Diterpenoid compounds that act on protein kinase C (PKC)

Abstract

This present disclosure relates to protein kinase C (PKC) modulating compounds, methods of treating a subject with cancer using the compounds, and combination treatments with a second therapeutic agent.

Description

1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62 / 905,253, filed September 24, 2019, the contents of which are incorporated herein in their entireties by reference thereto. 2. BACKGROUND

[0002] Diterpenoid Protein Kinase C (PKC) modulating compounds display anti-cancer and cytotoxic activities. Most studied of these compounds are tigliane diterpenoids, such as phorbol esters and prostratin. The biological effects of these compounds are thought to be mediated by transactivation, translocation and suppression of PKC enzymes, which play important roles in regulating signaling pathways that regulate or modulate cellular structure and gene expression.

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

[0004] In view of the therapeutic potential of diterpenoid PKC modulating compounds, it is desirable to further develop these class of compounds in applications for treating diseases and disorders capable of being affected by modulation of PKC activity. 3. SUMMARY

[0005] The present disclosure provides novel protein kinase C (PKC) modulating compounds. The compounds are diterpenoid PKC modulating compounds displaying enhanced pharmacological properties, including among others, potent PKC enzyme binding activity and anti-proliferative activity against different cancer cells. The PKC modulating compounds also have substituents that can enhance solubility and pharmacokinetic profiles. In one aspect, the compounds have the structure of formula (I): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein A is -OH, -C^OR1, or -NR13R13; R1 is H or a M+ counterion; R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-C6alkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is / Ra \O Rb wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C?cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R13 and R13 are each independently H or Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / OhR1. -SRj, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, GrGnlkvIG-OcvcIoalkv^ Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0006] In some embodiments, A is -OH. In some embodiments, A is -C(O)OR1, wherein R1 is H or a M+ counterion. In some embodiments, A is -NR13R13, wherein R13 and R13 are each independently H or Ci-C4alkyl.

[0007] In some embodiments, the present disclosure provides a compound of formula (II): R13 \ (CH2)n or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-C6alkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C?cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R13 and R13 are each independently H or Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / OhR1. -SRj, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, GrGnlkvIGX^cvcIoalkvI. Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0008] In some embodiments, the compound has the structure of formula (lie): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-C6alkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C?cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R13 and R13 are each independently H or Ci-C4alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S(O)2Ri, -SRj, -N(Ri)2, -Si(Ri)3, C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs- Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-CealkylCs-Cvcycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0009] In another aspect, the present disclosure provides a compound of formula (IV): R2^ L or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C7cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is Co-Cealkylarylene, Co-Cealkylheteroarylene, GrGalkvIG-GcycloalkvIc^ Ci-Cnalkylene or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Ci2alkenylene is optionally substituted with OH or Ci-C4alkyl; and R21 is H, -OH, -SH, -S(O)2Ri, -SRj, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1; and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl or, when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-C6alkylC3-C7cycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and Rk is H or M+ counterion.

[0010] In some embodiments, the compounds can be used in a method to activate protein kinase C, comprising contacting a mammalian cell with an effective amount of a compound disclosed herein. In some embodiments, the mammalian cell is a cancer cell.

[0011] In some embodiments, the compounds are used for treating cancer by administering a therapeutically effective amount to a subject in need thereof a compound disclosed herein.

[0012] In some embodiments, the cancer for treatment is adrenocortical cancer, anal cancer, biliary cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, intestinal cancer, liver cancer, lung cancer, oral cancer, ovarian cancer, pancreatic cancer, renal cancer, prostate cancer, salivary gland cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, or soft tissue carcinomas.

[0013] In some embodiments, the cancer for treatment is a hematological cancer, such as leukemia or lymphoma. In some embodiments, the hematological 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. 4. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds as assessed by measuring levels of phosphorylated PKC (p-PKC) and phosphorylated ERK1 / 2 proteins (p-ERKl / 2).

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

[0016] FIG. 3 shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds assessed by measuring levels of phosphorylated PKC (p-PKC) and phosphorylated ERK1 / 2 proteins (p-ERKl / 2), with prostratin (K101) provided for comparison.

[0017] FIG. 4A shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds based on levels of phosphorylated PKC (p-PKC) and phosphorylated ERK1 / 2 proteins (p-ERK1 / 2).

[0018] FIG. 4B shows PKC activation in A549 non-small cell lung cancer cells by diterpenoid compounds assessed by measuring levels of phosphorylated PKD / PKCp (p-PKC) and phosphorylated PKC8.

[0019] FIG. 5 shows effect of selected diterpenoid compounds on levels of phosphorylated CaMKii (p-CaMKii), a marker of K-Ras sternness pathway inhibition, in Panel pancreatic cancer cell line.

[0020] FIGS. 6A-6D show sphere formation by Panel pancreatic cancer cell line treated with different diterpenoid compounds.

[0021] FIG. 7 shows effect of intratumoral administration (7 daily injections) of diterpenoid compounds into Panc2.13 tumors in mice with Panc2.13 pancreatic cancer cell line xenografts. 5. DETAILED DESCRIPTION

[0022] As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to “a protein” includes more than one protein, and reference to “a compound” refers to more than one compound.

[0023] Also, the use of “or” means “and / or” unless stated otherwise. Similarly, “comprise,” “comprises,” “comprising” “include,” “includes,” and “including” are interchangeable and not intended to be limiting.

[0024] It is to be further understood that where descriptions of various embodiments use the term “comprising,” those skilled in the art would understand that in some specific instances, an embodiment can be alternatively described using language “consisting essentially of’ or “consisting of.”

[0025] 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 this disclosure. The section headings used herein are for organizational purposes only and not to be construed as limiting the subject matter described. 5.1. Definitions

[0026] In reference to the present disclosure, the technical and scientific terms used in the descriptions herein will have the meanings commonly understood by one of ordinary skill in the art, unless specifically defined otherwise. Accordingly, the following terms are intended to have the meanings as described below.

[0027] “Alkyl” refers to straight or branched chain hydrocarbon groups of 1 to 20 carbon atoms, particularly 1 to 12 carbon atoms (C1-C12 or C1-12), and more particularly (Ci-Cs or Ci^) carbon atoms. Exemplary “alkyl” includes, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.

[0028] “Alkenyl” refers to straight or branched chain hydrocarbon group of 2 to 20 carbon atoms, particularly 2 to 12 carbon atoms (C2-C12 or C2-12), and most particularly 2 to 8 (C2-C8 or C2-s)carbon atoms, having at least one double bond. Exemplary “alkenyl” includes, but are not limited to, vinyl ethenyl, allyl, isopropenyl, 1-propenyl, 2-methyl-l-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.

[0029] “Alkynyl” refers to a straight or branched chain hydrocarbon group of 2 to 12 carbon atoms (C2-C12 or C2-12), particularly 2 to 8 carbon atoms (C2-C8 or C2-8), containing at least one triple bond. Exemplary “alkynyl” includes 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.

[0030] “Alkylene”, “alkenylene” and “alkynylene” refers to a straight or branched chain divalent hydrocarbon radical of the corresponding alkyl, alkenyl, and alkynyl, respectively. The “alkylene”, “alkenylene” and “alkynylene” may be optionally substituted, for example with alkyl, alkyloxy, hydroxyl, carbonyl, carboxyl, halo, nitro, and the like.

[0031] “Aliphatic” refers to an organic compound characterized by substituted or unsubstituted, straight or branched, and / or cyclic chain arrangements of constituent carbon atoms. Aliphatic compounds do not contain aromatic rings as part of the molecular structure of the compounds. Aliphatic compound can have 1-20 (C1-C20 or C1.20) carbon atoms, 1-12 (C1-C12 or C1.12) carbon atoms, or particularly 1-8 (Ci-Cs or Ci-s) carbon atoms.

[0032] “Lower” in reference to substituents refers to a group having between one and six carbon atoms.

[0033] “Cycloalkyl” refers to any stable monocyclic or polycyclic system which consists of carbon atoms, any ring of which being saturated. “Cycloalkenyl” refers to any stable monocyclic or polycyclic system which consists of carbon atoms, with at least one ring thereof being partially unsaturated. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloalkyls and tricycloalkyls (e.g., adamantyl).

[0034] “Heterocycloalkyl” or “heterocyclyl” refers to a substituted or unsubstituted 3 to 14 membered, mono- or bicyclic, non-aromatic hydrocarbon, wherein 1 to 3 carbon atoms a (e replaced by a heteroatom. Heteroatoms and / or heteroatomic groups which can replace the carbon atoms include, but are not limited to, -O-, -S-, -S-O-, -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, azetidynyl, oxazolyl, thiazolidinyl, thiazolyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, azapanyl, and the like.

[0035] “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 even of higher order. Thus, the terms "carbocycle", "carbocyclyl", and "carbocyclic", encompass fused, bridged and spirocyclic systems: Preferably a carbocycle ring contains from 3 to 14 atoms, including 3 to 8 or 5 to 7 atoms, such as for example, 6 atoms.

[0036] “Aryl” refers to a six- to fourteen-membered, mono- or bi-carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic ring is aromatic. Unless stated otherwise, the valency of the 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.

[0037] “Heteroaryl” refers to an aromatic heterocyclic ring, including both monocyclic and bicyclic ring systems, where at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms of one or both of the rings are replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl can be a 5 to 6 membered monocyclic, or 7 to 11 membered bicyclic ring systems. 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.

[0038] “Bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 5 to 12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Such bridged bicyclic groups include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0039] “Fused ring” refers a ring system with two or more rings having at least one bond and two atoms in common. A “fused aryl” and a “fused heteroaryl” refer to ring systems having at least one aryl and heteroaryl, respectively, that share at least one bond and two atoms in common with another ring.

[0040] “Carbonyl” refers to -C(O)-. The carbonyl group may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, aldehydes, amides, esters, and ketones. For example, an -C(O)R’, wherein R’ is an alkyl is referred to as an alkylcarbonyl. In some embodiments, R’ is selected from an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0041] “Halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.

[0042] “Haloalkyl” refers to an alkyl substituted with 1 or more halogen atoms. Preferably, the alkyl is substituted with 1 to 3 halogen atoms.

[0043] “Hydroxy” refers to -OH.

[0044] “Oxy” refers to group -O-, which may have various substituents to form different oxy groups, including ethers and esters. In some embodiments, the oxy group is an -OR’, wherein R’ is selected from an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0045] “Acyl” refers to -C(O)R’, where R is hydrogen, or an optionally substituted alkyl, heteroalkyl, cylcoalkyl, 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.

[0046] “Alkyloxy” or “alkoxy” refers to -OR’, wherein R’ is an optionally substituted alkyl.

[0047] “Aryloxy” refers to -OR’, wherein R’ is an optionally substituted aryl.

[0048] “Carboxy” refers to -COO' or COOM, wherein H or a M+ counterion.

[0049] “Carbamoyl” refers to -C(O)NR’R’, wherein each R’ is independently selected from H or an optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocylcoalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0050] “Cyano” refers to -CN.

[0051] “Ester” refers to a group such as -C(=O)OR’, alternatively illustrated as -C(O)OR’, wherein R’ is selected from an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocyclolalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0052] “Silyl” refers to Si, which may have various substituents, for example -SiR’R’R’, where R’ is as defined in the specification. For example, each R’ is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. As defined herein, any heterocyloalkyl or heteroaryl group present in a silyl group has from 1 to 3 heteroatoms selected independently from O, N, and S.

[0053] “Thiol” refers to -SH.

[0054] “Sulfanyl” refers to -SR’, wherein R’ is selected from an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocyloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. For example, -SR, wherein R is an alkyl is an alkylsulfanyl.

[0055] “Sulfonyl” refers to -S(O)2-, which may have various substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones. For example, -S(O)2R’, wherein R’ is an alkyl refers to an alkylsulfonyl. In some embodiments of -S(O)2R’, R’ is selected from an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocyloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0056] “Amino” or “amine” refers to the group -NR’R’ or -NR’R’R’, wherein each R’ is independently selected from H and an optionally substituted: alkyl, cycloalkyl, heterocycloalkyl, alkyloxy, aryl, heteroaryl, heteroarylalkyl, acyl, alkyloxycarbonyl, sulfanyl, sulfinyl, sulfonyl, and the like. Exemplary amino groups include, but are not limited to, dimethylamino, diethylamino, trimethylammonium, triethylammonium, methylysulfonylamino, furanyl-oxy-sulfamino, and the like.

[0057] “Amide” refers to a group such as, -C(=O)NR’R’, wherein each R’ is independently selected from H and an optionally substituted: alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0058] “Spiroalkyl” as used herein refers to a monospiro compound having two alicyclic rings attached together through a single common carbon atom. In some embodiments, the spiro compounds have 5 to 12 total ring atoms (e.g., C5-C12 or C5-12). In some embodiments, one or more of the carbon atoms can be replaced with a heteroatom, such as oxygen, nitrogen or sulfur. Exemplary spiroalkyl compounds include, among others, spiro[3,3]heptyl, spiro[3.4]octyl, and spiro[3,5]decyl.

[0059] “Adamantyl” refers to a compound of structural formula: Ra where optional substitutions can be present on one or more of Ra, Rb, Rc, and Rd. Adamantyl includes substituted adamantyl, e.g., 1- or 2-adamantyl, substituted by one or more substituents, including alkyl, halo, OH, NH2, and alkoxy. Exemplary derivatives include methyladamatane, haloadamantane, hydroxyadamantane, and aminoadamantane (e.g., amantadine).

[0060] “N-protecting group” as used herein refers to those groups intended to protect a nitrogen atom against undesirable reactions during synthetic procedures. Exemplary N-protecting groups include, but is not limited to, acyl groups such acetyl and t-butylacetyl, pivaloyl, alkoxy carbonyl 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, P. G. M. Wuts, ed„ Wiley (2014).

[0061] “Optional” or “optionally” refers to a described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not. For example, “optionally substituted alkyl” refers to an alkyl group that may or may not be substituted and that the description encompasses both substituted alkyl group and unsubstituted alkyl group.

[0062] “ Substituted” as used herein means one or more hydrogen atoms of the group is replaced with a substituent atom or group commonly used in pharmaceutical chemistry. Each substituent can be the same or different. Examples of suitable substituents include, but are not limited to, 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 2, S(O)R, SO2R, NR R (e.g., primary amine (i.e., NH2), secondary amine, tertiary amine, amide, carbamate, urea, etc.), hydrazide, halo, nitrile, nitro, sulfide, sulfoxide, sulfone, sulfonamide, thiol, carboxy, aldehyde, keto, carboxylic acid, ester, amide, imine, and imide, including seleno and thio derivatives thereof, wherein each of the substituents can be optionally further substituted. In embodiments in which a functional group with an aromatic carbon ring is substituted, such substitutions will typically number less than about 10 substitutions, more preferably about 1 to 5, with about 1 or 2 substitutions being preferred.

[0063] “ Stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. Thus, “stereoisomer thereof’ with respect to a compound includes any stereoisomer of the compound and mixtures of stereoisomers, and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. A compound may have more than one chiral center such that the compound may exist as either an individual diastereomer or as a mixture of diastereomers.

[0064] “Tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. Thus, “tautomers thereof’ with respect to a compound includes any tautomers of the compound.

[0065] “Prodrug” refers to a derivative of an active compound (e.g., drug) that requires a transformation under the conditions of use, such as within the body or appropriate in vitro conditions, to release the active drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. Prodrugs can be obtained by masking a functional group in the drug believed to be in part required for activity with a progroup to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active drug. The cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature. The agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.

[0066] Various progroups, as well as the resultant promoieties, suitable for masking functional groups in the active drugs to yield prodrugs can be used. For example, a hydroxyl functional group may be masked as a sulfonate, ester or carbonate promoiety, which may be hydrolyzed in vivo to provide the hydroxyl group. An amino functional group may be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed, e.g., in vivo or under appropriate in vitro conditions, to provide the amino group. A carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group. Included within the scope of prodrugs are, among others, “biohydrolyzable carbonate”, “biohydrolyzable ureide”, “biohydrolyzable carbamate”, “biohydrolyzable ester”, “biohydrolyzable amide”, and “biohydrolyzable phosphate” groups.

[0067] “ Solvate” refers to a complex of variable stoichiometry formed by a solute, such as a PKC activator compound, and a solvent. Such solvents are selected to minimally interfere with the biological activity of the solute. Solvents may be, by way of example and not limitation, water, ethanol, or acetic acid.

[0068] “Hydrate” refers to a combination of water with a solute, such as a PKC activator compound, wherein the water retains its molecular state as water and is either absorbed, adsorbed or contained within a crystal lattice of the solute (e.g., PKC activating compound).

[0069] “Pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, phosphoric, partially neutralized phosphoric acids, sulfuric, partially neutralized sulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like 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 arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific 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 are 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.

[0070] “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” refers to an excipient, carrier or adjuvant that can be administered to a subject, together with at least one therapeutic agent, and which does not destroy the pharmacological activity thereof and is generally safe, nontoxic and neither biologically nor otherwise undesirable when administered in doses sufficient to deliver a therapeutic amount of the agent..

[0071] “K-RAS” refers to Kirsten rat sarcoma viral oncogene homolog, a small GTPase and a member of the RAS family of proteins involved in signal transduction. Exemplary human K-RAS nucleic acid and protein sequences are provided in GenBank Nos. M54968.1 and AAB414942.1, respectively. “K-RAS” as used herein encompasses variants, including orthologs and interspecies homologs, of the human K-RAS protein.

[0072] “Mutant K-RAS polypeptide”, “mutant K- RAS protein” and “mutant K- RAS” are used interchangeably and refer to a K- RAS polypeptide comprising at least one K- RAS mutation as 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.

[0073] “N-RAS” refers to Neuroblastoma RAS Viral (V-RAS) oncogene homolog, a small GTPase and a member of the RAS family of proteins involved in signal transduction. Exemplary human N-RAS nucleic acid and protein sequences are provided in NCBI Accession No. NP 002515 and GenBank Accession No. X02751, respectively. “N-RAS” as used herein encompasses variants, including orthologs and interspecies homologs of the human N-RAS protein.

[0074] “Mutant N- RAS polypeptide”, “mutant N- RAS protein” and “mutant N-RAS” are used interchangeably and refer to an N-RAS polypeptide comprising at least one N- RAS mutation as 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.

[0075] “H- RAS” refers to Harvey Rat Sarcoma viral oncogene homolog, a small GTPase and a member of the RAS family of proteins involved in signal transduction. Exemplary human H-RAS nucleic acid and protein sequences are provided in NCBI Accession No. P01112 and GenBank Accession No. NM_176795, respectively. “H- RAS” as used herein encompasses variants, including orthologs and interspecies homologs of the human H- RAS protein.

[0076] “Mutant H-RAS polypeptide”, “mutant H-RAS protein” and “mutant H-RAS” are used interchangeably and refer to an H-RAS polypeptide comprising at least one H- RAS mutation as 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.

[0077] “Activating K- RAS” refers to a form of K- RAS that has increased activity compared to wild-type K- RAS. The activation of K- RAS activity can result from a mutation or in some embodiments, overexpression of the K- RAS protein.

[0078] “Activating N- RAS” refers to a form of N- RAS that has increased activity compared to wild-type N- RAS. The activation of N- RAS activity can result from a mutation, or in some embodiments, overexpression of the N- RAS protein.

[0079] Activating H- RAS” refers to a form of H- RAS that has increased activity compared to wildtype H- RAS. The activation of H- RAS activity can result from a mutation, or in some embodiments, overexpression of the H- RAS protein.

[0080] “Mutation” or “mutant” refers to an amino acid or polynucleotide sequence which has been altered by substitution, insertion, and / or deletion. In some embodiments, a mutant or variant sequence can have increased, decreased, or substantially similar activities or properties in comparison to the parental sequence.

[0081] “Identified” or “determined” refers to analyzing for, detection of, or carrying out a process for the presence or absence of one or more specified characteristics.

[0082] “Wild-type” or “naturally occurring” refers to the form found in nature. For example, a naturally occurring or wild-type polypeptide or polynucleotide sequence is a sequence present in an organism that can be isolated from a source in nature and which has not been intentionally modified by human manipulation.

[0083] “Control” or “control sample” or “control group” refers to a sample or group that is compared to another sample or group, where generally the control sample or group are the same as a comparison group except for one or more factors being compared.

[0084] “Selecting” refers to the process of determining that a subject will receive an agent to treat the occurrence of a condition. Selecting can be based on an individual susceptibility to a particular disease or condition due to, for example, presence of an identifying cellular, physiological or environment factor or factors. In some embodiments, selecting can be based on determining or identifying whether that subject will be responsive to an agent, for example as assessed by identifying the presence of a biomarker and / or drug target marker that makes the subject sensitive, insensitive, responsive, or unresponsive to an agent or treatment.

[0085] “Biological sample” refers to any sample including a biomolecule, such as a protein, a peptide, a nucleic acid, a lipid, a carbohydrate or a combination thereof, that is obtained from an organism, particularly a mammal. Examples of mammals include humans; veterinary animals like cats, dogs, horses, cattle, and swine; and laboratory animals like mice, rats and primates. In some embodiments, a human subject in the clinical setting is referred to as a patient. Biological samples include tissue samples (such as tissue sections and needle biopsies of tissue), cell samples (for example, cytological smears such as Pap or blood smears or samples of cells obtained by microdissection), or cell fractions, fragments or organelles (such as obtained by lysing cells and separating their components by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (for example, obtained by a surgical biopsy or a needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. In particular 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 the serum.

[0086] “Subject” as used herein refers to a mammal, for example a dog, a cat, a horse, or a rabbit. In some embodiments, the subject is a non-human primate, for example a monkey, chimpanzee, or gorilla. In some embodiments, the subject is a human, sometimes referred to herein as a patient.

[0087] “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., causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experimentation by one of ordinary skill in the art, particularly in view of the guidance provided in the present disclosure.

[0088] “Therapeutically effective amount” refers to that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease, disorder, or condition. 5.2. Compounds

[0089] The present disclosure provides protein kinase C (PKC) modulating compounds. In particular, the compounds are diterpenoid PKC modulating compounds displaying potent PKC modulating activity, as well as enhanced solubility and pharmacokinetic profiles. The diterpenoid PKC modulating compounds show potent activity against tumor cells, and can be applied to treatment of cancer. In one aspect, the present disclosure provides a compound of formula (I): ---R18 R14 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein A is -OH, -C^OR1, or -NR13R13; R1 is H or a M+ counterion; R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-C6alkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-C6alkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C?cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R13 and R13 are each independently H or Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci- C6alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / OhR1. -SR3, -N(R3)2, -Si(R3)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Ci2cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R3 is independently Ci-Cealkyl, C2-Cealkenyl, GrGnlkvIG-GcvcIoalkv^ Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0090] In some embodiments of the compound of formula (I), the carbon atom marked with “* is chiral and thus can be present in S or R stereochemical configuration. In some embodiments, the stereochemical configuration is S isomer. In some embodiments, the stereochemical configuration is R isomer.

[0091] In some embodiments, A is -OH. In some embodiments, A is -C(O)OR1, wherein R1 is H or a M+ counterion. In some embodiments, A is -NR13R13, wherein R13 and R13 are each independently H or Ci-C4alkyl.

[0092] In the embodiments herein, M+ is a metal cation, an ammonium group, or a suitable organic cation. In some embodiments, M+ is a cation of an alkaline or alkaline earth metal, for example, K+, Na+, Li+, or Ca+2. In some embodiments, M+ is an ammonium ion NH / , or an organic cation derived from an amine.

[0093] In some embodiments, the compound has the structure of formula (la): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein A is -OH; R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-C6alkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is / ra \o rb wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C7cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R13 and R13 are each independently H or Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / O^R1. -SRj, -N(Rj)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Ci2cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-CealkylCs^cycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0094] In some embodiments of the compound of formula (la), the carbon atom marked with is chiral and thus can be present in S or R stereochemical configuration. In some embodiments, the stereochemical configuration is S isomer. In some embodiments, the stereochemical configuration is R isomer.

[0095] In some embodiments, the compound has the structure of formula (lb): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein A is -C^OR1; R1 is H or a M+ counterion; R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-C6alkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co- Cealkylaryl, or Co-Cealkylheteroaryl; R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-C6alkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C?cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R13 and R13 are each independently H or Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / OhR1. -SRj, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and 2020352641   29 Jun 2026 optionally substituted with C1-C4alkyl, or when an N atom is present an N-protecting group; each Rj is independently C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C7cycloalkyl, C0- C6alkylheterocyclyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl; and n is 0 or 1.

[0096] In some embodiments, of the compound of formula (Ib), the carbon atom marked with “*” (Ia) is chiral and thus can be present in S or R stereochemical configuration. In some embodiments, the stereochemical configuration is S isomer. In some embodiments, the stereochemical configuration is R isomer.

[0097] In some embodiments, the present disclosure provides a compound of formula (II): (II) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-C6alkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C?cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R13 and R13 are each independently H or Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-C^alkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S(O)2Rj, -SRj, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, GrGalkvICfXGvcIoalkvI. Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0098] In some embodiments of the compound of formula (II), the carbon atom marked with is chiral and thus compound may be present in S or R stereochemical configuration. In some embodiments, the stereochemical configuration is S isomer. In some embodiments, the stereochemical configuration is R isomer. In some embodiments, the compound of formula (II) has the structure of formula (II’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R5’, R6, R6’, R7, R7’, R9, R11, R12, R13, R13, R14, R17, R18, L and R21 are as defined for formula (II).

[0099] In some embodiments, the compound of formula (II) has the structure of formula (II”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R5’, R6, R6’, R7, R7’, R9, R11, R12, R13, R13, R14, R17, R18, L and R21 are as defined for formula (II).

[0100] In some embodiments, the compound has the structure of formula (Ila): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is / Ra \O Rb wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs- C7cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R13 and R13 are each independently H or Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci- C6alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / OhR1. -SRj, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-C6alkylC3-C7cycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0101] In some embodiments, the compound of formula (Ila) has the structure for formula (Ila’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R6, R7, R9, R11, R12, R13, R13, R14, R17, R18, L and R21 are as defined for formula (II).

[0102] In some embodiments, the compound of formula (Ila) has the structure for formula (Ila”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R6, R7, R9, R11, R12, R13, R13, R14, R17, R18, L and R21 are as defined for formula (II).

[0103] In some embodiments, the compound has the structure of formula (lib): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-C6alkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci- CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C?cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R13 and R13 are each independently H or Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / OhR1. -SRj, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Ci2cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-CealkylCs-Cvcycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0104] In some embodiments, the compound has the structure of formula (lib’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R6, R9, R11, R12, R13, R13, R14.R17, R18, L and R21 are as defined for formula (II).

[0105] In some embodiments, the compound has the structure of formula (lib”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R6, R9, R11, R12, R13, R13, R14.R17, R18, L and R21 are as defined for formula (II).

[0106] In some embodiments of the compound of formula (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), and (lib”), R3 is -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl. In some embodiments, the aryl of Co-Cealkylaryl is phenyl. In some embodiments, the aryl of Co-Cealkylaryl is optionally substituted with 1 to 3 of OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl. In some embodiments, Ral is selected from:

[0107] In some embodiments, Ral is selected from:

[0108] In some embodiments of the compound of formula (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (Hb), (lib’), and (Hb”), R3 is O double bonded to the carbon atom.

[0109] In some embodiments of the compound of formula (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), and (lib”), one or more of R2, R11, R17, and R18 are -CH3. In some embodiments, each of R2, R11, R17, and R18 is -CH3.

[0110] In some embodiments of the compound of formula (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), and (lib”), R4 and R5 are each independently H or -OH. [OlH] In some embodiments of the compound of formula (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), and (Hb”), R2, R11, R17, and R18 are -CH3; R3 is O double bonded to the carbon atom; and R4 and R5 are each independently H or -OH.

[0112] In some embodiments, the compound has the structure of formula (lie): R13 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-C6alkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-Cycycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R13 and R13 are each independently H or Ci-C4alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / OhR1. -SRj, -N(Ri)2, -Si(Ri)3, C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-CealkylCs-Cvcycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0113] In some embodiments, the compound has the structure of formula (lie’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R6, R12, R13, R13, L and R21 are as defined for formula (lie).

[0114] In some embodiments, the compound has the structure of formula (lie”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R6, R12, R13, R13, L and R21 are as defined for formula (lie).

[0115] In some embodiments, the compound has the structure of formula (lid): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-C6alkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is \O Rb rb / ra 'p wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C7cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R13 and R13 are each independently H or Ci-C4alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / OhR1. -SRj, -N(Ri)2, -Si(Ri)3, C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, GrGnlkvIGX^cvcIoalkvI. Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0116] In some embodiments, the compound has the structure of formula (lid’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R6, R12, R13, R13, L and R21 are as defined for formula (lid).

[0117] In some embodiments, the compound has the structure of formula (lid”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R6, R12, R13, R13, L and R21 are as defined for formula (lid).

[0118] In some embodiments of the compound of formula (I), (la), (lb), (II), (IF), (II”), (Ila), (Ila’), (Ila”), (lib), (lib), (lib”), (lie), (lie”), (lid), (lid’) and (lid”), R12 is -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Ci2aliphatic-C3-C7cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl. In some some embodiments, Rf is selected from

[0119] In some some embodiments, Rf is selected from:

[0120] In some embodiments, the compound has the structure of formula (III): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R13 and R13 are each independently H or Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / OhR1. -SRj, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, GrGalkvICfXGvcIoalkvI. Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0121] In some embodiments, the compound has the structure of formula (III’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R5’, R6’, R6, R6’, R7’, R7, R9, R11, R13, R13, R14 R17, R18, L and R21 are as defined for formula (III).

[0122] In some embodiments, the compound has the structure of formula (III”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R5’, R6’, R6, R6’, R7’, R7, R9, R11, R13, R13, R14 R17, R18, L and R21 are as defined for formula (III).

[0123] In some embodiments, the compound has the structure of formula (Illa): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R13 and R13 are each independently H or Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / O^R1. -SRj, -N(Rj)2, -Si(Ri)3, C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Ci2cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, GrGnlkylOX^cycloalkyl. Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0124] In some embodiments, the compound has the structure of formula (Illa’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R6, R7, R9, R11, R12, R13, R13, R14, R17, R18, L and R21 are as defined for formula (III).

[0125] In some embodiments, the compound has the structure of formula (Illa”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R6, R7, R9, R11, R12, R13, R13, R14, R17, R18, L and R21 are as defined for formula (III).

[0126] In some embodiments, the compound has the structure of formula (Illb): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci- CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R13 and R13 are each independently H or Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / OhR1. -SRj, -N(Ri)2, -Si(Ri)3, C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Ci2cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, GrGnlkvlC7X7cvcloalkvl. Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0127] In some embodiments, the compound has the structure of formula (Illb’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R6, R9, R11, R13, R13, R14, R17, R18, L and R21 are as defined for formula (III).

[0128] In some embodiments, the compound has the structure of formula (Illb”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R2, R3, R4, R5, R6, R9, R11, R13, R13, R14, R17, R18, L and R21 are as defined for formula (III).

[0129] In some embodiments of the compound of formula (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’) and (Illb”), R3 is -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl. In some embodiments, the aryl of Co-Cealkylaryl is phenyl. In some embodiments, the aryl of Co-Cealkylaryl is optionally substituted with 1 to 3 of OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl. In some embodiments, Ral is selected from:

[0130] In some embodiments, Ral is selected from:

[0131] In some embodiments of the compound of formula (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’) and (Illb”), R3 is O double bonded to the carbon atom.

[0132] In some embodiments of the compound of formula (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’) and (Illb”), one or more of R2, R11, R17, and R18 are -CH3. In some embodiments, each of R2, R11, R17, and R18 is -CH3.

[0133] In some embodiments of the compound of formula (III), (III’), (Illa), (Illa’), (Illb), and (Illb’), R4 and R5 are each independently H or -OH.

[0134] In some embodiments of the compound of formula (III), (III’), (Illa), (Illa’), (Illb), and (Illb’), R2, R11, R17, and R18 are -CH3; R3 is O double bonded to the carbon atom; and R4 and R5 are each independently H or -OH.

[0135] In some embodiments, the compound has the structure of formula (IIIc): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-C6alkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R13 and R13 are each independently H or Ci-C4alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S / O^R1. -SRj, -N(Rj)2, -Si(Ri)3, C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, GrGalkvICfXGvcIoalkvI. Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0136] In some embodiments, the compound has the structure of formula (Ilic’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R6, R13, R13, L and R21 are as defined for formula (IIIc).

[0137] In some embodiments, the compound has the structure of formula (IIIc”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R6, R13, R13, L and R21 are as defined for formula (IIIc).

[0138] In some embodiments, the compound has the structure of formula (Illd): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-C6alkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is I ra \o rb wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R13 and R13 are each independently H or Ci-C4alkyl; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S(O)2Ri, -SR’, -N(Ri)2, -Si(Ri)3, C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Ci2cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-CealkylCs-Cvcycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and n is 0 or 1.

[0139] In some embodiments, the compound has the structure of formula (Illd’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R6, R13, R13, L and R21 are as defined for formula (Illd).

[0140] In some embodiments, the compound has the structure of formula (Illd”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R6, R13, R13, L and R21 are as defined for formula (Illd).

[0141] In some embodiments for the compound of any of the foregoing embodiments, n is 0.

[0142] In some embodiments for the compound of any of the foregoing embodiments, each of R13 and R13’ is H.

[0143] In some embodiments, the compound has the structure of formula (Ilie): R21 \ or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-C6alkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S(O)2R3, -SR3, -N(Ri)2, -Si fR),. C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, GrGnlkvIGX^cvcIoalkvI. Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; and J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl.

[0144] In some embodiments, the compound has the structure of formula (Ilie’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R6, L and R21 are as defined for formula (Ilie).

[0145] In some embodiments, the compound has the structure of formula (Ilie”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R6, L and R21 are as defined for formula (Ilie).

[0146] In some embodiments, the compound has the structure of formula (Ulf): R21 \ L NH2 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-C6alkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; L is absent, Ci-Cnalkylene, or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Cnalkenylene is optionally substituted with Ci-C4alkyl; R21 is H, -S(O)2Ri, -SR’, -N(R’)2, -Si(Ri)3, C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroCs- Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl, or when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-CealkylCs-Cvcycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; Rk is H or M+ counterion; and J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl.

[0147] In some embodiments, the compound has the structure of formula (Illf’): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R6, L and R21 are as defined for formula (III!).

[0148] In some embodiments, the compound has the structure of formula (Illf”): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein R6, L and R21 are as defined for formula (Illf).

[0149] In some embodiments of the compounds of (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (Hb), (lib’), (Hb”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (IHb), (IHb’), (IHb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Illd’), (Illd”), (Ilie), (Ilie’), (Ilie”), (Illf), (Illf ), and (Illf’), R21 is C3-C7cycloalkyl, wherein the C3-C7cycloalkyl is optionally substituted with 1 to 3 of J1, wherein J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl. In some of the foregoing embodiments, the C3-C7cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0150] In some embodiments of the compounds of (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Illd’), (Illd”), (Ilie), (Ilie’), (Ilie”), (Illf), (Illf’), and (Illf’), R21 is a heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 to 3 of J1, wherein J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl. In some embodiments, the heterocyclyl is selected from oxiranyl, oxetanyl, azetidynyl, 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, Ci-C4alkyl, and haloCi-C4alkyl.

[0151] In some embodiments of the compounds of (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Illd’), (Illd”), (Ilie), (Ilie’), (Ilie”), (Illf), (Illf’), and (Illf’), R21 is aryl, wherein the aryl is optionally substituted with 1 to 3 of J1, wherein J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl. In some of the foregoing embodiments, R21 is a phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with 1 to 3 of OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl.

[0152] In some embodiments of the compounds of (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Illd’), (Illd”), (Ilie), (Ilie’), (Ilie”), (Illf), (Illf’), and (Illf’), R21 is heteroaryl, wherein the heteroaryl is optionally substituted with 1 to 3 of J1, wherein J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl. In some of the foregoing 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, wherein the heteroaryl is optionally substituted with 1 to 3 of OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl.

[0153] In some embodiments of the compounds of (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Illd’), (Illd”), (Ilie), (Ilie’), (Ilie”), (Illf), (Illf’), and (Illf’), R21 is adamantyl, wherein the adamantyl is optionally substituted with J1, wherein J1 is selected from OH, halo, Ci-C4alkyl, and haloCi-C4alkyl.

[0154] In some embodiments of the compounds of (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Hid’), (Illd”), (Ilie), (Ilie’), (Ilie”), (Illf), (Illf’), and (Illf’), R21 is spiroC5-Ci2 cycloalkyl, wherein the spiroCs-Cn cycloalkyl has 0-2 carbon atoms replaced with 0-2 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 3 of J1, wherein J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl, or when an N atom is present, is optionally substituted with an N-protecting group.

[0155] In some embodiments of the compounds of (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (Hb), (lib’), (Hb”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Illd’), (Illd”), (Ilie), (Ilie’), (Ilie”), (Illf), (Illf’), and (Illf’), R21 is 5 to 12 membered bridged bicyclyl, wherein the bridged bicyclyl has 0-2 carbon atoms replaced with 0-2 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 3 of J1, wherein J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl, or when anN atom is present, is optionally substituted with an N-protecting group.

[0156] In some embodiments of the compounds of formula (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Illd’), (Illd”), (Ilie), (Ilie’), (Ilie”), (Illf), (Illf’), and (Illf’), R21 is selected from the following: wherein J1 is OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl, and n is 0-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, haloCi-C4alkyl is-CH2F, -CHF2, or-CF3.

[0157] In some embodiments, for any of the compounds herein, L is C3-Ci2alkylene. In some embodiments, for any of the compounds herein, L is C.-Cealkylcnc, In some embodiments, for any of the compounds herein, L is Ci-Cealkylene.

[0158] In some embodiments, for any of the compounds herein, L is C3-Ci2alkenylene. In some embodiments, for any of the compounds herein, L is C.-Cealkcnylcnc. In some embodiments, for any of the compounds herein, L is Ci-Cealkenylene.

[0159] In some embodiments, L is Ci-Ci2alkylene, or C2-Ci2alkenylene, wherein the Ci-Ci2alkylene or C2-Ci2alkenylene is optionally substituted with Ci-C4alkyl; and R21 is H.

[0160] In some embodiments of the compounds of formula (I), (la), (lb), (II), (IF), (II”), (Ila), (Ila’), (Ila”), (Hb), (lib’), (Hb”), (III), (IIF), (III”), (Illa), (Illa’), (Illa”), (IHb), (HIb’), (IHb”), (IIIc), (Ilic’), (IIIc”), (Hid), (Hid’), (Hid”), (Hie), (IHe’), (Ilie”), (Ulf), (Ulf’), and (Illf ’), -L-R21 is a C2-C6alkenyl selected from:

[0161] In some embodiments for any of the foregoing compounds, e.g., formula (I), (la), (lb), (II), (IF), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (Hb”), (III), (IIF), (III”), (Illa), (Illa’), (Illa”), (IHb), (IHb’), (IHb”), (IIIc), (Ilic’), (IIIc”), (IHd), (Hid’), (Hid”), (Ilie), (Ilie’), (Hie”), (Illf), (Ulf’), and (Illf’), wherein R6 is each occurrence of RA is independently hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-l-yl (leucine), 1-methylpropan-l-yl (isoleucine), butan-l-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 (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutan-l-yl (lysine), 4-amino-3-hydroxybutan-l-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine), 3-guanidinopropan-l-yl (arginine), or3-ureido-propan-l-yl (citrulline); each occurrence of RB is independently H, or RB together with the adjacent Ra and the N atom form a prolyl side chain: p is 0, 1 or 2.

[0162] In some embodiments for any of the foregoing compounds, e.g., formula (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Hid’), (Hid”), (Ilie), (Ilie’), (Ilie”), (Ulf), (HIF), and (Illf’), wherein R6 is each occurrence of RA is independently methyl (alanine), propan-2-y 1 (valine), 2-methylpropan-l-yl (leucine), imidazol-4-y Im ethyl (histidine), hydroxymethyl (serine), 1-hydroxyethyl (threonine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), 4-aminobutan-l-yl (lysine), carboxymethyl (aspartic acid), 3-guanidinopropan-l-yl (arginine), benzyl (phenylalanine), or 4-aminobutan-l-yl (lysine); Rb is H; and p 0, 1, or 2.

[0163] In some embodiments for any of the foregoing compounds, e.g., formula (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Hid’), (Hid”), (Ilie), (Ilie’), (Ilie”), (Illf), (HIF), and (Illf’), wherein R6 is each occurrence of RA is independently propan-2-yl (valine), 2-methylpropan-l-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-l-yl (lysine); each Rb is H; and p is 0, 1, or 2.

[0164] In some embodiments for any of the foregoing compounds, e.g., formula (I), (la), (lb), (II), (IF), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Hid’), (Hid”), (Ilie), (Ilie’), (Ilie”), (Ulf), (Ulf’), and (Illf’), p is 0.

[0165] In some embodiments for any of the foregoing compounds, e.g., formula (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Hid), (Hid’), (Hid”), (Ilie), (Ilie’), (Ilie”), (Illf), (Illf), and (Illf ’), p is 1.

[0166] In some embodiments for any of the foregoing compounds, e.g., formula (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Hid’), (Hid”), (Ilie), (Ilie’), (Ilie”), (Illf), (Illf’), and (Illf’), wherein R6 is and p is 1; first of Ra is propan-2-yl (valine) and second of RA is propan-2-yl (valine); and each of RB is H (i.e., dipeptide Val-Val); or first of Ra is 2-methylpropan-l-yl (leucine), and second of RA is 2-methylpropan-l-yl (leucine); and each of RB is H (i.e., dipeptide Leu-Leu); or first of Ra is methyl (alanine) and second of RA is methyl (alanine); and each of RB is H (i.e., dipeptide Ala-Ala); or first of Ra is 4-aminobutan-l-yl (lysine); second of RA is 4-aminobutan-l-yl (lysine); and each of Rb is H (i.e., dipeptide Lys-Lys); or first of Ra is hydrogen; second of RAis 4-aminobutan-l-yl, and each of RB is H (i.e., dipeptide Gly-Lys).

[0167] In some embodiments for any of the foregoing compounds, e.g., formula (I), (la), (lb), (II), (II’), (II”), (Ila), (Ila’), (Ila”), (lib), (lib’), (lib”), (III), (III’), (III”), (Illa), (Illa’), (Illa”), (Illb), (Illb’), (Illb”), (IIIc), (Ilic’), (IIIc”), (Illd), (Illd’), (Illd”), (Ilie), (Ilie’), (Ilie”), (Illf), (Illf’), and (Illf’), wherein R6 is each of the a-carbon of the amino acid other than glycine is in the L or D configuration. In some embodiments, the a-carbon of the amino acid other than glycine is in the L configuration

[0168] In some embodiments, the compound is selected from the group consisting of the compounds or a pharmaceutical salt thereof in Table 1:

[0169] Table 1 Q L ,xNH2 p^o HO / A'X'H \H q'ho K101-C1303 k / NH2 0^0 qHO      oh K101-C1317 0 L ,,NH2 0^0 —OS? qHO    X-OH K101-C1319 Ok L 1Snh2 0^0 qHO K101-C1318 0 / o H2N —<V^TohTH JHO K101-C1325 K101-C1328 K101-C1330 K101-C1331 O K101-C1332 K101-C1340 K101-C1342 K101-C1337 K101-C1343 K101-C1344 K101-C134801 K101-C134802 K101-C1349 2020352641   29 Jun 2026 K101-C134901 K101-C1350 K101-C135601 K101-C1357 K101-C1364 K101-C1365 K101-C1375 K101-C134801C2003

[0170] In some embodiments, for each of the compounds of Table 1, the -OH on the C20 carbon atom, where appropriate, is substituted with / Ra \O Rb wherein, each occurrence of RA is independently selected from a side chain of a natural or non-natural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of Rb is same or different; and p is 0, 1, or 2;

[0171] In some embodiments of the amino acid moiety on the C20 carbon, each occurrence of RA is independently hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-l-yl (leucine), 1-methylpropan-l-yl (isoleucine), butan-l-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 (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutan-l-yl (lysine), 4-amino-3-hydroxybutan-l-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine), 3-guanidinopropan-l-yl (arginine), or3-ureido-propan-l-yl (citrulline); each occurrence of RB is independently H, or RB together with the adjacent Ra and the N atom form a prolyl side chain: p is 0, 1 or 2.

[0172] In some embodiments, each occurrence of RA is independently methyl (alanine), propan-2-yl (valine), 2-methylpropan-l-yl (leucine), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 1-hydroxyethyl (threonine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), 4-aminobutan-l-yl (lysine), carboxymethyl (aspartic acid), 3-guanidinopropan-l-yl (arginine), benzyl (phenylalanine), or 4-aminobutan-l-yl (lysine); Rb is H; and p 0, 1, or 2.

[0173] In some embodiments, each occurrence of RA is independently propan-2-yl (valine), 2-methylpropan-l-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-l-yl (lysine); each Rb is H; and p is 0, 1, or 2.

[0174] In some embodiments, p is 0.

[0175] In some embodiments, p is 1.

[0176] In some embodiments, P is 1; first of Ra is propan-2-yl (valine) and second of RA is propan-2-yl (valine); and each of RB is H (i.e., dipeptide Val-Val); or first of Ra is 2-methylpropan-l-yl (leucine), and second of RA is 2-methylpropan-l-yl (leucine); and each of RB is H (i.e., dipeptide Leu-Leu); or first of Ra is methyl (alanine) and second of RA is methyl (alanine); and each of RB is H (i.e., dipeptide Ala-Ala); or first of Ra is 4-aminobutan-l-yl (lysine); second of RA is 4-aminobutan-l-yl (lysine); and each of Rb is H (i.e., dipeptide Lys-Lys); or first of Ra is hydrogen; second of RAis 4-aminobutan-l-yl, and each of RB is H (i.e., dipeptide Gly-Lys).

[0177] In some embodiments, each of the a-carbon of the amino acid other than glycine is in the L or D configuration. In some embodiments, each of the a-carbon of the amino acid other than glycine is in the L configuration.

[0178] In another aspect, the present disclosure provides a compound of formula (IV): R2^ L or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C7cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is Co-Cealkylarylene, Co-Cealkylheteroarylene, Co-CealkylCs^cycloalkylene, Ci-Cnalkylene or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Ci2alkenylene is optionally substituted with OH or Ci-C4alkyl; and R21 is H, -OH, -SH, -S(O)2Ri, -SRj, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1; and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl or, when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-C6alkylC3-C7cycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and Rk is H or M+ counterion.

[0179] In some embodiments, excluded from the compounds of formula (IV) are compounds in which: -L-R21 is R2and R11 are CH3; R3 is =0; R4 is OH; R5, R5, R7 and R14 are H; R6’ and R7’ together form a bond; R9 is OH; R12 is H; R17 and R18 are -CH3; Ra is propan-2-yl (valine); Rb is H; and p is 0.

[0180] In some embodiments, the compound has the structure of formula (IVa): R24 L or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is / Ra \O Rb wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C7cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is Co-Cealkylarylene, Co-Cealkylheteroarylene, GrGalkvIG-GcycloalkvIc^ Ci-Cnalkylene or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Ci2alkenylene is optionally substituted with OH or Ci-C4alkyl; and R21 is H, -OH, -SH,-S(O)2Ri, -SRj, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1; and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl or, when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-C6alkylC3-C7cycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and Rk is H or M+ counterion.

[0181] In some embodiments, excluded from the compounds of formula (IVa) are compounds in which: -L-R21 is R2and R11 are CH3; R3 is =0; R4 is OH; R5, R7 and R14 are H; R9 is OH; R12 is H; R17 and R18 are -CH3; Ra is propan-2-yl (valine); Rb is H; and p is 0.

[0182] In some embodiments, the compound has the structure of formula (IVb) R2i L or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Cnaliphatic-Cs-C7cycloalkyl, -Co-Cnaliphatic-heterocycloalkyl, -Co-Cnaliphatic-aryl, or -Co-Cnaliphatic-heteroaryl; R14 is H or ORg; wherein Rg is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci- C6alkyl; L is Co-Cealkylarylene, Co-Cealkylheteroarylene, GrGalkvIG-GcycloalkvIc^ Ci-Cnalkylene or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Ci2alkenylene is optionally substituted with OH or Ci-C4alkyl; and R21 is H, -OH, -SH,-S(O)2Ri, -SRj, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Gi cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1; and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl or, when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-C6alkylC3-C7cycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and Rk is H or M+ counterion.

[0183] In some embodiments of the compound of formula (IV), (IVa), and (IVb), the C2-Cealkenyl of Ralis independently selected from:

[0184] In some embodiments, Ral is independently selected from:

[0185] In some embodiments, R3 is -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl. In some embodiments, the aryl of Co-Cealkylaryl is phenyl. In some embodiments, the aryl of Co-Cealkylaryl is optionally substituted with 1 to 3 of OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl.

[0186] In some embodiments of the compound of formula (IV), (IVa), and (IVb), R3 is O double bonded to the carbon atom.

[0187] In some embodiments of the compound of formula (IV), (IVa), and (IVb), the C2-Ci2alkenyl of Rf is independently selected from:

[0188] In some embodiments, Rf is independently selected from:

[0189] In some embodiments of the compound of formula (IV), (IVa), and (IVb), one or more of R2, R11, R17, and R18 are -CH3. In some embodiments, each of R2, R11, R17, and R18 is -CH3.

[0190] In some embodiments of the compound of formula (IV), (IVa), and (IVb), R4 and R5 are each independently H or -OH.

[0191] In some embodiments of the compound of formula (IV), (IVa), and (IVb), R2, R11, R17, and R18 are -CH3; R3 is O double bonded to the carbon atom; and R4 and R5 are each independently H or -OH.

[0192] In some embodiments, the compound has the structure of formula (V): r21 L or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRcl)2 or -Ci-CealkylC(O)ORk, Rcl is H, Ci-Cealkyl, or two Rcl together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is I ra \o rb wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is Co-Cealkylarylene, Co-Cealkylheteroarylene, Co-CealkylCs^cycloalkylene, Ci-Cnalkylene or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Ci2alkenylene is optionally substituted with OH or Ci-C4alkyl; and R21 is H, -OH, -SH,-S(O)2Ri, -SR’, -N(R’)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1; and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl or, when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-C6alkylC3-C7cycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and Rk is H or M+ counterion.

[0193] In some embodiments, excluded from the compounds of formula (V) are compounds in which: -L-R21 is R2and R11 are CH3; R3 is =0; R4 is OH; R5, R5, R7 and R14 are H; R6’ and R7’ together form a bond; R9 is OH; R17 and R18 are -CH3; Ra is propan-2-yl (valine); Rb is H; and p is 0.

[0194] In some embodiments, the compound has the structure of formula (Va): R2^ L or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRcl)2 or -Ci-CealkylC(O)ORk, Rcl is H, Ci-Cealkyl, or two Rcl together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R7 is H or OH; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci-C6alkyl; L is Co-Cealkylarylene, Co-Cealkylheteroarylene, Co-CealkylCs^cycloalkylene, Ci-Cnalkylene or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Ci2alkenylene is optionally substituted with OH or Ci-C4alkyl; and R21 is H, -OH, -SH,-S(O)2Ri, -SR’, -N(R’)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1; and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl or, when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-C6alkylC3-C7cycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and Rk is H or M+ counterion.

[0195] In some embodiments, excluded from the compounds of formula (V) are compounds in which: -L-R21 is R2and R11 are CH3; R3 is =0; R4 is OH; R5, R7 and R14 are H; R9 is OH; R17 and R18 are -CH3; Ra is propan-2-yl (valine); Rb is H; and p is 0.

[0196] In some embodiments, the compound has the structure of formula (Vb): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R2 is a Ci-C4alkyl; R3 is O double bonded to the ring carbon when (—) is a bond, or -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R4 and R5 are each independently H or -ORb, wherein Rb is H, Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl; R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-Cealkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; R9 is ORe, wherein Re is H, Ci-Cealkyl, or aryl; R11 is Ci-C4alkyl; R14 is H or OR8; wherein R8 is H or Ci-Cealkyl; R17 and R18 are each independently Ci-C4alkyl or Ci-C4alkyl-ORh, wherein Rh is H or Ci- C6alkyl; L is Co-Cealkylarylene, Co-Cealkylheteroarylene, Gi-CealkylCi-Ocycloalkylcnc. Ci-Cnalkylene or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Ci2alkenylene is optionally substituted with OH or Ci-C4alkyl; and R21 is H, -OH, -SH,-S(O)2Rj, -SR3, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1; and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl or, when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-C6alkylC3-C7cycloalkyl, Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and Rk is H or M+ counterion.

[0197] In some embodiments of the compound of formula (V), (Va), and (Vb), R3 is -ORa; wherein Ra is H or -C(O)Ral, wherein Ral is Ci-Cealkyl, C2-Cealkenyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl. In some embodiments, the aryl of Co-Cealkylaryl is phenyl. In some embodiments, the aryl of Co-Cealkylaryl is optionally substituted with 1 to 3 of OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl. In some embodiments, Ral is selected from:

[0198] In some embodiments, Ral is selected from:

[0199] In some embodiments of the compound of formula (V), (Va), and (Vb), R3 is O double bonded to the carbon atom.

[0200] In some embodiments of the compound of formula (V), (Va), and (Vb), one or more of R2, R11, R17, and R18 are -CH3. In some embodiments, each of R2, R11, R17, and R18 is -CH3.

[0201] In some embodiments of the compound of formula (V), (Va), and (Vb), R4 and R5 are each independently H or -OH.

[0202] In some embodiments of the compound of formula (V), (Va), and (Vb), R2, R11, R17, and R18 are -CH3; R3 is O double bonded to the carbon atom; and R4 and R5 are each independently H or -OH.

[0203] In some embodiments, the compound has the structure of formula (Vc): R2’ L O or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-C6alkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; L is Co-Cealkylarylene, Co-Cealkylheteroarylene, Co-CealkylCi-Ocycloalkylcnc. Ci-Cnalkylene or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Ci2alkenylene is optionally substituted with OH or Ci-C4alkyl; and R21 is H, -OH, -SH,-S(O)2Ri, -SR’, -N(Ri)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C?cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-Cn cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1; and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl or, when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, GrGnlkvIG-GcvcIoalkv^ Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C?cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and Rk is H or M+ counterion.

[0204] In some embodiments, excluded from the compounds of formula (Vc) are compounds in which: -L-R21 is Ra is propan-2-yl (valine); Rb is H; and p is 0.

[0205] In some embodiments, specifically excluded from the compounds of formula (IV), (IVa), (V), (Va) and (Vc) are compounds of the following structure:

[0206] In some embodiments, the compound has the structure of formula (Vd): or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; wherein R6 is OH, halo, or -OC(O)RC, wherein Rc is -Ci-Cealkyl, -Ci-C6alkyl-(NRC1)2 or -Ci-CealkylC(O)ORk, RC1 is H, Ci-Cealkyl, or two RC1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; or R6 is wherein, each occurrence of RA is independently selected from a side chain of a natural or nonnatural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of RB is same or different; and p is 0, 1, or 2; L is Co-Cealkylarylene, Co-Cealkylheteroarylene, GrGalkvlC>X7cvcloalkvlcnc. Ci-Cnalkylene or C2-Ci2alkenylene, wherein the Ci-Cnalkylene or C2-Ci2alkenylene is optionally substituted with OH or Ci-C4alkyl; and R21 is H, -OH, -SH,-S(O)2Ri, -SR’, -N(R’)2, -Si(Ri)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroCs-C 12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1; and wherein optionally 1 to 2 carbon atoms of the spiroCs-Cncycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with Ci-C4alkyl or, when an N atom is present an N-protecting group; each R1 is independently Ci-Cealkyl, C2-Cealkenyl, Co-GalkvICi-GcvcIoalkvI. Co-Cealkylheterocyclyl, Co-Cealkylaryl, or Co-Cealkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1; J1 is selected from OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl; and Rk is H or M+ counterion.

[0207] In some embodiments of the compounds of (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), R21 is C3-C?cycloalkyl, wherein the C3-C?cycloalkyl is optionally substituted with 1 to 3 of J1. In some of the foregoing embodiments, the C3-C?cycloalkyl is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0208] In some embodiments of the compounds of (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), R21 is a heterocyclyl, wherein the heterocyclyl is optionally substituted with 1 to 3 of J1. In some embodiments, the heterocycloalkyl is selected from oxiranyl, oxetanyl, azetidynyl, oxazolyl, thiazolidinyl, thiazolyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and azapanyl.

[0209] In some embodiments of the compounds of (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R21 is aryl, wherein the aryl is optionally substituted with 1 to 3 of J1. In some of the foregoing embodiments, R21 is a phenyl, wherein the phenyl is optionally substituted with 1 to 3 of OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl.

[0210] In some embodiments of the compounds of (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R21 is heteroaryl, wherein the heteroaryl is optionally substituted with 1 to 3 of J1. In some of the foregoing 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, wherein the heteroaryl is optionally substituted with 1 to 3 of OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl.

[0211] In some embodiments of the compounds of (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R21 is adamantyl, wherein the adamantyl is optionally substituted with OH, halo, or Ci-C4alkyl.

[0212] In some embodiments of the compounds of (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc), and (Vd), R21 is spiroCs-Cn cycloalkyl, wherein the spiroCs-Cn cycloalkyl has 0-2 carbon atoms replaced with 0-2 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 3 of OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl, or when an N atom is present an N-protecting group.

[0213] In some embodiments of the compounds of (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), R21 is 5 to 12 membered bridged bicyclyl, wherein the bridged bicyclyl has 0-2 carbon atoms replaced with 0-2 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 3 of OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl, or when an N atom is present an N-protecting group.

[0214] In some embodiments of the compounds of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), R21 is selected from the following: wherein J1 is OH, CN, halo, Ci-C4alkyl, and haloCi-C4alkyl, and n is 0-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, haloCi-C4alkyl is-CH2F, -CHF2, or-CF3.

[0215] In some embodiments, for any of the compounds herein, L is C3-Ci2alkylene. In some embodiments, for any of the compounds herein, L is C.-Cealkylcnc, In some embodiments, for any of the compounds herein, L is Ci-Cealkylene.

[0216] In some embodiments, for any of the compounds herein, L is C3-Ci2alkenylene. In some embodiments, for any of the compounds herein, L is Cs-Cealkenylene. In some embodiments, for any of the compounds herein, L is Ci-Cealkenylene.

[0217] In some embodiments of the compounds of formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), -L-R21 is a C2-Cealkenyl selected from:

[0218] In some embodiments for any of the foregoing compounds, e.g., formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), wherein R6 is each occurrence of RA is independently hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-l-yl (leucine), 1-methylpropan-l-yl (isoleucine), butan-l-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 (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutan-l-yl (lysine), 4-amino-3-hydroxybutan-l-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine), 3-guanidinopropan-l-yl (arginine), or3-ureido-propan-l-yl (citrulline); each occurrence of RB is H, or RB together with the adjacent Ra and the N atom form a prolyl side chain: p is 0, 1 or 2.

[0219] In some embodiments for any of the foregoing compounds, e.g., formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), each Ra is independently methyl (alanine), propan-2-yl (valine), 2-methylpropan-l-yl (leucine), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 1-hydroxyethyl (threonine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), 4-aminobutan-l-yl (lysine), carboxymethyl (aspartic acid), 3-guanidinopropan-l-yl (arginine), benzyl (phenylalanine), or 4-aminobutan-l-yl (lysine); Rb is H; and p 0, 1, or 2.

[0220] In some embodiments for any of the foregoing compounds, e.g., formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), wherein R6 is each occurrence of RA is independently propan-2-yl (valine), 2-methylpropan-l-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-l-yl (lysine); each Rb is H; and p is 0, 1, or 2.

[0221] In some embodiments for any of the foregoing compounds, e.g., formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), p is 0.

[0222] In some embodiments for any of the foregoing compounds, e.g., formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), p is 1.

[0223] In some embodiments for any of the foregoing compounds, e.g., formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), wherein R6 is and p is 1; first of Ra is propan-2-yl (valine) and second of RA is propan-2-yl (valine); and each of RB is H (i.e., dipeptide Val-Val); or first of Ra is 2-methylpropan-l-yl (leucine), and second of RA is 2-methylpropan-l-yl (leucine); and each of RB is H (i.e, dipeptide Leu-Leu); or first of Ra is methyl (alanine) and second of RA is methyl (alanine); and each of RB is H (i.e, dipeptide Ala-Ala); or first of Ra is 4-aminobutan-l-yl (lysine); second of RA is 4-aminobutan-l-yl (lysine); and each of Rb is H (i.e., dipeptide Lys-Lys); or first of RA is hydrogen; second of RAis 4-aminobutan-l-yl, and each of RB is H (i.e., dipeptide Gly-Lys).

[0224] In some embodiments for any of the foregoing compounds, e.g., formula (IV), (IVa), (IVb), (V), (Va), (Vb), (Vc) and (Vd), wherein R6 is each of the a-carbon of the amino acid other than glycine is in the L or D configuration. In some embodiments, each of the a-carbon of the amino acid other than glycine is in the L configuration.

[0225] In some embodiments, the compound is selected from the group consisting of the compounds or a pharmaceutical salt thereof, in Table 2.

[0226] Table 2 K101-C1301 K101-C1304 H N K101-C1305 K101-C1311 K101-C1308 or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

[0227] In some embodiments, for each of the compounds of Table 2, the -OH on the C20 carbon atom is substituted with wherein, each occurrence of RA is independently selected from a side chain of a natural or non-natural amino acid, wherein each occurrence of RA is same or different; each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of a natural or non-natural amino acid, wherein each occurrence of Rb is same or different; and p is 0, 1, or 2.

[0228] In some embodiments of the amino acid moiety on the C20 carbon, each occurrence of RA is independently hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-l-yl (leucine), 1-methylpropan-l-yl (isoleucine), butan-l-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 (cysteine), methylthiomethyl (S-methylcysteine), 2-mercaptoethyl (homocysteine), 2-methylthioethyl (methionine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-aminobutan-l-yl (lysine), 4-amino-3-hydroxybutan-l-yl (hydroxylysine), 3-aminopropan-1-yl (ornithine), 3-guanidinopropan-l-yl (arginine), or3-ureido-propan-l-yl (citrulline); each occurrence of RB is independently H, or RB together with the adjacent Ra and the N atom form a prolyl side chain: p is 0, 1 or 2.

[0229] In some embodiments, each occurrence of RA is independently methyl (alanine), propan-2-yl (valine), 2-methylpropan-l-yl (leucine), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 1-hydroxyethyl (threonine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), 4-aminobutan-l-yl (lysine), carboxymethyl (aspartic acid), 3-guanidinopropan-l-yl (arginine), benzyl (phenylalanine), or 4-aminobutan-l-yl (lysine); RB is H; and p 0, 1, or 2.

[0230] In some embodiments, each occurrence of RA is independently propan-2-yl (valine), 2-methylpropan-l-yl (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-l-yl (lysine); each Rb is H; and p is 0, 1, or 2.

[0231] In some embodiments, p is 0.

[0232] In some embodiments, p is 1.

[0233] In some embodiments, P is 1; first of Ra is propan-2-yl (valine) and second of RA is propan-2-yl (valine); and each of RB is H (dipeptide Val-Val); or first of Ra is 2-methylpropan-l-yl (leucine), and second of RA is 2-methylpropan-l-yl (leucine); and each of RB is H (dipeptide Leu-Leu); or first of Ra is methyl (alanine) and second of RA is methyl (alanine); and each of RB is H (dipeptide Ala-Ala); or first of Ra is 4-aminobutan-l-yl (lysine); second of RA is 4-aminobutan-l-yl (lysine); and each of RB is H (dipeptide Lys-Lys); or first of Ra is hydrogen; second of RA is 4-aminobutan-1 -y 1, and each of RB is H (dipeptide Gly-Lys).

[0234] In some embodiments, each of the a-carbon of the amino acid other than glycine is in the L or D configuration.

[0235] In some embodiments, compounds disclosed herein can be synthesized according to the general schemes shown outlined below in Scheme 1 and Scheme 2, where suitable reagents can be purchased form commercial sources or synthesized via known methods or methods adapted from the example procedures provided herein: Scheme 1

[0236] In Scheme 1, protection of SI (K101A shown as example) with trityl chloride (or triphenylmethyl chloride) provides S2 (K101-C20Tr-A shown as example). Hydrolysis of S2 (K101-C20Tr-A shown as example) provides S3 (K101-C20Tr-B, shown as example), which can then be coupled with compound S4 under esterification conditions using l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, or EDCI) as the carboxyl activating agent and 4-dimethylaminopyridine (DMAP) as the catalyst to provide S5. Deprotection of S5 followed by further separation and purification provides S6.

[0237] In Scheme 2, S7 is prepared by epoxidation of S5 with a peroxy carboxylic acid such as metachloroperoxybenzoic acid (m-CPBA). Further separation and purification of S7 provides S8.

[0238] Appropriate starting materials and reagents for use in Scheme 1 and Scheme 2 can be purchased or prepared by methods known to one of skill in the art.

[0239] In some embodiments of the methods of Scheme 1 and Scheme 2, the various substituents on the starting compounds (e.g., compounds SI and S3) are as defined for Formula I. However, it should also be appreciated that chemical derivatization and / or functional group interconversion, can be used to further modify of any of the compounds of Scheme 1 and Scheme 2 in order to provide the various compounds of Formula I.

[0240] In some embodiments, synthesis of the prodrugs are prepared by reacting protected amino acids (e.g., N-protected amino acids) with relevant compounds, e.g., compounds having an -OH group at the R6 position. Guidance is provided in Examples 63 and 64 illustrating synthesis of amino acid prodrugs as well as knowledge of general procedures available in the art for producing such prodrugs (see, e.g., Vale et al., 2018, Molecules. 23(9):2318; Beauchamp et al., 1992, Antiviral Chemistry & Chemotherapy 3(3): 157-164; incorporated herein by reference).

[0241] Other compounds of the disclosure can be synthesized using the synthetic routes above and adapting chemical synthetic procedures available to the skilled in the art. Exemplary methods of synthesis are provided in the Examples. It is to be understood that each of the procedures describing synthesis of exemplary compounds are part of the specification, and thus incorporated herein into the Detailed Description of this disclosure. 5.3. Pharmaceutically Acceptable Salts

[0242] In some embodiments, the PKC modulating compounds are in free form or where appropriate as pharmaceutically acceptable salt. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.

[0243] Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. In some embodiments, pharmaceutically acceptable salt of the compounds herein can be prepared during final isolation and purification of the compounds. For example, a pharmaceutically acceptable salt of the compounds herein can be prepared by (1) reacting the compound in free base form with a suitable organic or inorganic acid, and (2) isolating the salt thus formed. Examples of pharmaceutically acceptable, nontoxic acid addition salts are 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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, valerate salts, and the like.

[0244] Base addition salts can be prepared by (1) reacting the compound, such as the purified compound, in its acid form with a suitable organic or inorganic base, and (2) isolating the salt thus formed. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(Ci-Cialkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. 5.4.    Methods of Use

[0245] In another aspect, the compounds described herein are used in a method of treating cancer. In some embodiments, the method of treating cancer comprises administering to a subject in need thereof a therapeutically effective amount any of the compounds described herein.

[0246] In some embodiments, the compounds can be used as monotherapy, or as further provided below, in a combination therapy with one or more therapeutic treatments, particularly in combination with one or more chemotherapeutic agents. In some embodiments, the compounds are used in combination with a second therapeutic agent, where the compounds are used at levels that sensitizes the cancer or cancer cell to the second therapeutic agent, for example 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, either to sensitize the cells to radiation therapy or as an adjunct to radiation therapy (e.g., at doses sufficient to activate cell death pathway).

[0247] In some embodiments, the cancer for treatment with the compound can be selected from, among others, adrenocortical cancer, anal cancer, biliary cancer, bladder cancer, bone cancer (e.g., osteosarcoma), brain cancer (e.g., gliomas, astrocytoma, neuroblastoma, etc.), breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, hematologic cancer (e.g., leukemia and lymphoma), intestinal cancer (small intestine), liver cancer, lung cancer (e.g., bronchial cancer, small cell lung cancer, non-small cell lung cancer, etc.), oral cancer, ovarian cancer, pancreatic cancer, renal 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 carcinomas.

[0248] In some embodiments, the cancer for treatment with the compound is pancreatic cancer. In some embodiments, the pancreatic cancer for treatment with the compounds is pancreatic adenocarcinoma or metastatic pancreatic cancer. In some embodiments, the cancer for treatment with the compounds is stage 1, stage II, stage III, or stage IV pancreatic adenocarcinoma.

[0249] In some embodiments, the cancer for treatment with the compounds is lung cancer. In some embodiments, the lung cancer for treatment with the compounds is small cell lung cancer or nonsmall cell lung cancer. In some embodiments, the non-small cell lung cancer for treatment with the compounds is an adenocarcinoma, squamous cell carcinoma, or large cell carcinoma. In some embodiments, the lung cancer for treatment with the compounds is metastatic lung cancer.

[0250] In some embodiments, the cancer for treatment with the compounds is a hematologic cancer. In some embodiments, the hematologic 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.

[0251] In some embodiments, the cancer for treatment with the compounds 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.

[0252] In some embodiments, the cancer for treatment with the compound is a lymphoma selected from Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, and Burkitt’s lymphoma).

[0253] In some embodiments, the cancer for treatment with the compound is a cancer characterized by mesenchymal features or mesenchymal phenotype. In some cancers, gain of mesenchymal features is associated with migratory (e.g., intravasation) and invasiveness of cancers. Mesenchymal features can include, among others, enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and increased production of extracellular matrix (ECM) components. In addition to these physiological characteristics, the mesenchymal features can include expression of certain biomarkers, including among others, E-cadherin, N-cadherin, integrins, FSP-1, a-SMA, vimentin, P-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, the cancer selected for treatment with the compounds herein include, among others, breast cancer, lung cancer, head and neck cancer, prostate cancer, and colon cancer. In some embodiments, the mesenchymal features can be inherent to the cancer type or induced by or selected for by treatment of cancers with chemotherapy and / or radiation therapy.

[0254] In some embodiments, the cancer for treatment with the compound is identified as having or determined to have an activating or oncogenic RAS activity. In some embodiments, the RAS is KRAS, H-RAS or N-RAS. In some embodiments, the activating or oncogenic RAS is an activating or oncogenic RAS mutation.

[0255] In some embodiments, the cancer for treatment is identified as having or determined to have an activating or oncogenic K-RAS mutation. In some embodiments, the cancer selected for treatment is identified as having or determined to have an activating or oncogenic mutation in human K-RAS at one or more of 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, codon 117, codon 118, codon 119, codon 135, codon 138, codon 140, codon 146, codon 147, codon 153, codon 156, codon 160, codon 164, codon 171, codon 176, codon 185, and codon 188.

[0256] In some embodiments, the activating or oncogenic K-RAS mutation can be a mutation in which: codon 5 is K5E; codon 9 is V91; codon 12 is G12A, G12C, G12D, G12F, G12R, G12S, G12V, or G12Y; codon 13 is G13C, G13D, or G13V; codon 14 is V14I or V14L; codon 18 is A18D; codon 19 is L19F; 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; 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 Pl 10S; codon 115 is G115E; codon 117 is K117N; codon 118 is C118S; codon 119 is D119N; codon 135 is R135T; codon 138 is G138V; codon 140 is P140H; codon 146 is A146T or A146V; codon 147 is K147N; codon 153 is D153N; codon 156 is F156L; codon 160 is V160A; codon 164 is R164Q; codon 171 is I117M; codon 176 is K176Q; codon 185 is C185R or C185S; and codon 188 is M188V.

[0257] In particular, the cancer for treatment is identified as having or determined to have an oncogenic or activating K-RAS mutations 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.

[0258] In some embodiments, the cancer for treatment is identified as having or determined to have an activating or oncogenic N-RAS mutation. In some embodiments, the cancer is identified as having or determined to have an activating or oncogenic mutation in human N-RAS at one or more of codon 12, codon 13 and codon 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 mutation is a combination of activating or oncogenic N-RAS mutations at codon 12 and codon 13; codon 12 and codon 61; codon 13 and 61; or codon 12, codon 13 and codon 61.

[0259] In some embodiments, the cancer for treatment is identified as having or determined to have an activating or oncogenic H-RAS mutation. In some embodiments, the cancer selected for treatment is identified as having an activating or oncogenic mutation in human H-RAS at one or more of codon 12, codon 13 and codon 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 mutation is 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.

[0260] In some embodiments, the cancer for treatment can be a cancer having prevalence (e.g., at least about 10% or more, or about 15% or more of the cancers), of an activating or oncogenic RAS mutation, such as cancer of the biliary tract, cervix, endometrium, pancreas, lung, colon, head and neck, stomach (gastric), biliary tract, endometrium, hematologic (e.g., leukemia, lymphomas, etc.), large intestine, lung, ovary, pancreas, prostate, salivary gland, skin, small intestine, stomach thyroid, aerodigestive tract, urinary tract, and ovary, small intestine, and urinary tract.

[0261] Biological sample for the method herein include any samples are amenable to analysis herein, such as tissue or biopsy samples containing cancer cells, or any biological fluids that contain the material of interests (e.g., DNA), such as blood, plasma, saliva, tissue swabs, and intestinal fluids. In some embodiments, exosomes extruded by cancer cells and obtained from blood or other body fluids can be used to detect nucleic acids and proteins produced by the cancer cells.

[0262] General biological, biochemical, immunological and molecular biological methods applicable to the present disclosure are described in Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd Ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology, Ausubel et al., ed., John Wiley & Sons (2015); Current Protocols in Immunology, Coligan, JE ed., John Wiley & Sons (2015); and Methods in Enzymology, Vol. 200, Abelson et al., ed., Academic Press (1991). All publications are incorporated herein by reference. 5.5. Combination Treatments

[0263] In some embodiments, the diterpenoid PKC modulating compounds are used in combination with one or more second therapeutic agents. In some embodiments, the second therapeutic agent is selected from a platinating agent, alkylating agent, antibiotic agent, antimetabolic agent (e.g., folate antagonists, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibiting agent, antimicrotubule agent (e.g., taxanes, vinca alkaloids), hormonal agent (e.g., aromatase inhibitors), plant-derived agent and synthetic derivatives thereof, anti- angiogenic agent, differentiation inducing agent, cell growth arrest inducing agent, apoptosis inducing agent, cytotoxic agent, agent affecting cell bioenergetics, i.e., affecting cellular ATP levels and molecules / activities regulating these levels, anti-cancer biologic agent (e.g., monoclonal antibodies), kinase inhibitors and inhibitors of growth factors and their receptors.

[0264] In some embodiments, the second chemotherapeutic agent is selected from afatinib, afuresertib, alectinib, alisertib, alvocidib, amsacrine, amonafide, amuvatinib, axitinib, azacitidine, azathioprine, bafetinib, barasertib, bendamustine, bleomycin, bosutinib, bortezomib, busulfan, cabozantinib, camptothecin, canertinib, capecitabine, cabazitaxel, carboplatin, carmustine, cenisertib, ceritinib, chlorambucil, cisplatin, cladribine, clofarabine, crenolanib, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dacomitinib, dactinomycin, danusertib, dasatinib, daunorubicin, decitabine, dinaciclib, docetaxel, dovitinib, doxorubicin, epirubicin, epitinib, eribulin mesylate, errlotinib, 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 mepesuccinate, olaparib, orantinib, oxaliplatin, paclitaxel, palbociclib, palifosfamide tris, 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.

[0265] In some embodiments, the second therapeutic agent is selected from the group consisting of a phosphoinositol-3 kinase (PI3K) inhibitor, AKT inhibitor, mammalian target of rapamycin (mTOR) inhibitor, poly ADP ribose polymerase (PARP) inhibitor, platinum-based anti-cancer compound (PBAC), CBP / p-catenin inhibitor, Tankyrase (TNKS) inhibitor, probable protein-cysteine N-palmitoyltransferase (PORCN) inhibitor, scr kinase / bcr-abl kinase inhibitor, Smoothened (SMO) inhibitor, anti-cancer nucleoside analog or anti-metabolite, histone deacetylase (HDAC) inhibitor, Bromodomain and Extra-Terminal motif (BET) inhibitor, all-trans-retinoic acid (ATRA), Bruton’s tyrosine kinase (BTK) inhibitor, EGFR receptor inhibitor, and combinations thereof.

[0266] In some embodiments, the second therapeutic agent is selected from the group consisting of idelalisib, pictilisib, duvelisib, pilaralisib, alpelisib, copanlisib, voxtalisib, dactolisib, gedatolisib, apitolisib, perifosine, miltefosine, ipatasertib, sirolimus, everolimus, temsirolimus, tacrolimus, ridaforolimus, ridaforolimus, dactolisib, olaparib, veliparib, rucaparib, talazoparib, niraparib, cisplatin, 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, cyclopamine, vismodegib, glasdegib, SANT-1, sonidegib, saridegib, taladegib, GSK1210151A, GSK525762, CPI-0610, RVX-208, vorinostat (SAHA), entinostat, panobinostat, mocetinostat, belinostat, romidepsin, rocilinostat, abexinostat, resminostat, givinostat, quisinostat, pracinostat, kevetrin, CC-292, CNX-774, LFM-A13, CGI 1746, trastuzumab, pertuzumab, ado-trastuzumab emtansine, cetuximab, panitumumab, nimotuzuma, mAb806, rrindopepimut, lapatinib, erlotinib, gefitinib, afatinib, neratinib, osimertinib, rociletinib, canertinib, and dacomitinib. 5.6. Formulations and Administration

[0267] In some embodiments, the pharmaceutical compositions of the therapeutic agents can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in Remington: The Science and Practice of Pharmacy, 21st Ed. (2005). The therapeutic compounds and their physiologically acceptable salts, hydrates and solvates can be formulated for administration by any suitable route, including, among others, topically, nasally, orally, parenterally, rectally or by inhalation. 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 with a syringe or other devices. Transdermal administration is also contemplated, as are inhalation or aerosol administration. Tablets, capsules, and solutions can be administered orally, rectally or vaginally.

[0268] For oral administration, a pharmaceutical composition can take the form of, for example, a tablet or a capsule prepared by conventional means with a pharmaceutically acceptable excipient. Tablets and capsules comprising the active ingredient can be prepared together with excipients such as: (a) diluents or fdlers, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylates and / or calcium hydrogen phosphate, calcium sulfate; (b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, metallic stearates, colloidal silicon dioxide, hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate and / or polyethyleneglycol; (c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and / or hydroxypropyl methylcellulose; (d) disintegrants, e.g., starches (including potato starch or sodium starch), glycolate, agar, alginic acid or its sodium salt, or effervescent mixtures; (e) wetting agents, e.g., sodium lauryl sulphate, and / or (f) absorbents, colorants, flavors and sweeteners. The compositions are prepared according to conventional mixing, granulating or coating methods.

[0269] Tablets may be either fdm coated or enteric coated according to methods known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or they can be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable carriers and additives, for example, suspending agents, e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for example, methyl or propyl-p-hydroxybenzoates or sorbic acid. The preparations can also contain buffer salts, flavoring, coloring, and / or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated to give controlled release of the active compound.

[0270] The therapeutic agents can be formulated for parenteral administration, for example by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an optionally added preservative. Injectable compositions can be aqueous isotonic solutions or suspensions. In some embodiments for parenteral administration, the therapeutic agents can be prepared with a surfactant, such as Cremaphor, or lipophilic solvents, such as triglycerides or liposomes. The compositions may be sterilized and / or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. Alternatively, the therapeutic agent can be in powder form for reconstitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. In addition, they may also contain other therapeutically effective substances.

[0271] In some embodiments, the therapeutic agent, e.g., the diterpenoid PKC modulating compounds, are administered intratumorally. In some embodiments, the therapeutic agent is administered directly into the tumor, allowing for high local concentration of the therapeutic agent and in some embodiments, increased bioavailability of the therapeutic agent at the site of the tumor. Any formulation of the therapeutic agent suitable for intratumoral administration can be used in the embodiments herein. Intratumoral administration can be by injection of the therapeutic agent into the tumor (see, e.g., Celikoglu et al., 2008, Cancer Therapy, 6:545-552) or by intravenous administration to blood vessels feeding to the tumor. In some embodiments, the injection device has a porous delivery channel (e.g., needle) for wider distribution or infusion of the therapeutic agent for treating tumors with large volume.

[0272] For administration by inhalation, the therapeutic agent may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, 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 of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, for example, lactose or starch.

[0273] Suitable formulations for transdermal application include an effective amount of a therapeutic agent with a carrier. Preferred carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the subject. For example, transdermal devices are in the form of a bandage or patch comprising a backing member, a reservoir containing the therapeutic agent optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and a means to secure the device to the skin. Matrix transdermal formulations may also be used.

[0274] Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. The formulations may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0275] In some embodiments, the therapeutic agent can also be formulated as a rectal composition, for example, suppositories or retention enemas, for example, containing conventional suppository bases, for example, cocoa butter or other glycerides, or gel forming agents, such as carbomers.

[0276] In some embodiments, the therapeutic agent can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. The therapeutic agent can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil), ion exchange resins, biodegradable polymers, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0277] In some embodiments, the carrier is a cyclodextrins, such as to enhance solubility and / or bioavailability of the compounds herein. In some embodiments, the cyclodextrin for use in the pharmaceutical compositions can be selected from a-cyclodextrin, P-cyclodextrin, y-cyclodextrin, derivatives thereof, and combinations thereof. In particular, the cyclodextrin is selected from P-cyclodextrin, y-cyclodextrin, derivatives thereof, and combinations thereof.

[0278] In some embodiments, the compounds can be formulated with a cyclodextrin or derivative thereof selected from carboxyalkyl cyclodextrin, hydroxyalkyl cyclodextrin, sulfoalkylether cyclodextrin, and an alkyl cyclodextrin. In various embodiments, the alkyl group in the cyclodextrin is methyl, ethyl, propyl, butyl, or pentyl.

[0279] In some embodiments, the cyclodextrin is a-cyclodextrin or a derivative thereof. In some embodiments, the a-cyclodextrin or derivative thereof is selected from carboxyalkyl-a-cyclodextrin, hydroxyalkyl-a-cyclodextrin, sulfoalkylether-a-cyclodextrin, alkyl-a-cyclodextrin, and combinations thereof. In some embodiments, the alkyl group in the a-cyclodextrin derivative is methyl, ethyl, propyl, butyl, or pentyl.

[0280] In some embodiments, the cyclodextrin is (3-cyclodextrin or a derivative thereof. In some embodiments, the (3-cyclodextrin or derivative thereof is selected from carboxyalkyl-(3- cyclodextrin, hydroxy alky 1-(3-cyclodextrin, sulfoalkylether-(3-cyclodextrin, alkyl-(3-cyclodextrin, and combinations thereof. In some embodiments, the alkyl group in the (3-cyclodextrin derivative is methyl, ethyl, propyl, butyl, or pentyl.

[0281] In some embodiments, the (3-cyclodextrin or a derivative thereof is hydroxyalkyl-(3-cyclodextrin or sulfoalkylether-(3-cyclodextrin. In some embodiments, the hydroxyalkyl-(3-cyclodextrin is hydroxypropyl-(3-cyclodextrin. In some embodiments, the sulfoalkylether-(3-cyclodextrin is sulfobutylether-(3-cyclodextrin. In some embodiments, (3-cyclodextrin or a derivative thereof is alkyl-(3-cyclodextrin, in particular methyl-(3-cyclodextrin. In some embodiments using methyl-(3-cyclodextrin, the (3-cyclodextrin is randomly methylated (3-cyclodextrin.

[0282] In some embodiments, the cyclodextrin is y-cyclodextrin or a derivative thereof. In some embodiments, the y-cyclodextrin or derivative thereof is selected from carboxyalkyl-y-cyclodextrin, hydroxyalkyl-y-cyclodextrin, sulfoalkylether-y-cyclodextrin, and alkyl-y-cyclodextrin. In some embodiments, the alkyl group in the y-cyclodextrin derivative is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments, the y-cyclodextrin or derivative thereof is hydroxyalkyl-y-cyclodextrin or sulfoalkylether-y-cyclodextrin. In some embodiments, the hydroxyalkyl-y-cyclodextrin is hydroxypropyl-y-cyclodextrin.

[0283] When used in a formulation with the compound of the present disclosure, the cyclodextrin can be present at about 0.1 w / v to about 30% w / v, about 0.1 w / v to about 20% w / v, about 0.5% w / v to about 10% w / v, or about 1% w / v to about 5% w / v. In some embodiments, the cyclodextrin is present at about 0.1% w / v, about 0.2% w / v, about 0.5% w / v, about 1% w / v, about 2% w / v, about 3% w / v, about 4% w / v, about 5% w / v, about 6% w / v, about 7% w / v, about 8% w / v, about 9% w / v, about 10% w / v, about 12% w / v, about 14% w / v, about 16% w / v, about 18% w / v, about 20% w / v, about 25% w / v, or about 30% w / v or more.

[0284] The pharmaceutical compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient. The pack can, for example, comprise metal or plastic foil, for example, a blister pack. The pack or dispenser device can be accompanied by instructions for administration. 5.7. Effective Amount and Dosing

[0285] In some embodiments, a pharmaceutical composition of the therapeutic agent is 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 a response that at least partially arrests or slows the symptoms or complications of the condition or disease. An amount adequate to accomplish this is defined as “therapeutically effective dose” or “therapeutically effective amount.”

[0286] The dosage of therapeutic agents can take into consideration, among others, the species of warm-blooded animal (mammal), the body weight, age, condition being treated, the severity of the condition being treated, the form of administration, route of administration. The size of the dose also will be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular therapeutic compound in a particular subject.

[0287] In some embodiments, the diterpenoid PKC activating compound, the compound can be administered in a dose in the range from about 0.001 mg per kg of subject weight (0.001 mg / kg) to about 1000 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 can be administered once per day or divided into subdoses and administered in multiple doses, e.g., twice, three times, or four times per day.

[0288] In some embodiments, the diterpenoid PKC activator can be administered with one or more of the second therapeutic agent sequentially or concurrently, either by the same route or by different routes of administration. When administered sequentially, the time between administrations is selected to benefit, among others, the therapeutic efficacy and / or safety of the combination treatment. In some embodiments, the diterpenoid PKC activator can be administered first followed by a second therapeutic agent, or alternatively, the second therapeutic agent administered first followed by the diterpenoid PKC activator. By way of example and not limitation, the time between administrations is about 1 hr, about 2 hr, about 4hr, about 6 hr, about 12 hr, about 16 hr or about 20 hr. In some embodiments, the time between administrations is about 1, about 2, about 3, about 4, about 5, about 6, or about 7 more days. 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.

[0289] When administered concurrently, the diterpenoid PKC modulator can be administered separately at the same time as the second therapeutic agent, by the same or different routes, or administered in a single composition by the same route.

[0290] In some embodiments, the amount and frequency of administration of the second therapeutic agent can used standard dosages and standard administration frequencies used for the particular therapeutic agent. See, e.g., Physicians’ Desk Reference, 70th Ed., PDRNetwork, 2015; incorporated herein by reference.

[0291] In some embodiments, where administration of the therapeutic agent is to a localized site, for example, intratumoral injection, the dosages can be the dosages used for systemic administration, such as dosages used for intravenous, intramuscular, and intraperitoneal administration. In some embodiments, the dose for localized administration, e.g., intratumoral administration, is higher than those used for systemic administration. In some embodiments, the administered dose is sufficient for the intended effect, for example killing or necrotization of tumor tissue. In some embodiments, intratumoral administration is done once, twice, three times, four times, five time or up to six times or more, where each administration is separated in time, for example, until the desired outcome is achieved.

[0292] It to be understood that optimum dosages, toxicity, and therapeutic efficacy of such therapeutic agents may vary depending on the relative potency of individual therapeutic agent and can be determined by pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD5o (the dose lethal to 50% of the population) and the ED5o (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio, LD50 / ED50. 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 used to design a delivery system that targets such agents to the site of affected tissue to minimize potential damage to normal cells and, thereby, reduce side effects.

[0293] The data obtained from, for example, cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The dosage of such small molecule compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration. For any compounds used in the methods of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography (HPLC).

[0294] The following examples are provided to further illustrate the methods of the present disclosure, and the compounds and compositions for use in the methods. The examples described are illustrative only and are not intended to limit the scope of the invention in any way. 6. EXAMPLES Example 1:    Synthesis Scheme of KI01-Epoxide and K101-DI-OH.

[0295] The scheme for synthesis of compounds KI01-Epoxide and K101-DI-OH are illustrated below. Epoxide-Trt K101-Epoxide K101-DI-OH

[0296] Preparation of Compound K101-C20Tr-A. To a solution of K101A (1 g, 2.56 mmol, 1 eq) in pyridine (40 mL) was added Trityl chloride (2.14 g, 7.68 mmol, 3.00 eq). The mixture was stirred at 40°C for 14 hours (hr) to give a yellow solution. LC-MS showed desired mass was found, and K101A was remained. The mixture was stirred at 40°C for 12hr again. LC-MS and TLC (eluting with: PE / EtOAc=2 / l) 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 (eluting with: petroleum ether (PE) / ethyl acetate=100%PE to 20%) to give K101-C20Tr-A (1.6 g, 2.53 mmol, 98.73% yield) as a white solid. ’H NMR (400MHz, CDCh) 8 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), 2.092.06 (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).

[0297] Preparation of Compound Epoxide-Trt. To a solution of K101-C20Tr-A (30.00 mg, 47.41 pmol, 1.00 equivalent (hereafter as eq)) in dichloromethane (hereafter as DCM) (2.00 mL) was added NaHCOs (11.95 mg, 142.23 pmol, 5.53 uL, 3.00 eq), meta-chloroperoxybenzoic acid (m-CPBA) (14.44 mg, 71.11 pmol, 1.5eq, 85% purity), and the reaction mixture was stirred at 20°C for 2 hours (h) to give a suspension. LC-MS showed the reaction was complete, and the desired MS value was observed. Thin-layer chromatography (TLC) (petroleum ether / ethyl acetate mixture ration 2:1 (PE / EtOAc=2 / l), 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 (prep)-TLC (PE / EtOAc=2 / l, SiCL) to give Epoxide-Trt (20.10 mg, 65.34% yield) as a colorless gum.

[0298] 'H NMR (400MHz, CDC13) 8 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, 7=9.3 Hz, 1H), 3.08 (d, 7=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, . / =4,3 Hz, 1H), 0.89 (d, 7=6.5 Hz, 3H).

[0299] Preparation of Compound KlOl-Epoxide and K101-DI-OH. To a solution of Epoxide-Trt (10.00 mg, 15.41 pmol, 1.00 eq) in DCM (500.00 uL) was added trifluoroacetic acid (hereafter as TFA) (100.00 pL), and the reaction solution stirred at 0°C for Ih. TLC (PE / EtOAc=2 / l, SiO2) showed the reaction was complete. The reaction was quenched by saturated aqueous NaHCOs (2 mL) at 0°C, then extracted with DCM (5 mL x 2), dried over Na2SO4, fdtered, and concentrated under reduced pressure to give a colorless gum. The residue was combined with a second preparation of crude product and purified by prep-HPLC (column: Waters Xbridge 150 x 25 x 5 mm; mobile phase: A [A: water (0.05% ammonia hydroxide v / v)]; B [acetonitrile (ACN)]; gradient B%: 25%-55% in lOmin to give KlOl-Epoxide (1.51 mg, 3.71 pmol. 24.11% yield, 100% purity) and K101-DI-OH (1.20 mg, 2.60 pmol, 16.90% yield, 92.1% purity), both as white solid after lyophilization.

[0300] KlOl-Epoxide: LC-MS (m / z): 429.2 [M+Na]+

[0301] KlOl-Epoxide: 'H NMR (400MHz, CD3OD) 8 7.53 (s, IH), 3.48 (d, 7=11.9 Hz, IH), 3.443.39 (m, IH), 3.36 (s, IH), 3.16 (d,7=8.6 Hz, IH), 2.66 (d, 7=16.8 Hz, IH), 2.14-2.06 (m, 4H), 2.041.89 (m, 3H), 1.77-1.74 (m, 3H), 1.59 (dd, 7=11.2, 14.3 Hz, IH), 1.22 (s, 3H), 1.06 (s, 3H), 1.02 (d, 7=4.9 Hz, IH), 0.89 (d, 7=6.6 Hz, 3H).

[0302] K101-DI-OH: LC-MS (m / z): 447.1 [M+Na]+

[0303] K101-DI-OH: 1H NMR (400MHz, CD3OD) 5 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, . / =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). Example 2: Synthesis Scheme of K101-C13OH.

[0304] The scheme for synthesis of compound K101-C13OH is illustrated below. K101A                                 K101-C13OH

[0305] Preparation of Compound K101-C13OH. To a solution of K101A (40.00 mg, 102.44 pmol, 1.00 eq) in MeOH (20.00 mL) was added Ba(OH)2.8H2O (322.69 mg, 1.02 mmol, 10.00 eq). The mixture was stirred at 20°C for 4 hours to give a yellow suspension. LC-MS and TLC (eluting with: EtOAc=100%) showed the reaction was complete. The reaction mixture was quenched withsaturated NH4CI (10 mL) and extracted with di chloromethane (DCM) (100 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by prep-TLC (eluting with: EtOAc=2 / l) to give K101-C13OH (9.30 mg, 26.69 pmol. 26.05% yield, 100% purity) as a white solid.

[0306] LC-MS (m / z): 371.2 [M+Na]+

[0307] 'H NMR (400MHz, CD3OD) 5 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). Example 3:    Synthesis Scheme of K101-C1301.

[0308] The scheme for synthesis of compound K101-C1301 is illustrated below.

[0309] Preparation of Compound K101-C20Tr-A. To a solution of KI01A (500.00 mg, 1.28 mmol, 1.00 eq) in pyridine (10.00 mL) was added trityl chloride (TrtCl) (1.07 g, 3.84 mmol, 3.00 eq). The mixture was stirred at 20°C for 14 hours to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / l) showed the reaction was complete. The reaction mixture was concentrated by N2 to give the crude product. The product was purified by flash column (eluting with: EtOAc in PE 1% to 50%) to give K101-C20Tr-A (790.00 mg, 1.02 mmol, 79.78% yield, 81.795% purity) as a white solid.

[0310] Preparation of Compound K101-C20Tr-B. To a solution of K101-C20Tr-A (290.00 mg, 458.30 pmol, 1.00 eq) in MeOH (76.00 mL) was added Ba(OH)2.8H2O (1.44 g, 4.58 mmol, 10.00 eq) at 0°C. The mixture was stirred at 20°C for 3 hours to give yellow suspension. LC-MS showed the reaction was complete. The reaction mixture was quenched with saturated aqueous NELCl (50 mL) and extracted with dicholoromethane (DCM) (300 mL x 3). The organic layers were dried over Na2SO4. The organic layers was fdtered on silica gel and washed with EtOAc (50 mL). The organic layer was concentrated to give K101-C20Tr-B (260.00 mg, 425.57 pmol. 92.86% yield, 96.694% purity) as a white solid.

[0311] Preparation of Compound K101-C1301-A. To solution of K101-C1301-B (35.00 mg, 59.25 pmol, 1.00 eq) in DCM (500.00 uL) were added 3-cyclopentylpropanoic acid (10.11 mg, 71.10 pmol, 10.11 uL, 1.20 eq), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochlorideEDC (EDC) (22.72 mg, 118.49 pmol. 2.00 eq) and 4-Dimethylaminopyridine (DMAP) (14.48 mg, 118.50 pmol. 2.00 eq). The mixture was stirred at 20°C for 14 hoursto give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=4 / l) showed the reaction was complete. The reaction mixture was combined with a second preparation of the compound, quenched with H2O (10 mL) and extracted with DCM (15 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=4 / l) to give K101-C1301-A (32.00 mg, 44.76 pmol, 65.12% yield, 100% purity) as a white solid.

[0312] Preparation of Compound K101-C1301. To a solution of K101-C1301-A (32.00 mg, 44.76 pmol, 1.00 eq) in DCM (1.00 mL) was added TFA (385.00 mg, 3.38 mmol, 250.00 uL, 75.44 eq). The mixture was stirred at 20°C for 1 hour to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=l / l) showed the reaction was complete. The solvent was removed byN2 to give a crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=l / l) to give K101-C1301 (8.10 mg, 17.14 pmol, 38.29% yield, 100% purity) as a white solid.

[0313] LC-MS (m / z): 495.3 [M+Na]+

[0314] 'H NMR (400MHz, CD3OD) 5 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). Example 4: Synthesis Scheme of K101-C1302.

[0315] The scheme for synthesis of compound K101-C1302 is illustrated below. K101-C20Tr-B                          K101-C1302-A                       K101-C1302

[0316] Preparation of Compound K101-C1302-A. To a solution of K101-C20Tr-B (40.00 mg, 67.71 pmol, 1.00 eq) in DCM (1.00 mL) were added 3-[4-(trifluoromethyl)phenyl]propanoic acid (C13-02) (17.73 mg, 81.25 pmol, 1.20 eq), DMAP (16.54 mg, 135.42 pmol, 2.00 eq) and EDC (25.96 mg, 135.42 pmol, 2.00 eq). The mixture was stirred at 20°C for 2 hours to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / l) showed the reaction was complete. The mixture was combined with a second preparation of the compound, quenched with saturated NaHCOs (5 mL) and extracted with DCM (10 mL x 3). The organic layers were washed with H2O (5 mL), dried over Na2SO4 and then concentrated to give the crude product. The product was purified by prep-TLC 2020352641   29 Jun 2026 (eluting with: PE / EtOAc=2 / 1) to give K101-C1302-A (34.00 mg, 42.45 pmol, 53.72% yield, 98.736% purity) as a white solid.

[0317] Preparation of compound K101-C1302. To a solution of K101-C1302-A (28.00 mg, 35.40 pmol, 1.00 eq) in MeOH (1.00 mL) was added HClO4 (464.95 mg, 4.63 mmol, 280.09 uL, 130.73 eq). The mixture was stirred at 0°C for 0.5 hour to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was combined with a second preparation of the compound and purified by prep-HPLC (column: Waters XSELECT C18 150 x 30mm x 5um; mobile phase: [A: water (0.1%TFA)-B: B: ACN]; B%: 33%-63%, 10 min) to give K101-C1302 (10.60 mg, 18.56 ^mol, 52.42% yield, 96.032% purity) as a white solid.

[0318] LC-MS (m / z): 571.3 [M+Na]+

[0319] 1H NMR (400MHz, CD3OD) 8 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). Example 1:    Synthesis Scheme of K101-C1303 K101-C20Tr-B K101-C1303-A K101-C1303

[0320] Preparation of Compound K101-C1303-A: To a solution of K101-C20Tr-B (30.00 mg, 50.78 ^mol, 1.00 eq) in DCM (2.00 mL) were added (2S)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid (C13-03) (26.95 mg, 101.57 ^mol, 2.00 eq), DMAP (24.82 mg, 203.13 ^mol, 4.00 eq) and EDC (19.47 mg, 101.57 ^mol, 2.00 eq). The mixture was stirred at 20°C for 48 hours to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The reaction mixture was quenched with saturated NaHCO3 (5 mL) and extracted with DCM (10 mL*3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1303-A (30.00 mg, 34.85 ^mol, 68.63% yield, 97.349% purity) as a white solid.

[0321] 1H NMR (400MHz, CDCl3) 8 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 2020352641   29 Jun 2026 (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).

[0322] Preparation of Compound K101-C1303: To a solution of K101-C20Tr-B (30.00 mg, 35.80 pmol, 1.00 eq) in DCM (1.00 mL) was added TFA (154.00 mg, 1.35 mmol, 100.00 uL, 37.73 eq) at 0°C. The mixture was stirred at 0°C for 2hr to give a red-brown solution. The mixture was stirred at 20°C for 14 hours to give a red-brown solution again. The reaction mixture was quenched with H2O (5 mL) and the organic layer was separated. The water layer was lyophilized. The organic layer was dissolved in MeOH (3.00 mL) and added HClO4 (83.00 mg, 826.20 gmol, 50.00 uL, 23.08 eq) at 0°C. The mixture was stirred at 0°C for 2 hours to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was purified by prep-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 ^mol, 19.27% yield, 93.438% purity, TFA salt) as a white solid.

[0323] LC-MS (m / z): 519.3 [M+H]+

[0324] 1H NMR (400MHz, CD3OD) 8 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). Example 2:    Synthesis Scheme of K101-C1304.

[0325] The scheme for synthesis of compound K101-C1304 is illustrated below. K101-C20Tr-B                            K101-C1304-A                           K101-C1304

[0326] Preparation of Compound K101-C1304-A. To a solution of K101-C20Tr-B (40.00 mg, 67.71 ^mol, 1.00 eq) in DCM (2.00 mL) were added 2-phenylacetic acid (C13-04) (11.06 mg, 81.25 ^mol, 10.24 uL, 1.20 eq), DMAP (33.09 mg, 270.84 ^mol, 4.00 eq) and EDC (25.96 mg, 135.42 ^mol, 2.00 eq). The mixture was stirred at 20°C for 12 hours to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The reaction mixture was combined with a second preparation of the compound, quenched with H2O (5 mL) and extracted with DCM (15 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1304-A (40.00 mg, 56.43 ^mol, 65.78% yield) as a white solid. 2020352641   29 Jun 2026

[0327] Preparation of Compound K101-C1304. To a solution of K101-C1304-A (40.00 mg, 56.43 pmol, 1.00 eq) in MeOH (3.00 mL) was added HClO4(83.00 mg, 826.14 pmol, 50.00 uL, 14.64 eq) at 0°C. The mixture was stirred at 0°C for 0.5hr to give a yellow solution. LC-MS showed the reaction was complete. The mixture was purified by prep-HPLC (column: Waters XSELECT C18 150 x 30mm x 5um; mobile phase: [A: water (0.1%TFA)-B: B: ACN]; B%: 33%-63%, 10 min) to give K101-C1304 (16.30 mg, 34.94 pmol, 61.91% yield) as a white solid.

[0328] LC-MS (m / z): 489.3 [M+Na]+

[0329] 1H NMR (400MHz, CD3OD) 8 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). Example 3:    Synthesis Scheme of K101-C1305.

[0330] The scheme for synthesis of compound K101-C1305 is illustrated below.

[0331] Preparation of Compound K101-C1305-A. To a solution of K101-C20Tr-B (45.00 mg, 76.17 ^mol, 1.00 eq) in DCM (2.00 mL) were added 2-tert-butoxycarbonyl-2-azaspiro [3.3] heptane-6-carboxylic acid (C13-05) (27.57 mg, 114.26 ^mol, 1.50 eq), DMAP (37.22 mg, 304.68 gmol, 4.00 eq), N,N-diisopropylethylamine (DIEA) (19.69 mg, 152.34 ^mol, 26.61 uL, 2.00 eq) and EDC (29.21 mg, 152.34 ^mol, 2.00 eq). The mixture was stirred at 20°C for 48 hours to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The reaction mixture was combined with a second preparation of the compound, quenched with saturated NaHCO3 (5 mL) and extracted with DCM (10 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C13050-A (70.00 mg, crude) as a white solid.

[0332] Preparation of Compound K101-C1305. To a solution of K101-C1305-A (70.00 mg, 85.99 ^mol, 1.00 eq) in DCM (1.00 mL) was added TFA (154.00 mg, 1.35 mmol, 100.00 uL, 15.71 eq) at 0°C. The mixture was stirred at 0°C for 2hr give a red-brown solution. The mixture was stirred at 20°C for 16 hours (hr). LC-MS showed that the desired product was no present. The reaction 2020352641   29 Jun 2026 mixture was quenched with H2O (5 mL) and the organic layer was separated. LC-MSThe organic layer was dissolved in MeOH (3.00 mL) followed by addition of HC1O4 (83.00 mg, 826.20 pmol, 50.00 uL, 9.61 eq) at 0°C. The mixture was stirred at 0°C for 2hr to give a yellow solution. LC-MS showed the reaction was completecomplete. The mixture was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 10%-40%, 10min) to give K101-C1305 (11.80 mg, 20.15 pmol, 23.43% yield, TFA) as a yellow solid.

[0333] LC-MS (m / z): 494.2 [M+Na]+

[0334] 1H NMR (400MHz, CD3OD) 8 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). Example 4:    Synthesis Scheme of K101-C1306.

[0335] The scheme for synthesis of compound K101-C1306 is illustrated below. K101-C1306

[0336] Preparation of Compound K101-C1306-A. To a solution of K101-C20Tr-B (40.00 mg, 67.71 pmol, 1.00 eq) in DCM (2.00 mL) were added 2-(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan-6-yl)acetic acid (25.93 mg, 101.56 ^mol, 1.50 eq), DMAP (33.09 mg, 270.84 ^mol, 4.00 eq), DIEA (26.25 mg, 203.13 pmol, 35.47 uL, 3.00 eq) and EDC (25.96 mg, 135.42 pmol, 2.00 eq). The mixture was stirred at 20°C for 16hr to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was completecomplete. The mixture was combined with a 2020352641   29 Jun 2026 second preparation of the compound, quenched with Saturated NaHCO3 (5 mL) and extracted with DCM (10 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1306-A (40.00 mg, 47.90 p.mol, 70.74% yield, 99.157% purity) as a white solid.

[0337] Preparation of compound K101-C1312. To a solution of K101-C1306-A (10.00 mg, 12.08 pmol, 1.00 eq) in MeOH (3.00 mL) was added HClO4 (83.00 mg, 826.20 p.mol, 50.00 uL, 68.39 eq) at 0°C, and the mixture stirred at 0°C for 0.5hr. The mixture was stirred at 20°C for an additional 15.5 hr. LC-MS showed the reaction was completecomplete. The mixture was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 x 30 x 5um; mobile phase: [A: water (0.05% ammonia hydroxide v / v)-B: ACN]; B%: 45%-75%, 10min) to give K101-C1306-A (3.80 mg, 6.49 pmol, 53.71% yield) as a white solid.

[0338] LC-MS (m / z): 608.2 [M+Na]+

[0339] 1H NMR (400MHz, CD3OD) 8 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), 1.761.46 (m, 1H), 1.44(s, 9H), 1.18 (s, 3H), 1.08 (s, 3H), 0.93-0.86 (m, 4H).

[0340] Preparation of compound K101-C1306. To a solution of K101-C1312 (15.00 mg, 25.61 ^mol, 1.00 eq) in THF (500.00 uL) was added TFA (288.72 mg, 2.53 mmol, 187.48 uL, 98.88 eq), and the mixture stirred at 20°C for 4hr to give a colorless solution. LC-MS showed the reaction was completecomplete, but mass of P2 was found. The reaction mixture was concentrated byN2, and the resultant product dissolved in MeOH (500.00 uL) / H2O (50.00 uL). The mixture was stirred at 20°C for 14hr to give a colorless solution. LC-MS showed the reaction was completecomplete. The mixture was combined with a second preparation of the compound and concentrated byN2 to give the desired product. The product was lyophilized to give K101-C1306 (4.20 mg, 7.00 ^mol, 25.80% yield, TFA) as a yellow gum. The product (13.4 mg) was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [water (0.1%TFA)-ACN]; B%: 20%-50%, 10min) to give K101-C1306 (4.20 mg, 7.00 ^mol, 25.80% yield, TFA) as a white solid.

[0341] LC-MS (m / z): 508.2 [M+Na]+

[0342] 1H NMR (400MHz, CD3OD) 8 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). Example 5:    Synthesis Scheme of K101-C1311.

[0343] The scheme for synthesis of compound K101-C1311 is illustrated below. 2020352641   29 Jun 2026 de-protection K101-C1311

[0344] Preparation of Compound K101-C1311. To a solution of K101-C1305-A (22.00 mg, 27.03 ggmol, 1.00 eq) in MeOH (3.00 mL) was added HClO4 (26.09 mg, 259.73 gmol, 15.72 uL, 9.61 eq) at 0°C, and the mixture stirred at 0°C for 1hr. LC-MS showed the reaction was complete. The mixture was purified by prep-HPLC (column: Waters Xbridge 150 x 25 x 5u; mobile phase: [A: water (0.05% ammonia hydroxide v / v)-B: ACN]; B%: 40%-70%, 10min) to give K101-C1311 (3.30 mg, 5.77 ^mol, 21.36% yield, 100% purity) as a yellow solid.

[0345] LC-MS (m / z): 594.3 [M+Na]+

[0346] 1H NMR (400MHz, CD3OD) 8 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). Example 6:    Synthesis Scheme of K101-C1312.

[0347] The scheme for synthesis of compound K101-C1312 is illustrated below. K101-C1306-A                              K101-C1312

[0348] Preparation of compound K101-C1312. To a solution of K101-C1306-A (10.00 mg, 12.08 ^mol, 1.00 eq) in MeOH (3.00 mL) was added HClO4 (83.00 mg, 826.20 ^mol, 50.00 uL, 68.39 eq) at 0°C, and the mixture stirred at 0°C for 0.5 hr. The mixture was stirred at 20°C for an additional 15.5 2020352641   29 Jun 2026 hr to give a yellow solution. LC-MS showed the reaction was complete. The mixture was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 x 30 x 5u; mobile phase: [A: water (0.05% ammonia hydroxide v / v)-B: ACN]; B%: 45%-75%, 10 min) to give K101-C1306-A (3.80 mg, 6.49 pmol, 53.71% yield) as a white solid.

[0349] LC-MS (m / z): 608.2 [M+Na]+

[0350] 1H NMR (400MHz, CD3OD) 8 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), 1.761.46 (m, 1H), 1.44 (s, 9H), 1.18 (s, 3H), 1.08 (s, 3H), 0.93-0.86 (m, 4H). Example 7:    Synthesis Scheme of K101-C1313.

[0351] The scheme for synthesis of compound K101-C1313 is illustrated below.

[0352] Preparation of Compound K101-C1313-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DMF (2.00 mL) were added (E)-3-[4-(trifluoromethyl)phenyl]prop-2-enoic acid(C13-13) (21.95 mg, 101.56 ^mol, 2.00 eq), DIEA (19.69 mg, 152.34 ^mol, 26.61 uL, 3.00 eq), DMAP (24.82 mg, 203.12 ^mol, 4.00 eq) and Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium (HATU) (38.62 mg, 101.56 pmol , 2.00 eq). The mixture was stirred at 20°C for 14 hr to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc =2 / 1) showed the reaction was complete. The mixture was quenched with saturated NaHCO3 (5 mL) and extracted with methyl-tert-butyl ether (MTBE) (15 mL x 3). The organic layers were washed with (H2O), dried over Na2SO4 and then concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1313-A (21.00 mg, 26.62 ^mol, 45.19% yield) as a white solid.

[0353] Preparation of compound K101-C1313. To a solution of K101-C1313-A (21.00 mg, 26.62 ^mol, 1.00 eq) in MeOH (3.00 mL) was added HClO4 (83.00 mg, 826.28 ^mol, 50.00 uL, 31.04 eq) at 0°C. The mixture was stirred at 0°C for 1hr to give a yellow solution. LC-MS showed the reaction 2020352641   29 Jun 2026 was complete. The mixture was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 55%-85%, 10min) to give K101-C1313 (4.40 mg, 6.10 p.mol, 22.90% yield, 91.518% purity, TFA) as a yellow solid.

[0354] LC-MS (m / z): 569.1 [M+Na]+

[0355] 1H NMR (400MHz, CD3OD) 8 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). Example 8:    Synthesis Scheme of K101-C1315.

[0356] The scheme for synthesis of compound K101-C1315 is illustrated below.

[0357] Preparation of Compound K101-C1315-A. To a solution of K101-C20Tr-B (20.00 mg, 33.86 ^mol, 1.00 eq) and C13-15 (15.35 mg, 101.58 ^mol, 3.00 eq) in DCM (1.00 mL) was added EDC (19.47 mg, 101.58 pmol, 3.00 eq) and DMAP (20.68 mg, 169.30 gmol, 5.00 eq). The reaction solution was stirred at 25 °C for 3 hours to give a brown solution. LC-MS showed the reaction was complete. The reaction solution was diluted with DCM (5 mL), washed with brine (2 mL), dried over anhydrous Na2SO4, filtered, and the 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.

[0358] Preparation of compound K101-C1315. To a solution of K101-C1315-A (25.00 mg, crude) in MeOH (1.00 mL) was added HClO4 (30.00 uL) at 25 °C. The reaction solution was stirred at 25 °C for 0.5 hour to give a brown solution. LC-MS showed the reaction was complete. The reaction solution was quenched by adding K2CO3 (34 mg) in water (1 mL) dropwise at 0 °C to adjust the pH to 9. The mixture was filtered and the filtrate purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 15%-45%, 10min) to give K101-C1315 (3.60 mg, 97% purity, TFA salt) as a white solid after lyophilization.

[0359] LC-MS (m / z): 504.2 [M+Na]+ 2020352641   29 Jun 2026

[0360] 1H NMR (400MHz, CD3OD) 8 = 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). Example 9:    Synthesis Scheme of K101-C1316.

[0361] The scheme for synthesis of compound K101-C1316 is illustrated below. K101-C20Tr-B

[0362] Preparation of Compound K101-C1316-A. To a solution of K101-C20Tr-B (40.00 mg, 67.71 p.mol, 1.00 eq) in DCM (2.00 mL) were added C13-16 (51.18 mg, 338.55 jumol, 5.00 eq), DMAP (33.09 mg, 270.84 pmol, 4.00 eq), hydroxybenzotriazole (HOBt) (18.30 mg, 135.42 jumol, 2.00 eq) and EDC (25.96 mg, 135.42 ^mol, 2.00 eq). The mixture was stirred at 20°C for 12h to give a black solution. LC-MS showed 43.779% of the desired mass, with 16.864% of reactant remaining. The mixture was quenched with saturated NaHCO3 (10 mL) and extracted with DCM (15 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1316-A (27.00 mg, 37.30 ^mol, 48.97% yield) as a white solid.

[0363] Preparation of Compound K101-C1316. To a solution of K101-C1316-A (27.00 mg, 37.30 ^mol, 1.00 eq) in MeOH (2.00 mL) was added HClO4 (83.00 mg, 826.20 ^mol, 50.00 uL, 22.15 eq) at 0°C. The mixture was stirred at 0°C for 0.5 hr to give a yellow solution. LC-MS showed the reaction was complete. The mixture was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 20%-50%, 10min) to give K101-C1316 (11.40 mg, 18.81 jumol, 50.43% yield, 98.3% purity, TFA salt) as a white solid.

[0364] LC-MS (m / z): 504.2 [M+Na]+

[0365] 1H NMR (400MHz, CD3OD) 8 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), 2.152.03 (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). 2020352641   29 Jun 2026 Example 10:   Synthesis Scheme of K101-C1317.

[0366] The scheme for synthesis of compound K101-C1317 is illustrated below.

[0367] Preparation of Compound K101-C1317-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DCM (1.00 mL) were added (2S)-2-(tert-butoxycarbonylamino) hexanoic acid (C13-17) (23.49 mg, 101.57 ^mol, 2.00 eq), DMAP (24.82 mg, 203.13 ^mol, 4.00 eq) and EDC (19.47 mg, 101.57 ^mol, 2.00 eq). The mixture was stirred at 20°C for 5 h to give a colorless solution. LC-MS and TLC showed the reaction was complete. The mixture was quenched with H2O (15 mL) and extracted with DCM (15 mL x 5). The organic layers were dried over Na2SO4 and concentrated to give a yellow solid. The product was purified by prep-TLC (eluting with Petroleum ether: Ethyl acetate = 5 / 1) to give K101-C1317-A (35.00 mg, 43.53 ^mol, 85.73% yield) as a white solid.

[0368] Preparation of Compound K101-C1317. To a solution of K101-C1317-A (46.00 mg, 57.21 ^mol, 1.00 eq) in THF (2.00 mL) were added TFA (6.52 mg, 57.21 ^mol, 4.23 uL, 1.00 eq) and Et3SiH (6.65 mg, 57.21 ^mol, 9.11 uL, 1.00 eq). The mixture was stirred at 20°C for 2 h to give a colorless solution, which was concentrated to give yellow oil. TFA (1 mL) was added to the yellow oil in DCM (2 mL), and the mixture stirred at 20°C for 0.5h. LC-MS showed the reaction was complete. The reaction mixture was concentrated, dissolved with 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 prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; 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 ^mol, 21.26% yield, 100% purity, TFA) as a white solid.

[0369] LC-MS (m / z): 584.2 [M+Na]+

[0370] 1H NMR (400MHz, MeOD) 8 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). 2020352641   29 Jun 2026 Example 11:   Synthesis Scheme of K101-C1318.

[0371] The scheme for synthesis of compound K101-C1318 is illustrated below.

[0372] Preparation of Compound K101-C1318-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DCM (2.00 mL) were added (2S)-2-(tert-butoxycarbonylamino)-4-phenyl-butanoic acid (C13-18) (28.37 mg, 101.56 pmol, 2.00 eq), DMAP (24.82 mg, 203.12 pmol, 4.00 eq) and EDC (19.47 mg, 101.56 pmol, 2.00 eq). The mixture was stirred at 20°C for 12hr to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The reaction mixture combined a second preparation of the compound, the mixture quenched with H2O (10 mL) and then extracted with DCM (15 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1318-A (32.00 mg, 37.56 pmol, 63.38% yield) as a white solid.

[0373] Preparation of Compound K101-C1318. To a solution of K101-C1318-A (30.00 mg, 35.21 pmol, 1.00 eq) in THF (2.00 mL) were added TFA (308.00 mg, 2.70 mmol, 200.00 uL, 76.72 eq) and Et3SiH (4.91 mg, 42.25 pmol, 6.73 uL, 1.20 eq). The mixture was stirred at 20°C for 4hr to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated byN2, and the resultant residue dissolved in MeOH (20 mL). The mixture was stirred at 20°C for 12 hr. LC-MS showed the reaction was complete. The mixture was concentrated to give the crude product. The product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 23%-53%, 10 min) to give K101-C1318 (10.80 mg, 17.24 pmol, 48.98% yield, 99.58% purity, TFA) as a white solid.

[0374] LC-MS (m / z): 532.1 [M+Na]+

[0375] 1H NMR (400MHz, CD3OD) 8 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). Example 12:   Synthesis Scheme of K101-C1319. 2020352641   29 Jun 2026

[0376] The scheme for synthesis of compound K101-C1319 is illustrated below.

[0377] Preparation of compound K101-C1319-A. To a solution of K101-C20Tr-B (200.00 mg, 338.55 pmol, 1.00 eq) and C13-19 (119.18 mg, 406.26 pmol, 1.20 eq) in anhydrous DCM (2.00 mL) were added EDC (194.70 mg, 1.02 mmol, 3.00 eq) and DMAP (124.08 mg, 1.02 mmol, 3.00 eq). The reaction solution was stirred at 20°C for 16 hours to give a light brown solution. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to give the crude product, and the product purified by silica gel column chromatography (PE / EtOAc=3 / 1) to give K101-C1319-A (273.50 mg, 315.79 ^mol, 93.28% yield) as a colorless gum.

[0378] Preparation of compound K101-C1319. To a solution of K101-C1319-A (273.00 mg, 315.21 ^mol, 1.00 eq) in MeOH (5.00 mL) was added HCl / MeOH (4 M, 5.00 mL, 63.45 eq) at 0°C. The reaction solution was stirred at 0°C for 3.5 h to give a clear solution. LC-MS showed the reaction was not complete, and thus the reaction solution was stirred at 20°C for 1.5 h. LC-MS showed the reaction was complete. The reaction solution was bubbled with N2 for 0.5 hour to remove HCl, and the residual solution cooled to 0°C and the solution adjusted to pH 7 with saturated aqueous NaHCO3. The mixture was extracted with DCM (10 mL x 2), and the combined extract dried over Na2SO4 and concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by prep-TLC (DCM / MeOH=10 / 1, SiO2) to give K101-C1319 (78.70 mg, 140.52 gmol, 44.58% yield, 93.5% purity) as a colorless gum. The product was lyophilized to give a white solid.

[0379] MS (m / z): 546.2 [M+Na]+

[0380] 1H NMR (400MHz, CD3OD) 8 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). Example 13:   Synthesis Scheme of K101-C1320.

[0381] The scheme for synthesis of compound K101-C1320 is illustrated below. 2020352641   29 Jun 2026

[0382] Preparation of Compound K101-C1320-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) and C13-20 (26.09 mg, 152.34 pmol, 3.00 eq) in DCM (2.00 mL) were added EDC (58.41 mg, 304.68 ^mol, 6.00 eq) and DMAP (37.22 mg, 304.68 ^mol, 6.00 eq). The reaction solution was stirred at 25 °C for 16 hours to give a brown solution. TLC (PE / EtOAc=2 / 1, SiO2) showed the reaction was complete. The reaction solutions were combined 5 mg of K101-C20Tr-B, diluted with DCM (5 mL), and washed with brine (2 mL). The extracted layers were dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by prep-TLC (PE / EtOAc=2 / 1) to give K101-C1320-A (27.30 mg, 72.26% yield) as a colorless gum.

[0383] Preparation of Compound K101-C1320. To a solution of K101-C1320-A (25.00 mg, 33.60 ^mol, 1.00 eq) in MeOH (1.00 mL) was added HClO4 (30.00 uL). The reaction solution was stirred at 25 °C for 0.5 hour to give a clear solution. LC-MS showed the reaction was complete. The product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 25%-55%, 10min) to give K101-C1320 (9.50 mg, 18.46 gmol, 54.95% yield, 97.5% purity) as a white powder after lyophilization.

[0384] LC-MS (m / z): 524.1 [M+Na]+

[0385] 1H NMR (400MHz, METHANOL-d^ 8 = 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), 2.562.47 (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). Example 14:   Synthesis Scheme of K101-C1321.

[0386] The scheme for synthesis of compound K101-C1321 is illustrated below. 2020352641   29 Jun 2026

[0387] Preparation of Compound K101-C1321-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) and C13-21 (76.68 mg, 304.68 pmol, 6.00 eq) in DCM (1.00 mL) were added EDC (58.41 mg, 304.68 ^mol, 6.00 eq) and DMAP (37.22 mg, 304.68 ^mol, 6.00 eq). The reaction solution was stirred at 25 °C for 2 hours to give a light brown solution. LC-MS shows improved conversion to product. The reaction solution was combined with a second preparation of the compound, and the mixture partitioned between water (2 mL) and DCM (2 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by prep-TLC (PE / EtOAc=3 / 2) to give K101-C1321-A (32.70 mg, 39.67 ^mol, 78.11% yield) as a colorless gum.

[0388] Preparation of Compound K101-C1321. To a solution of K101-C1321-A (32.70 mg, 39.67 ^mol, 1.00 eq) in MeOH (1.00 mL) was added HClO4 (30.00 uL) at 25 °C. The reaction solution was stirred at 25 °C for 0.5 hour to give a brown solution. LC-MS showed the reaction was complete. The reaction solution was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um;mobile phase: [A: water(0.1%TFA)-B: ACN]; B%: 50%-80%, 10min) to give K101-C1321 (12.50 mg, 52.08% yield, 96.2% purity) as a white solid after lyophilization.

[0389] LC-MS (m / z): 604.1 [M+Na]+

[0390] 1H NMR (400MHz, CD3OD) 8 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), 2.552.47 (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). Example 15:   Synthesis Scheme of K101-C1322.

[0391] The scheme for synthesis of compound K101-C1322 is illustrated below.

[0392] Preparation of Compound K101-C1322-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ^mol, 1.00 eq) in DCM (2.00 mL) were added 3-(1H-pyrrolo [2, 3-b] pyridin-3-yl)propanoic acid (C13-22) (19.32 mg, 101.56 ^mol, 2.00 eq), DMAP (24.82 mg, 203.12 ^mol, 4.00 eq), HOBt (13.72 mg, 101.56 ^mol, 2.00 eq) and EDC (19.47 mg, 101.56 ^mol, 2.00 eq). The mixture was stirred at 20°C for 12h to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=1 / 1) showed the reaction was complete. The mixture was quenched with H2O (5 mL) and extracted with 2020352641   29 Jun 2026 DCM (15 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=1 / 1) to give K101-C1322-A (30.00 mg, 39.32 p.mol, 58.22% yield) as a white solid.

[0393] Preparation of Compound K101-C1322. To a solution of K101-C1322-A (30.00 mg, 39.32 pmol, 1.00 eq) in MeOH (2.00 mL) was added HClO4 (83.00 mg, 826.11 pmol, 50.00 uL, 21.01 eq) at 0°C. The mixture was stirred at 0°C for 0.5h to give a yellow solution. LC-MS showed the reaction was complete. The product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 22%-52%, 10min) to give K101-C1322 (17.40 mg, 27.42 ^mol, 69.73% yield, TFA salt) as a yellow solid.

[0394] LC-MS (m / z): 543.1 [M+Na]+

[0395] 1H NMR (400MHz, CD3OD) 88.19-8.18 (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), 2.782.73 (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). Example 16:   Synthesis Scheme of K101-C1323.

[0396] The scheme for synthesis of compound K101-C1323 is illustrated below.

[0397] Preparation of compound K101-C1323-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ^mol, 1.00 eq) and C13-23 (23.49 mg, 152.34 ^mol, 3.00 eq) in DCM (1.00 mL) were added EDC (58.41 mg, 304.68 ^mol, 6.00 eq) and DMAP (37.22 mg, 304.68 ^mol, 6.00 eq). The reaction solution was stirred at 25°C for 2 h to give a brown solution. TLC (PE / EtOAc=1 / 1, SiO2) showed the reaction was complete. The reaction solution was combined with a second preparation of 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 then concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by prep-TLC (PE / EtOAc=1 / 1) to give 32.5 mg of K101-C1323-A as a colorless gum.

[0398] Preparation of Compound K101-C1323. To a solution of K101-C1323-A (32.00 mg, 44.02 ^mol, 1.00 eq) in MeOH (1.00 mL) was added HQO4 (30.00 uL) at 25°C. The reaction solution was stirred at 25°C for 0.5 hour to give a clear solution. LC-MS showed the reaction was complete. The 2020352641   29 Jun 2026 reaction solution was directly purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25%-55%, 10min) to give K101-C1323 (9.10 mg, 40.48% yield, 94.9% purity) as a white solid.

[0399] LC-MS (m / z): 507.2 [M+Na]+

[0400] 1H NMR (400MHz, CD3OD ) 8 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), 2.632.57 (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). Example 17:   Synthesis Scheme of K101-C1324.

[0401] The scheme for synthesis of compound K101-C1324 is illustrated below.

[0402] Preparation of Compound K101-C1324-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) and C13-24 (25.01 mg, 152.34 pmol, 3.00 eq) in DCM (1.00 mL) were added EDC (58.41 mg, 304.68 ^mol, 6.00 eq) and DMAP (37.22 mg, 304.68 ^mol, 6.00 eq). The reaction solution was stirred at 25 °C for 2h to give a brown solution. TLC (PE / EtOAc=2 / 1, SiO2) showed the reaction was complete. The reaction solution was diluted with DCM (2 mL), washed with water (1 mL), brine (1 mL), and dried over anhydrous Na2SO4. The mixture was filtered and then concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by silica gel column chromatography (eluting with PE / EtOAc=5 / 1) to give K101-C1324-A (37.20 mg, 99.41% yield) as a colorless gum.

[0403] Preparation of Compound K101-C1324. To a solution of K101-C1324-A (37.20 mg, 50.48 pmol, 1.00 eq) in MeOH (1.00 mL) was added HClO4 (30.00 uL), and the reaction solution stirred at 25 °C for 1 hour to give a clear solution. LC-MS showed the reaction was complete. The product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 55%-85%, 10min) to give K101-C1324 (7.80 mg, 30.40% yield, 97.3% purity) as a white solid after lyophilization.

[0404] LC-MS (m / z): 517.2 [M+Na]+ 2020352641   29 Jun 2026

[0405] 1H NMR (400MHz, CD3OD) 8 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). Example 18:   Synthesis Scheme of K101-C1325.

[0406] The scheme for synthesis of compound K101-C1325 is illustrated below.

[0407] Preparation of Compound K101-C1325-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DCM (5.00 mL) were added (2S)-2-(tert-butoxycarbonylamino)-3-cyclobutyl-propanoic acid (C13-25) (24.71 mg, 101.56 pmol, 2.00 eq), DMAP (24.82 mg, 203.12 ^mol, 4.00 eq), HOBT (13.72 mg, 101.56 pmol, 2.00 eq) and EDC (19.47 mg, 101.56 pmol, 2.00 eq). The mixture was stirred at 20°C for 14h to give a yellow solution. LC-MS and TLC showed the reaction was complete. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM (15 mL x 5). The organic layers were dried over Na2SO4 and concentrated to give a yellow solid. The product was purified by prep-TLC (eluting with Petroleum ether: Ethyl acetate = 7 / 2) to give K101-C1325-A (33.50 mg, 41.05 pmol, 69.09% yield) as a white solid.

[0408] Preparation of Compound K101-C1325. To a solution of K101-C1325-A (33.50 mg, 41.05 pmol, 1.00 eq) in DMF (20.00 mL) in THF (2.00 mL) were added TFA (1.54 g, 13.51 mmol, 1.00 mL, 329.02 eq) and Et3SiH (4.77 mg, 41.05 ^mol, 6.53 uL, 1.00 eq). The mixture was stirred at 20°C for 5h to give a colorless solution, which was concentrated to give a yellow oil. The oil was dissolved with DCM (2 mL) followed by addition of TFA (0.5 mL). The mixture was stirred at 20°C for 1h 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 prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 20%-50%, 10min). The separated products were lyophilized to give K101-C1325 (10.00 mg, 17.02 pmol, 41.46% yield, 94.5% purity, TFA) as a white solid.

[0409] LC-MS (m / z): 596.2 [M+Na]+ 2020352641   29 Jun 2026

[0410] 1H NMR (400MHz, MeOH) 8 = 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 19:   Synthesis Scheme of K101-C1326.

[0411] The scheme for synthesis of compound K101-C1326 is illustrated below.

[0412] Preparation of Compound K101-C1326-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DCM (5.00 mL) were added (2S)-2-(tert-butoxycarbonylamino)-4-methylsulfonyl-butanoic acid (C13-26) (30.00 mg, 106.64 pmol, 2.10 eq), DMAP (30.00 mg, 245.78 ^mol, 4.84 eq), EDC (19.96 mg, 104.10 gmol, 2.05 eq), and HOBt (14.00 mg, 103.59 pmol, 2.04 eq). The mixture was stirred at 20°C for 19h to give a colorless solution. LC-MS and TLC showed the reaction was complete. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM (15 mL x 5). The organic layers were dried over Na2SO4 and concentrated to give a yellow oil. The product was purified by prep-TLC (eluting with Petroleum ether: Ethyl acetate = 3 / 2) to give K101-C1326-A (23.00 mg, 26.93 pmol, 53.03% yield, crude product) as a colorless solid.

[0413] Preparation of compound K101-C1326. To a solution of K101-C1326-A (25.00 mg, 29.27 pmol, 1.00 eq) in THF (2.00 mL) were added TFA (3.34 mg, 29.27 pmol, 2.17 uL, 1.00 eq) and Et3SiH (3.40 mg, 29.27 pmol, 4.66 uL, 1.00 eq). The mixture was stirred at 20°C for 3h to give a colorless solution. LC-MS showed some of the K101-C1326-A remained. Accordingly, the reaction mixture was concentrated to give a yellow oil, which was then dissolved with DCM (2 mL) followed by the addition of TFA (2 mL). The mixture was stirred at 20°C for 2h to give a colorless solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated to give a yellow oil, which was then purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 10%-40%, 10min). The separated layers were lyophilized to give K101-C1326 (4.20 mg, 6.04 pmol, 20.64% yield, 90% purity, TFA) as a yellow solid.

[0414] LC-MS (m / z): 534.1 [M+Na]+ 2020352641   29 Jun 2026

[0415] 1H NMR (400MHz, MeOD) 8 = 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). Example 20:   Synthesis Scheme of K101-C1327.

[0416] The scheme for synthesis of compound K101-C1327 is illustrated below.

[0417] Preparation of Compound K101-C1327-A. To a solution of K101-C20Tr-B (200.00 mg, 338.55 pmol, 1.00 eq) in DCM (2.00 mL) were added C13-27 (367.46 mg, 1.35 mmol, 4.00 eq), DMAP (330.89 mg, 2.71 mmol, 8.00 eq), HOBt (91.49 mg, 677.11 ^mol, 2.00 eq) and EDC (259.60 mg, 1.35 mmol, 4.00 eq). The mixture was stirred at 20°C for 12h to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The mixture was quenched with H2O (15 mL) and extracted with DCM (30 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1327-A (180.00 mg, 213.25 gmol, 62.99% yield) as a white solid.

[0418] Preparation of Compound K101-C1327. To a solution of K101-C1327-A (180.00 mg, 213.25 ^mol, 1.00 eq) in THF (3.00 mL) were added TFA (3.08 g, 27.01 mmol, 2.00 mL, 126.67 eq) and Et3SiH (49.59 mg, 426.50 ^mol, 67.93 uL, 2.00 eq). The mixture was stirred at 20°C for 24h to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated byN2, and the resultant residue dissolved in MeOH (20 mL) and then stirred at 20°C for 70h. 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 x 3) to give the desired product. The product was dissolved in saturated NaHCO3 (20 mL) and extracted with DCM (30 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the free desired product, which was then lyophilized to give K101-C1327 (70.00 mg, 136.05 jumol, 63.80% yield, 97.5% purity) as a white solid. 2020352641   29 Jun 2026

[0419] LC-MS (m / z): 524.2 [M+Na]+

[0420] 1H NMR (400MHz, CD3OD) 8 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), 1.731.60 (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).

[0421] Second Procedure for Preparation of Compound K101-C1327-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ^mol, 1.00 eq) in DCM (2.00 mL) were added (2S)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-propanoic acid (C13-27) (27.56 mg, 101.56 pmol, 2.00 eq), DMAP (24.82 mg, 203.12 pmol, 4.00 eq) and EDC (19.47 mg, 101.56 pmol, 2.00 eq). The mixture was stirred at 20°C for 12hr to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The mixture was quenched with H2O (10 mL) and extracted with DCM (15 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1327-A (24.00 mg, 28.43 ^mol, 47.97% yield) as a white solid.

[0422] Second Procedure for Preparation of Compound K101-C1327. To a solution of K101-C1327-A (24.00 mg, 28.43 pmol, 1.00 eq) in THF (2.00 mL) were added TFA (308.00 mg, 2.70 mmol, 200.00 uL, 95.02 eq) and Et3SiH (3.97 mg, 34.12 pmol, 5.43 uL, 1.20 eq). The mixture was stirred at 20°C for 4hr to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated byN2, and the resultant residue dissolved in MeOH (20 mL). The mixture was stirred at 20°C for 12hr. LC-MS showed the reaction was complete. The mixture was concentrated to give the crude product. The product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 25%-55%, 10min) to give K101-C1327 (5.10 mg, 7.95 gmol, 27.97% yield, 95.99% purity, TFA) as a white solid.

[0423] LC-MS (m / z): 524.2 [M+Na]+

[0424] 1H NMR (400MHz, CD3OD) 8 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). Example 21:   Synthesis Scheme of K101-C1328.

[0425] The scheme for synthesis of compound K101-C1328 is illustrated below. 2020352641   29 Jun 2026 K101-C20Tr-B K101-C1328-A K101-C1328

[0426] Preparation of Compound K101-C1328-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DCM (2.00 mL) were added (2S)-2-(tert-butoxycarbonylamino)-4, 4-dimethyl-pentanoic acid (C13-28) (24.92 mg, 101.56 ^mol, 2.00 eq), DMAP (24.82 mg, 203.12 pmol, 4.00 eq), HOBt (13.72 mg, 101.56 pmol, 2.00 eq) and EDC (19.47 mg, 101.56 gmol, 2.00 eq). The mixture was stirred at 20°C for 12h to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The mixture was quenched with H2O (10 mL) and extracted with DCM (15 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1328-A (28.00 mg, 34.23 ^mol, 67.40% yield) as a white solid.

[0427] Preparation of Compound K101-C1328. To a solution of K101-C1328-A (28.00 mg, 34.23 ^mol, 1.00 eq) in THF (2.00 mL) were added TFA (770.00 mg, 6.75 mmol, 500.00 uL, 197.29 eq) and Et3SiH (7.96 mg, 68.46 ^mol, 10.90 uL, 2.00 eq). The mixture was stirred at 20°C for 12h to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated byN2 and the resultant product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 30%-70%, 10min) to give K101-C1328 (9.50 mg, 15.88 ^mol, 46.38% yield, 98.54% purity, TFA) as a white solid.

[0428] LC-MS (m / z): 498.2 [M+Na]+

[0429] 1H NMR (400MHz, CD3OD) 8 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), 2.052.00 (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). Example 22:   Synthesis Scheme of K101-C1329.

[0430] The scheme for synthesis of compound K101-C1329 is illustrated below. 2020352641   29 Jun 2026

[0431] Preparation of Compound K101-C1329-A. To a solution of K101-C20Tr-B (20.00 mg, 33.86 pmol, 1.00 eq) and C13-29 (14.80 mg, 50.79 pmol, 1.50 eq) in DCM (2.00 mL) were added EDC (38.95 mg, 203.16 pmol, 6.00 eq) and DMAP (24.82 mg, 203.16 pmol, 6.00 eq). The reaction solution was stirred at 25 °C for 16 hours to give a brown solution. LC-MS showed the reaction was complete. The reaction solution was diluted with DCM (10 mL), then washed with water (3 mL), 0.5 M HCl (2 mL), brine (2 mL), and dried over anhydrous Na2SO4. The product was filtered and then concentrated under reduced pressure to give crude K101-C1329-A. The crude K101-C1329-A was purified by prep-TLC (PE / EtOAc=3 / 1, SiO2) to give 15.7 mg of K101-C1329-A as a colorless gum.

[0432] Preparation of Compound K101-C1329. To a solution of K101-C1329-A (15.70 mg, 18.17 pmol, 1.00 eq) in dioxane (400.00 pL) was added HCl / dioxane (4 M, 200.46 pL, 44.13 eq). The reaction mixture was stirred at 25 °C for 2 hours to give a light brown solution. LC-MS showed the reaction was not complete so the reaction solution was stirred at 25 °C for an additional 1 hour and then for an additional 16 hours. LC-MS showed the reaction was complete. A byproduct was also detected by the LC-MS analysis. The reaction solution was diluted with CH3CN (1mL) and the solution adjusted with K2CO3 (55 mg) in water (0.5 mL) to basic conditions. The product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 30%-60%, 10min) to give K101-C1329 (2.00 mg, 3.62 pmol, 19.92% yield, 94.4% purity) and K101-C1329-Cl (2.70 mg, 4.47 pmol, 24.60% yield, 92.4% purity), both as white solids after lyophilization.

[0433] K101-C1329 MS (m / z): 544.1 [M+Na]+

[0434] K101-C1329 1H NMR (400MHz, CD3OD) 8 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).

[0435] K101-C1329-Cl LC-MS (m / z): 562.1 [M+Na]+

[0436] K101-C1329-Cl 1H NMR (400MHz, CD3OD) 8 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 2020352641   29 Jun 2026 (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). Example 23:   Synthesis Scheme of K101-C1330.

[0437] The scheme for synthesis of compound K101-C1330 is illustrated below.

[0438] Preparation of Compound K101-C1330-A. To a solution of K101-C20Tr-B (20.00 mg, 33.86 pmol, 1.00 eq) and C13-30 (46.57 mg, 203.16 pmol, 6.00 eq) in DCM (2.00 mL) were added EDC (38.94 mg, 203.16 ^mol, 6.00 eq) and DMAP (24.82 mg, 203.16 ^mol, 6.00 eq). The reaction solution was stirred at 25 °C for 16 hours to give a brown solution. LC-MS showed the reaction was complete. The reaction solution was diluted with DCM (10 mL), then washed with water (3 mL), 0.5 M HCl (2 mL), brine (2 mL), and dried over anhydrous Na2SO4. The product was filtered and concentrated under reduced pressure to give the crude product. The product was purified by prep-TLC (PE / EtOAc=3 / 1, SiO2) to give 16.2 mg of K101-C1330-A as a colorless gum.

[0439] Preparation of Compound K101-C1330. To a solution of K101-C1330-A (10.00 mg, 12.47 ^mol, 1.00 eq) in dioxane (400.00 uL) was added HCl / dioxane (4 M, 200.17 uL, 64.21 eq). The reaction mixture was stirred at 25 °C for 2 hours to give a light brown solution. LC-MS showed the reaction was not complete so 0.2 mL of HCl / dioxane (4 M) was added and the reaction solution stirred at 25 °C for an additional 1 hour. LC-MS showed the reaction was almost complete. The reaction solution was combined with another preparation of K101-C1330-A and concentrated under reduced pressure. The residue was diluted with CH3CN (1mL) and water (1 mL) and the solution adjusted to pH 8 with addition of solid K2CO3 (5 mg). The product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1% TFA)-B: ACN]; B%: 25%-55%, 10min) to give K101-C1330 (4.70 mg, 65.05% yield, 99.0% purity, TFA salt) as a white powder after lyophilization.

[0440] MS (m / z): 482.1 [M+Na]+

[0441] 1H NMR (400MHz, CD3OD) 8 7.55 (s, 1H), 5.64-5.59 (m, 1H), 4.12 (dd, J=5.3, 7.8 Hz, 1H), 4.00-3.90 (m, 2H), 3.19-3.14 (m, 1H), 3.09-3.03 (m, 1H), 2.58-2.48 (m, 1H), 2.45-2.37 (m, 1H), 2.25 (dd, J=6.8, 14.6 Hz, 1H), 2.12-2.01 (m, 1H), 1.95-1.85 (m, 1H), 1.80-1.70 (m, 4H), 1.61 (dd, J=10.4, 2020352641   29 Jun 2026 14.7 Hz, 1H), 1.18 (s, 3H), 1.09 (s, 3H), 1.02-0.97 (m, 1H), 0.93 (d, J=6.8 Hz, 3H), 0.8-0.76 (m, 1H), 0.66-0.59 (m, 2H), 0.27-0.17 (m, 2H). Example 24:   Synthesis Scheme of K101-C1331.

[0442] The scheme for synthesis of compound K101-C1331 is illustrated below. o K101-C20Tr-B                           K101-C1331-A                               K101-C1331

[0443] Preparation of Compound K101-C1331-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DCM (2.00 mL) were added (E,2S)-2-(tert-butoxycarbonylamino)-5-phenyl-pent-4-enoic acid (C13-31) (29.59 mg, 101.56 pmol, 2.00 eq), DMAP (24.82 mg, 203.12 pmol, 4.00 eq), HOBt (13.72 mg, 101.56 pmol, 2.00 eq) and EDC (19.47 mg, 101.56 pmol, 2.00 eq). The mixture was stirred at 20°C for 12h to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The mixture was combined with a second preparation of K101-C1331-A and the mixture quenched with H2O (10 mL) and then extracted with DCM (15 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1331-A (32.00 mg, 37.03 pmol, 62.49% yield) as a white solid.

[0444] Preparation of Compound K101-C1331. To a solution of K101-C1331-A (32.00 mg, 37.03 pmol, 1.00 eq) in THF (2.00 mL) were added TFA (770.00 mg, 6.75 mmol, 500.00 uL, 182.37 eq) and Et3SiH (8.61 mg, 74.06 pmol, 11.79 uL, 2.00 eq). The mixture was stirred at 20°C for 12h to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated byN2, and the product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 27%-57%, 10min) to give K101-C1331 (10.00 mg, 15.73 pmol, 42.48% yield, 100% purity, TFA salt) as a white solid.

[0445] LC-MS (m / z): 524.2 [M+Na]+

[0446] 1H NMR (400MHz, CD3OD) 8 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). Example 25:   Synthesis Scheme of K101-C1332. 2020352641   29 Jun 2026

[0447] The scheme for synthesis of compound K101-C1332 is illustrated below. K101-C20Tr-B K101-C1332-A K101-C1332

[0448] Preparation of Compound K101-C1332-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DCM (5.00 mL) were added (2S)-2-(tert-butoxycarbonylamino)-3-cyclopentyl-propanoic acid (C13-32) (26.14 mg, 101.56 pmol, 2.00 eq), DMAP (24.82 mg, 203.12 pmol, 4.00 eq) and EDC (19.47 mg, 101.56 ^mol, 2.00 eq). The mixture was stirred at 20°C for 5h to give a yellow solution. LC-MS showed the reaction was incomplete. Additional EDC (10mg) was added, and mixture stirred at 20°C for 14hr. LC-MS showed some of the K101-C20Tr-B still remained. A further amount of EDC (11 mg) was added, and the mixture stirred at 20°C for another 5hr. LC-MS and TLC showed the reaction was complete. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM (15 mL x 5). The organic layers were dried over Na2SO4 and concentrated to give a yellow solid. The product was purified by prep-TLC (eluting with Petroleum ether: Ethyl acetate = 7 / 2) to give K101-C1332-A (23.00 mg, 27.71 ^mol, 54.57% yield) as a colorless solid.

[0449] Preparation of Compound K101-C1332. To a solution of K101-C1332-A (23.00 mg, 27.71 ^mol, 1.00 eq) in THF (2.00 mL) were added Et3SiH (3.22 mg, 27.71 ^mol, 4.41 uL, 1.00 eq) and TFA (770.00 mg, 6.75 mmol, 500.00 uL, 243.71 eq). The mixture was stirred at 20°C for 1.5h to give a colorless solution. The reaction mixture was concentrated to give a yellow oil, which was dissolved in DCM (2 mL) followed by addition of TFA (0.5 mL). The mixture was stirred at 20°C for 1hr and concentrated to give a yellow oil. LC-MS showed the reaction was complete. The reaction mixture was concentrated, and the product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25 mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 30%-60%, 10min). The separated layers were lyophilized to give K101-C1332 (8.00 mg, 13.03 ^mol, 47.03% yield, 98% purity, TFA salt) as a white solid.

[0450] LC-MS (m / z): 510.2 [M+Na]+

[0451] 1H NMR (400MHz, CDCh) 8= 7.57 (s, 1H), 5.64 (d, J=4.5 Hz, 1H), 4.02 - 3.99 (m, 1H), 3.97 (s, 2H), 3.18 (s, 1H), 3.15-3.02 (m, 1H), 2.60 - 2.36 (m, 2H), 2.26 (dd, J=6.9, 14.7 Hz, 1H), 2.05 (dd, J=6.9, 13.2 Hz, 1H), 2.02 - 1.97 (m, 1H), 1.94-1.83 (m, 2H), 1.83 (t, J=7.8 Hz, 1H), 1.77 (d, J=1.5 2020352641   29 Jun 2026 Hz, 4H), 1.74 - 1.54 (m, 5H), 1.35 - 1.14 (m, 6H), 1.11 (s, 3H), 1.02 (d, J=6.0 Hz, 1H), 0.95 (d, J=6.5 Hz, 3H) Example 26:   Synthesis Scheme of K101-C1333.

[0452] The scheme for synthesis of compound K101-C1333 is illustrated below.

[0453] Preparation of Compound K101-C1333-A: To a solution of K101-C20Tr-B (22.00 mg, 37.24 pmol, 1.17 eq) and DHA (10.50 mg, 31.96 gmol, 1.00 eq) in DCM (500.00 uL) was added EDCI (36.77 mg, 191.79 p.mol, 6.00 eq) and DMAP (23.43 mg, 191.79 p.mol, 6.00 eq). The reaction solution was stirred at 20°C for 16 hours to give a brown solution. LCMS showed the desired MS value. The reaction mixture was combined with reaction mixture of ES5329-184 (5 mg of K101-C20Tr-B was used in this batch) and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EtOAc=5 / 1) to give K101-C1333-A (7.00 mg, 7.77 gmol, 24.30% yield) as a colorless oil.

[0454] 1H NMR (400MHz, CDCh) 8 7.58 (s, 1H), 7.46-7.38 (m, 6H), 7.31-7.26 (m, 6H), 7.24-7.18 (m, 3H), 5.60 (d, J=3.5 Hz, 1H), 5.42-5.27 (m, 12H), 3.51 (s, 2H), 3.31-3.25 (m, 1H), 2.96-2.90 (m, 1H), 2.90-2.67 (m, 10H), 2.57-2.47 (m, 1H), 2.44-2.30 (m, 5H), 2.13-1.91 (m, 7H), 1.77 (dd, J=1.1, 2.9 Hz, 3H), 1.59-1.51 (m, 1H), 1.19 (s, 3H), 1.07 (s, 3H), 0.97 (t, J=7.5 Hz, 3H), 0.87 (d, J=6.3 Hz, 3H), 0.79 (d, J=5.3 Hz, 1H).

[0455] Preparation of Compound K101-C1333: To a solution of K101-C1333-A (6.00 mg, 6.66 ^mol, 1.00 eq) in MeOH (200.00 uL) was added HClO4 (9.96 mg, 99.17 ^mol, 6.00 uL, 14.89 eq) and Et3SiH (774.15 ug, 6.66 ^mol, 1.06 uL, 1.00 eq). Then the reaction mixture was stirred at 0 °C for 1.5 hour to give a white suspension. TLC (DCM / MeOH=20 / 1, SiO2) showed no starting material remained and a new spot was observed. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EtOAc=1 / 1) to give K101-C1333 (3.65 mg, 79.85% yield, 96.0% purity) as a white solid after lyophilization.

[0456] MS (m / z): 681.3 [M+Na]+

[0457] 1H NMR (400MHz, CD3OD) 8 7.56-7.53 (m, 1H), 5.62-5.58 (m, 1H), 5.51-5.20 (m, 12H), 3.99-3.88 (m, 2H), 3.20-3.14 (m, 1H), 3.09-3.03 (m, 1H), 2.92-2.80 (m, 10H), 2.56-2.48 (m, 1H), 2.47-2.38 (m, 5H), 2.15-2.06 (m, 3H), 2.06-1.99 (m, 1H), 1.74 (dd, J=1.3, 2.9 Hz, 3H), 1.55 (dd, 2020352641   29 Jun 2026 J=10.7, 14.4 Hz, 1H), 1.18 (s, 3H), 1.07 (s, 3H), 0.97 (t, J=7.5 Hz, 3H), 0.90 (d, J=6.4 Hz, 4H), 0.86 (d, J=5.5 Hz, 1H). Example 27:   Synthesis Scheme of K101-C1334.

[0458] The scheme for synthesis of compound K101-C1334 is illustrated below. PH K101-C20Tr-B EDCI, DMAP DCM

[0459] Preparation of Compound K101-C1334-A: To a solution of K101-C20Tr-B (35.00 mg, 59.25 pmol, 1.00 eq) and C13-34 (136.45 mg, 592.47 pmol, 10.00 eq) in DCM (1.00 mL) was added EDCI (34.07 mg, 177.74 pmol, 3.00 eq) and DMAP (21.71 mg, 177.74 pmol, 3.00 eq), then the mixture was stirred at 20°C for 14 hours to give colorless solution. The reaction was complete detected by LCMS (ES6477-17-P1B). The reaction solution was diluted with H2O (10 ml), extracted with DCM: MeOH = 10:1 (10 ml * 5). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give crude product. The crude product purified by prep-TLC (SiO2, PE:EA = 2:1) to give K101-C1334-A (26.40 mg, 32.88 pmol, 55.49% yield) as a white solid.

[0460] K101-C1334-A 1H NMR (400MHz, CDCh) 8 7.59 (s, 1H), 7.44-7.39 (m, 6H), 7.31-7.27 (m, 5H), 7.24-7.18 (m, 3H), 5.61 (s, 1H), 5.30 (s, 1H), 3.50 (s, 2H), 3.27 ( s, 1H), 2.97-2.86 (m, 3H), 2.582.47 (m, 1H), 2.38 (d, J=18.8 Hz, 3H), 2.28 (t, J=7.4 Hz, 4H), 2.08-1.90 (m, 3H), 1.76 (s, 3H), 1.601.49 (m, 3H), 1.25 (s, 16H), 1.20-1.16 (m, 1H), 1.18 (s, 3H), 1.06 (s, 3H), 0.92-0.75 (m, 5H).

[0461] Preparation of Compound K101-C1334: To a solution of K101-C1334-A (26.00 mg, 32.38 ^mol, 1.00 eq) in THF (3.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 uL, 208.56 eq). Then the solution was stirred at 0°C for 18 hours to give colorless solution. The reaction was complete detected by LCMS (ES6477-18-P1B). The reaction was concentrated under ordinary pressure to give yellow oil. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10um; mobile phase: [water (0.1%TFA)-ACN]; B%: 50%-80%, 10 min).The separated layers were lyophilized to give K101-C1334 (3.00 mg, 5.35 ^mol, 16.52% yield, 97.28% purity, Free) as a white solid.

[0462] K101-C1334: LC-MS (m / z): 583.1 [M+Na]+

[0463] 1H NMR (400MHz, MeOD) 8 7.56 (s, 1H), 5.63-5.58 (m, 1H), 3.99-3.89 (m, 2H), 3.20-3.15 (m, 1H), 3.09-3.04 (m, 1H), 2.56-2.49 (m, 1H), 2.47-2.40 (m, 1H), 2.37-2.26 (m, 4H), 2.22-2.10 (m, 2020352641   29 Jun 2026 1H), 2.10-1.99 (m, 2H), 1.77-1.73 (m, 3H), 1.66-1.51 (m, 5H), 1.32 (s, 12H), 1.18 (s, 3H), 1.07 (s, 3H), 0.91 (d, J=6.3 Hz, 3H), 0.86 (d, J=5.5 Hz, 1H). Example 28:   Synthesis Scheme of K101-C1335.

[0464] The scheme for synthesis of compound K101-C1335 is illustrated below. K101-C1335

[0465] Preparation of Compound K101-C1335-A: To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DCM (2.00 mL) were added tridecanedioic acid (62.04 mg, 253.90 pmol, 5.00 eq), DMAP (37.22 mg, 304.68 ^mol, 6.00 eq) and EDCI (58.41 mg, 304.68 ^mol, 6.00 eq). The mixture was stirred at 20°C for 14hr to give a colorless solution. The mixture was stirred at 20°C for 5hr to give a colorless solution. LCMS and TLC showed the reaction was completed. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM (15 mL * 5). The organic layers were dried over Na2SO4 and concentrated to give a yellow solid. The yellow solid was purified by prep-TLC (eluting with Petroleum ether: Ethyl acetate = 3 / 1) to give K101-C1335-A (24.00 mg, 29.37 ^mol, 57.84% yield) as a white solid.

[0466] 1H NMR (400MHz, CDCh) 8 = 7.65-7.55 (s, 1H), 7.45-7.35 (m, 6H), 7.32 - 7.27 (m, 6H), 7.25 - 7.19 (m, 3H), 5.65-5.55 (m, 1H), 3.55-3.45 (m, 2H), 3.30-3.25 (m, 1H), 3.00-2.90 (m, 1H), 2.59 - 2.22 (m, 6H), 2.20 (s, 3H), 2.13 - 1.90 (m, 4H), 1.80-1.72 (m, 3H), 1.45-1.20 (m, 14H), 1.19 (s, 3H), 1.07 (s, 3H), 0.88 (d, J=6.3 Hz, 3H), 0.79 (d, J=5.3 Hz, 1H). 2020352641   29 Jun 2026

[0467] Preparation of Compound K101-C1335: To a solution of K101-C1335-A (24.00 mg, 29.37 pmol, 1.00 eq) in THF (10.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 uL, 229.94 eq). The mixture was stirred at 0°C for 14hr to give a yellow solution. LCMS showed K101-C1335-A was remained, then added TFA (0.1 mL). The mixture was stirred at 0°C for 14hr to give a colorless solution. LCMS showed the reaction was completed. The reaction mixture was concentrated to give yellow oil. The yellow oil was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10um; mobile phase: [water (0.1%TFA)-ACN]; B%: 70%-70%, 10min). The separated layers were lyophilized to give K101-C1335 (5.40 mg, 9.15 p.mol, 31.16% yield, 97.4% purity, Free) as a white solid.

[0468] LC-MS (m / z): 597.3 [M+Na]+

[0469] 1H NMR (400MHz, MeOD) 8 = 7.60-7.50 (m, 1H), 5.62 (m, 1H), 4.03 - 3.84 (m, 2H), 3.25 3.14 (m, 1H), 3.12 - 3.01 (m, 1H), 2.61 - 2.41 (m, 2H), 2.41 - 2.23 (m, 4H), 2.19 - 1.99 (m, 2H), 1.83 -1.71 (m, 3H), 1.71 - 1.48 (m, 5H), 1.45-1.35 (m, 14H), 1.19 (s, 3H), 1.09 (s, 3H), 0.93 (d, J=6.3 Hz, 3H), 0.87 (d, J=5.8 Hz, 1H) is illustrated below. Example 29:   Synthesis Scheme of K101-C1336.

[0470] The scheme for synthesis of compound K101-C1336 K101-C20Tr-B                              K101-C1336-A

[0471] Preparation of Compound K101-C1336-A To a solution ofK101-C20Tr-B (30.00 mg, 50.78 ^mol, 1.00 eq) in DCM (5.00 mL) were added (2R)-2-(tert-butoxycarbonylamino)-3-phenyl-propanoic acid (C13-36) (26.95 mg, 101.56 ^mol, 2.00 eq), DMAP (30.00 mg, 245.78 ^mol, 4.84 eq) and EDC (19.96 mg, 104.10 ^mol, 2.05 eq). The mixture was stirred at 20°C for 19h to give a colorless solution. LC-MS and TLC showed the reaction was complete. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM (15 mL x 5). The organic layers were dried over Na2SO4 and concentrated to give a yellow solid. The product was purified by prep-TLC (eluting with Petroleum ether: Ethyl acetate = 3 / 1) to give K101-C1336-A (16.00 mg, 19.09 ^mol, 37.60% yield) as a colorless solid. 2020352641   29 Jun 2026

[0472] Preparation of Compound K101-C1336. To a solution of K101-C1336-A 16.00 mg, 19.09 pmol, 1.00 eq) in DCM (2.00 mL) were added TFA (770.00 mg, 6.75 mmol, 500.00 uL, 353.76 eq) and EtsSiH (2.22 mg, 19.09 p.mol, 3.04 uL, 1.00 eq). The mixture was stirred at 20°C for 5h to give a colorless solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated and the product purified by prep-HPLC column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 15%-45%, 10min). The separated layers were lyophilized to give K101-C1336 (6.00 mg, 9.84 p.mol, 51.55% yield, 100% purity, TFA salt) as a white solid.

[0473] LC-MS (m / z): 518.2 [M+Na]+

[0474] 1H NMR (400MHz, MeOD) 8 = 7.59 (s, 1H), 7.48 - 7.29 (m, 5H), 5.63 (s, 1H), 4.37 (dd, J=5.9, 8.2 Hz, 1H), 4.04 - 3.89 (m, 2H), 3.42 - 3.37 (m, 1H), 3.25 - 3.00 (m, 3H), 2.61 - 2.35 (m, 2H), 2.23 (dd, J=7.0, 15.1 Hz, 1H), 2.05 (s, 1H), 1.78 (d, J=1.5 Hz, 3H), 1.64 (dd, J=10.4, 14.7 Hz, 2H), 1.08 (d, J=7.8 Hz, 6H), 1.01 - 0.90 (m, 4H) Example 30:   Synthesis Scheme of K101-C1337.

[0475] The scheme for synthesis of compound K101-C1337 is illustrated below. K101-C20Tr-B

[0476] Preparation of Compound K101-C1337-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ^mol, 1.00 eq) in DCM (2.00 mL) were added (2R)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-propanoic acid (C13-37) (27.56 mg, 101.56 ^mol, 2.00 eq), DMAP (24.82 mg, 203.12 ^mol, 4.00 eq), HOBt (13.72 mg, 101.56 ^mol, 2.00 eq) and EDC (19.47 mg, 101.56 ^mol, 2.00 eq). The mixture was stirred at 20°C for 12 h to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The mixture was combined with a second preparation of K101-C1337-A, the mixture quenched with H2O (10 mL) and then extracted with DCM (20mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1337-A (18.00 mg, 21.32 ^mol, 41.99% yield) as a white solid. 2020352641   29 Jun 2026

[0477] Preparation of Compound K101-C1337. To a solution of K101-C1337-A (18.00 mg, 21.32 pmol, 1.00 eq) in THF (2.00 mL) were added TFA (770.00 mg, 6.75 mmol, 500.00 uL, 316.75 eq) and EtsSiH (7.44 mg, 63.96 ^mol, 10.19 uL, 3.00 eq). The mixture was stirred at 20°C for 2h to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated byN2, and the product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 25%-55%, 10min) to give K101-C1337 (5.20 mg, 10.37 ^mol, 48.62% yield, 100% purity) as a white solid.

[0478] LC-MS (m / z): 524.3 [M+Na]+

[0479] 1H NMR (400MHz, CD3OD) 8 7.58 (s, 1H), 5.64-5.63 (s, 1H), 4.12-4.09 (m, 1H), 4.00-3.94 (m, 2H), 3.18 (s, 1H), 3.08 (s, 1H), 2.53-2.45 (m, 1H), 2.40-2.32 (m, 1H), 2.26-2.24 (m, 1H), 2.052.03 (m, 1H), 1.84-1.64 (m, 12H), 1.33-1.31 (m, 3H), 1.20 (s, 3H), 1.11 (s, 3H), 1.01-0.95 (m, 6H). Example 31:   Synthesis Scheme of K101-C1338.

[0480] The scheme for synthesis of compound K101-C1338 is illustrated below. K101-C20Tr-B

[0481] Preparation of compound K101-C1338-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ^mol, 1.00 eq) in DCM (2.00 mL) were added (2S)-2-(tert-butoxycarbonylamino)-4-methylsulfanyl-butanoic acid (C13-38) (25.32 mg, 101.56 ^mol, 2.00 eq), DMAP (24.82 mg, 203.12 ^mol, 4.00 eq), HOBt (13.72 mg, 101.56 ^mol, 2.00 eq) and EDC (19.47 mg, 101.56 ^mol, 2.00 eq). The mixture was stirred at 20°C for 12h to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The mixture was combined with as second preparation of K101-C1338-A, and the mixture quenched with H2O (10 mL) and extracted with DCM (15 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1338-A (36.00 mg, 43.79 ^mol, 64.84% yield) as a white solid.

[0482] Preparation of compound K101-C1338. To a solution of K101-C1338-A (36.00 mg, 43.79 ^mol, 1.00 eq) in THF (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 308.44 eq). The mixture was stirred at 20°C for 12h to give a yellow solution. LC-MS showed the reaction was 2020352641   29 Jun 2026 complete. The reaction mixture was concentrated byN2 and the product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 20%-50%, 10min) to give K101-C1338 (13.20 mg, 20.95 gmol, 47.83% yield, 94.2% purity, TFA salt) as a white solid.

[0483] LC-MS (m / z): 502.1 [M+Na]+

[0484] 1H NMR (400MHz, CD3OD) 8 7.57 (s, 1H), 5.65-5.64 (m, 1H), 4.26-4.23 (m, 1H), 4.00-3.94 (m, 2H), 3.18 (s, 1H), 3.08 (s, 1H), 2.72-2.69 (m, 2H), 2.53-2.45 (m, 1H), 2.45-2.41 (m, 1H), 2.302.24 (m, 2H), 2.15-2.11 (m, 5H), 1.77 (s, 3H), 1.76-1.75 (m, 1H), 1.20 (s, 3H), 1.03 (s, 3H), 0.96-0.94 (m, 4H). Example 32:   Synthesis Scheme of K101-C1339.

[0485] The scheme for synthesis of compound K101-C1339 is illustrated below. K101-C20Tr-B K101-C1339-A K101-C1339

[0486] Preparation of Compound K101-C1339-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ^mol, 1.00 eq) in DCM (2.00 mL) were added (2R)-2-(tert-butoxycarbonylamino)-3-methylsulfanyl-propanoic acid (C13-39) (23.90 mg, 101.56 ^mol, 2.00 eq), DMAP (24.82 mg, 203.12 ^mol, 4.00 eq), HOBt (13.72 mg, 101.56 ^mol, 2.00 eq) and EDC (19.47 mg, 101.56 ^mol, 2.00 eq). The mixture was stirred at 20°C for 12hr to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The mixture was combined with a second preparation, which was quenched with H2O (10 mL) and then extracted with DCM (15 mL). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1339-A (35.00 mg, 43.32 ^mol, 85.30% yield) as a white solid.

[0487] Preparation of Compound K101-C1339. To a solution of K101-C1339-A (35.00 mg, 43.32 ^mol, 1.00 eq) in THF (2.00 mL) was added TFA (4.94 mg, 43.32 ^mol, 3.21 uL, 1.00 eq). The mixture was stirred at 20°C for 3h to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated byN2 and the product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; 2020352641   29 Jun 2026 B%: 18%-48%, 10min) to give K101-C1339 (4.40 mg, 7.11 pmol, 16.41% yield, 93.63% purity, TFA salt) as a white solid.

[0488] LC-MS (m / z): 488.1 [M+Na]+

[0489] 1H NMR (400MHz, CD3OD) 8 7.57 (s, 1H), 5.65-5.64 (m, 1H), 4.33-4.30 (m, 1H), 4.00-3.97 (m, 2H), 3.19-3.14 (m 2H), 3.07 (s, 1H), 3.00-2.97 (m, 1H), 2.53-2.45 (m, 1H), 2.40-2.32 (m, 1H), 2.25-2.23 (m, 4H), 2.10-2.05 (m, 1H), 1.77 (s, 3H), 1.20 (s, 3H), 1.11 (s, 3H), 1.05-1.03 (m, 1H), 0.96-0.94 (m, 3H). Example 33:   Synthesis Scheme of K101-C1340.

[0490] The scheme for synthesis of compound K101-C1340 is illustrated below.

[0491] Preparation of compound K101-C1340-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) and C13-40 in DCM (3.00 mL) were added EDC (19.47 mg, 101.56 ^mol, 2.00 eq) and DMAP (37.22 mg, 304.68 ^mol, 6.00 eq). The reaction solution was stirred at 20 °C for 14 hours to give colorless solution. TLC (PE / EtOAc=1 / 1, SiO2) and LC-MS showed the reaction was complete. The reaction solution was combined with a second preparation, and then diluted with H2O (5 ml x 2) followed by extraction with DCM (10 ml x 5). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude product as a pale yellow solid. The product was purified by prep-TLC (PE / EtOAc=1 / 1, SiO2) to give K101-C1340-A (20.30 mg, 23.15 ^mol, 39.29% yield) as a white solid.

[0492] Preparation of Compound K101-C1340. To a solution of K101-C1343-A (20.00 mg, 22.80 ^mol, 1.00 eq) in THF (2.00 mL) were added sequentially TFA (770.00 mg, 6.75 mmol, 500.00 uL, 296.19 eq) followed by Et3SiH (2.65 mg, 22.80 ^mol, 3.63 uL, 1.00 eq). The mixture was stirred at 20°C for 18 hours to give a pale yellow solution. The reaction was complete detected by LC-MS. The reaction was concentrated under reduced pressure to give a yellow solid, and the product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 55%-95%, 10 min). The separated layers were lyophilized to give K101-C1340 (3.80 mg, 7.11 ^mol, 31.17% yield, 96.78% purity, TFA salt) as a pale yellow solid.

[0493] LC-MS (m / z): 557.1 [M+Na]+ 2020352641   29 Jun 2026

[0494] 1H NMR (400MHz, MeOD) 8 7.58 (d, J=7.5 Hz, 1H), 7.54-7.51 (m, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 7.17-7.12 (m, 1H), 7.10 -7.05 (m, 1H), 5.59-5.54 (m, 1H), 4.58 (s, 2H), 4.17-4.09 (m, 1H), 3.99-3.90 (m, 2H), 3.17-3.11 (m, 1H), 3.02-2.96 (m, 1H), 2.55-2.46 (m, 1H), 2.45-2.36 (m, 1H), 2.04-1.92 (m, 2H), 1.78-1.71 (m, 3H), 1.43-1.32 (m, 1H), 1.04-0.97 (m, 6H), 0.83 (d, J=6.0 Hz, 3H), 0.78-0.74 (m,1H). Example 34:   Synthesis Scheme of K101-C1341.

[0495] The scheme for synthesis of compound K101-C1341 is illustrated below. K101-C20Tr-B                              K101-C1341-A                             K101-C1341

[0496] Preparation of Compound K101-C1341-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DCM (1.00 mL) were added (2R)-2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)propanoic acid (C13-41) (154.55 mg, 507.83 pmol, 10.00 eq), EDC (19.47 mg, 101.57 gmol, 2.00 eq) and DMAP (37.22 mg, 304.70 |omol, 6.00 eq). The mixture was stirred at 20°C for 5hr to give a colorless solution. LC-MS and TLC showed the reaction was complete. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM (15 mL x 5). The organic layers were dried over Na2SO4 and concentrated to give a yellow solid. The product was purified by prep-TLC (eluting with Petroleum ether: Ethyl acetate = 2 / 1) to give K101-C1341-A (35.00 mg, 39.91 |omol, 67.35% yield) as a white solid.

[0497] Preparation of Compound K101-C1341. To a solution of K101-C1341-A (35.00 mg, 39.91 ^mol, 1.00 eq) in THF (2.00 mL) were added TFA (770.00 mg, 6.75 mmol, 500.00 uL, 169.21 eq) and Et3SiH (4.64 mg, 39.91 pmol, 6.36 uL, 1.00 eq). The mixture was stirred at 20°C for 5hr to give a colorless solution. The reaction mixture was concentrated and the resultant yellow oil dissolved with DCM (2 mL) followed by addition of TFA (0.5 mL). The mixture was stirred at 20°C for 2hr to give a yellow solution. The reaction mixture was concentrated and dissolved with DCM (2 mL) followed by addition of TFA (0.5 mL). This reaction mixture was stirred at 20°C for 1hr to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated to give a yellow oil, which was then dissolved in MeOH (4 mL) and stirred at 20°C for 14hr to give a yellow liquid. The product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 20%-50%, 10min). The separated layers 2020352641   29 Jun 2026 were lyophilized to give K101-C1341 (4.00 mg, 5.59 p.mol, 14.01% yield, 90.7% purity, TFA salt) as a white solid.

[0498] LC-MS (m / z): 557.1 [M+Na]+

[0499] 1H NMR (400MHz, MeOD) 8 = 7.61 (d, J=7.5 Hz, 1H), 7.57 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.26 (s, 1H), 7.23 - 7.10 (m, 2H), 5.60-5.50 (m, 1H), 4.33 (t, J=7.4 Hz, 1H), 4.06 - 3.92 (m, 2H), 3.60 - 3.45 (m, 1H), 3.22 - 3.13 (m, 1H), 3.05-2.95 (m, 1H), 2.59 - 2.38 (m, 2H), 2.17 (dd, J=6.8, 14.6 Hz, 1H), 2.04 (d, J=8.8 Hz, 1H), 1.77 (d, J=1.5 Hz, 3H), 1.63 (dd, J=10.5, 14.8 Hz, 1H), 1.40-1.25(m, 2H), 1.04 (s, 3H), 0.93 (d, J=6.5 Hz, 3H), 0.87 (s, 3H), 0.69 (d, J=5.8 Hz, 1H) Example 35:   Synthesis Scheme of K101-C1342.

[0500] The scheme for synthesis of compound K101-C1342 is illustrated below. o

[0501] Preparation of Compound K101-C1342-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) and C13-42 (25.39 mg, 76.17 pmol, 1.50 eq) in DCM (1.00 mL) were added EDC (58.41 mg, 304.68 ^mol, 6.00 eq) and DMAP (18.61 mg, 152.35 ^mol, 3.00 eq). The mixture was stirred at 20°C for 14h to give a yellow solution. The reaction was complete as detected by LC-MS. The reaction solution was combined with a second preparation, and diluted with H2O (10 mL) followed by extraction with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow solid. The product was purified by prep-TLC (PE / EtOAc=2 / 1, SiO2) to give K101-C1342-A (50.30 mg, 55.52 ^mol, 93.44% yield) as a white solid.

[0502] Preparation of Compound K101-C1342. To a solution of K101-C1342-A (50.00 mg, 55.19 ^mol, 1.00 eq) in MeOH (500.00 uL) was added HCl / MeOH (4 M, 500.00 uL, 36.24 eq). The reaction was stirred at 20°C for 3.5 hours to give a pale yellow solution. LC-MS showed the reaction was almost complete. The solution was adjusted to pH 8 with saturated aqueous NaHCO3 and then extracted with DCM (2 ml x 3). The combined organic layers were concentrated under reduced pressure to give a yellow solid. The product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25 mm x 10 um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 25%-55%, 10 min) to give K101-C1342 (10.70 mg, 18.99 ^mol, 34.40% yield, 98.84% purity, TFA salt) as a white solid.

[0503] LC-MS (m / z): 586.1 [M+Na]+ 2020352641   29 Jun 2026

[0504] 1H NMR (400MHz, MeOD) 8 7.71 (d, J=8.0 Hz, 2H), 7.56-7.51 (m, 3H), 5.62-5.57 (m, 1H), 4.47-4.40 (m, 1H), 3.94 (s, 2H), 3.47-4.40 (m, 1H), 3.25-3.18 (m, 1H), 3.18-3.13 (m, 1H), 3.07-2.99 (m, 1H), 2.57-2.47 (m, 1H), 2.45-2.36 (m, 1H), 2.17 (dd, J=7.2, 14.7 Hz, 1H), 2.07-1.98 (m, 1H), 1.78-1.73 (m, 3H), 1.53-1.43 (m, 1H), 1.10 (s, 3H), 1.06 (s, 3H), 0.96 (d, J=5.8 Hz, 1H), 0.91 (d, J=6.5 Hz, 3H). Example 36:    Synthesis Scheme of K101-C1343.

[0505] The scheme for synthesis of compound K101-C1343 is illustrated below.

[0506] Preparation of Compound K101-C1343-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) and C13-43 were added EDC (58.41 mg, 304.68 pmol, 6.00 eq) and DMAP (37.22 mg, 304.68 ^mol, 6.00 eq). The reaction solution was stirred at 25 °C for 1 hour to give a brown solution. TLC (PE / EtOAc=1 / 1, SiO2) showed the reaction was complete. The reaction solution was diluted with DCM (2 mL), washed with brine (1 mL), and dried over anhydrous Na2SO4. The product was filtered and concentrated under reduced pressure to give the crude product as a brown gum. The product was purified by prep-TLC (PE / EtOAc=1 / 1, SiO2) to give K101-C1343-A (33.30 mg, 78.25% yield) as a colorless gum.

[0507] Preparation of Compound K101-C1343. To a solution of K101-C1343-A (25.00 mg, 29.83 pmol, 1.00 eq) in MeOH (1.00 mL) was added HCl / MeOH (4 M, 1 mL), and the reaction solution stirred at 20°C for 2.5 hours to give a clear solution. LC-MS showed the reaction was almost complete so the reaction solution was stirred at 20°C for an additional 1hr. The reaction solution was combined with a second preparation of the compound, and then cooled to 0°C. The solution was adjusted to pH 8 with saturated aqueous NaHCO3. The solution was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.05% HCl)-B: ACN]; B%: 15%-45%, 10min) to give K101-C1343 (7.60 mg, 47.02% yield, 98.2% purity, HCl salt) as a white solid.

[0508] LC-MS (m / z): 518.1 [M+Na]+

[0509] 1H NMR (400MHz, CD3OD) 8 7.53 (s, 1H), 7.50-7.43 (m, 5H), 5.57 (d, J=4.2 Hz, 1H), 4.73 (t, J=7.3 Hz, 1H), 4.00-3.88 (m, 2H), 3.18-3.04 (m, 3H), 3.01 (t, J=5.5 Hz, 1H), 2.56-2.46 (m, 1H), 2020352641   29 Jun 2026 2.44-2.36 (m, 1H), 2.11-1.93 (m, 2H), 1.78-1.71 (m, 3H), 1.38 (dd, J=10.1, 14.3 Hz, 1H), 1.01 (s, 3H), 0.96 (s, 3H), 0.90-0.80 (m, 4H). Example 37:   Synthesis Scheme of K101-C1344.

[0510] The scheme for synthesis of compound K101-C1344 is illustrated below.

[0511] Preparation of Compound K101-C1344-A. To a solution of K101-C20Tr-B (35.00 mg, 59.25 pmol, 1.00 eq) and C13-44 (41.37 mg, 148.12 p.mol, 2.50 eq) in DCM (1.00 mL) were added EDC (68.15 mg, 355.48 p.mol, 6.00 eq) and DMAP (21.71 mg, 177.74 ^mol, 3.00 eq). The mixture was stirred at 20°C for 18hr to give a yellow solution. The reaction was complete as detected by LC-MS. The reaction solution was diluted with H2O (10 mL), extracted with DCM (10 mL x 3), and the combined organic layers dried over Na2SO4. The solution was concentrated under reduced pressure and purified by prep-TLC (SiO2, PE: EA = 3:1). Concentration under reduced pressure yielded K101-C1344-A (43.60 mg, 51.17 ^mol, 86.36% yield) as a white solid.

[0512] Preparation of Compound K101-C1344. To a solution of K101-C1344-A (35.00 mg, 41.08 ^mol, 1.00eq) in MeOH (500.00 uL) was added HCl / MeOH (4 M, 583.29 uL, 56.80 eq). The solution was stirred at 20°C for 18hr to give a yellow solution. The reaction was complete as detected by LC-MS. The reaction solution was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 20%-50%, 10min). The separated layers were lyophilized to give K101-C1344 (5.00 mg, 8.02 ^mol, 19.52% yield, TFA salt) as a white solid.

[0513] LC-MS (m / z): 532.3 [M+Na]+

[0514] 1H NMR (400MHz, CD3OD)8 7.53 (s, 1H), 7.40-7.37 (m, 2H), 7.34-7.33 (m, 1H), 7.29- 7.27(m, 2H), 5.59 (s, 1H), 3.98 (s, 2H), 3.88-3.85 (m, 1H), 3.15 (s, 1H), 3.06-3.03 (m, 2H), 2.95-2.93 (m, 1H), 2.72-2.64 (m, 2H), 2.55-2.44 (m, 2H), 2.12-1.98 (m, 2H), 1.75 (s, 3H), 1.59-1.55 (m, 1H), 1.30-1.25 (m, 3H), 1.14 (s, 3H), 1.06 (s, 3H), 0.91-0.89 (m, 3H), 0.84-0.83 (m, 1H). 2020352641   29 Jun 2026 Example 38:   Synthesis Scheme of K101-C1345.

[0515] The scheme for synthesis of compound K101-C1345 is illustrated below. K101-C20Tr-B K101-C1345-A K101-C1345

[0516] Preparation of Compound K101-C1345-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) and C13-45 (36.23 mg, 126.96 p.mol, 2.50 eq) in DCM (1.00 mL) were added EDC (48.68 mg, 253.91 p.mol, 5.00 eq) and DMAP (18.61 mg, 152.35 ^mol, 3.00 eq). The reaction mixture was stirred at 20°C for 18hr. The reaction was complete as detected by LC-MS. The reaction solution was diluted with H2O (10 mL) and extracted with DCM (8 mL x 5). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give pale yellow solution. The product was purified by prep-TLC (SiO2, PE: EA = 3:1) to give K101-C1345-A (26.30 mg, 30.65 ^mol, 60.36% yield) as a white solid.

[0517] Preparation of Compound K101-C1345. To a solution of K101-C1345-A (25.00 mg, 29.13 ^mol, 1.00 eq) in MeOH (500.00 uL) was added HCl / MeOH (4 M, 7.28 uL, 1.00 eq). The solution was stirred at 20°C for 18 hr to give a yellow solution. The reaction was complete as detected by LC-MS. The reaction solution was diluted with H2O (10 mL), neutralized with NaHCO3 aqueous solution and then extracted with DCM (8 mL x 5). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN];B%: 25%-55%,10min), and the separated layers lyophilized to give K101-C1345 (4.30 mg, 8.34 ^mol, 28.63% yield) as a white solid.

[0518] LC-MS (m / z): 538.3 [M+Na]+

[0519] 1H NMR (400MHz, CD3OD) 8 7.56 (s, 1H), 5.62 (s, 1H), 5.49 (m, 1H), 4.02-3.95 (m, 3H), 3.16-3.06 (m, 2H), 2.56-2.44 (m, 2H), 2.39-2.22 (m, 1H), 2.04-1.94 (m, 3H), 1.76-1.57 (m, 9H), 1.301.25 (m, 7H), 1.18 (s, 3H), 1.01 (s, 3H), 0.99-0.93 (m, 5H). Example 39:   Synthesis Scheme of K101-C1346.

[0520] The scheme for synthesis of compound K101-C1346 is illustrated below. 2020352641   29 Jun 2026 EDC, DMAP DCM. K101-C20Tr-B 0 C13-46 K101-C1346-A K101-C1346

[0521] Preparation of Compound K101-C1346-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DCM (1.00 mL) were added (2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoic acid (C13-46) (70.47 mg, 304.68 ^mol, 6.00 eq) DMAP (43.43 mg, 355.46 ^mol, 7.00 eq) and EDC (58.41 mg, 304.68 ^mol, 6.00 eq). The mixture was stirred at 20°C for 5hr to give a yellow solution. TLC showed the reaction was complete. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM (15 mL x 5). The organic layers were dried over Na2SO4 and concentrated to give a yellow solid. The product was purified by prep-TLC (eluting with Petroleum ether: Ethyl acetate = 3 / 1) to give K101-C1346-A (28.00 mg, 34.83 ^mol, 68.58% yield) as a colorless solid.

[0522] Preparation of Compound K101-C1346. To a solution of K101-C1346-A (28.00 mg, 34.83 ^mol, 1.00 eq) in MeOH (500.00 uL) was added HCl / MeOH (4 M, 8.71 uL, 1.00 eq). The mixture was stirred at 20°C for 19hr to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was adjusted to pH 6 with saturated NaHCO3 and the resultant product purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 20%-50%, 10min). The organic layers were lyophilized to give K101-C1346 (7.80 mg, 13.55 ^mol, 38.91% yield, 100% purity, TFA salt) as a white solid.

[0523] LC-MS (m / z): 584.2 [M+Na]+

[0524] 1H NMR (400MHz, MeOD) 8 = 7.60-7.54 (m, 1H), 5.70-5.60 (m, 1H), 4.04 - 3.92 (m, 2H), 3.86 (s, 1H), 3.33-3.20 (m, 1H), 3.20-3.12 (m, 1H), 2.60 - 2.38 (m, 2H), 2.26 (dd, J=7.0, 14.6 Hz, 1H), 2.19 - 2.02 (m, 1H), 1.77 (d, J=1.5 Hz, 3H), 1.60 (dd, J=10.8, 14.6 Hz, 1H), 1.26 (s, 3H), 1.17 (s, 9H), 1.13 (s, 3H), 1.02 (d, J=5.8 Hz, 1H), 0.95 (d, J=6.3 Hz, 3H). Example 40:   Synthesis Scheme of K101-C1347.

[0525] The scheme for synthesis of compound K101-C1347 is illustrated below. 2020352641   29 Jun 2026 K101-C20Tr-B                               K101-C1347-A                        K101-C1347

[0526] Preparation of Compound K101-C1347-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 pmol, 1.00 eq) in DCM (2.00 mL) were added (2S)-2-(1-adamantyl)-2-(tert-butoxycarbonylamino) acetic acid (C13-47) (94.27 mg, 304.68 ^mol, 6.00 eq), EDC (58.41 mg, 304.68 ^mol, 6.00 eq) and DMAP (43.43 mg, 355.46 ^mol, 7.00 eq). The mixture was stirred at 20°C for 14h to give a yellow solution. LC-MS and TLC showed the reaction was complete. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM (15 mL x 5). The organic layers were dried over Na2SO4 and concentrated to give a yellow solid. The product was purified by prep-TLC (eluting with Petroleum ether: Ethyl acetate = 3 / 1) to give K101-C1347-A (13.00 mg, 14.74 ^mol, 24.80% yield) as a white solid.

[0527] Preparation of Compound K101-C1347. To a solution of K101-C1347-A (13.00 mg, 14.74 ^mol, 1.00 eq) in THF (1.00 mL) were added TFA (500.55 mg, 4.39 mmol, 325.03 uL, 297.89 eq) and Et3SiH (1.71 mg, 14.74 ^mol, 2.35 uL, 1.00 eq). The mixture was stirred at 20°C for 3h to give a colorless solution. The reaction mixture was concentrated, dissolved with DCM (2 mL) and then followed by addition of TFA (0.5 mL). The mixture was stirred at 20°C for 2h to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was concentrated to give a yellow oil, which was dissolved with MeOH (2 mL) and stirred at 20°C for 14h to give a buff liquid. The product was purified by prep-HPLC (column: Phenomenex Gemini 150 x 25mm x 10um; mobile phase: [A: water (0.1%TFA)-B: ACN]; B%: 25%-55%, 10min). The separated layers were lyophilized to give K101-C1347 (6.50 mg, 9.94 ^mol, 67.44% yield, 100% purity, TFA salt) as a white solid.

[0528] LC-MS (m / z): 562.3 [M+Na]+

[0529] 1H NMR (400MHz, MeOD) 8 = 7.62-7.55 (s, 1H), 5.70-5.60 (m, 1H), 4.05 - 3.90 (m, 2H), 3.75 - 3.56 (m, 1H), 3.25-3.15 (m, 1H), 3.16-3.08 (m, 1H), 2.62 - 2.38 (m, 2H), 2.27 (dd, J=6.9, 14.7 Hz, 1H), 2.15-2.06 (m, 4H), 1.91 - 1.53 (m, 16H), 1.27 (s, 3H), 1.13 (s, 3H), 1.03 (d, J=5.5 Hz, 1H), 0.96 (d, J=6.5 Hz, 3H) Example 41:   Synthesis Scheme of K101-C1348.

[0530] The scheme for synthesis of compound K101-C1348 is illustrated below. 2020352641   29 Jun 2026 K101-C20Tr-B K101-C1348-A Preparation of C13-48: o C13-48-A LAH, THF, r.t.                                       (COCI)2, DMSO --------► HO              Ph ---------►                  Ph C13-48-B                                      C13-48-C C13-48-E C13-48-D C13-48

[0531] Preparation of compound C13-48-B. LiAlH4 (413.84 mg, 10.91 mmol, 1.50 eq) was suspended in THF (10.00 mL) at 0°C, then C13-48-A (1.50 g, 7.27 mmol, 1.00 eq) in THF (10.00 mL) was added dropwise at 0°C. The mixture was allowed to stir at 20°C for 4hr to give a brown solution. LC-MS showed the reaction was complete. Following quenching with H2O (0.5 mL), aqueous NaOH (0.5 mL, 15%) and H2O (1.5 mL) were added. The mixture was filtered on Celite and the filtrate was concentrated to give the 7-phenylheptan-1-ol (1.30 g, 6.76 mmol, 92.99% yield) as a yellow oil.

[0532] Preparation of compound C13-48-C. To a solution of oxalyl dichloride (1.72 g, 13.52 mmol, 1.18 mL, 2.00 eq) in DCM (20.00 mL) was added dropwise DMSO (2.64 g, 33.80 mmol, 2.64 mL, 5.00 eq) at -78°C. The mixture was stirred at -78°C for 0.5hr. Compound C13-48-B (1.30 g, 6.76 mmol, 1.00 eq) in DCM (10.00 mL) was added at -78°C. The mixture was stirred at -78°C for 1hr, and the Et3N (3.42 g, 33.80 mmol, 4.68 mL, 5.00 eq) was added dropwise at -78°C. The mixture was 2020352641   29 Jun 2026 allowed to stir at 20°C for 2.5hr to give a yellow suspension. LC-MS and TLC (eluting with: PE / EtOAc=5 / 1) showed the reaction was complete. The reaction mixture was quenched with H2O (30 mL) and extracted with DCM (50 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by column chromatography on silica gel (eluting with: PE / EtOAc=100%PE to 5 / 1) to give C13-48-C (1.10 g, 5.78 mmol, 85.52% yield) as a yellow oil.

[0533] Preparation of compound C13-48-E. To a solution of C13-48-C (1.05 g, 5.52 mmol, 1.00 eq) in EtOH (10.00 mL) were added trimethylsilyl cyanide (TMSCN) (547.46 mg, 5.52 mmol, 692.99 uL, 1.00 eq) and NH3.H2O (851.01 mg, 6.07 mmol, 935.18 uL, 25% purity, 1.10 eq). The mixture was stirred at 20°C for 7hr to give a yellow solution. LC-MS showed the reaction was complete. The reaction mixture was quenched with H2O (30 mL) and extracted with DCM (50mL x 3). The organic layers were dried over Na2SO4 and concentrated to give C13-48-E (1.10 g, crude) as a yellow oil.

[0534] Preparation of compound C13-48-D. To a solution of C13-48-E (1.10 g, 5.09 mmol, 1.00 eq) in EtOH (5.00 mL) was added NaOH (610.21 mg, 15.26 mmol, 3.00 eq). The mixture was stirred at 20°C for 2hr followed by the addition of H2O (1.00 mL). The mixture was stirred at 90°C for 2hr to give a yellow solution. LC-MS showed the reaction was complete.

[0535] Preparation of Compound C13-48. Boc anhydride (Boc2O) (2.23 g, 10.20 mmol, 2.34 mL, 2.00 eq) was added to the preparation of C13-48-E, and the mixture stirred at 20°C for 2hr to give a yellow suspension. LC-MS and TLC (eluting with: 100%EtOAc) showed the reaction was complete. The mixture was combined with a second preparation, and the combined mixture was diluted with H2O (20 mL) followed by extraction with PE (20 mL x 3). The water layer was adjusted to pH 5 with HCl (1N) and extracted with EtOAc (30 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by column chromatography on silica gel (eluting with: PE / EtOAc=1 / 1 to 100%EtOAc) to give C13-48 (700.00 mg, 2.09 mmol, 40.92% yield) as a yellow oil.

[0536] Preparation of Compound K101-C1348-A. To a solution of K101-C20Tr-B (30.00 mg, 50.78 ^mol, 1.00 eq) in DCM (2.00 mL) were added C13-48 (34.07 mg, 101.56 ^mol, 2.00 eq), DMAP (24.82 mg, 203.12 ^mol, 4.00 eq), HOBt (13.72 mg, 101.56 ^mol, 2.00 eq) and EDC (19.47 mg, 101.56 ^mol, 2.00 eq). The mixture was stirred at 10°C for 12hr to give a yellow solution. LC-MS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The mixture was combined with a second preparation, and the combined mixture was quenched with saturated NaHCO3 (10 mL) followed by extraction with DCM (20 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The product was purified by prep-TLC (eluting with: PE / EtOAc=2 / 1) to give K101-C1348-A (18.00 mg, 19.82 ^mol, 39.03% yield) as a white solid. 2020352641   29 Jun 2026

[0537] 1H NMR (400MHz, CDCI3) 8 7.57 (s, 1H), 7.44-7.42 (m, 5H), 7.31-7.29 (m, 7H), 7.24-7.18 (m, 8H), 5.59 -5.58 (m, 1H), 3.51-3.50 (m, 2H), 3.28 (s, 1H), 2.93 (s, 1H), 2.60-2.56 (m, 2H), 2.502.42 (m, 1H), 2.05-1.99 (m, 2H), 1.97-1.95 (m, 3H), 1.77 (s, 2H), 1.55-1.54 (m, 2H), 1.34 (s, 9H), 1.25-1.19 (m, 12H), 1.08 (s, 3H), 0.87-0.79 (m, 4H).

[0538] Preparation of Compound K101-C1348 (as a mixture of K101-C134801 and K101-C134802). To a solution of K101-C1348-A (48.00 mg, 52.85 pmol, 1.00 eq) in THF (2.00 mL) was added TFA (6.03 mg, 52.85 pmol, 3.91 uL, 1.00 eq). The mixture was stirred at 10°C for 12hr to give a yellow solution. LC-MS and TLC (eluting with: EtOAc / MeOH=10 / 1) showed the reaction was complete. The reaction mixture was concentrated byN2 and the resultant product dissolved in MeOH (30 mL). The reaction mixture was stirred at 20°C for 12hr. After the mixture was concentrated, the product of K101-C1348 was purified by prep-TLC (eluting with: EtOAc / MeOH=10 / 1) to give K101-C1348 as a mixture of stereoisomers of K101-C134801 (11.10 mg, 19.62 pmol, 37.12% yield, 100% purity) and K101-C134802 (10.30 mg, 17.73 ^mol, 33.55% yield, 97.4% purity), each as a white solid.

[0539] K101-C134801: LC-MS (m / z): 588.2 [M+Na]+ K101-C134801: 1H NMR (400MHz, CD3OD) 8 7.53 (s, 1H), 7.30-7.10 (m, 5H), 5.65-5.55 (m, 1H), 4.00-3.90 (m, 2H), 3.50-3.45(m, 1H), 3.25-3.20 (m, 1H), 3.15-3.05 (m, 1H), 2.65-2.55 (m, 2H), 2.552.40 (m, 2H), 2.20-1.95 (m, 2H), 1.807-1.55 (m, 8H), 1.40-1.25 (m, 6H), 1.20 (s,3H), 1.10 (s,3H), 0.95-0.85 (m, 4H).

[0540] K101-C134802: LC-MS (m / z): 588.3 [M+Na]+

[0541] K101-C134802: 1H NMR (400MHz, CD3OD) 8 7.53 (s, 1H), 7.30-7.10 (m, 5H), 5.65-5.55 (m, 1H), 4.0-3.85 (m, 2H), 3.70-3.60 (m, 1H), 3.20-3.10 (m, 1H), 3.05-3.0 (m, 1H), 2.70-2.55 (m, 2H), 2.55-2.40 (m, 2H), 2.15-2.15 (m, 2H), 1.85-1.45 (m, 8H), 1.45-1.30 (m, 6H), 1.20 (s, 3H), 1.09 (s, 3H), 0.95-0.90 (m, 4H). Example 45A: Synthesis Scheme of K101-C134801

[0542] The scheme for synthesis of compound K101-C134801 is illustrated below. 2020352641   29 Jun 2026 C1348-D LiOH aq. NHBoc C134801-A K101-C20Tr-B C134802-C Pd(dppf)CI2 Cui, DMA NHBoc C134801-C NHBoc BB-C134801 NHBoc C134801-B H2, Pd ---► MeOH NHBoc C134801-D K101-C134801 TFA □ CM

[0543] Preparation of compound C134801-C. To a solution of C1348-D (2 g, 7.35 mmol, 1 eq) in DMA (2 mL) were added CuI (139.97 mg, 734.96 pmol, 0.1 eq) and C134801-B (4.06 g, 10.29 mmol, 1.4 eq) and Pd(dppf)Cl2 (537.77 mg, 734.96 ^mol, 0.1 eq) under N2. The mixture was stirred under N2 at 90°C for 5hr to give a black suspension. LCMS and TLC (eluting with: PE / EtOAc=3 / 1) showed the reaction was complete. The reaction mixture was quenched with H2O (100 mL) and extracted with MBTE (40 mLx 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by a flash column (eluting with: PE / EtOAc=100%PE to 20%) to give C134801-C (750 mg, 2.16 mmol, 29.37% yield) as a yellow oil. 2020352641   29 Jun 2026

[0544] 1H NMR (400MHz, CDCI3): 8 7.30-7.20 (m, 2H), 7.20-7.16 (m, 3H), 5.58-5.51 (m, 1H), 5.34-5.27 (m, 1H), 5.02-5.00 (m, 1H), 4.37-4.33 (m, 1H), 3.73 (s, 3H), 2.62-2.58 (m, 2H), 2.46-2.44 (m, 2H), 2.07-2.02 (m, 2H), 1.70-1.66 (m, 2H), 1.44 (s, 9H).

[0545] Preparation of compound C134801-D. To a solution of C134801-C (0.75 g, 2.16 mmol, 1 eq) in MeOH (15 mL) was added Pd / C (500 mg, 2.16 mmol, 50% purity, 1 eq) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15psi) at 20°C for 12 hours. LCMS showed the reaction was complete. The reaction mixture was filtered on celite. The filtrate was concentrated to give C134801-D (750 mg, 2.15 mmol, 99.42% yield) as a black oil, which was used for next step without further purification.

[0546] 1H NMR (400MHz, CDCl3): 8 7.29-7.26 (m, 2H), 7.19-7.16 (m, 3H), 4.99-4.84 (m, 1H), 4.29-4.28 (m, 1H), 3.73 (s, 3H), 2.61-2.51 (m, 2H), 1.78-1.60 (m, 4H), 1.45 (s, 9H), 1.33-1.28 (m, 6H).

[0547] Preparation of compound BB-C134801. To a solution of C134801-D (750 mg, 2.15 mmol, 1 eq) in THF (5 mL) / H2O (1 mL) was added LiOH.H2O (90.06 mg, 2.15 mmol, 1 eq) at 0°C. The mixture was allowed to stir at 20°C for 12hr to give a yellow solution. LCMS showed the reaction was complete. The reaction mixture was acidified to pH=4 with HCl (1N) and extracted with MBTE (20 mLx 3). The organic layers were dried over Na2SO4 and concentrated to give BB-C134801 (700 mg, 2.09 mmol, 97.24% yield) as a yellow oil, which was used for next step without further purification.

[0548] Preparation of compound C134801-B. Zinc (6 g) was treated with 1N HCl aqueous (30 mL) with stirring for 10 min. Then it was filtered and washed with water (30 mL), EtOH (30 mL) and toluene (30 mL) in sequence, dried in vacuum to afford the zinc powder for next step. A mixture of activated Zn (2.62 g, 40.11 mmol, 4 eq) and I2 (127.24 mg, 501.32 ^mol, 100.98 uL, 0.05 eq) in DMA (10 mL) was stirred at 20°C for 5 min. Then C134801-A (3.3 g, 10.03 mmol, 1 eq) in DMA (10 mL) was added dropwise. The reaction mixture was stirred at 20°C for 25 min to give a black suspension. The reaction mixture (about 0.5015 mmol / mL) was used for next step without further purification.

[0549] Preparation of compound K101-C134801-A. To a solution of K101-C20Tr-B (200 mg, 338.55 ^mol, 1 eq) in DCM (3 mL) were added BB-C134801 (193.06 mg, 575.54 ^mol, 1.7 eq), DMAP (165.44 mg, 1.35 mmol, 4 eq), HOBt (50.32 mg, 372.41 ^mol, 1.1 eq) and EDCI (110.33 mg, 575.54 ^mol, 1.7 eq). The mixture was stirred at 20°C for 12hr to give a yellow solution. LCMS showed the desired mass was found, and K101-C20Tr-B was remained. The mixture was stirred at 20°C for 12hr again. LCMS showed the desired mass was found, and K101-C20Tr-B was remained. The mixture was stirred at 20°C for 12hr to give a yellow solution again. LCMS and TLC (eluting with: PE / EtOAc=2 / 1) showed the reaction was complete. The reaction mixture was quenched with H2O (10 mL) and extracted with MBTE (15 mL x 3). The organic layers were dried over Na2SO4 and 2020352641   29 Jun 2026 concentrated to give the crude product. The crude product was purified by flash column (eluting with: PE / EtOAc=100% PE to 40%) to give K101-C134801-A (210 mg, 231.23 pmol, 68.30% yield) as a yellow solid.

[0550] 1H NMR (400MHz, CDCh) 8 7.58 (s, 1H), 7.44-7.42 (m, 6H), 7.31-7.26 (m, 7H), 7.26-7.17 (m, 7H), 5.60-5.59 (m, 1H), 5.26-5.17 (m, 1H), 5.95-5.93 (m, 1H), 4.28-4.27 (m, 1H), 3.52 (s, 2H), 3.27 (s, 1H), 2.94 (s, 1H), 2.61-2.43 (m, 5H), 2.09-2.05 (m, 1H), 2.04-1.99 (m, 1H), 1.78-1.77 (m, 4H), 1.58-1.56 (m, 1H), 1.54-1.52 (m, 1H), 1.44 (s, 9H), 1.33-1.28 (m, 6H), 1.19 (s, 3H), 1.08 (s, 3H), 0.88-0.78 (m, 4H).

[0551] Preparation of compound K101-C134801 and K101-C134801-C. To a solution of K101-C134801-A (610.00 mg, 671.68 ^mol, 1.00 eq) in DCM (5 mL) was added TFA (2.76 g, 24.23 mmol, 1.79 mL, 36.08 eq). The mixture was stirred at 20°C for 1hr to give a yellow solution. LCMS and TLC (eluting with: EtOAc / MeOH=10 / 1) showed the reaction was complete. The reaction mixture was concentrated by purging with N2. The residue from concentration was dissolved in MeOH (50 mL). The reaction mixture was stirred at 40°C for 12hr. LCMS showed the reaction was complete. The reaction mixture was concentrated to give K101-C134801 (158 mg, 255.88 ^mol, 38.10% yield, 91.62% purity) as a white solid, which was the final product, and K101-C134801-C (130 mg, 160.88 gmol, 23.95% yield) as a yellow solid, which was an intermediate.

[0552] K101-C134801: LC-MS (m / z): 588.2 [M+Na]+

[0553] K101-C134801: 1H NMR (400MHz, CD3OD) 8 7.56 (s, 1H), 7.30-7.10 (m, 5H), 5.65-5.55 (m, 1H), 4.00-3.90 (m, 2H), 3.50-3.45(m, 1H), 3.25-3.20 (m, 1H), 3.15-3.05 (m, 1H), 2.65-2.40 (m, 4H), 2.20-1.95 (m, 2H), 1.807-1.55 (m, 8H), 1.40-1.25 (m, 6H), 1.20 (s,3H), 1.10 (s,3H), 0.95-0.85 (m, 4H).

[0554] K101-C134801-C: 1H NMR (400MHz, CDCl3) 8 7.51 (s, 1H), 7.36-7.35 (m, 6H), 7.24-7.22 (m, 7H), 7.18-7.10 (m, 7H), 5.54 (s, 1H), 5.26 (brs, 1H), 3.45-3.42 (m, 2H), 3.36-3.34(m, 1H), 3.21 (s, 1H), 2.87 (s, 1H), 2.54-2.36 (m, 4H), 1.99-1.97 (m, 3H), 1.71 (s, 3H), 1.27-1.21 (m, 6H), 1.13 (s,3H), 1.01 (s,3H), 0.81-0.71 (m, 4H).

[0555] Preparation of compound K101-C134801. To a solution of K101-C134801-C (130 mg, 160.88 gmol, 1 eq) in MeOH (5 mL) was added HClO4 (32.32 mg, 321.76 gmol, 19.47 uL, 2 eq) at 0°C. The mixture was stirred at 0°C for 0.5hr to give a yellow solution. LCMS and TLC (eluting with: EtOAc=10 / 1) showed the reaction was complete. The reaction mixture was quenched with saturated NaHCO3 (10 mL) and extracted with EtOAc (20 mL x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude 2020352641   29 Jun 2026 product was purified by prep-TLC (eluting with: EtOAc=10 / 1) to give K101-C134801 (20.5 mg, 30.07 pmol, 18.69% yield, 82.99% purity) as a white solid

[0556] LC-MS (m / z): 588.2 [M+Na]+

[0557] 1H NMR (400MHz, CD3OD): 8 7.56 (s, 1H), 7.30-7.10 (m, 5H), 5.65-5.55 (m, 1H), 4.00 3.90 (m, 2H), 3.50-3.45(m, 1H), 3.25-3.20 (m, 1H), 3.15-3.05 (m, 1H), 2.65-2.40 (m, 4H), 2.20-1.95 (m, 2H), 1.807-1.55 (m, 8H), 1.40-1.25 (m, 6H), 1.20 (s,3H), 1.10 (s,3H), 0.95-0.85 (m, 4H). Example 45B: Synthesis Scheme of K101-C134802

[0558] The scheme for synthesis of compound K101-C134802 is illustrated below. Tf2O, 2,6-lutidine DCM. -78°C C1348-E n-BuLi, THF C1348-G TBAF THF ZrCp2HCI, l2 THF C1348-D C134802-C Pd(dppf)CI2 Cui, DMA NHBoc C134802-D H2, Pd MeOH C1348-H

[0559] Preparation of compound C1348-F. To a solution of C1348-E (20 g, 146.85 mmol, 20.00 mL, 1 eq) in DCM (200 mL) was added 2,4-lutidine (25.18 g, 234.96 mmol, 27.16 mL, 1.6 eq) at -78°C. Then triflic anhydride (Tf2O) (45.58 g, 161.54 mmol, 26.65 mL, 1.1 eq) was added dropwise at -78°C. The mixture was stirred at -78°C for 0.5hr to give a yellow suspension. TLC (eluting with: PE / EtOAc=3 / 1) showed the reaction was complete. The reaction mixture was diluted with PE (40 2020352641   29 Jun 2026 mL). The mixture was poured into silica gel and washed with PE / EtOAc (4L, 4 / 1) to give C1348-F (30.5 g, 113.70 mmol, 77.42% yield) as yellow oil.

[0560] Preparation of compound C1348-G. To a solution of ethynyl(trimethyl)silane (15.25 g, 155.30 mmol, 21.51 mL, 1.49 eq) in THF (200 mL) was added dropwise n-BuLi (2.5 M, 51.67 mL, 1.24 eq) at -78°C. The mixture was warmed to 0°C for 30min. Then C1348-F (28 g, 104.38 mmol, 1 eq) was added dropwise at -78°C. The mixture was warmed to 0°C for 1hr to give a yellow solution. TLC (eluting with: PE / EtOAc=10 / 1) showed the reaction was complete. The reaction mixture was quenched with saturated NH4Cl (200 mL) and extracted with MBTE (150 mLx 2). The organic layers were dried over Na2SO4 and concentrated to give C1348-G (25 g, crude) as a yellow oil, which was used for next step without further purification.

[0561] 1H NMR (400MHz, CDCh): 8 7.30-7.18 (m, 5H), 3.80-3.70 (m, 1H), 2.80-2.69 (m, 2H), 2.26-2.22 (m, 2H), 1.89-1.84 (m, 2H), 0.23-0.09 (m, 9H).

[0562] Preparation of compound C1348-H. To a solution of C1348-G (25 g, 115.53 mmol, 1 eq) in THF (50 mL) was added tetra-n-butylammonium fluoride (TBAF) (1 M, 150.19 mL, 1.3 eq). The mixture was stirred at 20°C for 1hr to give a yellow solution. TLC (eluting with: PE / EtOAc=10 / 1) showed the reaction was complete. The reaction mixture was quenched with H2O (300 mL) and extracted with EtOAc (150 x 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by a flash column (eluting with: PE / EtOAc=100%PE to 5%) to give C1348-H (9.5 g, 65.88 mmol, 57.02% yield) as a colorless oil.

[0563] 1H NMR (400MHz, CDCl3): 8 7.32-7.13 (m, 5H), 2.74-2.65 (m, 2H), 2.14-2.11 (m, 5H), 1.93 (s, 1H), 1.80-1.67 (m, 2H).

[0564] Preparation of compound C1348-D. To a solution of C1348-H (3 g, 20.80 mmol, 1 eq) in THF (50 mL) was added ZrCp2HCl (8.88 g, 33.28 mmol, 1.6 eq) at 0°C. The mixture was stirred at 0°C for 2.5hr, then stirred at 20°C for1hr. I2 (6.34 g, 24.96 mmol, 5.03 mL, 1.2 eq) in THF (10 mL) was added at -78°C. The mixture was stirred at -78°C for 1hr. The mixture was allowed to stir at 0°C for 1hr to give a brown suspension. TLC (eluting with:PE=100%) showed the reaction was completed. The reaction mixture was quenched with HCl (0.1N, 200 mL). The mixture was extracted with EtOAc (30 mLx 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by column silica (eluting with: PE=100%) to give C1348-D (3.8 g, 13.96 mmol, 67.13% yield) as a yellow oil.

[0565] 1H NMR (400MHz, CDCl3): 8 7.34-7.21 (m, 2H), 7.19-7.15 (m, 3H), 6.55-6.51 (m, 1H), 6.02-5.99 (m, 1H), 2.64-2.60 (m, 2H), 2.10-2.07 (m, 2H), 1.73-1.71 (m, 2H).

[0566] Preparation of compound C134802-D. To a solution of C134802-C (4.35 g, 11.02 mmol, 1.5 eq) in DMA (10 mL) were added Cui (139.97 mg, 734.96 gmol, 0.1 eq) and C1348-D (2 g, 7.35 2020352641   29 Jun 2026 mmol, 1 eq) and Pd(dppf)Cb (537.77 mg, 734.96 p.mol, 0.1 eq) under N2. The mixture was stirred under N2 at 90°C for 12hr to give a black suspension. LCMS and TLC (eluting with: PE / EtOAc=4 / 1) showed the reaction was complete. The reaction mixture was quenched with H2O (200 mL) and extracted with MBTE (100mLx 3). The organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by flash column (eluting with: PE / EtOAc=100%PE to 10%) to give C134802-D (1 g, 2.88 mmol, 39.16% yield) as a yellow oil.

[0567] 1H NMR (400MHz, CDCh) 8 7.30-7.27 (m, 1H), 7.20-7.16 (m, 1H), 5.58-5.1 (m, 1H), 5.345.26 (m, 1H), 5.02-5.00 (m, 2H), 4.37-4.32 (m, 1H), 3.73 (s, 3H), 2.62-2.58 (m, 2H), 2.48-2.44 (m, 2H), 2.07-2.02 (m, 2H), 1.71-1.66 (m, 2H), 1.44 (s, 9H).

[0568] Preparation of compound C134802-E. To a solution of C134802-D (1 g, 2.88 mmo...

Claims

1. A compound having the structure of formula (II):(II)or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; whereinR2 is a C1-C4alkyl;R3 is O double bonded to the ring carbon when (---) is a bond, or -ORa; wherein Ra is H or -C(O)Ra1, wherein Ra1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;R4 and R5 are each independently H or -ORb, wherein Rb is H, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency;R6 is OH, halo, or -OC(O)Rc, wherein Rc is -C1-C6alkyl, -C1-C6alkyl-(NRc1)2 or -C1-C6alkylC(O)ORk, Rc1 is H, C1-C6alkyl, or two Rc1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; orR6 iswherein,each occurrence of RA is independently selected from a side chain of an amino acid, wherein each occurrence of RA is same or different;2020352641   29 Jun 2026each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of an amino acid, wherein each occurrence of RB is same or different; andp is 0, 1, or 2;R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency;R7 is H or OH;R9 is ORe, wherein Re is H, C1-C6alkyl, or aryl;R11 is C1-C4alkyl;R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Cnalkenyl, -Co-Ci2aliphatic-C3-C7cycloalkyl, -C0-C12aliphatic-heterocycloalkyl, or -C0-C12aliphatic-heteroaryl;R13 and R13’ are each independently H or C1-C4alkyl;R14 is H or ORg; wherein Rg is H or C1-C6alkyl;R17 and R18 are each independently C1-C4alkyl or C1-C4alkyl-ORh, wherein Rh is H or C1-C6alkyl;L is absent, C1-C12alkylene, or C2-C12alkenylene, wherein the C1-C12alkylene or C2-C12alkenylene is optionally substituted with C1-C4alkyl;R21 is H, -S(O)2Rj, -SRj, -N(Rj)2, -Si(Rj)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-Ci2 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroC5-C12cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with C1-C4alkyl, or when an N atom is present an N-protecting group;each Rj is independently C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C7cycloalkyl, C0-C6alkylheterocyclyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1;Rk is H or M+ counterion;J1 is selected from OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl; and n is 0 or 1.

2. The compound of claim 1, having the structure of formula (II’):2020352641   29 Jun 2026or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

3. The compound of claim 1, having the structure of formula (IIa):(IIa)or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof;whereinR2 is a C1-C4alkyl;R3 is O double bonded to the ring carbon when (- - -) is a bond, or -ORa; wherein Ra is H or -C(O)Ra1, wherein Ra1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;R4 and R5 are each independently H or -ORb, wherein Rb is H, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;R6 is OH, halo, or -OC(O)Rc, wherein Rc is -C1-C6alkyl, -C1-C6alkyl-(NRc1)2 or -C1-C6alkylC(O)ORk, Rc1 is H, C1-C6alkyl, or two Rc1 together with the N atom form a 5 to 7 membered2020352641   29 Jun 2026heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; orR6 is / ra \o rbwherein,each occurrence of RA is independently selected from a side chain of an amino acid, wherein each occurrence of RA is same or different;each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of an amino acid, wherein each occurrence of RB is same or different; andp is 0, 1, or 2;R7 is H or OH;R9 is ORe, wherein Re is H, C1-C6alkyl, or aryl;R11 is C1-C4alkyl;R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Ci2alkyl, Ci-Ciialkenyl, -Co-Ci2aliphatic-C3-C7cycloalkyl, -C0-C12aliphatic-heterocycloalkyl, or -C0-C12aliphatic-heteroaryl;R13 and R13’ are each independently H or C1-C4alkyl;R14 is H or ORg; wherein Rg is H or C1-C6alkyl;R17 and R18 are each independently C1-C4alkyl or C1-C4alkyl-ORh, wherein Rh is H or C1-C6alkyl;L is absent, C1-C12alkylene, or C2-C12alkenylene, wherein the C1-C12alkylene or C2-C12alkenylene is optionally substituted with C1-C4alkyl;R21 is H, -S(O)2Rj, -SRj, -N(Rj)2, -Si(Rj)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-Ci2 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroC5-C12cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with C1-C4alkyl, or when an N atom is present an N-protecting group;each Rj is independently C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C7cycloalkyl, C0-C6alkylheterocyclyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1;Rk is H or M+ counterion;J1 is selected from OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl; and n is 0 or 1.2020352641   29 Jun 20264.      The compound of claim 3, having the structure of formula (IIa’):R13or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

5. The compound of claim 1, having the structure of formula (IIb):(IIb)or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof;whereinR2 is a C1-C4alkyl;R3 is O double bonded to the ring carbon when (- - -) is a bond, or -ORa; wherein Ra is H or -C(O)Ra1, wherein Ra1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;R4 and R5 are each independently H or -ORb, wherein Rb is H, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;2020352641   29 Jun 2026R6 is OH, halo, or -OC(O)Rc, wherein Rc is -C1-C6alkyl, -C1-C6alkyl-(NRc1)2 or -C1-C6alkylC(O)ORk, Rc1 is H, C1-C6alkyl, or two Rc1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; orR6 iswherein,each occurrence of RA is independently selected from a side chain of an amino acid, wherein each occurrence of RA is same or different;each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of an amino acid, wherein each occurrence of RB is same or different; andp is 0, 1, or 2;R9 is ORe, wherein Re is H, C1-C6alkyl, or aryl;R11 is C1-C4alkyl;R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Ci2alkenyl, -Co-Ci2aliphatic-C3-C7cycloalkyl, -C0-C12aliphatic-heterocycloalkyl, or -C0-C12aliphatic-heteroaryl;R13 and R13’ are each independently H or C1-C4alkyl;R14 is H or ORg; wherein Rg is H or C1-C6alkyl;R17 and R18 are each independently C1-C4alkyl or C1-C4alkyl-ORh, wherein Rh is H or C1-C6alkyl;L is absent, C1-C12alkylene, or C2-C12alkenylene, wherein the C1-C12alkylene or C2-C12alkenylene is optionally substituted with C1-C4alkyl;R21 is H, -S(O)2Rj, -SRj, -N(Rj)2, -Si(Rj)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroC5-C12cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with C1-C4alkyl, or when an N atom is present an N-protecting group;each Rj is independently C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C7cycloalkyl, C0-C6alkylheterocyclyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1;Rk is H or M+ counterion;2020352641   29 Jun 2026J1 is selected from OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl; and n is 0 or 1.

6. The compound of claim 3, having the structure of formula (IIc):(IIc)or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof;whereinR6 is OH, halo, or -OC(O)Rc, wherein Rc is -C1-C6alkyl, -C1-C6alkyl-(NRc1)2 or -C1-C6alkylC(O)ORk, Rc1 is H, C1-C6alkyl, or two Rc1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; orR6 iswherein,each occurrence of RA is independently selected from a side chain of an amino acid, wherein each occurrence of RA is same or different;each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of an amino acid, wherein each occurrence of RB is same or different; andp is 0, 1, or 2;R12 is H, -OH, -OC(O)Rf, wherein Rf is Ci-Cnalkyl, C2-Cnalkenyl, -Co—Ci2aliphatic-C3— C7cycloalkyl, -C0-C12aliphatic-heterocycloalkyl, or -C0-C12aliphatic-heteroaryl;R13 and R13’ are each independently H or C1-C4alkyl;L is absent, C1-C12alkylene, or C2-C12alkenylene, wherein the C1-C12alkylene or C2-2020352641   29 Jun 2026C12alkenylene is optionally substituted with C1-C4alkyl;R21 is H, -S(O)2Rj, -SRj, -N(Rj)2, -Si(Rj)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-Ci2 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroC5-C12cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with C1-C4alkyl, or when an N atom is present an N-protecting group;each Rj is independently C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C7cycloalkyl, C0-C6alkylheterocyclyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1;Rk is H or M+ counterion;J1 is selected from OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl; and n is 0 or 1.

7. The compound of claim 1 having the structure of formula (III):(III)or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof;whereinR2 is a C1-C4alkyl;R3 is O double bonded to the ring carbon when (- - -) is a bond, or -ORa; wherein Ra is H or -C(O)Ra1, wherein Ra1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;R4 and R5 are each independently H or -ORb, wherein Rb is H, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;R5’ and R6’ are H, or R5’ and R6’ form a bond or are bonded to a common O atom to form an epoxide ring as permitted by valency;2020352641   29 Jun 2026R6 is OH, halo, or -OC(O)Rc, wherein Rc is -C1-C6alkyl, -C1-C6alkyl-(NRc1)2 or -C1-C6alkylC(O)ORk, Rc1 is H, C1-C6alkyl, or two Rc1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; orR6 iswherein,each occurrence of RA is independently selected from a side chain of an amino acid, wherein each occurrence of RA is same or different;each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of an amino acid, wherein each occurrence of RB is same or different; andp is 0, 1, or 2;R6’ and R7’ are H, or R6’ and R7’ form a bond or are bonded to a common O atom to form an epoxide ring, as permitted by valency;R7 is H or OH;R9 is ORe, wherein Re is H, C1-C6alkyl, or aryl;R11 is C1-C4alkyl;R13 and R13’ are each independently H or C1-C4alkyl;R14 is H or ORg; wherein Rg is H or C1-C6alkyl;R17 and R18 are each independently C1-C4alkyl or C1-C4alkyl-ORh, wherein Rh is H or C1-C6alkyl;L is absent, C1-C12alkylene, or C2-C12alkenylene, wherein the C1-C12alkylene or C2-C12alkenylene is optionally substituted with C1-C4alkyl;R21 is H, -S(O)2Rj, -SRj, -N(Rj)2, -Si(Rj)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroC5-C12cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with C1-C4alkyl, or when an N atom is present an N-protecting group;each Rj is independently C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C7cycloalkyl, C0-C6alkylheterocyclyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1;Rk is H or M+ counterion;2020352641   29 Jun 2026J1 is selected from OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl; and n is 0 or 1.

8. The compound of claim 7 having the structure of formula (III’):(III’)or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

9. The compound of claim 7 having the structure of formula (IIIa):(IIIa)or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof;whereinR2 is a C1-C4alkyl;R3 is O double bonded to the ring carbon when (- - -) is a bond, or -ORa; wherein Ra is H or -2020352641   29 Jun 2026C(O)Ra1, wherein Ra1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;R4 and R5 are each independently H or -ORb, wherein Rb is H, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;R6 is OH, halo, or -OC(O)Rc, wherein Rc is -C1-C6alkyl, -C1-C6alkyl-(NRc1)2 or -C1-C6alkylC(O)ORk, Rc1 is H, C1-C6alkyl, or two Rc1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; orR6 iswherein,each occurrence of RA is independently selected from a side chain of an amino acid, wherein each occurrence of RA is same or different;each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of an amino acid, wherein each occurrence of RB is same or different; andp is 0, 1, or 2;R7 is H or OH;R9 is ORe, wherein Re is H, C1-C6alkyl, or aryl;R11 is C1-C4alkyl;R13 and R13’ are each independently H or C1-C4alkyl;R14 is H or ORg; wherein Rg is H or C1-C6alkyl;R17 and R18 are each independently C1-C4alkyl or C1-C4alkyl-ORh, wherein Rh is H or C1-C6alkyl;L is absent, C1-C12alkylene, or C2-C12alkenylene, wherein the C1-C12alkylene or C2-C12alkenylene is optionally substituted with C1-C4alkyl;R21 is H, -S(O)2Rj, -SRj, -N(Rj)2, -Si(Rj)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroC5-C12cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with C1-C4alkyl, or when an N atom is present an N-protecting group;each Rj is independently C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C7cycloalkyl, C0-C6alkylheterocyclyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1;2020352641   29 Jun 2026Rk is H or M+ counterion;J1 is selected from OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl; and n is 0 or 1.

10. The compound of claim 7 having the structure of formula (IIIb):(IIIb)or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof; whereinR2 is a C1-C4alkyl;R3 is O double bonded to the ring carbon when (- - -) is a bond, or -ORa; wherein Ra is H or -C(O)Ra1, wherein Ra1 is C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;R4 and R5 are each independently H or -ORb, wherein Rb is H, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl;R6 is OH, halo, or -OC(O)Rc, wherein Rc is -C1-C6alkyl, -C1-C6alkyl-(NRc1)2 or -C1-C6alkylC(O)ORk, Rc1 is H, C1-C6alkyl, or two Rc1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; orwherein,each occurrence of RA is independently selected from a side chain of an amino acid, wherein each occurrence of RA is same or different;2020352641   29 Jun 2026each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of an amino acid, wherein each occurrence of RB is same or different; andp is 0, 1, or 2;R9 is ORe, wherein Re is H, C1-C6alkyl, or aryl;R11 is C1-C4alkyl;R13 and R13’ are each independently H or C1-C4alkyl;R14 is H or ORg; wherein Rg is H or C1-C6alkyl;R17 and R18 are each independently C1-C4alkyl or C1-C4alkyl-ORh, wherein Rh is H or C1-C6alkyl;L is absent, C1-C12alkylene, or C2-C12alkenylene, wherein the C1-C12alkylene or C2-C12alkenylene is optionally substituted with C1-C4alkyl;R21 is H, -S(O)2Rj, -SRj, -N(Rj)2, -Si(Rj)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-Ci2 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroC5-C12cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with C1-C4alkyl, or when an N atom is present an N-protecting group;each Rj is independently C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C7cycloalkyl, C0-C6alkylheterocyclyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1;Rk is H or M+ counterion;J1 is selected from OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl; and n is 0 or 1.

11. The compound of claim 7 having the structure of formula (IIIc):2020352641   29 Jun 2026(IIIc)or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof;whereinR6 is OH, halo, or -OC(O)Rc, wherein Rc is -C1-C6alkyl, -C1-C6alkyl-(NRc1)2 or -C1-C6alkylC(O)ORk, Rc1 is H, C1-C6alkyl, or two Rc1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; orR6 iswherein,each occurrence of RA is independently selected from a side chain of an amino acid, wherein each occurrence of RA is same or different;each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of an amino acid, wherein each occurrence of RB is same or different; andp is 0, 1, or 2;R13 and R13’ are each independently H or C1-C4alkyl;L is absent, C1-C12alkylene, or C2-C12alkenylene, wherein the C1-C12alkylene or C2-C12alkenylene is optionally substituted with C1-C4alkyl;R21 is H, -S(O)2Rj, -SRj, -N(Rj)2, -Si(Rj)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-Ci2 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroC5-2020352641   29 Jun 2026C12cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with C1-C4alkyl, or when an N atom is present an N-protecting group;each Rj is independently C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C7cycloalkyl, C0-C6alkylheterocyclyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1;Rk is H or M+ counterion;J1 is selected from OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl; andn is 0 or 1.

12. The compound of claim 11 having the structure of formula (IIIe):(IIIe)or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof;whereinR6 is OH, halo, or -OC(O)Rc, wherein Rc is -C1-C6alkyl, -C1-C6alkyl-(NRc1)2 or -C1-C6alkylC(O)ORk, Rc1 is H, C1-C6alkyl, or two Rc1 together with the N atom form a 5 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O, and S; orR6 iswherein,each occurrence of RA is independently selected from a side chain of an amino acid, wherein each occurrence of RA is same or different;each occurrence of RB is independently H, or RB together with the adjacent RA and the N atom to which it is attached form a heterocyclic ring of an amino acid, wherein each occurrence of RB is same or different; andp is 0, 1, or 2;2020352641   29 Jun 2026L is absent, C1-C12alkylene, or C2-C12alkenylene, wherein the C1-C12alkylene or C2-C12alkenylene is optionally substituted with C1-C4alkyl;R21 is H, -S(O)2Rj, -SRj, -N(Rj)2, -Si(Rj)3, C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-Ci2 cycloalkyl, 5 to 12 membered bridged bicyclyl, adamantyl, or -C(O)ORk, wherein the C3-C7cycloalkyl, heterocyclyl, aryl, heteroaryl, spiroC5-C12 cycloalkyl, bridged bicyclyl, or adamantyl is optionally substituted with 1 to 3 of J1, and wherein optionally 1 to 2 carbon atoms of the spiroC5-C12cycloalkyl or bridged bicyclyl is replaced with a heteroatom selected from N, O and S, and optionally substituted with C1-C4alkyl, or when an N atom is present an N-protecting group;each Rj is independently C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C7cycloalkyl, C0-C6alkylheterocyclyl, C0-C6alkylaryl, or C0-C6alkylheteroaryl, wherein the C3-C7cycloalkyl, heterocyclyl, alkylaryl, or heteroaryl is optionally substituted with 1 to 3 of J1;Rk is H or M+ counterion; andJ1 is selected from OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl.

13. The compound of any one of claims 1 to 12, wherein R21 is C3-C7cycloalkyl, whereinthe C3-C7cycloalkyl is optionally substituted with 1 to 3 of J1.

14. The compound of claim 13, wherein the C3-C7cycloalkyl is selected from the groupconsisting of cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, wherein the C3-C7cycloalkyl is optionally substituted with 1 to 3 of J1.

15. The compound of any one of claims 1 to 12, wherein R21 is heterocyclyl, wherein theheterocyclyl is optionally substituted with 1 to 3 of J1.

16. The compound of claim 15, wherein the heterocyclyl is selected from the groupconsisting of oxiranyl, oxetanyl, azetidynyl, 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 J1.

17. The compound of any one of claims 1 to 12, whereinR21 is aryl, wherein the aryl is optionally substituted with 1 to 3 of J1.

18. The compound of claim 17, whereinR21 is a phenyl or naphthyl, wherein the phenyl or naphthyl is optionally substituted with 1 to 3 of J1.2020352641   29 Jun 202619.    The compound of any one of claims 1 to 12, whereinR21 is heteroaryl, wherein the heteroaryl is optionally substituted with 1 to 3 of J1.

20. The compound of claim 19, wherein the heteroaryl is selected from the groupconsisting of pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, and quinolyl, wherein the heteroaryl is optionally substituted with 1 to 3 of J1.

21. The compound of any one of claims 1 to 12 whereinR21 is adamantyl, wherein the adamantyl is optionally substituted with OH, halo, or C1-C4alkyl.

22. The compound of any one of claims 1 to 12, whereinR21 is spiroC5-C12 cycloalkyl, wherein the spiroC5-C12 cycloalkyl has 0-2 carbon atoms replaced with 0-2 heteroatoms selected from N, O and S, and is optionally substituted with 1 to 3 of J1, or when an N atom is present an N-protecting group.

23. The compound of any one of claims 1 to 12, whereinR21 is 5 to 12 membered bridged bicyclyl, wherein the bridged bicyclyl has 0-2 carbon atoms replaced with 0-2 heteroatoms selected from N, O or S, and is optionally substituted with 1 to 3 of J1, or when an N atom is present an N-protecting group.

24. The compound of any one of claims 1 to 12, wherein R21 is selected from:2020352641   29 Jun 2026wherein J1 is OH, CN, halo, C1-C4alkyl, and haloC1-C4alkyl, and n is 0-3.

25. The compound of any one of claims 1 to 12, wherein L is C1-C6alkylene, C3-C6alkylene, or C3-C12alkylene.

26. The compound of any one of claims 1 to 12, wherein L is C1-C6alkenylene, C3-C6alkenylene, or C3-C12alkenylene.

27. The compound of any one of claims 1 to 12, wherein n is 0.

28. The compound of claim 1 selected from the group consisting of the followingcompounds:2020352641   29 Jun 2026oK101-C1325K101-C1327K101-C1328K101-C1329K101-C1329-ClK101-C13302020352641   29 Jun 20260K101-C13310K101-C1332K101-C1336K101-C13372020352641   29 Jun 2026K101-C13440K101-C1345h2n oK101-C1347K101-C1348022020352641   29 Jun 20262020352641   29 Jun 2026K101-C1357K101-C1358K101-C1359K101-C135901K101-C1361K101-C1361022020352641   29 Jun 2026( / \.,\NH ° A 1 1 1, , / hLiA / ^ / T \ H — JHO      OH K101-C1364 F pJXX L ,nh2 p^o i / ,,. / —H Jho Y-oh K101-C1370 F F^\_ Q o / o H2NZ- 2 / It,,, / H z~Y / £\'HH -\ l°H / J HO       OH K101-C137002 Ny2 0^j / / HV"H ft OH 0 K101-C1365 F F"\^x o o c O ii,,. /    'T'T2-— h- / zvzvhH —\L-X°H / / J HO      OH K101-C137001 F^__ Zi 0 o H2N / --X / 111,, / \ H —czl °H# JHO    —OH K101-C13732020352641   29 Jun 2026K101-C13730129.    The compound of any one of claims 1 to 27, wherein:R6 iswherein,each occurrence of RA is independently selected from a side chain of an amino acid, wherein each occurrence of RA is same or different;each occurrence of RB is independently H, or RB together with RA and the N atom to which it is attached form a heterocyclic ring of an amino acid, wherein each occurrence of RB is same or different; andp is 0, 1, or 2.

30. The compound of claim 29, whereineach RA is independently hydrogen (glycine), methyl (alanine), propan-2-yl (valine), propan-1-y1 (norvaline), 2-methylpropan-1-y1 (leucine), 1-methylpropan-1-y1 (isoleucine), butan-1-y12020352641   29 Jun 2026(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 (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-y1 (lysine), 4-amino-3-hydroxybutan-1-y1 (hydroxylysine), 3-aminopropan-1-y1 (ornithine), 3-guanidinopropan-1-y1 (arginine), or 3-ureido-propan-1-yl (citrulline);each RB is H, or RB together with the adjacent RA and the N atom form a prolyl side chain:; andp is 0, 1 or 2.

31. The compound of claim 30, wherein:each RA is independently methyl (alanine), propan-2-y1 (valine), 2-methylpropan-1-y1 (leucine), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 1-hydroxyethyl (threonine), carbamoylmethyl (asparagine), 2-carbamoylethyl (glutamine), 4-aminobutan-1-y1 (lysine), carboxymethyl (aspartic acid), 3-guanidinopropan-1-y1 (arginine), benzyl (phenylalanine), or 4-aminobutan-1-y1 (lysine);RB is H; andp 0, 1, or 2.

32. The compound of claim 30, whereineach RA is independently propan-2-y1 (valine), 2-methylpropan-1-y1 (leucine), carboxymethyl (aspartic acid), benzyl (phenylalanine), or 4-aminobutan-1-y1 (lysine);each RB is H; andp is 0, 1, or 2.

33. The compound of claim 30, wherein p is 0.

34. The compound of claim 30, wherein p is 1.

35. The compound of claim 30, wherein p is 1;first of RA is propan-2-y1 (valine) and second of RA is propan-2-y1 (valine); and each of RB isH (dipeptide Val-Val); orfirst of RA is 2-methylpropan-1-y1 (leucine), and second of RA is 2-methylpropan-1-y1 (leucine); and each of RB is H (dipeptide Leu-Leu); orfirst of RA is methyl (alanine) and second of RA is methyl (alanine); and each of RB is H2020352641   29 Jun 2026(dipeptide Ala-Ala); orfirst of RA is 4-aminobutan-1-y1 (lysine); second of RA is 4-aminobutan-1-y1 (lysine); and each of RB is H (dipeptide Lys-Lys); orfirst of RA is hydrogen; second of RAis 4-aminobutan-1-y1, and each of RB is H (dipeptide Gly-Lys).

36. The compound of any one of claims 29 to 35, wherein each of the a-carbon of theamino acid other than glycine is in the L or D configuration.

37. A pharmaceutical composition comprising a compound of any one of claims 1 to 36,and a pharmaceutically acceptable carrier.

38. A method of activating protein kinase C, comprising contacting a mammalian cellwith an effective amount of a compound of any one of claims 1 to 36.

39. The method of claim 38, wherein the cell is a cancer cell.

40. A method of treating cancer, comprising administering to a subject in need thereof aneffective amount of a compound of any one of claims 1 to 36, or a pharmaceutical composition of claim 37.

41. Use of a compound of any one of claims 1 to 36, or a pharmaceutical composition ofclaim 37, in the manufacture of a medicament for treating cancer, wherein the treating comprises administering to a subject in need thereof an effective amount of the compound of any one of claims 1 to 36, or the pharmaceutical composition of claim 37.

42. The method of claim 40 or the use of claim 41, wherein the cancer is selected fromthe group consisting of adrenocortical cancer, anal cancer, biliary cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, intestinal cancer, liver cancer, lung cancer, oral cancer, ovarian cancer, pancreatic cancer, renal cancer, prostate cancer, salivary gland cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, and soft tissue carcinomas.

43. The method or use of any one of claims 40 to 42, wherein the cancer is ahematological cancer.

44. The method or use of claim 43, wherein the hematological cancer is a leukemia orlymphoma.2020352641   29 Jun 202645.    The method or use of claim 44, wherein the hematological cancer is selected from thegroup consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), lymphoma (optionally, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, Burkitt’s lymphoma), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), Hairy Cell chronic myelogenous leukemia (CML), and multiple myeloma.

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