_qA ring of-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 substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a compound of formula-A- (CH)₂)_rA substituent of-B-, wherein A and B are independently-CRR' -, -O-, -NR-, -S (O)₂-、-S(O)₂NR' -, or a single bond, and r is an integer of 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by a compound of formula- (CRR')_s-X'-(C”R”R”')_dWherein S and d are independently integers of 0 to 3, and X 'is-O-, -NR' -, -S (O)₂-or-S (O)₂NR' -. The 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" includes oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), boron (B), and silicon (Si).

As used herein, "substituent group" refers to a moiety selected from:

(A) oxo, halogen, -SO₂F、SO₂Cl、-SO₂Br、-SO₂I、-CCl₃、-CBr₃、-CF₃、-CI₃、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCF₃、-OCBr₃、-OCI₃、-OCHCl₂、-OCHBr₂、-OCHI₂、-OCHF₂Unsubstituted alkyl (e.g. C)₁-C₈Alkyl radical, C₁-C₆Alkyl, or C₁-C₄Alkyl), unsubstituted heteroalkyl (e.g., 2-to 8-membered heteroalkyl,2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C)₃-C₈Cycloalkyl radical, C₃-C₆Cycloalkyl radicals, or C₅-C₆Cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-to 8-membered heterocycloalkyl, 3-to 6-membered heterocycloalkyl, or 5-to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C)₆-C₁₀Aryl radical, C₁₀Aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, or 5-to 6-membered heteroaryl), and

(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one of the following substituents:

(i) oxo, halogen, -SO₂F、SO₂Cl、-SO₂Br、-SO₂I、-CCl₃、-CBr₃、-CF₃、-CI₃、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCF₃、-OCBr₃、-OCI₃、-OCHCl₂、-OCHBr₂、-OCHI₂、-OCHF₂Unsubstituted alkyl (e.g. C)₁-C₈Alkyl radical, C₁-C₆Alkyl, or C₁-C₄Alkyl), unsubstituted heteroalkyl (e.g., 2-to 8-membered heteroalkyl, 2-to 6-membered heteroalkyl, or 2-to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C)₃-C₈Cycloalkyl radical, C₃-C₆Cycloalkyl radicals, or C₅-C₆Cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-to 8-membered heterocycloalkyl, 3-to 6-membered heterocycloalkyl, or 5-to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C)₆-C₁₀Aryl radical, C₁₀Aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, or 5-to 6-membered heteroaryl), and

(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one of the following substituents:

(a) oxo, halogen, -SO₂F、SO₂Cl、-SO₂Br、-SO₂I、-CCl₃、-CBr₃、-CF₃、-CI₃、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCF₃、-OCBr₃、-OCI₃、-OCHCl₂、-OCHBr₂、-OCHI₂、-OCHF₂Unsubstituted alkyl (e.g. C)₁-C₈Alkyl radical, C₁-C₆Alkyl, or C₁-C₄Alkyl), unsubstituted heteroalkyl (e.g., 2-to 8-membered heteroalkyl, 2-to 6-membered heteroalkyl, or 2-to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C)₃-C₈Cycloalkyl radical, C₃-C₆Cycloalkyl radicals, or C₅-C₆Cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-to 8-membered heterocycloalkyl, 3-to 6-membered heterocycloalkyl, or 5-to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C)₆-C₁₀Aryl radical, C₁₀Aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, or 5-to 6-membered heteroaryl),

(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, substituted with at least one of the following substituents: oxo, halogen, -SO₂F、SO₂Cl、-SO₂Br、-SO₂I、-CCl₃、-CBr₃、-CF₃、-CI₃、-CN、-OH、-NH₂、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl₃、-OCF₃、-OCBr₃、-OCI₃、-OCHCl₂、-OCHBr₂、-OCHI₂、-OCHF₂Unsubstituted alkyl (e.g. C)₁-C₈Alkyl radical, C₁-C₆Alkyl, or C₁-C₄Alkyl), unsubstituted heteroalkyl (e.g., 2-to 8-membered heteroalkyl, 2-to 6-membered heteroalkyl, or 2-to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C)₃-C₈Cycloalkyl radical, C₃-C₆Cycloalkyl radicals, or C₅-C₆Cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-to 8-membered heterocycloalkyl, 3-to 6-membered heterocycloalkyl, or 5-to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C)₆-C₁₀Aryl radical, C₁₀Aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5-to 10-membered heteroaryl, 5-to 9-membered heteroaryl, or 5-to 6-membered heteroaryl).

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

As used herein, "lower substituent" or "lower substituent group" refers to a group selected from all of the substituents described above for "substituent group", wherein each substituted or unsubstituted alkyl group is substituted or unsubstituted C₁-C₈Each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, and each substituted or unsubstituted cycloalkyl is a substituted or unsubstitutedC of (A)₃-C₇Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl.

In some embodiments, each substituent group described in the compounds herein is substituted with at least one substituent group. 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 of the compounds described herein is substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limiting substituent group. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

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

In some embodiments, each substituted or unsubstituted alkyl is substituted or unsubstituted C₁-C₈Alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, and each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₇Cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is substituted or unsubstituted C₁-C₈Alkylene, each substituted or unsubstituted heteroalkylene being a substituted or unsubstituted 2-to 8-membered heteroalkylene, each substituted or unsubstituted cycloalkylene being a substituted or unsubstituted C₃-C₇Cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-to 7-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted phenylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5-to 6-membered heteroarylene. In some embodiments, the compound is a chemical entity recited in the claims, examples section, figures, or tables below.

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

In some 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 group, wherein, if the substituted moiety is substituted with multiple size-limiting substituent groups, each size-limiting substituent group may optionally be different. In some embodiments, if the substituted moiety is substituted with a plurality of size-limiting substituent groups, each size-limiting substituent group is different.

In some 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 group, size-limiting substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limiting substituent groups and lower substituent groups; each substituent group, size-limiting substituent group and/or lower substituent group may optionally be different. In some embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limiting substituent groups, and lower substituent groups; each substituent group, size-limiting substituent group and/or lower substituent group is different.

Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers, as defined (in terms of absolute stereochemistry) according to amino acid (R) -or (S) -or (D) -or (L) -are included within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art that are too unstable to be synthesized and/or isolated. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R) -or (S) -or (D) -or (L) -isomers may be prepared using chiral synthons or chiral reagents, or separated using conventional techniques. Unless otherwise indicated, when a compound described herein contains an olefinic bond or other geometrically asymmetric center, the compound includes both E and Z geometric isomers.

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

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

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

Unless otherwise indicated, structures described herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configuration of each asymmetric center. Thus, individual stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

Unless otherwise indicated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, by removing deuterium or tritium for hydrogen or¹³C-or¹⁴In addition to the C-rich carbon substituted carbons, compounds having the current structure are within the scope of the present disclosure.

The compounds of the present disclosure may also be constitutedSuch compounds contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (A), (B), (C), (D), (³H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) In that respect All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

It should be noted that throughout this 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 individually to include another embodiment, and that the Markush group should not be read as a single unit.

"analog" or "analog" is used according to its ordinary meaning in chemistry and biology and refers to a compound that is similar in structure to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., in that one atom is replaced by an atom of a different element, or that a particular functional group is present, or that one functional group is replaced by another functional group, or the absolute stereochemistry of one or more chiral centers of a reference compound. Thus, an analog is a compound that is similar or equivalent in function and appearance to a reference compound, but dissimilar in structure or origin to the reference compound.

The terms "a" or "an," as used herein, refer to one or more. Further, the phrase "substituted" as used herein means that the specified group may be substituted with one or more of any or all of the named substituents. For example, when a group, such as an alkyl or heteroaryl group, "unsubstituted C₁-C₂₀Substituted by alkyl or unsubstituted 2-to 20-membered heteroalkyl ", which radical may contain one or more unsubstituted C₁-C₂₀Alkyl 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 "R substituted. Wherein a moiety is R-substituted, the moiety being substituted with at least one R substituent and each R substituent may beOptionally different. If a particular R group is present in the description of the chemical genus (as in formula (i)), Roman letter symbols may be used to distinguish each form of that particular R group. For example, when there are a plurality of R¹³When a substituent is present, each R¹³The substituents can be distinguished as R^13A、R^13B、R^13C、R^13DEtc. wherein R is^13A、R^13B、R^13C、R^13DEach being in R¹³Are defined within the definition of (1) and optionally are different.

The term "covalent modifier" is used according to its common meaning in chemistry and refers to a chemical group that is capable of forming a covalent bond with a second chemical group. In some embodiments, the covalent modifier is a chemical group capable of forming a covalent bond with an amino acid or protein (e.g., a side chain of an amino acid, e.g., lysine or cysteine). A "covalent modifying group moiety" is a monovalent covalent modifying agent. In some embodiments, the covalent modification agent is an electrophile, and the covalent modification agent is capable of contacting and forming a covalent bond with a nucleophile.

The description of the compounds of the present disclosure 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 substituents are selected to comply with the principles of chemical bonding and to give compounds that are inherently unstable and/or known to one of ordinary skill in the art, as may be unstable under environmental conditions, such as aqueous solutions, neutrality, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl group is attached to the rest of the molecule via a ring heteroatom, according to chemical bonding principles known to the person skilled in the art, thus avoiding compounds which are themselves unstable.

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

Thus, the compounds of the present disclosure may be present in salt form, such as with a pharmaceutically acceptable acid. The present disclosure 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 mixtures thereof, including racemic mixtures), succinate, benzoate and amino acid-containing salts such as glutamic acid and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

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

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

Certain compounds of the present disclosure may exist in unsolvated 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 disclosure. Certain compounds of the present disclosure may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are contemplated as within the scope of the present disclosure.

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 contain an amino acid. The terms apply to amino acid polymers (in which one or more amino acid residues are artificial chemical mimetics of the corresponding natural amino acid), as well as naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

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

By "co-administration" is meant administration of a composition as described herein, either simultaneously with, prior to, or after administration of one or more other therapies. The compounds of the invention may be administered alone, or may be co-administered to a patient. Co-administration refers to the simultaneous or sequential administration of the compounds, either alone or in combination (more than one compound). Thus, the formulations may also be combined with other active substances (e.g., to reduce metabolic degradation) if desired. The compositions of the present invention may be administered transdermally, by a topical route or formulated as sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

As used herein, the term "bioconjugate" or "bioconjugate linker" refers to the resulting bond between atoms or molecules of a bioconjugate reactive group. The binding may be direct or indirect. For example, the first bioconjugate reactive group (e.g., -NH) provided herein₂The conjugate between-COOH, -N-hydroxysuccinimide or-maleimide) and the second bioconjugate reactive group (e.g., thiol, sulfur-containing amino acid, amine, amino acid-containing amine side chain, or carboxylate) can be direct, e.g., via a covalent bond or a linker (e.g., the first linker of the second linker), or indirect, e.g., via a non-covalent bond (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der waals interactions (e.g., dipole-dipole, dipole induced dipole, london dispersion), ring packing (pi effect), hydrophobic interactions, etc.). In some embodiments, bioconjugate or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the combination of two bioconjugate reactive groups), including but not limited to nucleophilic substitutions (e.g., the reaction of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions), and addition of carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reactions, Diels-Alder additions). For example, these and other useful reactions are described in March, ADVANCED ORGANICCHEMISTRY,3rd Ed., John Wiley&Sons, New York, 1985; hermanson, BIOCONJUGATETECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al, MODIFICATION offroteins; advances in Chemistry Series, Vol.198, American Chemical Society, Washington, D.C., 1982. In some embodiments, the first bioconjugate reactive group (e.g.,maleimide moiety) to the second bioconjugate reactive group (e.g., thiol). In some embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., thiol). In some embodiments, the first bioconjugate reactive group (e.g., a pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl group). In some embodiments, the first bioconjugate reactive group (e.g., -N-hydroxysuccinimide moiety) is covalently linked to the second bioconjugate reactive group (e.g., amine). In some embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently linked to the second bioconjugate reactive group (e.g., thiol). In some embodiments, the first bioconjugate reactive group (e.g., -sulfo-N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., amine). A bioconjugate reactive group is a group that is capable of forming a bioconjugate in a bioconjugate reaction. The bioconjugate reactive moiety is a monovalent bioconjugate reactive group.

Useful bioconjugate reactive moieties for use herein in bioconjugate chemistry include, for example:

(a) carboxyl and its various derivatives, including but not limited to N-hydroxy succinimide ester, N-hydroxy benzotriazole ester, acid halides, acyl imidazoles, thioesters, p-nitrophenyl ester, alkyl, alkenyl, alkynyl, and aromatic esters;

(b) hydroxyl groups that can be converted into esters, ethers, aldehydes, etc.;

(c) haloalkyl groups, wherein the halide may subsequently be substituted with a nucleophilic group, such as, for example, an amine, carboxylic acid anion, thiol anion, carbocation, or alkoxy ion, resulting in covalent attachment of a new group at the site of the halogen atom;

(d) dienophilic groups capable of participating in a Diels-Alder reaction, e.g., maleimido or maleimido groups;

(e) aldehyde or ketone groups, so as to be subsequently derivatised by forming carbonyl derivatives (such as imines, hydrazones, semicarbazides or oximes) or by a mechanism such as grignard or alkyllithium addition;

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

(g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or reacted with maleimides;

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

(i) olefins such as cycloaddition, acylation, Michael addition, etc. may occur;

(j) epoxides, such as may be reacted with amines and hydroxyl compounds, and the like;

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

(l) Bonded metallic silicon oxide;

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

(n) azides coupled to alkynes using copper-catalyzed cycloaddition click chemistry; and

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

The bioconjugate reactive group can be selected so that it does not participate in or interfere with the chemical stability of the conjugates described herein. Alternatively, the reactive functional group may be protected from participating in the crosslinking reaction by the presence of a protecting group. In some embodiments, the bioconjugate includes a molecular entity derived from the reaction of an unsaturated bond (such as maleimide) and a thiol group.

As used herein, "cell" refers to a cell that performs a metabolic or other function sufficient to preserve or replicate its genomic DNA. Cells can be identified by methods well known in the art, for example, the presence of an intact membrane, staining by a specific dye, the ability to produce progeny, or in the case of a gamete, the ability to produce a viable offspring in combination with a second gamete. 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 plant and animal derived cells, e.g., mammalian, insect (e.g., arachnida) and human cells. Cells may be useful when they are not naturally adherent or treated to adhere to a surface (e.g., by trypsinization).

The term "treatment" or "method of treatment" refers to any indication of successful treatment or amelioration of an injury, disease (e.g., cancer), pathology, or condition, including any objective or subjective parameter, such as remission; (iii) alleviating; reduced symptoms or making the injury, pathology or condition more tolerable to the patient; a reduced rate of degeneration or decline; the final point of degeneration is less debilitating; improving the physical or mental health of the patient. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including results of physical examination, neuropsychiatric examination, and/or mental assessment. For example, certain methods described herein successfully treat cancer by reducing the incidence of cancer and/or causing remission of cancer. In some embodiments of the compositions or methods described herein, treating cancer comprises slowing the growth or spread rate of cancer cells, reducing metastasis, or reducing the growth of metastatic tumors. The term "treating" and combinations thereof include preventing injury, pathology, condition or disease. In some embodiments, treatment does not include prophylaxis.

An "effective amount" refers to an amount sufficient to effect administration of a compound for a stated purpose (e.g., to effect administration, treat a disease, decrease enzyme activity, increase enzyme activity, decrease signaling pathways, reduce one or more symptoms of a disease or disorder (e.g., decrease signaling pathways stimulated by XIAP, cIAP1, or cIAP2, or decrease signaling pathway activity of XIAP, cIAP1, or cIAP2) relative to the absence of the compound.an example of an "effective amount" is an amount sufficient to facilitate treatment, prevention, or reduction of disease symptoms, an example of an "effective amount" is an amount sufficient to facilitate treatment, prevention, or reduction of disease symptoms, and also of a "therapeutically effective amount". a "reduction" of symptoms (and grammatical equivalents of this phrase) refers to a reduction in the severity or frequency of symptoms, or elimination of symptoms, "a prophylactically effective amount" refers to administration to an individual, the amount of drug that will have the intended prophylactic effect, e.g., to prevent or delay the onset (or recurrence) of an injury, disease, pathology, or condition, or to reduce the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A single administration does not necessarily result in a complete prophylactic effect, but may only occur after a series of administrations. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, "activity-reducing amount" refers to an amount of antagonist required to reduce the activity of an enzyme relative to the absence of the antagonist. As used herein, "functionally disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amount will depend on The therapeutic purpose and will be determined by one of skill in The Art using known techniques (see, e.g., Lieberman, Pharmaceutical delivery Forms (vols.1-3,1992); Lloyd, The Art, Science and technology of Pharmaceutical Compounding (1999); Pickar, document Calculations (1999); and Remington, The Science and Practice of Pharmacy,20th Edition,2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

"control" or "control experiment" is used in its ordinary sense and refers to an experiment in which the individual or reagents of the experiment are treated in parallel experiments, except that certain procedures, reagents or variables of the experiment are omitted. In some cases, the control is used as a comparative standard to evaluate the effect of the experiment. In some embodiments, a control is a measurement of protein activity (e.g., a signaling pathway) in the absence of a compound described herein (including embodiments, examples, figures, or tables).

"contacting" is used in its ordinary sense and refers to a process that allows at least two different substances (e.g., compounds, including biomolecules or cells) to react, interact, or physically contact in sufficient proximity. It should be noted, however, that the resulting reaction product may result directly from the reaction between the added reagents or from one or more intermediates of the added reagents (which may be produced in the reaction mixture).

The term "contacting" can include allowing two substances to react, interact, or physically contact, wherein the two substances can be a compound and a protein or enzyme as described herein (e.g., XIAP, cIAP1, or cIAP 2). In some embodiments, contacting comprises allowing the compounds described herein to interact with a protein or enzyme involved in a signaling pathway.

As defined herein, the terms "inhibit", "inhibiting", and the like with respect to a protein-inhibitor interaction, refer to a negative effect on the activity or function of a protein (e.g., a decrease in the signaling pathway stimulated by XIAP, cIAP1, or cIAP 2; or a decrease in inhibitory activity on the XIAP, cIAP1, or cIAP2 signaling pathway) relative to the activity or function of the protein in the absence of the inhibitor. In some embodiments, inhibition refers to the reduction of a disease or disease symptom. In some embodiments, inhibition refers to a decrease in the activity of a signal transduction pathway or signaling pathway (e.g., a decrease in a pathway involving XIAP, cIAP1, or cIAP 2). Thus, inhibition includes, at least partially, partially or fully blocking stimulation, reducing, preventing or delaying activation, or inactivating, desensitizing or down-regulating a signaling pathway or enzymatic activity or amount of protein (e.g., XIAP, cIAP1 or cIAP 2).

The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of a molecular target (e.g., the target can be XIAP, cIAP1, or cIAP2) relative to a control (e.g., the composition is not present).

The term "modulate" is used in its ordinary sense and refers to an act of changing or modifying one or more properties. Modulation "refers to the process of changing or altering one or more properties. For example, methods for modulating the effect of a modulator on a target protein by increasing or decreasing the property or function of the target molecule or the amount of the target molecule.

"patient" or "individual in need thereof" refers to a living organism that has or is predisposed to developing a disease or disorder that can be treated by administration of a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human.

"disease" or "disorder" refers to a state or health condition of a patient or subject that is capable of being treated by a compound or method provided herein. In some embodiments, the disease is a disease associated with (e.g., caused by) XIAP, cIAP1, or cIAP 2. In some embodiments, the disease is a disease associated with (e.g., caused by) XIAP, cIAP1, or cIAP2 signaling pathway activity. In some embodiments, the disease is a disease associated with (e.g., caused by) overexpression of XIAP, cIAP1, or cIAP2 signaling pathway activity. Examples of diseases, abnormalities, or conditions include, but are not limited to, cancer. In some cases, a "disease" or "disorder" refers to cancer. In some other instances, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, acute lymphocytic leukemia, and the like, including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, endometrial, esophageal, stomach, ovarian, prostate, pancreatic, stomach, brain, head and neck, skin, uterine, testicular, glioma, esophageal, and liver cancers, including liver, lymphoma, including B-acute lymphocytic lymphoma, non-hodgkin's lymphoma (e.g., Burkitt's small cell lymphoma and large cell lymphoma), hodgkin's lymphoma, acute lymphocytic leukemia (including AML, ALL, and CML), or multiple myeloma. In some embodiments, the cancer is acute lymphocytic leukemia and lymphoma, including AML, ALL, CML, CLL, multiple myeloma, solid tumor breast cancer, triple negative breast cancer, HER-2 negative metastatic breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, hepatocellular carcinoma, head and neck cancer, liver cancer, lung cancer, lymphoma, melanoma, myelodysplastic syndrome, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, gastric cancer, testicular cancer, thyroid cancer, urothelial cancer, or ALL relapsed and/or chemotherapy-resistant and/or radiotherapy-resistant cancers driven by XIAP overexpression, including caspase 3 deficient cancers.

As used herein, the term "cancer" refers to all types of cancer, tumors, or malignant tumors found in mammals (e.g., humans), including acute lymphocytic leukemia, lymphoma, cancer, and sarcoma. Exemplary cancers that can be treated using the compounds or methods provided herein include thyroid cancer, endocrine system, brain cancer, 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, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, pancreatic cancer. Other 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 insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortex cancer, pancreatic endocrine or exocrine tumors, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer. In some embodiments, the cancer is acute lymphocytic leukemia and lymphoma, including AML, ALL, CML, CLL, multiple myeloma, bladder cancer, brain glioma, solid tumor breast cancer, triple negative breast cancer, HER-2 negative metastatic breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, head and neck cancer, hepatocellular cancer, liver cancer, lung cancer, lymphoma, melanoma, myelodysplastic syndrome, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, gastric cancer, testicular cancer, thyroid cancer, urothelial cancer, or ALL relapsed and/or chemotherapy-and/or radiotherapy-resistant cancers driven by XIAP overexpression, including caspase 3-deficient cancers.

The term "acute lymphocytic leukemia" broadly refers to a progressive, malignant disease of the hematopoietic organs and is generally characterized by the distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Acute lymphocytic leukemia is generally clinically classified based on the following factors: (1) duration and character of acute or chronic disease; (2) (ii) a cell type is involved; bone marrow cells (myeloid), lymphocytes (lymphoid), or monocytes; (3) an increase or no increase in the number of abnormal cells in hematologic acute lymphocytic leukemia or non-acute lymphocytic leukemia (subacute lymphocytic leukemia). Exemplary acute lymphocytic leukemias treated by the compounds or methods provided herein include, for example, acute non-lymphocytic acute lymphocytic leukemia, chronic lymphocytic acute lymphocytic leukemia, acute myelocytic acute lymphocytic leukemia, chronic myelocytic acute lymphocytic leukemia, acute promyelocytic acute lymphocytic leukemia, adult T-cell acute lymphocytic leukemia, non-leukemic acute lymphocytic leukemia, leukemic acute lymphocytic leukemia (leukacytic leukemia), basophilic acute lymphocytic leukemia, blastic acute lymphocytic leukemia, bovine acute lymphocytic leukemia, chronic myelocytic acute lymphocytic leukemia, cutaneous acute lymphocytic leukemia, stem cell acute lymphocytic leukemia, eosinophilic acute lymphocytic leukemia, myelocytic leukemia, acute lymphocytic leukemia, myelocytic leukemia, and myelocytic leukemia, Gross acute lymphocytic leukemia, hairy cell acute lymphocytic leukemia, hemablastic acute lymphocytic leukemia, histiocytic acute lymphocytic leukemia, stem cell acute lymphocytic leukemia, acute monocytic acute lymphocytic leukemia, lymphopenia acute lymphocytic leukemia, lymphoblastic acute lymphocytic leukemia, mastocytic acute lymphocytic leukemia, megakaryocytic acute lymphocytic leukemia, myeloblastic acute lymphocytic leukemia (myeloblastic leukemia), Monocytic acute lymphocytic leukemia, myeloblastic acute lymphocytic leukemia, myelogenous acute lymphocytic leukemia, monocytic acute lymphocytic leukemia, Naegeli acute lymphocytic leukemia, plasma cell acute lymphocytic leukemia, multiple myeloma, plasma cell acute lymphocytic leukemia, promyelocytic acute lymphocytic leukemia, Rieder cell acute lymphocytic leukemia, Schilling acute lymphocytic leukemia, stem cell acute lymphocytic leukemia, sub-leukemic acute lymphocytic leukemia, and undifferentiated acute lymphocytic leukemia.

The term "lymphoma" refers to a tumor of hematopoietic and lymphoid tissue (e.g., blood, bone marrow, lymphoid or lymphoid tissue). Non-limiting examples of lymphomas include B-acute lymphoblastic lymphoma, non-hodgkin's lymphoma (e.g., Burkitt's small cell lymphoma and large cell lymphoma), or hodgkin's lymphoma.

The term "sarcoma" generally refers to a tumor composed of a substance resembling embryonic connective tissue, usually composed of closely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that can be treated using the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanoma, myxosarcoma, osteosarcoma, Abemethy sarcoma, liposarcoma, alveolar soft tissue sarcoma, amelogenic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms 'sarcoma, interstitial sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblast sarcoma, giant cell sarcoma, granulocyte sarcoma, hodgkin's sarcoma, idiopathic multiple-pigment hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's cell sarcoma, angiosarcoma, leukocytosarcoma, interstitial sarcoma, paraosteosarcoma, reticulocyarcoma, Rous sarcoma, serosal cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

The term "melanoma" refers to tumors that originate in the melanocytic system of the skin and other organs. Melanoma that may be treated using the compounds or methods provided herein include, for example, sacral freckle-like melanoma, leucomelanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo melanoma, malignant melanoma, nodular melanoma, sub-ungual melanoma, or superficial spreading melanoma.

The term "cancer" refers to a malignant new growth consisting of epithelial cells that tends to infiltrate surrounding tissues and cause metastasis. Exemplary cancers that can be treated using the compounds or methods provided herein include, for example, medullary thyroid cancer, familial medullary thyroid cancer, acinar cancer, adenoid cancer, cystic adenoid cancer, adenoid cystic cancer, adenoma, adrenocortical cancer, alveolar cell cancer, basal cell like cancer, basal-like cancer, basal squamous cell cancer, bronchioloalveolar carcinoma, bronchogenic cancer, cerebroid cancer, cholangiocellular cancer, choriocarcinoma, jelly-like cancer, acne cancer, uterine corpus cancer, cribriform cancer, thyroid cancer, skin cancer, columnar cell cancer, ductal cancer, hard cancer, embryonic cancer, medullary cancer, epidermoid cancer, epithelioid cancer, exogenous cancer, ulcerative cancer, fibrous cancer, jelly-like cancer, colloidal cancer, giant cell cancer, adenocarcinoma, granular cell cancer, hairy stromal cancer, leukemia, and leukemia, Hepatocellular carcinoma, Hurthle cell carcinoma, clear cell carcinoma, adenoid carcinoma of the kidney, immature embryonic carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, bean carcinoma, lipoma carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, squamous carcinoma, mucinous carcinoma (mucouscarcinosoma), mucinous carcinoma (mucoma mucoparum), mucinous carcinoma, mucoepidermoid carcinoma, mucosal carcinoma, mucinous carcinoma (mucouscarcinosoma), mucinous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossified carcinoma, osteocarcinoma, papillary carcinoma, periportal vein carcinoma, precancer, spiny cell carcinoma, brain-like carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, schneider-like carcinoma, gastrichard cancer, stoste cell carcinoma, withdrawal cell carcinoma, small cell carcinoma, squamous cell carcinoma, simple squamous cell carcinoma, medullary carcinoma, simple spindle cell carcinoma, medullary carcinoma, squamous cell carcinoma, medullary carcinoma, or squamous cell carcinoma, Squamous cell carcinoma, chordal carcinoma (string carcinosoma), dilated capillary carcinoma (carcinosatelmangiectatic), dilated vascular carcinoma (carcinosoma telangiectatics), transitional cell carcinoma, nodular carcinoma (carcinosum), nodular carcinoma (tuberous carcinosum), verrucous carcinoma, or choriocarcinoma (carcinosum).

"XIAP-associated cancer" (also referred to herein as "XIAP-associated cancer") refers to a cancer that is caused by aberrant XIAP activity or signaling or that can be treated by inhibition of XIAP activity (e.g., normal activity or abnormality). Other cancers associated with aberrant XIAP activity are well known in the art (see Mohamed et al, Apoptosis 2017,22,1487-1509) and it is within the skill of the person skilled in the art to determine such cancers.

A "cIAP 1-related cancer" (also referred to herein as a "cIAP 1-related cancer") refers to a cancer caused by aberrant cIAP1 activity or signaling or that can be treated by inhibition of cIAP1 activity (e.g., normal activity or abnormality). Other cancers associated with aberrant activity of clAP1 are well known in the art, and determining such cancers is within the skill of one of skill in the art.

A "cIAP 2-related cancer" (also referred to herein as a "cIAP 2-related cancer") refers to a cancer caused by aberrant cIAP2 activity or signaling or that can be treated by inhibition of cIAP2 activity (e.g., normal activity or abnormality). Other cancers associated with aberrant activity of clAP2 are well known in the art, and determining such cancers is within the skill of one of skill in the art.

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

The term "formulation" is intended to include a preparation of the active compound with encapsulating material as the carrier, providing a capsule in which the active component, with or without other carriers, is surrounded by, and thus associated with, a carrier. Similarly, sachets and lozenges are also included. Tablets, powders, capsules, pills, sachets, lozenges may be included as solid dosage forms suitable for oral administration.

As used herein, the term "administering" refers to oral administration, suppository administration, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration, or implantation of a sustained release device, such as a mini osmotic pump, to a subject. Administration by any route, including parenteral and transmucosal administration (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal administration). For example, parenteral administration includes intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intracerebroventricular, and intracranial administration. Other modes of administration include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. By "co-administration" is meant the simultaneous administration of a composition as described herein before or after the administration of one or more other therapies (e.g., cancer therapies such as chemotherapy, hormonal therapy, radiation therapy or immunotherapy). The compounds of the invention may be administered alone or may also be co-administered to a patient. The compounds of the present invention may be administered alone or simultaneously to a patient. Co-administration refers to the simultaneous or sequential administration of the compounds, either alone or in combination (more than one compound). Thus, the formulations may also be combined with other active substances (e.g., to reduce metabolic degradation) if desired. The compositions of the present invention may be administered transdermally, by a topical route or formulated as sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

The compounds described herein can be used in conjunction with each other, with other active agents known to be useful in the treatment of diseases associated with cells expressing XIAP, cIAP1 and/or cIAP2 (e.g., XIAP, cIAP1 and/or cIAP 2-related cancers), or with adjunctive drugs that may be ineffective alone but may contribute to the therapeutic efficacy of the active drug.

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

By way of non-limiting example, the compounds described herein may be administered in combination with conventional chemotherapeutic agents, including alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosourea, and the like), antimetabolites (e.g., 5-fluorouracil, azathioprine, methotrexate, folinic acid, capecitabine, cytarabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, and the like), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, and the like), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate, teniposide, and the like), antitumor antibiotics (e.g., doxorubicin, adriamycin, and the like), Daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaliplatin, carboplatin, etc.), and the like. In some embodiments, the compounds described herein may be administered in combination with a Bcl-2 family antagonist (e.g., venetoclax (venetoclax) or nevirala (navitoclax)), which is further described below: lessene et al, Nat Rev Drug Discov.2008Dec; 7(12) 989-1000, the entire contents of which are incorporated herein for all purposes.

The compounds described herein can also be administered in combination with conventional hormonal therapy agents, including but not limited to steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, tamoxifen, and gonadotropin releasing hormone agonists (GnRH, such as goserelin).

In addition, the compounds described herein can be administered in combination with conventional immunotherapeutic agents, including, but not limited to, immunostimulants (e.g., bacillus calmette-guerin (BCG), levamisole, interleukin-2, α -interferon, etc.), monoclonal antibodies (e.g., anti-CD 20, anti-HER 2, anti-CD 52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD 33 monoclonal antibody-calicheamicin conjugates, anti-CD 22 monoclonal antibody-pseudomonas exotoxin conjugates, etc.), and radioimmunotherapy (e.g., with anti-CD 33 monoclonal antibody-calicheamicin conjugates, etc.), and radioimmunother¹¹¹In、⁹⁰Y is or¹³¹I-conjugated anti-CD 20 monoclonal antibody, etc.).

In a further embodiment, the compounds described herein may be administered in combination with conventional radiotherapeutic agents, including but not limited to radionuclides, such as⁴⁷Sc、⁶⁴Cu、⁶⁷Cu、⁸⁹Sr、⁸⁶Y、⁸⁷Y、⁹⁰Y、¹⁰⁵Rh、¹¹¹Ag、¹¹¹In、^117mSn、¹⁴⁹Pm、¹⁵³Sm、¹⁶⁶Ho、¹⁷⁷Lu、¹⁸⁶Re、¹⁸⁸Re、²¹¹At, and²¹²bi, optionally conjugated to an antibody directed against a tumor antigen.

In therapeutic use for the treatment of cancer, the compounds used in the pharmaceutical compositions of the present invention may be administered daily at an initial dose of about 0.001mg/kg to about 1000 mg/kg. Daily dosages in the range of about 0.01mg/kg to about 500mg/kg, or about 0.1mg/kg to about 200mg/kg, or about 1mg/kg to about 100mg/kg, or about 10mg/kg to about 50mg/kg may be used. However, the dosage may vary based on the requirements of the patient, the severity of the condition being treated, and the compound or drug being used. For example, the dosage may be determined empirically, taking into account the type and stage of cancer diagnosed in a particular patient. In the context of the present invention, the dose administered to a patient should be sufficient to affect the patient's beneficial therapeutic response over time. The size of the dose will also be determined by the presence, nature and extent of any adverse side effects associated with administration of the compound in a particular patient. Determining the appropriate dosage for a particular situation is within the skill of the participating personnel. Typically, treatment is initiated at lower doses than the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimum effect is achieved under the appropriate circumstances. For convenience, the total daily dose may be administered in portions during the day as required.

The compounds described herein may be used in conjunction with each other, with other active agents known to be useful in the treatment of cancer, or with adjunctive drugs that may be ineffective alone but may contribute to the efficacy of the active agent.

The term "associated with" or "associated with" in the context of a substance or substance activity or function associated with a disease (e.g., a protein-related disease, a cancer associated with aberrant XIAP activity, an XIAP-related cancer, a mutant XIAP-related cancer, an activated XIAP-related cancer, an abnormal cIAP1 activity, a cIAP 1-related cancer, a mutant cIAP 1-related cancer, an activated cIAP 1-related cancer, an abnormal cIAP2 activity, a cIAP 2-related cancer, a mutant cIAP 2-related cancer, an activated cIAP 2-related cancer) refers to (all or part of) a disease (e.g., a cancer) symptoms of the disease caused by (all or part of) the substance or substance activity or function. For example, a cancer associated with aberrant XIAP activity or function may be a cancer that is caused (in whole or in part) by aberrant XIAP activity or function (e.g., enzymatic activity, protein-protein interactions, signaling pathways), or a cancer that causes (in whole or in part) disease-specific symptoms caused by aberrant XIAP activity or function. As used herein, a substance described as being associated with a disease (if a pathogen) may be a target for treatment of the disease. For example, in cases where an increase in XIAP activity or function (e.g., signaling pathway activity) results in cancer, cancers associated with XIAP activity or dysfunction or XIAP-associated cancers may be treated with XIAP modulators or XIAP inhibitors.

As used herein, the term "abnormal" refers to a condition other than normal. When used to describe enzymatic activity, abnormal refers to an activity that is greater than or less than the average of normal control or normal disease-free control samples. Abnormal activity can refer to an amount of activity that causes a disease, wherein the abnormal activity returns to a normal or non-disease related amount (e.g., by administering a compound or using the methods described herein), resulting in a reduction of the disease or one or more symptoms of the disease.

An "anti-cancer drug" is used in its ordinary sense and refers to a composition (e.g., a compound, drug, antagonist, inhibitor, modulator) that has anti-tumor properties or is capable of inhibiting the growth or proliferation of a cell. In some embodiments, the anti-cancer drug is a chemotherapeutic drug. In some embodiments, the anti-cancer drug is a drug identified herein as useful in a method of treating cancer. In some embodiments, an anti-cancer drug refers to a drug approved by the FDA or similar regulatory agency in countries outside the united states for the treatment of cancer.

"chemotherapy" or "chemotherapeutic drug" is used in its ordinary sense and refers to a chemical composition or compound that has anti-tumor properties or is capable of inhibiting cell growth or proliferation.

As used herein, the term "electrophilic" refers to a chemical group capable of accepting an electron density. An "electrophilic substituent", "electrophilic chemical moiety" or "electrophilic moiety" refers to an electron-deficient chemical group, substituent or moiety (monovalent chemical group) that can react with a nucleophilic group (e.g., affinity reagent) by accepting an electron pair or electron density to form a bond. In some embodiments, the electrophilic substituent of the compound is capable of reacting with a cysteine residue. In some embodiments, the electrophilic substituent is capable of forming a covalent bond with a cysteine residue (e.g., XIAP cysteine residue, cIAP1 cysteine residue, cIAP2 cysteine residue) and can be referred to as a "covalent cysteine modifying group moiety" or a "covalent cysteine modifier substituent. The covalent bond formed between the electrophilic substituent and the thiol group of the cysteine may be a reversible or irreversible bond. In some embodiments, the electrophilic substituent is capable of forming a covalent bond with a lysine residue (e.g., a XIAP lysine residue), and can be referred to as a "covalent lysine modifying group moiety" or a "covalent lysine modifier substituent".

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

As used herein, the term "signaling pathway" refers to a series of interactions between a cell and an optional extracellular component (e.g., protein, nucleic acid, small molecule, ion, lipid) that communicates a change in one component to one or more other components, which in turn may communicate the change to the other components, which optionally selectively propagate to the other signaling pathway components. For example, binding of an XIAP, cIAP1, or cIAP2 protein (e.g., to a BIR domain such as BIR3 or BIR2) to a compound described herein can result in a change in one or more protein-protein interactions of XIAP, cIAP1, or cIAP2 (e.g., with caspase-3, caspase-7, and/or caspase-9), or a change in the interaction between XIAP, cIAP1, or cIAP2 and a membrane, resulting in a change in cell growth, proliferation, or survival.

The term "apoptosis-inducing agent" is used in its ordinary sense in biology and refers to an agent that is capable of increasing apoptosis (e.g., in a cell, when contacted with a protein, when contacted with a cell, relative to the absence of the drug).

The term "Bcl-2 (B-cell lymphoma 2) family antagonist" is used according to its ordinary meaning in biology and refers to an agent that is capable of reducing (e.g., inhibiting) the activity or function of a Bcl-2 family protein, wherein the Bcl-2 family protein is a protein comprising a Bcl-2 homology domain, relative to the absence of the Bcl-2 family antagonist. In some embodiments, the Bcl-2 family protein modulates apoptosis. In some embodiments, the Bcl-2 family protein modulates mitochondrial outer membrane permeability. In some embodiments, the Bcl-2 family antagonist is capable of contacting a Bcl-2 family protein and reducing the activity or function of the Bcl-2 family protein (e.g., relative to the absence of the Bcl-2 family antagonist).

The terms "XIAP" and "X-linked inhibitor of apoptosis protein" refer to proteins (including homologs, isoforms, and functional fragments thereof), also known as inhibitor of apoptosis protein 3(IAP3) and baculovirus IAP repeat protein 4(BIRC4), which are proteins involved in apoptotic death of cells, and include one or more BIR domains (e.g., BIR2 domain or BIR3 domain). In some embodiments, the XIAP protein encoded by the XIAP gene has the amino acid sequence shown in or corresponding to Entrez 331, UniProt P98170, RefSeq (protein) NP-001191330, or RefSeq (protein) NP-001158 (SEQ ID NO: 1). In some embodiments, the XIAP gene has the nucleic acid sequence set forth in refseq (mrna) NM — 001167.3. In some embodiments, the XIAP gene has the nucleic acid sequence set forth in refseq (mrna) NM — 001204401.1. In some embodiments, the XIAP protein refers to the amino acid sequence NP _ 001158.2. In some embodiments, the XIAP protein refers to the amino acid sequence NP _ 001191330.1. In some embodiments, the XIAP protein has the following amino acid sequence:

MTFNSFEGSKTCVPADINKEEEFVEEFNRLKTFANFPSGSPVSASTLARAGFLYTGEGDTVRCFSCHAAVDRWQYGDSAVGRHRKVSPNCRFINGFYLENSATQSTNSGIQNGQYKVENYLGSRDHFALDRPSETHADYLLRTGQVVDISDTIYPRNPAMYSEEARLKSFQNWPDYAHLTPRELASAGLYYTGIGDQVQCFCCGGKLKNWEPCDRAWSEHRRHFPNCFFVLGRNLNIRSESDAVSSDRNFPNSTNLPRNPSMADYEARIFTFGTWIYSVNKEQLARAGFYALGEGDKVKCFHCGGGLTDWKPSEDPWEQHAKWYPGCKYLLEQKGQEYINNIHLTHSLEECLVRTTEKTPSLTRRIDDTIFQNPMVQEAIRMGFSFKDIKKIMEEKIQISGSNYKSLEVLVADLVNAQKDSMQDESSQTSLQKEISTEEQLRRLQEEKLCKICMDRNIAIVFVPCGHLVTCKQCAEAVDKCPMCYTVITFKQKIFMS(SEQ ID NO:1)

the terms "cIAP 1" and "apoptosis-inhibiting protein 1" refer to proteins (including homologs, isomers, and functional fragments thereof), also known as baculovirus IAP repeat protein 2(BIRC2), that are proteins involved in apoptotic death and include one or more BIR domains (e.g., BIR2 domain or BIR3 domain). In some embodiments, the cIAP1 protein has the amino acid sequence shown in or corresponding to Entrez 329, UniProt Q13490, RefSeq (mrna) NM _001256163, RefSeq (mrna) NM _001166, RefSeq (protein) NP _001157, or RefSeq (protein) NP _001243092 (seq id no: 2). In some embodiments, the cIAP1 has the nucleic acid sequence set forth in refseq (mrna) NM _ 001256163.1. In some embodiments, the cIAP1 has the nucleic acid sequence set forth in refseq (mrna) NM _ 001166.4. In some embodiments, the cIAP1 protein refers to the amino acid sequence NP _ 001157.1. In some embodiments, the cIAP1 protein refers to the amino acid sequence NP _ 001243092.1. In some embodiments, the cIAP1 protein has the amino acid sequence:

MHKTASQRLFPGPSYQNIKSIMEDSTILSDWTNSNKQKMKYDFSCELYRMSTYSTFPAGVPVSERSLARAGFYYTGVNDKVKCFCCGLMLDNWKLGDSPIQKHKQLYPSCSFIQNLVSASLGSTSKNTSPMRNSFAHSLSPTLEHSSLFSGSYSSLSPNPLNSRAVEDISSSRTNPYSYAMSTEEARFLTYHMWPLTFLSPSELARAGFYYIGPGDRVACFACGGKLSNWEPKDDAMSEHRRHFPNCPFLENSLETLRFSISNLSMQTHAARMRTFMYWPSSVPVQPEQLASAGFYYVGRNDDVKCFCCDGGLRCWESGDDPWVEHAKWFPRCEFLIRMKGQEFVDEIQGRYPHLLEQLLSTSDTTGEENADPPIIHFGPGESSSEDAVMMNTPVVKSALEMGFNRDLVKQTVQSKILTTGENYKTVNDIVSALLNAEDEKREEEKEKQAEEMASDDLSLIRKNRMALFQQLTCVLPILDNLLKANVINKQEHDIIKQKTQIPLQARELIDTILVKGNAAANIFKNCLKEIDSTLYKNLFVDKNMKYIPTEDVSGLSLEEQLRRLQEERTCKVCMDKEVSVVFIPCGHLVVCQECAPSLRKCPICRGIIKGTVRTFLS(SEQ ID NO:2)

the terms "cIAP 2" and "apoptosis-inhibiting protein 2" refer to proteins (including homologs, isomers, and functional fragments thereof), also known as baculovirus IAP repeat protein 3(BIRC3), that are proteins involved in apoptotic death and include one or more BIR domains (e.g., BIR2 domain or BIR3 domain). In some embodiments, the cIAP2 protein has an amino acid sequence shown in or corresponding to Entrez 330, UniProt Q13489, RefSeq (mrna) NM _001165, RefSeq (mrna) NM _182962, RefSeq (protein) NP _001156, or RefSeq (protein) NP _892007 (SEQ id no: 3). In some embodiments, the cIAP2 has the nucleic acid sequence set forth in refseq (mrna) NM _ 001165.4. In some embodiments, the cIAP2 has the nucleic acid sequence set forth in refseq (mrna) NM _ 182962.2. In some embodiments, the cIAP2 protein refers to the amino acid sequence NP _ 001156.1. In some embodiments, the cIAP2 protein refers to the amino acid sequence NP _ 892007.1. In some embodiments, inhibiting cIAP2 activity is modulating an apoptotic pathway (e.g., modulating the activity or function of CASP9, RIPK1, TRAF1, TRAF2, or UBE2D 2). In some embodiments, the cIAP2 protein has the amino acid sequence:

MNIVENSIFLSNLMKSANTFELKYDLSCELYRMSTYSTFPAGVPVSERSLARAGFYYTGVNDKVKCFCCGLMLDNWKRGDSPTEKHKKLYPSCRFVQSLNSVNNLEATSQPTFPSSVTNSTHSLLPGTENSGYFRGSYSNSPSNPVNSRANQDFSALMRSSYHCAMNNENARLLTFQTWPLTFLSPTDLAKAGFYYIGPGDRVACFACGGKLSNWEPKDNAMSEHLRHFPKCPFIENQLQDTSRYTVSNLSMQTHAARFKTFFNWPSSVLVNPEQLASAGFYYVGNSDDVKCFCCDGGLRCWESGDDPWVQHAKWFPRCEYLIRIKGQEFIRQVQASYPHLLEQLLSTSDSPGDENAESSIIHFEPGEDHSEDAIMMNTPVINAAVEMGFSRSLVKQTVQRKILATGENYRLVNDLVLDLLNAEDEIREEERERATEEKESNDLLLIRKNRMALFQHLTCVIPILDSLLTAGIINEQEHDVIKQKTQTSLQARELIDTILVKGNIAATVFRNSLQEAEAVLYEHLFVQQDIKYIPTEDVSDLPVEEQLRRLQEERTCKVCMDKEVSIVFIPCGHLVVCKDCAPSLRKCPICRSTIKGTVRTFLS(SEQ ID NO:3)

the term "BIR domain" is used in its ordinary sense and refers to a Baculovirus IAP Repeat (BIR) domain, which is a structural motif found in proteins (e.g., proteins involved in the apoptotic pathway), typically including 3 conserved cysteines and 1 conserved histidine, which coordinates zinc ions. Non-limiting examples of BIR-containing proteins are known as Inhibitor of Apoptosis Proteins (IAPs), BIRC1(NAIP), BIRC2(cIAP1), BIRC3(cIAP2), BIRC4(XIAP), BIRC5 or BIRC 6.

The term "leaving group" is used in its ordinary sense chemically and refers to the moiety (e.g., atom, functional group, molecule) and the complementary reactive moiety (i.e., the chemical moiety that reacts with the leaving group reactive moiety) that is separated from the molecule after a chemical reaction (e.g., bond formation, reductive elimination, condensation, cross-coupling reaction) involving the atom or chemical group to which the leaving group is attached (also referred to herein as a "leaving group reactive moiety"), forming a new bond between the residue of the leaving group reactive moiety and the complementary reactive moiety. Thus, the leaving group-reactive moiety and the complementary-reactive moiety form a complementary-reactive group pair. Non-limiting examples of such leaving groups include hydrogen, hydroxides, organotin moieties (e.g., organotin heteroalkyl), halogens (e.g., Br), perfluoroalkylsulfonates (e.g., triflates), tosylates, methylsulfonates, water, alcohols, nitrates, phosphates, thioethers, amines, ammonia, fluorides, carboxylates, phenoxides, boric acid, borates, and alkoxy groups. In some embodiments, two molecules having a leaving group are allowed to contact, and the leaving group is separated from the respective molecules upon reaction and/or bond formation (e.g., acyl condensation, aldol condensation, Claisen condensation, Stille reaction). In some embodiments, the leaving group is a bioconjugate reactive moiety. In some embodiments, at least two leaving groups (e.g., R6 and a substituent on a divalent linking group) are allowed to contact such that the leaving groups are sufficiently close to react, interact, or physically contact. In some embodiments, the leaving group is designed to facilitate the reaction.

Compounds and compositions

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

R¹is-CX¹ ₃、-CHX¹ ₂、-CH₂X¹Substituted or unsubstituted C₁-C₄An alkyl group. L is²Is a bond, -NH-, -O-, -S-, -C (O) NH-, -NHC (O) NH-, -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. R²Independently hydrogen, halogen, -CX² ₃、-CHX² ₂、-CH₂X²、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX² ₃、-OCHX² ₂、-OCH₂X²、-SO₂CH₃、-SO₂CX² ₃、-SO₂CH₃、-SO₂X²、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X²、-NHSO₂X²、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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. L is³Is a bond, -NH-, -O-, -S-, -C (O) -, -C (O) NH-, -NHC (O) -, -NHC (O) NH-, -C (O) O-, -OC (O) -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted alkylenearyl, or substituted or unsubstituted alkylenearylUnsubstituted alkyleneheteroaryl. Ring a is cycloalkyl, heterocycloalkyl, aryl or heteroaryl. R³Independently of one another is halogen, -CX³ ₃、-CHX³ ₂、-CH₂X³、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX³ ₃、-OCHX³ ₂、-OCH₂X³、-SO₂X³、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X³、-NHSO₂X³、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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. Two adjacent R³Substituents may optionally be linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁴Independently hydrogen, halogen, -CX⁴ ₃、-CHX⁴ ₂、-CH₂X⁴、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX⁴ ₃、-OCHX⁴ ₂、-OCH₂X⁴、-NHC(NH)NH₂、-SO₂X⁴、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X⁴、-NHSO₂X⁴、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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. R⁵Independently hydrogen, halogen, -CX⁵ ₃、-CHX⁵ ₂、-CH₂X⁵、-CN、-OH、-NH₂、-COH、-COOH、-CONH₂、-NO₂、-SH、-SO₃H、-SO₄H、-SO₂NH₂、-NHNH₂、-ONH₂、-NHC(O)NHNH₂、-NHC(O)NH₂、-NHSO₂H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCX⁵ ₃、-OCHX⁵ ₂、-OCH₂X⁵、-NHC(NH)NH₂、-SO₂X⁵、-SO₂CH＝CH₂、-NHSO₂CH＝CH₂、-OSO₂X⁵、-NHSO₂X⁵、-B(OH)₂-CO-oxiranyl, -CO-aziridinyl, oxiranyl, oxaziranyl, aziridinyl, -OCH₂C ≡ CH, 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. L is⁶Is a bond or unsubstituted methylene. R⁶Independently hydrogen, 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. X¹、X²、X³、X⁴And X⁵Each independently is-F, -Cl, -Br or-I. The symbols z3 are independently integers from 0 to 3.