Diterpenoid compounds that act on protein kinase c (PKC)

Abstract

To provide protein kinase C (PKC) modulating compounds and methods of treating a subject with cancer using the compounds.SOLUTION: There are provided tricyclic compounds, such as K101-C1301 compounds shown below or pharmaceutically acceptable salts thereof, tautomers thereof, or stereoisomers thereof.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 905,253, filed September 24, 2019, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Diterpenoid protein kinase C (PKC)-modulating compounds have demonstrated anticancer and cytotoxic activity. Most of these compounds have been studied as tigliane diterpenoids, such as phorbol esters and prostratin. The biological effects of these compounds are thought to be mediated by the transactivation, translocation, and inhibition of PKC enzymes, which play important roles in regulating signal transduction pathways that regulate or modulate cellular structure and gene expression.

[0003] The association of PKC enzyme activation with cancer cell proliferation and its inhibitory effect are supported by studies of PKC mutations in human cancers, which found that most PKC mutations were loss-of-function mutations (Antal et al., 2015, Cell 160:489-502). The presence of PKC loss-of-function mutations in various cancer types suggests that PKC enzymes may act as tumor suppressors. Studies using prostratin suggest that its antitumor effect occurs through activation of PKC enzymes that specifically target the oncogene K-RAS (see Wang et al., 2015, Cell 163(5):1237-1251). A different tigliane diterpenoid compound, phorbol myristate 13-acetate (PMA), also exhibits inhibitory effects on tumor growth through its action on PKC enzymes, although non-PKC mechanisms were also involved (Bond et al., 2007, Int. J. Cancer 121:1445-1454).

[0004] In view of the therapeutic potential of diterpenoid PKC modulating compounds, it is desirable to further develop these classes of compounds for use in treating diseases and disorders that can be affected by modulation of PKC activity. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Antal et al.,2015,Cell 160:489-502 [Non-patent document 2] Wang et al.,2015,Cell 163(5):1237-1251 [Non-patent document 3] Bond et al.,2007,Int.J.Cancer 121:1445-1454 Summary of the Invention

[0006] The present disclosure provides novel protein kinase C (PKC) modulating compounds. The compounds are diterpenoid PKC modulating compounds that exhibit enhanced pharmacological properties, including, inter alia, potent PKC enzyme binding activity and antiproliferative activity against different cancer cells. The PKC modulating compounds also have substituents that can enhance solubility and pharmacokinetic profile. In one aspect, the compounds are represented by formula (I): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony A is -OH, -C(O)OR 1 , or -NR 13 R 13’ and R 1 is H or M + is the counterion, R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5’ and R 6’ is H or R 5’ and R 6’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent RA and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 6’ and R 7’ is H or R 6’ and R 7’ forms a bond or an atom and, if permitted by valence, are joined to a common O atom to form an epoxide ring; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl, R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is not present or C1~C 12Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0007] In some embodiments, A is -OH. In some embodiments, A is -C(O)OR 1where R 1 is H or M + In some embodiments, A is -NR 13 R 13’ where R 13 and R 13’ are each independently H or C1-C4 alkyl.

[0008] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -ORb, where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5’ and R 6’ is H or R 5’ and R 6’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and Rc1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 6’ and R 7’ is H or R 6’ and R 7’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl, R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R jare independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0009] In some embodiments, the compound has the formula (IIc): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR C1 )2 or -C1-C6 alkylC(O)OR k and R C1 is H, C1-C6 alkyl, or two R C1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R BEach occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0010] In another aspect, the present disclosure provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -ORb, where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R5’ and R 6’ is H or R 5’ and R 6’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 6’ and R 7’ is H or R 6’ and R 7’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 7 is H or OH, R 9 is OR e where R eis H, C1-C6 alkyl or aryl , R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkylC3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, and -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR kwherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; R k is H or M + It is a counter ion.

[0011] In some embodiments, the compounds can be used in methods of activating protein kinase C, comprising contacting a mammalian cell with an effective amount of a compound disclosed herein. In some embodiments, the mammalian cell is a cancer cell.

[0012] In some embodiments, the compounds are used to treat cancer by administering a therapeutically effective amount of a compound disclosed herein to a subject in need thereof.

[0013] In some embodiments, the cancer for treatment is adrenocortical carcinoma, anal cancer, biliary tract cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, intestinal cancer, liver cancer, lung cancer, oral cancer, ovarian cancer, pancreatic cancer, kidney cancer, prostate cancer, salivary gland cancer, skin cancer, stomach cancer, testicular cancer, pharyngeal cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, or soft tissue cancer.

[0014] In some embodiments, the cancer for treatment is a blood cancer, such as leukemia or lymphoma. In some embodiments, the blood cancer is lymphocytic leukemia (ALL), acute myeloid leukemia (AML), lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell chronic myelogenous leukemia (CML), and multiple myeloma. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds, as assessed by measuring the levels of phosphorylated PKC (p-PKC) and phosphorylated ERK1 / 2 protein (p-ERK1 / 2).

[0016] [Figure 2] FIG. 2 shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds, as assessed by measuring the levels of phosphorylated PKC (p-PKC) and phosphorylated ERK1 / 2 protein (p-ERK1 / 2).

[0017] [Figure 3] Figure 3 shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds, as assessed by measuring the levels of phosphorylated PKC (p-PKC) and phosphorylated ERK1 / 2 protein (p-ERK1 / 2), with prostratin (K101) for comparison.

[0018] [Figure 4A]FIG. 4A shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds based on the levels of phosphorylated PKC (p-PKC) and phosphorylated ERK1 / 2 protein (p-ERK1 / 2).

[0019] [Figure 4B] FIG. 4B shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds, as assessed by measuring the levels of phosphorylated PKD / PKCμ (p-PKC) and phosphorylated PKCδ.

[0020] [Figure 5] FIG. 5 shows the effect of selected diterpenoid compounds on the levels of phosphorylated CaMKii (p-CaMKii), a marker of K-Ras stem cell pathway inhibition, in the Panc1 pancreatic cancer cell line.

[0021] [Figure 6A] FIG. 6A shows sphere formation by the Panc1 pancreatic cancer cell line treated with one of various diterpenoid compounds. [Figure 6B] FIG. 6B shows sphere formation by the Panc1 pancreatic cancer cell line treated with one of various diterpenoid compounds. [Figure 6C] FIG. 6C shows sphere formation by the Panc1 pancreatic cancer cell line treated with one of various diterpenoid compounds. [Figure 6D] FIG. 6D shows sphere formation by the Panc1 pancreatic cancer cell line treated with one of various diterpenoid compounds.

[0022] [Figure 7] FIG. 7 shows the effect of intratumoral administration (7 daily injections) of diterpenoid compounds to Panc2.13 tumors in mice bearing Panc2.13 pancreatic cancer cell line xenografts. DETAILED DESCRIPTION OF THE INVENTION

[0023] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a "protein" includes one or more proteins, and a reference to a "compound" refers to one or more compounds.

[0024] Additionally, the use of "or" means "and / or" unless expressly stated otherwise. Similarly, "comprise," "comprises," "comprising," "include," "includes," and "including" are interchangeable and are not intended to be limiting.

[0025] When the description of various embodiments uses the term "comprising" It is further understood that those skilled in the art will understand that in some specific instances, embodiments can alternatively be described using the terms "consisting essentially of" or "consisting of."

[0026] It is to be understood that both the foregoing general description, including the drawings, and the following detailed description are exemplary and explanatory only and are not restrictive of the present disclosure. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0027] 5.1.Definition In connection with the present disclosure, technical and scientific terms used in the description herein have the meanings that are commonly understood by those of ordinary skill in the art unless otherwise defined. Accordingly, the following terms are intended to have the meanings set forth below:

[0028] "Alkyl" refers to alkyl groups having 1 to 20 carbon atoms, especially 1 to 12 carbon atoms (C1-C 12 or C 1~12 ), more specifically (C1 to C8 or C 1~8) refers to a straight or branched chain hydrocarbon group of carbon atoms. Exemplary "alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.

[0029] "Alkenyl" refers to an alkyl group having 2 to 20 carbon atoms, particularly 2 to 12 carbon atoms (C2-C6), with at least one double bond. 12 or C 2~12 ), most specifically 2 to 8 (C2 to C8 or C 2~8 ) refers to a straight or branched chain hydrocarbon group of carbon atoms. Exemplary "alkenyl" groups include, but are not limited to, vinylethenyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

[0030] "Alkynyl" refers to an alkyl group having 2 to 12 carbon atoms (C2-C6) containing at least one triple bond. 12 or C 2~12 ), in particular 2 to 8 carbon atoms (C2 to C8 or C 2~8 ) refers to a straight or branched chain hydrocarbon group. Exemplary "alkynyl" groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.

[0031] "Alkylene," "alkenylene," and "alkynylene" refer to the corresponding alkyl, alkenyl, and alkynyl straight- or branched-chain divalent hydrocarbon radicals, respectively. "Alkylene," "alkenylene," and "alkynylene" may be optionally substituted, for example, with alkyl, alkyloxy, hydroxyl, carbonyl, carboxyl, halo, nitro, etc.

[0032] "Aliphatic compound" refers to an organic compound characterized by substituted or unsubstituted, straight or branched chain and / or cyclic chain arrangement of its constituent carbon atoms. Aliphatic compounds do not contain aromatic rings as part of the compound's molecular structure. Aliphatic compounds are those that contain 1 to 20 carbon atoms (C1 to C6). 20 or C 1~20 ) carbon atoms, 1 to 12 (C1 to C 12 or C 1~12 ) carbon atoms, or in particular 1 to 8 (C1 to C8 or C 1~8 ) carbon atoms.

[0033] "Lower" with respect to a substituent refers to a group having 1 to 6 carbon atoms.

[0034] "Cycloalkyl" refers to any stable monocyclic or polycyclic ring system composed of carbon atoms in which any ring is saturated. "Cycloalkenyl" refers to any stable monocyclic or polycyclic ring system composed of carbon atoms in which at least one ring is partially unsaturated. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloalkyl, and tricycloalkyl (e.g., adamantyl).

[0035] "Heterocycloalkyl" or "heterocyclyl" refers to a substituted or unsubstituted 3- to 14-membered, monocyclic or bicyclic non-aromatic hydrocarbon in which 1 to 3 carbon atoms are replaced by heteroatoms. Heteroatoms and / or heteroatom groups that can replace carbon atoms include, but are not limited to, -O-, -S-, -SO-, -NR'-, -PH-, -S(O)-, -S(O)2-, -S(O)NR'-, -S(O)2NR'-, etc. (including combinations thereof), where each R' is independently hydrogen or lower alkyl. Examples include oxiranyl, oxetanyl, azetidinyl, oxazolyl, thiazolidinyl, thiazolyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, azapanyl, and the like.

[0036] As used herein, "carbocycle," "carbocyclyl," and "carbocyclic" refer to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon. The ring may be monocyclic, bicyclic, tricyclic, or higher. Thus, the terms "carbocycle," "carbocyclyl," and "carbocyclic" encompass fused, bridged, and spiro ring systems. Preferably, the carbocycle contains 3 to 14 atoms, such as 3 to 8 or 5 to 7 atoms, e.g., 6 atoms.

[0037] "Aryl" refers to a 6- to 14-membered monocyclic or bicarbocyclic ring in which the monocyclic ring is aromatic and at least one of the rings in a bicyclic ring is aromatic. Unless otherwise specified, the valency of the group can be located on any atom of any ring within the radical, valence rules permitting. Examples of "aryl" groups include phenyl, naphthyl, indenyl, biphenyl, phenanthrenyl, naphthacenyl, and the like.

[0038] "Heteroaryl" refers to an aromatic heterocycle, including both monocyclic and bicyclic ring systems, in which at least one carbon atom on one or both rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms on one or both rings are replaced with heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl can be a 5- to 6-membered monocyclic or a 7- to 11-membered bicyclic ring system. Examples of "heteroaryl" groups include pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolyl, and the like.

[0039] "Bridged bicyclic" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or valence bonds connecting two bridgeheads, and a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, bridged bicyclic groups have 5 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Such bridged bicyclic groups include the groups shown below, each of which terminates the molecule at any substitutable carbon or nitrogen atom: is bonded to the remainder of the aliphatic group. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as described for an aliphatic group. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include: [ka]

[0040] "Fused ring" refers to a ring system having two or more rings that have at least one bond and two atoms in common. "Fused aryl" and "fused heteroaryl" refer to ring systems having at least one aryl and heteroaryl, respectively, that share at least one bond and two atoms in common with another ring.

[0041] "Carbonyl" refers to -C(O)-. The carbonyl group may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones. For example, -C(O)R', where R' is alkyl, is referred to as alkylcarbonyl. In some embodiments, R' is selected from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0042] "Halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

[0043] "Haloalkyl" refers to an alkyl substituted with one or more halogen atoms. Preferably, the alkyl is substituted with 1 to 3 halogen atoms.

[0044] "Hydroxy" refers to --OH.

[0045] "Oxy" refers to the group -O-, which can have a variety of substituents to form different oxy groups, including ethers and esters. In some embodiments, the oxy group is -OR', where R' is selected from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0046] "Acyl" refers to -C(O)R', where R is hydrogen or an acyl group as defined herein. and optionally substituted alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, such as aryl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. Exemplary acyl groups include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

[0047] "Alkyloxy" or "alkoxy" refers to --OR', where R' is an optionally substituted alkyl.

[0048] "Aryloxy" refers to --OR', where R' is an optionally substituted aryl.

[0049] "Carboxy" refers to -COO- or COOM, where H or M + It is a counter ion.

[0050] "Carbamoyl" refers to -C(O)NR'R', where each R' is independently selected from H or optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocylcoalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0051] "Cyano" refers to -CN.

[0052] An "ester" refers to a group such as, or represented as, -C(=O)OR', where R' is selected from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0053] "Silyl" refers to Si and can have a variety of substituents, such as -SiR'R'R', where R' is as defined herein. For example, each R' is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. As defined herein, any heterocyloalkyl or heteroaryl group present in a silyl group has 1 to 3 heteroatoms independently selected from O, N, and S.

[0054] "Thiol" refers to -SH.

[0055] "Sulfanyl" refers to -SR', where R' is selected from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. For example, -SR, where R is alkyl, is alkylsulfanyl.

[0056] "Sulfonyl" refers to -S(O)-, which can have a variety of substituents to form different sulfonyl groups, including sulfonic acids, sulfonamides, sulfonate esters, and sulfones. For example, -S(O)R', where R' is alkyl, refers to alkylsulfonyl. In some embodiments of -S(O)R', R' is selected from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0057] "Amino" or "amine" refers to the group -NR'R' or -NR'R'R', where each R' is independently selected from H and optionally substituted alkyl, cycloalkyl, heterocycloalkyl, alkyloxy, aryl, heteroaryl, heteroarylalkyl, acyl, alkyloxycarbonyl, sulfanyl, sulfinyl, sulfonyl, etc. Exemplary amino groups include, but are not limited to, dimethylamino, diethylamino, trimethylammonium, triethylammonium, methylsulfonylamino, furanyl-oxy-sulfamino, etc.

[0058] "Amido" refers to groups such as -C(=O)NR'R', where each R' is independently selected from H and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0059] As used herein, "spiroalkyl" refers to a monospiro compound having two alicyclic rings joined together through a single common carbon atom. In some embodiments, the spiro compound has 5 to 12 total ring atoms (e.g., C5 to C6). 12 or C 5~12 In some embodiments, one or more of the carbon atoms can be replaced with a heteroatom such as oxygen, nitrogen, or sulfur. Exemplary spiroalkyl compounds include spiro[3,3]heptyl, spiro[3.4]octyl, and spiro[3,5]decyl, among others.

[0060] "Adamantyl" refers to a compound having the structural formula: [ka] In the formula, R a , R b , R c , and R dOptional substitutions can be present at one or more of the following groups. Adamantyl includes substituted adamantyl, e.g., 1- or 2-adamantyl, substituted with one or more substituents including alkyl, halo, OH, NH, and alkoxy. Exemplary derivatives include methyladamantane, haloadamantane, hydroxyadamantane, and aminoadamantane (e.g., amantadine).

[0061] As used herein, "N-protecting group" refers to a group intended to protect a nitrogen atom from undesired reactions during synthetic procedures. Exemplary N-protecting groups include, but are not limited to, acyl groups such as acetyl and t-butylacetyl, pivaloyl, alkoxycarbonyl groups such as methyloxycarbonyl and t-butyloxycarbonyl (Boc), aryloxycarbonyl groups such as benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc), and aroyl groups such as benzoyl. N-protecting groups are defined in Greene's Protective Groups in Organic Synthesis. Synthesis, 5th Edition, PGM Wuts, ed., Wiley (2014).

[0062] "Optional" or "optionally" refers to a described event or circumstance that may or may not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "optionally substituted alkyl" refers to an alkyl group that may or may not be substituted; The description includes both substituted and unsubstituted alkyl groups.

[0063] As used herein, "substituted" means that one or more hydrogen atoms of the group have been replaced with a substituting atom or group commonly used in pharmaceutical chemistry. Each substituent may be the same or different. Examples of suitable substituents include alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, OR' (e.g., hydroxyl, alkyloxy (e.g., methoxy, ethoxy, and propoxy), aryloxy, heteroaryloxy, arylalkyloxy, ether, ester, carbamate, etc.), hydroxyalkyl, alkyloxycarbonyl, alkyloxyalkyloxy, perhaloalkyl, alkyloxyalkyl, SR' (e.g., thiol, alkylthio, arylthio, heteroarylthio, arylalkylthio, etc.), S + Examples of substituents include, but are not limited to, R', S(O)R', SOR', NR'R'' (e.g., primary amine (i.e., NH), secondary amine, tertiary amine, amide, carbamate, urea, etc.), hydrazide, halo, nitrile, nitro, sulfide, sulfoxide, sulfone, sulfonamide, thiol, carboxy, aldehyde, keto, carboxylic acid, ester, amide, imine, and imide, and seleno and thio derivatives thereof, each of which may be optionally further substituted. In embodiments where the aromatic carbocyclic functional group is substituted, such substitutions are typically less than about 10 substitutions, more preferably about 1 to 5 substitutions, with about 1 or 2 substitutions being preferred.

[0064] "Stereoisomers" refer to compounds that are composed of the same atoms connected by the same bonds but have different three-dimensional structures and are not interchangeable. Thus, "stereoisomers thereof" in reference to a compound includes any stereoisomer of the compound and mixtures of stereoisomers, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. A compound may have two or more chiral centers, such that the compound can exist as either an individual diastereomer or a mixture of diastereomers.

[0065] "Tautomer" refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. Thus, "a tautomer thereof" in reference to a compound includes any tautomer of that compound.

[0066] A "prodrug" refers to a derivative of an active compound (e.g., a drug) that requires transformation under use conditions, e.g., in vivo or under appropriate in vitro conditions, to release the active drug. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to the active drug. A prodrug can be obtained by masking a functional group in the drug believed to be partially required for activity with a progroup to form a promoiety that undergoes a transformation, such as cleavage, under specific use conditions to release the functional group and, hence, the active drug. Cleavage of the promoiety may proceed spontaneously, such as by hydrolysis, or may be catalyzed or induced by other agents, such as enzymes, light, acid, or changes in or exposure to physical or environmental parameters, such as a change in temperature. The drug may be endogenous to the use conditions, such as enzymes present in cells to which the prodrug is administered or the acidic conditions of the stomach, or may be supplied exogenously.

[0067] A variety of progroups, and the resulting promoieties, suitable for masking functional groups in active drugs to generate prodrugs can be used. For example, a hydroxyl functional group can be masked as a sulfonate, ester, or carbonate promoiety, which can be hydrolyzed in vivo to provide the hydroxyl group. An amino functional group can be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl, or sulfenyl promoiety, which can be hydrolyzed, for example, in vivo or under suitable in vitro conditions to provide the amino group. A carboxyl group can be masked as an ester (silyl esters and thioesters). (including), amide, or hydrazide promoieties, which can be hydrolyzed in vivo to provide the carboxyl group. Included within the scope of prodrugs, inter alia, are "biohydrolyzable carbonate," "biohydrolyzable ureido," "biohydrolyzable carbamate," "biohydrolyzable ester," "biohydrolyzable amide," and "biohydrolyzable phosphate" groups.

[0068] "Solvate" refers to a complex of variable stoichiometry formed by a solute, such as a PKC activator compound, and a solvent. Such a solvent is selected to minimize interference with the biological activity of the solute. The solvent can be, by way of example and not limitation, water, ethanol, or acetic acid.

[0069] "Hydrate" refers to a combination of water and a solute, such as a PKC activator compound, where the water retains its molecular state as water and is either absorbed, adsorbed, or contained within the crystal lattice of the solute (e.g., a PKC activator compound).

[0070] "Pharmaceutically acceptable salts" is intended to include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either pure or 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 a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either pure or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, phosphoric acid, partially neutralized phosphoric acid, sulfuric acid, partially neutralized sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid or galactunoric acid. Certain specific compounds of the present disclosure may contain both basic and acidic functional groups, allowing the compounds to be converted into either base or acid addition salts. A list of suitable salts can be found in Remington's Pharmaceuticals, Inc. Sciences, 17th Ed., Mack Publishing Company, Easton, Pa., (1985) and Journal of Pharmaceutical Science, 66:2 (1977), each of which is incorporated herein by reference in its entirety.

[0071] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to an excipient, carrier, or adjuvant that can be administered to a subject with at least one therapeutic agent, does not destroy the pharmacological activity thereof, and is generally safe, non-toxic, and not biologically or otherwise undesirable when administered in a dosage sufficient to deliver a therapeutic amount of the agent.

[0072] "K-RAS" refers to Kirsten rat sarcoma viral oncogene homolog, a member of the RAS family of proteins that are small GTPases and involved in signal transduction. Exemplary human K-RAS nucleic acid and protein sequences are provided in GenBank Nos. M54968.1 and AAB414942.1, respectively. As used herein, "K-RAS" encompasses variants, including orthologs and interspecies homologs, of the human K-RAS protein.

[0073] "Mutant K-RAS polypeptide," "mutant K-RAS protein," and "mutant K-RAS" "S" are used interchangeably to refer to a K-RAS polypeptide that contains at least one K-RAS mutation compared to the corresponding wild-type K-RAS sequence. Certain exemplary mutant K-RAS polypeptides include, but are not limited to, allelic variants, splice variants, derivative variants, substitution variants, deletion variants, insertion variants, and fusion polypeptides.

[0074] "N-RAS" refers to the viral neuroblastoma RAS (V-RAS) oncogene homolog, a small GTPase and member of the RAS family of proteins involved in signal transduction. Exemplary human N-RAS nucleic acid and protein sequences are provided in NCBI Accession No. NP_002515 and GenBank Accession No. X02751, respectively. As used herein, "N-RAS" encompasses variants, including orthologs and interspecies homologs, of the human N-RAS protein.

[0075] "Mutant N-RAS polypeptide," "mutant N-RAS protein," and "mutant N-RAS" are used interchangeably and refer to an N-RAS polypeptide that contains at least one N-RAS mutation compared to the corresponding wild-type N-RAS sequence. Specific exemplary mutant N-RAS polypeptides include, but are not limited to, allelic variants, splice variants, derivative variants, substitution variants, deletion variants, insertion variants, and fusion polypeptides.

[0076] "H-RAS" refers to Harvey rat sarcoma viral oncogene homolog, a member of the RAS family of proteins that are small GTPases and involved in signal transduction. Exemplary human H-RAS nucleic acid and protein sequences are provided in NCBI Accession No. P01112 and GenBank Accession No. NM_176795, respectively. As used herein, "H-RAS" encompasses variants, including orthologs and interspecies homologs, of the human H-RAS protein.

[0077] "Mutant H-RAS polypeptide," "mutant H-RAS protein," and "mutant H-RAS" are used interchangeably and refer to an H-RAS polypeptide that contains at least one H-RAS mutation compared to the corresponding wild-type H-RAS sequence. Specific exemplary mutant H-RAS polypeptides include, but are not limited to, allelic variants, splice variants, derivative variants, substitution variants, deletion variants, insertion variants, and fusion polypeptides.

[0078] "Activated K-RAS" refers to a form of K-RAS that has increased activity compared to wild-type K-RAS. Activated K-RAS activity can result from mutations in the K-RAS protein, or, in some embodiments, overexpression of the K-RAS protein.

[0079] "Activated N-RAS" refers to a form of N-RAS that has increased activity compared to wild-type N-RAS. Activated N-RAS activity can result from mutations in the N-RAS protein or, in some embodiments, overexpression of the N-RAS protein.

[0080] "Activated H-RAS" refers to a form of H-RAS that has increased activity compared to wild-type H-RAS. Activated H-RAS activity can result from mutations in the H-RAS protein or, in some embodiments, overexpression of the H-RAS protein.

[0081] "Mutation" or "variant" refers to an amino acid or polynucleotide sequence that has been altered by substitution, insertion, and / or deletion. In some embodiments, a mutant or variant sequence may have increased, decreased, or substantially similar activity or properties compared to the parent sequence.

[0082] "Identified" or "determined" refers to analyzing, detecting, or performing a process for the presence or absence of one or more specified characteristics.

[0083] "Wild-type" or "naturally-occurring" refers to a form found in nature. For example, a naturally-occurring or wild-type polypeptide or polynucleotide sequence is a sequence present in an organism that can be isolated from a natural source and has not been intentionally modified by human manipulation.

[0084] "Control" or "control sample" or "control group" refers to a sample or group that is compared to another sample or group; generally, the control sample or group is the same as the comparison group except for the factor or factors being compared.

[0085] "Selecting" refers to the process of determining that a subject will be administered an agent to treat the occurrence of a condition. Selection can be based on an individual's susceptibility to a particular disease or condition, for example, due to the presence of particular cellular, physiological, or environmental factor(s). In some embodiments, selecting can be based on determining or identifying whether a subject is responsive to an agent, as assessed, for example, by identifying the presence of biomarkers and / or drug target markers that render the subject sensitive, insensitive, responsive, or non-responsive to the agent or treatment.

[0086] A "biological sample" refers to any sample containing biomolecules, such as proteins, peptides, nucleic acids, lipids, carbohydrates, or combinations thereof, obtained from an organism, particularly a mammal. Examples of mammals include humans; veterinary animals such as cats, dogs, horses, cows, and pigs; and laboratory animals such as mice, rats, and primates. In some embodiments, a human subject in a clinical setting is referred to as a patient. Biological samples include tissue samples (such as tissue sections and needle biopsies of tissue), cell samples (e.g., cytological smears such as Pap or blood smears, or samples of cells obtained by microdissection), or cell fractions, fragments, or organelles (e.g., obtained by lysing cells and separating their components, such as by centrifugation). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any substance containing biomolecules derived from a first biological sample. In certain embodiments, the biological sample is an "acellular sample," such as acellular or extracellular polynucleotides and acellular or extracellular proteins. In some embodiments, cell-free DNA or cfDNA refers to extracellular DNA obtained from blood, particularly serum.

[0087] As used herein, a "subject" refers to a mammal, such as a dog, cat, horse, or rabbit. In some embodiments, the subject is a non-human primate, such as a monkey, chimpanzee, or gorilla. In some embodiments, the subject is a human, sometimes referred to herein as a patient.

[0088] As used herein, "treating" or "treatment" of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a subject, i.e., preventing clinical symptoms of the disease, disorder, or syndrome from developing in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome, but that has not yet experienced or displayed symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) alleviating the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As known in the art, various therapeutic approaches are used to treat the disease, disorder, or syndrome, taking into account factors such as systemic versus local delivery, age, weight, general Adjustments for health, sex, diet, time of administration, drug interactions, and severity of the condition may be necessary and can be ascertained by routine experimentation by one of ordinary skill in the art, especially in light of the guidance provided in this disclosure.

[0089] A "therapeutically effective amount" refers to the amount that, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease, disorder or condition.

[0090] 5.2. Compounds The present disclosure provides protein kinase C (PKC) modulating compounds. In particular, the compounds are diterpenoid PKC modulating compounds that exhibit potent PKC modulating activity and improved solubility and pharmacokinetic profile. The diterpenoid PKC modulating compounds exhibit potent activity against tumor cells and can be applied to the treatment of cancer. In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony A is -OH, -C(O)OR 1 , or -NR 13 R 13’ and R 1 is H or M + is the counterion, R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5’ and R 6’ is H or R 5’ and R 6’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 6’ and R 7’ is H or R 6’ and R 7’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl, R 14is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by Rk is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0091] In some embodiments of the compounds of Formula (I), [ka] Carbon atoms marked with an "*" are chiral and therefore can exist in either the S or R stereochemical configuration. In some embodiments, the stereochemical configuration is the S isomer. In some embodiments, the stereochemical configuration is the R isomer.

[0092] In some embodiments, A is -OH. In some embodiments, A is -C(O)OR 1 where R 1 is H or M + In some embodiments, A is -NR 13 R 13’ where R 13 and R 13’ are each independently H or C1-C4 alkyl.

[0093] In the embodiments herein, M + is a metal cation, an ammonium group, or a suitable organic cation. In some embodiments, M + is an alkali metal or alkaline earth metal cation, e.g., K + , Na + , Li + , or Ca +2 In some embodiments, M + is the ammonium ion NH4 + or an organic cation derived from an amine.

[0094] In some embodiments, the compound has formula (Ia): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony A is -OH, R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5’ and R 6’ is H or R 5’ and R 6’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 6’ and R 7’ is H or R 6’ and R 7’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl, R 14 is H or OR g where R g is H or C1-C6 alkyl, R17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0095] In some embodiments of the compound of Formula (Ia), [ka] Carbon atoms marked with an "*" are chiral and therefore can exist in either the S or R stereochemical configuration. In some embodiments, the stereochemical configuration is the S isomer. In some embodiments, the stereochemical configuration is the R isomer.

[0096] In some embodiments, the compound has formula (Ib): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony A is -C(O)OR 1 and R 1 is a H or M counterion, R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5’ and R 6’ is H or R5’ and R 6’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 6’ and R 7’ is H or R 6’ and R 7’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl, R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0097] In some embodiments of the compound of Formula (Ib), [ka] Carbon atoms marked with an "*" are chiral and therefore can exist in either the S or R stereochemical configuration. In some embodiments, the stereochemical configuration is the S isomer. In some embodiments, the stereochemical configuration is the R isomer.

[0098] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -ORb, where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5’ and R 6’ is H or R 5’ and R 6’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R Aand together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 6’ and R 7’ is H or R 6’ and R 7’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl, R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0099] In some embodiments of the compound of Formula (II), [ka] The carbon atom marked with "*" is chiral, and therefore the compound can exist in either the S or R stereochemical configuration. In some embodiments, the stereochemical configuration is the S isomer. In some embodiments, the stereochemical configuration is the R isomer. In some embodiments, the compound of formula (II) has formula (II'): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 5’ , R 6 , R 6’ , R 7 , R 7’ , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 、 R 17 , R 18 , L and R 21 is as defined for formula (II).

[0100] In some embodiments, the compound of formula (II) has the formula (II″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 5’ , R 6 , R 6’ , R 7 , R 7’ , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 、 R 17 , R 18 , L and R21 is as defined for formula (II).

[0101] In some embodiments, the compound has the formula (IIa): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R Aeach occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl, R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is not present or C1~C 12Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl. Selected, n is 0 or 1.

[0102] In some embodiments, the compound of formula (IIa) has the formula (IIa'): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 、 R 17 , R 18 , L and R 21 is as defined for formula (II).

[0103] In some embodiments, the compound of formula (IIa) has the formula (IIa″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 、 R 17 , R 18 , L and R 21 is as defined for formula (II).

[0104] In some embodiments, the compound has the formula (IIb): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2is a C1-C4 alkyl; R 3 When (- - -) is a bond, it is an O double-bonded to a ring carbon, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl, R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0105] In some embodiments, the compound has the formula (IIb'): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 、 R 17 , R18 , L and R 21 is as defined for formula (II).

[0106] In some embodiments, the compound has the formula (IIb″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 、 R 17 , R 18 , L and R 21 is as defined for formula (II).

[0107] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), and (IIb''), R 3 HA-OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl. In some embodiments, the aryl of the C0-C6 alkylaryl is phenyl. In some embodiments, the aryl of the C0-C6 alkylaryl is optionally substituted with 1-3 of OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl. In some embodiments, R a1 is selected from the following: [ka]

[0108] In some embodiments, R a1 is selected from the following: [ka]

[0109] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (II"), (IIa), (IIa'), (IIa"), (IIb), (IIb'), and (IIb"): R 3 is an O double-bonded to a carbon atom.

[0110] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), and (IIb''), R 2 , R 11 , R 17 , and R 18 In some embodiments, one or more of R 2 , R 11 , R 17 , and R 18 Each of is -CH3.

[0111] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (II"), (IIa), (IIa'), (IIa"), (IIb), (IIb'), and (IIb"), R 4 and R 5 are each independently H or —OH.

[0112] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II'), (II"), (IIa), (IIa'), (IIa"), (IIb), (IIb'), and (IIb"): R 2 , R 11 , R 17 , and R 18 is -CH3, R 3 is an O double-bonded to a carbon atom, R 4 and R 5 are each independently H or —OH.

[0113] In some embodiments, the compound has the formula (IIc): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR C1 )2 or -C1-C6 alkylC(O)OR k and R C1 is H, C1-C6 alkyl, or two R C1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 12 are H, -OH, -OC(O)R f where Rf is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R jare independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0114] In some embodiments, the compound has the formula (IIc'): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 12 , R 13 , R 13’ , L and R 21 is as defined for formula (IIc).

[0115] In some embodiments, the compound has the formula (IIc″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 12 , R 13 , R 13’ , L and R 21 is as defined for formula (IIc).

[0116] In some embodiments, the compound has the formula (IId): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, each occurrence of (IId') is independently H or C1-C4 alkyl; L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0117] In some embodiments, the compound has the formula (IId'): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 12 , R 13 , R 13’ , L and R 21 is as defined for formula (IId).

[0118] In some embodiments, the compound has the formula (IId″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 12 , R 13 , R 13’ , L and R 21 is as defined for formula (IId).

[0119] Formula (I), (Ia), (Ib), (II), (II'), (II''), (IIa), In some embodiments of compounds (IIa′), (IIa″), (IIb), (IIb′), (IIb″), (IIc), (IIc″), (IId), (IId′), and (IId″), R 12 Ha-OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 In some embodiments, R f is selected from the following: [ka]

[0120] In some embodiments, R f is selected from the following: [ka]

[0121] In some embodiments, the compound has formula (III): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5’ and R 6’ is H or R 5’ and R 6’ forms a bond or an atom and, if permitted by valence, are joined to a common O atom to form an epoxide ring; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 6’ and R 7’ is H or R 6’ and R 7’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 13 and R 13’ are each independently H or C1-C4 alkyl, R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR kwherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0122] In some embodiments, the compound has formula (III'): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 5’ , R 6’ , R 6 , R 6’ , R 7’ , R 7 , R 9 , R 11 , R 13 , R 13’ , R 14 、 R 17, R 18 , L and R 21 is as defined for formula (III).

[0123] In some embodiments, the compound has formula (III″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 5’ , R 6’ , R 6 , R 6’ , R 7’ , R 7 , R 9 , R 11 , R 13 , R 13’ , R 14 、 R 17 , R 18 , L and R 21 is as defined for formula (III).

[0124] In some embodiments, the compound has the formula (IIIa): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -ORb where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl , R 11 is a C1-C4 alkyl; R 13 and R 13’ are each independently H or C1-C4 alkyl, R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0125] In some embodiments, the compound has the formula (IIIa'): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 、 R 17 , R 18 , L and R 21 is as defined for formula (III).

[0126] In some embodiments, the compound has the formula (IIIa″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 11 , R 12 , R 13 , R 13’ , R 14 、 R 17 , R 18 , L and R 21is as defined for formula (III).

[0127] In some embodiments, the compound has the formula (IIIb): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R 3 When (- - -) is a bond, it is an O double-bonded to a ring carbon, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R Aeach occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 13 and R 13’ are each independently H or C1-C4 alkyl, R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0128] In some embodiments, the compound has the formula (IIIb'): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 11 , R 13 , R 13’ , R 14 、 R 17 , R 18 , L and R21 is as defined for formula (III).

[0129] In some embodiments, the compound has the formula (IIIb″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 11 , R 13 , R 13’ , R 14 、 R 17 , R 18 , L and R 21 is as defined for formula (III).

[0130] In some embodiments of compounds of Formula (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), and (IIIb''), R 3 HA-OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl. In some embodiments, the aryl of the C0-C6 alkylaryl is phenyl. In some embodiments, the aryl of the C0-C6 alkylaryl is selected from the group consisting of 1-3 of OH, CN, halo, C1-C4 alkyl, and haloC1 In some embodiments, R a1 is selected from the following: [ka]

[0131] In some embodiments, Ra1 is selected from the following: [ka]

[0132] In some embodiments of compounds of Formula (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), and (IIIb''): R 3 is an O double-bonded to a carbon atom.

[0133] In some embodiments of compounds of Formula (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), and (IIIb''), R 2 , R 11 , R 17 and R 18 In some embodiments, one or more of R 2 , R 11 , R 17 , and R 18 Each of is -CH3.

[0134] In some embodiments of compounds of Formula (III), (III'), (IIIa), (IIIa'), (IIIb), and (IIIb'), R 4 and R 5 are each independently H or —OH.

[0135] In some embodiments of compounds of Formula (III), (III'), (IIIa), (IIIa'), (IIIb), and (IIIb'), R 2 , R 11 , R 17 , and R 18 is -CH3, R 3 is an O double-bonded to a carbon atom, R 4 and R 5 are each independently H or —OH.

[0136] In some embodiments, the compound has the formula (IIIc): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR C1 )2 or -C1-C6 alkylC(O)OR k and R C1 is H, C1-C6 alkyl, or two R C1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 13 and R 13’ are each independently H or C1-C4 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0137] In some embodiments, the compound has the formula (IIIc'): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 13 , R 13’ , L and R 21 is as defined for formula (IIIc).

[0138] In some embodiments, the compound has the formula (IIIc″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 13 , R 13’ , L and R 21 is as defined for formula (IIIc).

[0139] In some embodiments, the compound has formula (IIId): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR C1 )2 or -C1-C6 alkylC(O)OR k and R C1 is H, C1-C6 alkyl, or two R C1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R Aeach occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 13 and R 13’ are each independently H or C1-C4 alkyl, L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 Cycloalkyl or bridged bicyclyl 1-2 carbon atoms of the alkyl group are optionally replaced with a heteroatom selected from N, O and S, and are optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R jare independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0140] In some embodiments, the compound has formula (IIId'): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 13 , R 13’ , L and R 21 is as defined for formula (IIId).

[0141] In some embodiments, the compound has the formula (IIId″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , R 13 , R 13’ , L and R 21 is as defined for formula (IIId).

[0142] In some embodiments of the compounds of any of the preceding embodiments, n is 0.

[0143] In some embodiments of the compounds of any of the preceding embodiments, R 13 and R13’ Each of is H.

[0144] In some embodiments, the compound has the formula (IIIe): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR C1 )2 or -C1-C6 alkylC(O)OR k and R C1 is H, C1-C6 alkyl, or two R C1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0145] In some embodiments, the compound has formula (IIIe'): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , L and R21 is as defined for formula (IIIe).

[0146] In some embodiments, the compound has the formula (IIIe″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , L and R 21 is as defined for formula (IIIe).

[0147] In some embodiments, the compound has the formula (IIIf): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR C1 )2 or -C1-C6 alkylC(O)OR k and R C1 is H, C1-C6 alkyl, or two R C1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is the adjacent R Aand together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; L is not present or C1~C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkyl C3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by R k is H or M + is the counterion, J 1is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0148] In some embodiments, the compound has the formula (IIIf'): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, In the formula, R 6 , L and R 21 is as defined for formula (IIIf).

[0149] In some embodiments, the compound has the formula (IIIf″): [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , L and R 21 is as defined for formula (IIIf).

[0150] In some embodiments of compounds (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 21 is a C3-C7 cycloalkyl, wherein the C3-C7 cycloalkyl optionally contains 1 to 3 J 1 where J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl. In some of the foregoing embodiments, C3-C7 cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0151] In some embodiments of compounds (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 21 is heterocyclyl, wherein the heterocyclyl optionally contains 1 to 3 J 1 where J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl. In some embodiments, heterocyclyl is selected from oxiranyl, oxetanyl, azetidinyl, oxazolyl, thiazolidinyl, thiazolyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and azapanyl, wherein the heterocyclyl is optionally substituted with one to three of OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0152] In some embodiments of compounds (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 21 is aryl, where aryl optionally contains 1 to 3 J 1 where J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl. In some of the foregoing embodiments, R 21 is phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with 1 to 3 of OH, CN, halo, C1-C4 alkyl and haloC1-C4 alkyl.

[0153] In some embodiments of compounds (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 21 is heteroaryl, where heteroaryl optionally contains 1 to 3 J 1 where J 1is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl. In some of the foregoing embodiments, heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, and quinolyl, wherein heteroaryl is optionally substituted with one to three of OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0154] In some embodiments of compounds (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 21 is adamantyl, where adamantyl is optionally selected from J 1 where J 1 is selected from OH, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0155] In some embodiments of compounds (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 21 Spiro C5~C12 cycloalkyl, where spiro C5-C 12 Cycloalkyl has 0-2 carbon atoms replaced by 0-2 heteroatoms selected from N, O, and S, and 1-3 J 1 where J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl, or, if an N atom is present, is optionally substituted with an N-protecting group.

[0156] In some embodiments of compounds (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 21 is a 5-12 membered bridged bicyclyl, where the bridged bicyclyl has 0-2 carbon atoms replaced by 0-2 heteroatoms selected from N, O and S, and 1-3 J 1 where J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl, or, if an N atom is present, is optionally substituted with an N-protecting group.

[0157] In some embodiments of compounds (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 21 is selected from the following equation: [ka] During the ceremony, J. 1 is OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl, and n is 0 to 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, haloC1-C4 alkyl is —CH2F, —CHF2, or —CF3.

[0158] In some embodiments, for any of the compounds herein, L is C3-C 12 In some embodiments, for any of the compounds herein, L is C3-C6 alkylene. In some embodiments, for any of the compounds herein, L is C1-C6 alkylene.

[0159] In some embodiments, for any of the compounds herein, L is C3-C 12 In some embodiments, for any of the compounds herein, L is C3-C6 alkenylene. In some embodiments, for any of the compounds herein, L is C1-C6 alkenylene.

[0160] In some embodiments, L is C1-C 12 Alkylene or C2-C 12Alkenylene, C1-C 12 Alkylene or C2-C 12 Alkenylene is optionally substituted with C1-C4 alkyl, R 21 is H.

[0161] In some embodiments of the compounds of Formula (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), -LR 21 is a C2-C6 alkenyl selected from the following: [ka]

[0162] In some embodiments of any of the foregoing compounds, e.g., of Formula (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 6 is the following equation: [ka] R Aeach occurrence independently represents hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propane-1-yl (norvaline), 2-methylpropane-1-yl (leucine), 1-methylpropane-1-yl (isoleucine), butane-1-yl (norleucine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercaptomethyl (serine), 2-hydroxyethyl (threonine), 2-methylpropane-1-yl (leucine), 2-methylpropane-1-yl (leucine), 2-methylpropane-1-yl (isoleucine), 2-methylpropane-1-yl (threon ... 2-mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutane-1-yl (lysine), 4-amino-3-hydroxybutane-1-yl (hydroxylysine), 3-aminopropane-1-yl (ornithine), 3-guanidinopropane-1-yl (arginine), or 3-ureido-propan-1-yl (citrulline); R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom form a prolyl side chain, [ka] p is 0, 1 or 2.

[0163] Compounds of the foregoing, such as formulas (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa '), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf In some embodiments of either (IIIf′), and (IIIf″), R 6 is the following equation: [ka] R A each occurrence of is independently methyl(alanine), propane-2-yl(valine), 2-methylpropane-1-yl(leucine), imidazol-4-ylmethyl(histidine), hydroxymethyl(serine), 1-hydroxyethyl(threonine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), 4-aminobutane-1-yl(lysine), carboxymethyl(aspartic acid), 3-guanidinopropane-1-yl(arginine), benzyl(phenylalanine), or 4-aminobutane-1-yl(lysine); R B is H, p is 0, 1, or 2.

[0164] In some embodiments of any of the foregoing compounds, e.g., of Formula (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 6 is the following equation: [ka] R A each occurrence is independently propane-2-yl (valine), 2-methylpropane-1-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutane-1-yl (lysine); Each R B is H, p is 0, 1, or 2.

[0165] In some embodiments of any of the foregoing compounds, e.g., any of Formulas (I), (Ia), (Ib), (II), (II'), (II"), (IIa), (IIa'), (IIa"), (IIb), (IIb'), (IIb"), (III), (III'), (III"), (IIIa), (IIIa'), (IIIa"), (IIIb), (IIIb'), (IIIb"), (IIIc), (IIIc'), (IIIc"), (IIId), (IIId'), (IIId"), (IIIe), (IIIe'), (IIIe"), (IIIf), (IIIf'), and (IIIf"), p is 0.

[0166] The aforementioned compounds, for example, compounds of formula (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), ( In some embodiments of any of IIb″), (III), (III′), (III″), (IIIa), (IIIa′), (IIIa″), (IIIb), (IIIb′), (IIIb″), (IIIc), (IIIc′), (IIIc″), (IIId), (IIId′), (IIId″), (IIIe), (IIIe′), (IIIe″), (IIIf), (IIIf′), and (IIIf″), p is 1.

[0167] In some embodiments of any of the foregoing compounds, e.g., of Formula (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 6 is the following equation: [ka] p is 1, The first R A is propane-2-yl (valine), and the second R A is propane-2-yl (valine), and each R B is H (i.e., the dipeptide Val-Val), or The first R A is 2-methylpropane-1-yl (leucine), and the second R A is 2-methylpropane-1-yl (leucine), and each R B is H (i.e., the dipeptide Leu-Leu), or The first R A is methyl (alanine) and the second R A is methyl (alanine), and each R B is H (i.e., the dipeptide Ala-Ala), or The first R A is 4-aminobutane-1-yl (lysine), and the second R A is 4-aminobutane-1-yl (lysine), and each R B is H (i.e., the dipeptide Lys-Lys), or The first R A is hydrogen and the second R A is 4-aminobutane-1-yl, and each R B is H (i.e., the dipeptide Gly-Lys).

[0168] In some embodiments of any of the foregoing compounds, e.g., of Formula (I), (Ia), (Ib), (II), (II'), (II''), (IIa), (IIa'), (IIa''), (IIb), (IIb'), (IIb''), (III), (III'), (III''), (IIIa), (IIIa'), (IIIa''), (IIIb), (IIIb'), (IIIb''), (IIIc), (IIIc'), (IIIc''), (IIId), (IIId'), (IIId''), (IIIe), (IIIe'), (IIIe''), (IIIf), (IIIf'), and (IIIf''), R 6 is the following equation: [ka] Each of the α-carbons of amino acids other than glycine is in the L or D configuration. In some embodiments, the α-carbons of amino acids other than glycine are in the L configuration.

[0169] In some embodiments, the compound is selected from the group consisting of the compounds in Table 1 or a pharmaceutical salt thereof.

[0170] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0171] In some embodiments, for each compound in Table 1, —OH is on the C20 carbon atom and, when appropriate, is substituted with: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2.

[0172] In some embodiments of the amino acid moiety on the C20 carbon, R AEach occurrence independently represents hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropan-1-yl (isoleucine), butan-1-yl (norleucine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercapto 2-mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutane-1-yl (lysine), 4-amino-3-hydroxybutane-1-yl (hydroxylysine), 3-aminopropane-1-yl (ornithine), 3-guanidinopropane-1-yl (arginine), or 3-ureido-propan-1-yl (citrulline); R B Each occurrence of is independently H or R B is the adjacent R A and together with N atoms to form a prolyl side chain, [ka] p is 0, 1 or 2.

[0173] In some embodiments, R Aeach occurrence is independently methyl(alanine), propane-2-yl(valine), 2-methylpropane-1-yl(leucine), imidazol-4-ylmethyl(histidine), hydroxymethyl(serine), 1-hydroxyethyl(threonine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), 4-aminobutane-1-yl(lysine), carboxymethyl(aspartic acid), 3-guanidinopropane-1-yl(arginine), benzyl(phenylalanine), or 4-aminobutane-1-yl(lysine); R B is H, p is 0, 1, or 2.

[0174] In some embodiments, R A is independently propane-2-yl (valine), 2-methylpropane-1-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutane-1-yl (lysine); Each R B is H, p is 0, 1, or 2.

[0175] In some embodiments, p is 0.

[0176] In some embodiments, p is 1.

[0177] In some embodiments, p is 1, The first R A is propane-2-yl (valine), and the second R A is propane-2-y1 (valine), and R B are each H (i.e., the dipeptide Val-Val), or The first R A is 2-methylpropane-1-yl (leucine), and the second R A is 2-methylpropane-1-yl(leucine), and R B are each H (i.e., the dipeptide Leu-Leu), or The first R A is methyl (alanine) and the second R A is methyl(alanine), and R B are each H (i.e., the dipeptide Ala-Ala), or The first R A is 4-aminobutane-1-yl (lysine), and the second R A is 4-aminobutane-1-yl(lysine), and R B are each H (i.e., the dipeptide Lys-Lys), or The first R A is hydrogen and the second R A is 4-aminobutane-1-yl, and R B are H (i.e., the dipeptide Gly-Lys).

[0178] In some embodiments, each of the α-carbons of amino acids other than glycine is in the L or D configuration. In some embodiments, each of the α-carbons of amino acids other than glycine is in the L configuration.

[0179] In another aspect, the present disclosure provides a compound of formula (IV): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -ORb, where R bis H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5’ and R 6’ is H or R 5’ and R 6’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 6’ and R 7’ is H or R 6’ and R 7’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 7is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl , R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkylC3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, and -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; R k is H or M + It is a counter ion.

[0180] In some embodiments, the compounds of formula (IV) exclude: -LR 21 but, [ka] and R 2 and R 11 is CH3, R 3 is =O, R 4 is OH, R 5 , R 5’ , R 7 and R 14 is H, R6’ and R 7’ together form a bond, R 9 is OH, R 12 is H, R 17 and R 18 is -CH3, R A is propan-2-yl(valine), R B is H, p is 0.

[0181] In some embodiments, the compound has formula (IVa): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl , R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkylC3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, and -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by J1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; R k is H or M + It is a counter ion.

[0182] In some embodiments, the compounds of formula (IVa) exclude: -LR 21 but, [ka] and R 2 and R 11 is CH3, R 3 is =O, R 4 is OH, R 5 , R 7 and R 14 is H, R 9 is OH, R 12 is H, R 17 and R 18 is -CH3, R A is propan-2-yl(valine), R B is H, p is 0.

[0183] In some embodiments, the compound has formula (IVb): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R ais H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 7 is H or OH, R 9 is OR e where Re is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f where R f is C1~C 12 Archi Lu, C2~C 12 Alkenyl, -C0-C 12 Aliphatic -C3-C7 cycloalkyl, -C0-C 12 Aliphatic heterocycloalkyl, -C0-C 12 Aliphatic-aryl or -C0-C 12 aliphatic-heteroaryl; R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkylC3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, and -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR kwherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; R k is H or M + It is a counter ion.

[0184] In some embodiments of compounds of Formula (IV), (IVa) and (IVb), R a1 The C2-C6 alkenyl is independently selected from the following: [ka]

[0185] In some embodiments, R a1 are independently selected from: [ka]

[0186] In some embodiments, R 3 -O Ra where R ais H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl. In some embodiments, the aryl of the C0-C6 alkylaryl is phenyl. In some embodiments, the aryl of the C0-C6 alkylaryl is optionally substituted with 1-3 of OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0187] In some embodiments of compounds of Formula (IV), (IVa) and (IVb), R 3 is an O double-bonded to a carbon atom.

[0188] In some embodiments of compounds of Formula (IV), (IVa) and (IVb), R f C2~C 12 Alkenyl is independently selected from the following: [ka]

[0189] In some embodiments, R f are independently selected from: [ka]

[0190] In some embodiments of compounds of Formula (IV), (IVa) and (IVb), R 2 , R 11 , R 17 , and R 18 In some embodiments, one or more of R 2 , R 11 , R 17 , and R 18 Each of is -CH3.

[0191] In some embodiments of compounds of Formula (IV), (IVa), and (IVb), R4 and R 5 are each independently H or —OH.

[0192] In some embodiments of compounds of Formula (IV), (IVa), and (IVb), R 2 , R 11 , R 17 , and R 18 is -CH3, R 3 is an O double-bonded to a carbon atom, R 4 and R 5 are each independently H or —OH.

[0193] In some embodiments, the compound has formula (V): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5’ and R 6’ is H or R 5’ and R 6’form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 6’ and R 7’ is H or R 6’ and R 7’ form a bond or, if allowed by valence, are attached to a common O atom to form an epoxide ring; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkylC3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, and -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 1 to 2 carbon atoms of a cycloalkyl or bridged bicyclyl are replaced by a heteroatom selected from N, O and S. optionally substituted and optionally substituted with C1-C4 alkyl or an N-protecting group if an N atom is present; Each R jare independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; R k is H or M + It is a counter ion.

[0194] In some embodiments, the compounds of formula (V) exclude: -LR 21 but, [ka] and R 2 and R 11 is CH3, R 3 is =O, R 4 is OH, R 5 , R 5’ , R 7 and R 14 is H, R 6’ and R 7’ together form a bond, R 9 is OH, R 17 and R 18 is -CH3, R A is propan-2-yl(valine), R B is H, p is 0.

[0195] In some embodiments, the compound has the formula (Va): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or RB is R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 7 is H or OH, R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkylC3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, and -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkyl C3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkyla C-C cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; R k is H or M + It is a counter ion.

[0196] In some embodiments, the compounds of formula (V) exclude: -LR 21 but, [ka] and R 2 and R 11 is CH3, R 3 is =O, R 4 is OH, R 5 , R 7 and R 14 is H, R 9 is OH, R 17 and R 18 is -CH3, R A is propan-2-yl(valine), R B is H, p is 0.

[0197] In some embodiments, the compound has the formula (Vb): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R 2 is a C1-C4 alkyl; R3 is O double bonded to a ring carbon when (- - -) is a bond, or -OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 4 and R 5 are each independently H or -OR b where R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR c1 )2 or -C1-C6 alkylC(O)OR k and R c1 is H, C1-C6 alkyl, or two R c1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; R 9 is OR e where R e is H, C1-C6 alkyl or aryl, R 11 is a C1-C4 alkyl; R 14 is H or OR g where R g is H or C1-C6 alkyl, R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h where R h is H or C1-C6 alkyl, L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkylC3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, and -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; R k is H or M + It is a counter ion.

[0198] In some embodiments of compounds of Formula (V), (Va), and (Vb), R 3 HA-OR a where R a is H or -C(O)R a1 and R a1 is C1-C6 alkyl, In some embodiments, the aryl of the C0-C6 alkylaryl is phenyl. In some embodiments, the aryl of the C0-C6 alkylaryl is optionally substituted with 1-3 of OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl. In some embodiments, R a1 is selected from the following: [ka]

[0199] In some embodiments, R a1 is selected from the following: [ka]

[0200] In some embodiments of compounds of Formula (V), (Va) and (Vb), R 3 is an O double-bonded to a carbon atom.

[0201] In some embodiments of compounds of Formula (V), (Va) and (Vb), R 2 , R 11 , R 17 , and R 18 In some embodiments, one or more of R 2 , R 11 , R 17 , and R 18 Each of is -CH3.

[0202] In some embodiments of compounds of Formula (V), (Va), and (Vb), R 4 and R 5 are each independently H or —OH.

[0203] In some embodiments of compounds of Formula (V), (Va), and (Vb), R 2 , R 11 , R 17 , and R 18 is -CH3, R 3 is an O double-bonded to a carbon atom, R 4 and R 5 are each independently H or —OH.

[0204] In some embodiments, the compound has the formula (Vc): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR C1 )2 or -C1-C6 alkylC(O)OR k and R C1 is H, C1-C6 alkyl, or two R C1 together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkylC3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, and -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; R k is H or M + It is a counter ion.

[0205] In some embodiments, the compounds of formula (Vc) exclude: -LR 21 but [ka] and R A is propan-2-yl(valine), R B is H, p is 0.

[0206] In some embodiments, specifically excluded from the compounds of formula (IV), (IVa), (V), (Va), and (Vc) are compounds of the following structure: [ka]

[0207] In some embodiments, the compound has the formula (Vd): [ka] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R 6 is OH, halo, or -OC(O)R c where R c is -C1-C6 alkyl, -C1-C6 alkyl-(NR C1 )2 or -C1-C6 alkylC(O)OR k and R C1 is H, C1-C6 alkyl, or two R C1 which, together with the N atom, form a 5- to 7-membered ring containing 1 to 3 heteroatoms selected from N, O, and S. forming a heterocyclyl, or R 6 is the following equation: [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R A each occurrence of may be the same or different, R B Each occurrence of is independently H or R B is R Aand together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R B each occurrence of may be the same or different, p is 0, 1, or 2; L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkylC3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, and -S(O)R j , -SR j , -N(R j )2, -Si(R j )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k wherein C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 The cycloalkyl, bridged bicyclyl, or adamantyl may optionally contain 1 to 3 J 1 where spiro C5-C 12 one to two carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, optionally substituted with a C1-C4 alkyl or an N-protecting group if an N atom is present; Each R j are independently C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylC3-C7 cycloalkyl, C0-C6 alkylheterocyclyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl, wherein the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is selected from the group consisting of 1 to 3 J 1 optionally replaced by J 1is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; R k is H or M + It is a counter ion.

[0208] In some embodiments of compounds (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21 is a C3-C7 cycloalkyl, and the C3-C7 cycloalkyl optionally has 1 to 3 J 1 In some of the foregoing embodiments, the C3-C7 cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0209] In some embodiments of compounds (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21 is heterocyclyl, and the heterocyclyl optionally contains 1 to 3 J 1 In some embodiments, heterocycloalkyl is substituted with oxiranyl, oxetanyl, azetidinyl, oxazolyl, thiazolidinyl, thiazolyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydro It is selected from pyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and azapanyl.

[0210] In some embodiments of compounds (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21 is aryl, and the aryl optionally contains 1 to 3 J 1 In some of the foregoing embodiments, R 21 is phenyl, wherein the phenyl is optionally substituted with 1-3 of OH, CN, halo, C1-C4 alkyl and haloC1-C4 alkyl.

[0211] In some embodiments of compounds (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21 is heteroaryl, and the heteroaryl optionally contains 1 to 3 J 1 In some of the foregoing embodiments, heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, and quinolyl, wherein heteroaryl is optionally substituted with 1-3 of OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0212] In some embodiments of compounds (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21 is adamantyl, which is optionally substituted with OH, halo, or C1-C4 alkyl.

[0213] In some embodiments of compounds (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21 Spiro C5~C 12 cycloalkyl, where spiro C5-C 12 Cycloalkyl has 0-2 carbon atoms replaced by 0-2 heteroatoms selected from N, O and S, and is optionally substituted with 1-3 OH, CN, halo, C1-C4 alkyl and haloC1-C4 alkyl, or an N-protecting group, if an N atom is present.

[0214] In some embodiments of compounds (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21is a 5-12 membered bridged bicyclyl, the bridged bicyclyl having 0-2 carbon atoms replaced by 0-2 heteroatoms selected from N, O and S, and optionally substituted with 1-3 OH, CN, halo, C1-C4 alkyl and haloC1-C4 alkyl, or N-protecting groups, when N atoms are present.

[0215] In some embodiments of compounds of Formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21 is selected from the following: [ka] During the ceremony, J. 1 is OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl, and n is 0 to 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, haloC1-C4 alkyl is —CH2F, —CHF2, or —CF3.

[0216] In some embodiments, for any of the compounds herein, L is C3-C 12 In some embodiments, for any of the compounds herein, L is C3-C6 alkylene. In some embodiments, for any of the compounds herein, L is C1-C6 alkylene.

[0217] In some embodiments, for any of the compounds herein, L is C3-C 12 In some embodiments, for any of the compounds herein, L is C3-C6 alkenylene. In some embodiments, for any of the compounds herein, L is C1-C6 alkenylene.

[0218] In some embodiments of compounds of Formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), -LR 21is a C2-C6 alkenyl selected from the following: [ka]

[0219] In some embodiments of any of the foregoing compounds, e.g., of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 6 is the following equation: [ka] R A Each occurrence independently represents hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropan-1-yl (isoleucine), butan-1-yl (norleucine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercaptoethanol, methyl ketone ... 2-mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutane-1-yl (lysine), 4-amino-3-hydroxybutane-1-yl (hydroxylysine), 3-aminopropane-1-yl (ornithine), 3-guanidinopropane-1-yl (arginine) or 3-ureido-propan-1-yl (citrulline); R B Each occurrence of is H or R B is the adjacent R A and together with the N atom form a prolyl side chain, [ka] p is 0, 1 or 2.

[0220] In some embodiments of any of the foregoing compounds, e.g., of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), Each R A are independently methyl(alanine), propane-2-yl(valine), 2-methylpropane-1-yl(leucine), imidazol-4-ylmethyl(histidine), hydroxymethyl(serine), 1-hydroxyethyl(threonine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), 4-aminobutane-1-yl(lysine), carboxymethyl(aspartic acid), 3-guanidinopropane-1-yl(arginine), benzyl(phenylalanine), or 4-aminobutane-1-yl(lysine); R B is H, p is 0, 1, or 2.

[0221] In some embodiments of any of the foregoing compounds, e.g., of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 6 is the following equation: [ka] R A each occurrence is independently propane-2-yl (valine), 2-methylpropane-1-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutane-1-yl (lysine); Each R B is H, p is 0, 1, or 2.

[0222] In some embodiments of any of the foregoing compounds, e.g., of Formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), p is 0.

[0223] In some embodiments of any of the foregoing compounds, e.g., of Formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), p is 1.

[0224] In some embodiments of any of the foregoing compounds, e.g., of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 6 is the following equation: [ka] p is 1, The first R A is propane-2-yl (valine), and the second R A is propane-2-y1 (valine), and R B are each H (i.e., the dipeptide Val-Val), or The first R A is 2-methylpropane-1-yl (leucine), and the second R A is 2-methylpropane-1-yl(leucine), and R B are each H (i.e., the dipeptide Leu-Leu), or The first R A is methyl (alanine) and the second R A is methyl(alanine), and R B are each H (i.e., the dipeptide Ala-Ala), or The first R A is 4-aminobutane-1-yl (lysine), and the second R A is 4-aminobutane-1-yl(lysine), and R B are each H (i.e., the dipeptide Lys-Lys), or The first R A is hydrogen and the second R A is 4-aminobutane-1-yl, and R B are H (i.e., the dipeptide Gly-Lys).

[0225] In some embodiments of any of the foregoing compounds, e.g., of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 6 is the following equation: [ka] Each of the α-carbons of the amino acids other than glycine is in the L or D configuration. In some embodiments, each of the α-carbons of the amino acids other than glycine is in the L configuration.

[0226] In some embodiments, the compound is selected from the group consisting of the compounds in Table 2 or a pharmaceutical salt thereof.

[0227] [Table 2-1] [Table 2-2] [Table 2-3] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

[0228] In some embodiments, for each compound in Table 2, —OH on the C20 carbon atom is of the formula: is replaced by [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, A each occurrence of may be the same or different, R B each occurrence of is independently H or R B is R A and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Beach occurrence of may be the same or different, p is 0, 1, or 2.

[0229] In some embodiments of the amino acid moiety on the C20 carbon, R A Each occurrence independently represents hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropan-1-yl (isoleucine), butan-1-yl (norleucine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercapto 2-mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutane-1-yl (lysine), 4-amino-3-hydroxybutane-1-yl (hydroxylysine), 3-aminopropane-1-yl (ornithine), 3-guanidinopropane-1-yl (arginine), or 3-ureido-propan-1-yl (citrulline); R B Each occurrence of is independently H or R B is the adjacent R A and together with the N atom form a prolyl side chain, [ka] p is 0, 1 or 2.

[0230] In some embodiments, R Aeach occurrence is independently methyl(alanine), propane-2-yl(valine), 2-methylpropane-1-yl(leucine), imidazol-4-ylmethyl(histidine), hydroxymethyl(serine), 1-hydroxyethyl(threonine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), 4-aminobutane-1-yl(lysine), carboxymethyl(aspartic acid), 3-guanidinopropane-1-yl(arginine), benzyl(phenylalanine), or 4-aminobutane-1-yl(lysine); R B is H, p is 0, 1, or 2.

[0231] In some embodiments, R A is independently propane-2-yl (valine), 2-methylpropane-1-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutane-1-yl (lysine); Each R B is H, p is 0, 1, or 2.

[0232] In some embodiments, p is 0.

[0233] In some embodiments, p is 1.

[0234] In some embodiments, p is 1, The first R A is propane-2-yl (valine), and the second R A is propane-2-y1 (valine), and R B are each H (dipeptide Val-Val), or The first R A is 2-methylpropane-1-yl (leucine), and the second R A is 2-methylpropane-1-yl(leucine), and R B are each H (the dipeptide Leu-Leu), or The first R A is methyl (alanine) and the second R A is methyl(alanine), and R B are each H (dipeptide Ala-Ala), or The first R A is 4-aminobutane-1-yl (lysine), and the second R A is 4-aminobutane-1-yl(lysine), and R B are each H (dipeptide Lys-Lys), or The first R A is hydrogen and the second R A is 4-aminobutane-1-yl, and R B are H (dipeptide Gly-Lys), respectively.

[0235] In some embodiments, each of the α-carbons of amino acids other than glycine is in the L or D configuration.

[0236] In some embodiments, compounds disclosed herein can be synthesized according to the general schemes outlined below in Scheme 1 and Scheme 2, where the appropriate reagents can be purchased from commercial sources or synthesized via known methods or methods adapted from the exemplary procedures provided herein.

[0237] Scheme 1 [ka] Scheme 2 [ka] In Scheme 1, protection of S1 (K101A shown as an example) with trityl chloride (or triphenylmethyl chloride) gives S2 (K101-C20Tr-A shown as an example). Hydrolysis of S2 (K101-C20Tr-A shown as an example) gives S3 (K101-C20Tr-B shown as an example), which can then be coupled with compound S4 under esterification conditions using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, or EDCI) as a carboxyl activator and 4-dimethylaminopyridine (DMAP) as a catalyst to give compound S5. Deprotection of S5, followed by further separation and purification, gives compound S6.

[0238] In Scheme 2, S7 is prepared by epoxidation of S5 with a peroxycarboxylic acid such as meta-chloroperbenzoic acid (m-CPBA). Further isolation and purification of S7 provides S8.

[0239] Suitable starting materials and reagents for use in Scheme 1 and Scheme 2 can be purchased commercially or prepared by methods known to those skilled in the art.

[0240] In some embodiments of the methods of Scheme 1 and Scheme 2, the various substituents on the starting compounds (e.g., compounds S1 and S3) are as defined for Formula I. However, it should be understood that any of the compounds of Scheme 1 and Scheme 2 can be further modified using chemical derivatization and / or functional group interconversion to provide various compounds of Formula I.

[0241] In some embodiments, the synthesis of a prodrug involves the addition of a protected amino acid (e.g., an N-protected amino acid) to the related compound, e.g., R 6The amino acid prodrug is prepared by reacting with a compound having an -OH group at the position. Guidance showing the synthesis of amino acid prodrugs and the knowledge of the general procedures available in the art for producing such prodrugs is provided in Examples 63 and 64 (see, for example, Vale et al., 2018, Molecules. 23(9):2318; Beauchamp et al., 1992, Antiviral Chemistry & Chemotherapy 3(3):157-164, which are incorporated herein by reference).

[0242] Other compounds of the present disclosure can be synthesized using the above synthetic routes and by adapting chemical synthesis procedures available to those skilled in the art. Exemplary synthetic methods are provided in the Examples. It should be understood that each of the procedures describing the synthesis of exemplary compounds is part of the present specification and is therefore incorporated herein into the "Detailed Description of the Invention" of the present disclosure.

[0243] 5.3. Pharmaceutically Acceptable Salts In some embodiments, PKC modulator compound is in free form or, if appropriate, in the form of pharmaceutically acceptable salt.Pharmaceutically acceptable salt is well known in the art.For example, S.M. Berge et al. describes pharmaceutically acceptable salt in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.

[0244] Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. In some embodiments, pharmaceutically acceptable salts of the compounds herein can be prepared during the final isolation and purification of the compounds. For example, pharmaceutically acceptable salts of the compounds herein can be prepared by (1) reacting the free base form of the compound with a suitable organic or inorganic acid and (2) isolating the salt thus formed. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphor, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Acid salts include, but are not limited to, hydroxybenzoates ...

[0245] Base addition salts can be prepared by (1) reacting a compound, such as the purified compound, in its acid form with a suitable organic or inorganic base and (2) isolating the salt thus formed. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N +Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl salts. These include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as ammonium nitrate, ...

[0246] 5.4.How to use In another aspect, the compounds described herein are used in methods for treating cancer. In some embodiments, the method for treating cancer comprises administering a therapeutically effective amount of any of the compounds described herein to a subject in need thereof.

[0247] In some embodiments, the compounds can be used as monotherapy or in combination with one or more therapeutic treatments, particularly in combination with one or more chemotherapeutic agents, as further provided below. In some embodiments, the compounds are used in combination with a second therapeutic agent, and the compounds are used at levels that sensitize the cancer or cancer cells to the second therapeutic agent, e.g., at levels of the compound that do not cause significant cell death. In some embodiments, the compounds can be used in combination with radiation therapy to sensitize cells to radiation therapy or as an adjunct to radiation therapy (e.g., at a dose sufficient to activate cell death pathways).

[0248] In some embodiments, the cancer for treatment with the compound can be selected from adrenocortical carcinoma, anal cancer, biliary tract cancer, bladder cancer, bone cancer (e.g., osteosarcoma), brain cancer (e.g., glioma, astrocytoma, neuroblastoma, etc.), breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, blood cancer (e.g., leukemia and lymphoma), intestinal cancer (small intestine), liver cancer, lung cancer (e.g., bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, etc.), oral cancer, ovarian cancer, pancreatic cancer, kidney cancer, prostate cancer, salivary gland cancer, skin cancer (e.g., basal cell carcinoma, melanoma), stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, and soft tissue cancer, among others.

[0249] In some embodiments, the cancer for treatment with the compound is pancreatic cancer. In some embodiments, the pancreatic cancer for treatment with the compound is pancreatic adenocarcinoma or metastatic pancreatic cancer. In some embodiments, the cancer for treatment with the compound is stage 1, stage II, stage III, or stage IV pancreatic adenocarcinoma.

[0250] In some embodiments, the cancer to be treated with the compound is lung cancer. In some embodiments, the lung cancer to be treated with the compound is small cell lung cancer or non-small cell lung cancer. In some embodiments, the non-small cell lung cancer to be treated with the compound is adenocarcinoma, squamous cell carcinoma, or large cell carcinoma. In some embodiments, the lung cancer to be treated with the compound is metastatic lung cancer.

[0251] In some embodiments, the cancer for treatment with the compound is a hematological cancer, hi some embodiments, the hematological cancer is selected from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell chronic myelogenous leukemia (CML), and multiple myeloma.

[0252] In some embodiments, the cancer for treatment with the compound is a leukemia selected from acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell chronic myelogenous leukemia (CML), and multiple myeloma.

[0253] In some embodiments, the cancer for treatment with the compound is a lymphoma selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, and Burkitt's lymphoma.

[0254] In some embodiments, cancers for treatment with the compounds are cancers characterized by mesenchymal features or a mesenchymal phenotype. In some cancers, the acquisition of mesenchymal features is associated with cancer migration (e.g., intravasation) and invasiveness. Mesenchymal features may include, among other things, enhanced migration, invasiveness, increased resistance to apoptosis, and increased production of extracellular matrix (ECM) components. In addition to these physiological features, mesenchymal features may include, among other things, the expression of certain biomarkers, including E-cadherin, N-cadherin, integrins, FSP-1, α-SMA, vimentin, β-catenin, collagen I, collagen II, collagen III, collagen IV, fibronectin, laminin 5, SNAIL-1, SNAIL-2, Twist-1, Twist-2, and Lef-1. In some embodiments, cancers selected for treatment with the compounds herein include, among other things, breast cancer, lung cancer, head and neck cancer, prostate cancer, and colon cancer. In some embodiments, mesenchymal characteristics may be inherent to the cancer type or may be induced or selected by treatment of the cancer with chemotherapy and / or radiation therapy.

[0255] In some embodiments, the cancer for treatment with the compound is identified or determined to have activated or oncogenic RAS activity. In some embodiments, the RAS is K-RAS, H-RAS, or N-RAS. In some embodiments, the activated or oncogenic RAS is an activated or oncogenic RAS mutation.

[0256] In some embodiments, the cancer for treatment is identified as or determined to have an activating or oncogenic K-RAS mutation. In some embodiments, the cancer selected for treatment is a K-RAS mutation occurring at codon 5, codon 9, codon 12, codon 13, codon 14, codon 18, codon 19, codon 22, codon 23, codon 24, codon 26, codon 33, codon 36, codon 57, codon 59, codon 61, codon 62, codon 63, codon 64, codon 68, codon 74, codon 84, codon 92, codon 35, codon 97, codon 11 The subject is identified as or determined to have an activating or oncogenic mutation of human K-RAS at one or more of codons 0, 115, 117, 118, 119, 135, 138, 140, 146, 147, 153, 156, 160, 164, 171, 176, 185, and 188.

[0257] In some embodiments, the activating or oncogenic K-RAS mutation is such that codon 5 is K5E, codon 9 is V91, codon 12 is G12A, G12C, G12D, G12F, G12R, G12S, G12V or G12Y, codon 13 is G13C, G13D or G13V, codon 14 is V14I or V14L, codon 18 is A18D, codon 19 is L19F, and codon 20 is A20I or A20L. codon 22 is Q22K, codon 23 is L23R, codon 24 is I24N, codon 26 is N26K, codon 33 is D33E, codon 36 is I36L or I36M, codon 57 is D57N, codon 59 is A59E, A59G or A59T, codon 61 is Q61H, Q61K, Q61L or Q61R, codon 62 is E62G or E62K, and codon codon 63 is E63K, codon 64 is Y64D, Y64H or Y64N, codon 68 is R68S, codon 74 is T74P, codon 84 is I84T, codon 92 is D92Y, codon 97 is R97I, codon 110 is P110H or P110S, codon 115 is G115E, codon 117 is K117N, codon 118 is C118S, and codon codon 119 is D119N, codon 135 is R135T, codon 138 is G138V, codon 140 is P140H, codon 146 is A146T or A146V, codon 147 is K147N, codon 153 is D153N, codon 156 is F156L, codon 160 is V160A, codon 164 is R164Q, and codon 171 is I117M, The mutation may be such that codon 176 is K176Q, codon 185 is C185R or C185S, and codon 188 is M188V.

[0258] In particular, the cancer for treatment is identified as or determined to have an oncogenic or activating K-RAS mutation at codon 12, codon 13, and / or codon 61. In some embodiments, the oncogenic or activating K-RAS mutation at codon 12 is G12A, G12C, G12D, G12F, G12R, G12S, G12V, or G12Y; at codon 13, it is G13C, G13D, or G13V; and at codon 61, it is Q61H, Q61K, Q61L, or Q61R. In some embodiments, the oncogenic or activating K-RAS mutation is a combination of oncogenic or activating K-RAS mutations at codon 12 and codon 13; codon 12 and codon 61; codon 13 and 61; or codon 12, codon 13, and codon 61.

[0259] In some embodiments, the cancer for treatment is identified as or determined to have an activating or oncogenic N-RAS mutation. In some embodiments, the cancer is identified as or determined to have an activating or oncogenic mutation in human N-RAS at one or more of codons 12, 13, and 61. In some embodiments, the activating or oncogenic N-RAS mutation at codon 12 is G12A, G12C, G12D, G12R, G12S, or G12V. In some embodiments, the activating or oncogenic N-RAS mutation at codon 13 is G13A, G13C, G13D, G13R, G13S, or G13V. In some embodiments, the activating or oncogenic N-RAS mutation at codon 61 is Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the oncogenic or activating N-RAS mutations are a combination of activating or oncogenic N-RAS mutations at codon 12 and codon 13; codon 12 and codon 61; codon 13 and 61; or codon 12, codon 13 and codon 61.

[0260] In some embodiments, the cancer for treatment is identified or determined to have an activating or oncogenic H-RAS mutation. In some embodiments, the cancer selected for treatment is identified as having an activating or oncogenic mutation in human H-RAS at one or more of codons 12, 13, and 61. In some embodiments, the activating or oncogenic H-RAS mutation at codon 12 is G12A, G12C, G12D, G12R, G12S, or G12V. In some embodiments, the activating or oncogenic H-RAS mutation at codon 13 is G13A, G13C, G13D, G13R, G13S, or G13V. In some embodiments, the activating or oncogenic H-RAS mutation at codon 61 is Q61E, Q61H, Q61K, Q61L, Q61P, or Q61R. In some embodiments, the oncogenic or activating H-RAS mutations are a combination of activating or oncogenic H-RAS mutations at codon 12 and codon 13; codon 12 and codon 61; codon 13 and 61; or codon 12, codon 13 and codon 61.

[0261] In some embodiments, the cancer for treatment can be a cancer with a prevalence of activating or oncogenic RAS mutations (e.g., at least about 10% or more, or about 15% or more cancers), such as biliary tract cancer, cervical cancer, endometrial cancer, pancreatic cancer, lung cancer, colon cancer, head and neck cancer, gastric (stomach) cancer, biliary tract cancer, endometrial cancer, blood (e.g., leukemia, lymphoma, etc.), colorectal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, skin cancer, small intestine cancer, gastric thyroid cancer, aerodigestive tract cancer, urinary tract cancer and ovarian cancer, small intestine cancer and urinary tract cancer.

[0262] Biological samples for the methods herein include any sample suitable for analysis herein, such as tissue or biopsy samples containing cancer cells, or samples such as blood, plasma, saliva, tissue swabs, and intestinal fluids. Any biological fluid containing a substance of interest (e.g., DNA) is included. In some embodiments, exosomes extruded by cancer cells and obtained from blood or other bodily fluids can be used to detect nucleic acids and proteins produced by cancer cells.

[0263] General biological, biochemical, immunological and molecular biological methods applicable to this disclosure are described by Sambrook et al., Molecular Cloning: A Laboratory Manual 2 nd Ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology, Ausubel et al., ed., John Wiley & Sons (2015); Current Protocols in Immunology, Coligan, JE ed., John Wiley & Sons (2015); and Methods in Enzymology, Vol. 200, Abelson et al., ed., Academic Press (1991). All publications are incorporated herein by reference.

[0264] 5.5. Combination treatment In some embodiments, the diterpenoid PKC modulating compounds are used in combination with one or more second therapeutic agents, which in some embodiments are selected from the group consisting of platinizing agents, alkylating agents, antibiotic agents, antimetabolites (e.g., antifolates, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibitors, microtubule inhibitors (e.g., taxanes, vinca alkaloids), hormonal agents (e.g., aromatase inhibitors), plant-derived agents and their synthetic derivatives, anti-angiogenic agents, differentiation inducers, cell growth arrest inducers, apoptosis inducers, cytotoxic agents, agents affecting cellular bioenergetics, i.e., agents affecting cellular ATP levels and the molecules / activities that regulate these levels, anti-cancer biological agents (e.g., monoclonal antibodies), kinase inhibitors, and inhibitors of growth factors and their receptors.

[0265] In some embodiments, the second chemotherapeutic agent is afatinib, afuresertib, alectinib, alisertib, alvocidib, amsacrine, amonafide, amuvatinib, axitinib, azacitidine, azathioprine, bafetinib, barasertib, bendamustine, bleomycin, bosutinib, bortezomib, busulfan, cabozantinib, camptothecin, canertinib, capecitabine, cabazitaxel, carboplatin, carmustine, cenisertib, ceritinib, chlorambucil, cisplatin, tinib, cladribine, clofarabine, crenolanib, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dacomitinib, dactinomycin, danusertib, dasatinib, daunorubicin, decitabine, dinaciclib, docetaxel, dovitinib, doxorubicin, epirubicin, epitinib, eribulin mesylate, erlotinib, etirinotecan, etoposide, everolimus, exemestane, floxuridine, fludarabine, fluorouracil, gefitinib, gemcitabine Bin, hydroxyurea, ibrutinib, icotinib, idarubicin, idelalisib, ifosfamide, imatinib, immertelstat, ipatasertib, irinotecan, ixabepilone, lapatinib, lenalidomide, lestaurtinib, lomustine, lucitanib, masitinib, mechlorethamine, melphalan, mercaptopurine, methotrexate, midostaurin, mitomycin, mitoxantrone, mubritinib, nelarabine, neratinib, nilotinib, nintedanib, omacetaxine mepesuxinate, Olaparib, orantinib, oxaliplatin, paclitaxel, palbociclib, palifosfamide, pazopanib, pelitinib, pemetrexed, pentostatin, plicamycin, ponatinib, poziotinib, pralatrexate, procarbazine, quizartinib, raltitrexed, regorafenib, ruxolitinib, celecilib, sorafenib, streptozocin, surufatinib, sunitinib, tamoxifen, tandutinib, temozolomide, temsirolimus, teniposide, and teritinib , thioguanine, thiotepa, topotecan, uramustine, valrubicin, vandetanib, vemurafenib (Zelborae), vincristine, vinblastine, vinorelbine, vindesine, and the like.

[0266] In some embodiments, the second therapeutic agent is selected from the group consisting of phosphoinositol-3 kinase (PI3K) inhibitors, AKT inhibitors, mammalian target of rapamycin (mTOR) inhibitors, poly ADP-ribose polymerase (PARP) inhibitors, platinum-based anticancer compounds (PBACs), CBP / β-catenin inhibitors, tankyrase (TNKS) inhibitors, stochastic protein-cysteine ​​N-palmitoyltransferase (PORCN) inhibitors, scr kinase / bcr-abl kinase inhibitors, smoothened (SMO) inhibitors, anticancer nucleoside analogs or antimetabolites, histone deacetylase (HDAC) inhibitors, bromodomain and extra-terminal motif (BET) inhibitors, all-trans-retinoic acid (ATRA), Bruton's tyrosine kinase (BTK) inhibitors, EGFR receptor inhibitors, and combinations thereof.

[0267] In some embodiments, the second therapeutic agent is idelalisib, pictilisib, duvelisib, pilalisib, alpelisib, copanlisib, voxtalisib, dactolisib, gedatolisib, apitolisib, perifosine, miltefosine, ipatasertib, sirolimus, everolimus, temsirolimus, tacrolimus, ridaforolimus, dactolisib, olaparib, veliparib, rucaparib, talazolinone, thiazolinone, thiazolinone, thiazolinone riboplatin, niraparib, cisplatin, carboplatin, oxaliplatin, dicycloplatin, nedaplatin, lobaplatin, heptaplatin, phenatriplatin, phosphaplatin, LA-12, ICG-001, PRI-724, XAV-939, G007-LK, LGK-974, ETC-159, staurosporine, nilotinib, imatinib, ponatinib, saracatinib, dasatinib, bosutinib, saracatinib , cyclopamine, vismodegib, glasdegib, SANT-1, sonidegib, salidegib, taladegib, GSK1210151A, GSK525762, CPI-0610, RVX-208, vorinostat (SAHA), entinostat, panobinostat, mocetinostat, belinstat, romidepsin, rosirinostat, abexinostat, resminostat, gibinostat, xynostat, pra Selected from the group consisting of: cinostat, quevetlin, CC-292, CNX-774, LFM-A13, CGI1746, trastuzumab, pertuzumab, ado-trastuzumab emtansine, cetuximab, panitumumab, nimotuzumab, mAb806, rindopepimut, lapatinib, erlotinib, gefitinib, afatinib, neratinib, osimertinib, rociletinib, canertinib, and dacomitinib.

[0268] 5.6. Formulation and Administration In some embodiments, pharmaceutical compositions of the therapeutic agent can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in Remington: The Science and Practice of Pharmacy, 21 stEd. (2005). Therapeutic compounds and their physiologically acceptable salts, hydrates, and solvates can be formulated for administration by any suitable route, including topical, nasal, oral, parenteral, rectal, or inhalation, among others. In some embodiments, the compounds and pharmaceutical compositions thereof are administered by intradermal, subcutaneous, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary, or intratumoral injection, for example, using a syringe or other device. Transdermal administration is also contemplated, as is inhalation or aerosol administration. Tablets, capsules, and liquids can be administered orally, rectally, or vaginally.

[0269] For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients. and capsules may contain excipients such as (a) diluents or fillers, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylates, and / or calcium hydrogen phosphate, calcium sulfate; (b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts, metal stearates, colloidal silicon dioxide, hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate, and / or polyethylene glycol. (c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and / or hydroxypropylmethylcellulose; (d) disintegrating agents, such as starches (including potato starch or sodium starch), glycolate, agar, alginic acid or its sodium salt, or effervescent mixtures; (e) wetting agents, such as sodium lauryl sulfate, and / or (f) absorbents, colorants, flavors, and sweeteners. The compositions are prepared according to conventional mixing, granulating, or coating methods.

[0270] Tablets can be either film-coated or enteric-coated according to methods known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or can be provided as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable carriers and additives, such as suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid. Preparations can also contain buffer salts, flavoring agents, coloring agents, and / or sweeteners as needed. If desired, preparations for oral administration can be suitably formulated to give a controlled release of the active compound.

[0271] Therapeutic agents can be formulated for parenteral administration, for example, by bolus injection or continuous infusion. Injectable preparations can be provided in unit dosage form, e.g., ampoules or multi-dose containers, with an optional added preservative. The injectable composition can be an isotonic aqueous solution or suspension. In some embodiments for parenteral administration, the therapeutic agent can be prepared using a surfactant, such as Cremaphor, or a lipophilic solvent, such as a triglyceride or liposome. The composition may be sterilized and / or contain adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts for adjusting osmotic pressure, and / or buffers. Alternatively, the therapeutic agent can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Additionally, they may also contain other therapeutically effective substances.

[0272] In some embodiments, the therapeutic agent (e.g., a diterpenoid PKC-modulating compound) is administered intratumorally. In some embodiments, the therapeutic agent is administered directly into the tumor, allowing for high local concentrations of the therapeutic agent and, in some aspects, increased bioavailability of the therapeutic agent at the site of the tumor. Any formulation of the therapeutic agent suitable for intratumoral administration can be used in the embodiments herein. Intratumoral administration can be by injection of the therapeutic agent into the tumor (see, e.g., Celikoglu et al., 2008, Cancer Therapy, 6:545-552) or intravenous administration into blood vessels supplying the tumor. In some embodiments, the injection device has a porous delivery channel (e.g., a needle) for wider distribution or infusion of the therapeutic agent to treat tumors in large volumes.

[0273] For administration by inhalation, the therapeutic agent is inhaled in a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable propellant. The compounds can be conveniently delivered in the form of an aerosol spray from pressurized packs or nebulizers using an appropriate gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0274] Suitable formulations for transdermal application include an effective amount of a therapeutic agent and a carrier.Preferred carriers include absorbable pharmacologically acceptable solvents to help the therapeutic agent pass through the subject's skin.For example, a transdermal device is in the form of a bandage or patch, which includes a backing member, a reservoir containing a therapeutic agent optionally containing a carrier, a rate-controlling barrier for delivering the compound to the host's skin at a controlled, predetermined rate over an extended period of time, and a means for fixing the device to the skin.Matrix transdermal formulations can also be used.

[0275] Formulations suitable for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams, or gels well known in the art. Formulations may contain solubilizers, stabilizers, osmolality enhancers, buffers, and preservatives.

[0276] In some embodiments, the therapeutic agents may also be formulated in rectal compositions, e.g., suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides, or gel-forming agents such as carbomer.

[0277] In some embodiments, the therapeutic agent can be formulated as a depot preparation. Such long-acting preparations can be administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. The therapeutic agent can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil), ion exchange resins, biodegradable polymers, or as sparingly soluble derivatives, such as a sparingly soluble salt.

[0278] In some embodiments, the carrier is a cyclodextrin that enhances the solubility and / or bioavailability of the compounds herein. In some embodiments, the cyclodextrin for use in the pharmaceutical composition can be selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, derivatives thereof, and combinations thereof. In particular, the cyclodextrin is selected from β-cyclodextrin, γ-cyclodextrin, derivatives thereof, and combinations thereof.

[0279] In some embodiments, the compounds can be formulated with cyclodextrin or a derivative thereof selected from carboxyalkyl cyclodextrins, hydroxyalkyl cyclodextrins, sulfoalkyl ether cyclodextrins, and alkyl cyclodextrins. In various embodiments, the alkyl group in the cyclodextrin is methyl, ethyl, propyl, butyl, or pentyl.

[0280] In some embodiments, the cyclodextrin is α-cyclodextrin or a derivative thereof. In some embodiments, the α-cyclodextrin or a derivative thereof is selected from carboxyalkyl-α-cyclodextrins, hydroxyalkyl-α-cyclodextrins, sulfoalkylether-α-cyclodextrins, alkyl-α-cyclodextrins, and combinations thereof. In some embodiments, the alkyl group in the α-cyclodextrin derivative is methyl, ethyl, propyl, butyl, or pentyl.

[0281] In some embodiments, the cyclodextrin is β-cyclodextrin or a derivative thereof. In some embodiments, the β-cyclodextrin or a derivative thereof is The β-cyclodextrin derivative is selected from the group consisting of carboxyalkyl-β-cyclodextrin, hydroxyalkyl-β-cyclodextrin, sulfoalkylether-β-cyclodextrin, alkyl-β-cyclodextrin, and combinations thereof. In some embodiments, the alkyl group in the β-cyclodextrin derivative is methyl, ethyl, propyl, butyl, or pentyl.

[0282] In some embodiments, the β-cyclodextrin or derivative thereof is a hydroxyalkyl-β-cyclodextrin or a sulfoalkylether-β-cyclodextrin. In some embodiments, the hydroxyalkyl-β-cyclodextrin is hydroxypropyl-β-cyclodextrin. In some embodiments, the sulfoalkylether-β-cyclodextrin is sulfobutylether-β-cyclodextrin. In some embodiments, the β-cyclodextrin or derivative thereof is an alkyl-β-cyclodextrin, particularly methyl-β-cyclodextrin. In some embodiments using methyl-β-cyclodextrin, the β-cyclodextrin is a randomly methylated β-cyclodextrin.

[0283] In some embodiments, the cyclodextrin is γ-cyclodextrin or a derivative thereof. In some embodiments, the γ-cyclodextrin or a derivative thereof is selected from carboxyalkyl-γ-cyclodextrin, hydroxyalkyl-γ-cyclodextrin, sulfoalkylether-γ-cyclodextrin, and alkyl-γ-cyclodextrin. In some embodiments, the alkyl group in the γ-cyclodextrin derivative is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments, the γ-cyclodextrin or a derivative thereof is hydroxyalkyl-γ-cyclodextrin or sulfoalkylether-γ-cyclodextrin. In some embodiments, the hydroxyalkyl-γ-cyclodextrin is hydroxypropyl-γ-cyclodextrin.

[0284] When used in formulations with compounds of the present disclosure, cyclodextrins can be present at about 0.1% w / v to about 30% w / v, about 0.1% w / v to about 20% w / v, about 0.5% w / v to about 10% w / v, or about 1% w / v to about 5% w / v. In some embodiments, the cyclodextrin is present at about 0.1% w / v, about 0.2% w / v, about 0.5% w / v, about 1% w / v, about 2% w / v, about 3% w / v, about 4% w / v, about 5% w / v, about 6% w / v, about 7% w / v, about 8% w / v, about 9% w / v, about 10% w / v, about 12% w / v, about 14% w / v, about 16% w / v, about 18% w / v, about 20% w / v, about 25% w / v, or about 30% w / v or more.

[0285] The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0286] 5.7. Effective Dose and Administration In some embodiments, pharmaceutical compositions of therapeutic agents are administered to a subject, preferably a human, at a therapeutically effective dose to prevent, treat, or control a condition or disease described herein. The pharmaceutical composition is administered to a subject in an amount sufficient to elicit an effective therapeutic response in the subject. An effective therapeutic response is one that at least partially arrests or delays the symptoms or complications of the condition or disease. An amount sufficient to accomplish this is defined as a "therapeutically effective dose" or "therapeutically effective amount."

[0287] The dosage of the therapeutic agent depends, inter alia, on the species of warm-blooded animal (mammal), its weight, age, and the condition being treated. The size of the dose will also be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular therapeutic compound in a particular subject.

[0288] In some embodiments, the compound, which is a diterpenoid PKC activating compound, may be administered at a dose ranging from about 0.001 mg per kg of subject body weight (0.001 mg / kg) to about 1000 mg / kg. In some embodiments, the dose ranges from about 0.001 mg / kg to about 500 mg / kg. In some embodiments, the dose ranges from about 1 mg / kg to about 500 mg / kg. In some embodiments, the dose ranges from about 2 mg / kg to about 250 mg / kg. In another embodiment, the dose ranges from about 5 mg / kg to about 100 mg / kg. In another embodiment, the dose ranges from about 5 mg / kg to about 100 mg / kg. In some embodiments, the dose is about 0.001 mg / kg, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg, 40 mg / kg, 50 mg / kg, 100 mg / kg, 200 mg / kg, or 500 mg / kg. In some embodiments, the dose is administered once daily or divided into subdoses and administered in multiple doses, for example, two, three, or four times daily.

[0289] In some embodiments, the diterpenoid PKC activator can be administered sequentially or simultaneously with one or more second therapeutic agents, either by the same or different routes of administration. When administered sequentially, the time between administrations is selected to benefit, among other things, the therapeutic efficacy and / or safety of the combined treatment. In some embodiments, the diterpenoid PKC activator can be administered first, followed by the second therapeutic agent; or, alternatively, the second therapeutic agent can be administered first, followed by the diterpenoid PKC activator. By way of example and not limitation, the time between administrations can be about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 16 hours, or about 20 hours. In some embodiments, the time between administrations can be even about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more. In some embodiments, the time between administrations can be about 1 week, 2 weeks, 3 weeks, or 4 weeks or more. In some embodiments, the time between administrations can be about 1 month, 2 months, or more.

[0290] When co-administered, the diterpenoid PKC modulator can be administered simultaneously with the second therapeutic agent, separately, by the same or different route, or in a single composition by the same route.

[0291] In some embodiments, the dosage and frequency of administration of the second therapeutic agent can be the standard dosage and frequency used for the particular therapeutic agent, see, for example, Physicians' Desk Reference, 70 th Ed., PDR Network, 2015.

[0292] In some embodiments, when administration of a therapeutic agent is to a local site, e.g., intratumoral injection, the dose can be a dose used for systemic administration, such as a dose used for intravenous, intramuscular, and intraperitoneal administration. In some embodiments, the dose for local administration, e.g., intratumoral administration, is higher than a dose used for systemic administration. In some embodiments, the dose administered is sufficient for the intended effect, e.g., death or necrosis of tumor tissue. In some embodiments, intratumoral administration is performed one, two, three, four, five, or up to six or more times, each administration being separated in time, e.g., until a desired result is achieved.

[0293] Optimal dosages, toxicity, and therapeutic efficacy of such therapeutic agents may vary depending on the relative potency of the individual therapeutic agents and may be determined by pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50 ( Lethal dose for 50% of the population) and ED 50 It should be understood that the dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD ratio can be determined by determining the dose that is therapeutically effective in 50% of the population. 50 / ED 50 The therapeutic index can be expressed as: Therapeutic agents or combinations thereof that exhibit large therapeutic indices are preferred. Certain agents that exhibit toxic side effects can be used, but care should be taken to design a delivery system that targets such agents to the site of the affected tissue, minimizing potential damage to normal cells, thereby reducing side effects.

[0294] For example, the data obtained from cell culture assays and animal studies can be used to formulate a range of dosage for use in humans. The dosage of such small molecule compounds is preferably within the ED range with little or no toxicity. 50 The therapeutically effective dose of any compound used in the methods of the present invention can be estimated initially from cell culture assays. The IC as determined in cell culture is used to estimate the therapeutically effective dose. 50Doses can be formulated in animal models to achieve a circulating plasma concentration range that includes (the concentration of the test compound that achieves half-maximal inhibition of symptoms). Such information can be used to more accurately determine useful doses in humans. Plasma levels can be measured, for example, by high performance liquid chromatography (HPLC).

[0295] The following examples are provided to further illustrate the disclosed methods, and compounds and compositions for use in the methods. The examples provided are illustrative only and are not intended to limit the scope of the invention in any way.

[0296] 6. Working Example Example 1: Synthesis scheme of K101-epoxide and K101-DI-OH. The synthesis schemes of the compounds K101-epoxide and K101-DI-OH are shown below. [ka]

[0297] Preparation of compound K101-C20Tr-A. To a solution of K101A (1 g, 2.56 mmol, 1 eq) in pyridine (40 mL) was added trityl chloride (2.14 g, 7.68 mmol, 3.00 eq). The mixture was stirred at 40 °C for 14 hours (hr) to give a yellow solution. LC-MS showed that the desired mass was found, indicating that K101A remained. The mixture was again stirred at 40 °C for 12 h. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed that the reaction was complete. The reaction mixture was concentrated by drumming with N2 to give the crude product. The crude product was purified by flash column (eluted with petroleum ether (PE) / ethyl acetate = 100% PE to 20%) to give K101-C20Tr-A (1.6 g, 2.53 mmol, 98.73% yield) as a white solid. 1H NMR(400MHz,CDCl3)δ 7.59(s,1H),7.44-7.42(m,6H),7.31-7.29(m,6H),7.24-7.21(m,3H),5.63(brs,1H),3.51(s,2H),3.28(s,1H),2.93(s,1H),2.49 -2.41(m,2H),2.09-2.06(m,5H),2.09-2.03(m,7H),1.99-1.94(m,1H),1.78(s,3H),1.20(s,3H),1.07(s,3H),0.89-0.81(m,4H).

[0298] Preparation of compound epoxide-Trt. To a solution of K101-C20Tr-A (30.00 mg, 47.41 μmol, 1.00 equivalents (eq)) in dichloromethane (DCM) (2.00 mL), NaHCO3 (11.95 mg, 142.23 μmol, 5.53 μL, 3.00 eq) and meta-chloroperbenzoic acid (m-CPBA) (14.44 mg, 71.11 μmol, 1.5 eq, 85% purity) were added. The reaction mixture was stirred at 20 °C for 2 hours (h) to obtain a suspension. LC-MS indicated the reaction was complete, and the desired MS values ​​were observed. Thin-layer chromatography (TLC) (petroleum ether / ethyl acetate mixture 2:1 (PE / EtOAc = 2 / 1), SiO2) analysis showed no new spots. The reaction mixture was mixed with DCM (5 mL) and brine (2 mL), and the organic layer was separated and concentrated under reduced pressure to give 35.5 mg of crude product as a colorless gum. The product was purified by prep-TLC (PE / EtOAc = 2 / 1, SiO) to give epoxide-Trt (20.10 mg, 65.34% yield) as a colorless gum.

[0299] 1H NMR(400MHz,CDCl3)δ 7.63(s,1H),7.37-7.30(m,6H),7.30-7.18(m,11H),5.54(brs,1H),3.96-3.89(m,1H),3.17(d,J=9.3 Hz,1H),3.08(d,J=8.5 Hz,1H),2.85-2.74(m,2H),2.09(s,3H),2.07-2.03(m,1H),2.02(s,1H),1.98(s,1H),1.96-1.87(m,1 H),1.86-1.81(m,1H),1.80-1.74(m,3H),1.66-1.59(m,1H),1.21(s,3H),1.04(s,3H),0.97(d,J=4.3 Hz,1H),0.89(d,J=6.5 Hz,3H).

[0300] Preparation of Compounds K101-Epoxide and K101-DI-OH. To a solution of epoxide-Trt (10.00 mg, 15.41 μmol, 1.00 eq) in DCM (500.00 μL) was added trifluoroacetic acid (TFA) (100.00 μL), and the reaction solution was stirred at 0 °C for 1 hour. TLC (PE / EtOAc = 2 / 1, SiO 2 ) showed the reaction was complete. The reaction was quenched with saturated aqueous NaHCO 3 solution (2 mL) at 0 °C, then extracted with DCM (5 mL × 2), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a colorless gum. The residue was combined with a second preparation of the crude product and purified by preparative HPLC (column: Waters Xbridge 150x25x5 mm; mobile phase: A [A: water (0.05% ammonia hydroxide v / v)]; B [acetonitrile (ACN)]; gradient B%: 25% to 55% in 10 min) to give both K101-epoxide (1.51 mg, 3.71 μmol, 24.11% yield, 100% purity) and K101-DI-OH (1.20 mg, 2.60 μmol, 16.90% yield, 92.1% purity) as white solids after lyophilization.

[0301] K101-epoxide: LC-MS (m / z): 429.2 [M+Na] +

[0302] K101-epoxide:1 H NMR(400MHz,CD3OD)δ 7.53(s,1H),3.48(d,J=11.9 Hz,1H),3.44-3.39(m,1H),3.36(s,1H),3.16(d,J=8.6 Hz,1H),2.66(d,J=16.8 Hz,1H),2.14-2.06(m,4H),2.04-1.89(m,3H),1.77-1.74(m,3H),1.59(dd,J=11.2,14.3 Hz,1H),1.22(s,3H),1.06(s,3H),1.02(d,J=4.9 Hz,1H),0.89(d,J=6.6 Hz,3H).

[0303] K101-DI-OH:LC-MS(m / z):447.1[M+Na] +

[0304] K101-DI-OH: 1 H NMR(400MHz,CD3OD)δ 7.70(s,1H),3.89(s,1H),3.72-3.68(m,1H),3.53(d,J=2.6 Hz,2H),2.45(d,J=7.9 Hz,1H),2.21-2.07(m,2H),2.03(s,3H),1.85-1.79(m,1H),1.79-1.74(m,3H),1.60-1.48(m,2H),1.14(s,3H),1.08(s,4H),0.92(d,J=6.8 Hz,3H).

[0305] Example 2: Synthesis of K101-C13OH. The synthesis method of compound K101-C13OH is shown below.

change

[0306] Preparation of compound K101-C13OH. To a solution of K101A (40.00 mg, 102.44 μmol, 1.00 eq) in MeOH (20.00 mL) was added Ba(OH)28H2O (322.69 mg, 1.02 mmol, 10.00 eq). The mixture was stirred at 20 °C for 4 h to give a yellow suspension. LC-MS and TLC (eluted with 100% EtOAc) showed the reaction was complete. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with dichloromethane (DCM) (100 mL x 3). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (eluted with EtOAc=2 / 1) to give K101-C13OH (9.30 mg, 26.69 μmol, 26.05% yield, 100% purity) as a white solid.

[0307] LC-MS(m / z):371.2[M+Na] +

[0308] 1 H NMR(400MHz,CD3OD)δ 7.29(s,1H),5.18(s,1H),4.58(s,2H),3.81-3.75(m,1H),3.50-3.46(m,1H),3.20-3.11(m,3H),2.16-2. 11(m,1H),1.76-1.63(m,5H),1.27(m,1H),1.17(m,3H),1.74-1.53(m,8H),1.17(s,3H),1.05(s,3H),1.06 -0.88(m,6H).

[0309] Example 3: Synthesis scheme of K101-C1301. The synthesis scheme of compounds K101-C1301 is shown below. [ka]

[0310] Preparation of compound K101-C20Tr-A. To a solution of K101A (500.00 mg, 1.28 mmol, 1.00 eq) in pyridine (10.00 mL) was added trityl chloride (TrtCl) (1.07 g, 3.84 mmol, 3.00 eq). The mixture was stirred at 20 °C for 14 h to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) indicated the reaction was complete. The reaction mixture was concentrated with N2 to give the crude product. The product was purified by flash column (eluted with 1% to 50% PE EtOAc) to give K101-C20Tr-A (790.00 mg, 1.02 mmol, 79.78% yield, 81.795% purity) as a white solid.

[0311] Preparation of compound K101-C20Tr-B. To a solution of K101-C20Tr-A (290.00 mg, 458.30 μmol, 1.00 eq) in MeOH (76.00 mL) was added Ba(OH)28H2O (1.44 g, 4.58 mmol, 10.00 eq) at 0 °C. The mixture was stirred at 20 °C for 3 h to give a yellow suspension. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with dichloromethane (DCM) (300 mL × 3). The organic layer was dried over Na2SO4. The organic layer was filtered through silica gel and washed with EtOAc (50 mL). The organic layer was concentrated to give K101-C20Tr-B (260.00 mg, 425.57 μmol, yield 92.86%, purity 96.694%) as a white solid.

[0312] Preparation of Compound K101-C1301-A. To a solution of K101-C1301-B (35.00 mg, 59.25 μmol, 1.00 eq) in DCM (500.00 uL) was added 3-cyclopentylpropanoic acid (10.11 mg, 71.10 μmol, 10.11 uL, 1.20 eq), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EDC (EDC) (22.72 mg, 118.49 μmol, 2.00 eq) and 4-dimethylaminopyridine (DMAP) (14.48 mg, 118.50 μmol, 2.00 eq) was added. The mixture was stirred at 20 °C for 14 hours to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 4 / 1) showed the reaction was complete. The reaction mixture was combined with a second preparation of the compound, quenched with HO (10 mL), and extracted with DCM (15 mL x 3). The combined organic layers were dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 4 / 1) to give K101-C1301-A (32.00 mg, 44.76 μmol, 65.12% yield, 100% purity) as a white solid.

[0313] Preparation of compound K101-C1301. To a solution of K101-C1301-A (32.00 mg, 44.76 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (385.00 mg, 3.38 mmol, 250.00 μL, 75.44 eq). The mixture was stirred at 20 °C for 1 hour to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 1 / 1) showed that the reaction was complete. The solvent was removed with N to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 1 / 1) to give K101-C1301 (8.10 mg, 17.14 μmol, 38.29% yield, 100% purity) as a white solid.

[0314] LC-MS(m / z):495.3[M+Na] +

[0315] 1 H NMR(400MHz,CD3OD)δ 7.53(s,1H),5.59(s,1H),4.54-4.49(m,2H),3.95-3.88(m,2H),3.14(s,1H),3.04(s,1H),2.53-2.43(m,2H),2.35- 2.31(m,2H),2.10-1.90(m,2H),1.77-1.72(m,6H),1.62-1.52(m,7H),1.15(s,3H),1.05(s,3H),0.89-0.83(m,4H).

[0316] Example 4: Synthesis scheme of K101-C1302. The synthesis scheme of compounds K101-C1302 is shown below. [ka]

[0317] Preparation of compound K101-C1302-A. To a solution of K101-C20Tr-B (40.00 mg, 67.71 μmol, 1.00 eq) in DCM (1.00 mL) was added 3-[4-(trifluoromethyl)phenyl]propanoic acid (C13-02) (17.73 mg, 81.25 μmol, 1.20 eq), DMAP (16.54 mg, 135.42 μmol, 2.00 eq), and EDC (25.96 mg, 135.42 μmol, 2.00 eq). The mixture was stirred at 20°C for 2 hours to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed that the reaction was complete. The mixture was combined with the second preparation of the compound, quenched with saturated NaHCO3 (5 mL), and extracted with DCM (10 mL x 3). The organic layer was washed with H2O (5 mL), dried over Na2SO4, and then concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1302-A (34.00 mg, 42.45 μmol, yield 53.72%, purity 98.736%) as a white solid.

[0318] Preparation of compound K101-C1302. To a solution of K101-C1302-A (28.00 mg, 35.40 μmol, 1.00 eq) in MeOH (1.00 mL) was added HClO (464.95 mg, 4.63 mmol, 280.09 uL, 130.73 eq). The mixture was stirred at 0 °C for 0.5 h to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was combined with a second preparation of the compound and purified by preparative HPLC (column: Waters XSELECT C18 150x30mmx5um; mobile phase: [A:water (0.1% TFA)-B:ACN]; B%: 33%-63%, 10 min) to give K101-C1302 (10.60 mg, 18.56 μmol, 52.42% yield, 96.032% purity) as a white solid.

[0319] LC-MS(m / z):571.3[M+Na] +

[0320] 1 H NMR(400MHz,CD3OD)δ 7.58-7.52(m,2H),7.43-7.41(m,2H),5.55(s,1H),3.95-3.87(m,2H),3.29-2.99(m,4H),2.72-2.68(m,2H),2.47- 2.37(m,2H),2.05-1.96(m,2H),1.72(s,3H),1.43-1.40(m,1H),1.01(s,6H),0.85-0.83(m,3H),0.75-0.73(m,3H).

[0321] Example 5: Synthesis scheme of K101-C1303. [ka] Preparation of compound K101-C1303-A: To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid (C13-03) (26.95 mg, 101.57 μmol, 2.00 eq), DMAP (24.82 mg, 203.13 μmol, 4.00 eq), and EDC (19.47 mg, 101.57 μmol, 2.00 eq). The mixture was stirred at 20 °C for 48 h to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed the reaction was complete. The reaction mixture was quenched with saturated NaHCO3 (5 mL) and extracted with DCM (10 mL * 3). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1303-A (30.00 mg, 34.85 μmol, yield 68.63%, purity 97.349%) as a white solid.

[0322] 1 H NMR(400MHz,CDCl3)δ 7.50(s,1H),7.37-7.35(m,5H),7.24-7.22(m,8H),7.17-7.12(m,7H),5.54(s,1 H),5.04(m,1H),4.87-4.85(m,1H),4.49(m,1H),3.18(s,1H),3.02(m,1H),2.83( m,1H),2.46-2.41(m,1H),2.32-2.28(m,1H),1.98-1.93(m,2H),1.70(m,3H),1. 35(s,9H),1.19(s,3H),0.99-0.98(m,3H),0.78-0.77(m,3H),0.70-0.69(m,1H).

[0323] Preparation of compound K101-C1303: To a solution of K101-C20Tr-B (30.00 mg, 35.80 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (154.00 mg, 1.35 mmol, 100.00 uL, 37.73 eq) at 0 °C. The mixture was stirred at 0 °C for 2 hours to give a reddish-brown solution. The mixture was stirred at 20 °C for 14 hours to give a reddish-brown solution again. The reaction mixture was quenched with HO (5 mL) and the organic layer was separated. The aqueous layer was lyophilized. The organic layer was dissolved in MeOH (3.00 mL) and HClO (83.00 mg, 826.20 μmol, 50.00 uL, 23.08 eq) was added at 0 °C. The mixture was stirred at 0 °C for 2 hours to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (column: Phenomenex Gemini 150*25mm*10um; mobile phase: [A:water (0.1% TFA)-B:ACN]; B%: 18%~48%, 10 min) to give K101-C1303 (4.50mg, 6.90μmol, yield 19.27%, purity 93.438%, TFA salt) as a white solid.

[0324] LC-MS(m / z):519.3[M+H] +

[0325] 1 H NMR(400MHz,CD3OD)δ 7.45(s,1H),7.31-7.21(m,5H),5.51(s,1H),4.27-4.21(m,1H),3.84(s,2H),3.25(m,1H),3.06-3.00(m,3H),2.40-2.33(m,1) H),2.33-2.28(m,1H),2.08(m,1H),2.04(m,1H),1.65(s,3H),1.44-1.40(m,1H),1.03(s,3H),0.97(s,3H),0.87-0.81(m,4H).

[0326] Example 6: Synthesis scheme of K101-C1304. The synthesis scheme of compounds K101-C1304 is shown below. [ka]

[0327] Preparation of compound K101-C1304-A. To a solution of K101-C20Tr-B (40.00 mg, 67.71 μmol, 1.00 eq) in DCM (2.00 mL) was added 2-phenylacetic acid (C13-04) (11.06 mg, 81.25 μmol, 10.24 μL, 1.20 eq), DMAP (33.09 mg, 270.84 μmol, 4.00 eq), and EDC (25.96 mg, 135.42 μmol, 2.00 eq). The mixture was stirred at 20 °C for 12 h to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) indicated the reaction was complete. The reaction mixture was combined with a second preparation of compound K101-C1304-A, quenched with HO (5 mL), and extracted with DCM (15 mL x 3). The organic layer was dried over NaSO and concentrated to give the crude product, which was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1304-A (40.00 mg, 56.43 μmol, yield 65.78%) as a white solid.

[0328] Preparation of compound K101-C1304. To a solution of K101-C1304-A (40.00 mg, 56.43 μmol, 1.00 eq) in MeOH (3.00 mL) was added HClO4 (83.00 mg, 826.14 μmol, 50.00 μL, 14.64 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h to give a yellow solution. LC-MS showed the reaction was complete. The mixture was purified by preparative HPLC (column: Waters XSELECT C18 150 x 30 mm x 5 μm; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 33%-63%, 10 min) to give K101-C1304 (16.30 mg, 34.94 μmol, 61.91% yield) as a white solid.

[0329] LC-MS(m / z):489.3[M+Na] +

[0330] 1H NMR(400MHz,CD3OD)δ 7.53(s,1H),7.33-7.28(m,5H),5.57(s,1H),3.95-3.88(m,2H),3.64(s,2H),3.14-3.03(m,2H),2.48- 2.39(m,2H),2.12-2.02(m,2H),1.73(s,3H),1.56-1.50(m,1H),1.03-1.01(m,6H),0.88-0.78(m,4H).

[0331] Example 7: Synthesis scheme of K101-C1305. The synthesis scheme of compounds K101-C1305 is shown below. [ka]

[0332] Preparation of compound K101-C1305-A. To a solution of K101-C20Tr-B (45.00 mg, 76.17 μmol, 1.00 eq) in DCM (2.00 mL) was added 2-tert-butoxycarbonyl-2-azaspiro[3.3]heptane-6-carboxylic acid (C13-05) (27.57 mg, 114.26 μmol, 1.50 eq), DMAP (37. To the resulting solution were added K101-C13050-A (22 mg, 304.68 μmol, 4.00 eq), N,N-diisopropylethylamine (DIEA) (19.69 mg, 152.34 μmol, 26.61 uL, 2.00 eq), and EDC (29.21 mg, 152.34 μmol, 2.00 eq). The mixture was stirred at 20 °C for 48 h to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed the reaction was complete. The reaction mixture was combined with a second preparation of the compound, quenched with saturated NaHCO3 (5 mL), and extracted with DCM (10 mL x 3). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C13050-A (70.00 mg, crude) as a white solid.

[0333] Preparation of compound K101-C1305. To a solution of K101-C1305-A (70.00 mg, 85.99 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (154.00 mg, 1.35 mmol, 100.00 μL, 15.71 eq) at 0 °C. The mixture was stirred at 0 °C for 2 hours to give a reddish-brown solution. The mixture was stirred at 20 °C for 16 hours (hr). LC-MS showed the absence of the desired product. The reaction mixture was quenched with HO (5 mL) and the organic layer was separated. LC-MS showed the organic layer was dissolved in MeOH (3.00 mL), followed by the addition of HClO (83.00 mg, 826.20 μmol, 50.00 μL, 9.61 eq) at 0 °C. The mixture was stirred at 0 °C for 2 hours to give a yellow solution. LC-MS showed the reaction was complete. The mixture was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 10% to 40%, 10 min) to give K101-C1305 (11.80 mg, 20.15 μmol, yield 23.43%, TFA) as a yellow solid.

[0334] LC-MS(m / z):494.2[M+Na] +

[0335] 1 H NMR(400MHz,CD3OD)δ 7.56(s,1H),5.63(s,1H),4.11-4.09(m,4H),4.00-3.96(m,2H),3.19-3.07(m,3H),2.60-2.46(m,6 H),2.16-2.12(m,2H),1.77(s,3H),1.76-1.53(m,1H),1.17(s,3H),1.09(s,3H),0.93-0.89(m,4H).

[0336] Example 8: Synthesis scheme of K101-C1306. The synthesis scheme of compounds K101-C1306 is shown below. [ka]

[0337] Preparation of compound K101-C1306-A. To a solution of K101-C20Tr-B (40.00 mg, 67.71 μmol, 1.00 eq) in DCM (2.00 mL) was added 2-(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan-6-yl)acetic acid (25.93 mg, 101.56 μmol, 1.50 eq), DMAP (33.09 mg, 270.84 μmol, 4.00 eq), DIEA (26.25 mg, 203.13 μmol, 35.47 uL, 3.00 eq), and EDC (25.96 mg, 135.42 μmol, 2.00 eq). The mixture was stirred at 20 °C for 16 hours to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed the reaction was complete. The mixture was combined with the second preparation of the compound, quenched with saturated NaHCO3 (5 mL), and extracted with DCM (10 mL x 3). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1306-A (40.00 mg, 47.90 μmol, 70.74% yield, 99.157% purity) as a white solid.

[0338] Preparation of compound K101-C1312. To a solution of K101-C1306-A (10.00 mg, 12.08 μmol, 1.00 eq) in MeOH (3.00 mL) was added HClO (83.00 mg, 826.20 μmol, 50.00 uL, 68.39 eq) at 0° C., and the mixture was stirred at 0° C. for 0.5 hours. The mixture was stirred at 20° C. for an additional 15.5 hours. LC-MS showed the reaction was complete. The mixture was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150x30x5um; mobile phase: [A: water (0.05% ammonia hydroxide v / v)-B: ACN]; B%: 45%-75%, 10 min) to give K101-C1306-A (3.80 mg, 6.49 μmol, 53.71% yield) as a white solid.

[0339] LC-MS(m / z):608.2[M+Na] +

[0340] 1 H NMR(400MHz,CD3OD)δ 7.56(s,1H),5.62(s,1H),4.60-4.58(m,3H),3.99-0.96(m,4H),3.92-3.82(m,2H),3.19-3.18(m,2H),2.52-2.37(m ,7H),2.10-1.94(m,4H),1.77(s,3H),1.76-1.46(m,1H),1.44(s,9H),1.18(s,3H),1.08(s,3H),0.93-0.86(m,4H).

[0341] Preparation of compound K101-C1306. To a solution of K101-C1312 (15.00 mg, 25.61 μmol, 1.00 eq) in THF (500.00 uL) was added TFA (288.72 mg, 2.53 mmol, 187.48 uL, 98.88 eq), and the mixture was stirred at 20 °C for 4 hours to give a colorless solution. LC-MS showed that the reaction was complete, but a large amount of P2 was found. The reaction mixture was concentrated with N2, and the resulting product was dissolved in MeOH (500.00 uL) / HO (50.00 uL). The mixture was stirred at 20 °C for 14 hours to give a colorless solution. LC-MS showed that the reaction was complete. The mixture was combined with a second preparation of compound K101-C1312 and concentrated with N2 to give the desired product. The product was lyophilized to give K101-C1306 (4.20 mg, 7.00 μmol, 25.80% yield, TFA) as a yellow gum. The product (13.4 mg) was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 20% to 50%, 10 min) to give K101-C1306 (4.20 mg, 7.00 μmol, 25.80% yield, TFA) as a white solid.

[0342] LC-MS(m / z):508.2[M+Na] +

[0343] 1H NMR(400MHz,CD3OD)δ 7.55(s,1H),5.62-5.60(m,1H),4.14(s,2H),4.00(s,2H),3.95(s,2H),3.18(s,1H),3.07(s,1H),2.52-2. 46(m,7H),2.10-2.02(m,4H),1.77(s,3H),1.54-1.52(m,1H),1.18(s,3H),1.08(s,3H),0.93-0.86(m,4H).

[0344] Example 9: Synthesis scheme of K101-C1311. The synthesis scheme of compounds K101-C1311 is shown below. [ka]

[0345] Preparation of compound K101-C1311. To a solution of K101-C1305-A (22.00 mg, 27.03 μmol, 1.00 eq) in MeOH (3.00 mL), HClO (26.09 mg, 259.73 μmol, 15.72 μL, 9.61 eq) was added at 0 °C, and the mixture was stirred at 0 °C for 1 h. LC-MS showed the reaction was complete. The mixture was purified by preparative HPLC (column: Waters Xbridge 150 x 25 x 5 μL; mobile phase: [A: water (0.05% ammonia hydroxide v / v) - B: ACN]; B%: 40% to 70%, 10 min) to give K101-C1311 (3.30 mg, 5.77 μmol, 21.36% yield, 100% purity) as a yellow solid.

[0346] LC-MS(m / z):594.3[M+Na] +

[0347] 1H NMR(400MHz,CD3OD)δ 7.57(s,1H),5.63(s,1H),3.99-0.89(m,5H),3.18-3.05(m,3H),2.56-2.42(m,5H),2.15-2.04(m ,2H),1.76(m,3H),1.44(s,9H),1.36-1.31(m,3H),1.17(s,3H),1.09(s,3H),0.93-0.88(m,4H).

[0348] Example 10: Synthesis scheme of K101-C1312. The synthesis scheme of compound K101-C1312 is shown below. [ka]

[0349] Preparation of compound K101-C1312. To a solution of K101-C1306-A (10.00 mg, 12.08 μmol, 1.00 eq) in MeOH (3.00 mL) was added HClO (83.00 mg, 826.20 μmol, 50.00 uL, 68.39 eq) at 0° C., and the mixture was stirred at 0° C. for 0.5 hours. The mixture was stirred at 20° C. for an additional 15.5 hours to give a yellow solution. LC-MS showed that the reaction was complete. The mixture was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150x30x5u; mobile phase: [A: water (0.05% ammonia hydroxide v / v)-B: ACN]; B%: 45%-75%, 10 min) to give K101-C1306-A (3.80 mg, 6.49 μmol, 53.71% yield) as a white solid.

[0350] LC-MS(m / z):608.2[M+Na] +

[0351] 1 H NMR(400MHz,CD3OD)δ 7.56(s,1H),5.62(s,1H),4.60-4.58(m,3H),3.99-0.96(m,4H),3.92-3.82(m,2H),3.19-3.18(m,2H),2.52-2.37(m ,7H),2.10-1.94(m,4H),1.77(s,3H),1.76-1.46(m,1H),1.44(s,9H),1.18(s,3H),1.08(s,3H),0.93-0.86(m,4H).

[0352] Example 11: Synthesis scheme of K101-C1313. The synthesis scheme of compound K101-C1313 is shown below. [ka]

[0353] Preparation of Compound K101-C1313-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DMF (2.00 mL) was added (E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoic acid (C13-13) (21.95 mg, 101.56 μmol, 2.00 eq), DIEA (19.69 mg, 152.34 μmol, 26.61 μL, 3.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), and hexafluorophosphate azabenzotriazole tetramethyluronium (HATU) (38.62 mg, 101.56 μmol, 2.00 eq). The mixture was stirred at 20 °C for 14 hours to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed the reaction was complete. The mixture was quenched with saturated NaHCO3 (5 mL) and extracted with methyl tert-butyl ether (MTBE) (15 mL × 3). The organic layer was washed with HO, dried over Na2SO4, and then concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1313-A (21.00 mg, 26.62 μmol, 45.19% yield) as a white solid.

[0354] Preparation of compound K101-C1313. To a solution of K101-C1313-A (21.00 mg, 26.62 μmol, 1.00 eq) in MeOH (3.00 mL) was added HClO4 (83.00 mg, 826.28 μmol, 50.00 uL, 31.04 eq) at 0°C. The mixture was stirred at 0°C for 1 hour to give a yellow solution. LC-MS showed that the reaction was complete. The mixture was purified by preparative HPLC (column: Phenomenex Gemini Purification by HPLC using a 150x25mmx10um column (150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 55%-85%, 10 min) gave K101-C1313 (4.40mg, 6.10µmol, yield 22.90%, purity 91.518%, TFA) as a yellow solid.

[0355] LC-MS(m / z):569.1[M+Na] +

[0356] 1 H NMR(400MHz,CD3OD)δ 7.74-7.68(m,3H),7.63-7.58(m,2H),7.48-7.16(m,1H),6.60-6.56 (m,1H),5.60-5.50(m,1H),3.89-3.82(m,2H),3.12-3.08(m,1H),3.07-2.90(m,1H),2.42-2.33(m,2H),2.13- 2.11(m,1H),2.07-1.99(m,1H),1.66(s,3H),1.58-1.51(m,1H),1.14(s,3H),1.02(s,3H),0.88-0.83(m,4H).

[0357] Example 12: Synthesis scheme of K101-C1315. The synthesis scheme of compound K101-C1315 is shown below. [ka]

[0358] Preparation of compound K101-C1315-A. To a solution of K101-C20Tr-B (20.00 mg, 33.86 μmol, 1.00 eq) and C13-15 (15.35 mg, 101.58 μmol, 3.00 eq) in DCM (1.00 mL) was added EDC (19.47 mg, 101.58 μmol, 3.00 eq) and DMAP (20.68 mg, 169.30 μmol, 5.00 eq). The reaction solution was stirred at 25 °C for 3 hours, resulting in a brown solution. LC-MS showed the reaction was complete. The reaction solution was diluted with DCM (5 mL), washed with brine (2 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to afford K101-C1315-A (28.70 mg, crude) as a brown gum, which was used directly in the next step without further purification.

[0359] Preparation of compound K101-C1315. To a solution of K101-C1315-A (25.00 mg, crude) in MeOH (1.00 mL) was added HClO (30.00 uL) at 25 °C. The reaction solution was stirred at 25 °C for 0.5 hours to give a brown solution. LC-MS showed that the reaction was complete. The reaction solution was quenched by dropwise addition of KCO (34 mg) in water (1 mL) at 0 °C to adjust the pH to 9. The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 15%-45%, 10 min) to give K101-C1315 (3.60 mg, purity 97%, TFA salt) as a white solid after lyophilization.

[0360] LC-MS(m / z):504.2[M+Na] +

[0361] 1H NMR(400MHz,CD3OD)δ=8.72(d,J=6.5 Hz,2H),7.95(d,J=6.5 Hz,2H),7.53(s,1H),5.61-5.55(m,1H),3.99-3.89(m,2H),3.24(t,J=7.3 Hz,2H),3.17-3.11(m,1H),3.06-3.01(s,1H),2.90(t,J=7.2 Hz,2H),2.57-2.47(m,1H),2.45-2.37(m,1H),2.15-1.95(m,2H),1.77-1.72(m,3H ),1.48(dd,J=10.5,14.3 Hz,1H),1.10(s,3H),1.05(s,3H),0.92-0.83(m,4H).

[0362] Example 13: Synthesis scheme of K101-C1316. The synthesis scheme of compound K101-C1316 is shown below. [ka]

[0363] Preparation of compound K101-C1316-A. To a solution of K101-C20Tr-B (40.00 mg, 67.71 μmol, 1.00 eq) in DCM (2.00 mL) was added C13-16 (51.18 mg, 338.55 μmol, 5.00 eq), DMAP (33.09 mg, 270.84 μmol, 4.00 eq), hydroxybenzotriazole (HOBt) (18.30 mg, 135.42 μmol, 2.00 eq), and EDC (25.96 mg, 135.42 μmol, 2.00 eq). The mixture was stirred at 20 °C for 12 h, resulting in a black solution. LC-MS showed 43.779% of the desired mass, with 16.864% of the reactant remaining. The mixture was quenched with saturated NaHCO (10 mL) and extracted with DCM (15 mL x 3). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1316-A (27.00 mg, 37.30 μmol, 48.97% yield) as a white solid.

[0364] Preparation of compound K101-C1316. To a solution of K101-C1316-A (27.00 mg, 37.30 μmol, 1.00 eq) in MeOH (2.00 mL) was added HClO (83.00 mg, 826.20 μmol, 50.00 uL, 22.15 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hours to give a yellow solution. LC-MS showed that the reaction was complete. The mixture was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 20%-50%, 10 min) to give K101-C1316 (11.40 mg, 18.81 μmol, 50.43% yield, 98.3% purity, TFA salt) as a white solid.

[0365] LC-MS(m / z):504.2[M+Na] +

[0366] 1 H NMR (400 MHz, CD3OD) δ 8.72-8.71(d,J=5.2Hz,1H),8.45-8.41(t,J=8.0Hz,1H),7.95-7.93(d,J=8. 0Hz,1H),7.86-7.83(t,J=6.8Hz,1H),7.55(s,1H),5.60-5.59(m,1H),3.99- 3.95(m,2H),3.31-3.29(m,2H),3.16(s,1H),3.05(s,1H),3.00-2.96(m,2H) ,2.51-2.40(m,2H),2.15-2.03(m,2H),1.76-1.75(m,3H),1.51-1.47(m,3H), 1.10(s,3H),1.06(s,3H),0.90-0.86(m,4H).

[0367] Example 14: Synthesis scheme of K101-C1317. The synthesis scheme of compound K101-C1317 is shown below. [ka]

[0368] Preparation of compound K101-C1317-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (1.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)hexanoic acid (C13-17) (23.49 mg, 101.57 μmol, 2.00 eq), DMAP (24.82 mg, 203.13 μmol, 4.00 eq), and EDC (19.47 mg, 101.57 μmol, 2.00 eq). The mixture was stirred at 20 °C for 5 h to give a colorless solution. LC-MS and TLC showed the reaction was complete. The mixture was quenched with HO (15 mL) and extracted with DCM (15 mL x 5). The organic layer was dried over NaSO and concentrated to give a yellow solid. The product was purified by preparative TLC (eluted with petroleum ether:ethyl acetate=5 / 1) to give K101-C1317-A (35.00 mg, 43.53 μmol, yield 85.73%) as a white solid.

[0369] Preparation of compound K101-C1317. To a solution of K101-C1317-A (46.00 mg, 57.21 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (6.52 mg, 57.21 μmol, 4.23 μL, 1.00 eq) and EtSiH (6.65 mg, 57.21 μmol, 9.11 μL, 1.00 eq). The mixture was stirred at 20 °C for 2 h to give a colorless solution, which was concentrated to give a yellow oil. TFA (1 mL) was added to the yellow oil in DCM (2 mL), and the mixture was stirred at 20 °C for 0.5 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated, dissolved in MeOH (20 mL), and stirred at 20 °C for 14 h to give a yellow liquid. The product was concentrated to give a yellow solid, which was then purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 30% to 60%, 8 min). The separated layers were lyophilized to give K101-C1317 (7.00 mg, 12.16 μmol, 21.26% yield, 100% purity, TFA) as a white solid.

[0370] LC-MS (m / z): 584.2 [M+Na] +

[0371] 1 H NMR(400MHz,MeOD)δ 7.57(s,1H),5.64(d,J=4.5 Hz,1H),4.04(t,J=6.4 Hz,1H),4.00-3.94(m,2H),3.20-3.15(m,1H),3.10-3.05(m,1H),2.59-2.39(m,2H),2.27(dd,J=7.0,14.8 Hz,1H),2.13-1.93(m,2H),1.90-1.80(m,1H),1.80- 1.70(d,J=1.5 Hz,3H),1.60-1.50(dd,J=10.4,14.9 Hz,1H),1.53-1.37(m,4H),1.20(s,3H),1.11(s,3H),1.05-0.91(m,7H).

[0372] Example 15: Synthesis of K101-C1318. The synthesis method of compound K101-C1318 is shown below.

change

[0373] Preparation of compound K101-C1318-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)-4-phenyl-butanoic acid (C13-18) (28.37 mg, 101.56 μmol, 2.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), and EDC (19.47 mg, 101.56 μmol, 2.00 eq). The mixture was stirred at 20 °C for 12 hours to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed the reaction was complete. The reaction mixture was combined with the second preparation of the compound, and the mixture was quenched with HO (10 mL) and then extracted with DCM (15 mL x 3). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1318-A (32.00 mg, 37.56 μmol, 63.38% yield) as a white solid.

[0374] Preparation of compound K101-C1318. To a solution of K101-C1318-A (30.00 mg, 35.21 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (308.00 mg, 2.70 mmol, 200.00 μL, 76.72 eq) and EtSiH (4.91 mg, 42.25 μmol, 6.73 μL, 1.20 eq). The mixture was stirred at 20° C. for 4 hours to give a yellow solution. LC-MS showed that the reaction was complete. The reaction mixture was concentrated with N2, and the resulting residue was dissolved in MeOH (20 mL). The mixture was stirred at 20° C. for 12 hours. LC-MS showed that the reaction was complete. The mixture was concentrated to give the crude product. The product was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 23%-53%, 10 min) to give K101-C1318 (10.80 mg, 17.24 μmol, 48.98% yield, 99.58% purity, TFA) as a white solid.

[0375] LC-MS(m / z):532.1[M+Na] +

[0376] 1 H NMR(400MHz,CD3OD)δ 7.58(s,1H),7.36-7.33(m,2H),7.27-7.23(m,3H),5.65(s,1H),4.0 7-4.03(m,1H),3.97(s,2H),3.18(s,1H),3.08(m,1H),2.83-2.81(m,2H),2.53-2.41(m,2H),2.10-2.09 (m,2H),1.77(s,3H),1.64-1.61(m,1H),1.21(s,3H),1.12(s,3H),1.05-1.04(m,1H),0.97-0.95(m,3H).

[0377] Example 16: Synthesis scheme of K101-C1319. The synthesis scheme of compound K101-C1319 is shown below. [ka]

[0378] Preparation of compound K101-C1319-A. To a solution of K101-C20Tr-B (200.00 mg, 338.55 μmol, 1.00 eq) and C13-19 (119.18 mg, 406.26 μmol, 1.20 eq) in anhydrous DCM (2.00 mL) was added EDC (194.70 mg, 1.02 mmol, 3.00 eq) and DMAP (124.08 mg, 1.02 mmol, 3.00 eq). The reaction solution was stirred at 20 °C for 16 hours to give a light brown solution. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to give the crude product, and the product was purified by silica gel column chromatography (PE / EtOAc=3 / 1) to give K101-C1319-A (273.50 mg, 315.79 μmol, 93.28% yield) as a colorless gum.

[0379] Preparation of compound K101-C1319. To a solution of K101-C1319-A (273.00 mg, 315.21 μmol, 1.00 eq) in MeOH (5.00 mL) was added HCl / MeOH (4 M, 5.00 mL, 63.45 eq) at 0 °C. The reaction solution was stirred at 0 °C for 3.5 h to obtain a clear solution. LC-MS showed that the reaction was not complete, so the reaction solution was stirred at 20 °C for 1.5 h. LC-MS showed that the reaction was complete. N2 was bubbled through the reaction solution for 0.5 h to remove HCl, and the remaining solution was cooled to 0 °C. The solution was adjusted to pH 7 with saturated aqueous NaHCO3. The mixture was extracted with DCM (10 mL x 2), and the combined extracts were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product as a brown gum. The product was purified by preparative TLC (DCM / MeOH=10 / 1, SiO) to give K101-C1319 (78.70 mg, 140.52 μmol, 44.58% yield, 93.5% purity) as a colorless gum. The product was lyophilized to give a white solid.

[0380] MS (m / z): 546.2 [M + Na] +

[0381] 1 H NMR(400MHz,CD3OD)δ 7.55(s,1H),7.29-7.23(m,2H),7.21-7.13(m,3H),5.60(d,J=5.0 Hz,1H),4.00-3.88(m,2H),3.47(t,J=5.8 Hz,1H ),3.19-3.14(m,1H),3.10-3.03(m,1H),2.65(t,J=7.0 Hz,2H),2.57-2.48(m,1H),2.48-2.38(m,1H),2.17-1.99(m,2H),1.80-1.62(m,7H),1.51(dd,J=10.5,14.3 Hz,1H),1.15(s,3H),1.07(s,3H),0.90(d,J=6.3 Hz,4H).

[0382] Example 17: Synthesis scheme of K101-C1320. The synthesis scheme of compound K101-C1320 is shown below. [ka]

[0383] Preparation of compound K101-C1320-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) and C13-20 (26.09 mg, 152.34 μmol, 3.00 eq) in DCM (2.00 mL) was added EDC (58.41 mg, 304.68 μmol, 6.00 eq) and DMAP (37.22 mg, 304.68 μmol, 6.00 eq). The reaction solution was stirred at 25 °C for 16 h, resulting in a brown solution. TLC (PE / EtOAc = 2 / 1, SiO2) showed the reaction was complete. The reaction solution was combined with 5 mg of K101-C20Tr-B, diluted with DCM (5 mL), and washed with brine (2 mL). The extracted layer was dried over anhydrous NaSO, filtered, and then concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by preparative TLC (PE / EtOAc = 2 / 1) to give K101-C1320-A (27.30 mg, 72.26% yield) as a colorless gum.

[0384] Preparation of compound K101-C1320. To a solution of K101-C1320-A (25.00 mg, 33.60 μmol, 1.00 eq) in MeOH (1.00 mL) was added HClO (30.00 μL). The reaction solution was stirred at 25 °C for 0.5 h to obtain a clear solution. LC-MS showed the reaction was complete. The product was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 25%-55%, 10 min) to obtain K101-C1320 (9.50 mg, 18.46 μmol, 54.95% yield, 97.5% purity) as a white powder after lyophilization.

[0385] LC-MS(m / z):524.1[M+Na] +

[0386] 1H NMR(400MHz,METHANOL-d4)δ=9.04(s,1H),7.56-7.51(m,1H),5.58(d,J=4.3 Hz,1H),3.99-3.89(m,2H),3.19-3.13(m,3H),3.04(t,J=5.4 Hz,1H),2.72(dt,J=1.6,7.0 Hz,2H),2.56-2.47(m,1H),2.46-2.39(m,4H),2.13-1.98(m,2H),1.74(dd,J=1.3,3.0 Hz,3H),1.47(dd,J=10.4,14.2 Hz,1H),1.06(d,J=10.5 Hz,6H),0.88(d,J=6.3 Hz,3H),0.82(d,J=5.8 Hz,1H).

[0387] Example 18: Synthesis scheme of K101-C1321. The synthesis scheme of compound K101-C1321 is shown below. [ka]

[0388] Preparation of compound K101-C1321-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) and C13-21 (76.68 mg, 304.68 μmol, 6.00 eq) in DCM (1.00 mL) was added EDC (58.41 mg, 304.68 μmol, 6.00 eq) and DMAP (37.22 mg, 304.68 μmol, 6.00 eq). The reaction solution was stirred at 25 °C for 2 h to give a light brown solution. LC-MS showed improved conversion to the product. The reaction solution was combined with a second preparation of the compound, and the mixture was partitioned between water (2 mL) and DCM (2 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by preparative TLC (PE / EtOAc=3 / 2) to give K101-C1321-A (32.70 mg, 39.67 μmol, 78.11% yield) as a colorless gum.

[0389] Preparation of compound K101-C1321. To a solution of K101-C1321-A (32.70 mg, 39.67 μmol, 1.00 eq) in MeOH (1.00 mL), HClO (30.00 μL) was added at 25 °C. The reaction solution was stirred at 25 °C for 0.5 h to give a brown solution. LC-MS showed the reaction was complete. The reaction solution was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 50%-80%, 10 min) to give K101-C1321 (12.50 mg, 52.08% yield, 96.2% purity) as a white solid after lyophilization.

[0390] LC-MS(m / z):604.1[M+Na] +

[0391] 1 H NMR(400MHz,CD3OD)δ 7.69-7.65(m,2H),7.54-7.50(m,1H),7.48-7.41(m,3H),5.56-5.52(m,1H),3.95-3.87(m,2H),3.20-3.12(m,3H), 3.06-3.01(m,1H),2.94-2.89(m,2H),2.55-2.47(m,1H),2.45-2.38(m,1H),2.13-1.98(m,2H),1.73(dd,J=1.3,3.0 Hz,3H),1.60-1.52(m,1H),1.12(s,3H),1.04(s,3H),0.89-0.83(m,4H).

[0392] Example 19: Synthesis scheme of K101-C1322. The synthesis scheme of compound K101-C1322 is shown below. [ka]

[0393] Preparation of compound K101-C1322-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid (C13-22) (19.32 mg, 101.56 μmol, 2.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), HOBt (13.72 mg, 101.56 μmol, 2.00 eq), and EDC (19.47 mg, 101.56 μmol, 2.00 eq). The mixture was stirred at 20 °C for 12 hours to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 1 / 1) showed the reaction was complete. The mixture was quenched with HO (5 mL) and extracted with DCM (15 mL x 3). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 1 / 1) to give K101-C1322-A (30.00 mg, 39.32 μmol, 58.22% yield) as a white solid.

[0394] Preparation of compound K101-C1322. To a solution of K101-C1322-A (30.00 mg, 39.32 μmol, 1.00 eq) in MeOH (2.00 mL) was added HClO (83.00 mg, 826.11 μmol, 50.00 uL, 21.01 eq) at 0° C. The mixture was stirred at 0° C. for 0.5 hours to give a yellow solution. LC-MS showed that the reaction was complete. The product was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 22%-52%, 10 min) to give K101-C1322 (17.40 mg, 27.42 μmol, 69.73% yield, TFA salt) as a yellow solid.

[0395] LC-MS(m / z):543.1[M+Na] +

[0396] 1H NMR(400MHz,CD3OD)δ8.19-8.18(m,1H),8.06-8.04(m,1H),7.55(s,1H),7.24( s,1H),7.15-7.12(m,1H),5.55-5.54(m,1H),3.99-3.95(m,2H),3.16-3.10(m, 3H),3.01(s,1H),2.78-2.73(m,2H),2.50-2.46(m,2H),2.01-2.96(m,2H),1.4 2-1.41(m,1H),1.00(s,3H),0.91(s,3H),0.86-0.85(m,1H),0.63-0.62(m,3H).

[0397] Example 20: Synthesis scheme of K101-C1323. The synthesis scheme of compound K101-C1323 is shown below. [ka]

[0398] Preparation of compound K101-C1323-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) and C13-23 (23.49 mg, 152.34 μmol, 3.00 eq) in DCM (1.00 mL) was added EDC (58.41 mg, 304.68 μmol, 6.00 eq) and DMAP (37.22 mg, 304.68 μmol, 6.00 eq). The reaction solution was stirred at 25 °C for 2 hours to give a brown solution. TLC (PE / EtOAc = 1 / 1, SiO2) showed the reaction was complete. The reaction solution was combined with a second preparation of compound K101-C1323-A, diluted with DCM (2 mL), washed with water (1 mL), brine (1 mL), and dried over anhydrous Na2SO4. The mixture was filtered and then concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by preparative TLC (PE / EtOAc=1 / 1) to give 32.5 mg of K101-C1323-A as a colorless gum.

[0399] Preparation of compound K101-C1323. To a solution of K101-C1323-A (32.00 mg, 44.02 μmol, 1.00 eq) in MeOH (1.00 mL) was added HClO (30.00 μL) at 25 °C. The reaction solution was stirred at 25 °C for 0.5 h to obtain a clear solution. LC-MS showed the reaction was complete. The reaction solution was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 25% to 55%, 10 min) to obtain K101-C1323 (9.10 mg, 40.48% yield, 94.9% purity) as a white solid.

[0400] LC-MS(m / z):507.2[M+Na] +

[0401] 1 H NMR (400 MHz, CD3OD) ) δ 7.56-7.53(m,1H),7.46(s,1H),7.36(s,1H),5.61-5.57(m,1H),3.98-3.90(m,2H),3.84(s,3H),3.18-3.14(m,1H),3.07-3.0 1(m,1H),2.81-2.76(m,2H),2.63-2.57(m,2H),2.55-2.47(m,1H),2.46-2.39(m,1H),2.12-1.98(m,2H),1.74(dd,J=1.3,2.8 Hz,3H),1.47(dd,J=10.4,14.2 Hz,1H),1.08(s,3H),1.05(s,3H),0.89(d,J=6.3 Hz,3H),0.79(d,J=5.8 Hz,1H).

[0402] Example 21: Synthesis scheme of K101-C1324. The synthesis scheme of compound K101-C1324 is shown below. [ka]

[0403] Preparation of compound K101-C1324-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) and C13-24 (25.01 mg, 152.34 μmol, 3.00 eq) in DCM (1.00 mL) was added EDC (58.41 mg, 304.68 μmol, 6.00 eq) and DMAP (37.22 mg, 304.68 μmol, 6.00 eq). The reaction solution was stirred at 25 °C for 2 h to give a brown solution. TLC (PE / EtOAc = 2 / 1, SiO2) showed the reaction was complete. The reaction solution was diluted with DCM (2 mL), washed with water (1 mL), brine (1 mL), and dried over anhydrous Na2SO4. The mixture was filtered and then concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by silica gel column chromatography (eluted with PE / EtOAc=5 / 1) to give K101-C1324-A (37.20 mg, 99.41% yield) as a colorless gum.

[0404] Preparation of compound K101-C1324. To a solution of K101-C1324-A (37.20 mg, 50.48 μmol, 1.00 eq) in MeOH (1.00 mL), HClO (30.00 μL) was added, and the reaction solution was stirred at 25 °C for 1 h to obtain a clear solution. LC-MS showed the reaction was complete. The product was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 55%-85%, 10 min) to obtain K101-C1324 (7.80 mg, 30.40% yield, 97.3% purity) as a white solid after lyophilization.

[0405] LC-MS(m / z):517.2[M+Na] +

[0406] 1H NMR(400MHz,CD3OD)δ 7.55(s,1H),7.30-7.24(m,2H),7.21-7.14(m,3H),5.63-5.58(m,1H), 4.00-3.89(m,2H),3.19-3.15(m,1H),3.09-3.03(m,1H),2.65(t,J=7.7 Hz,2H),2.57-2.48(m,1H),2.47-2.39(m,1H),2.34(t,J=7.3 Hz,2H),2.15-2.07(m,1H),2.07-1.98(m,1H),1.97-1.88(m,2H),1.74(dd,J=1.3,2.8 Hz,3H),1.53(dd,J=10.5,14.3 Hz,1H),1.16(s,3H),1.07(s,3H),0.91(d,J=6.3 Hz,3H),0.85(d,J=5.5 Hz,1H).

[0407] Example 22: Synthesis of K101-C1325. The synthesis method of compound K101-C1325 is shown below.

change

[0408] Preparation of compound K101-C1325-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (5.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)-3-cyclobutyl-propanoic acid (C13-25) (24.71 mg, 101.56 μmol, 2.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), HOBT (13.72 mg, 101.56 μmol, 2.00 eq), and EDC (19.47 mg, 101.56 μmol, 2.00 eq). The mixture was stirred at 20 °C for 14 hours to give a yellow solution. LC-MS and TLC showed the reaction was complete. The reaction mixture was quenched with HO (15 mL) and extracted with DCM (15 mL x 5). The organic layer was dried over NaSO and concentrated to give a yellow solid. The product was purified by preparative TLC (eluted with petroleum ether:ethyl acetate = 7 / 2) to give K101-C1325-A (33.50 mg, 41.05 μmol, yield 69.09%) as a white solid.

[0409] Preparation of compound K101-C1325. To a solution of K101-C1325-A (33.50 mg, 41.05 μmol, 1.00 eq) in THF (2.00 mL) and DMF (20.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 329.02 eq) and EtSiH (4.77 mg, 41.05 μmol, 6.53 μL, 1.00 eq). The mixture was stirred at 20 °C for 5 hours to give a colorless solution, which was concentrated to give a yellow oil. The oil was dissolved in DCM (2 mL), followed by the addition of TFA (0.5 mL). The mixture was stirred at 20 °C for 1 hour to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated to give a yellow oil, which was then purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 20% to 50%, 10 min). The isolated product was lyophilized to give K101-C1325 (10.00 mg, 17.02 μmol, 41.46% yield, 94.5% purity, TFA) as a white solid.

[0410] LC-MS (m / z): 596.2 [M+Na] +

[0411] 1 H NMR(400MHz,MeOH)δ=7.54(s,1H),5.60(d,J=4.0 Hz,1H),3.99-3.83(m,3H),3.14(s,1H),3.07-2.98(m,1H),2.57-2.33(m,3H),2.26-1.84(m,8H),1.79-1.65(s,5H),1.58(dd,J=10.4,14.8 Hz,1H),1.17(s,3H),1.07(s,3H),0.99-0.95(m,1H),0.97(d,J=6.0 Hz,1H),0.92(d,J=6.6 Hz,3H)

[0412] Example 23: Synthesis of K101-C1326. The synthesis method of compound K101-C1326 is shown below.

change

[0413] Preparation of compound K101-C1326-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (5.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)-4-methylsulfonylbutanoic acid (C13-26) (30.00 mg, 106.64 μmol, 2.10 eq), DMAP (30.00 mg, 245.78 μmol, 4.84 eq), EDC (19.96 mg, 104.10 μmol, 2.05 eq), and HOBt (14.00 mg, 103.59 μmol, 2.04 eq). The mixture was stirred at 20 °C for 19 hours to give a colorless solution. LC-MS and TLC showed the reaction was complete. The reaction mixture was quenched with HO (15 mL) and extracted with DCM (15 mL x 5). The organic layer was dried over NaSO and concentrated to give a yellow oil. The product was purified by preparative TLC (eluted with petroleum ether:ethyl acetate = 3 / 2) to give K101-C1326-A (23.00 mg, 26.93 μmol, yield 53.03%, crude product) as a colorless solid.

[0414] Preparation of compound K101-C1326. To a solution of K101-C1326-A (25.00 mg, 29.27 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (3.34 mg, 29.27 μmol, 2.17 μL, 1.00 eq) and EtSiH (3.40 mg, 29.27 μmol, 4.66 μL, 1.00 eq). The mixture was stirred at 20 °C for 3 h to give a colorless solution. LC-MS showed that some K101-C1326-A remained. Therefore, the reaction mixture was concentrated to give a yellow oil, which was then dissolved in DCM (2 mL), followed by the addition of TFA (2 mL). The mixture was stirred at 20 °C for 2 h to give a colorless solution. LC-MS showed that the reaction was complete. The reaction mixture was concentrated to give a yellow oil, which was then purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 10% to 40%, 10 min). The separated layers were lyophilized to give K101-C1326 (4.20 mg, 6.04 μmol, 20.64% yield, 90% purity, TFA) as a yellow solid.

[0415] LC-MS(m / z):534.1[M+Na] +

[0416] 1 H NMR(400MHz,MeOD)δ=7.58(s,1H),5.66(s,1H),4.62(s,1H),4.16(s,1H),3.97( s,2H),3.23-3.11(m,1H),3.06(s,4H),2.61-2.35(m,3H),2.27(dd,J=7.2,14.7 Hz,2H),2.06(s,1H),1.77(d,J=1.5 Hz,3H),1.62(dd,J=10.8,14.8 Hz,1H),1.40-1.28(m,2H),1.21(s,3H),1.12(s,3H),1.05(d,J=6.0 Hz,1H),0.96(d,J=6.5 Hz,3H).

[0417] Example 24: Synthesis scheme of K101-C1327. The synthesis scheme of compound K101-C1327 is shown below. [ka]

[0418] Preparation of compound K101-C1327-A. To a solution of K101-C20Tr-B (200.00 mg, 338.55 μmol, 1.00 eq) in DCM (2.00 mL) was added C13-27 (367.46 mg, 1.35 mmol, 4.00 eq), DMAP (330.89 mg, 2.71 mmol, 8.00 eq), HOBt (91.49 mg, 677.11 μmol, 2.00 eq), and EDC (259.60 mg, 1.35 mmol, 4.00 eq). The mixture was stirred at 20 °C for 12 h to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) indicated the reaction was complete. The mixture was quenched with HO (15 mL) and extracted with DCM (30 mL x 3). The organic layer was dried over NaSO and concentrated to give the crude product, which was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1327-A (180.00 mg, 213.25 μmol, yield 62.99%) as a white solid.

[0419] Preparation of compound K101-C1327. To a solution of K101-C1327-A (180.00 mg, 213.25 μmol, 1.00 eq) in THF (3.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 126.67 eq) and EtSiH (49.59 mg, 426.50 μmol, 67.93 μL, 2.00 eq). The mixture was stirred at 20 °C for 24 hours to give a yellow solution. LC-MS showed that the reaction was complete. The reaction mixture was concentrated with N, and the resulting residue was dissolved in MeOH (20 mL) and then stirred at 20 °C for 70 hours. LC-MS showed that the reaction was complete. The mixture was concentrated to give the crude product. The crude product was triturated with PE (30 mL x 3) to give the desired product. The product was dissolved in saturated NaHCO (20 mL) and extracted with DCM (30 mL x 3). The organic layer was dried over NaSO and concentrated to give the free desired product, which was then lyophilized to give K101-C1327 (70.00 mg, 136.05 μmol, 63.80% yield, 97.5% purity) as a white solid.

[0420] LC-MS(m / z):524.2[M+Na] +

[0421] 1 H NMR(400MHz,CD3OD)δ 7.57(s,1H),5.64-5.63(m,1H),4.00-3.93(m,2H),3.53-3.49(m,1H),3.19(s,1H),3.09(s,1H),2.57-2.47(m,2H),2.19-2.17(m,2H),1. 80-1.77(m,8H),1.73-1.60(m,2H),1.48-1.47(m,2H),1.29-1.26(m, 3H),1.21(s,3H),1.10(s,3H),1.02-1.01(m,2H),0.95-0.92(m,3H).

[0422] Second procedure for the preparation of compound K101-C1327-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-propanoic acid (C13-27) (27.56 mg, 101.56 μmol, 2.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), and EDC (19.47 mg, 101.56 μmol, 2.00 eq). The mixture was stirred at 20 °C for 12 h to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed the reaction was complete. The mixture was quenched with HO (10 mL) and extracted with DCM (15 mL x 3). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1327-A (24.00 mg, 28.43 μmol, 47.97% yield) as a white solid.

[0423] Second procedure for the preparation of compound K101-C1327. To a solution of K101-C1327-A (24.00 mg, 28.43 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (308.00 mg, 2.70 mmol, 200.00 uL, 95.02 eq) and EtSiH (3.97 mg, 34.12 μmol, 5.43 uL, 1.20 eq). The mixture was stirred at 20 °C for 4 hours to give a yellow solution. LC-MS showed that the reaction was complete. The reaction mixture was concentrated with N, and the resulting residue was dissolved in MeOH (20 mL). The mixture was stirred at 20 °C for 12 hours. LC-MS showed that the reaction was complete. The mixture was concentrated to give the crude product. The product was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25%-55%, 10 min) to give K101-C1327 (5.10 mg, 7.95 μmol, yield 27.97%, purity 95.99%, TFA) as a white solid.

[0424] LC-MS(m / z):524.2[M+Na] +

[0425] 1 H NMR(400MHz,CD3OD)δ 7.57(s,1H),5.64(s,1H),4.10-4.07(m,1H),4.00-3.93(s,2H),3.18(s,1H),3.08(s,1H),2.53-2.45(m,1H),2.45-2.41(m ,1H),2.29-2.27(m,1H),2.05(m,1H),1.84-1.29(m,16H),1.19(s,3H),1.11(s,3H),1.02-1.01(m,2H),0.96-0.94(m,3H).

[0426] Example 25: Synthesis scheme of K101-C1328. The synthesis scheme of compound K101-C1328 is shown below. [ka]

[0427] Preparation of compound K101-C1328-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (C13-28) (24.92 mg, 101.56 μmol, 2.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), HOBt (13.72 mg, 101.56 μmol, 2.00 eq), and EDC (19.47 mg, 101.56 μmol, 2.00 eq). The mixture was stirred at 20 °C for 12 hours to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed the reaction was complete. The mixture was quenched with HO (10 mL) and extracted with DCM (15 mL × 3). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1328-A (28.00 mg, 34.23 μmol, 67.40% yield) as a white solid.

[0428] Preparation of compound K101-C1328. To a solution of K101-C1328-A (28.00 mg, 34.23 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL, 197.29 eq) and EtSiH (7.96 mg, 68.46 μmol, 10.90 μL, 2.00 eq). The mixture was stirred at 20 °C for 12 hours to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated with N2, and the resulting product was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 30%-70%, 10 min) to give K101-C1328 (9.50 mg, 15.88 μmol, yield 46.38%, purity 98.54%, TFA) as a white solid.

[0429] LC-MS(m / z):498.2[M+Na] +

[0430] 1 H NMR(400MHz,CD3OD)δ 7.57(s,1H),5.64-5.63(m,1H),4.07-4.00(m,1H),3.97-3.93(m,2H), 3.18(s,1H),3.09(s,1H),2.52-2.45(m,1H),2.45-2.38(m,1H),2.27- 2.23(m,1H),2.05-2.00(m,2H),1.77(s,3H),1.64-1.61(m,2H),1.21( s,3H),1.12(s,3H),1.05(s,9H),1.03-1.01(m,1H),0.96-0.94(m,3H).

[0431] Example 26: Synthesis scheme of K101-C1329. The synthesis scheme of compound K101-C1329 is shown below. [ka]

[0432] Preparation of compound K101-C1329-A. K101-C20Tr-B (20.00 mg, 33.86 μmol, 1.00 eq) and C13-29 (14.80 mg, 50.79 To a solution of K101-C1329-A (1.50 eq) in DCM (2.00 mL) were added EDC (38.95 mg, 203.16 μmol, 6.00 eq) and DMAP (24.82 mg, 203.16 μmol, 6.00 eq). The reaction solution was stirred at 25 °C for 16 h to give a brown solution. LC-MS showed the reaction was complete. The reaction solution was diluted with DCM (10 mL) and then washed with water (3 mL), 0.5 M HCl (2 mL), brine (2 mL), and dried over anhydrous Na2SO4. The product was filtered and then concentrated under reduced pressure to give crude K101-C1329-A. The crude K101-C1329-A was purified by preparative TLC (PE / EtOAc = 3 / 1, SiO2) to give 15.7 mg of K101-C1329-A as a colorless gum.

[0433] Preparation of Compound K101-C1329. To a solution of K101-C1329-A (15.70 mg, 18.17 μmol, 1.00 eq) in dioxane (400.00 μL) was added HCl / dioxane (4 M, 200.46 μL, 44.13 eq). The reaction mixture was stirred at 25°C for 2 hours to give a light brown solution. LC-MS indicated that the reaction was not complete, so the reaction solution was stirred at 25°C for an additional hour, then for an additional 16 hours. LC-MS indicated that the reaction was complete. By-products were also detected by LC-MS analysis. The reaction solution was diluted with CHCN (1 mL), and the solution was adjusted to basic conditions with KCO (55 mg) in water (0.5 mL). The product was purified by preparative HPLC (column: Phenomenex Purification by Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 30%-60%, 10 min) afforded both K101-C1329 (2.00 mg, 3.62 μmol, 19.92% yield, 94.4% purity) and K101-C1329-Cl (2.70 mg, 4.47 μmol, 24.60% yield, 92.4% purity) as white solids after lyophilization.

[0434] K101-C1329 MS(m / z):544.1[M+Na] +

[0435] K101-C1329 1 H NMR(400MHz,CD3OD)δ 7.53(s,1H),7.26-7.20(m,2H),7.20-7.14(m,2H),5.63-5.57(m,1H),4.22(d,J=6.0 Hz,1H),3.99-3.89(m,2H),3.23-3.13(m,3H),3.10-2.97(m,4H),2.57- 2.47(m,1H),2.45-2.36(m,1H),2.05-1.93(m,2H),1.75(dd,J=1.3,2.8 Hz,3H),1.34-1.23(m,1H),1.18(s,3H),1.06(s,3H),0.95(d,J=6.0 Hz,1H),0.86(d,J=6.0 Hz,3H).

[0436] K101-C1329-Cl LC-MS(m / z):562.1[M+Na] +

[0437] K101-C1329-Cl 1 H NMR(400MHz,CD3OD)δ 7.52(s,1H),7.26-7.20(m,2H),7.19-7.14(m,2H),5.81-5.76(m,1H),4.22(d,J=5.8 Hz,1H),4.17-4.02(m,2H),3.22-3.11(m,3H),3.08-2.97(m,4H),2.68-2.41(m,2H),2.04-1.93(m,2H),1. 78-1.73(m,3H),1.30-1.22(m,1H),1.22-1.18(m,3H),1.10-1.04(m,3H),0.98-0.93(m,1H),0.85(d,J=6.3 Hz,3H).

[0438] Example 27: Synthesis of K101-C1330. The synthesis method of compound K101-C1330 is shown below.

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[0439] Preparation of compound K101-C1330-A. To a solution of K101-C20Tr-B (20.00 mg, 33.86 μmol, 1.00 eq) and C13-30 (46.57 mg, 203.16 μmol, 6.00 eq) in DCM (2.00 mL) was added EDC (38.94 mg, 203.16 μmol, 6.00 eq) and DMAP (24.82 mg, 203.16 μmol, 6.00 eq). The reaction solution was stirred at 25 °C for 16 hours to give a brown solution. LC-MS showed the reaction was complete. The reaction solution was diluted with DCM (10 mL) and then washed with water (3 mL), 0.5 M HCl (2 mL), brine (2 mL), and dried over anhydrous Na2SO4. The product was filtered and concentrated under reduced pressure to give the crude product. The product was purified by preparative TLC (PE / EtOAc=3 / 1, SiO 2 ) to give 16.2 mg of K101-C1330-A as a colorless gum.

[0440] Preparation of Compound K101-C1330. To a solution of K101-C1330-A (10.00 mg, 12.47 μmol, 1.00 eq) in dioxane (400.00 uL) was added HCl / dioxane (4 M, 200.17 uL, 64.21 eq). The reaction mixture was stirred at 25 °C for 2 h, resulting in a light brown solution. LC-MS indicated the reaction was not complete, so 0.2 mL of HCl / dioxane (4 M) was added, and the reaction solution was stirred at 25 °C for an additional 1 h. LC-MS indicated the reaction was nearly complete. The reaction solution was combined with another preparation of K101-C1330-A and concentrated under reduced pressure. The residue was diluted with CH CN (1 mL) and water (1 mL), and the solution was adjusted to pH 8 by adding solid KCO (5 mg). The product was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25%-55%, 10 min) to give K101-C1330 (4.70 mg, yield 65.05%, purity 99.0%, TFA salt) as a white powder after lyophilization.

[0441] MS (m / z): 482.1 [M+Na] +

[0442] 1 H NMR(400MHz,CD3OD)δ 7.55(s,1H),5.64-5.59(m,1H),4.12(dd,J=5.3,7.8 Hz,1H),4.00-3.90(m,2H),3.19-3.14(m,1H),3.09-3.03(m,1H),2.58-2.48(m,1H),2.45-2.37(m,1H),2.25(dd,J=6.8,14.6 Hz,1H),2.12-2.01(m,1H),1.95-1.85(m,1H),1.80-1.70(m,4H),1.61(dd,J=10.4,14.7 Hz,1H),1.18(s,3H),1.09(s,3H),1.02-0.97(m,1H),0.93(d,J=6.8 Hz,3H),0.8-0.76(m,1H),0.66-0.59(m,2H),0.27-0.17(m,2H).

[0443] Example 28: Synthesis of K101-C1331. The synthesis method of compound K101-C1331 is shown below.

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[0444] Preparation of compound K101-C1331-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added (E,2S)-2-(tert-butoxycarbonylamino)-5-phenyl-pent-4-enoic acid (C13-31) (29.59 mg, 101.56 μmol, 2.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), HOBt (13.72 mg, 101.56 μmol, 2.00 eq), and EDC (19.47 mg, 101.56 μmol, 2.00 eq). The mixture was stirred at 20 °C for 12 hours to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed the reaction was complete. The mixture was combined with the second preparation of K101-C1331-A, and the mixture was quenched with HO (10 mL) and then extracted with DCM (15 mL × 3). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1331-A (32.00 mg, 37.03 μmol, 62.49% yield) as a white solid.

[0445] Preparation of compound K101-C1331. To a solution of K101-C1331-A (32.00 mg, 37.03 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL, 182.37 eq) and EtSiH (8.61 mg, 74.06 μmol, 11.79 μL, 2.00 eq). The mixture was stirred at 20 °C for 12 hours to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated with N2, and the product was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 27%-57%, 10 min) to give K101-C1331 (10.00 mg, 15.73 μmol, 42.48% yield, 100% purity, TFA salt) as a white solid.

[0446] LC-MS(m / z):524.2[M+Na] +

[0447] 1 H NMR(400MHz,CD3OD)δ 7.57(s,1H),5.64(s,1H),4.10-4.07(m,1H),4.00-3.93(s,2H),3.18(s,1H),3.08(s,1H),2.53-2.45(m,1H),2.45-2.41(m ,1H),2.29-2.27(m,1H),2.05(m,1H),1.84-1.29(m,16H),1.19(s,3H),1.11(s,3H),1.02-1.01(m,2H),0.96-0.94(m,3H).

[0448] Example 29: Synthesis scheme of K101-C1332. The synthesis scheme of compound K101-C1332 is shown below. [ka]

[0449] Preparation of compound K101-C1332-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (5.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)-3-cyclopentyl-propanoic acid (C13-32) (26.14 mg, 101.56 μmol, 2.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), and EDC (19.47 mg, 101.56 μmol, 2.00 eq). The mixture was stirred at 20 °C for 5 h, resulting in a yellow solution. LC-MS showed that the reaction was incomplete. Additional EDC (10 mg) was added, and the mixture was stirred at 20 °C for 14 h. LC-MS showed that some of K101-C20Tr-B still remained. An additional amount of EDC (11 mg) was added, and the mixture was stirred at 20 °C for another 5 h. LC-MS and TLC showed that the reaction was complete. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM (15 mL x 5). The organic layer was dried over Na2SO4 and concentrated to give a yellow solid. The product was purified by preparative TLC (eluted with petroleum ether:ethyl acetate = 7 / 2) to give K101-C1332-A (23.00 mg, 27.71 μmol, 54.57% yield) as a colorless solid.

[0450] Preparation of compound K101-C1332. To a solution of K101-C1332-A (23.00 mg, 27.71 μmol, 1.00 eq) in THF (2.00 mL) was added EtSiH (3.22 mg, 27.71 μmol, 4.41 μL, 1.00 eq) and TFA (770.00 mg, 6.75 mmol, 500.00 μL, 243.71 eq). The mixture was stirred at 20° C. for 1.5 hours to give a colorless solution. The reaction mixture was concentrated to give a yellow oil, which was dissolved in DCM (2 mL), followed by the addition of TFA (0.5 mL). The mixture was stirred at 20° C. for 1 hour and concentrated to give a yellow oil. LC-MS showed the reaction was complete. The reaction mixture was concentrated, and the product was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 30% to 60%, 10 min). The separated layers were lyophilized to give K101-C1332 (8.00 mg, 13.03 μmol, 47.03% yield, 98% purity, TFA salt) as a white solid.

[0451] LC-MS(m / z):510.2[M+Na] +

[0452] 1 H NMR(400MHz,CDCl3)δ=7.57(s,1H),5.64(d,J=4.5 Hz,1H),4.02-3.99(m,1H),3.97(s,2H),3.18(s,1H),3.15-3.02(m,1H),2.60-2.36(m,2H),2.26(dd,J=6.9,14.7 Hz,1H),2.05(dd,J=6.9,13.2 Hz,1H),2.02-1.97(m,1H),1.94-1.83(m,2H),1.83(t,J=7.8 Hz,1H),1.77(d,J=1.5 Hz,4H),1.74-1.54(m,5H),1.35-1.14(m,6H), 1.11(s,3H),1.02(d,J=6.0 Hz,1H),0.95(d,J=6.5 Hz,3H)

[0453] Example 30: Synthesis scheme of K101-C1333. The synthesis scheme of compound K101-C1333 is shown below. [ka]

[0454] Preparation of compound K101-C1333-A: To a solution of K101-C20Tr-B (22.00 mg, 37.24 μmol, 1.17 eq) and DHA (10.50 mg, 31.96 μmol, 1.00 eq) in DCM (500.00 μL) was added EDCI (36.77 mg, 191.79 μmol, 6.00 eq) and DMAP (23.43 mg, 191.79 μmol, 6.00 eq). The reaction solution was stirred at 20 °C for 16 hours to give a brown solution. LCMS showed the desired MS values. The reaction mixture was combined with the reaction mixture of ES5329-184 (5 mg of K101-C20Tr-B was used in this run) and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc=5 / 1) to give K101-C1333-A (7.00 mg, 7.77 μmol, yield 24.30%) as a colorless oil.

[0455] 1 H NMR(400MHz,CDCl3)δ 7.58(s,1H),7.46-7.38(m,6H),7.31-7.26(m,6H),7.24-7.18(m,3H),5.60(d,J=3.5 Hz,1H),5.42-5.27(m,12H),3.51(s,2H),3.31-3.25(m,1H),2.96-2.90(m,1H),2.90-2. 67(m,10H),2.57-2.47(m,1H),2.44-2.30(m,5H),2.13-1.91(m,7H),1.77(dd,J=1.1,2.9 Hz,3H),1.59-1.51(m,1H),1.19(s,3H),1.07(s,3H),0.97(t,J=7.5 Hz,3H),0.87(d,J=6.3 Hz,3H),0.79(d,J=5.3 Hz,1H).

[0456] Preparation of compound K101-C1333: To a solution of K101-C1333-A (6.00 mg, 6.66 μmol, 1.00 eq) in MeOH (200.00 μL) was added HClO (9.96 mg, 99.17 μmol, 6.00 μL, 14.89 eq) and EtSiH (774.15 μg, 6.66 μmol, 1.06 μL, 1.00 eq). The reaction mixture was then stirred at 0° C. for 1.5 hours to give a white suspension. TLC (DCM / MeOH=20 / 1, SiO) showed no starting material remaining, and a new spot was observed. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc=1 / 1) to give K101-C1333 (3.65 mg, 79.85% yield, 96.0% purity) as a white solid after lyophilization.

[0457] MS (m / z): 681.3 [M + Na] +

[0458] 1 H NMR(400MHz,CD3OD)δ 7.56-7.53(m,1H),5.62-5.58(m,1H),5.51-5.20(m,12H),3.99-3.88(m,2H),3.20-3.14(m,1H),3.09-3.03(m,1H), 2.92-2.80(m,10H),2.56-2.48(m,1H),2.47-2.38(m,5H),2.15-2.06(m,3H),2.06-1.99(m,1H),1.74(dd,J=1.3,2.9 Hz,3H),1.55(dd,J=10.7,14.4 Hz,1H),1.18(s,3H),1.07(s,3H),0.97(t,J=7.5 Hz,3H),0.90(d,J=6.4 Hz,4H),0.86(d,J=5.5 Hz,1H).

[0459] Example 31: Synthesis scheme of K101-C1334. The synthesis scheme of compound K101-C1334 is shown below. [ka]

[0460] Preparation of compound K101-C1334-A: To a solution of K101-C20Tr-B (35.00 mg, 59.25 μmol, 1.00 eq) and C13-34 (136.45 mg, 592.47 μmol, 10.00 eq) in DCM (1.00 mL), EDCI (34.07 mg, 177.74 μmol, 3.00 eq) and DMAP (21.71 mg, 177.74 μmol, 3.00 eq) were added, and the mixture was stirred at 20 °C for 14 h to obtain a colorless solution. The reaction was detected to be complete by LCMS (ES6477-17-P1B). The reaction solution was diluted with HO (10 mL) and extracted with DCM:MeOH = 10:1 (10 mL * 5). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (SiO, PE:EA=2:1) ​​to give K101-C1334-A (26.40 mg, 32.88 μmol, 55.49% yield) as a white solid.

[0461] K101-C1334-A 1 H NMR(400MHz,CDCl3)δ 7.59(s,1H),7.44-7.39(m,6H),7.31-7.27(m,5H),7.24-7.18(m,3H),5.61(s,1H),5.30 (s,1H),3.50(s,2H),3.27(s,1H),2.97-2.86(m,3H),2.58-2.47(m,1H),2.38(d,J=18.8 Hz,3H),2.28(t,J=7.4 Hz,4H),2.08-1.90(m,3H),1.76(s,3H),1.60-1.49(m,3H),1.25(s,16H),1.20-1.16(m,1H),1.18(s,3H),1.06(s,3H),0.92-0.75(m,5H).

[0462] Preparation of compound K101-C1334: To a solution of K101-C1334-A (26.00 mg, 32.38 μmol, 1.00 eq) in THF (3.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL, 208.56 eq). The solution was then stirred at 0 °C for 18 hours to give a colorless solution. Completion of the reaction was detected by LCMS (ES6477-18-P1B). The reaction was concentrated under atmospheric pressure to give a yellow oil. The residue was purified by preparative HPLC (column: Phenomenex Gemini 150*25 mm*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 50%-80%, 10 min). The separated layers were lyophilized to give K101-C1334 (3.00 mg, 5.35 μmol, 16.52% yield, 97.28% purity, free) as a white solid.

[0463] K101-C1334:LC-MS(m / z):583.1[M+Na] +

[0464] 1 H NMR(400MHz,MeOD)δ 7.56(s,1H),5.63-5.58(m,1H),3.99-3.89(m,2H),3.20-3.15(m,1H) ,3.09-3.04(m,1H),2.56-2.49(m,1H),2.47-2.40(m,1H),2.37-2.26 (m,4H),2.22-2.10(m,1H),2.10-1.99(m,2H),1.77-1.73(m,3H),1.6 6-1.51(m,5H),1.32(s,12H),1.18(s,3H),1.07(s,3H),0.91(d,J=6.3 Hz,3H), 0.86(d,J=5.5 Hz,1H).

[0465] Example 32: Synthesis scheme of K101-C1335. The synthesis scheme of compound K101-C1335 is shown below. [ka]

[0466] Preparation of compound K101-C1335-A: To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added tridecanedioic acid (62.04 mg, 253.90 μmol, 5.00 eq), DMAP (37.22 mg, 304.68 μmol, 6.00 eq), and EDCI (58.41 mg, 304.68 μmol, 6.00 eq). The mixture was stirred at 20 °C for 14 h to give a colorless solution. The mixture was stirred at 20 °C for 5 h to give a colorless solution. LCMS and TLC showed the reaction was complete. The reaction mixture was quenched with HO (15 mL) and extracted with DCM (15 mL * 5). The organic layer was dried over NaSO and concentrated to give a yellow solid. The yellow solid was purified by preparative TLC (eluted with petroleum ether:ethyl acetate=3 / 1) to give K101-C1335-A (24.00 mg, 29.37 μmol, yield 57.84%) as a white solid.

[0467] 1 H NMR(400MHz,CDCl3)δ=7.65-7.55(s,1H),7.45-7.35(m,6H),7.32-7.27(m,6H),7.25-7.19 (m,3H),5.65-5.55(m,1H),3.55-3.45(m,2H),3.30-3.25(m,1H),3.00-2.90(m,1H),2.59-2.22(m,6H),2.2 0(s,3H),2.13-1.90(m,4H),1.80-1.72(m,3H),1.45-1.20(m,14H),1.19(s,3H),1.07(s,3H),0.88(d,J=6.3 Hz,3H),0.79(d,J=5.3 Hz,1H).

[0468] Preparation of compound K101-C1335: To a solution of K101-C1335-A (24.00 mg, 29.37 μmol, 1.00 eq) in THF (10.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 uL, 229.94 eq). The mixture was stirred at 0° C. for 14 hours to give a yellow solution. LCMS showed that K101-C1335-A remained, and then TFA (0.1 mL) was added. The mixture was stirred at 0° C. for 14 hours to give a colorless solution. LCMS showed that the reaction was complete. The reaction mixture was concentrated to give a yellow oil. The yellow oil was purified by preparative HPLC (column: Phenomenex Gemini 150*25mm*10um; mobile phase: [water (0.1% TFA)-ACN]; B%: 70%-70%, 10 min). The separated layers were lyophilized to give K101-C1335 (5.40 mg, 9.15 μmol, 31.16% yield, 97.4% purity, free) as a white solid.

[0469] LC-MS(m / z):597.3[M+Na] +

[0470] 1 H NMR(400MHz,MeOD)δ=7.60-7.50(m,1H),5.62(m,1H),4.03-3.84(m,2H),3.25-3.14(m,1H),3.12-3.01(m,1H),2.61-2.41(m,2H),2.4 1-2.23(m,4H),2.19-1.99(m,2H),1.83-1.71(m,3H),1.71-1.48(m,5H),1.45-1.35(m,14H),1.19(s,3H),1.09(s,3H),0.93(d,J=6.3 Hz,3H),0.87(d,J=5.8Hz,1H)

[0471] Example 33: Synthesis scheme of K101-C1336. The synthesis scheme of compound K101-C1336 is shown below. [ka]

[0472] Preparation of compound K101-C1336-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (5.00 mL) was added (2R)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid (C13-36) (26.95 mg, 101.56 μmol, 2.00 eq), DMAP (30.00 mg, 245.78 μmol, 4.84 eq) and EDC (19.96 mg, 104.1 0 μmol, 2.05 eq) was added. The mixture was stirred at 20 °C for 19 h to give a colorless solution. LC-MS and TLC showed the reaction was complete. The reaction mixture was quenched with HO (15 mL) and extracted with DCM (15 mL × 5). The organic layer was dried over NaSO and concentrated to give a yellow solid. The product was purified by preparative TLC (eluted with petroleum ether:ethyl acetate = 3 / 1) to give K101-C1336-A (16.00 mg, 19.09 μmol, 37.60% yield) as a colorless solid.

[0473] Preparation of compound K101-C1336. To a solution of K101-C1336-A (16.00 mg, 19.09 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL, 353.76 eq) and EtSiH (2.22 mg, 19.09 μmol, 3.04 μL, 1.00 eq). The mixture was stirred at 20 °C for 5 h to give a colorless solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated, and the product was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 15% to 45%, 10 min). The separated layers were lyophilized to give K101-C1336 (6.00 mg, 9.84 μmol, 51.55% yield, 100% purity, TFA salt) as a white solid.

[0474] LC-MS(m / z):518.2[M+Na] +

[0475] 1H NMR(400MHz,MeOD)δ=7.59(s,1H),7.48-7.29(m,5H),5.63(s,1H),4.37(dd,J=5.9,8.2 Hz,1H),4.04-3.89(m,2H),3.42-3.37(m,1H),3.25-3.00(m,3H),2.61-2.35(m,2H),2.23(dd,J=7.0,15.1 Hz,1H),2.05(s,1H),1.78(d,J=1.5 Hz,3H),1.64(dd,J=10.4,14.7 Hz,2H),1.08(d,J=7.8 Hz,6H),1.01-0.90(m,4H)

[0476] Example 34: Synthesis scheme of K101-C1337. The synthesis scheme of compound K101-C1337 is shown below. [ka]

[0477] Preparation of Compound K101-C1337-A: To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added (2R)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-propanoic acid (C13-37) (27.56 mg, 101.56 μmol, 2.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), HOBt (13.72 mg, 101.56 μmol, 2.00 eq), and EDC (19.47 mg, 101.56 μmol). , 2.00 eq) was added. The mixture was stirred at 20 °C for 12 h to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed the reaction was complete. The mixture was combined with the second preparation of K101-C1337-A, and the mixture was quenched with HO (10 mL) and then extracted with DCM (20 mL × 3). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1337-A (18.00 mg, 21.32 μmol, 41.99% yield) as a white solid.

[0478] Preparation of compound K101-C1337. To a solution of K101-C1337-A (18.00 mg, 21.32 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL, 316.75 eq) and EtSiH (7.44 mg, 63.96 μmol, 10.19 μL, 3.00 eq). The mixture was stirred at 20 °C for 2 hours to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated with N2, and the product was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25%-55%, 10 min) to give K101-C1337 (5.20 mg, 10.37 μmol, 48.62% yield, 100% purity) as a white solid.

[0479] LC-MS(m / z):524.3[M+Na] +

[0480] 1 H NMR(400MHz,CD3OD)δ 7.58(s,1H),5.64-5.63(s,1H),4.12-4.09(m,1H),4.00-3.94(m,2H),3.18(s,1H),3.08(s,1H),2.53-2.45(m,1H),2.40-2.32(m ,1H),2.26-2.24(m,1H),2.05-2.03(m,1H),1.84-1.64(m,12H),1.33-1.31(m,3H),1.20(s,3H),1.11(s,3H),1.01-0.95(m,6H).

[0481] Example 35: Synthesis scheme of K101-C1338. The synthesis scheme of compound K101-C1338 is shown below. [ka]

[0482] Preparation of compound K101-C1338-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)-4-methylsulfanyl-butanoic acid (C13-38) (25.32 mg, 101.56 μmol, 2.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), HOBt (13.72 mg, 101.56 μmol, 2.00 eq), and EDC (19.47 mg, 101.56 μmol, 2.00 eq). The mixture was stirred at 20 °C for 12 hours to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed the reaction was complete. The mixture was combined with the second preparation of K101-C1338-A, and the mixture was quenched with HO (10 mL) and extracted with DCM (15 mL × 3). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1338-A (36.00 mg, 43.79 μmol, 64.84% yield) as a white solid.

[0483] Preparation of compound K101-C1338. To a solution of K101-C1338-A (36.00 mg, 43.79 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 308.44 eq). The mixture was stirred at 20 °C for 12 hours to give a yellow solution. LC-MS showed that the reaction was complete. The reaction mixture was concentrated with N2, and the product was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 20%-50%, 10 min) to give K101-C1338 (13.20 mg, 20.95 μmol, 47.83% yield, 94.2% purity, TFA salt) as a white solid.

[0484] LC-MS(m / z):502.1[M+Na] +

[0485] 1 H NMR(400MHz,CD3OD)δ 7.57(s,1H),5.65-5.64(m,1H),4.26-4.23(m,1H),4.00-3.94(m,2H),3.18(s,1H),3.08(s,1H),2.72-2.69(m,2H),2.53-2.45(m,1H), 2.45-2.41(m,1H),2.30-2.24(m,2H),2.15-2.11(m,5H),1.77(s,3H),1.76-1.75(m,1H),1.20(s,3H),1.03(s,3H),0.96-0.94(m,4H).

[0486] Example 36: Synthesis scheme of K101-C1339. The synthesis scheme of compound K101-C1339 is shown below. [ka]

[0487] Preparation of compound K101-C1339-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added (2R)-2-(tert-butoxycarbonylamino)-3-methylsulfanyl-propanoic acid (C13-39) (23.90 mg, 101.56 μmol, 2.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), HOBt (13.72 mg, 101.56 μmol, 2.00 eq), and EDC (19.47 mg, 101.56 μmol, 2.00 eq). The mixture was stirred at 20° C. for 12 hours to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed the reaction was complete. The mixture was combined with the second preparation, quenched with HO (10 mL), and then extracted with DCM (15 mL). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1339-A (35.00 mg, 43.32 μmol, 85.30% yield) as a white solid.

[0488] Preparation of compound K101-C1339. To a solution of K101-C1339-A (35.00 mg, 43.32 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (4.94 mg, 43.32 μmol, 3.21 uL, 1.00 eq). The mixture was stirred at 20° C. for 3 hours to give a yellow solution. LC-MS showed that the reaction was complete. The reaction mixture was concentrated with N2, and the product was purified by preparative HPLC (column: Phenomenex Purification by Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 18%-48%, 10 min) gave K101-C1339 (4.40 mg, 7.11 μmol, 16.41% yield, 93.63% purity, TFA salt) as a white solid.

[0489] LC-MS(m / z):488.1[M+Na] +

[0490] 1 H NMR(400MHz,CD3OD)δ 7.57(s,1H),5.65-5.64(m,1H),4.33-4.30(m,1H),4.00-3.97(m,2H),3.19-3.14(m 2H),3.07(s,1H),3.00-2.97(m,1H),2.53-2.45(m,1H),2.40-2.32(m,1H),2.25-2.23(m,4H),2 .10-2.05(m,1H),1.77(s,3H),1.20(s,3H),1.11(s,3H),1.05-1.03(m,1H),0.96-0.94(m,3H).

[0491] Example 37: Synthesis scheme of K101-C1340. The synthesis scheme of compound K101-C1340 is shown below. [ka]

[0492] Preparation of compound K101-C1340-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) and C13-40 in DCM (3.00 mL) was added EDC (19.47 mg, 101.56 μmol, 2.00 eq) and DMAP (37.22 mg, 304.68 μmol, 6.00 eq). The reaction solution was stirred at 20 °C for 14 h to give a colorless solution. TLC (PE / EtOAc = 1 / 1, SiO ) and LC-MS indicated the reaction was complete. The reaction solution was combined with the second preparation and then diluted with H 0 (5 ml × 2), followed by extraction with DCM (10 ml × 5). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the crude product as a pale yellow solid. The product was purified by preparative TLC (PE / EtOAc = 1 / 1, SiO2) to give K101-C1340-A (20.30 mg, 23.15 μmol, yield 3 9.29%) as a white solid.

[0493] Preparation of compound K101-C1340. To a solution of K101-C1343-A (20.00 mg, 22.80 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL, 296.19 eq), followed by EtSiH (2.65 mg, 22.80 μmol, 3.63 μL, 1.00 eq). The mixture was stirred at 20 °C for 18 hours to give a pale yellow solution. The reaction was determined to be complete by LC-MS. The reaction mixture was concentrated under reduced pressure to give a yellow solid, and the product was purified by preparative HPLC (Phenomenex Gemini 150x25mmx10um column; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 55%-95%, 10 min). The separated layers were lyophilized to give K101-C1340 (3.80 mg, 7.11 μmol, 31.17% yield, 96.78% purity, TFA salt) as a pale yellow solid.

[0494] LC-MS(m / z):557.1[M+Na] +

[0495] 1H NMR(400MHz,MeOD)δ 7.58(d,J=7.5 Hz,1H),7.54-7.51(m,1H),7.38(d,J=8.0 Hz,1H),7.19(s,1H),7.17-7.12(m,1H),7.10-7.05(m,1H),5.59-5.54(m, 1H),4.58(s,2H),4.17-4.09(m,1H),3.99-3.90(m,2H),3.17-3.11(m,1H) ,3.02-2.96(m,1H),2.55-2.46(m,1H),2.45-2.36(m,1H),2.04-1.92(m,2 H),1.78-1.71(m,3H),1.43-1.32(m,1H),1.04-0.97(m,6H),0.83(d,J=6.0 Hz,3H),0.78-0.74(m,1H).

[0496] Example 38: Synthesis scheme of K101-C1341. The synthesis scheme of compound K101-C1341 is shown below. [ka]

[0497] Preparation of compound K101-C1341-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (1.00 mL) was added (2R)-2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)propanoic acid (C13-41) (154.55 mg, 507.83 μmol, 10.00 eq), EDC (19.47 mg, 101.57 μmol, 2.00 eq), and DMAP (37.22 mg, 304.70 μmol, 6.00 eq). The mixture was stirred at 20 °C for 5 hours to give a colorless solution. LC-MS and TLC showed the reaction was complete. The reaction mixture was quenched with HO (15 mL) and extracted with DCM (15 mL x 5). The organic layer was dried over NaSO and concentrated to give a yellow solid. The product was purified by preparative TLC (eluted with petroleum ether:ethyl acetate = 2 / 1) to give K101-C1341-A (35.00 mg, 39.91 μmol, 67.35% yield) as a white solid.

[0498] Preparation of compound K101-C1341. To a solution of K101-C1341-A (35.00 mg, 39.91 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL, 169.21 eq) and EtSiH (4.64 mg, 39.91 μmol, 6.36 μL, 1.00 eq). The mixture was stirred at 20°C for 5 hours to give a colorless solution. The reaction mixture was concentrated, and the resulting yellow oil was dissolved in DCM (2 mL), followed by the addition of TFA (0.5 mL). The mixture was stirred at 20°C for 2 hours to give a yellow solution. The reaction mixture was concentrated and dissolved in DCM (2 mL), followed by the addition of TFA (0.5 mL). The reaction mixture was stirred at 20°C for 1 hour to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated to give a yellow oil, which was then dissolved in MeOH (4 mL) and stirred at 20 °C for 14 h to give a yellow liquid. The product was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 20% to 50%, 10 min). The separated layers were lyophilized to give K101-C1341 (4.00 mg, 5.59 μmol, 14.01% yield, 90.7% purity, TFA salt) as a white solid.

[0499] LC-MS(m / z):557.1[M+Na] +

[0500] 1H NMR(400MHz,MeOD)δ=7.61(d,J=7.5 Hz,1H),7.57(s,1H),7.42(d,J=8.3 Hz,1H),7.26(s,1H),7.23-7.10(m,2H),5.60-5.50(m,1H),4.33(t,J=7.4 Hz,1H),4.06-3.92(m,2H),3.60-3.45(m,1H),3.22-3.13(m,1H),3.05-2.95(m,1H),2.59-2.38(m,2H),2.17(dd,J=6.8,14.6 Hz,1H),2.04(d,J=8.8 Hz,1H),1.77(d,J=1.5 Hz,3H),1.63(dd,J=10.5,14.8 Hz,1H),1.40-1.25(m,2H),1.04(s,3H),0.93(d,J=6.5 Hz,3H),0.87(s,3H),0.69(d,J=5.8 Hz,1H)

[0501] Example 39: Synthesis scheme of K101-C1342. The synthesis scheme of compound K101-C1342 is shown below. [ka]

[0502] Preparation of compound K101-C1342-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) and C13-42 (25.39 mg, 76.17 μmol, 1.50 eq) in DCM (1.00 mL) was added EDC (58.41 mg, 304.68 μmol, 6.00 eq) and DMAP (18.61 mg, 152.35 μmol, 3.00 eq). The mixture was stirred at 20 °C for 14 hours to give a yellow solution. The reaction was complete as detected by LC-MS. The reaction solution was combined with the second preparation, diluted with HO (10 mL), and then extracted with DCM (10 mL x 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a yellow solid. The product was purified by preparative TLC (PE / EtOAc=2 / 1, SiO2) to give K101- C1342-A (50.30 mg, 55.52 μmol, 93.44% yield) was obtained as a white solid.

[0503] Preparation of compound K101-C1342. To a solution of K101-C1342-A (50.00 mg, 55.19 μmol, 1.00 eq) in MeOH (500.00 uL) was added HCl / MeOH (4 M, 500.00 uL, 36.24 eq). The reaction was stirred at 20 °C for 3.5 hours to give a pale yellow solution. LC-MS showed that the reaction was almost complete. The solution was adjusted to pH 8 with saturated aqueous NaHCO3 and then extracted with DCM (2 ml x 3). The combined organic layers were concentrated under reduced pressure to give a yellow solid. The product was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25%-55%, 10 min) to give K101-C1342 (10.70 mg, 18.99 μmol, 34.40% yield, 98.84% purity, TFA salt) as a white solid.

[0504] LC-MS(m / z):586.1[M+Na] +

[0505] 1 H NMR(400MHz,MeOD)δ 7.71(d,J=8.0 Hz,2H),7.56-7.51(m,3H),5.62-5.57(m,1H),4.47-4.40(m,1H),3.94(s,2H),3.47-4.40(m,1H),3.25-3.1 8(m,1H),3.18-3.13(m,1H),3.07-2.99(m,1H),2.57-2.47(m,1H),2.45-2.36(m,1H),2.17(dd,J=7.2,14.7 Hz,1H),2.07-1.98(m,1H),1.78-1.73(m,3H),1.53-1.43(m,1H),1.10(s,3H),1.06(s,3H),0.96(d,J=5.8 Hz,1H),0.91(d,J=6.5 Hz,3H).

[0506] Example 40: Synthesis scheme of K101-C1343. The synthesis scheme of compound K101-C1343 is shown below. [ka]

[0507] Preparation of compound K101-C1343-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) and C13-43, EDC (58.41 mg, 304.68 μmol, 6.00 eq) and DMAP (37.22 mg, 304.68 μmol, 6.00 eq) were added. The reaction solution was stirred at 25 °C for 1 h, resulting in a brown solution. TLC (PE / EtOAc = 1 / 1, SiO2) showed the reaction was complete. The reaction solution was diluted with DCM (2 mL), washed with brine (1 mL), and dried over anhydrous Na2SO4. The product was filtered and concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by preparative TLC (PE / EtOAc=1 / 1, SiO.sub.2) to give K101-C1343-A (33.30 mg, 78.25% yield) as a colorless gum.

[0508] Preparation of compound K101-C1343. To a solution of K101-C1343-A (25.00 mg, 29.83 μmol, 1.00 eq) in MeOH (1.00 mL), HCl / MeOH (4 M, 1 mL) was added, and the reaction solution was stirred at 20 °C for 2.5 hours to obtain a clear solution. LC-MS showed that the reaction was nearly complete, so the reaction solution was stirred at 20 °C for an additional hour. The reaction solution was combined with a second preparation of the compound and then cooled to 0 °C. The solution was adjusted to pH 8 with saturated aqueous NaHCO3. The solution was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.05% HCl)-B: ACN]; B%: 15%-45%, 10 min) to give K101-C1343 (7.60 mg, 47.02% yield, 98.2% purity, HCl salt) as a white solid.

[0509] LC-MS(m / z):518.1[M+Na] +

[0510] 1 H NMR(400MHz,CD3OD)δ 7.53(s,1H),7.50-7.43(m,5H),5.57(d,J=4.2 Hz,1H),4.73(t,J=7.3 Hz,1H),4.00-3.88(m,2H),3.18-3.04(m,3H),3.01(t,J=5.5 Hz,1H),2.56-2.46(m,1H),2.44-2.36(m,1H),2.11-1.93(m,2H),1.78-1.71(m,3H),1.38(dd,J=10.1,14.3 Hz,1H),1.01(s,3H),0.96(s,3H),0.90-0.80(m,4H).

[0511] Example 41: Synthesis scheme of K101-C1344. The synthesis scheme of compound K101-C1344 is shown below. [ka]

[0512] Preparation of compound K101-C1344-A. To a solution of K101-C20Tr-B (35.00 mg, 59.25 μmol, 1.00 eq) and C13-44 (41.37 mg, 148.12 μmol, 2.50 eq) in DCM (1.00 mL) was added EDC (68.15 mg, 355.48 μmol, 6.00 eq) and DMAP (21.71 mg, 177.74 μmol, 3.00 eq). The mixture was stirred at 20 °C for 18 h to give a yellow solution. The reaction was complete as detected by LC-MS. The reaction solution was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3), and the combined organic layers were dried over Na2SO4. The solution was concentrated under reduced pressure and purified by preparative TLC (SiO2, PE:EA = 3:1). Concentration under reduced pressure gave K101-C1344-A (43.60 mg, 51.17 μmol, 86.36% yield) as a white solid.

[0513] Preparation of compound K101-C1344. To a solution of K101-C1344-A (35.00 mg, 41.08 μmol, 1.00 eq) in MeOH (500.00 uL) was added HCl / MeOH (4 M, 583.29 uL, 56.80 eq). The solution was stirred at 20° C. for 18 h. The mixture was stirred for 1 hour to give a yellow solution. The reaction was complete as detected by LC-MS. The reaction solution was diluted with HO (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give a yellow solid. The product was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 20% to 50%, 10 min). The separated layers were lyophilized to give K101-C1344 (5.00 mg, 8.02 μmol, 19.52% yield, TFA salt) as a white solid.

[0514] LC-MS(m / z):532.3[M+Na] +

[0515] 1 H NMR(400MHz,CD3OD)δ 7.53(s,1H),7.40-7.37(m,2H),7.34-7.33(m,1H),7.29-7.27(m,2H),5.59(s,1H),3 .98(s,2H),3.88-3.85(m,1H),3.15(s,1H),3.06-3.03(m,2H),2.95-2.93(m,1H),2. 72-2.64(m,2H),2.55-2.44(m,2H),2.12-1.98(m,2H),1.75(s,3H),1.59-1.55(m,1H ),1.30-1.25(m,3H),1.14(s,3H),1.06(s,3H),0.91-0.89(m,3H),0.84-0.83(m,1H).

[0516] Example 42: Synthesis scheme of K101-C1345. The synthesis scheme of compound K101-C1345 is shown below. [ka]

[0517] Preparation of compound K101-C1345-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) and C13-45 (36.23 mg, 126.96 μmol, 2.50 eq) in DCM (1.00 mL) was added EDC (48.68 mg, 253.91 μmol, 5.00 eq) and DMAP (18.61 mg, 152.35 μmol, 3.00 eq). The reaction mixture was stirred at 20 °C for 18 h. The reaction was complete as detected by LC-MS. The reaction solution was diluted with H2O (10 mL) and extracted with DCM (8 mL x 5). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a pale yellow solution. The product was purified by preparative TLC (SiO2, PE:EA=3:1) to give K101-C1345-A (26.30 mg, 30.65 μmol, 60.36% yield) as a white solid.

[0518] Preparation of compound K101-C1345. To a solution of K101-C1345-A (25.00 mg, 29.13 μmol, 1.00 eq) in MeOH (500.00 uL) was added HCl / MeOH (4 M, 7.28 uL, 1.00 eq). The solution was stirred at 20 °C for 18 h to give a yellow solution. The reaction was complete as detected by LC-MS. The reaction solution was diluted with H2O (10 mL), neutralized with aqueous NaHCO3, and then extracted with DCM (8 mL x 5). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow solution. The residue was purified by preparative HPLC (column: Phenomenex Gemini 150x25mmx10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25%-55%, 10 min), and the separated layers were lyophilized to give K101-C1345 (4.30 mg, 8.34 μmol, 28.63% yield) as a white solid.

[0519] LC-MS(m / z):538.3[M+Na] +

[0520] 1 H NMR(400MHz,CD3OD)δ 7.56(s,1H),5.62(s,1H),5.49(m,1H),4.02-3.95(m,3H),3.16-3.06(m,2H),2.56-2.44(m,2H),2.39-2.22( m,1H),2.04-1.94(m,3H),1.76-1.57(m,9H),1.30-1.25(m,7H),1.18(s,3H),1.01(s,3H),0.99-0.93(m,5H).

[0521] Example 43: Synthesis scheme of K101-C1346. The synthesis scheme of compound K101-C1346 is shown below. [ka]

[0522] Preparation of compound K101-C1346-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (1.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (C13-46) (70.47 mg, 304.68 μmol, 6.00 eq), DMAP (43.43 mg, 355.46 μmol, 7.00 eq), and EDC (58.41 mg, 304.68 μmol, 6.00 eq). The mixture was stirred at 20 °C for 5 h, resulting in a yellow solution. TLC showed the reaction was complete. The reaction mixture was quenched with HO (15 mL) and extracted with DCM (15 mL x 5). The organic layer was dried over NaSO and concentrated to give a yellow solid. The product was purified by preparative TLC (eluted with petroleum ether:ethyl acetate = 3 / 1) to give K101-C1346-A (28.00 mg, 34.83 μmol, yield 68.58%) as a colorless solid.

[0523] Preparation of compound K101-C1346. To a solution of K101-C1346-A (28.00 mg, 34.83 μmol, 1.00 eq) in MeOH (500.00 uL) was added HCl / MeOH (4 M, 8.71 uL, 1.00 eq). The mixture was stirred at 20 °C for 19 h to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was adjusted to pH 6 with saturated NaHCO3, and the resulting product was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 um; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 20% to 50%, 10 min). The organic layer was lyophilized to give K101-C1346 (7.80 mg, 13.55 μmol, 38.91% yield, 100% purity, TFA salt) as a white solid.

[0524] LC-MS(m / z):584.2[M+Na] +

[0525] 1 H NMR(400MHz,MeOD)δ=7.60-7.54(m,1H),5.70-5.60(m,1H),4.04-3.92(m,2H),3.86( s,1H),3.33-3.20(m,1H),3.20-3.12(m,1H),2.60-2.38(m,2H),2.26(dd,J=7.0,14.6 Hz,1H),2.19-2.02(m,1H),1.77(d,J=1.5 Hz,3H),1.60(dd,J=10.8,14.6 Hz,1H),1.26(s,3H),1.17(s,9H),1.13(s,3H),1.02(d,J=5.8 Hz,1H),0.95(d,J=6.3 Hz,3H).

[0526] Example 44: Synthesis scheme of K101-C1347. The synthesis scheme of compound K101-C1347 is shown below. [ka]

[0527] Preparation of compound K101-C1347-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added (2S)-2-(1-adamantyl)-2-(tert-butoxycarbonylamino)acetic acid (C13-47) (94.27 mg, 304.68 μmol, 6.00 eq), EDC (58.41 mg, 304.68 μmol, 6.00 eq), and DMAP (43.43 mg, 355.46 μmol, 7.00 eq). The mixture was stirred at 20 °C for 14 h to give a yellow solution. LC-MS and TLC showed the reaction was complete. The reaction mixture was quenched with HO (15 mL) and extracted with DCM (15 mL x 5). The organic layer was dried over NaSO and concentrated to give a yellow solid. The product was purified by preparative TLC (eluted with petroleum ether:ethyl acetate=3 / 1) to give K101-C1347-A (13.00 mg, 14.74 μmol, yield 24.80%) as a white solid.

[0528] Preparation of compound K101-C1347. To a solution of K101-C1347-A (13.00 mg, 14.74 μmol, 1.00 eq) in THF (1.00 mL) was added TFA (500.55 mg, 4.39 mmol, 325.03 μL, 297.89 eq) and EtSiH (1.71 mg, 14.74 μmol, 2.35 μL, 1.00 eq). The mixture was stirred at 20°C for 3 hours to give a colorless solution. The reaction mixture was concentrated and dissolved in DCM (2 mL), followed by the addition of TFA (0.5 mL). The mixture was stirred at 20°C for 2 hours to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated to give a yellow oil, which was dissolved in MeOH (2 mL) and stirred at 20°C for 14 hours to give a light tan liquid. The product was purified by preparative HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 25% to 55%, 10 min). The separated layers were lyophilized to give K101-C1347 (6.50 mg, 9.94 μmol, 67.44% yield, 100% purity, TFA salt) as a white solid.

[0529] LC-MS(m / z):562.3[M+Na] +

[0530] 1 H NMR(400MHz,MeOD)δ=7.62-7.55(s,1H),5.70-5.60(m,1H),4.05-3.90(m,2H),3.75-3.5 6(m,1H),3.25-3.15(m,1H),3.16-3.08(m,1H),2.62-2.38(m,2H),2.27(dd,J=6.9,14.7 Hz,1H),2.15-2.06(m,4H),1.91-1.53(m,16H),1.27(s,3H),1.13(s,3H),1.03(d,J=5.5 Hz,1H),0.96(d,J=6.5 Hz,3H)

[0531] Example 45: Synthesis scheme of K101-C1348. The synthesis scheme of compound K101-C1348 is shown below. [ka]

[0532] Preparation of compound C13-48-B. LiAlH4 (413.84 mg, 10.91 mmol, 1.50 eq) was suspended in THF (10.00 mL) at 0 °C, and then C13-48-A (1.50 g, 7.27 mmol, 1.00 eq) in THF (10.00 mL) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 4 hours to give a brown solution. LC-M S indicated the reaction was complete. After quenching with HO (0.5 mL), aqueous NaOH (0.5 mL, 15%) and HO (1.5 mL) were added. The mixture was filtered through Celite, and the filtrate was concentrated to give 7-phenylheptan-1-ol (1.30 g, 6.76 mmol, 92.99% yield) as a yellow oil.

[0533] Preparation of compound C13-48-C. To a solution of oxalyl dichloride (1.72 g, 13.52 mmol, 1.18 mL, 2.00 eq) in DCM (20.00 mL) was added DMSO (2.64 g, 33.80 mmol, 2.64 mL, 5.00 eq) dropwise at −78° C. The mixture was stirred at −78° C. for 0.5 hours. Compound C13-48-B (1.30 g, 6.76 mmol, 1.00 eq) in DCM (10.00 mL) was added at −78° C. The mixture was stirred at −78° C. for 1 hour, and EtN (3.42 g, 33.80 mmol, 4.68 mL, 5.00 eq) was added dropwise at −78° C. The mixture was stirred at 20° C. for 2.5 hours to give a yellow suspension. LC-MS and TLC (eluted with PE / EtOAc = 5 / 1) showed the reaction was complete. The reaction mixture was quenched with HO (30 mL) and extracted with DCM (50 mL x 3). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by column chromatography on silica gel (eluted with PE / EtOAc = 100% PE ~ 5 / 1) to give C13-48-C (1.10 g, 5.78 mmol, 85.52% yield) as a yellow oil.

[0534] Preparation of compound C13-48-E. To a solution of C13-48-C (1.05 g, 5.52 mmol, 1.00 eq) in EtOH (10.00 mL), trimethylsilyl cyanide (TMSCN) (547.46 mg, 5.52 mmol, 692.99 uL, 1.00 eq) and NH3.HO (851.01 mg, 6.07 mmol, 935.18 uL, 25% purity, 1.10 eq) were added. The mixture was stirred at 20 °C for 7 h to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was quenched with HO (30 mL) and extracted with DCM (50 mL x 3). The organic layer was dried over Na2SO4 and concentrated to give C13-48-E (1.10 g, crude) as a yellow oil.

[0535] Preparation of compound C13-48-D. To a solution of C13-48-E (1.10 g, 5.09 mmol, 1.00 eq) in EtOH (5.00 mL) was added NaOH (610.21 mg, 15.26 mmol, 3.00 eq). The mixture was stirred at 20 °C for 2 hours, and then HO (1.00 mL) was added. The mixture was stirred at 90 °C for 2 hours to give a yellow solution. LC-MS showed that the reaction was complete.

[0536] Preparation of compound C13-48. Boc anhydride (BocO) (2.23 g, 10.20 mmol, 2.34 mL, 2.00 eq) was added to the preparation of C13-48-E, and the mixture was stirred at 20 °C for 2 h to give a yellow suspension. LC-MS and TLC (eluted with 100% EtOAc) indicated the reaction was complete. The mixture was combined with the second preparation, and the combined mixture was diluted with HO (20 mL) and then extracted with PE (20 mL x 3). The aqueous layer was adjusted to pH 5 with HCl (1 N) and extracted with EtOAc (30 mL x 3). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by column chromatography on silica gel (eluted with PE / EtOAc = 1 / 1 to 100% EtOAc) to give C13-48 (700.00 mg, 2.09 mmol, 40.92% yield) as a yellow oil.

[0537] Preparation of compound K101-C1348-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 eq) in DCM (2.00 mL) was added C13-48 (34.07 mg, 101.56 μmol, 2.00 eq), DMAP (24.82 mg, 203.12 μmol, 4.00 eq), HOBt (13.72 mg, 101.56 μmol, 2.00 eq), and EDC (19.47 mg, 101.56 μmol, 2.0 0 eq) was added. The mixture was stirred at 10 °C for 12 hours to give a yellow solution. LC-MS and TLC (eluted with PE / EtOAc = 2 / 1) showed that the reaction was complete. The mixture was combined with the second preparation, and the combined mixture was quenched with saturated NaHCO3 (10 mL), followed by extraction with DCM (20 mL x 3). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The product was purified by preparative TLC (eluted with PE / EtOAc = 2 / 1) to give K101-C1348-A (18.00 mg, 19.82 μmol, 39.03% yield) as a white solid.

[0538] 1 H NMR (400 MHz, CDCl3) δ 7.57(s,1H),7.44-7.42(m,5H),7.31-7.29(m,7H),7.24-7.18(m,8H),5.59- 5.58(m,1H),3.51-3.50(m,2H),3.28(s,1H),2.93(s,1H),2.60-2.56(m,2H), 2.50-2.42(m,1H),2.05-1.99(m,2H),1.97-1.95(m,3H),1.77(s,2H),1.55-1 .54(m,2H),1.34(s,9H),1.25-1.19(m,12H),1.08(s,3H),0.87-0.79(m,4H).

[0539] Preparation of compound K101-C1348 (as a mixture of K101-C134801 and K101-C134802). To a solution of K101-C1348-A (48.00 mg, 52.85 μmol, 1.00 eq) in THF (2.00 mL) was added TFA (6.03 mg, 52.85 μmol, 3.91 μL, 1.00 eq). The mixture was stirred at 10° C. for 12 hours to give a yellow solution. LC-MS and TLC (eluted with EtOAc / MeOH = 10 / 1) showed the reaction was complete. The reaction mixture was concentrated with N2, and the resulting product was dissolved in MeOH (30 mL). The reaction mixture was stirred at 20° C. for 12 hours. After the mixture was concentrated, the product K101-C1348 was purified by preparative TLC (eluted with EtOAc / MeOH = 10 / 1) to give K101-C134801 (11.10 mg, 19.62 μmol, yield 37.12%, purity 100%) and K101-C134802 (10.30 mg, 17.73 μmol, yield 33.55%, purity 97.4%) as a mixture of stereoisomers, K101-C1348, respectively, as white solids.

[0540] K101-C134801:LC-MS(m / z):588.2[M+Na] + K101-C134801: 1 H NMR(400MHz,CD3OD)δ 7.53(s,1H),7.30-7.10(m,5H),5.65-5.55(m,1H),4.00-3.90(m,2H),3.50-3.45(m,1H),3.25-3.20(m,1H),3.15-3.05(m,1H),2.65-2 .55(m,2H),2.55-2.40(m,2H),2.20-1.95(m,2H),1.807-1.55(m,8H),1.40-1.25(m,6H),1.20(s,3H),1.10(s,3H),0.95-0.85(m,4H).

[0541] K101-C134802:LC-MS(m / z):588.3[M+Na] +

[0542] K101-C134802: 1H NMR(400MHz,CD3OD)δ 7.53(s,1H),7.30-7.10(m,5H),5.65-5.55(m,1H),4.0-3.85(m,2H),3.70-3.60(m,1H),3.20-3.10(m,1H),3.05-3.0(m,1H),2.70-2 .55(m,2H),2.55-2.40(m,2H),2.15-2.15(m,2H),1.85-1.45(m,8H),1.45-1.30(m,6H),1.20(s,3H),1.09(s,3H),0.95-0.90(m,4H).

[0543] Example 45A: Synthesis scheme of K101-C134801. The synthesis scheme of compound K101-C134801 is shown below. [ka]

[0544] Preparation of compound C134801-C. To a solution of C1348-D (2 g, 7.35 mmol, 1 eq) in DMA (2 mL) was added CuI (139.97 mg, 734.96 μmol, 0.1 eq), C134801-B (4.06 g, 10.29 mmol, 1.4 eq), and Pd(dppf)Cl (537.77 mg, 734.96 μmol, 0.1 eq) under N. The mixture was stirred at 90 °C under N for 5 h to give a black suspension. LCMS and TLC (eluted with PE / EtOAc = 3 / 1) showed the reaction was complete. The reaction mixture was quenched with H2O (100 mL) and extracted with MBTE (40 mL x 3). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by flash column (eluted with PE / EtOAc = 100% PE to 20%) to give C134801-C (750 mg, 2.16 mmol, 29.37% yield) as a yellow oil.

[0545] 1 H NMR(400MHz,CDCl3):δ 7.30-7.20(m,2H), 7.20-7.16(m,3H),5.58-5.51(m,1H),5.34-5.27(m,1H),5.02-5.00(m,1H),4.37-4.33(m,1H),3.7 3(s,3H),2.62-2.58(m,2H),2.46-2.44(m,2H),2.07-2.02(m,2H),1.70-1.66(m,2H),1.44(s,9H).

[0546] Preparation of compound C134801-D. To a solution of C134801-C (0.75 g, 2.16 mmol, 1 eq) in MeOH (15 mL) was added Pd / C (500 mg, 2.16 mmol, 50% purity, 1 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20 °C for 12 h. LCMS showed that the reaction was complete. The reaction mixture was filtered through Celite. The filtrate was concentrated to give C134801-D (750 mg, 2.15 mmol, 99.42% yield) as a black oil, which was used in the next step without further purification.

[0547] 1 H NMR(400MHz,CDCl3):δ 7.29-7.26(m,2H),7.19-7.16(m,3H),4.99-4.84(m,1H),4.29-4.28(m,1H),3.7 3(s,3H),2.61-2.51(m,2H),1.78-1.60(m,4H),1.45(s,9H),1.33-1.28(m,6H).

[0548] Preparation of compound BB-C134801. To a solution of C134801-D (750 mg, 2.15 mmol, 1 eq) in THF (5 mL) / HO (1 mL) was added LiOH.HO (90.06 mg, 2.15 mmol, 1 eq) at 0 °C. The mixture was stirred at 20 °C for 12 hours to give a yellow solution. LCMS showed that the reaction was complete. The reaction mixture was acidified to pH = 4 with HCl (1 N) and extracted with MBTE (20 mL x 3). The organic layer was dried over NaSO and concentrated to give BB-C134801 (700 mg, 2.09 mmol, 97.24% yield) as a yellow oil, which was used in the next step without further purification.

[0549] Preparation of Compound C134801-B. Zinc (6 g) was treated with 1N aqueous HCl (30 mL) with stirring for 10 minutes. It was then filtered, washed successively with water (30 mL), EtOH (30 mL), and toluene (30 mL), and dried in vacuo to obtain zinc powder for the next step. A mixture of activated Zn (2.62 g, 40.11 mmol, 4 eq) and I2 (127.24 mg, 501.32 μmol, 100.98 μL, 0.05 eq) in DMA (10 mL) was stirred at 20 °C for 5 minutes. C134801-A (3.3 g, 10.03 mmol, 1 eq) in DMA (10 mL) was then added dropwise. The reaction mixture was stirred at 20 °C for 25 minutes, resulting in a black suspension. The reaction mixture (approximately 0.5015 mmol / mL) was used in the next step without further purification.

[0550] Preparation of compound K101-C134801-A. To a solution of K101-C20Tr-B (200 mg, 338.55 μmol, 1 eq) in DCM (3 mL) was added BB-C134801 ...

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony A is -OH, -C(O)OR １ , or -NR １３ R １３’ and R １ is a H or M counterion, R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ５’ and R ６’ is H or R ５’ and R ６’ form a bond or, if allowed by valences, are attached to a common O atom to form an epoxide ring; R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 2】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is the adjacent R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ６’ and R ７’ is H or R ６’ and R ７’ form a bond or, if allowed by valences, are attached to a common O atom to form an epoxide ring; R ７ is H or OH, R ９ is OR ｅ where R ｅ is H, C １ ~C ６ is alkyl or aryl, R １１ is C １ ~C ４ is alkyl, R １２ is H, —OH, —OC(O)R ｆ wherein R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -C ０ ~C １２ Aliphatic-C ３ ~C ７ Cycloalkyl, —C ０ ~C １２ Aliphatic-heterocycloalkyl, —C ０ ~C １２ Aliphatic-aryl, or -C ０ ~C １２ aliphatic-heteroaryl; R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl, R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is absent or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, the bridged bicyclyl or the adamantyl may optionally contain 1 to 3 J １ wherein spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by R ｋ is H or M ＋ is the counterion, J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, n is 0 or 1; A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

2. The compound of claim 1 , wherein A is —OH.

3. A is -C(O)OR １ and R １ Is H or M ＋ The compound of claim 1 , which is a counterion.

4. The compound of claim 1 having the structure of formula (II): 【Transformation 3】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ５’ and R ６’ is H or R ５’ and R ６’ form a bond or, if allowed by valences, are attached to a common O atom to form an epoxide ring; R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 4】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is the adjacent R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ６’ and R ７’ is H or R ６’ and R ７’ form a bond or, if allowed by valences, are attached to a common O atom to form an epoxide ring; R ７ is H or OH, R ９ is OR ｅ where R ｅ is H, C １ ~C ６ is alkyl or aryl, R １１ is C １ ~C ４ is alkyl, R １２ is H, —OH, —OC(O)R ｆ wherein R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -C ０ ~C １２ Aliphatic-C ３ ~C ７ Cycloalkyl, —C ０ ~C １２ Aliphatic-heterocycloalkyl, —C ０ ~C １２ Aliphatic-aryl, or -C ０ ~C １２ aliphatic-heteroaryl; R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl, R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is absent or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by R ｋ is H or M ＋ is the counterion, J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, n is 0 or 1; A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

5. The compound of claim 4 having the structure of formula (II'): 【Transformation 5】 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

6. The compound of claim 4 having the structure of formula (IIa): 【Transformation 6】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ is an N atom together form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Transformation 7】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is the adjacent R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ７ is H or OH, R ９ is OR ｅ where R ｅ is H, C １ ~C ６ is alkyl or aryl, R １１ is C １ ~C ４ is alkyl, R １２ is H, —OH, —OC(O)R ｆ wherein R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -C ０ ~C １２ Aliphatic-C ３ ~C ７ Cycloalkyl, —C ０ ~C １２ Aliphatic-heterocycloalkyl, —C ０ ~C １２ Aliphatic-aryl, or -C ０ ~C １２ aliphatic-heteroaryl; R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl, R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is absent or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by R ｋ is H or M ＋ is the counterion, J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, n is 0 or 1; A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

7. The compound of claim 6 having the structure of formula (IIa'): 【Transformation 8】 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

8. The compound of claim 4 having the structure of formula (IIb): 【Chemistry 9】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 10】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is the adjacent R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ９ is OR ｅ where R ｅ is H, C １ ~C ６ is alkyl or aryl, R １１ is C １ ~C ４ is alkyl, R １２ is H, —OH, —OC(O)R ｆ wherein R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -C ０ ~C １２ Aliphatic-C ３ ~C ７ Cycloalkyl, —C ０ ~C １２ Aliphatic-heterocycloalkyl, —C ０ ~C １２ Aliphatic-aryl, or -C ０ ~C １２ aliphatic-heteroaryl; R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl, R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is absent or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by R ｋ is H or M ＋ is the counterion, J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, n is 0 or 1; A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

9. The compound of claim 6 having the structure of formula (IIc): 【Chemistry 11】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR Ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R Ｃ１ is H, C １ ~C ６ alkyl or two R Ｃ１ together with the N atom form a 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 12】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is the adjacent R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R １２ is H, —OH, —OC(O)R ｆ wherein R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -C ０ ~C １２ Aliphatic-C ３ ~C ７ Cycloalkyl, —C ０ ~C １２ Aliphatic-heterocycloalkyl, —C ０ ~C １２ Aliphatic-aryl, or -C ０ ~C １２ aliphatic-heteroaryl; R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl, L is absent or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by R ｋ is H or M ＋ is the counterion, J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, n is 0 or 1; A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

10. The compound of claim 4 having the structure of formula (III): 【Chemistry 13】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ５’ and R ６’ is H or R ５’ and R ６’ form a bond or, if allowed by valences, are attached to a common O atom to form an epoxide ring; R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 14】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is the adjacent R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ６’ and R ７’ is H or R ６’ and R ７’ form a bond or, if allowed by valences, are attached to a common O atom to form an epoxide ring; R ７ is H or OH, R ９ is OR ｅ where R ｅ is H, C １ ~C ６ is alkyl or aryl, R １１ is C １ ~C ４ is alkyl, R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl, R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is absent or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by R ｋ is H or M ＋ is the counterion, J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, n is 0 or 1; A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

11. The compound of claim 10 having the structure of formula (III'): 【Chemistry 15】 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

12. The compound of claim 10 having the structure of formula (IIIa): 【Chemistry 16】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 17】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is the adjacent R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ７ is H or OH, R ９ is OR ｅ where R ｅ is H, C １ ~C ６ is alkyl or aryl, R １１ is C １ ~C ４ is alkyl, R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl, R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is absent or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by R ｋ is H or M ＋ is the counterion, J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, n is 0 or 1; A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

13. The compound of claim 10 having the structure of formula (IIIb): [Chemistry 18] or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 19】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is the adjacent R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ９ is OR ｅ where R ｅ is H, C １ ~C ６ is alkyl or aryl, R １１ is C １ ~C ４ is alkyl, R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl, R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is absent or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by R ｋ is H or M ＋ is the counterion, J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, n is 0 or 1; A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

14. The compound of claim 10 having the structure of formula (IIIc): 【Chemistry 20】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR Ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R Ｃ１ is H, C １ ~C ６ alkyl or two R Ｃ１ together with the N atom form a 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 21】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is the adjacent R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl, L is absent or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by R ｋ is H or M ＋ is the counterion, J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, n is 0 or 1; A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

15. The compound of claim 14 having the structure of formula (IIIe): 【Chemistry 22】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR Ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R Ｃ１ is H, C １ ~C ６ alkyl or two R Ｃ１ together with the N atom form a 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 23】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is the adjacent R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; L is absent or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ Cycloa alkyl, heterocyclyl, alkylaryl, or heteroaryl may have 1 to 3 J １ optionally replaced by R ｋ is H or M ＋ is the counterion, J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ selected from alkyl, A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

16. R ２１ is C ３ ~C ７ cycloalkyl, ３ ~C ７ Cycloalkyl optionally has 1 to 3 J １ 16. The compound of any one of claims 1 to 15, substituted with:

17. Said C ３ ~C ７ cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; ３ ~C ７ Cycloalkyl is 1 to 3 J １ 17. The compound of claim 16, optionally substituted with

18. R ２１ is heterocyclyl, and said heterocyclyl optionally has 1 to 3 J １ 16. The compound of any one of claims 1 to 15, substituted with:

19. the heterocyclyl is selected from the group consisting of oxiranyl, oxetanyl, azetidinyl, oxazolyl, thiazolidinyl, thiazolyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and azapanyl; and the heterocyclyl is selected from the group consisting of 1 to 3 J １ 20. The compound of claim 18, optionally substituted with

20. R ２１ is aryl, and said aryl is optionally selected from 1 to 3 J １ 16. The compound of any one of claims 1 to 15, substituted with:

21. R ２１ is phenyl or naphthyl, wherein said phenyl or naphthyl optionally contains 1 to 3 J １ 21. The compound of claim 20 substituted with:

22. R ２１ is heteroaryl, and said heteroaryl optionally has 1 to 3 J １ 16. The compound of any one of claims 1 to 15, substituted with:

23. wherein the heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, and quinolyl, and the heteroaryl optionally contains 1 to 3 J １ 23. The compound of claim 22 substituted with:

24. R ２１ is adamantyl, said adamantyl optionally being OH, halo, or C １ ~C ４ The compound of any one of claims 1 to 15, which is substituted with alkyl.

25. R ２１ But Spiro C ５ ~C １２ cycloalkyl, wherein said spiro C ５ ~C １２ Cycloalkyl has 0-2 carbon atoms replaced by 0-2 heteroatoms selected from N, O, and S, and optionally 1-3 J １ or, if an N atom is present, is substituted with an N-protecting group.

26. R ２１ is a 5-12 membered bridged bicyclyl, said bridged bicyclyl having 0-2 carbon atoms replaced by 0-2 heteroatoms selected from N, O or S, and optionally 1 ~3 Js １ or, if an N atom is present, is substituted with an N-protecting group.

27. R ２１ is expressed by the following formula: 【Chemistry 24】 is selected from In the ceremony, J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, and n is 0 to 3; A compound according to any one of claims 1 to 15.

28. L is C １ ~C ６ Alkylene, C ３ ~C ６ Alkylene, or C ３ ~C １２ The compound of any one of claims 1 to 27, which is alkylene.

29. L is C １ ~C ６ Alkenylene, C ３ ~C ６ Alkenylene, or C ３ ~C １２ The compound of any one of claims 1 to 27, which is alkenylene.

30. 30. The compound of any one of claims 1 to 29, wherein n is 0.

30. 2. The compound of claim 1, selected from the group consisting of the compounds of Table 1 or amino acid prodrugs thereof.

31. A compound of formula (IV), 【Chemistry 25】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ５’ and R ６’ is H or R ５’ and R ６’ form a bond or, if allowed by valences, are attached to a common O atom to form an epoxide ring; R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 26】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ６’ and R ７’ is H or R ６’ and R ７’ form a bond or, if allowed by valences, are attached to a common O atom to form an epoxide ring; R ７ is H or OH, R ９ is OR ｅ where R ｅ is H, C １ ~C ６ alkyl or aryl 、 R １１ is C １ ~C ４ is alkyl, R １２ is H, —OH, —OC(O)R ｆ wherein R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -C ０ ~C １２ Aliphatic-C ３ ~C ７ Cycloalkyl, —C ０ ~C １２ Aliphatic-heterocycloalkyl, —C ０ ~C １２ Aliphatic-aryl, or -C ０ ~C １２ aliphatic-heteroaryl; R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is C ０ ~C ６ Alkylarylene, C ０ ~C ６ Alkylheteroarylene, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkylene, C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is OH or C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -OH, SH, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, R ｋ is H or M ＋ The counter ion is A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

32. 32. The compound of claim 31 having the structure of formula (IVa): 【Chemistry 27】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 28】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ７ is H or OH, R ９ is OR ｅ where R ｅ is H, C １ ~C ６ is alkyl or aryl, R １１ is C １ ~C ４ is alkyl, R １２ is H, —OH, —OC(O)R ｆ wherein R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -C ０ ~C １２ Aliphatic-C ３ ~C ７ Cycloalkyl, —C ０ ~C １２ Aliphatic-heterocycloalkyl, —C ０ ~C １２ Aliphatic-aryl, or -C ０ ~C １２ aliphatic-heteroaryl; R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is C ０ ~C ６ Alkylarylene, C ０ ~C ６ Alkylheteroarylene, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkylene, C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is OH or C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -OH, -SH, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ Alkyl, or when a N atom is present is substituted with an N-protecting group, Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, R ｋ is H or M ＋ The counter ion is A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

33. 32. The compound of claim 31 having the structure of formula (IVb): 【Chemistry 29】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Transformation 30】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ７ is H or OH, R ９ is OR ｅ where R ｅ is H, C １ ~C ６ is alkyl or aryl, R １１ is C １ ~C ４ is alkyl, R １２ is H, —OH, —OC(O)R ｆ wherein R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -C ０ ~C １２ Aliphatic-C ３ ~C ７ Cycloalkyl, —C ０ ~C １２ Aliphatic-heterocycloalkyl, —C ０ ~C １２ Aliphatic-aryl, or -C ０ ~C １２ aliphatic-heteroaryl; R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is C ０ ~C ６ Alkylarylene, C ０ ~C ６ Alkylheteroarylene, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkylene, C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is OH or C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -OH, -SH, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, R ｋ is H or M ＋ The counter ion is A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

34. 32. The compound of claim 31 having the structure of formula (V): 【Chemistry 31】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ５’ and R ６’ is H or R ５’ and R ６’ form a bond or, if allowed by valences, are attached to a common O atom to form an epoxide ring; R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Chemistry 32】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ６’ and R ７’ is H or R ６’ and R ７’ form a bond or, if allowed by valences, are attached to a common O atom to form an epoxide ring; R ７ is H or OH, R ９ is OR ｅ where R ｅ is H, C １ ~C ６ alkyl or aryl 、 R １１ is C １ ~C ４ is alkyl, R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is C ０ ~C ６ Alkylarylene, C ０ ~C ６ Alkylheteroarylene, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkylene, C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is OH or C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -OH, SH, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, R ｋ is H or M ＋ The counter ion is A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

35. 32. The compound of claim 31 having the structure of formula (Va): 【Transformation 33】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or an enantiomer or a pharmaceutically acceptable salt thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Transformation 34】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ７ is H or OH, R ９ is OR ｅ where R ｅ is H, C １ ~C ６ is alkyl or aryl, R １１ is C １ ~C ４ is alkyl, R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is C ０ ~C ６ Alkylarylene, C ０ ~C ６ Alkylheteroarylene, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkylene, C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is OH or C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -OH, -SH, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, R ｋ is H or M ＋ The counter ion is A compound, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, or an enantiomer or pharmaceutically acceptable salt thereof.

36. 32. The compound of claim 31 having the structure of formula (Vb): 【Chemistry 35】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony R ２ is C １ ~C ４ is alkyl, R ３ When (- - -) is a bond, it is O double-bonded to a ring carbon, or -OR ａ wherein R ａ is H or -C(O)R ａ１ and R ａ１ is C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ４ and R ５ are each independently H or -OR ｂ where R ｂ is H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R ｃ１ is H, C １ ~C ６ alkyl or two R ｃ１ together with the N atom form a 5- to 7-membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R ６ is the following equation: 【Transformation 36】 During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; R ９ is OR ｅ where R ｅ is H, C １ ~C ６ is alkyl or aryl, R １１ is C １ ~C ４ is alkyl, R １４ is H or OR ｇ wherein R ｇ is H or C １ ~C ６ is alkyl, R １７ and R １８ are each independently C １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ wherein R ｈ is H or C １ ~C ６ is alkyl, L is C ０ ~C ６ Alkylarylene, C ０ ~C ６ Alkylheteroarylene, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkylene, C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is OH or C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -OH, -SH, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, R ｋ is H or M ＋ The counter ion is A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

37. 32. The compound of claim 31 having the structure of formula (Vc): 【Chemistry 37】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR Ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R Ｃ１ is H, C １ ~C ６ alkyl or two R Ｃ１ which together with the N atom form a 5- to 7-membered ring containing 1 to 3 heteroatoms selected from N, O, and S forming a heterocyclyl, or R ６ teeth 【Transformation 38】 and During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; L is C ０ ~C ６ Alkylarylene, C ０ ~C ６ Alkylheteroarylene, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkylene, C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is OH or C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -OH, -SH, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ substituted with alkyl, or N-protecting groups if N atoms are present; Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, R ｋ is H or M ＋ The counter ion is A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

38. 32. The compound of claim 31 having the structure of formula (Vd): 【Chemistry 39】 or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, During the ceremony, R ６ is OH, halo, or —OC(O)R ｃ where R ｃ is -C １ ~C ６ Alkyl, -C １ ~C ６ Alkyl-(NR Ｃ１ ) ２ or -C １ ~C ６ AlkylC(O)OR ｋ and R Ｃ１ is H, C １ ~C ６ alkyl or two R Ｃ１ together with the N atom form a 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R ６ teeth 【Chemistry 40】 and During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ Each occurrence of is independently H or R Ｂ is R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2; L is C ０ ~C ６ Alkylarylene, C ０ ~C ６ Alkylheteroarylene, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkylene, C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, wherein said C １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene is OH or C １ ~C ４ optionally substituted with alkyl; R ２１ is H, -OH, -SH, -S(O) ２ R ｊ , -SR ｊ , -N(R ｊ ) ２ , -Si(R ｊ ) ３ , C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or —C(O)OR ｋ wherein said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl or adamantyl may optionally have 1 to 3 J １ wherein said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are optionally replaced with a heteroatom selected from N, O and S, and optionally C １ ~C ４ Alkyl, or when a N atom is present is substituted with an N-protecting group, Each R ｊ is independent, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkyl C ３ ~C ７ Cycloalkyl, C ０ ~C ６ Alkylheterocyclyl, C ０ ~C ６ Alkylaryl or C ０ ~C ６ alkylheteroaryl, wherein said C ３ ~C ７ The cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl may be selected from 1 to 3 J １ optionally replaced by J １ OH, CN, halo, C １ ~C ４ Alkyl and haloC １ ~C ４ alkyl, R ｋ is H or M ＋ The counter ion is A compound, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

39. R ２１ is C ３ ~C ７ cycloalkyl, ３ ~C ７ Cycloalkyl optionally has 1 to 3 J １ 39. The compound of any one of claims 31 to 38, substituted with:

40. Said C ３ ~C ７ cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; ３ ~C ７ Cycloalkyl is 1 to 3 J １ 40. The compound of claim 39, optionally substituted with

41. R ２１ is heterocyclyl, and said heterocyclyl optionally has 1 to 3 J １ 39. The compound of any one of claims 31 to 38, substituted with:

42. the heterocyclyl is selected from the group consisting of oxiranyl, oxetanyl, azetidinyl, oxazolyl, thiazolidinyl, thiazolyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and azapanyl; and the heterocyclyl is selected from the group consisting of 1 to 3 J １ 42. The compound of claim 41, optionally substituted with:

43. R ２１ is aryl, and said aryl is optionally selected from 1 to 3 J １ 39. The compound of any one of claims 31 to 38, substituted with:

44. R ２１ is phenyl or naphthyl, wherein said phenyl or naphthyl optionally contains 1 to 3 J １ 44. The compound of claim 43, substituted with:

45. R ２１ is heteroaryl, and said heteroaryl optionally has 1 to 3 J １ 39. The compound of any one of claims 31 to 38, substituted with:

46. wherein the heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, and quinolyl, and the heteroaryl optionally contains 1 to 3 J １ 46. ​​The compound of claim 45 substituted with:

47. R ２１ is adamantyl, and said adamantyl is optionally substituted with 1 to 3 J １ 39. The compound of any one of claims 31 to 38, substituted with:

48. R ２１ But Spiro C ５ ~C １２ cycloalkyl, wherein said spiro C ５ ~C １２ Cycloalkyl has 0-2 carbon atoms replaced by 0-2 heteroatoms selected from N, O, and S, and optionally 1-3 J １ or N-protected if N atom is present The compound of any one of claims 31 to 38, substituted with a group.

49. R ２１ is a 5- to 12-membered bridged bicyclyl, said bridged bicyclyl having 0-2 carbon atoms replaced by 0-2 heteroatoms selected from N, O, or S, and optionally 1-3 J １ or, if present, N atoms are substituted with N-protecting groups.

50. L is C １ ~C ６ Alkylene, C ３ ~C ６ Alkylene, or C ３ ~C １２ 50. The compound of any one of claims 31 to 49, which is alkylene.

51. L is C １ ~C ６ Alkenylene, C ３ ~C ６ Alkenylene, or C ３ ~C １２ 50. The compound of any one of claims 31 to 49, which is alkenylene.

52. 32. The compound of claim 31 , selected from the group consisting of the compounds of Table 2 or amino acid prodrugs thereof.

53. R ６ is of the following formula: 【Chemistry 41】 and During the ceremony, R Ａ each occurrence of is independently selected from the side chain of a natural or unnatural amino acid, where R Ａ each occurrence of may be the same or different, R Ｂ each occurrence of is independently H or R Ｂ is R Ａ and together with the N atom to which it is attached form a heterocyclic ring of a natural or unnatural amino acid, R Ｂ each occurrence of may be the same or different, p is 0, 1, or 2 53. The compound of any one of claims 1 to 52.

54. Each R Ａ are independently hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propane-1-yl (norvaline), 2-methylpropane-1-yl (leucine), 1-methylpropane-1-yl (isoleucine), butane-1-yl (norleucine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indol-3-ylmethyl (tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercapto methyl(cysteine), methylthiomethyl(S-methylcysteine), 2-mercaptoethyl(homocysteine), 2-methylthioethyl(methionine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), carboxymethyl(aspartic acid), 2-carboxyethyl(glutamic acid), 4-aminobutane-1-yl(lysine), 4-amino-3-hydroxybutane-1-yl(hydroxylysine), 3-aminopropane-1-yl(ornithine), 3-guanidinopropane-1-yl(arginine) or 3-ureido-propan-1-yl(citrulline); Each R Ｂ is H or R Ｂ is the adjacent R Ａ and together with the N atom form a prolyl side chain, 【Chemistry 42】 54. The compound of claim 53, wherein p is 0, 1, or 2.

55. Each R Ａ are independently methyl(alanine), propane-2-yl(valine), 2-methylpropane-1-yl(leucine), imidazol-4-ylmethyl(histidine), hydroxymethyl(serine), 1-hydroxyethyl(threonine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), 4-aminobutane-1-yl(lysine), carboxymethyl(aspartic acid), 3-guanidinopropane-1-yl(arginine), benzyl(phenylalanine), or 4-aminobutane-1-yl(lysine); R Ｂ is H, 55. The compound of claim 54, wherein p is 0, 1, or 2.

56. Each R Ａ are independently propane-2-yl (valine), 2-methylpropane-l-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutane-l-yl (lysine); Each R Ｂ is H, 55. The compound of claim 54, wherein p is 0, 1, or 2.

57. 55. The compound of claim 54, wherein p is 0.

58. 55. The compound of claim 54, wherein p is 1.

59. p is 1, First R Ａ is propane-2-yl (valine), and the second R Ａ is propane-2-yl (valine), and R Ｂ are each H (dipeptide Val-Val), or First R Ａ is 2-methylpropane-1-yl (leucine), and the second R Ａ is 2-methylpropane-1-yl (leucine), and R Ｂ are each H (the dipeptide Leu-Leu), or First R Ａ is methyl (alanine) and the second R Ａ is methyl (alanine), and R Ｂ are each H (dipeptide Ala-Ala), or First R Ａ is 4-aminobutane-1-yl (lysine), and the second R Ａ is 4-aminobutane-1-yl (lysine), and R Ｂ are each H (the dipeptide Lys-Lys), or First R Ａ is hydrogen, and the second R Ａ is 4-aminobutane-1-y1, and R Ｂ is H (dipeptide Gly-Lys).

60. 60. The compound of any one of claims 53-59, wherein each of the α-carbons of said amino acids other than glycine is in the L or D configuration.

61. 61. A pharmaceutical composition comprising a compound of any one of claims 1 to 60 and a pharmaceutically acceptable carrier.

62. 61. A method of activating protein kinase C, comprising contacting a mammalian cell with an effective amount of a compound of any one of claims 1-60.

63. 63. The method of claim 62, wherein the cell is a cancer cell.

64. 61. A method of treating cancer, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-60.

65. 65. The method of claim 64, wherein the cancer is selected from the group consisting of adrenocortical carcinoma, anal cancer, biliary tract cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, intestinal cancer, liver cancer, lung cancer, oral cancer, ovarian cancer, pancreatic cancer, kidney cancer, prostate cancer, salivary gland cancer, skin cancer, stomach cancer, testicular cancer, pharyngeal cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, and soft tissue cancer.

66. 65. The method of claim 64, wherein the cancer is a hematological cancer.

67. 67. The method of claim 66, wherein the hematological cancer is leukemia or lymphoma.

68. 68. The method of claim 67, wherein the hematological cancer is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell chronic myelogenous leukemia (CML), and multiple myeloma.

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