Diterpenoid compounds acting on protein kinase C (PKC)

Abstract

The present disclosure relates to methods of stimulating an immune response using compounds that activate protein kinase C (PKC), including methods for treating cancer, precancerous lesions, benign tumors, or wounds.

Description

[Technical Field]

[0001] Diterpenoid protein kinase C (PKC)-modulating compounds exhibit anticancer and cytotoxic activity. Most of these compounds studied are tigliane diterpenoids, such as phorbol esters and prostratin. The biological effects of these compounds are thought to be mediated by transactivation, translocation, and inhibition of PKC enzymes, which play important roles in regulating signaling pathways that control or regulate cellular structure and gene expression. [Background technology]

[0002] The link between PKC enzyme activation and its inhibitory effect on cancer cell proliferation is supported by studies of PKC mutations in human cancers, which found that the majority of PKC mutations were loss-of-function mutations (Antal et al., Cell, 2015, 160:489-502). The presence of PKC loss-of-function mutations in various cancer types suggests that PKC enzymes may function as tumor suppressors. Studies with prostratin suggest that its antitumor effect may be mediated by PKC enzyme activation that specifically targets the oncogene K-RAS (see Wang et al., Cell, 2015, 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 as well as PKC-independent mechanisms (Bond et al., Int. J. Cancer, 2007, 121:1445-1454).

[0003] In addition to their anti-cancer effects, PKC enzymes also appear to regulate immune responses (Isakov & Altman, Front Immunol., 2013, 4: 384). For example, PKC-θ has been implicated in T cell receptor clustering and TCR-mediated T cell activation (Sun et al., Nature, 2000, 404:402-407; Anderson et al., Autoimmunity, 2006, 39(6):469-478), whereas PKCε appears to be involved in LPS-mediated signaling in activated macrophages (Castrillo et al., J Exp Med., 2001, 194(9):1231-1242). However, the role of PKC enzymes in immune responses may be more complex. Deficiency of PKCδ may be involved in the activation of tolerance (i.e., self-tolerance) in B cells but not in the activation of immunogenic B cell responses (Mecklenbrauker et al., Nature, 2002, 416:860-865). Human patients with PKCδ deficiency exhibit severe autoimmunity and immunodeficiency-like B cell defects (Salzer et al., Blood, 2013, 121(16):3112-6). Another PKC isoform, PKCβ, also appears to be involved in regulating B cell activity. Mice with PKCβ knockouts exhibit impaired B cell activation, an inability to proliferate after B cell receptor stimulation, and defects in other T cell-independent immune responses (Lim et al., Immunology, 2015, 146:508-522). PKCμ is essential for the MyD88-dependent TLR signaling pathway, and PKCμ signaling is required for full maturation of the NLRP3 inflammasome (Park et al., J Immunol., 2009, 182(10): 6316-6327; Zhang et al., J Exp Med., 2017, 214(9): 2671-2693). Summary of the Invention

[0004] The present disclosure is based on the discovery presented herein that the protein kinase C (PKC)-modulating compounds disclosed herein enhance or stimulate the immune system. In one study, intratumoral injection of a PKC-modulating compound not only caused tumor necrosis in most animals, but also resulted in a durable immune memory that prevented tumor cell re-establishment after re-exposure in animals in which the original tumor had been eradicated. This durable immune memory was specific to the cancer cell type treated with the PKC-modulating compound, as exposure to a different cancer cell type in animals in which the original tumor had been eradicated did not prevent the establishment of the different cancer cell type. This effect was not observed in studies involving xenografts of human cancer cells in immunodeficient mice, supporting the involvement of the immune response in preventing re-establishment.

[0005] The results indicate that PKC-modulating compounds enhance or stimulate the immune response against cancer cells, with implications for the use of such compounds in the treatment of cancer, particularly cancers that have metastasized or established at different sites, and for the use of such compounds to enhance or stimulate the immune response in other diseases or conditions where such effects would be beneficial.

[0006] Thus, in one aspect, the present disclosure provides methods and uses of PKC modulating compounds, particularly the PKC activating compounds of the present disclosure, for enhancing or stimulating the immune system. In some embodiments, the present disclosure provides methods of enhancing or stimulating an immune response in a subject by administering to a subject in need thereof an amount of a PKC activator effective to enhance or stimulate the immune system in the subject.

[0007] In some embodiments, the stimulated or enhanced immune response is directed against a cancer or cancer antigen, or a precancerous lesion or growth, or a benign tumor. In some embodiments, a method of treating a cancer, or a precancerous lesion or growth, or a benign tumor comprises administering to a subject in need thereof an effective amount of a PKC activator sufficient to stimulate or enhance an immune response against the cancer or cancer antigen, or the precancerous lesion or growth, or the benign tumor.

[0008] In some embodiments, the PKC-activating compound is administered locally, e.g., intratumorally, or topically, where tolerated, to the site of the cancer or cancer antigen, or to a precancerous lesion or growth, or to a benign tumor.

[0009] In some embodiments, the method or use comprises administering or administering one or more additional doses of an effective amount of a PKC activator to further stimulate or enhance an immune response to a cancer or cancer antigen, or a precancerous lesion or growth, or a benign tumor. In some embodiments, the one or more additional doses or administrations are to at least a locus, mass, or site of a second cancer different from the locus, mass, or site of a first cancer or cancer antigen, or a second precancerous lesion or growth at a site different from the first precancerous lesion or growth, or a locus, mass, or site of a second benign tumor different from the locus, mass, or site of a first benign tumor.

[0010] In some embodiments, the effective amount administered is sufficient to induce necrosis of cancer or cancer antigen-containing cells, or precancerous lesions or growths, or benign tumors. In some embodiments, the administration or treatment is effective to induce regression in non-target cancer loci or masses, or non-target cancer antigen-expressing cells, or non-target precancerous lesions or growths, or non-target benign tumors. In some embodiments, the administration or treatment is effective to generate immunological memory against cancer, cancer antigens, or precancerous lesions or growths, or benign tumors.

[0011] In some embodiments, the cancer to be treated is adenocarcinoma, adrenocortical carcinoma, anal cancer, angiosarcoma, biliary tract cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, cutaneous lymphoma, endometrial cancer, esophageal cancer, fibrosarcoma, fibroxanthoma, head and neck cancer, intestinal cancer, liver cancer, lung cancer, mast cell tumor, oral cancer, ovarian cancer, pancreatic cancer, kidney cancer, prostate cancer, salivary gland cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, or soft tissue carcinoma.

[0012] In some embodiments, the cancer to be treated is a blood cancer, such as leukemia or lymphoma. In some embodiments, the blood cancer is lymphoblastic 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.

[0013] In some embodiments, the precancerous lesion or growth to be treated with the compound is an actinic keratosis.

[0014] In some embodiments, the stimulating or enhancing immune response is to treat a benign tumor.

[0015] In some embodiments, the benign tumor treated with the compound is an adenoma, fibroma, lipoma, fibroma, neuroma, papilloma, or osteochondrosarcoma, hi some embodiments, the benign tumor treated with the compound is a basal cell carcinoma, neurofibroma, dermatofibroma, epidermoid, or hemangioma.

[0016] In some embodiments, the stimulating or enhancing immune response is for the treatment of a wound, hi some embodiments, a method of treating a wound comprises administering to a subject in need thereof an effective amount of a PKC activator compound to treat the wound.

[0017] In some embodiments, the PKC activator is administered locally to the wound. In some embodiments, the PKC activator is administered topically to the wound.

[0018] In some embodiments, treating a wound comprises administering an effective amount of a PKC activator compound to promote wound healing and / or to treat or prevent infection of the wound. In some embodiments, an effective amount of a PKC activator is administered to prevent infection of the wound or to treat a persistent or existing infection of the wound.

[0019] In some embodiments, an effective amount of a PKC activator is administered to increase the rate of wound healing. In some embodiments, an effective amount of a PKC activator is administered to reduce scarring, particularly excessive scarring, in wound tissue.

[0020] In some embodiments, the administered effective amount of a PKC activator reduces scarring that is a keloid or hypertrophic scar.

[0021] In some embodiments, the PKC activator compound for use in the methods is a diterpenoid PKC activator compound. In some embodiments, the compound is a compound of formula (I):

[0022] [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 a H or M counterion; R 2 is C1-C4 alkyl; R 3is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5 ' and R 6 Each ' is independently H or OH, or R 5 ' and R 6 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0023] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2; R 6 ' is H or OH, and R 7 ' is H, or R 6 ' and R 7 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 7 is H or OH; R 9 is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl; R 14 is H or OR g and;Rg is H or C1-C6 alkyl; R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-OR h and R h is H or C1-C6 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0024] In some embodiments, A is -OH. In some embodiments, A is -C(O)OR 1 and R 1 is H or M + In some embodiments, A is -NR 13 R 13’ and R 13 and R 13’ are each independently H or C1-C4 alkyl.

[0025] In some embodiments, the compound is a compound of formula (II):

[0026] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R bis H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5 ' and R 6 Each ' is independently H or OH, or R 5 ' and R 6 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0027] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, BEach occurrence of may be the same or different; p is 0, 1, or 2; R 6 ' is H or OH, and R 7 ' is H, or R 6 ' and R 7 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 7 is H or OH; R 9 is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0028] In some embodiments, the compound is a compound of formula (IIc):

[0029] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0030] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and R fis C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0031] In some embodiments, the compound is a compound of formula (IV):

[0032] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5 ' and R 6Each ' is independently H or OH, or R 5 ' and R 6 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0033] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2; R 6 ' is H or OH, and R 7 ' is H, or R6 ' and R 7 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 7 is H or OH; R 9 is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 is H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkyl, C3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein the C1 to C 12 Alkylene or C2-C 12 alkenylene is optionally substituted by OH or C1-C4 alkyl; R 21 are H, -OH, -SH, -S(O)2R j , -SR j , -N(Rj )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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1-2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and are optionally substituted by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is 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. [Brief explanation of the drawings]

[0034] [Figure 1] Figure 1 shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds, as assessed by measuring the levels of phosphorylated PKC protein (p-PKC) and phosphorylated ERK1 / 2 protein (p-ERK1 / 2). [Figure 2]Figure 2 shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds, as assessed by measuring the levels of phosphorylated PKC protein (p-PKC) and phosphorylated ERK1 / 2 protein (p-ERK1 / 2). [Figure 3] Figure 3 shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds, assessed by measuring the levels of phosphorylated PKC protein (p-PKC) and phosphorylated ERK1 / 2 protein (p-ERK1 / 2); prostratin (K101) is provided for comparison. [Figure 4-1] FIG. 4A shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds based on the levels of phosphorylated PKC protein (p-PKC) and phosphorylated ERK1 / 2 protein (p-ERK1 / 2). [Figure 4-2] 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. [Figure 5] FIG. 5 shows the effect of selected diterpenoid compounds on the levels of phosphorylated CaMKii (p-CaMKii), a marker of K-Ras stemness pathway inhibition, in the Panc1 pancreatic cancer cell line. [Figure 6-1] Figures 6A-6D show sphere formation by the Panc1 pancreatic cancer cell line treated with different diterpenoid compounds. [Figure 6-2] Figures 6A-6D show sphere formation by the Panc1 pancreatic cancer cell line treated with different diterpenoid compounds. [Figure 6-3] Figures 6A-6D show sphere formation by the Panc1 pancreatic cancer cell line treated with different diterpenoid compounds. [Figure 6-4] Figures 6A-6D show sphere formation by the Panc1 pancreatic cancer cell line treated with different diterpenoid compounds. [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. [Figure 8-1] Figure 8 (Panels A-F) shows the levels of various cytokines in peripheral blood mononuclear cell (PMBC) preparations treated with PKC activating compounds. Panel A: IFNγ; Panel B: GM-CSF; Panel C: IL-13; Panel D: IL-2; Panel E: TNF-α; and Panel F: IL-6. IFNγ, GM-CSF, and IL-13 expression were potently induced by PKC activator compounds in a dose-dependent manner (up to a 10-fold increase over DMSO). The symbols are as follows: PMA + Iono. = PMA 50 ng / mL + ionomycin 1 μg / mL; Resi. = resiquimod (TLR7 / 8); LPS = lipopolysaccharide derived from the outer membrane of gram-negative bacteria; K-47 = K101-C1347; K-802 = K101-C134802; and K-801 = K101-C134801. [Figure 8-2] Figure 8 (Panels A-F) shows the levels of various cytokines in peripheral blood mononuclear cell (PMBC) preparations treated with PKC activating compounds. Panel A: IFNγ; Panel B: GM-CSF; Panel C: IL-13; Panel D: IL-2; Panel E: TNF-α; and Panel F: IL-6. IFNγ, GM-CSF, and IL-13 expression were potently induced by PKC activator compounds in a dose-dependent manner (up to a 10-fold increase over DMSO). The symbols are as follows: PMA + Iono. = PMA 50 ng / mL + ionomycin 1 μg / mL; Resi. = resiquimod (TLR7 / 8); LPS = lipopolysaccharide derived from the outer membrane of gram-negative bacteria; K-47 = K101-C1347; K-802 = K101-C134802; and K-801 = K101-C134801. [Figure 9-1]Figure 9 (Panels A-D) shows the in vivo efficacy results of compound K101-C134801 in the orthotopic 4T1-luc2 breast cancer metastasis model. Panel A: Bioluminescence signals of individual female Balb / c mice bearing 4T1-luc2 tumors after treatment with vehicle (upper panel) or K101-C134801 (lower panel). Panel B: Bioluminescence images of representative female Balb / c mice bearing 4T1-luc2 tumors after treatment with vehicle (left) or K101-C134801 (right). Panel C: Animal survival curves after administration of vehicle or K101-C134801 to female Balb / c mice bearing 4T1-luc2 tumors. Mortality included animal death or sacrifice. Panel D: Bioluminescence images of lung metastases in representative female Balb / c mice bearing 4T1-luc2 tumors after treatment with vehicle (top row) or K101-C134801 (bottom row) on day 28. The primary tumor location (abdomen) of vehicle-treated mice was masked to allow proper visualization of the bioluminescence signal. [Figure 9-2] Figure 9 (Panels A-D) shows the in vivo efficacy results of compound K101-C134801 in the orthotopic 4T1-luc2 breast cancer metastasis model. Panel A: Bioluminescence signals from individual female Balb / c mice bearing 4T1-luc2 tumors after treatment with vehicle (top panel) or K101-C134801 (bottom panel). Panel B: Bioluminescence images of representative female Balb / c mice bearing 4T1-luc2 tumors after treatment with vehicle (left) or K101-C134801 (right). Panel C: Animal survival curves after administration of vehicle or K101-C134801 to female Balb / c mice bearing 4T1-luc2 tumors. Mortality included animal death or sacrifice. Panel D: Bioluminescence images of lung metastases in representative female Balb / c mice bearing 4T1-luc2 tumors after treatment with vehicle (top row) or K101-C134801 (bottom row) on day 28. The primary tumor location (abdomen) of vehicle-treated mice was masked to allow proper visualization of the bioluminescence signal. [Figure 9-3]Figure 9 (Panels A-D) shows the in vivo efficacy results of compound K101-C134801 in the orthotopic 4T1-luc2 breast cancer metastasis model. Panel A: Bioluminescence signals from individual female Balb / c mice bearing 4T1-luc2 tumors after treatment with vehicle (top panel) or K101-C134801 (bottom panel). Panel B: Bioluminescence images of representative female Balb / c mice bearing 4T1-luc2 tumors after treatment with vehicle (left) or K101-C134801 (right). Panel C: Animal survival curves after administration of vehicle or K101-C134801 to female Balb / c mice bearing 4T1-luc2 tumors. Mortality included animal death or sacrifice. Panel D: Bioluminescence images of lung metastases in representative female Balb / c mice bearing 4T1-luc2 tumors after treatment with vehicle (top row) or K101-C134801 (bottom row) on day 28. The primary tumor location (abdomen) of vehicle-treated mice was masked to allow proper visualization of the bioluminescence signal. [Figure 10] Figure 10 shows the results of an in vivo efficacy study of K101-C134801 as a single agent or in combination with an anti-PD1 antibody in the MC38 syngenic model. Animal survival rates after administration of K101-C134801 as a single agent or in combination with anti-PD1 to MC38 tumor-bearing female C57 / 6J mice (left panel: low-dose group; right panel: high-dose group). [Figure 11-1]Figure 11 (Panels A-C) shows the results of an in vivo efficacy study of compound K101-C134801 as a single agent in the CT26 syngenic model by intratumoral (IT) injection. Panel A: Tumor volume after administration of vehicle or compound K101-C134801 to CT26 tumor-bearing female Balb / c mice; data points represent group mean tumor volume. Error bars represent standard error of the mean (SEM). Panel B: Animal survival curves for vehicle- or K101-C134801-treated groups; mortality events included animal death and sacrifice. Panel C: Tumor volume after reimplantation of CT26 cells (left panel) and 4T1 cells (right panel) into control mice and tumor-eradicated mice pretreated with compound K101-C134801; data points represent group means, and error bars represent standard error of the mean (SEM). [Figure 11-2] Figure 11 (Panels A-C) shows the results of an in vivo efficacy study of compound K101-C134801 as a single agent in the CT26 syngenic model by intratumoral (IT) injection. Panel A: Tumor volume after administration of vehicle or compound K101-C134801 to CT26 tumor-bearing female Balb / c mice; data points represent group mean tumor volume. Error bars represent standard error of the mean (SEM). Panel B: Animal survival curves for vehicle- or K101-C134801-treated groups; mortality events included animal death and sacrifice. Panel C: Tumor volume after reimplantation of CT26 cells (left panel) and 4T1 cells (right panel) into control mice and tumor-eradicated mice pretreated with compound K101-C134801; data points represent group means, and error bars represent standard error of the mean (SEM). [Figure 12] FIG. 12 shows the analysis of tumor tissue sections by hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) with anti-CD31 antibody 24 hours after a single intratumoral injection of compound K101-C134801C2003. DETAILED DESCRIPTION OF THE INVENTION

[0035] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to "a protein" includes two or more proteins, and reference to "a compound" refers to two or more compounds.

[0036] Also, unless otherwise stated, the use of "or" means "and / or." Similarly, "comprise," "comprises," "comprising," "include," "includes," and "including" are interchangeable and are not intended to be limiting.

[0037] Additionally, it should be understood that when the description of various embodiments uses the word "comprising," those skilled in the art will understand that in some instances, the embodiments may instead be described using the phrase "consisting essentially of" or "consisting of."

[0038] 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 of the invention described.

[0039] 1.Definition For the purposes of this disclosure, the technical and scientific terms used in the description herein have the meanings commonly understood by those skilled in the art unless otherwise defined. Accordingly, the following terms are intended to have the meanings set forth below:

[0040] "Alkyl" refers to an alkyl group having 1 to 20 carbon atoms, specifically 1 to 12 carbon atoms (C1 to C 12or C 1~12 ), more specifically (C1 to C8 or C 1~8 ) 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.

[0041] "Alkenyl" refers to an alkyl group having 2 to 20 carbon atoms, specifically 2 to 12 carbon atoms (C2 to C 12 or C 2~12 ), most specifically 2 to 8 (C2 to C8 or C 2~8 ) carbon atoms and having at least one double bond. 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.

[0042] "Alkynyl" means an alkyl group containing 2 to 12 carbon atoms (C2-C 12 or C 2-12 ), specifically 2 to 8 carbon atoms (C2 to C8 or C 2~8 ) and containing at least one triple bond. 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.

[0043] "Alkylene," "alkenylene," and "alkynylene" refer to the corresponding alkyl, alkenyl, and alkynyl straight-chain or branched-chain divalent hydrocarbon radicals, which may be optionally substituted, for example, with alkyl, alkyloxy, hydroxyl, carbonyl, carboxyl, halo, nitro, etc.

[0044] "Aliphatic" refers to an organic compound characterized by a chain of constituent carbon atoms that is substituted or unsubstituted, linear or branched, and / or cyclic. Aliphatic compounds do not contain aromatic rings as part of the compound's molecular structure. Aliphatic compounds are defined as compounds 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.

[0045] "Lower" with reference to a substituent means that the group has from 1 to 6 carbon atoms.

[0046] "Cycloalkyl" refers to any stable mono- or multi-cyclic ring system composed of carbon atoms, all of whose rings are saturated. "Cycloalkenyl" refers to any stable mono- or multi-cyclic ring system composed of carbon atoms, all of whose rings are partially unsaturated. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloalkyl, and tricycloalkyl (e.g., adamantyl).

[0047] "Heterocycloalkyl" or "heterocyclyl" refers to a substituted or unsubstituted, 3- to 14-membered, monocyclic or bicyclic, non-aromatic hydrocarbon in which one to three 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'-, and the like, 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.

[0048] "Carbocycle," "carbocyclyl," and "carbocyclic," as used herein, 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 a higher-order ring. Thus, the terms "carbocycle," "carbocyclyl," and "carbocyclic" encompass fused, bridged, and spiro ring systems; preferably, a carbocycle contains 3 to 14 atoms, e.g., 3 to 8 or 5 to 7 atoms, e.g., 6 atoms.

[0049] "Aryl" refers to a 6- to 14-membered, monocyclic or bicyclic carbocyclic ring, where the monocyclic ring is aromatic and at least one ring in a bicyclic ring is aromatic. Unless otherwise specified, the valency of this group may be located on any atom of any ring within the radical, valency rules permitting. Examples of "aryl" groups include phenyl, naphthyl, indenyl, biphenyl, phenanthrenyl, naphthacenyl, and the like.

[0050] "Heteroaryl" refers to an aromatic heterocycle, including both monocyclic and bicyclic ring systems, in which at least one carbon atom in one or both rings is replaced independently with a heteroatom selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms in one or both rings are replaced independently with a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, 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.

[0051] "Bridged bicyclic" refers to any bicyclic ring system, i.e., a carbocyclic or heterocyclic, saturated or partially unsaturated, bicyclic ring system, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or atoms or valence bond connecting two bridgeheads, where a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 5 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Such bridged bicyclic groups include the groups described below, each group being attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, as described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic groups include:

[0052] [ka] "Fused ring" refers to a ring system in which two or more rings share at least one bond and two atoms. "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 with another ring.

[0053] "Carbonyl" refers to -C(O)-. The carbonyl radical 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.

[0054] "Halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine.

[0055] "Haloalkyl" refers to an alkyl substituted with one or more halogen atoms. Preferably, the alkyl is substituted with 1 to 3 halogen atoms.

[0056] "Hydroxy" refers to --OH.

[0057] "Oxy" refers to an -O- group, 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 an optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0058] "Acyl" refers to -C(O)R', where R is hydrogen or an optionally substituted alkyl, heteroalkyl, cyclo(cylco)alkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, as defined herein. Exemplary acyl groups include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

[0059] "Alkyloxy" or "alkoxy" refers to --OR', where R' is an optionally substituted alkyl.

[0060] "Aryloxy" refers to --OR', where R' is an optionally substituted aryl.

[0061] "Carboxy" means -COO - or COOM (H or M + Counterion).

[0062] "Carbamoyl" refers to -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.

[0063] "Cyano" refers to -CN.

[0064] "Ester" refers to a group such as -C(=O)OR', or alternatively designated -C(O)OR', where R' is an optionally substituted group selected from: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0065] "Silyl" refers to Si and may have various substituents, such as -SiR'R'R', where R' is as defined herein. For example, each R' is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyclo(heterocylo)alkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. As defined herein, any heterocycloalkyl or heteroaryl group present in a silyl group has 1 to 3 heteroatoms independently selected from O, N, and S.

[0066] "Thiol" refers to -SH.

[0067] "Sulfanyl" refers to -SR', where R' is an optionally substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyclo(heterocylo)alkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. For example, -SR, where R is alkyl, is alkylsulfanyl.

[0068] "Sulfonyl" refers to -S(O)-, which can have various substituents to form various sulfonyl groups, including sulfonic acids, sulfonamides, sulfonate esters, and sulfones. For example, -S(O)R', where R' is alkyl, is referred to as alkylsulfonyl. In some -S(O)R' embodiments, R' is selected from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocyclo(heterocylo)alkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0069] "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.

[0070] "Amido" refers to a group such as --C(.dbd.O)NR'R', where each R' is independently selected from H and optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0071] "Spiroalkyl," as used herein, refers to a monospiro compound having two alicyclic rings joined through a common carbon atom. In some embodiments, the spiro compound has a total of 5 to 12 ring atoms (e.g., C5 to C6). 12 or C5~ 12 In some embodiments, one or more carbon atoms may 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.

[0072] "Adamantyl" refers to a compound having the following structural formula:

[0073] [ka] Optional substitutions are R a , R b , R c , and Rd and 2-adamantyl. Adamantyl includes substituted adamantyl, e.g., 1-adamantyl 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).

[0074] As used herein, the term "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 described in Greene's Protective Groups in Organic Synthesis, 5th Edition, PGM Wuts, ed., Wiley (2014).

[0075] "Optionally present" or "optionally" means that the described event or circumstance may or may not occur, and that the statement encompasses 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 be substituted or unsubstituted, and that the statement encompasses both substituted and unsubstituted alkyl groups.

[0076] "Substituted," as used herein, means that one or more hydrogen atoms of a group are replaced with an atom or group commonly used as a substituent in pharmaceutical chemistry. Each substituent can 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+R', S(O)R', SO2R', NR 'R' includes, but is not limited to, primary amines (i.e., NH), secondary amines, tertiary amines, amides, carbamates, ureas, etc., hydrazide, halo, nitrile, nitro, sulfide, sulfoxide, sulfone, sulfonamide, thiol, carboxy, aldehyde, keto, carboxylic acid, ester, amide, imine, and imide, including seleno and thio derivatives thereof, each of the foregoing substituents optionally being further substituted. In embodiments where the aromatic carbocyclic functional group is substituted, such substitutions are typically less than about 10 substitutions, more preferably about 1-5 substitutions, with about 1 or 2 substitutions being preferred.

[0077] "Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but with different three-dimensional structures and are not interchangeable. Thus, "the stereoisomer" of a compound includes all stereoisomers and mixtures of stereoisomers of that compound, and also includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. If a compound has multiple chiral centers, the compound can exist as individual diastereomers or as a mixture of diastereomers.

[0078] "Tautomer" refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. Thus, "a tautomer of a compound" refers to all tautomers of that compound.

[0079] A "prodrug" refers to a derivative of an active compound (e.g., a drug) that requires transformation under use conditions, such as in vivo or 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 within the drug, believed to be partially necessary for activity, with a progroup, which undergoes a transformation, such as cleavage, to form a promoiety that releases the functional group and thus the active drug, under specific use conditions. Cleavage of the promoiety may proceed spontaneously, such as by hydrolysis, or may be catalyzed or induced by another agent (e.g., an enzyme), light, acid, or a change in exposure to a physical or environmental parameter (e.g., 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 it may be supplied exogenously.

[0080] A variety of progroups and resulting promoieties suitable for masking functional groups of active drugs to yield prodrugs can be used. For example, a hydroxyl functional group can be masked as a sulfonic acid, ester, or carbonate promoiety, which can be hydrolyzed in vivo to yield a 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 yield an amino group. A carboxyl group can be masked as an ester (including silyl esters and thioesters), amide, or hydrazide promoiety, which can be hydrolyzed in vivo to yield a carboxyl group. Included within the scope of prodrugs are, among others, "biohydrolyzable carbonate" groups, "biohydrolyzable ureido" groups, "biohydrolyzable carbamate" groups, "biohydrolyzable ester" groups, "biohydrolyzable amide" groups, and "biohydrolyzable phosphate" groups.

[0081] "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. By way of example and not limitation, the solvent can be water, ethanol, or acetic acid.

[0082] "Hydrate" refers to a combination of water and a solute, such as a PKC activator compound, where the water is absorbed, adsorbed, or contained within the crystal lattice of the solute (e.g., a PKC activator compound) while retaining its molecular state as water.

[0083] "Pharmaceutically acceptable salts" are intended to encompass salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents present on the compounds described herein. When a compound of the present invention contains a relatively acidic functionality, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts. When a compound of the present invention contains a relatively basic functionality, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, phosphoric, partially neutralized phosphoric, sulfuric, partially neutralized sulfuric, hydroiodic, or phosphorous acids, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic or galactunoric acid. Certain compounds of the present disclosure may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Lists of suitable salts can be found in Remington's Pharmaceutical 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.

[0084] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to an excipient, carrier, or adjuvant that can be administered to a subject along with at least one therapeutic agent, does not destroy the pharmacological activity of the agent, and is generally safe, non-toxic, and not biologically or otherwise objectionable when administered in a dose sufficient to deliver a therapeutic amount of the agent.

[0085] "K-RAS" refers to Kirsten rat sarcoma viral oncogene homolog, a small GTPase and member of the RAS protein family 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.

[0086] "Mutant K-RAS polypeptide," "mutant K-RAS protein," and "mutant K-RAS" are used interchangeably and refer to a K-RAS polypeptide that contains at least one K-RAS mutation when 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.

[0087] "N-RAS" refers to the viral neuroblastoma RAS (V-RAS) oncogene homolog, a member of the RAS protein family, which is a small GTPase and is involved in signal transduction. The nucleic acid sequence and protein sequence of an exemplary human N-RAS are provided in NCBI Accession No. NP_002515 and GeneBank Accession No. X02751, respectively. "N-RAS" as used herein encompasses variants, including orthologs and interspecies homologs, of the human N-RAS protein.

[0088] "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 when compared to the corresponding wild-type N-RAS sequence. Certain 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.

[0089] "H-RAS" refers to Harvey rat sarcoma viral oncogene homolog, a small GTPase and member of the RAS protein family involved in signal transduction. Exemplary human H-RAS nucleic acid and protein sequences are provided in NCBI Accession No. P01112 and GeneBank Accession No. NM_176795, respectively. "H-RAS," as used herein, encompasses variants, including orthologs and interspecies homologs, of the human H-RAS protein.

[0090] "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 when compared to the corresponding wild-type H-RAS sequence. Certain 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.

[0091] "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 be due to mutations or, in some embodiments, due to overexpression of the K-RAS protein.

[0092] "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 be due to mutations or, in some embodiments, due to overexpression of the N-RAS protein.

[0093] "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 be due to mutations or, in some embodiments, overexpression of the H-RAS protein.

[0094] "Mutation" or "variant" refers to an amino acid or polynucleotide sequence that has been altered by substitution, insertion, and / or deletion. In some embodiments, the mutated or variant sequence may have increased, decreased, or substantially the same activity or property as the parent sequence.

[0095] "Identified" or "determined" refers to analyzing, detecting, or performing an action on the presence or absence of one or more particular characteristics.

[0096] "Wild-type" or "naturally occurring" refers to a form that occurs in nature. For example, a naturally occurring or wild-type polypeptide or polynucleotide sequence is a sequence that can be isolated from a source in nature and that is present in an organism without being intentionally modified by human manipulation.

[0097] "Control" or "control sample" or "control group" refers to a sample or group that is compared to another sample or group; typically, the control sample or control group is the same as the comparison group except for one or more comparison elements.

[0098] "Selecting" refers to the process of determining that a subject will be administered a drug to treat the occurrence of a condition. Selection can be based on, for example, an individual's susceptibility to a particular disease or condition due to the presence of one or more identifiable cellular, physiological, or environmental factors. In some embodiments, selection can be based on determining or identifying whether a subject is responsive to a drug, 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 drug or treatment.

[0099] 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 tests such as Pap smears or blood smears, or cell samples obtained by microdissection), or cell fractions, debris, or organelles (such as those obtained by lysing cells and centrifuging or otherwise separating their compartments). Other examples of biological samples include blood, serum, urine, semen, feces, cerebrospinal fluid, interstitial fluid, mucous membranes, tears, sweat, pus, biopsy tissue (e.g., obtained by surgical biopsy or needle biopsy), nipple aspirate, milk, vaginal fluid, saliva, swab (e.g., buccal swab), or any material containing biomolecules derived from a first biological sample. In certain embodiments, the biological sample is a "cell-free sample," such as cell-free or extracellular polynucleotides and cell-free or extracellular proteins. In some embodiments, cell-free DNA or cfDNA refers to extracellular DNA obtained from blood, particularly serum.

[0100] "Subject," as used herein, refers to a mammal, e.g., a dog, cat, horse, or rabbit. In some embodiments, the subject is a non-human primate, e.g., a monkey, chimpanzee, or gorilla. In some embodiments, the subject is a human, and may be referred to herein as a patient.

[0101] "Treating" or "treatment" of a disease, disorder, or syndrome, as used herein, 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 occurring in an animal that may have been exposed to or may be predisposed to the disease, disorder, or syndrome, but that has not yet experienced or exhibited symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its occurrence; and (iii) alleviating the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As known in the art, adjustments for systemic versus local delivery, age, weight, overall health, sex, diet, timing of administration, drug interactions, and severity of the condition may be necessary and can be ascertained by one of ordinary skill in the art with routine experimentation, especially in light of the guidance provided in this disclosure.

[0102] A "therapeutically effective amount" refers to the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for such disease, disorder or condition.

[0103] 2. Use and Methods As mentioned above, the present disclosure describes results demonstrating the effectiveness of PKC activation in stimulating or enhancing immune responses. Diterpenoid PKC-activating compounds, particularly those disclosed herein, activate cytokine production in PMBCs and activate NFκB expression, a transcription factor that plays a crucial role in the development of innate immunity. Surprisingly, a single intratumoral administration of a PKC-activating compound appears to induce durable immunological memory against cancer cells treated with the compounds herein, as demonstrated by the resistance of treated animals to cancer cell recolonization after reinoculation. As noted above, the lack of resistance to recolonization after reinoculation in cancer cell xenograft models using immunodeficient animals with impaired adaptive immune responses strongly supports the role of the immune system in resistance to tumor cell recolonization. Because reinoculation with cancer cells from a different tissue does not confer robust resistance to recolonization, durable immunological memory is specific to the cancer type treated.

[0104] These results provide a basis for the treatment of tumors, particularly cancers that have established themselves in multiple sites, such as metastatic cancers; the treatment of precancerous lesions or growths; the treatment of benign tumors; and other disorders or conditions that would benefit from an activated or enhanced immune response, such as the treatment of wounds.

[0105] Thus, in some embodiments, the present disclosure provides a method for stimulating or enhancing an immune response, comprising administering to a subject in need thereof an effective amount of a PKC-activating compound. In some embodiments, the PKC-activating compound is a diterpenoid PKC-activating compound, as further described below. In some embodiments, the PKC-activating compound is a compound disclosed herein.

[0106] In some embodiments, the stimulated or enhanced immune response is directed against a cancer or cancer antigen, or a precancerous lesion or growth, or a benign tumor in a subject in need thereof. In some embodiments, the method for stimulating or enhancing an immune response against a cancer or cancer antigen, or a precancerous lesion or growth, or a benign tumor comprises administering to a subject in need thereof an effective amount of a PKC activating compound. The amount of the compound administered is an amount effective to stimulate or enhance an immune response against the cancer, cancer antigen, or precancerous lesion or growth, or a benign tumor.

[0107] In some embodiments, the compound is administered locally to a first cancer locus, mass, or site, or a first precancerous lesion or growth, or a first benign tumor locus, mass, or site. In some embodiments, a first cancer locus, mass, or site, or a first precancerous lesion or growth, or a first benign tumor locus, mass, or site refers to a primary cancer locus, mass, or site, or a primary precancerous lesion or growth, or a primary benign tumor locus, mass, or site. Local administration refers to administration to a cancer mass or site, the location of cells expressing a cancer antigen, or a precancerous lesion or growth mass or site, or a benign tumor mass or site. This is in contrast to systemic administration, such as intravenous or oral administration.

[0108] In some embodiments of the method, the compound is administered locally intratumorally (e.g., via intratumoral injection) to the cancer, or directly to the precancerous lesion or growth, or intratumorally to the benign tumor.

[0109] In some embodiments, where acceptable or appropriate, the compounds are administered topically, i.e., by topical administration.

[0110] In some embodiments, one or more additional effective doses of the compound are administered to further stimulate or enhance the immune response to cancer or cancer antigens, or precancerous lesions or growths, or benign tumors.

[0111] In some embodiments, the one or more additional administrations include one, two, three, four, five, six, seven, eight, nine, or up to ten administrations. In some embodiments, the one or more additional administrations can be to the same locus or mass of a cancer or cancer antigen, or to a locus or mass of a precancerous lesion or growth, or to a locus or mass of a benign tumor. In some embodiments, the additional administrations can be to overlapping areas, for example, based on the zone or size or area of ​​necrosis induced by administration of the compound. In some embodiments, the additional administrations can be to non-overlapping zones or areas, for example, beyond the zone or size of the necrotic area induced by administration of the compound. In some embodiments, administration to non-overlapping zones or areas is used to administer the compound to part or all of the locus or mass where a cancer or cancer antigen is present, or to a locus or mass of a precancerous lesion or growth, or to a locus or mass of a benign tumor.

[0112] In some embodiments, the one or more additional administrations can be spaced apart by, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours, or by 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, or by 1 week, 2 weeks, 3 weeks, or 4 weeks. Each period can include one or more administrations to constitute a treatment. For example, a first or initial treatment with one or more administrations of the compound can be followed by a second treatment with one or more administrations of the compound, with the first treatment being spaced apart from the second or subsequent treatment. In some embodiments, the treatment period can be 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, or 4 weeks between treatments.

[0113] In some embodiments, the compound can be administered systemically after local administration, for example, by intravenous administration or oral administration.In some embodiments, the compound can be administered systemically after systemic administration.For example, in some embodiments, the compound can be administered locally, for example, intratumorally, to treat cancer, or to enhance or stimulate the immune response to cancer antigens, or to treat precancerous lesions or benign tumors, and can be administered systemically (a) to further induce immune responses against cancer or cancer cells expressing cancer antigens at multiple sites within the subject, i.e., to reduce the risk of metastatic tumor establishment; (b) to further induce immune responses against precancerous lesions, i.e., to reduce the risk of precancerous lesions transforming into cancer; or (c) to further induce immune responses against benign tumors, i.e., to treat benign tumors present at multiple sites or reduce the risk of benign tumor recurrence, etc.

[0114] In some embodiments, the one or more additional administrations or treatments are to at least a cancer or cancer antigen locus or mass, or a precancerous lesion or growth locus or mass, or a benign tumor locus or mass at a different location, e.g., distal, from the location of the first cancer or cancer antigen cancer locus or mass, or the first precancerous lesion or growth, or the first benign tumor locus or mass. In some embodiments, the compound is administered locally at the first or primary cancer or cancer antigen locus or mass, or the first or primary precancerous lesion or growth, or the first or primary benign tumor locus or mass, and locally at the second cancer or cancer antigen locus or mass, or the second precancerous lesion or growth, or the second benign tumor locus or mass, or the second benign tumor locus or mass. In some embodiments, the locus, mass, or site of the second cancer or cancer antigen, or the locus, mass, or site of the second precancerous lesion or growth, or the locus, mass, or site of the second benign tumor, is distal to the locus, mass, or site of the first or primary cancer or cancer antigen, or the locus, mass, or site of the first or primary precancerous lesion or growth, or the first or primary benign tumor.

[0115] In some embodiments, the compound is administered in an amount effective to induce necrosis of cancer cells, cells expressing a cancer antigen, or necrosis of a precancerous lesion or growth, or necrosis of benign tumor cells.

[0116] In some embodiments, the compound is administered in an amount effective to induce regression or reduction of a non-target cancer locus or mass or a satellite cancer locus or mass, in some embodiments, the non-target cancer locus or mass, also referred to as a satellite cancer locus or mass, is distal to the cancer locus or mass or site being treated, e.g., by local administration.

[0117] In some embodiments, the cancer that is treated with the compound by enhancing or stimulating the immune response against cancer is a secondary cancer or a metastatic cancer. As used herein, a secondary cancer refers to a cancer that occurs in multiple locations in a subject. A secondary cancer may occur from spontaneous development in a different location or from the metastasis of cancer cells from one location to another. In some embodiments, the cancer that is treated with the compound is a metastatic cancer.

[0118] In some embodiments, treatment of metastatic cancer involves administering a PKC activator compound locally, e.g., intratumorally, to a locus or mass or site of the primary cancer that is detectable and of sufficient size for treatment with the compounds herein, followed by systemic therapy with the compound to further enhance the immune response against cancer cells that may be present at distant sites, e.g., cancer that has metastasized but is not detectable.

[0119] In some embodiments, treatment of metastatic cancer involves administering a PKC activating compound systemically, e.g., to prime the immune system, followed by local administration, e.g., intratumorally, to the first locus or mass or site of the cancer.

[0120] In some embodiments, the compound is administered in an amount effective to generate immunological memory against the cancer or cancer antigen. In some embodiments, the cancer or cancer antigen is an immunogenic cancer or immunogenic cancer antigen. Immunogenic cancer antigens, including immunogenic cancer antigens expressed internally or on the cell surface that can be released upon cell death, include, among others, NY-ESO-1 (bladder cancer); Her2 (breast cancer); HPV16 E7 (cervical cancer); CEA-carcinoembryonic antigen (colorectal cancer), WT1 (leukemia); MART-1, gp100, and tyrosinase (melanoma); URLC10, VEGFR1, and VEGFR2 (non-small cell lung cancer); survivin (ovarian cancer); MUC1 (pancreatic cancer); and MUC2 (prostate cancer). In some embodiments, cancer cells expressing the cancer antigen can be treated with a PKC-activating compound to stimulate or enhance the immune response against the cancer antigen and cells expressing the cancer antigen.

[0121] In some embodiments, the cancer to be treated with the compound may be selected from adenosarcoma, adrenocortical carcinoma, anal cancer, angiosarcoma, biliary tract cancer, bladder cancer, bone cancer (e.g., osteosarcoma), brain cancer (e.g., glioma, astrocytoma, neuroblastoma, etc.), breast cancer, cervical cancer, colon cancer, cutaneous lymphoma, endometrial cancer, esophageal cancer, fibrosarcoma, fibroxanthomas, head and neck cancer, blood system 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.), mast cell carcinoma, oral cancer, ovarian cancer, pancreatic cancer, renal cancer, prostate cancer, salivary gland cancer, skin cancer (e.g., basal cell carcinoma, melanoma, squamous cell carcinoma), stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, and soft tissue cancer, among others.

[0122] In some embodiments, the cancer to be treated with the compound is pancreatic cancer. In some embodiments, the pancreatic cancer to be treated with the compound is pancreatic adenocarcinoma or metastatic pancreatic cancer. In some embodiments, the cancer to be treated with the compound is stage 1, stage II, stage III, or stage IV pancreatic adenocarcinoma.

[0123] 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.

[0124] In some embodiments, the cancer to be treated with the compound is a hematological cancer. In some embodiments, the hematological cancer is selected from acute lymphoblastic 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.

[0125] In some embodiments, the cancer being treated with the compound is a leukemia selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell chronic myelogenous leukemia (CML), and multiple myeloma.

[0126] In some embodiments, the cancer being treated with the compound is a lymphoma selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, and Burkitt's lymphoma.

[0127] In some embodiments, the cancer to be treated with the compound is characterized by mesenchymal features or mesenchymal phenotype. In some cancers, the acquisition of mesenchymal features is associated with cancer metastasis (e.g., intravasation) and invasiveness. Mesenchymal features may include, among others, enhanced metastatic potential, invasiveness, increased resistance to apoptosis, and increased production of extracellular matrix (ECM) components. In addition to these physiological features, mesenchymal features may include, among others, the expression of certain biomarkers, including E-cadherin, N-cadherin, integrin, 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 breast cancer, lung cancer, head and neck cancer, prostate cancer, and colon cancer, among others. In some embodiments, mesenchymal characteristics may be inherent to the cancer type or may be induced by or selected for treatment of cancer with chemotherapy and / or radiation therapy.

[0128] In some embodiments, the cancer to be treated with the compound is considered to have or has been confirmed 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.

[0129] In some embodiments, the cancer to be treated is one that is considered to have or has been confirmed to have an activating or oncogenic K-RAS mutation. In some embodiments, the cancer selected for treatment is one that has a mutation 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 110, codon 115, These genes are considered to have or have been confirmed to have activating or oncogenic mutations in human K-RAS at one or more of codons 117, 118, 119, 135, 138, 140, 146, 147, 153, 156, 160, 164, 171, 176, 185, and 188.

[0130] In some embodiments, the activating or oncogenic K-RAS mutation is at codon 5 is K5E; at codon 9 is V91; at codon 12 is G12A, G12C, G12D, G12F, G12R, G12S, G12V, or G12Y; at codon 13 is G13C, G13D, or G13V; at codon 14 is V14I or V14L; at codon 18 is A18D; at codon 19 is L19F; and at 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; codon 63 is E63K; and 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; codon 119 is D119N; codon 135 is R135T; codon 138 is G138V, The mutations may be: 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; codon 171 is I117M; codon 176 is K176Q; codon 185 is C185R or C185S; and codon 188 is M188V.

[0131] In particular, the cancer to be treated is considered to have or has been confirmed 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 is G13C, G13D, or G13V; and at codon 61 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.

[0132] In some embodiments, the cancer to be treated is considered to have or has been confirmed to have an activating or oncogenic N-RAS mutation. In some embodiments, the cancer is considered to have or has been confirmed to have an activating or oncogenic human N-RAS mutation 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 codons 12 and 13; codons 12 and 61; codons 13 and 61; or codons 12, 13, and 61.

[0133] In some embodiments, the cancer to be treated is considered to have or has been confirmed to have an activating or oncogenic H-RAS mutation. In some embodiments, the cancer selected for treatment is considered to have an activating or oncogenic human H-RAS mutation 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.

[0134] In some embodiments, the cancer to be treated may 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 of cancers), such as cancers of the biliary tract, cervix, endometrium, pancreas, lung, colon, head and neck, stomach, biliary tract, endometrium, blood system (e.g., leukemia, lymphoma, etc.), colon, lung, ovary, pancreas, prostate, salivary gland, skin, small intestine, stomach, thyroid, aerodigestive tract, urinary tract, and ovarian, small intestine, and urinary tract.

[0135] In some embodiments, the method is used to treat a precancerous lesion or growth. In some embodiments, the method for treating a precancerous lesion or growth comprises administering an effective amount of a PKC activating compound to cause reduction or eradication of the precancerous lesion or growth.

[0136] As mentioned above, in some embodiments, the compound is administered systemically. In some embodiments, the compound is administered locally, e.g., directly to a precancerous lesion or growth. In some embodiments, where appropriate, the compound is administered topically in an effective amount to a subject in need thereof to treat a precancerous lesion or growth, e.g., to cause reduction or eradication of a precancerous lesion or growth.

[0137] In some embodiments, the precancerous lesion or growth to be treated with the compound is a precancerous lesion or growth on the skin, hi some embodiments, the precancerous lesion or growth to be treated is an actinic keratosis.

[0138] In some embodiments, other types of precancerous lesions or growths that are subject to treatment with PKC-activating compounds are precancerous colon cancer formations; renal cysts in renal cancer; atypical ductal hyperplasia (ADH), atypical lobular hyperplasia, flat epithelial atypia, lobular carcinoma in situ, or papillary lesions in breast cancer; hyperplasia and dysplasia in bladder cancer; dermatofibroma; neurofibroma; epidermoid tumor; and precancerous polyps, such as hemangiomas.

[0139] In some embodiments, the method is used to treat a benign tumor. In some embodiments, the method for treating a benign tumor comprises administering an effective amount of a PKC activating compound to cause reduction or eradication of the benign tumor.

[0140] In some embodiments, the benign tumor being treated with the compound is an adenoma, fibroma, lipoma, myoma, neuroma, papilloma, or osteochondrosarcoma.

[0141] In some embodiments, the benign tumor to be treated is a basal cell carcinoma, a neurofibroma, a dermatofibroma, an epidermoid, or a hemangioma.

[0142] In some embodiments, stimulating or enhancing an immune response is used for treating a wound. In some embodiments, treating a wound with the compound is for promoting wound healing and / or treating or preventing wound infection in a subject in need thereof. In some embodiments, a method for treating a wound comprises administering an effective amount of a PKC activator to a subject in need thereof to treat the wound.

[0143] In some embodiments, the wound treatment is used to promote wound healing. In some embodiments, the wound treatment is used to treat wound infection (e.g., a pre-existing infection), including persistent wound infection. In some embodiments, the wound treatment is to prevent wound infection. The ability of PKC activating compounds to increase levels of pro-inflammatory cytokines and some anti-inflammatory cytokines suggests that treatment with PKC activating compounds may promote wound healing and / or treat or prevent wound infection by increasing such cytokines in a balanced manner.

[0144] In some embodiments for treating wounds, the compound is administered topically to the wound. In some embodiments, where appropriate, the compound is administered topically to the wound (e.g., skin).

[0145] In some embodiments, the compound is administered in an amount effective to promote wound healing by increasing the rate of wound healing.

[0146] In some embodiments, the compound is administered in an effective amount to promote wound healing by reducing scarring in wound tissue, hi some embodiments, the compound is administered in an effective amount to promote wound healing by reducing the formation of keloid or hypertrophic scars.

[0147] In some embodiments, one or more additional doses of the compound may be administered to the wound. In some embodiments, the one or more additional doses may be 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10 doses. In some embodiments, the one or more additional doses may be spaced apart, for example, by 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, or 24 hours, or by 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, or by 1 week, 2 weeks, 3 weeks, or 4 weeks. One or more doses may be administered to constitute a treatment in each period. For example, an initial or first treatment with one or more doses of the compound may be followed by a second treatment with one or more doses of the compound, with the first treatment being spaced apart from the second or subsequent treatment. In some embodiments, the treatment period can be 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 1 week, 2 weeks, 3 weeks, or 4 weeks between treatments.

[0148] 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, such as chemotherapeutic agents for the treatment of cancer or precancerous lesions or growths, 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 doses sufficient to activate cell death pathways).

[0149] 3. Use as an adjuvant In some embodiments, PKC-activating compounds may be used as adjuvants in combination with cancer cell preparations or cancer antigens to stimulate or enhance responses to the cancer cells or cancer antigens.

[0150] In some embodiments, the adjuvant composition comprises a diterpenoid PKC-activating compound and cancer cells or cancer antigens. In some embodiments, the cancer cells in the composition are cancer cells that have been disrupted or killed, for example, by sonication, homogenization, or chemical disruption. In some embodiments, the cancer cells in the adjuvant composition are tumor cell lysates. In some embodiments, the tumor cell lysates are prepared from cancer or tumor cells isolated from a subject receiving treatment, such as from a biopsy. In some embodiments, the tumor cell lysates are prepared from a primary culture of cancer cells obtained from a patient receiving treatment.

[0151] In some embodiments, the adjuvant composition comprises a diterpenoid PKC-activating compound and a cancer antigen. In some embodiments, the cancer antigen is a cancer antigen expressed in cancer cells of a subject receiving adjuvant treatment. In some embodiments, the cancer antigen selected for preparation of the adjuvant is determined by the cancer to be treated. In some embodiments, the cancer antigen is selected from NY-ESO-1 (bladder cancer); Her2 (breast cancer); HPV16 E7 (cervical cancer); CEA-carcinoembryonic antigen (colorectal cancer), WT1 (leukemia); MART-1, gp100, and tyrosinase (melanoma); URLC10, VEGFR1, and VEGFR2 (non-small cell lung cancer); survivin (ovarian cancer); MUC1 (pancreatic cancer); and MUC2 (prostate cancer).

[0152] In some embodiments, cancer antigens are obtained by preparing primary cultures of cancer cells obtained from a patient undergoing treatment and recovering cell surface antigens shed from the cultured cancer cells from the serum, as described, for example, in U.S. Patent Application Publication No. 20020164358.

[0153] In some embodiments, cancer cell or tumor lysates for use in the adjuvant compositions are generated 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.

[0154] In some embodiments, the cancer cells or tumor lysate for use in the adjuvant composition is pancreatic cancer. In some embodiments, the pancreatic cancer for use in the adjuvant composition is pancreatic adenocarcinoma or metastatic pancreatic cancer. In some embodiments, the cancer to be treated with the compound is stage 1, stage II, stage III, or stage IV pancreatic adenocarcinoma.

[0155] In some embodiments, the cancer cells or tumor lysate for use in the adjuvant composition is lung cancer. In some embodiments, the cancer cells or tumor lysate for use in the adjuvant composition is small cell lung cancer or non-small cell lung cancer. In some embodiments, the cancer cells or tumor lysate for use in the adjuvant composition is adenocarcinoma, squamous cell carcinoma, or large cell carcinoma. In some embodiments, the lung cancer cancer cells or tumor lysate for use in the adjuvant composition is metastatic lung cancer.

[0156] In some embodiments, the cancer cells or tumor lysate for use in the adjuvant composition is a hematological cancer, in some embodiments, the hematological cancer is selected from acute lymphoblastic 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.

[0157] In some embodiments, the cancer cell or tumor lysate for use in the adjuvant composition is a leukemia selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell chronic myelogenous leukemia (CML), and multiple myeloma.

[0158] In some embodiments, the adjuvant composition is administered in an effective amount to treat cancer. In some embodiments, the adjuvant composition is administered in an effective amount to a subject in need thereof for the treatment of cancer in the subject. In some embodiments, the adjuvant is administered intradermally, intravenously, intramuscularly, or subcutaneously. In some embodiments, the adjuvant composition is administered to the locus or mass of cancer in the subject.

[0159] 4.Compound In some embodiments, the compounds for use in the methods are protein kinase C (PKC) modulating compounds. In particular, the compounds are diterpenoid PKC modulating compounds that exhibit potent PKC activating activity and further exhibit enhanced solubility and pharmacokinetic profiles.

[0160] In some embodiments, the diterpenoid compound having a PKC activating compound is selected from the group consisting of U.S. Pat. No. 6,432,452; U.S. Pat. No. 8,022,103; U.S. Pat. No. 8,067,632; U.S. Pat. No. 8,431,612; U.S. Pat. No. 8,536,378; U.S. Pat. No. 8,816,122; U.S. Patent Application Publication No. 20090187046; U.S. Patent Application Publication No. 20110014699; U.S. Patent Application Publication No. 20120101283; U.S. Patent Application Publication No. 2011 / 0224297; WO2017083783; WO2017156350; Wender, et al., 2008, “Practical Synthesis of Prostratin, DPP, and Their Analogs, Adjuvant Leads Against Latent HIV,” Science. 320(5876):649-652; Beans et al., 2013, “Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo,” Proc Natl Acad Sci USA 110(29):11698-11703; Tsai et al., 2016, “Isolation of Phorbol Esters from Euphorbia grandicornis and Evaluation of Protein Kinase C- and Human Platelet-Activating Effects of Euphorbiaceae Diterpenes,” J Nat Prod. 79(10):2658-2666; Duran-Pena et al., 2014, Natural Product Reports 31:940-952; Shi et al., 2008, Chem. Rev. 108:4295-4327; and US Pat. No. 10,183,922 (eg, wound healing); all publications are incorporated herein by reference.

[0161] In some embodiments, a PKC activating compound Diterpenoid compounds having the formula (diterpenoid compound) are based on an ingenane or ingenol structure, and are described, for example, in U.S. Pat. No. 6,432,452; U.S. Pat. No. 8,022,103; U.S. Pat. No. 8,106,092; U.S. Pat. No. 8,431,612; U.S. Pat. No. 8,901,356; U.S. Pat. No. 9,102,687; U.S. Patent Application Publication No. 20080069809; U.S. Patent Application Publication No. 2010204318; U.S. Patent Application Publication No. 20130324600; U.S. Patent Application Publication No. 20130331446; U.S. Patent Application Publication No. 20140371311; U.S. Patent Application Publication No. 20150175622; WO 20130182688; WO 2014066967; Jorgensen et al., 2013, “14-Step Synthesis of (+)-Ingenol from (+)-3-Carene,” Science 341(6148):878-882; McKerral et al., 2014, “Development of a Concise Synthesis of (+)-Ingenol,” J. Am Chem Soc. 136 (15):5799-5810; Liang et al., 2013, Bioorg Med Chem Lett. 23:5624-5629; Grue-Sorensen et al., 2014, “Synthesis, biological evaluation and SAR of 3-benzoates of ingenol for treatment of actinic keratosis and non-melanoma skin cancer,”Bioorg Med Chem Lett. 24:54-60; Duran-Pena et al., 2014, Natural Product Reports 31:940-952; Shi et al., 2008, Chem. Rev. 108:4295-4327; and Yang et al., 2014, Fitoterapia 97:211-218; all of which are incorporated herein by reference.

[0162] In some embodiments, the present invention relates to a compound disclosed herein. In some embodiments, the compound is for use in the methods described herein. In some embodiments, the compound is a compound of formula (I):

[0163] [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 a H or M counterion; R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5 ' and R 6 Each ' is independently H or OH, or R 5 ' and R 6' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0164] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2; R 6 ' is H or OH, and R 7 ' is H, or R 6 ' and R 7' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 7 is H or OH; R 9 is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 is H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R j , -SR j , -N(R j )2, -Si(Rj )3, C3-C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5-C 12 Cycloalkyl, 5- to 12-membered bridged bicyclyl, adamantyl, or -C(O)OR k and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0165] In some embodiments of the compounds of Formula (I),

[0166] [ka] " *The carbon atom labeled " is chiral and may 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.

[0167] In some embodiments, A is -OH. In some embodiments, A is -C(O)OR 1 and R 1 is H or M + In some embodiments, A is -NR 13 R 13’ and R 13 and R 13’ are each independently H or C1-C4 alkyl.

[0168] 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.

[0169] In some embodiments, the compound has Formula (Ia):

[0170] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, A is -OH; R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -ORa and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5 ' and R 6 Each ' is independently H or OH, or R 5 ' and R 6 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0171] [ka] wherein: R Aeach occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2; R 6 ' is H or OH, and R 7 ' is H, or R 6 ' and R 7 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 7 is H or OH; R 9 is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 is H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M+ is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0172] In some embodiments of the compound of Formula (Ia),

[0173] [ka] " * The carbon atom labeled " is chiral and may 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.

[0174] In some embodiments, the compound has Formula (Ib):

[0175] [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 C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and Rb is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5 ' and R 6 Each ' is independently H or OH, or R 5 ' and R 6 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0176] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid,B Each occurrence of may be the same or different; p is 0, 1, or 2; R 6 ' is H or OH, and R 7 ' is H, or R 6 ' and R 7 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 7 is H or OH; R 9 is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 is H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0177] In some embodiments of the compound of Formula (Ib),

[0178] [ka] " * The carbon atom labeled " is chiral and may 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.

[0179] In some embodiments, the compound is a compound of formula (II):

[0180] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5 ' and R 6 Each ' is independently H or OH, or R 5 ' and R 6 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 6 OH, halo, -OP(O)(OR b')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0181] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2; R 6 ' is H or OH, and R 7 ' is H, or R 6 ' and R 7 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 7 is H or OH; R 9 is OR eand R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 is H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 kand the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0182] In some embodiments of the compound of Formula (II),

[0183] [ka] " * The carbon atom labeled " is chiral, and therefore the compound may 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'):

[0184] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, 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 in formula (II).

[0185] In some embodiments, the compound of formula (II) has the formula (II"):

[0186] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, 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 in formula (II).

[0187] In some embodiments, the compound has the formula (IIa):

[0188] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0189] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 is H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl; R 14 is H or OR g and;R g is H or C1-C6 alkyl; R 17 and R 18 are each independently C1-C4 alkyl or C1-C4 alkyl-ORh and R h is H or C1-C6 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0190] In some embodiments, the compound of Formula (IIa) has the formula (IIa'):

[0191] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, 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 in formula (II).

[0192] In some embodiments, the compound of formula (IIa) has the formula (IIa"):

[0193] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, 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 R21 is as defined in formula (II).

[0194] In some embodiments, the compound has the formula (IIb):

[0195] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 c1together with the N atom form a 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0196] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2; R 9 is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 is H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl; R 14 is H or OR gand;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 and R h is H or C1-C6 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0197] In some embodiments, the compound has the formula (IIb'):

[0198] [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 in formula (II).

[0199] In some embodiments, the compound has the formula (IIb″):

[0200] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, 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 in formula (II).

[0201] 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 and;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:

[0202] [ka] In some embodiments, R a1 is selected from:

[0203] [ka] 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.

[0204] 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.

[0205] 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.

[0206] 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.

[0207] In some embodiments, the compound has the formula (IIc):

[0208] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0209] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12-Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0210] In some embodiments, the compound has the formula (IIc'):

[0211] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, R 6 , R 12 , R 13 , R 13’ , L, and R 21 is as defined in formula (IIc).

[0212] In some embodiments, the compound has the formula (IIc"):

[0213] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, R 6 , R 12 , R 13 , R 13’ , L, and R 21 is as defined in formula (IIc).

[0214] In some embodiments, the compound has the formula (IId):

[0215] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0216] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12-Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 13 and R 13’ are each independently H or C1-C4 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0217] In some embodiments, the compound has the formula (IId'):

[0218] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, R 6 , R 12 , R 13 , R 13’ , L, and R 21 is as defined in formula (IId).

[0219] In some embodiments, the compound has the formula (IId"):

[0220] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, R 6 , R 12 , R 13 , R 13’ , L, and R 21 is as defined in formula (IId).

[0221] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (II′), (II″), (IIa), (IIa′), (IIa″), (IIb), (IIb′), (IIb″), (IIc), (IIc″), (IId), (IId′), and (IId″), R 12 Ha-OC(O)R f and R f is C1~C12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl. In some embodiments, R f is selected from the following

[0222] [ka] In some embodiments, R f is selected from:

[0223] [ka] In some embodiments, the compound has Formula (III):

[0224] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R bis H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5 ' and R 6 Each ' is independently H or OH, or R 5 ' and R 6 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0225] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, BEach occurrence of may be the same or different; p is 0, 1, or 2; R 6 ' is H or OH, and R 7 ' is H, or R 6 ' and R 7 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 7 is H or OH; R 9 is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 13 and R 13’ are each independently H or C1-C4 alkyl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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)ORk and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0226] In some embodiments, the compound has the formula (III'):

[0227] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, R 2 , R 3 , R 4 , R 5 , R 5 ', R 6 ', R 6 , R 6 ', R 7 ', R7 , R 9 , R 11 , R 13 , R 13’ , R 14 、 R 17 , R 18 , L, and R 21 is as defined in formula (III).

[0228] In some embodiments, the compound has formula (III"):

[0229] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, 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 in formula (III).

[0230] In some embodiments, the compound has the formula (IIIa):

[0231] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0232] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or RB But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 13 and R 13’ are each independently H or C1-C4 alkyl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 kand the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0233] In some embodiments, the compound has the formula (IIIa'):

[0234] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; In the formula, 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 in formula (III).

[0235] In some embodiments, the compound has the formula (IIIa″):

[0236] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; In the formula, 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 in formula (III).

[0237] In some embodiments, the compound has the formula (IIIb):

[0238] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0239] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, BEach occurrence of may be the same or different; p is 0, 1, or 2; R 9 is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 13 and R 13’ are each independently H or C1-C4 alkyl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 121 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0240] In some embodiments, the compound has the formula (IIIb'):

[0241] [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 in formula (III).

[0242] In some embodiments, the compound has the formula (IIIb″):

[0243] [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 in formula (III).

[0244] In some embodiments of compounds of Formula (III), (III'), (III"), (IIIa), (IIIa'), (IIIa"), (IIIb), (IIIb'), and (IIIb"), R 3 HA-OR a and;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:

[0245] [ka] In some embodiments, R a1 is selected from:

[0246] [ka] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] In some embodiments, the compound has the formula (IIIc):

[0251] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0252] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0253] In some embodiments, the compound has the formula (IIIc'):

[0254] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, R 6 , R 13 , R 13’ , L, and R 21 is as defined in formula (IIIc).

[0255] In some embodiments, the compound has the formula (IIIc"):

[0256] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, R 6 , R 13 , R 13’ , L, and R 21 is as defined in formula (IIIc).

[0257] In some embodiments, the compound has the formula (IIId):

[0258] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0259] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R j , -SRj , -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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl; n is 0 or 1.

[0260] In some embodiments, the compound has the formula (IIId'):

[0261] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, R 6 , R 13 , R 13’ , L, and R 21 is as defined in formula (IIId).

[0262] In some embodiments, the compound has the formula (IIId"):

[0263] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, R 6 , R 13 , R 13’ , L, and R 21 is as defined in formula (IIId).

[0264] In some embodiments of the compounds of any of the above embodiments, n is 0.

[0265] In some embodiments of the compounds of any of the above embodiments, R 13 and R 13 Each of ' is H.

[0266] In some embodiments, the compound has the formula (IIIe):

[0267] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; Rc 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0268] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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)ORk and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0269] In some embodiments, the compound has the formula (IIIe'):

[0270] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, R 6 , L, and R 21 is as defined in formula (IIIe).

[0271] In some embodiments, the compound has the formula (IIIe"):

[0272] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, In the formula, R 6 , L, and R 21 is as defined in formula (IIIe).

[0273] In some embodiments, the compound has the formula (IIIf):

[0274] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0275] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But the adjacent R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2; L does not exist or C1~C 12 Alkylene or C2-C 12 Alkenylene, C1-C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is replaced by; R k is H or M + is a counterion; J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0276] In some embodiments, the compound has the formula (IIIf'):

[0277] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; In the formula, R 6 , L, and R 21 is as defined in formula (IIIf).

[0278] In some embodiments, the compound has the formula (IIIf"):

[0279] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R 6 , L, and R 21 is as defined in formula (IIIf).

[0280] In some embodiments, 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″) 21 is a C3-C7 cycloalkyl, and the C3-C7 cycloalkyl optionally contains 1 to 3 J 1 is substituted with J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl. In some of the above embodiments, C3-C7 cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0281] In some embodiments, 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″) 21 is heterocyclyl, and the heterocyclyl optionally contains 1 to 3 J 1 is substituted with J 1is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl. In some embodiments, the 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 1 to 3 of OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0282] In some embodiments, 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″) 21 is aryl, and the aryl optionally contains 1 to 3 J 1 is substituted with J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl. In some of the above embodiments, R 21 is phenyl or naphthyl, said phenyl or naphthyl being optionally substituted with 1 to 3 of OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0283] In some embodiments, 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″) 21 is heteroaryl, and the heteroaryl optionally contains 1 to 3 J 1 is substituted with J 1 is selected from OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl. In some of the above embodiments, 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 is optionally substituted with 1 to 3 of OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0284] In some embodiments, 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″) 21 is adamantyl, said adamantyl optionally being selected from the group consisting of J 1 is substituted with J 1is selected from OH, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0285] In some embodiments, 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″) 21 Spiro C5~C 12 cycloalkyl, and the spiro C5-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 is substituted with 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.

[0286] In some embodiments, 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″) 21 is a 5-12 membered bridged bicyclyl in which 0-2 carbon atoms are replaced by 0-2 heteroatoms selected from N, O, and S, and optionally 1-3 J 1 is substituted with J1 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.

[0287] In some embodiments, 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″) 21 is selected from the following:

[0288] [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.

[0289] In some embodiments, 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″) 6In some such embodiments, R 6 is OH. In other such embodiments, R 6 is OH and R 5 is H and R 5 In other such embodiments, R 6 is OH and R 5 is H and R 5 ' is H and R 4 is OH. In other such embodiments, the compound is not:

[0290] [ka] or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, 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″) 5 is OH. In some such embodiments, R 5 In other such embodiments, R 6 In other such embodiments, R 6 ' is H.

[0292] In some embodiments, 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″) 6 is OP(O)(OR b ')2, and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl. 6 -OP(O)(OR b ')2, and each R b ' is independently C1-C6 alkyl. In some embodiments, R 6 is OP(O)(OR b ')2, and each R b ' is independently C2-C6 alkenyl, C0-C6 alkylaryl. In some embodiments, R 6 is OP(O)(OR b ')2, and each R b In some such above embodiments, R 6 In other such embodiments, R 6 ' is OH.

[0293] In some embodiments, 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″) 6 Ha-OC(O)R c and 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; R k is H or M + In some such above embodiments, R6' is H. In other such embodiments, R6' is OH.

[0294] In some embodiments, in any of the compounds herein, L is C3-C 12 In some embodiments, in any of the compounds herein, L is C3-C6 alkylene. In some embodiments, in any of the compounds herein, L is C1-C6 alkylene.

[0295] In some embodiments, in any of the compounds herein, L is C3-C 12In some embodiments, in any of the compounds herein, L is C3-C6 alkenylene. In some embodiments, in any of the compounds herein, L is C1-C6 alkenylene.

[0296] In some embodiments, L is C1-C 12 Alkylene or C2-C 12 alkenylene, wherein the C1 to C 12 Alkylene or C2-C 12 Alkenylene is optionally substituted with C1-C4 alkyl; R 21 is H.

[0297] In some embodiments, 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") may be -LR. 21 is a C2-C6 alkenyl selected from:

[0298] [ka] In some embodiments of any of the above 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

[0299] [ka] R A Each occurrence is independently 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), mercaptomethyl (serine), 2-hydroxyethyl (threon ... 4-aminobutan-1-yl (lysine), 4-amino-3-hydroxybutan-1-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine), 3-guanidinopropan-1-yl (arginine), or 3-ureidopropan-1-yl (citrulline); R B Each occurrence of is independently H or R BBut the adjacent R A and together with the N atom, a prolyl side chain:

[0300] [ka] It forms; p is 0, 1, or 2.

[0301] In some embodiments of any of the above 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

[0302] [ka] R A each occurrence of is independently methyl(alanine), propan-2-yl(valine), 2-methylpropan-1-yl(leucine), imidazol-4-ylmethyl(histidine), hydroxymethyl(serine), 1-hydroxyethyl(threonine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), 4-aminobutan-1-yl(lysine), carboxymethyl(aspartic acid), 3-guanidinopropan-1-yl(arginine), benzyl(phenylalanine), or 4-aminobutan-1-yl(lysine); R B is H; p is 0, 1, or 2.

[0303] In some embodiments of any of the above 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

[0304] [ka] R A each occurrence of is independently propan-2-yl (valine), 2-methylpropan-1-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-1-yl (lysine); Each R B is H; p is 0, 1, or 2.

[0305] In some embodiments of any of the above 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"), p is 0.

[0306] In some embodiments of any of the above 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"), p is 1.

[0307] In some embodiments of any of the above 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

[0308] [ka] p is 1; The first R A is propan-2-yl (valine), and the second R A is propan-2-yl(valine); R B each of which is H (i.e., the dipeptide Val-Val); or The first R A is 2-methylpropan-1-yl(leucine), and the second R A is 2-methylpropan-1-yl(leucine); R B each of which is H (i.e., the dipeptide Leu-Leu); or The first RA is methyl (alanine), and the second R A is methyl(alanine); R B each of which is H (i.e., the dipeptide Ala-Ala); or The first R A is 4-aminobutan-1-yl(lysine); the second R A is 4-aminobutan-1-yl(lysine); R B each of which is H (i.e., the dipeptide Lys-Lys); or The first R A is hydrogen; the second R A is 4-aminobutan-1-yl and R B is H (i.e., the dipeptide Gly-Lys).

[0309] In some embodiments of any of the above 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

[0310] [ka] Each α-carbon of an amino acid other than glycine is in the L or D configuration. In some embodiments, the α-carbon of an amino acid other than glycine is in the L configuration.

[0311] In some embodiments, the compound is selected from the group consisting of the compounds in Table 1, or a pharmaceutical salt thereof:

[0312] [Table 1-1]

[0313] [Table 1-2]

[0314] [Table 1-3]

[0315] [Table 1-4]

[0316] [Table 1-5]

[0317] [Table 1-6]

[0318] [Table 1-7]

[0319] [Table 1-8] In some embodiments, in each of the compounds in Table 1, a substituent on the C20 carbon atom, e.g., —OH, -halo, or an amino acid progroup, is —OP(O)(OR b ')2 and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl. In some embodiments, each R b In some embodiments, each R b' is independently C1-C6 alkyl. In some embodiments, each R b ' is independently C2-C6 alkenyl. In some embodiments, each R b ' is independently C0-C6 alkylaryl. In some embodiments, each R b ' is independently C0-C6 alkylheteroaryl.

[0320] In some embodiments, in each of the compounds in Table 1, the substituent on the C20 carbon atom, e.g., -OH, -halo, or an amino acid progroup, is -OC(O)R c has been replaced by 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; R k is H or M + It is a counter ion.

[0321] In some embodiments, in each of the compounds in Table 1, where appropriate, a substituent on the C20 carbon atom, such as -OH or -halo, is replaced with:

[0322] [ka] During the ceremony, R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But R A and R Btogether with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2.

[0323] In some embodiments of the amino acid moiety on the C20 carbon, R A Each occurrence is independently 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), mercaptomethyl (serine), 2-hydroxyethyl (threon ... 4-aminobutan-1-yl (lysine), 4-amino-3-hydroxybutan-1-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine), 3-guanidinopropan-1-yl (arginine), or 3-ureidopropan-1-yl (citrulline); R B Each occurrence of is independently H or R B But the adjacent R A and together with the N atom, a prolyl side chain:

[0324] [ka] It forms; p is 0, 1, or 2.

[0325] In some embodiments, R A each occurrence of is independently methyl(alanine), propan-2-yl(valine), 2-methylpropan-1-yl(leucine), imidazol-4-ylmethyl(histidine), hydroxymethyl(serine), 1-hydroxyethyl(threonine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), 4-aminobutan-1-yl(lysine), carboxymethyl(aspartic acid), 3-guanidinopropan-1-yl(arginine), benzyl(phenylalanine), or 4-aminobutan-1-yl(lysine); R B is H; p 0, 1, or 2.

[0326] In some embodiments, R A each occurrence of is independently propan-2-yl (valine), 2-methylpropan-1-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-1-yl (lysine); Each R B is H; p is 0, 1, or 2.

[0327] In some embodiments, p is 0.

[0328] In some embodiments, p is 1.

[0329] In some embodiments, p is 1; The first R A is propan-2-yl (valine), and the second R A is propan-2-yl(valine); R B each of which is H (i.e., the dipeptide Val-Val); or The first R A is 2-methylpropan-1-yl(leucine), and the second R Ais 2-methylpropan-1-yl(leucine); R B each of which is H (i.e., the dipeptide Leu-Leu); or The first R A is methyl (alanine), and the second R A is methyl(alanine); R B each of which is H (i.e., the dipeptide Ala-Ala); or The first R A is 4-aminobutan-1-yl(lysine); the second R A is 4-aminobutan-1-yl(lysine); R B each of which is H (i.e., the dipeptide Lys-Lys); or The first R A is hydrogen; the second R A is 4-aminobutan-1-yl and R B is H (i.e., the dipeptide Gly-Lys).

[0330] In some embodiments, the α-carbons of amino acids other than glycine are each in the L or D configuration. In some embodiments, the α-carbons of amino acids other than glycine are each in the L configuration.

[0331] In another aspect, the present disclosure provides a compound of formula (IV):

[0332] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5 ' and R 6 Each ' is independently H or OH, or R 5 ' and R 6 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0333] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2; R 6 ' is H or OH, and R 7 ' is H, or R 6 ' and R 7 ' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 7 is H or OH; R 9 is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkyl, C3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein the C1 to C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is 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.

[0334] In some embodiments, excluded from the compounds of formula (IV) are the following compounds: -LR 21 but,

[0335] [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 12 is H; R 17 and R 18 is -CH3; R A is propan-2-yl(valine); R B is H; The compound wherein p is 0.

[0336] In some embodiments, the compound has the formula (IVa):

[0337] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0338] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or RB But R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 is H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkyl, C3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein the C1 to C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R21 are H, -OH, -SH, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is 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.

[0339] In some embodiments, excluded from the compounds of formula (IVa) are the following compounds: -LR 21 but,

[0340] [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; The compound wherein p is 0.

[0341] In some embodiments, the compound has the formula (IVb):

[0342] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R bis H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0343] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and R eis H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 12 are H, -OH, -OC(O)R f and R f is C1~C 12 Alkyl, C2-C 12 Alkenyl, -aliphatic C0-C 12 -C3-C7 cycloalkyl, -Aliphatic C0-C 12 -Heterocycloalkyl, -Aliphatic C0-C 12 -Aryl or -Aliphatic C0-C 12 -heteroaryl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkyl, C3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein the C1 to C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is 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.

[0344] In some embodiments of compounds of Formula (IV), (IVa), and (IVb), R a1 The C2-C6 alkenyl is independently selected from the following:

[0345] [ka] In some embodiments, R a1 are independently selected from:

[0346] [ka] In some embodiments, R 3 HA-OR a and;R a is H or -C(O)R a1 and Ra1 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.

[0347] In some embodiments of compounds of Formula (IV), (IVa), and (IVb), R 3 is an O double-bonded to a carbon atom.

[0348] In some embodiments of compounds of Formula (IV), (IVa), and (IVb), R f C2~C 12 Alkenyl is independently selected from:

[0349] [ka] In some embodiments, R f are independently selected from:

[0350] [ka] 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.

[0351] In some embodiments of compounds of Formula (IV), (IVa), and (IVb), R 4 and R 5are each independently H or —OH.

[0352] 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.

[0353] In some embodiments, the compound has formula (V):

[0354] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 5 ' and R 6 Each ' is independently H or OH, or R 5 ' and R 6' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0355] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2; R 6 ' is H or OH, and R 7 ' is H, or R 6 ' and R 7' forms a bond or is joined to a common O atom to form an epoxide ring where valence permits; R 7 is H or OH; R 9 is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkyl, C3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein the C1 to C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is 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.

[0356] In some embodiments, excluded from the compounds of formula (V) are the following compounds: -LR 21 but,

[0357] [ka] 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 18is -CH3; R A is propan-2-yl(valine); R B is H; The compound wherein p is 0.

[0358] In some embodiments, the compound has the formula (Va):

[0359] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0360] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkyl, C3-C7 cycloalkylene, C1-C 12Alkylene or C2-C 12 alkenylene, wherein the C1 to C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is 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.

[0361] In some embodiments, excluded from the compounds of formula (V) are the following compounds: -LR 21 but,

[0362] [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; The compound wherein p is 0.

[0363] In some embodiments, the compound has the formula (Vb):

[0364] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 2 is C1-C4 alkyl; R 3 is an O double-bonded to a ring carbon where (---) is a bond, or -OR a and;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 and R b is H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0365] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2; R 9is OR e and R e is H, C1-C6 alkyl, or aryl; R 11 is C1-C4 alkyl; R 14 is H or OR g and;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 and R h is H or C1-C6 alkyl; L is C0-C6 alkylarylene, C0-C6 alkylheteroarylene, C0-C6 alkyl, C3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein the C1 to C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is 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.

[0366] In some embodiments of compounds of Formula (V), (Va), and (Vb), R 3 HA-OR a and;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:

[0367] [ka] In some embodiments, R a1 is selected from:

[0368] [ka] In some embodiments of compounds of Formula (V), (Va), and (Vb), R 3 is an O double-bonded to a carbon atom.

[0369] 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.

[0370] In some embodiments of compounds of Formula (V), (Va), and (Vb), R 4 and R 5 are each independently H or —OH.

[0371] 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.

[0372] In some embodiments, the compound has the formula (Vc):

[0373] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each Rb ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0374] [ka] wherein: R A each occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 alkyl, C3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein the C1 to C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is 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.

[0375] In some embodiments, excluded from the compounds of formula (Vc) are the following compounds: -LR 21 but,

[0376] [ka] and R Ais propan-2-yl(valine); R B is H; The compound wherein p is 0.

[0377] In some embodiments, specifically excluded from the compounds of formula (IV), (IVa), (V), (Va), and (Vc) are compounds of the following structure:

[0378] [ka] In some embodiments, the compound has the formula (Vd):

[0379] [ka] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R 6 OH, halo, -OP(O)(OR b ')2, or -OC(O)R c and each R b ' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl; 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 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O, and S; or R 6 teeth,

[0380] [ka] wherein: R Aeach occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 alkyl, C3-C7 cycloalkylene, C1-C 12 Alkylene or C2-C 12 alkenylene, wherein the C1 to C 12 Alkylene or C2-C 12 alkenylene is optionally substituted with OH or C1-C4 alkyl; R 21 are H, -OH, -SH, -S(O)2R 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 and the C3 to C7 cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C5 to C 12 The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J 1 and optionally, the spiro C5-C 12 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced by heteroatoms selected from N, O, and S, and optionally by C1-C4 alkyl or, if an N atom is present, by an N-protecting group; 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, and the C3-C7 cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J 1 is 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.

[0381] 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 contains 1 to 3 J 1 In some of the above embodiments, the C3-C7 cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0382] 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, the heterocycloalkyl 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.

[0383] 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 above embodiments, R 21 is phenyl, said phenyl being optionally substituted with 1 to 3 of OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0384] 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 above embodiments, 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 is optionally substituted with 1-3 of OH, CN, halo, C1-C4 alkyl, and haloC1-C4 alkyl.

[0385] In some embodiments of compounds (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21 is adamantyl, said adamantyl being optionally substituted with OH, halo, or C1-C4 alkyl.

[0386] In some embodiments of compounds (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21 Spiro C5~C 12 cycloalkyl, and the spiro C5-C 12Cycloalkyl 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.

[0387] In some embodiments of compounds (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21 is a 5-12 membered bridged bicyclyl in which 0-2 carbon atoms are 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, if an N atom is present, an N-protecting group.

[0388] In some embodiments of compounds of Formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 21 is selected from:

[0389] [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.

[0390] In some embodiments, in any of the compounds herein, L is C3-C 12 In some embodiments, in any of the compounds herein, L is C3-C6 alkylene. In some embodiments, in any of the compounds herein, L is C1-C6 alkylene.

[0391] In some embodiments, in any of the compounds herein, L is C3-C 12 In some embodiments, in any of the compounds herein, L is C3-C6 alkenylene. In some embodiments, in any of the compounds herein, L is C1-C6 alkenylene.

[0392] In some embodiments of compounds of Formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), -LR 21 is a C2-C6 alkenyl selected from:

[0393] [ka] In some embodiments of any of the above compounds, e.g., of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 6 teeth,

[0394] [ka] and R AEach occurrence is independently 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), mercaptomethyl (serine), 2-hydroxyethyl (threon ... 4-aminobutan-1-yl (lysine), 4-amino-3-hydroxybutan-1-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine), 3-guanidinopropan-1-yl (arginine), or 3-ureidopropan-1-yl (citrulline); R B Each occurrence of is either H or R B But the adjacent R A and together with the N atom, a prolyl side chain:

[0395] [ka] It forms; p is 0, 1, or 2.

[0396] In some embodiments of any of the above compounds, e.g., of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), Each R Aare independently methyl(alanine), propan-2-yl(valine), 2-methylpropan-1-yl(leucine), imidazol-4-ylmethyl(histidine), hydroxymethyl(serine), 1-hydroxyethyl(threonine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), 4-aminobutan-1-yl(lysine), carboxymethyl(aspartic acid), 3-guanidinopropan-1-yl(arginine), benzyl(phenylalanine), or 4-aminobutan-1-yl(lysine); R B is H; p 0, 1, or 2.

[0397] In some embodiments of any of the above compounds, e.g., of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 6 teeth,

[0398] [ka] and R A each occurrence of is independently propan-2-yl (valine), 2-methylpropan-1-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-1-yl (lysine); Each R B is H; p is 0, 1, or 2.

[0399] In some embodiments of any of the above compounds, e.g., formulas (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), p is 0.

[0400] In some embodiments of any of the above compounds, e.g., formulas (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), p is 1.

[0401] In some embodiments of any of the above compounds, e.g., of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 6 teeth,

[0402] [ka] and p is 1; The first R A is propan-2-yl (valine), and the second R A is propan-2-yl(valine); R B each of which is H (i.e., the dipeptide Val-Val); or The first R A is 2-methylpropan-1-yl(leucine), and the second R A is 2-methylpropan-1-yl(leucine); R B each of which is H (i.e., the dipeptide Leu-Leu); or The first R A is methyl (alanine), and the second R A is methyl(alanine); R B each of which is H (i.e., the dipeptide Ala-Ala); or The first R A is 4-aminobutan-1-yl(lysine); the second R A is 4-aminobutan-1-yl(lysine); R B each of which is H (i.e., the dipeptide Lys-Lys); or The first R A is hydrogen; the second R A is 4-aminobutan-1-yl and R B is H (i.e., the dipeptide Gly-Lys).

[0403] In some embodiments of any of the above compounds, e.g., of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R 6 teeth,

[0404] [ka] and Each α-carbon of an amino acid other than glycine is in the L or D configuration. In some embodiments, each α-carbon of an amino acid other than glycine is in the L configuration.

[0405] In some embodiments, the compound is selected from the group consisting of the compounds in Table 2, or a pharmaceutical salt thereof:

[0406] [Table 2-1]

[0407] [Table 2-2]

[0408] [Table 2-3]

[0409] [Table 2-4] or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0410] In some embodiments, in each of the compounds in Table 2, the substituent on the C20 carbon atom, e.g., —OH, is —OP(O)(OR b ')2 and each R b' is independently H, C1-C6 alkyl, C2-C6 alkenyl, C0-C6 alkylaryl, or C0-C6 alkylheteroaryl. b Each ' is H. In some embodiments, R b Each R ' is H. In some embodiments, each R b ' is independently C1-C6 alkyl. In some embodiments, each R b ' is independently C2-C6 alkenyl. In some embodiments, each R b ' is independently C0-C6 alkylaryl. In some embodiments, each R b ' is independently C0-C6 alkylheteroaryl.

[0411] In some embodiments, in each of the compounds in Table 2, the substituent on the C20 carbon atom, e.g., —OH, is —OC(O)R c has been replaced by 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; R k is H or M + It is a counter ion.

[0412] In some embodiments, in each of the compounds in Table 2, where appropriate, a substituent on the C20 carbon atom, such as -OH or -halo, is replaced with:

[0413] [ka] During the ceremony, R Aeach occurrence of is independently selected from the side chain of a natural amino acid or an unnatural amino acid, and R A Each occurrence of may be the same or different; R B Each occurrence of is independently H or R B But R A and R B together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, B Each occurrence of may be the same or different; p is 0, 1, or 2.

[0414] In some embodiments of the amino acid moiety on the C20 carbon, R A Each occurrence is independently 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), mercaptomethyl (serine), 2-hydroxyethyl (threon ... 4-aminobutan-1-yl (lysine), 4-amino-3-hydroxybutan-1-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine), 3-guanidinopropan-1-yl (arginine), or 3-ureidopropan-1-yl (citrulline); R B Each occurrence of is independently H or R B But the adjacent R Aand together with the N atom, a prolyl side chain:

[0415] [ka] It forms; p is 0, 1, or 2.

[0416] In some embodiments, R A each occurrence of is independently methyl(alanine), propan-2-yl(valine), 2-methylpropan-1-yl(leucine), imidazol-4-ylmethyl(histidine), hydroxymethyl(serine), 1-hydroxyethyl(threonine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), 4-aminobutan-1-yl(lysine), carboxymethyl(aspartic acid), 3-guanidinopropan-1-yl(arginine), benzyl(phenylalanine), or 4-aminobutan-1-yl(lysine); R B is H; p 0, 1, or 2.

[0417] In some embodiments, R A each occurrence of is independently propan-2-yl (valine), 2-methylpropan-1-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-1-yl (lysine); Each R B is H; p is 0, 1, or 2.

[0418] In some embodiments, p is 0.

[0419] In some embodiments, p is 1.

[0420] In some embodiments, p is 1; The first R Ais propan-2-yl (valine), and the second R A is propan-2-yl(valine); R B each of which is H (dipeptide Val-Val); or The first R A is 2-methylpropan-1-yl(leucine), and the second R A is 2-methylpropan-1-yl(leucine); R B each of which is H (the dipeptide Leu-Leu); or The first R A is methyl (alanine), and the second R A is methyl(alanine); R B each of which is H (the dipeptide Ala-Ala); or The first R A is 4-aminobutan-1-yl(lysine); the second R A is 4-aminobutan-1-yl(lysine); R B each of which is H (the dipeptide Lys-Lys); or The first R A is hydrogen; the second R A is 4-aminobutan-1-yl and R B Each of is H (dipeptide Gly-Lys).

[0421] In some embodiments, the α-carbon of amino acids other than glycine is in the L or D configuration, respectively.

[0422] In some embodiments, compounds disclosed herein can be synthesized according to the general schemes outlined in Scheme 1 and Scheme 2 below, where suitable reagents can be purchased from commercial sources or synthesized via known methods or methods adapted from the example procedures provided herein:

[0423] [ka]

[0424] [ka] In Scheme 1, S1 (K101A is shown as an example) is protected with trityl chloride (or triphenylmethyl chloride) to give S2 (K101-C20Tr-A is shown as an example). Hydrolysis of S2 (K101-C20Tr-A is shown as an example) gives S3 (K101-C20Tr-B is shown as an example), which can 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.

[0425] In Scheme 2, S7 is prepared by epoxidation of S5 with a peroxycarboxylic acid such as metachloroperbenzoic acid (m-CPBA). Further separation and purification of S7 affords S8.

[0426] Suitable starting materials and reagents for use in Scheme 1 and Scheme 2 can be purchased or prepared by methods known to those skilled in the art.

[0427] 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 chemical derivatization and / or functional group interconversion can be used to further modify any of the compounds of Scheme 1 and Scheme 2 to provide various compounds of Formula I.

[0428] 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 relevant compound, e.g., R 6The compound is prepared by reacting with a compound having an -OH group at the -OH position. Guidance is provided in Examples 63 and 64, which illustrate the general procedures available in the art for synthesizing amino acid prodrugs and purifying such prodrugs (see, for example, Vale et al., 2018, Molecules. 23(9):2318; Beauchamp et al., 1992, Antiviral Chemistry & Chemotherapy 3(3):157-164; incorporated herein by reference).

[0429] Other compounds of the present disclosure can be synthesized using the synthetic routes described above 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 into the detailed description of the present disclosure.

[0430] 5. Pharmaceutically acceptable salts In some embodiments, PKC modulator compound is in free form or, if appropriate, as pharmaceutically acceptable salt.Pharmaceutical acceptable salt is well known in the art.For example, S.M. Berge et al., in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference, describe pharmaceutically acceptable salt in detail.

[0431] 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 include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with 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, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of the salts include phonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0432] Base addition salts can be prepared by (1) reacting a compound, such as a purified compound, in its acid form with a suitable organic or inorganic base and (2) isolating the salt so formed. Suitable base-derived salts include alkali metal salts, alkaline earth metal salts, ammonium salts, and N-type salts.+ (C1-C4 alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharmaceutically acceptable salts include non-toxic ammonium cations, quaternary ammonium cations, and amine cations, formed, where appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0433] 6. Combination therapy with second-line treatment In some embodiments, a diterpenoid PKC modulating compound is used in combination with one or more second therapeutic agents. In some embodiments, the second therapeutic agent selected is one that is appropriate or suitable for the disease or condition being treated.

[0434] In some embodiments for the treatment of cancer, the second therapeutic agent is selected from platinating agents, alkylating agents, antibiotics, 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 drugs, agents that affect cellular biogenesis, i.e., agents that affect cellular ATP levels and molecules / activities that control cellular ATP levels, anti-cancer biological agents (e.g., monoclonal antibodies), kinase inhibitors, and inhibitors of growth factors and their receptors.

[0435] 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, cabazitaxin, Cel, carboplatin, carmustine, cenisertib, ceritinib, chlorambucil, cisplatin, cladribine, clofarabine, crenolanib, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dacomitinib, dactinomycin, danusertib, dasatinib, daunorubicin, decitabine, dinaciclib, docetaxel, dovitinib, doxorubicin, epirubicin, epirubicin Nib, eribulin mesylate, erlotinib, etirinotecan, etoposide, everolimus, exemestane, floxuridine, fludarabine, fluorouracil, gefitinib, gemcitabine, hydroxyurea, ibrutinib, icotinib, idarubicin, idelalisib, ifosfamide, imatinib, imetelstat, 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 tris(palifosfamidetris), pazopanib, pelitinib, pemetrexed, pentostatin, plicamycin, ponatinib, poziotinib, pralatrexate, procarbazine, quizartinib, raltitrexed, regorafenib, ruxolitinib, seliciclib, sorafenib, streptozocin, sulfatinib, sunitinib, tamoxifen, tandutinib, temozolomide, temsirolimus, teniposide, theliatinib, thioguanine, thiotepa, topotecan, uramustine, valrubicin, vandetanib, vemurafenib (Zelborae), vincristine, vinblastine, vinorelbine, vindesine, and the like.

[0436] In some embodiments, the second therapeutic agent is selected from the group consisting of a phosphoinositol-3 kinase (PI3K) inhibitor, an AKT inhibitor, a mammalian target of rapamycin (mTOR) inhibitor, a poly ADP-ribose polymerase (PARP) inhibitor, a platinum-based anticancer compound (PBAC), a CBP / β-catenin inhibitor, a tankyrase (TNKS) inhibitor, a probable protein-cysteine ​​N-palmitoyltransferase (PORCN) inhibitor, a scr kinase / bcr-abl kinase inhibitor, a smoothened (SMO) inhibitor, an anticancer nucleoside analog or antimetabolite, a histone deacetylase (HDAC) inhibitor, a bromodomain and extra-terminal motif (BET) inhibitor, all-trans retinoic acid (ATRA), a Bruton's tyrosine kinase (BTK) inhibitor, an EGFR receptor inhibitor, and combinations thereof.

[0437] In some embodiments, the second therapeutic agent is selected from the group consisting of idelalisib, pictilisib, duvelisib, pilalisib, alpelisib, copanlisib, voxtalisib, dactolisib, gedatolisib, apitolisib, perifosine, miltefosine, ipatasertib, sirolimus, everolimus, temsirolimus, tacrolimus, ridaforolimus, dactolisib, olaparib, veliparib, rucaparib, talazoparib, niraparib, cisplatin ... Platin, carboplatin, oxaliplatin, dicycloplatin, nedaplatin, lobaplatin, heptaplatin, phenathriplatin, phosphaplatin, LA-12, ICG-001, PRI-724, XAV-939, G007-LK, LGK-974, ETC-159, staurosporine, nilotinib, imatinib, ponatinib, saracatinib, dasatinib, bosutinib, saracatinib, cycloplatin Pamine, vismodegib, glasdegib, SANT-1, sonidegib, salidegib, taladegib, GSK1210151A, GSK525762, CPI-0610, RVX-208, vorinostat (SAHA), entinostat, panobinostat, mocetinostat, belinostat, romidepsin, rosilinostat, abequinostat, resminostat, gibinostat, xinostat, prasinostat, quevetrine, CC- 292, CNX-774, LFM-A13, CGI1746, trastuzumab, pertuzumab, ado-trastuzumab etansine, cetuximab, panitumumab, nimotuzumab, mAb806, rindopepimut, lapatinib, erlotinib, gefitinib, afatinib, neratinib, osimertinib, rociletinib, canertinib, and dacomitinib.

[0438] In some embodiments for the treatment of cancer, one or more second immunostimulatory or immunoenhancing agents are administered in an effective amount, eg, to treat cancer in a subject in need thereof.

[0439] In some embodiments, the second immune stimulatory or immune enhancing agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is an anti-CTLA4 antibody, an anti-PD-L1 antibody, or an anti-PD-1 antibody, or a combination thereof. In some embodiments, the administered immune checkpoint inhibitor is an anti-CTLA4 antibody such as atezolizumab. In some embodiments, the administered immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody. Exemplary anti-PD-1 or anti-PD-L1 antibodies may be selected from pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, camrelizumab, cemiplimab, sintilimab, tislelizumab, and toripalimab.

[0440] In some embodiments, the immune stimulatory or immune enhancing agent is a cytokine. In some embodiments, the cytokine is selected from IFN-α, IL-2, IL-10, IL-12, IL-15, IL-21, IFN-γ, TNF-α, and GM-CSF. In some embodiments, the cytokine selected is appropriate or suitable for the indication of the disease being treated. In some embodiments, the cytokine is effective in stimulating or enhancing an immune response against cancer cells.

[0441] 7.Combination therapy with CAR-T therapy or CAR-NK therapy In some embodiments for the treatment of cancer, diterpenoid-based PKC-modulating compounds are used in combination with chimeric antigen receptor T cell (CAR-T) therapy or chimeric antigen receptor NK cell (CAR-NK) therapy. The selected CAR-T or CAR-NK therapy is appropriate for the cancer being treated with the diterpenoid-based PKC-activating compound. CAR-T and CAR-NK refer to T cells and NK cells, respectively, genetically engineered to express a recombinant T cell receptor or NK cell receptor containing an antigen-binding region, e.g., an antibody single-chain variable fragment (scFV), that binds to an antigen on target cells, e.g., cancer cells. The antigen-binding region is attached via a linker or spacer sequence (e.g., a hinge region) to a transmembrane domain coupled to an intracellular signaling domain. An exemplary intracellular signaling domain for use in T cells is the immunoreceptor activation tyrosine motif in the cytoplasmic domain of CD3-zeta. To further enhance T cell responses, CARs include costimulatory molecules such as CD28, 4-1BB (CD-137), ICOS, or OX40 (CD134) in addition to CD3-zeta. Exemplary transmembrane domains for use in T cells are those of CD4, TCR, and CD8. CAR-NK cells can use similar structural elements used in CAR-T, including CAR-T-based intracellular signaling domains (see, e.g., Guedan et al., Mol Therapy Methods, Clin Dev., 2019, 12:145-156). In some embodiments, CAR-T and CAR-NK therapies use modular systems, such as universal adapters, in which an antigen-binding region for a cancer antigen or the like is separated from a signaling module consisting of a spacer / hinge, a transmembrane domain, and an intracellular signaling domain, and attached to the signaling module via an adapter.This allows for the use of different antigen-binding regions with the same signaling module but tags such as neoepitopes, SpyTags, leucine zippers, biotin, and FITC, allowing for easy switching of antigen-binding regions to target different cancer antigens on different cancer types (see, e.g., Sutherland et al., Int'l J Mol Sci., 2020, 21:7222). In some embodiments, CAR-T or CAR-NK incorporate a "safety switch" to control the response in the CAR-T or CAR-NK cells.

[0442] CAR-T therapy and CAR-NK therapy have been developed to treat hematological cancers, such as leukemia and lymphoma, for example, chronic lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and lymphoma. CAR-T cells and CAR-NK cells for various cancers have been reported, among others, in WO 2008121420; WO 2011041093; WO 2011059836; WO 2012058460; WO 2012079000; WO 2012082841; WO 2012 / 099973; U.S. Patent No. 9868774; U.S. Patent No. 9447194; U.S. Patent No. 9359447; U.S. Patent No. 9765342; U.S. Patent No. 9999973; U.S. Patent No. 9999974 ... 855297; WO 2016201300; WO 2017049166; WO 2017027291; WO 2018061012; WO 2019077062; WO 2020227595; WO 2021035078; WO 2021041486; WO 2021038036; and WO 2021045975; all publications are incorporated herein by reference.

[0443] 8. Formulation and Administration In some embodiments, pharmaceutical compositions of the therapeutic agent may be formulated using standard techniques with one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in Remington: The Science and Practice of Pharmacy, 21 st Ed. (2005). The therapeutic compounds, as well as 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, subdermal, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary, or intratumoral injection, such as by a syringe or other device. Transdermal administration is also contemplated, as are inhalation and aerosol administration. Tablets, capsules, and solutions can be administered orally, rectally, or vaginally.

[0444] For oral administration, the pharmaceutical composition may take the form of, for example, a tablet or capsule prepared by conventional methods using pharmaceutically acceptable excipients. Tablets and capsules containing an active ingredient may be prepared with excipients such as: (a) diluents or fillers, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylate, and / or calcium hydrogen phosphate, calcium sulfate; (b) lubricants, such as silica, talc, 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, flavorings, and sweeteners. The compositions are prepared according to conventional mixing, granulating, or coating methods.

[0445] Tablets may be film-coated or enteric-coated according to methods known in the art.Liquid preparations for oral administration can be in the form of, for example, solutions, syrups, or suspensions, or can be presented as dry products to be reconstituted with a suitable solvent such as water before use.Such liquid preparations can be prepared by conventional methods using pharmaceutically acceptable carriers and additives, such as suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible oils and fats; emulsifiers, for example, lecithin or acacia; non-aqueous solvents, for example, almond oil, oil esters, ethyl alcohol, or vegetable fractionated oils; and preservatives, for example, methyl or propyl p-hydroxybenzoate or sorbic acid.This preparation can also contain buffer salts, flavoring agents, coloring agents, and / or sweeteners as needed.If desired, the preparation for oral administration can be suitably formulated to provide controlled release of active compounds.

[0446] Therapeutic agents may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Injectable formulations may be provided in unit dosage form, e.g., in ampoules or multidose containers, optionally with added preservatives. The injectable composition may be an aqueous isotonic solution or suspension. In some parenteral administration embodiments, the therapeutic agent may be prepared with a surfactant, such as Cremaphor, or a lipophilic solvent, such as a triglyceride or liposome. The composition may be sterilized and / or contain auxiliary agents, such as preservatives, stabilizers, wetting agents, emulsifiers, solubilizers, salts for controlling osmotic pressure, and / or buffers. Alternatively, the therapeutic agent may be in powder form for reconstitution with a suitable solvent, e.g., sterile pyrogen-free water, before use. Additionally, the composition may contain other therapeutically active substances.

[0447] In some embodiments, a therapeutic agent, such as a diterpenoid PKC-modulating compound, is administered intratumorally. In some embodiments, the therapeutic agent is administered directly to the tumor, allowing for high local concentrations of the therapeutic agent and, in some embodiments, increased bioavailability of the therapeutic agent at the site of the tumor. Any formulation of a 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 more widespread distribution or infusion of the therapeutic agent to treat bulky tumors.

[0448] For administration by inhalation, the therapeutic agent can be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable 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, for example, made of 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.

[0449] A formulation suitable for transdermal administration comprises an effective amount of a therapeutic agent together with a carrier. Preferred carriers include absorbable pharmacologically acceptable solvents that assist passage through the subject's skin. For example, a transdermal device is in the form of a bandage or patch, comprising a backing member, a reservoir containing the therapeutic agent and optionally a carrier, optionally a rate-controlling barrier for delivering the compound to the recipient's skin at a controlled, predetermined rate over an extended period of time, and a means for securing the device to the skin. Matrix-type transdermal formulations can also be used.

[0450] Formulations suitable for topical administration, for example to the skin and eyes, are preferably aqueous solutions, ointments, creams, or gels well known in the art, which may contain solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0451] In some embodiments, the Therapeutic Agents may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides, or gel-forming agents such as carbomer.

[0452] In some embodiments, the therapeutic agent can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) 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, e.g., as a sparingly soluble salt.

[0453] In some embodiments, the carrier is a cyclodextrin, such as to enhance 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.

[0454] In some embodiments, the compounds may be formulated with cyclodextrin or a derivative thereof selected from carboxyalkylcyclodextrins, hydroxyalkylcyclodextrins, sulfoalkylethercyclodextrins, and alkylcyclodextrins. In various embodiments, the alkyl group of the cyclodextrin is methyl, ethyl, propyl, butyl, or pentyl.

[0455] 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-cyclodextrin, hydroxyalkyl-α-cyclodextrin, sulfoalkylether-α-cyclodextrin, alkyl-α-cyclodextrin, and combinations thereof. In some embodiments, the alkyl group of the α-cyclodextrin derivative is methyl, ethyl, propyl, butyl, or pentyl.

[0456] In some embodiments, the cyclodextrin is β-cyclodextrin or a derivative thereof. In some embodiments, the β-cyclodextrin or a derivative thereof is selected from carboxyalkyl-β-cyclodextrin, hydroxyalkyl-β-cyclodextrin, sulfoalkylether-β-cyclodextrin, alkyl-β-cyclodextrin, and combinations thereof. In some embodiments, the alkyl group of the β-cyclodextrin derivative is methyl, ethyl, propyl, butyl, or pentyl.

[0457] 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.

[0458] 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 of 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.

[0459] When used in the compounds and formulations of the present disclosure, cyclodextrins may 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.

[0460] The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil (e.g., a blister pack). The pack or dispenser device may be accompanied by instructions for administration.

[0461] 9. Effective Dose and Administration In some embodiments, pharmaceutical compositions of the therapeutic agents are administered to a subject, preferably a human, at a therapeutically effective dose to prevent, treat, or control a condition or disease as 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 prevents or slows the symptoms or complications of the condition or disease. An amount adequate to accomplish this is defined as a "therapeutically effective dose" or "therapeutically effective amount."

[0462] The dosage of a therapeutic agent may take into account, among other things, the species of warm-blooded animal (mammal), body weight, age, the condition being treated, the severity of the condition being treated, the dosage form, and the route of administration. The size of the dose will also be determined by the presence, nature, and extent of any adverse effects that accompany the administration of a particular therapeutic compound in a particular subject.

[0463] In some embodiments, the diterpenoid PKC activating compound may be administered at a dose ranging from about 0.001 mg / kg to about 1000 mg / kg of subject body weight (0.001 mg / kg). In some embodiments, the dose is in the range of about 0.001 mg / kg to about 500 mg / kg. In some embodiments, the dose is in the range of about 1 mg / kg to about 500 mg / kg. In some embodiments, the dose is about 2 mg / kg to about 250 mg / kg. In another embodiment, the dose is about 5 mg / kg to about 100 mg / kg. In another embodiment, the dose is 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 may be administered once daily or may be divided into sub-doses and administered, for example, two, three, or four times daily.

[0464] In some embodiments, the diterpenoid PKC activator can be administered sequentially or simultaneously with one or more second therapeutic agents, 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 therapy. In some embodiments, the diterpenoid PKC activator can be administered first, followed by the second therapeutic agent, or the second therapeutic agent can be administered first, followed by the diterpenoid PKC activator. Non-limiting examples of the time between administrations are 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 is 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 is about 1 week, 2 weeks, 3 weeks, or 4 weeks or more. In some embodiments, the time between administrations is about 1 month, or 2 months or more.

[0465] When administered simultaneously, the diterpenoid PKC modulator may be administered separately by the same or different route simultaneously with the second therapeutic agent, or may be administered in a single composition by the same route.

[0466] In some embodiments, the amount and frequency of administration of the second therapeutic agent can be the standard dosage and frequency used for that particular therapeutic agent. See, for example, Physicians' Desk Reference, 70 th Ed., PDR Network, 2015.

[0467] In some embodiments, when the administration of the therapeutic agent is to a local site (e.g., intratumoral injection), the dosage may be that used for systemic administration, such as that used for intravenous, intramuscular, and intraperitoneal administration. In some embodiments, the dosage for local administration, e.g., intratumoral administration, is higher than that used for systemic administration. In some embodiments, the administered dosage is sufficient to achieve the desired effect, e.g., tumor tissue death or necrosis. In some embodiments, intratumoral administration is performed one, two, three, four, five, or up to six or more times, with each administration separated in time, e.g., until the desired result is achieved.

[0468] It should be understood that optimal dosage, toxicity, and therapeutic efficacy of such therapeutic agents may vary depending on the relative potency of the individual therapeutic agents, and may be achieved by pharmaceutical techniques in cell culture or experimental animals, e.g., LD 50 (lethal dose for 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 The therapeutic index can be expressed as a ratio of . Therapeutic agents or combinations thereof that exhibit large therapeutic indices are preferred. While certain agents that exhibit toxic side effects can be used, care should be taken to design delivery systems that target such agents to the site of affected tissue in order to minimize the potential for damage to normal cells, thereby reducing side effects.

[0469] The data obtained from cell culture assays, animal studies, and the like can be used in formulating a range of dosage for use in humans. The dosage of such small molecule compounds is preferably administered at or above the ED 50The therapeutically effective dose of any compound used in the methods of the present invention can be estimated initially from cell culture assays. In animal models, the IC 50 Doses can be titrated 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).

[0470] The following examples are provided to further illustrate the disclosed methods, and compounds and compositions for use in said methods. The described examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way. [Example]

[0471] Example 1: Synthesis scheme of K101-epoxide and K101-di-OH The synthesis scheme for compounds K101-epoxide and K101-di-OH is shown below.

[0472] [ka] Preparation of compound K101-C20Tr-A To a solution of K101A (1 g, 2.56 mmol, 1 equiv.) in pyridine (40 mL) was added trityl chloride (2.14 g, 7.68 mmol, 3.00 equiv.). The mixture was stirred at 40 °C for 14 h to give a yellow solution. LC-MS showed the desired mass was present, indicating that K101A remained. Again, the mixture was stirred at 40 °C for 12 h. LC-MS and TLC (eluent: PE / EtOAc = 2 / 1) showed the reaction was complete. The reaction mixture was concentrated by drumming N2 to give the crude product. The crude product was purified by flash column chromatography (eluent: 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. 1 H 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).

[0473] Preparation of compound epoxide-Trt in dichloromethane (hereafter referred to as DCM) (2.00 mL) K101-C20Tr-ATo a solution of (30.00 mg, 47.41 μmol, 1.00 equivalent (hereafter referred to as equivalent (eq))), NaHCO3 (11.95 mg, 142.23 μmol, 5.53 μL, 3.00 equivalents), metachloroperbenzoic acid (m-CPBA) (14.44 mg, 71.11 μmol, 1.5 equivalents, 85% purity) were added, and the reaction mixture was stirred at 20 °C for 2 h to give a suspension. LC-MS showed the reaction was complete and confirmed the desired MS values. 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 preparative TLC (PE / EtOAc=2 / 1, SiO 2 ) to give epoxide-Trt (20.10 mg, 65.34% yield) as a colorless gum.

[0474] 1 H 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, 1H), 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).

[0475] Preparation of compounds K101-epoxide and K101-di-OH To a solution of epoxide-Trt (10.00 mg, 15.41 μmol, 1.00 equiv) in DCM (500.00 μL) was added trifluoroacetic acid (hereafter TFA) (100.00 μL), and the reaction was stirred at 0 °C for 1 h. TLC (PE / EtOAc = 2 / 1, SiO 2 ) showed the reaction was complete. The reaction was quenched with saturated aqueous NaHCO 3 (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 crude product preparation and purified by preparative HPLC (column: Waters Xbridge 150 × 25 × 5 mm; mobile phase: A [A: water (0.05% ammonium hydroxide, v / v)]; B [acetonitrile (ACN)]; gradient B: 25% to 55% in 10 min) to give 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), both as white solids after lyophilization. K101-epoxide: LC-MS (m / z): 429.2 [M+Na] + 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).

[0476] K101-di-OH:LC-MS(m / z):447.1[M+Na] + K101-di-OH: 1H 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).

[0477] Example 2: Synthesis scheme of K101-C13OH The synthesis scheme of compound K101-C13OH is shown below.

[0478] [ka] Preparation of compound K101-C13OH To a solution of K101A (40.00 mg, 102.44 μmol, 1.00 equiv) in MeOH (20.00 mL) was added Ba(OH)2.8H2O (322.69 mg, 1.02 mmol, 10.00 equiv). The mixture was stirred at 20 °C for 4 h to give a yellow suspension. LC-MS and TLC (elution: EtOAc = 100%) showed the reaction was complete. The reaction mixture was quenched with saturated NH4Cl (10 mL) and extracted with dichloromethane (DCM) (100 mL × 3). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by preparative TLC (elution: EtOAc = 2 / 1) to give K101-C13OH (9.30 mg, 26.69 μmol, 26.05% yield, 100% purity) as a white solid.

[0479] LC-MS(m / z):371.2[M+Na] + 1H 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).

[0480] Example 3: Synthesis scheme of K101-C1301 The synthesis scheme of compounds K101-C1301 is shown below.

[0481] [ka] Preparation of compound K101-C20Tr-A To a solution of K101A (500.00 mg, 1.28 mmol, 1.00 equiv) in pyridine (10.00 mL) was added trityl chloride (TrtCl) (1.07 g, 3.84 mmol, 3.00 equiv). The mixture was stirred at 20 °C for 14 h to give a yellow solution. LC-MS and TLC (eluent: PE / EtOAc = 2 / 1) showed the reaction was complete. The reaction mixture was concentrated with N2 to give the crude product. The product was purified by flash column chromatography (eluent: 1% to 50% EtOAc in PE) to give K101-C20Tr-A (790.00 mg, 1.02 mmol, 79.78% yield, 81.795% purity) as a white solid.

[0482] Preparation of compound K101-C20Tr-B To a solution of K101-C20Tr-A (290.00 mg, 458.30 μmol, 1.00 equiv) in MeOH (76.00 mL) was added Ba(OH)2.8H2O (1.44 g, 4.58 mmol, 10.00 equiv) 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, 92.86% yield, 96.694% purity) as a white solid.

[0483] Preparation of compound K101-C1301-A To a solution of K101-C1301-B (35.00 mg, 59.25 μmol, 1.00 equiv.) in DCM (500.00 μL) was added 3-cyclopentylpropanoic acid (10.11 mg, 71.10 μmol, 10.11 μL, 1.20 equiv.), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EDC (EDC) (22.72 mg, 118.49 μmol, 2.00 equiv.), and 4-dimethylaminopyridine (DMAP) (14.48 mg, 118.50 μmol, 2.00 equiv.). The mixture was stirred at 20 °C for 14 h to give a yellow solution. LC-MS and TLC (elution: PE / EtOAc = 4 / 1) indicated the reaction was complete. This reaction mixture was combined with the second preparation of the compound, quenched with HO (10 mL), and extracted with DCM (15 mL × 3). The combined organic layers were dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (elution: PE / EtOAc = 4 / 1) to give K101-C1301-A (32.00 mg, 44.76 μmol, 65.12% yield, 100% purity) as a white solid.

[0484] Preparation of compounds K101-C1301 To a solution of K101-C1301-A (32.00 mg, 44.76 μmol, 1.00 equiv) in DCM (1.00 mL) was added TFA (385.00 mg, 3.38 mmol, 250.00 μL, 75.44 equiv). The mixture was stirred at 20 °C for 1 h to give a yellow solution. LC-MS and TLC (elution: PE / EtOAc = 1 / 1) showed the reaction was complete. The solvent was removed with N to give the crude product. The product was purified by preparative TLC (elution: PE / EtOAc = 1 / 1) to give K101-C1301 (8.10 mg, 17.14 μmol, 38.29% yield, 100% purity) as a white solid.

[0485] LC-MS(m / z):495.3[M+Na] + 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).

[0486] Example 4: Synthesis scheme of K101-C1302 The synthesis scheme of compounds K101-C1302 is shown below.

[0487] [ka] Preparation of compound K101-C1302-A To a solution of K101-C20Tr-B (40.00 mg, 67.71 μmol, 1.00 equiv.) in DCM (1.00 mL), 3-[4-(trifluoromethyl)phenyl]propanoic acid (C13-02) (17.73 mg, 81.25 μmol, 1.20 equiv.), DMAP (16.54 mg, 135.42 μmol, 2.00 equiv.), and EDC (25.96 mg, 135.42 μmol, 2.00 equiv.) were added. The mixture was stirred at 20 °C for 2 h to give a yellow solution. LC-MS and TLC (elution: PE / EtOAc = 2 / 1) indicated the reaction was complete. This mixture was combined with a second preparation of the compound, quenched with saturated NaHCO3 (5 mL), and extracted with DCM (10 mL × 3). The organic layer was washed with HO (5 mL), dried over NaSO, and then concentrated to give the crude product, which was purified by preparative TLC (eluent: 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.

[0488] Preparation of compounds K101-C1302 To a solution of K101-C1302-A (28.00 mg, 35.40 μmol, 1.00 equiv) in MeOH (1.00 mL) was added HClO (464.95 mg, 4.63 mmol, 280.09 μL, 130.73 equiv). The mixture was stirred at 0° C. for 0.5 h to give a yellow solution. LC-MS showed the reaction was complete. This reaction mixture was combined with a second preparation of the compound and purified by preparative HPLC (column: Waters XSELECT C18 150 x 30 mm x 5 um; mobile phase: [A: water (0.1% TFA)-B: 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.

[0489] LC-MS(m / z):571.3[M+Na] + 1H 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).

[0490] Example 5: Synthesis scheme of K101-C1303

[0491] [ka] Preparation of compound K101-C1303-A: To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 equiv.) in DCM (2.00 mL), (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid (C13-03) (26.95 mg, 101.57 μmol, 2.00 equiv.), DMAP (24.82 mg, 203.13 μmol, 4.00 equiv.), and EDC (19.47 mg, 101.57 μmol, 2.00 equiv.) were added. The mixture was stirred at 20 °C for 48 h to give a yellow solution. LC-MS and TLC (elution: 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 times). The organic layer was dried over NaSO and concentrated to give a crude product, which was purified by preparative TLC (eluent: 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.

[0492] 1H 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, 1H), 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).

[0493] Preparation of compounds K101-C1303 : To a solution of K101-C20Tr-B (30.00 mg, 35.80 μmol, 1.00 equiv) in DCM (1.00 mL) was added TFA (154.00 mg, 1.35 mmol, 100.00 μL, 37.73 equiv) at 0 °C. The mixture was stirred at 0 °C for 2 h to give a red-brown solution. The mixture was stirred at 20 °C for 14 h to give a red-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 μL, 23.08 equiv) was added at 0 °C. The mixture was stirred at 0 °C for 2 h 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: B: ACN]; B%: 18%-48%, 10 min) to give K101-C1303 (4.50 mg, 6.90 μmol, yield 19.27%, purity 93.438%, TFA salt) as a white solid.

[0494] LC-MS(m / z):519.3[M+H] + 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, 1H), 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).

[0495] Example 6: Synthesis scheme of K101-C1304 The synthesis scheme of compounds K101-C1304 is shown below.

[0496] [ka] Preparation of compound K101-C1304-A To a solution of K101-C20Tr-B (40.00 mg, 67.71 μmol, 1.00 equiv) in DCM (2.00 mL) was added 2-phenylacetic acid (C13-04) (11.06 mg, 81.25 μmol, 10.24 μL, 1.20 equiv), DMAP (33.09 mg, 270.84 μmol, 4.00 equiv), and EDC (25.96 mg, 135.42 μmol, 2.00 equiv). The mixture was stirred at 20 °C for 12 h to give a yellow solution. LC-MS and TLC (elution: PE / EtOAc = 2 / 1) indicated the reaction was complete. The reaction mixture was combined with a second preparation of the compound, quenched with HO (5 mL), and extracted with DCM (15 mL × 3). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The product was purified by preparative TLC (elution: PE / EtOAc=2 / 1) to give K101-C1304-A (40.00 mg, 56.43 μmol, yield 65.78%) as a white solid.

[0497] Preparation of compounds K101-C1304 To a solution of K101-C1304-A (40.00 mg, 56.43 μmol, 1.00 equiv) in MeOH (3.00 mL) was added HClO (83.00 mg, 826.14 μmol, 50.00 μL, 14.64 equiv) 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 × 30 mm × 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.

[0498] LC-MS(m / z):489.3[M+Na] + 1 H 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).

[0499] Example 7: Synthesis scheme of K101-C1305 The synthesis scheme of compounds K101-C1305 is shown below.

[0500] [ka] Preparation of compound K101-C1305-A To a solution of K101-C20Tr-B (45.00 mg, 76.17 μmol, 1.00 equiv) 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 equiv), DMAP (37.22 mg, 304.68 μmol, 4.00 equiv), N,N-diisopropylethylamine (DIEA) (19.69 mg, 152.34 μmol, 26.61 μL, 2.00 equiv), and EDC (29.21 mg, 152.34 μmol, 2.00 equiv). The mixture was stirred at 20 °C for 48 h to give a yellow solution. LC-MS and TLC (elution: PE / EtOAc = 2 / 1) showed the reaction was complete. The reaction mixture was combined with the second preparation of the compound, 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 product was purified by preparative TLC (elution: PE / EtOAc = 2 / 1) to give K101-C13050-A (70.00 mg, crude) as a white solid.

[0501] Preparation of compounds K101-C1305 To a solution of K101-C1305-A (70.00 mg, 85.99 μmol, 1.00 equiv) in DCM (1.00 mL) was added TFA (154.00 mg, 1.35 mmol, 100.00 μL, 15.71 equiv) at 0 °C. The mixture was stirred at 0 °C for 2 h to give a reddish-brown solution. The mixture was stirred at 20 °C for 16 h. 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 The organic layer was dissolved in MeOH (3.00 mL) and HClO (83.00 mg, 826.20 μmol, 50.00 μL, 9.61 equiv) was added at 0 °C. The mixture was stirred at 0 °C for 2 h to give a yellow solution. LC-MS showed the reaction was complete. This mixture was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 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.

[0502] LC-MS(m / z):494.2[M+Na] + 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, 6H), 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).

[0503] Example 8: Synthesis scheme of K101-C1306 The synthesis scheme of compounds K101-C1306 is shown below.

[0504] [ka] Preparation of compound K101-C1306-A To a solution of K101-C20Tr-B (40.00 mg, 67.71 μmol, 1.00 equiv) 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 equiv), DMAP (33.09 mg, 270.84 μmol, 4.00 equiv), DIEA (26.25 mg, 203.13 μmol, 35.47 μL, 3.00 equiv), and EDC (25.96 mg, 135.42 μmol, 2.00 equiv). The mixture was stirred at 20 °C for 16 h to give a yellow solution. LC-MS and TLC (elution: PE / EtOAc = 2 / 1) indicated the reaction was complete. This mixture was combined with the second preparation of the compound, quenched with saturated NaHCO (5 mL), and extracted with DCM (10 mL × 3). The organic layer was dried over NaSO and concentrated to give the crude product. The product was purified by preparative TLC (elution: 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.

[0505] Preparation of compounds K101-C1312 To a solution of K101-C1306-A (10.00 mg, 12.08 μmol, 1.00 equiv) in MeOH (3.00 mL) was added HClO (83.00 mg, 826.20 μmol, 50.00 μL, 68.39 equiv) at 0° C., and the mixture was stirred at 0° C. for 0.5 h. The mixture was stirred at 20° C. for an additional 15.5 h. LC-MS showed the reaction was complete. This mixture was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 30 × 5 μm; mobile phase: [A: water (0.05% ammonium 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.

[0506] LC-MS(m / z):608.2[M+Na] + 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).

[0507] Preparation of compounds K101-C1306 To a solution of K101-C1312 (15.00 mg, 25.61 μmol, 1.00 equiv) in THF (500.00 μL) was added TFA (288.72 mg, 2.53 mmol, 187.48 μL, 98.88 equiv), and the mixture was stirred at 20 °C for 4 h to give a colorless solution. LC-MS indicated the reaction was complete, but a mass of P2 was still present. The reaction mixture was concentrated with N2, and the resulting product was dissolved in MeOH (500.00 μL) / HO (50.00 μL). The mixture was stirred at 20 °C for 14 h to give a colorless solution. LC-MS indicated the reaction was complete. This mixture was combined with a second preparation of the compound and concentrated with N2 to give the desired product. Lyophilization of this product afforded K101-C1306 (4.20 mg, 7.00 μmol, 25.80% yield, TFA) as a yellow gum. Purification of this product (13.4 mg) by preparative HPLC (Phenomenex Gemini 150 × 25 mm × 10 μm column; mobile phase: [water (0.1% TFA)-ACN]; B%: 20%–50%, 10 min) afforded K101-C1306 (4.20 mg, 7.00 μmol, 25.80% yield, TFA) as a white solid.

[0508] LC-MS(m / z):508.2[M+Na] + 1 H 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).

[0509] Example 9: Synthesis scheme of K101-C1311 The synthesis scheme of compounds K101-C1311 is shown below.

[0510] [ka] Preparation of compounds K101-C1311 To a solution of K101-C1305-A (22.00 mg, 27.03 μmol, 1.00 equiv) in MeOH (3.00 mL) was added HClO (26.09 mg, 259.73 μmol, 15.72 μL, 9.61 equiv) 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 × 25 × 5 μL; Mobile phase: [A: water (0.05% ammonium hydroxide, v / v) - B: ACN]; B%: 40%–70%, 10 min) to give K101-C1311 (3.30 mg, 5.77 μmol, 21.36% yield, 100% purity) as a yellow solid.

[0511] LC-MS(m / z):594.3[M+Na] + 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).

[0512] Example 10: Synthesis scheme of K101-C1312 The synthesis scheme of compound K101-C1312 is shown below.

[0513] [ka] Preparation of compounds K101-C1312 To a solution of K101-C1306-A (10.00 mg, 12.08 μmol, 1.00 equiv) in MeOH (3.00 mL) was added HClO4 (83.00 mg, 826.20 μmol, 50.00 μL, 68.39 equiv) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The mixture was stirred at 20 °C for an additional 15.5 h to give a yellow solution. LC-MS showed the reaction was complete. This mixture was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 30 × 5u; mobile phase: [A: water (0.05% ammonium 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.

[0514] LC-MS(m / z):608.2[M+Na] + 1H 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).

[0515] Example 11: Synthesis scheme of K101-C1313 The synthesis scheme of compound K101-C1313 is shown below.

[0516] [ka] Preparation of compound K101-C1313-A To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 equiv.) in DMF (2.00 mL) was added (£)-3-[4-(trifluoromethyl)phenyl]prop-2-enoic acid (C13-13) (21.95 mg, 101.56 μmol, 2.00 equiv.), DIEA (19.69 mg, 152.34 μmol, 26.61 μL, 3.00 equiv.), DMAP (24.82 mg, 203.12 μmol, 4.00 equiv.), and hexafluorophosphate azabenzotriazole tetramethyluronium (HATU) (38.62 mg, 101.56 μmol, 2.00 equiv.) The mixture was stirred at 20 °C for 14 h to give a yellow solution. LC-MS and TLC (eluent: 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 concentrated to give the crude product. The product was purified by preparative TLC (eluent: PE / EtOAc = 2 / 1) to give K101-C1313-A (21.00 mg, 26.62 μmol, 45.19% yield) as a white solid.

[0517] Preparation of compounds K101-C1313 To a solution of K101-C1313-A (21.00 mg, 26.62 μmol, 1.00 equiv) in MeOH (3.00 mL) was added HClO (83.00 mg, 826.28 μmol, 50.00 μL, 31.04 equiv) at 0 °C. The mixture was stirred at 0 °C for 1 h to give a yellow solution. LC-MS showed the reaction was complete. The mixture was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 55%–85%, 10 min) to give K101-C1313 (4.40 mg, 6.10 μmol, 22.90% yield, 91.518% purity, TFA) as a yellow solid.

[0518] LC-MS(m / z):569.1[M+Na]+ 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).

[0519] Example 12: Synthesis scheme of K101-C1315 The synthesis scheme of compound K101-C1315 is shown below.

[0520] [ka] Preparation of compound K101-C1315-A To a solution of K101-C20Tr-B (20.00 mg, 33.86 μmol, 1.00 equiv) and C13-15 (15.35 mg, 101.58 μmol, 3.00 equiv) in DCM (1.00 mL) was added EDC (19.47 mg, 101.58 μmol, 3.00 equiv) and DMAP (20.68 mg, 169.30 μmol, 5.00 equiv). The reaction was stirred at 25 °C for 3 h to give a brown solution. LC-MS showed the reaction was complete. The reaction was diluted with DCM (5 mL), washed with brine (2 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give K101-C1315-A (28.70 mg, crude) as a brown gum, which was used directly in the next step without further purification.

[0521] Preparation of compounds K101-C1315 To a solution of K101-C1315-A (25.00 mg, crude) in MeOH (1.00 mL) was added HClO (30.00 μL) at 25 °C. The reaction was stirred at 25 °C for 0.5 h to give a brown solution. LC-MS showed the reaction was complete. The reaction was quenched by adding KCO (34 mg) in water (1 mL) dropwise at 0 °C to adjust the pH to 9. The mixture was filtered, and the filtrate was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 15% to 45%, 10 min) to give K101-C1315 (3.60 mg, 97% purity, TFA salt) as a white solid after lyophilization.

[0522] LC-MS(m / z):504.2[M+Na] + 1 H 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).

[0523] Example 13: Synthesis scheme of K101-C1316 The synthesis scheme of compound K101-C1316 is shown below.

[0524] [ka] Preparation of compound K101-C1316-A To a solution of K101-C20Tr-B (40.00 mg, 67.71 μmol, 1.00 equiv.) in DCM (2.00 mL) was added C13-16 (51.18 mg, 338.55 μmol, 5.00 equiv.), DMAP (33.09 mg, 270.84 μmol, 4.00 equiv.), hydroxybenzotriazole (HOBt) (18.30 mg, 135.42 μmol, 2.00 equiv.), and EDC (25.96 mg, 135.42 μmol, 2.00 equiv.). The mixture was stirred at 20 °C for 12 h to give a black solution. LC-MS showed 43.779% of the desired mass and 16.864% of the reactant remained. The mixture was quenched with saturated NaHCO3 (10 mL) and extracted with DCM (15 mL × 3). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The product was purified by preparative TLC (elution: PE / EtOAc = 2 / 1) to give K101-C1316-A (27.00 mg, 37.30 μmol, 48.97% yield) as a white solid.

[0525] Preparation of compounds K101-C1316 To a solution of K101-C1316-A (27.00 mg, 37.30 μmol, 1.00 equiv) in MeOH (2.00 mL) was added HClO (83.00 mg, 826.20 μmol, 50.00 μL, 22.15 equiv) 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: Phenomenex Gemini 150 × 25 mm × 10 μm; mobile phase: [A: water (0.1% TFA) - B: ACN]; B%: 20% to 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.

[0526] LC-MS(m / z):504.2[M+Na] + 1H NMR (400MHz, 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).

[0527] Example 14: Synthesis scheme of K101-C1317 The synthesis scheme of compound K101-C1317 is shown below.

[0528] [ka] Preparation of compound K101-C1317-A To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 equiv.) in DCM (1.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)hexanoic acid (C13-17) (23.49 mg, 101.57 μmol, 2.00 equiv.), DMAP (24.82 mg, 203.13 μmol, 4.00 equiv.), and EDC (19.47 mg, 101.57 μmol, 2.00 equiv.). 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 × 5). The organic layer was dried over Na2SO4 and concentrated to give a yellow solid. The product was purified by preparative TLC (eluent: petroleum ether:ethyl acetate=5 / 1) to give K101-C1317-A (35.00 mg, 43.53 μmol, yield 85.73%) as a white solid.

[0529] Preparation of Compound K101-C1317 To a solution of K101-C1317-A (46.00 mg, 57.21 μmol, 1.00 equiv) in THF (2.00 mL) was added TFA (6.52 mg, 57.21 μmol, 4.23 μL, 1.00 equiv) and EtSiH (6.65 mg, 57.21 μmol, 9.11 μL, 1.00 equiv). 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 × 25 mm × 10 μm; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 30%-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.

[0530] LC-MS (m / z): 584.2 [M+Na] + 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).

[0531] Example 15: Synthesis of K101-C1318 The synthesis method of compound K101-C1318 is shown below.

[0532]

change

[0533] Preparation of Compound K101-C1318 To a solution of K101-C1318-A (30.00 mg, 35.21 μmol, 1.00 equiv) in THF (2.00 mL) was added TFA (308.00 mg, 2.70 mmol, 200.00 μL, 76.72 equiv) and EtSiH (4.91 mg, 42.25 μmol, 6.73 μL, 1.20 equiv). The mixture was stirred at 20 °C for 4 hours to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated with N and the residue was dissolved in MeOH (20 mL). The mixture was stirred at 20 °C for 12 hours. LC-MS showed the reaction was complete. The mixture was concentrated to give the crude product. This product was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 23% to 53%, 10 min) to give K101-C1318 (10.80 mg, 17.24 μmol, yield 48.98%, purity 99.58%, TFA) as a white solid.

[0534] LC-MS(m / z):532.1[M+Na] + 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), 4.07-4.03 (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).

[0535] Example 16: Synthesis scheme of K101-C1319 The synthesis scheme of compound K101-C1319 is shown below.

[0536] [ka] Preparation of compound K101-C1319-A To a solution of K101-C20Tr-B (200.00 mg, 338.55 μmol, 1.00 equiv) and C13-19 (119.18 mg, 406.26 μmol, 1.20 equiv) in anhydrous DCM (2.00 mL) was added EDC (194.70 mg, 1.02 mmol, 3.00 equiv) and DMAP (124.08 mg, 1.02 mmol, 3.00 equiv). The reaction was stirred at 20 °C for 16 h to give a light brown solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a crude product, which 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.

[0537] Preparation of compounds K101-C1319 To a solution of K101-C1319-A (273.00 mg, 315.21 μmol, 1.00 equiv) in MeOH (5.00 mL) was added HCl / MeOH (4 M, 5.00 mL, 63.45 equiv) at 0 °C. The reaction was stirred at 0 °C for 3.5 h to give a clear solution. LC-MS showed that the reaction was not complete, so the reaction was stirred at 20 °C for 1.5 h. LC-MS showed that the reaction was complete. N2 was bubbled through the reaction for 0.5 h to remove HCl, and the remaining solution was cooled to 0 °C, and the solution was adjusted to pH 7 with saturated aqueous NaHCO3. The mixture was extracted with DCM (10 mL × 2), and the combined extracts were dried over Na2SO4 and concentrated under reduced pressure to give 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, which was lyophilized to give a white solid.

[0538] MS (m / z): 546.2 [M+Na] + 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).

[0539] Example 17: Synthesis of K101-C1320 The synthesis method of compound K101-C1320 is shown below.

[0540]

change

[0541] Preparation of compounds K101-C1320 To a solution of K101-C1320-A (25.00 mg, 33.60 μmol, 1.00 equiv) in MeOH (1.00 mL) was added HClO (30.00 μL). The reaction was stirred at 25 °C for 0.5 h to give a clear solution. LC-MS showed the reaction was complete. The product was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25%–55%, 10 min) to give K101-C1320 (9.50 mg, 18.46 μmol, 54.95% yield, 97.5% purity) as a white powder after lyophilization.

[0542] LC-MS(m / z):524.1[M+Na] + 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).

[0543] Example 18: Synthesis scheme of K101-C1321 The synthesis scheme of compound K101-C1321 is shown below.

[0544] [ka] Preparation of compound K101-C1321-A To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 equiv.) and C13-21 (76.68 mg, 304.68 μmol, 6.00 equiv.) in DCM (1.00 mL) was added EDC (58.41 mg, 304.68 μmol, 6.00 equiv.) and DMAP (37.22 mg, 304.68 μmol, 6.00 equiv.). The reaction was stirred at 25 °C for 2 h to give a light brown solution. LC-MS showed improved conversion to product. This reaction 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 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.

[0545] Preparation of compounds K101-C1321 To a solution of K101-C1321-A (32.70 mg, 39.67 μmol, 1.00 equiv) in MeOH (1.00 mL) was added HClO (30.00 μL) at 25 °C. The reaction was stirred at 25 °C for 0.5 h to give a brown solution. LC-MS showed the reaction was complete. The reaction was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 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.

[0546] LC-MS(m / z):604.1[M+Na] + 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).

[0547] Example 19: Synthesis scheme of K101-C1322 The synthesis scheme of compound K101-C1322 is shown below.

[0548] [ka] Preparation of compound K101-C1322-A To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 equiv.) in DCM (2.00 mL), 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoic acid (C13-22) (19.32 mg, 101.56 μmol, 2.00 equiv.), DMAP (24.82 mg, 203.12 μmol, 4.00 equiv.), HOBt (13.72 mg, 101.56 μmol, 2.00 equiv.), and EDC (19.47 mg, 101.56 μmol, 2.00 equiv.) were added. The mixture was stirred at 20 °C for 12 h to give a yellow solution. LC-MS and TLC (elution: PE / EtOAc = 1 / 1) indicated the reaction was complete. The mixture was quenched with HO (5 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 (elution: PE / EtOAc = 1 / 1) to give K101-C1322-A (30.00 mg, 39.32 μmol, 58.22% yield) as a white solid.

[0549] Preparation of Compound K101-C1322 To a solution of K101-C1322-A (30.00 mg, 39.32 μmol, 1.00 equiv) in MeOH (2.00 mL) was added HClO (83.00 mg, 826.11 μmol, 50.00 μL, 21.01 equiv) 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 product was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; 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.

[0550] LC-MS(m / z):543.1[M+Na] + 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), 1.42-1.41 (m, 1H), 1.00 (s, 3H), 0.91 (s, 3H), 0.86-0.85 (m, 1H), 0.63-0.62 (m, 3H).

[0551] Example 20: Synthesis scheme of K101-C1323 The synthesis scheme of compound K101-C1323 is shown below.

[0552] [ka] Preparation of compound K101-C1323-A To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 equiv.) and C13-23 (23.49 mg, 152.34 μmol, 3.00 equiv.) in DCM (1.00 mL) was added EDC (58.41 mg, 304.68 μmol, 6.00 equiv.) and DMAP (37.22 mg, 304.68 μmol, 6.00 equiv.). The reaction was stirred at 25 °C for 2 h to give a brown solution. TLC (PE / EtOAc = 1 / 1, SiO2) showed the reaction to be complete. This reaction was combined with a second preparation of the compound, diluted with DCM (2 mL), washed with water (1 mL), brine (1 mL), and dried over anhydrous Na2SO4. The mixture 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) to give 32.5 mg of K101-C1323-A as a colorless gum.

[0553] Preparation of Compound K101-C1323 To a solution of K101-C1323-A (32.00 mg, 44.02 μmol, 1.00 equiv) in MeOH (1.00 mL) was added HClO (30.00 μL) at 25 °C. The reaction was stirred at 25 °C for 0.5 h to give a clear solution. LC-MS showed the reaction was complete. The reaction was directly purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25%-55%, 10 min) to give K101-C1323 (9.10 mg, 40.48% yield, 94.9% purity) as a white solid.

[0554] LC-MS(m / z):507.2[M+Na] + 1 H NMR (400MHz, 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), 3.07-3.01 (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).

[0555] Example 21: Synthesis scheme of K101-C1324 The synthesis scheme of compound K101-C1324 is shown below.

[0556] [ka] Preparation of compound K101-C1324-A To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 equiv) and C13-24 (25.01 mg, 152.34 μmol, 3.00 equiv) in DCM (1.00 mL) was added EDC (58.41 mg, 304.68 μmol, 6.00 equiv) and DMAP (37.22 mg, 304.68 μmol, 6.00 equiv). The reaction 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 was diluted with DCM (2 mL), washed with water (1 mL), brine (1 mL), and dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by silica gel column chromatography (elution: PE / EtOAc=5 / 1) to give K101-C1324-A (37.20 mg, 99.41% yield) as a colorless gum.

[0557] Preparation of Compound K101-C1324 To a solution of K101-C1324-A (37.20 mg, 50.48 μmol, 1.00 equiv) in MeOH (1.00 mL), HClO (30.00 μL) was added, and the reaction was stirred at 25 °C for 1 h to give a clear solution. LC-MS showed the reaction was complete. The product was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 55%–85%, 10 min) to give K101-C1324 (7.80 mg, 30.40% yield, 97.3% purity) as a white solid after lyophilization.

[0558] LC-MS(m / z):517.2[M+Na] + 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).

[0559] Example 22: Synthesis of K101-C1325 The synthesis method of compound K101-C1325 is shown below.

[0560]

change

[0561] Preparation of Compound K101-C1325 To a solution of K101-C1325-A (33.50 mg, 41.05 μmol, 1.00 equiv) in DMF (20.00 mL) in THF (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 329.02 equiv) and EtSiH (4.77 mg, 41.05 μmol, 6.53 μL, 1.00 equiv). The mixture was stirred at 20 °C for 5 h to give a colorless solution, which was concentrated to give a yellow oil. The oil was dissolved in DCM (2 mL) and TFA (0.5 mL) was added. The mixture was stirred at 20 °C for 1 h 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 × 25 mm × 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.

[0562] LC-MS(m / z):596.2[M+Na] + 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) Example 23: Synthesis scheme of K101-C1326 The synthesis scheme of compound K101-C1326 is shown below.

[0563] [ka] Preparation of compound K101-C1326-A To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 equiv.) in DCM (5.00 mL) was added (2S)-2-(tert-butoxycarbonylamino)-4-methylsulfonyl-butanoic acid (C13-26) (30.00 mg, 106.64 μmol, 2.10 equiv.), DMAP (30.00 mg, 245.78 μmol, 4.84 equiv.), EDC (19.96 mg, 104.10 μmol, 2.05 equiv.), and HOBt (14.00 mg, 103.59 μmol, 2.04 equiv.). The mixture was stirred at 20 °C for 19 h, resulting in 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 oil. The product was purified by preparative TLC (eluent: 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.

[0564] Preparation of Compound K101-C1326 To a solution of K101-C1326-A (25.00 mg, 29.27 μmol, 1.00 equiv) in THF (2.00 mL) was added TFA (3.34 mg, 29.27 μmol, 2.17 μL, 1.00 equiv) and EtSiH (3.40 mg, 29.27 μmol, 4.66 μL, 1.00 equiv). 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 × 25 mm × 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.

[0565] LC-MS(m / z):534.1[M+Na] + 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).

[0566] Example 24: Synthesis scheme of K101-C1327 The synthesis scheme of compound K101-C1327 is shown below.

[0567] [ka] Preparation of compound K101-C1327-A To a solution of K101-C20Tr-B (200.00 mg, 338.55 μmol, 1.00 equiv) in DCM (2.00 mL) was added C13-27 (367.46 mg, 1.35 mmol, 4.00 equiv), DMAP (330.89 mg, 2.71 mmol, 8.00 equiv), HOBt (91.49 mg, 677.11 μmol, 2.00 equiv), and EDC (259.60 mg, 1.35 mmol, 4.00 equiv). The mixture was stirred at 20 °C for 12 h to give a yellow solution. LC-MS and TLC (elution: PE / EtOAc = 2 / 1) showed the reaction was complete. The mixture was quenched with HO (15 mL) and extracted with DCM (30 mL × 3). The organic layer was dried over NaSO and concentrated to give the crude product, which was purified by preparative TLC (eluent: PE / EtOAc = 2 / 1) to give K101-C1327-A (180.00 mg, 213.25 μmol, 62.99% yield) as a white solid.

[0568] Preparation of Compound K101-C1327 To a solution of K101-C1327-A (180.00 mg, 213.25 μmol, 1.00 equiv) in THF (3.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 126.67 equiv) and EtSiH (49.59 mg, 426.50 μmol, 67.93 μL, 2.00 equiv). The mixture was stirred at 20 °C for 24 h to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated with N, and the resulting residue was dissolved in MeOH (20 mL) and stirred at 20 °C for 70 h. LC-MS showed the reaction was complete. The mixture was concentrated to give the crude product. The crude product was triturated with PE (30 mL × 3) to give the desired product. The product was dissolved in saturated NaHCO (20 mL) and extracted with DCM (30 mL × 3). The organic layer was dried over NaSO and concentrated to give the free form of the 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.

[0569] LC-MS(m / z):524.2[M+Na] + 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).

[0570] Second preparation procedure for compound K101-C1327-A To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 equiv.) in DCM (2.00 mL), (2S)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-propanoic acid (C13-27) (27.56 mg, 101.56 μmol, 2.00 equiv.), DMAP (24.82 mg, 203.12 μmol, 4.00 equiv.), and EDC (19.47 mg, 101.56 μmol, 2.00 equiv.) were added. The mixture was stirred at 20 °C for 12 h to give a yellow solution. LC-MS and TLC (elution: 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, which was purified by preparative TLC (eluent: PE / EtOAc = 2 / 1) to give K101-C1327-A (24.00 mg, 28.43 μmol, 47.97% yield) as a white solid.

[0571] Second preparation procedure for compound K101-C1327 To a solution of K101-C1327-A (24.00 mg, 28.43 μmol, 1.00 equiv) in THF (2.00 mL) was added TFA (308.00 mg, 2.70 mmol, 200.00 μL, 95.02 equiv) and EtSiH (3.97 mg, 34.12 μmol, 5.43 μL, 1.20 equiv). The mixture was stirred at 20 °C for 4 hours to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated with N and the residue was dissolved in MeOH (20 mL). The mixture was stirred at 20 °C for 12 hours. LC-MS showed the reaction was complete. The mixture was concentrated to give the crude product. This product was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25% to 55%, 10 min) to give K101-C1327 (5.10 mg, 7.95 μmol, yield 27.97%, purity 95.99%, TFA) as a white solid.

[0572] LC-MS(m / z):524.2[M+Na] + 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).

[0573] Example 25: Synthesis scheme of K101-C1328 The synthesis scheme of compound K101-C1328 is shown below.

[0574] [ka] Preparation of compound K101-C1328-A To a solution of K101-C20Tr-B (30.00 mg, 50.78 μmol, 1.00 equiv.) 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 equiv.), DMAP (24.82 mg, 203.12 μmol, 4.00 equiv.), HOBt (13.72 mg, 101.56 μmol, 2.00 equiv.), and EDC (19.47 mg, 101.56 μmol, 2.00 equiv.) The mixture was stirred at 20 °C for 12 h to give a yellow solution. LC-MS and TLC (elution: 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 (elution: PE / EtOAc = 2 / 1) to give K101-C1328-A (28.00 mg, 34.23 μmol, 67.40% yield) as a white solid.

[0575] Preparation of Compound K101-C1328 To a solution of K101-C1328-A (28.00 mg, 34.23 μmol, 1.00 equiv) in THF (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL, 197.29 equiv) and EtSiH (7.96 mg, 68.46 μmol, 10.90 μL, 2.00 equiv). 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 150 × 25 mm × 10 μm; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 30% to 70%, 10 min) to give K101-C1328 (9.50 mg, 15.88 μmol, yield 46.38%, purity 98.54%, TFA) as a white solid.

[0576] LC-MS(m / z):498.2[M+Na] + 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).

[0577] Example 26: Synthesis scheme of K101-C1329 The synthesis scheme of compound K101-C1329 is shown below.

[0578] [ka] Preparation of compound K101-C1329-A To a solution of K101-C20Tr-B (20.00 mg, 33.86 μmol, 1.00 equiv) and C13-29 (14.80 mg, 50.79 μmol, 1.50 equiv) in DCM (2.00 mL) was added EDC (38.95 mg, 203.16 μmol, 6.00 equiv) and DMAP (24.82 mg, 203.16 μmol, 6.00 equiv). The reaction was stirred at 25 °C for 16 h to give a brown solution. LC-MS showed the reaction was complete. The reaction was diluted with DCM (10 mL) and 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 crude K101-C1329-A. The crude K101-C1329-A was purified by preparative TLC (PE / EtOAc=3 / 1, SiO 2 ) to give 15.7 mg of K101-C1329-A as a colorless gum.

[0579] Preparation of Compound K101-C1329 To a solution of K101-C1329-A (15.70 mg, 18.17 μmol, 1.00 equiv) in dioxane (400.00 μL) was added HCl / dioxane (4 M, 200.46 μL, 44.13 equiv). 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 the reaction was stirred at 25 °C for an additional 1 h and then for an additional 16 h. LC-MS indicated the reaction was complete. A by-product was also detected by LC-MS analysis. The reaction was diluted with CH3CN (1 mL), and the solution was adjusted to basic conditions with K2CO3 (55 mg) in water (0.5 mL). This product was purified by preparative HPLC (column: Phenomenex Gemini 150 × 25 mm × 10 μm; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 30%-60%, 10 min) to give 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), both as white solids after lyophilization.

[0580] K101-C1329 MS(m / z):544.1[M+Na] + K101-C1329 1H 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).

[0581] K101-C1329-Cl LC-MS(m / z):562.1[M+Na] + 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).

[0582] Example 27: Synthesis of K101-C1330 The synthesis method of compound K101-C1330 is shown below.

[0583]

change

Claims

1. A pharmaceutical composition for stimulating an immune response in a subject, comprising a PKC activating compound.

2. The stimulating immune response is against a cancer or cancer antigen, a precancerous lesion or growth, or a benign tumor in a subject in need thereof. Preferably, the compound is administered locally to a first cancer locus or mass or site, a first precancerous lesion or growth, or a first benign tumor locus or mass; More preferably, the compound is administered intratumorally to a locus or mass or site of a first cancer, or to a first precancerous lesion or growth, or to a locus or mass of a first benign tumor; More preferably, the first cancer locus or mass or site, or the first precancerous lesion or growth is a skin cancer or a first precancerous skin lesion, and preferably, the compound is administered locally by topical administration; Most preferably, the first precancerous lesion or growth is an actinic keratosis. The pharmaceutical composition of claim 1.

3. further comprising administering one or more additional doses of an effective amount of a PKC activator to further stimulate an immune response to the cancer or cancer antigen, or precancerous lesion or growth; Preferably, said one or more additional administrations are to at least a second cancer locus or mass or site that is different in location to said first cancer locus or mass or site; and / or the effective amount administered is sufficient to induce necrosis of said cancer, or the effective amount administered is effective to induce regression of a non-target cancer locus or mass or a satellite cancer locus or mass, and / or and / or, the effective amount administered is an amount that creates immune memory against the cancer or cancer antigen; The cancer or cancer antigen is an immunogenic cancer or cancer antigen, preferably, the cancer is a secondary or metastatic cancer; The pharmaceutical composition according to claim 2.

4. further comprising administering an effective amount of one or more second immunostimulatory or immune enhancing therapeutic agents; Preferably, the second immune stimulant is an immune checkpoint inhibitor, more preferably, the immune checkpoint inhibitor is an anti-CTLA4 antibody, an anti-PD-1 antibody, or an anti-PD-L1 antibody; or Preferably, said immune stimulating or immune enhancing agent is an immune stimulating or immune enhancing cytokine, more preferably said cytokine is IFN-α, IL-2, IL-10, IL-12, IL-15, IL-21, IFN-γ, TNF-α, or GM-CSF; The pharmaceutical composition according to claim 2 or 3.

5. the PKC activating compound is administered in combination with a second cancer therapeutic or therapy to stimulate an immune response against the cancer; Preferably, said second cancer therapeutic agent or therapy is a second cancer chemotherapeutic agent or radiation, or said second cancer therapeutic agent or therapy is a chimeric antigen receptor T cell (CAR-T or CART) therapy or a chimeric antigen receptor NK cell (CAR-NK) therapy, appropriate for said cancer. A pharmaceutical composition according to any one of claims 2 to 4.

6. the cancer is metastatic cancer, and / or the cancer is selected from adenocarcinoma, adrenal cortical carcinoma, anal cancer, angiosarcoma, biliary tract cancer, bladder cancer, bone cancer (e.g., osteosarcoma), brain cancer (e.g., glioma, astrocytoma, neuroblastoma, etc.), breast cancer, cervical cancer, colon cancer, skin lymphoma, endometrial cancer, esophageal cancer, fibrosarcoma, fibroxanthomas, head and neck cancer, blood system 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.), mast cell tumor, oral cancer, ovarian cancer, pancreatic cancer, renal cancer, prostate cancer, salivary gland cancer, skin cancer (e.g., basal cell carcinoma, melanoma, squamous cell carcinoma), stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, and soft tissue cancer; Preferably, the cancer is a hematological cancer, more preferably The hematological cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell chronic myelogenous leukemia (CML), and multiple myeloma, more preferably from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell chronic myelogenous leukemia (CML), and multiple myeloma, or the cancer is a lymphoma selected from Hodgkin's lymphoma, non-Hodgkin's lymphoma, and Burkitt's lymphoma; A pharmaceutical composition according to any one of claims 2 to 5.

7. the immune response is to treat a benign tumor; Preferably, the benign tumor is an adenoma, a fibroma, a lipoma, a myoma, a neuroma, a papilloma, or an osteochondrosarcoma, or The benign tumor is a basal cell carcinoma or a neurofibroma, a dermatofibroma, an epidermoid, or a hemangioma; The pharmaceutical composition according to claim 2.

8. for treating a wound in a subject in need thereof, Preferably, the treatment of the wound is for promoting wound healing and / or for treating or preventing a wound infection, more preferably, the wound infection is a persistent wound infection, and / or The promotion of wound healing increases the rate of wound healing or the promotion of wound healing reduces scarring of wound tissue, preferably wherein the scarring is a keloid or hypertrophic scar. The pharmaceutical composition of claim 1.

9. The PKC activating compound is a compound of formula (I): 【Chemistry 1】 or a pharma- ceutically 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+ counterion; R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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 Each ' is independently H or OH; or R ５ ' and R ６ ' form a bond or are joined to a common O atom to form an epoxide ring where valences permit; R ６ is OH, halo, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 2】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ is adjacent R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, Ｂ each occurrence of may be the same or different; p is 0, 1, or 2; R ６ ' is H or OH, R ７ ' is H, or R ６ ' and R ７ ' form a bond or are joined to a common O atom to form an epoxide ring where valences permit; R ７ is H or OH; R ９ Is OR ｅ and 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 and R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -Aliphatic C ０ ~C １２ -C ３ ~C ７ Cycloalkyl, -aliphatic C ０ ~C １２ -heterocycloalkyl, -aliphatic C ０ ~C １２ -aryl, or -aliphatic C ０ ~C １２ -heteroaryl; R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl; R １４ is H or OR ｇ and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and R ｈ is H or C １ ~C ６ is alkyl; L does not exist or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, C １ ~C １２ Alkylene or C ２ ~C １２ The alkenylene optionally is C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally substituted by said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is replaced by; R ｋ is H or M ＋ is a counter ion; J １ OH, CN, halo, C １ ~C ４ Alkyl, and haloC １ ~C ４ alkyl; n is 0 or 1; Preferably, A is -OH or A is -C(O)OR １ and R １ is H or M ＋ The counter ion is A pharmaceutical composition according to any one of claims 1 to 8.

10. The PKC activating compound is a compound of formula (II): 【Chemistry 3】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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 Each ' is independently H or OH; or R ５ ' and R ６ ' form a bond or are joined to a common O atom to form an epoxide ring where valences permit; R ６ is OH, halo, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; R ｃ Ha-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 4】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ is adjacent R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, Ｂ each occurrence of may be the same or different; p is 0, 1, or 2; R ６ ' is H or OH, R ７ ' is H, or R ６ ' and R ７ ' form a bond or are joined to a common O atom to form an epoxide ring where valences permit; R ７ is H or OH; R ９ Is OR ｅ and 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 and R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -Aliphatic C ０ ~C １２ -C ３ ~C ７ Cycloalkyl, -aliphatic C ０ ~C １２ -heterocycloalkyl, -aliphatic C ０ ~C １２ -aryl, or -aliphatic C ０ ~C １２ -heteroaryl; R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl; R １４ is H or OR ｇ and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and R ｈ is H or C １ ~C ６ is alkyl; L does not exist or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, C １ ~C １２ Alkylene or C ２ ~C １２ The alkenylene optionally is C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally substituted by said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is replaced by; R ｋ is H or M ＋ is a counter ion; J １ OH, CN, halo, C １ ~C ４ Alkyl, and haloC １ ~C ４ alkyl; n is 0 or 1; or The PKC activating compound is a compound of formula (II'): 【Chemistry 5】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; or The PKC activating compound is a compound of formula (IIa): 【Chemistry 6】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 7】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ is adjacent R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and 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 and R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -Aliphatic C ０ ~C １２ -C ３ ~C ７ Cycloalkyl, -aliphatic C ０ ~C １２ -heterocycloalkyl, -aliphatic C ０ ~C １２ -aryl, or -aliphatic C ０ ~C １２ -heteroaryl; R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl; R １４ is H or OR ｇ and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and R ｈ is H or C １ ~C ６ is alkyl; L does not exist or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, C １ ~C １２ Alkylene or C ２ ~C １２ The alkenylene optionally is C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally substituted by said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is replaced by; R ｋ is H or M ＋ is a counter ion; J １ OH, CN, halo, C １ ~C ４ Alkyl, and haloC １ ~C ４ alkyl; n is 0 or 1; or The PKC activating compound is a compound of formula (IIa'): 【Chemistry 8】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; or The PKC activating compound is a compound of formula (IIb): 【Chemistry 9】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 10】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ is adjacent R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, Ｂ each occurrence of may be the same or different; p is 0, 1, or 2; R ９ Is OR ｅ and 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 and R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -Aliphatic C ０ ~C １２ -C ３ ~C ７ Cycloalkyl, -aliphatic C ０ ~C １２ -heterocycloalkyl, -aliphatic C ０ ~C １２ -aryl, or -aliphatic C ０ ~C １２ -heteroaryl; R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl; R １４ is H or OR ｇ and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and R ｈ is H or C １ ~C ６ is alkyl; L does not exist or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, C １ ~C １２ Alkylene or C ２ ~C １２ The alkenylene optionally is C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ Cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally substituted by said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is replaced by; R ｋ is H or M ＋ is a counter ion; J １ OH, CN, halo, C １ ~C ４ Alkyl, and haloC １ ~C ４ alkyl; n is 0 or 1; or The PKC activating compound is a compound of formula (IIc): 【Chemistry 11】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ６ is OH, halo, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 12】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ is adjacent R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -Aliphatic C ０ ~C １２ -C ３ ~C ７ Cycloalkyl, -aliphatic C ０ ~C １２ -heterocycloalkyl, -aliphatic C ０ ~C １２ -aryl, or -aliphatic C ０ ~C １２ -heteroaryl; R １３ and R １３’ are each independently H or C １ ~C ４ is alkyl; L does not exist or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, C １ ~C １２ Alkylene or C ２ ~C １２ The alkenylene optionally is C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally substituted by said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is replaced by; R ｋ is H or M ＋ is a counter ion; J １ OH, CN, halo, C １ ~C ４ Alkyl, and haloC １ ~C ４ alkyl; n is 0 or 1; The pharmaceutical composition according to claim 9.

11. The PKC activating compound is a compound of formula (III): 【Chemistry 13】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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 Each ' is independently H or OH; or R ５ ' and R ６ ' form a bond or are joined to a common O atom to form an epoxide ring where valences permit; R ６ is OH, halo, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 14】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ is adjacent R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, Ｂ each occurrence of may be the same or different; p is 0, 1, or 2; R ６ ' is H or OH, R ７ ' is H, or R ６ ' and R ７ ' form a bond or are joined to a common O atom to form an epoxide ring where valences permit; R ７ is H or OH; R ９ Is OR ｅ and R ｅ is H, C １ ~C ６ 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 and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and R ｈ is H or C １ ~C ６ is alkyl; L does not exist or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, C １ ~C １２ Alkylene or C ２ ~C １２ The alkenylene optionally is C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ Cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally substituted by said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is replaced by; R ｋ is H or M ＋ is a counter ion; J １ OH, CN, halo, C １ ~C ４ Alkyl, and haloC １ ~C ４ alkyl; n is 0 or 1; or The PKC activating compound is a compound of formula (III'): 【Chemistry 15】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; or The PKC activating compound is a compound of formula (IIIa): 【Chemistry 16】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 17】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ is adjacent R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and R ｅ is H, C １ ~C ６ 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 and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and R ｈ is H or C １ ~C ６ is alkyl; L does not exist or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, C １ ~C １２ Alkylene or C ２ ~C １２ The alkenylene optionally is C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally substituted by said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is replaced by; R ｋ is H or M ＋ is a counter ion; J １ OH, CN, halo, C １ ~C ４ Alkyl, and haloC １ ~C ４ alkyl; n is 0 or 1; or The PKC activating compound is a compound of formula (IIIb): 【Chemistry 18】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 19】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ is adjacent R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, Ｂ each occurrence of may be the same or different; p is 0, 1, or 2; R ９ Is OR ｅ and R ｅ is H, C １ ~C ６ 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 and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and R ｈ is H or C １ ~C ６ is alkyl; L does not exist or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, C １ ~C １２ Alkylene or C ２ ~C １２ The alkenylene optionally is C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally substituted by said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is replaced by; R ｋ is H or M ＋ is a counter ion; J １ OH, CN, halo, C １ ~C ４ Alkyl, and haloC １ ~C ４ alkyl; n is 0 or 1; or The PKC activating compound is a compound of formula (IIIc): 【Chemistry 20】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ６ is OH, halo, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 21】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ is adjacent R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 does not exist or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, C １ ~C １２ Alkylene or C ２ ~C １２ The alkenylene optionally is C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ Cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally substituted by said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is replaced by; R ｋ is H or M ＋ is a counter ion; J １ OH, CN, halo, C １ ~C ４ Alkyl, and haloC １ ~C ４ alkyl; n is 0 or 1; or The PKC activating compound is a compound of formula (IIIe): 【Chemical 22】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ６ is OH, halo, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 23】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ is adjacent R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, Ｂ each occurrence of may be the same or different; p is 0, 1, or 2; L does not exist or C １ ~C １２ Alkylene, or C ２ ~C １２ alkenylene, C １ ~C １２ Alkylene or C ２ ~C １２ The alkenylene optionally is C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ Cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally substituted by said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is replaced by; R ｋ is H or M ＋ is a counter ion; J １ OH, CN, halo, C １ ~C ４ Alkyl, and haloC １ ~C ４ selected from alkyl, The pharmaceutical composition according to claim 10.

12. R ２１ C ３ ~C ７ cycloalkyl, ３ ~C ７ Cycloalkyl optionally has 1 to 3 J １ is replaced by Preferably, the C ３ ~C ７ cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; ３ ~C ７ Cycloalkyl optionally has 1 to 3 J １ has been replaced by or R ２１ is heterocyclyl, said heterocyclyl optionally containing 1 to 3 J １ is replaced by Preferably, said 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 said heterocyclyl optionally contains 1 to 3 J １ has been replaced by or R ２１ is aryl, said aryl optionally having 1 to 3 J １ is replaced by Preferably, R ２１ is phenyl or naphthyl, and said phenyl or naphthyl optionally has 1 to 3 J １ has been replaced by or R ２１ is heteroaryl, said heteroaryl optionally having 1 to 3 J １ is replaced by Preferably, said 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 said heteroaryl optionally contains 1 to 3 J １ has been replaced by or R ２１ is adamantyl, said adamantyl optionally being OH, halo, or C １ ~C ４ is substituted with alkyl, or R ２１ Spiro C ５ ~C １２ cycloalkyl, and the 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, by an N-protecting group, or R ２１ is a 5-12 membered bridged bicyclyl in which 0-2 carbon atoms are replaced by 0-2 heteroatoms selected from N, O, and S, and optionally 1-3 J １ or, if an N atom is present, by an N-protecting group, or R ２１ is selected from: 【Chemistry 24】 In the ceremony, J １ OH, CN, halo, C １ ~C ４ Alkyl, and haloC １ ~C ４ alkyl, n is 0 to 3; A pharmaceutical composition according to any one of claims 9 to 11.

13. The PKC activating compound is a compound of formula (IV): 【Chemistry 25】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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 Each ' is independently H or OH; or R ５ ' and R ６ ' form a bond or are joined to a common O atom to form an epoxide ring where valences permit; R ６ is OH, halo, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 26】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ But, R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, Ｂ each occurrence of may be the same or different; p is 0, 1, or 2; R ６ ' is H or OH, R ７ ' is H, or R ６ ' and R ７ ' form a bond or are joined to a common O atom to form an epoxide ring where valences permit; R ７ is H or OH; R ９ Is OR ｅ and 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 and R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -Aliphatic C ０ ~C １２ -C ３ ~C ７ Cycloalkyl, -aliphatic C ０ ~C １２ -heterocycloalkyl, -aliphatic C ０ ~C １２ -aryl, or -aliphatic C ０ ~C １２ -heteroaryl; R １４ is H or OR ｇ and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and 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, １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene optionally includes OH or C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ Cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally, said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is 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 or The PKC activating compound is a compound of formula (IVa): 【Chemical 27】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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, -OP(O)(OR ｂ ') ２ , halo, or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 28】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ But, R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and 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 and R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -Aliphatic C ０ ~C １２ -C ３ ~C ７ Cycloalkyl, -aliphatic C ０ ~C １２ -heterocycloalkyl, -aliphatic C ０ ~C １２ -aryl, or -aliphatic C ０ ~C １２ -heteroaryl; R １４ is H or OR ｇ and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and 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, １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene optionally includes OH or C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally, said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is 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 or The PKC activating compound is a compound of formula (IVb) 【Chemical 29】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 30】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ But, R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and 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 and R ｆ is C １ ~C １２ Alkyl, C ２ ~C １２ Alkenyl, -Aliphatic C ０ ~C １２ -C ３ ~C ７ Cycloalkyl, -aliphatic C ０ ~C １２ -heterocycloalkyl, -aliphatic C ０ ~C １２ -aryl, or -aliphatic C ０ ~C １２ -heteroaryl; R １４ is H or OR ｇ and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and 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, １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene optionally includes OH or C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally, said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is 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 or The PKC activating compound is a compound of formula (V): 【Chemistry 31】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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 Each ' is independently H or OH; or R ５ ' and R ６ ' form a bond or are joined to a common O atom to form an epoxide ring where valences permit; R ６ is OH, halo, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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 32】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ But, R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, Ｂ each occurrence of may be the same or different; p is 0, 1, or 2; R ６ ' is H or OH, R ７ ' is H, or R ６ ' and R ７ ' form a bond or are joined to a common O atom to form an epoxide ring where valences permit; R ７ is H or OH; R ９ Is OR ｅ and 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 and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and 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, １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene optionally includes OH or C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally, said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is 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 or The PKC activating compound is a compound of formula (Va): 【Chemical 33】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; or an enantiomer or a pharma- ceutically acceptable salt thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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, 【Chemical 34】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ But, R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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 and 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 and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and 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, １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene optionally includes OH or C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally, said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is 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 or The PKC activating compound is a compound of formula (Vb) 【Chemistry 35】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ２ is C １ ~C ４ is alkyl; R ３ is O double bonded to a ring carbon where (- - -) is a bond, or -OR ａ and 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 and 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, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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, 【Chemical Formula 36】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ But, R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, Ｂ each occurrence of may be the same or different; p is 0, 1, or 2; R ９ Is OR ｅ and 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 and R ｇ is H or C １ ~C ６ is alkyl; R １７ and R １８ are each independently １ ~C ４ Alkyl or C １ ~C ４ Alkyl-OR ｈ and 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, １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene optionally includes OH or C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally, said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is 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 or The PKC activating compound is a compound of formula (Vc): 【Chemical 37】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ６ is OH, halo, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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, 【Chemical 38】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ But, R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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, １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene optionally includes OH or C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally, said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is 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 or The PKC activating compound is a compound of formula (Vd): 【Chemical 39】 or a pharma- ceutically acceptable salt, tautomer, or stereoisomer thereof; During the ceremony, R ６ is OH, halo, -OP(O)(OR ｂ ') ２ or -OC(O)R ｃ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; 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】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ But, R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, 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, １ ~C １２ Alkylene or C ２ ~C １２ Alkenylene optionally includes OH or C １ ~C ４ is 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 and said C ３ ~C ７ Cycloalkyl, heterocyclyl, aryl, heteroaryl, spiro C ５ ~C １２ The cycloalkyl, bridged bicyclyl, or adamantyl optionally contains 1 to 3 J １ and optionally, said spiro C ５ ~C １２ 1 to 2 carbon atoms of the cycloalkyl or bridged bicyclyl are replaced with a heteroatom selected from N, O, and S, and optionally C １ ~C ４ substituted by alkyl or, if an N atom is present, by an N-protecting group; Each R ｊ is independently 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, ３ ~C ７ Cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl optionally contain 1 to 3 J １ is 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 pharmaceutical composition according to any one of claims 1 to 8.

14. R ２１ C ３ ~C ７ cycloalkyl, ３ ~C ７ Cycloalkyl optionally has 1 to 3 J １ is replaced by Preferably, the C ３ ~C ７ cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; ３ ~C ７ Cycloalkyl optionally has 1 to 3 J １ has been replaced by or R ２１ is heterocyclyl, said heterocyclyl optionally containing 1 to 3 J １ is replaced by Preferably, said 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 said heterocyclyl optionally contains 1 to 3 J １ has been replaced by or R ２１ is aryl, said aryl optionally having 1 to 3 J １ is replaced by Preferably, R ２１ is phenyl or naphthyl, said phenyl or naphthyl optionally having 1 to 3 J １ has been replaced by or R ２１ is heteroaryl, said heteroaryl optionally having 1 to 3 J １ is replaced by Preferably, said 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 said heteroaryl optionally contains 1 to 3 J １ has been replaced by or R ２１ is adamantyl, said adamantyl optionally having 1 to 3 J １ has been replaced by or R ２１ Spiro C ５ ~C １２ cycloalkyl, and the 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, by an N-protecting group, or R ２１ is a 5-12 membered bridged bicyclyl in which 0-2 carbon atoms are replaced by 0-2 heteroatoms selected from N, O, and S, and optionally 1-3 J １ or, if an N atom is present, by an N-protecting group, A pharmaceutical composition according to claim 12 or 13.

15. L is C １ ~C ６ Alkylene, C ３ ~C ６ Alkylene, or C ３ ~C １２ is alkyl, or L is C １ ~C ６ Alkenylene, C ３ ~C ６ Alkenylene, or C ３ ~C １２ is alkenylene; A pharmaceutical composition according to any one of claims 9 to 14.

16. R ６ is -OH; or R ６ -OP(O)(OR ｂ ') ２ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; or R ６ Ga-OC(O)R ｃ and R ｃ Ha-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; R ｋ is H or M ＋ The counter ion is or R ６ but, 【Chemistry 41】 where: R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ But, R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, Ｂ each occurrence of may be the same or different; p is 0, 1, or 2; Preferably, each R Ａ are independently 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), mercaptome tyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutan-1-yl (lysine), 4-amino-3-hydroxybutan-1-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine), 3-guanidinopropan-1-yl (arginine), or 3-ureido-propan-1-yl (citrulline); Each R Ｂ is H or R Ｂ is adjacent R Ａ and together with the N atom, a prolyl side chain: 【Chemistry 42】 forming p is 0, 1, or 2; or Each R Ａ are independently methyl(alanine), propan-2-yl(valine), 2-methylpropan-1-yl(leucine), imidazol-4-ylmethyl(histidine), hydroxymethyl(serine), 1-hydroxyethyl(threonine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), 4-aminobutan-1-yl(lysine), carboxymethyl(aspartic acid), 3-guanidinopropan-1-yl(arginine), benzyl(phenylalanine), or 4-aminobutan-1-yl(lysine); R Ｂ is H; p is 0, 1, or 2; or Each R Ａ is independently propan-2-yl (valine), 2-methylpropan-1-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-1-yl (lysine); Each R Ｂ is H; p is 0, 1, or 2; or p is 1; The first R Ａ is propan-2-yl (valine), and the second R Ａ is propan-2-yl(valine); R Ｂ are H (the dipeptide Val-Val); or The first R Ａ is 2-methylpropan-1-yl (leucine), and the second R Ａ is 2-methylpropan-1-yl(leucine); R Ｂ are H (the dipeptide Leu-Leu); or The first R Ａ is methyl (alanine) and the second R Ａ is methyl(alanine); R Ｂ is H (dipeptide Ala-Ala); or The first R Ａ is 4-aminobutan-1-yl(lysine); the second R Ａ is 4-aminobutan-1-yl(lysine); R Ｂ is H (the dipeptide Lys-Lys); or The first R Ａ is hydrogen; the second R Ａ is 4-aminobutan-1-yl, R Ｂ is H (the dipeptide Gly-Lys), Preferably, The α-carbons of amino acids other than glycine are each in the L or D configuration; A pharmaceutical composition according to any one of claims 9 to 15.

17. 10. The pharmaceutical composition of claim 9, wherein the PKC activating compound is selected from the group consisting of the compounds in Table 1.

18. 13. The pharmaceutical composition of claim 12, wherein the PKC activating compound is selected from the group consisting of the compounds in Table 2.

19. The substituent on the C20 carbon atom of the PKC activating compound is -OP(O)(OR ｂ ') ２ and each R ｂ ' is independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ０ ~C ６ Alkylaryl, or C ０ ~C ６ alkylheteroaryl; or The substituent on the C20 carbon atom of the PKC activating compound is —OC(O)R ｃ It has been replaced by R ｃ Ha-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; R ｋ is H or M ＋ The counter ion is or The substituents on the C20 carbon atom of the PKC activating compound are, where appropriate, substituted with 【Chemistry 43】 During the ceremony, R Ａ is independently selected from the side chains of natural or unnatural amino acids; Ａ each occurrence of may be the same or different; R Ｂ Each occurrence of is independently H or R Ｂ But, R Ａ And, R Ｂ together with the N atom attached to R to form a heterocyclic ring of a natural or unnatural amino acid, Ｂ each occurrence of may be the same or different; p is 0, 1, or 2; Preferably, each R Ａ are independently 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), mercaptome tyl (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutan-1-yl (lysine), 4-amino-3-hydroxybutan-1-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine), 3-guanidinopropan-1-yl (arginine), or 3-ureido-propan-1-yl (citrulline); Each R Ｂ is H or R Ｂ is adjacent R Ａ and together with the N atom, a prolyl side chain: 【Chemistry 44】 forming p is 0, 1, or 2; Preferably, each R Ａ are independently methyl(alanine), propan-2-yl(valine), 2-methylpropan-1-yl(leucine), imidazol-4-ylmethyl(histidine), hydroxymethyl(serine), 1-hydroxyethyl(threonine), carbamoylmethyl(asparagine), 2-carbamoylethyl(glutamine), 4-aminobutan-1-yl(lysine), carboxymethyl(aspartic acid), 3-guanidinopropan-1-yl(arginine), benzyl(phenylalanine), or 4-aminobutan-1-yl(lysine); R Ｂ is H; p is 0, 1, or 2; Or preferably, each R Ａ is independently propan-2-yl (valine), 2-methylpropan-1-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-1-yl (lysine); Each R Ｂ is H; p is 0, 1, or 2; or Preferably, p is 1; The first R Ａ is propan-2-yl (valine), and the second R Ａ is propan-2-yl(valine); R Ｂ are H (the dipeptide Val-Val); or The first R Ａ is 2-methylpropan-1-yl (leucine), and the second R Ａ is 2-methylpropan-1-yl(leucine); R Ｂ are H (the dipeptide Leu-Leu); or The first R Ａ is methyl (alanine) and the second R Ａ is methyl(alanine); R Ｂ is H (dipeptide Ala-Ala); or The first R Ａ is 4-aminobutan-1-yl(lysine); the second R Ａ is 4-aminobutan-1-yl(lysine); R Ｂ is H (the dipeptide Lys-Lys); or The first R Ａ is hydrogen; the second R Ａ is 4-aminobutan-1-yl, R Ｂ is H (the dipeptide Gly-Lys), 18. A pharmaceutical composition according to claim 16 or 17.

20. 20. The pharmaceutical composition of claim 16 or 19, wherein the α-carbon of the amino acid other than glycine is in the L or D configuration, respectively.

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