Pradienolide compound and application thereof

Abstract

The invention relates to a praladienolide compound and application thereof. The present disclosure provides novel pradienolide compounds, pharmaceutical compositions containing such compounds, and methods of using these compounds as therapeutic agents. These compounds are useful in the treatment of cancer, in particular cancers in which agents that target spliceosomes and mutations therein are known to be useful. Also provided herein are methods of treating cancer by administering at least one compound disclosed herein and at least one additional therapy.

Description

[0001] This application is a divisional application of Chinese invention patent application No. 201980039253.0 (PCT application number PCT / US2019 / 026313), whose application date is April 8, 2019 and whose invention name is “Pradienolide compounds and their uses”.

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 655,021, filed April 9, 2018; U.S. Provisional Application No. 62 / 679,653, filed June 1, 2018; U.S. Provisional Application No. 62 / 814,838, filed March 6, 2019; and U.S. Provisional Application No. 62 / 814,843, filed March 6, 2019, all of which are incorporated herein by reference.

[0003] Disclosed herein are novel organic compounds and pharmaceutical compositions containing such compounds. These compounds are useful for treating cancer, particularly cancers for which agents targeting the spliceosome and mutations therein are known to be useful. These compounds are also useful for treating cancer when administered in combination with at least one additional therapy.

[0004] In eukaryotes, newly synthesized messenger RNA often contains multiple introns, which are removed to produce the mature mRNA. The spliceosome is a multi-subunit complex that accomplishes this task. The spliceosome is composed of five small nuclear RNAs (snRNAs; U1-6) combined with a variety of proteins.

[0005] Mutations in the spliceosome's splicing factor 3B subunit 1 (SF3B1) are present in a variety of cancers and constitute a target for anticancer drugs. A compound isolated from the bacterium Streptomyces platensis (Sakai, Takashi; Sameshima, Tomohiro; Matsufuji, Motoko; Kawamura, Naoto; Dobashi, Kazuyuki; Mizui, Yoshiharu. Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107. I. Taxonomy, Fermentation, Isolation and Screening. The Journal of Antibiotics. 2004, Vol. 57, No. 3), known as pladienolide, was discovered during a screening for inhibitors of the vascular endothelial growth factor (VEGF) promoter. It inhibits the expression of a reporter gene controlled by the human VEGF promoter, and this inhibition is known to be a useful mechanism of action for anticancer drugs.

[0006] These compounds also inhibited the proliferation of U251 human glioma cells in vitro. The most potent of these compounds, pradienolide B, had an IC of 1.8 nM. 50 Inhibits VEGF-promoted gene expression with an IC of 3.5 nM 50Inhibits glioma cell proliferation. The structure of pladienolide B is known (Sakai, Takashi; Sameshima, Tomohiro; Matsufuji, Motoko; Kawamura, Naoto; Dobashi, Kazuyuki; Mizui, Yoshiharu. Pladienolides, New Substances from Culture of Streptomyces platensis Mer-11107. II. Physico-chemical Properties and Structure Elucidation. The Journal of Antibiotics. Vol. 57, No. 3. (2004)), and pladienolide B is known to target the SF3b spliceosome to inhibit splicing and alter gene expression patterns (Kotake et al., "Splicing factor SF3bas a target of the antitumor natural product "Splicing factor SF3b as a target of the antitumor natural product pladienolide", Nature Chemical Biology, 2007, 3, 570-575).

[0007] Certain pradienolide B analogs are also known: WO 2002 / 060890; WO 2004 / 011459; WO 2004 / 011661; WO 2004 / 050890; WO 2005 / 052152; WO 2006 / 009276; WO 2008 / 126918; and WO 2015 / 175594. For example, the pradienolide compound (8E,12E,14E)-7-((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosaccharide-8,12,14-triene-11-olide, also known as E7107, is a semisynthetic derivative of the natural product pradienolide D, and its Phase I study results have been reported. As another example, the praldiolide pyridine compound (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-((R,2E,4E)-6-(pyridin-2-yl)hept-2,4-dien-2-yl)oxacyclododecan-4-en-6-yl 4-methylpiperazine-1-carboxylate (also known as "(2S,3S,4E,6S,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-((2E,4E,6R)-6-(pyridin-2-yl)hept-2,4-dien-2-yl)oxacyclododecan-4-en-6-yl 4-methylpiperazine-1-carboxylate"), also known as H3B-8800, has received orphan drug designation for the treatment of certain hematological cancers.

[0008] However, there is a need for additional agents that can be used to treat cancer, particularly cancers for which agents targeting the spliceosome and mutations therein are known to be useful.

[0009] Immune checkpoint blockade (ICB) has recently been shown to be a paradigm shift in the treatment of several different cancer types. However, not all patients show a robust / durable response to ICB. See, for example, Zappasodi, R. et al. Emerging Concepts for Immune Checkpoint Blockade-Based Combination Therapies [emerging concepts for combined therapies based on immune checkpoint blockade]. Cancer Cell [cancer cells] 33, 581-598, doi: 10.1016 / j.ccell.2018.03.005 (2018); and Wolchok, JD et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma [overall survival rate of combined treatment with Nivolumab and Ipilimumab in advanced melanoma]. N Engl J Med [New England Journal of Medicine] 377, 1345-1356, doi: 10.1056 / NEJMoa1709684 (2017). Therefore, there remains a need to discover complementary therapeutic agents to be administered in combination with ICBs or any other therapy to improve and / or maximize patient response.

[0010] Disclosed herein are compounds having Formula I:

[0011]

[0012] and pharmaceutically acceptable salts thereof,

[0013] in:

[0014] n is selected from 0, 1, 2 and 3;

[0015] R 1 Selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, -NR 9 R 10 Group, Group, Group, Group, Group, Group, Group, Groups, and group;

[0016] R 9 Selected from hydrogen, -NR 11 R 12C1-C6 alkyl group, -(C1-C6 alkyl)-CO2H group, C3-C8 cycloalkyl group, and C3-C8 heterocyclyl group, wherein these C3-C8 cycloalkyl group and C3-C8 heterocyclyl group may be unsubstituted or substituted 1-3 times by groups independently selected from C1-C6 alkyl group, -(C1-C6 alkyl)-CO2H group, hydroxyl group, halogen group, and C1-C6 alkoxy group;

[0017] R 10 is selected from hydrogen and C1-C6 alkyl groups;

[0018] R 2 or R 3 One of them is selected from hydrogen and C1-C6 alkyl groups, and the other is selected from hydrogen, -OR 10 、-OC(O)R 10 、-OC(O)R 1 , and C1-C6 alkyl groups;

[0019] R 4 is hydrogen or hydroxyl;

[0020] R 5 and R 6 Each independently selected from C1-C6 alkyl groups;

[0021] R7 and R8 are each independently selected from hydrogen, hydroxyl, C1-C6 alkoxy group, and C1-C6 alkyl group; and

[0022] Y is selected from phenyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, wherein Y may be unsubstituted or independently selected from hydroxyl, oxo, C1-C6 alkyl, C3-C5 cycloalkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, methoxy C1-C6 alkyl, -NR 11 R 12 Group, as well as The group is substituted 1-3 times, wherein R 11 and R 12 are each independently selected from hydrogen and a C1-C6 alkyl group.

[0023] Also disclosed herein are compounds having Formula II:

[0024]

[0025] and pharmaceutically acceptable salts thereof,

[0026] in:

[0027] X is selected from O, NR' groups, and CH2, wherein R' is selected from hydrogen and C1-C6 alkyl groups;

[0028] R 1 Selected from methyl, NR 11 R 12 Group, Groups, and Group,

[0029] R 10 is selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and halo-C1-C6 alkyl groups, wherein these C3-C8 cycloalkyl groups may be unsubstituted or substituted 1-3 times by groups independently selected from C1-C6 alkyl groups, hydroxyl groups, halo groups, and C1-C6 alkoxy groups;

[0030] R 11 and R 12 Each independently selected from C1-C6 alkyl groups;

[0031] R 2 or R 3 One of the is hydrogen or a C1-C6 alkyl group, and the other is selected from hydrogen, hydroxyl and a C1-C6 alkyl group;

[0032] R 4 or R 5 One of is hydrogen, and the other is selected from hydrogen, hydroxyl, and

[0033] R 6 and R 7 Each independently selected from C1-C6 alkyl groups;

[0034] R 8 and R 9 are each independently selected from hydrogen and a C1-C6 alkyl group; or R 8 and R 9 together form a cyclopropyl ring; and

[0035] Y is selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, methoxy groups, and

[0036] -NR 13 R 14 Group, where R 13 and R 14 are each independently selected from hydrogen, a C1-C6 alkyl group, and a methoxy C1-C6 alkyl group; or R 13 and R 14 Together with N, it can form a group selected from the following

[0037] morpholine, piperidine, thiazolidine, indole, indoline, and isoindoline rings;

[0038] wherein Y may be unsubstituted or independently selected from C1-C6 alkyl groups, hydroxyl, hydroxy C1-C6 alkyl groups, methoxy, methoxy C1-C6 alkyl groups, halogen, halogenated C1-C6 alkyl groups, -C(O)NH2, -NHCOO-C1-C6 alkyl groups, -COOH, and -NR 15 R 16 The group is substituted 1-3 times, wherein R 15 and R 16 are each independently selected from hydrogen and a C1-C6 alkyl group.

[0039] Also disclosed herein are compounds having the formula III:

[0040]

[0041] and pharmaceutically acceptable salts thereof,

[0042] in:

[0043] n is selected from 0, 1, 2 and 3;

[0044] m is selected from 1, 2 and 3;

[0045] R 1 Selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, -NR 11 R 12 Group,

[0046] Group, Group, Group, Group, Group, Group, Group, Groups, and group;

[0047] R 11 Selected from hydrogen, -NR 16 R 17 group, C1-C6 alkyl group, C3-C8 cycloalkyl group, -(C1-C6 alkyl)-CO2H group, -(C1-C6 alkyl)-CO2R 12 Group, -(C1-C6 alkyl)-NR 16 R 17 Groups, and C3-C8 heterocyclyl groups, wherein these -NR 16 R 17Groups, C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and C3-C8 heterocyclyl groups may be unsubstituted or substituted 1-3 times by groups independently selected from C1-C6 alkyl groups, -(C1-C6 alkyl)-CO2H groups, hydroxyl groups, halogen groups, and C1-C6 alkoxy groups;

[0048] R 12 is selected from hydrogen and C1-C6 alkyl groups;

[0049] R 2 or R 3 One of them is selected from hydrogen and C1-C6 alkyl groups, and the other is selected from hydrogen, -OR 10 、-OC(O)R 10 、-OC(O)R 1 and C1-C6 alkyl groups;

[0050] R 4 selected from hydrogen and hydroxyl;

[0051] R 5 and R 6 Each independently selected from C1-C6 alkyl groups;

[0052] R7 and R8 are each independently selected from hydrogen, hydroxyl, C1-C6 alkoxy group, and C1-C6 alkyl group; and

[0053] R 9 and R 10 are each independently selected from hydrogen, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group; or, R 9 or R 10 One of the is oxo and the other is absent;

[0054] Z is selected from C1-C6 alkyl groups, -C(O)-C1-C6 alkyl groups, -OR 13 , and -NR 14 R 15 Group,

[0055] where R 13 is selected from hydrogen, a C1-C6 alkyl group, and a -C(O)-C1-C6 alkyl group,

[0056] where R 14 and R 15 are each independently selected from hydrogen, a C1-C6 alkyl group, and a methoxy C1-C6 alkyl group; or R 14 and R 15 Together with N, it can form a group selected from the following

[0057] morpholine, piperidine, thiazolidine, indole, indoline, and isoindoline rings;

[0058] wherein Z may be unsubstituted or independently selected from C1-C6 alkyl groups, C3-C5 cycloalkyl groups, hydroxy C1-C6 alkyl groups, C1-C6 alkoxy groups, methoxy C1-C6 alkyl groups, -NR 16 R 17 Group, as well as The group is substituted 1-3 times, wherein R 16 and R 17 are each independently selected from hydrogen and a C1-C6 alkyl group.

[0059] Also disclosed herein are pharmaceutical compositions comprising at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0060] Also disclosed herein are methods for treating a subject with cancer, comprising administering to the subject a therapeutically acceptable amount of at least one compound of formula I, at least one compound of formula II, at least one compound of formula III, and / or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the cancer may be selected from myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer, breast cancer, uveal melanoma, gastric cancer, bile duct cancer, and / or lung cancer. In some embodiments, the cancer is selected from cancers that test positive for one or more mutations in the splicing factor 3B subunit 1 (SF3B1) gene or protein. In some embodiments, the cancer is selected from cancers that test positive for one or more mutations in spliceosome genes or proteins, such as those listed in Table 1. In some embodiments, administration of at least one compound of formula I, at least one compound of formula II, at least one compound of formula III, and / or a pharmaceutically acceptable salt of any of the foregoing induces at least one new antigen and / or T cell response.

[0061] Also disclosed herein is the use of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing in therapeutic methods of treatment, such as treating cancer. In some embodiments, the cancer may be selected from myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer, breast cancer, uveal melanoma, gastric cancer, bile duct cancer, and / or lung cancer. In some embodiments, the cancer is selected from cancers that test positive for one or more mutations in the splicing factor 3B subunit 1 (SF3B1) gene or protein. In some embodiments, the cancer is selected from cancers that test positive for one or more mutations in spliceosome genes or proteins, such as those listed in Table 1. In some embodiments, administration of at least one compound of formula I, at least one compound of formula II, at least one compound of formula III, and / or a pharmaceutically acceptable salt of any of the foregoing induces at least one new antigen and / or T cell response.

[0062] Also disclosed herein is the use of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing in the preparation of a drug. In some embodiments, the drug can be used to treat cancer. In some embodiments, the cancer can be selected from myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer, breast cancer, uveal melanoma, gastric cancer, bile duct cancer, and / or lung cancer. In some embodiments, the cancer is selected from cancers that test positive for one or more mutations in the splicing factor 3B subunit 1 (SF3B1) gene or protein. In some embodiments, the cancer is selected from cancers that test positive for one or more mutations in spliceosome genes or proteins, such as those listed in Table 1. In some embodiments, administration of at least one compound of formula I, at least one compound of formula II, at least one compound of formula III, and / or a pharmaceutically acceptable salt of any of the foregoing induces at least one new antigen and / or T cell response.

[0063] Also disclosed herein is the use of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing for targeting the spliceosome, such as subunit 1 of the SF3B spliceosome. As used herein, the following definitions shall apply unless otherwise indicated.

[0064] Also disclosed herein are methods of inducing at least one neoantigen, comprising contacting tumor cells with a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, such contact can induce the production of at least one neoantigen.

[0065] Also disclosed herein are methods of inducing at least one neoantigen and / or T cell response in a subject having or suspected of having a neoplastic disease, comprising administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and pharmaceutically acceptable salts of any of the foregoing.

[0066] Also disclosed herein is a method for treating a subject suffering from or suspected of having a neoplastic disease. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing, wherein administration may result in induction of at least one new antigen and / or T cell response. In some embodiments, the method may further comprise detecting one or more new antigens and / or T cell responses in the subject after administering at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the method may further comprise continuing to administer at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing if one or more new antigens and / or T cell responses are detected.

[0067] Also provided herein are methods of treating a subject having or suspected of having a neoplastic disease, comprising administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing.

[0068] Also provided herein are neoantigen vaccines comprising at least one neoantigenic peptide. In some embodiments, the at least one neoantigenic peptide comprises a modified or novel neoantigen sequence induced by contacting tumor cells with a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing.

[0069] In some embodiments, the methods and uses provided herein can further comprise administering at least one additional therapy. In some embodiments, the methods and uses provided herein can result in lower systemic toxicity and / or improved tolerability.

[0070] Also disclosed herein is a method of treating cancer in a subject in need thereof, comprising administering at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and at least one additional therapy. Also disclosed herein is a method of treating a subject having or suspected of having a neoplastic disease, comprising administering at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and at least one additional therapy.

[0071] This application relates to the following items:

[0072] Item 1. A compound selected from the group consisting of compounds having Formula I:

[0073]

[0074] and pharmaceutically acceptable salts thereof,

[0075] in:

[0076] n is selected from 0, 1, 2 or 3;

[0077] R 1 Selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, -NR 9 R 10 、 Group, Group, Group, Group, Group, Group, Groups, and group;

[0078] R 9 Selected from hydrogen, -NR 11 R 12 Groups, C1-C6 alkyl groups, -(C1-C6 alkyl)-CO2H groups, C3-C8 cycloalkyl groups, and C3-C8 heterocyclyl groups, wherein these -NR 11 R 12Groups, C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and C3-C8 heterocyclyl groups may be unsubstituted or substituted 1-3 times by groups independently selected from C1-C6 alkyl groups, -(C1-C6 alkyl)-CO2H groups, hydroxyl groups, halogen groups, and C1-C6 alkoxy groups;

[0079] R 10 is selected from hydrogen and C1-C6 alkyl groups;

[0080] R 2 or R 3 One of them is selected from hydrogen and C1-C6 alkyl groups, and the other is selected from hydrogen, -OR 10 、-OC(O)R 10 、-OC(O)R 1 , and C1-C6 alkyl groups;

[0081] R 4 selected from hydrogen and hydroxyl;

[0082] R 5 and R 6 Each independently selected from C1-C6 alkyl groups;

[0083] R7 and R8 are each independently selected from hydrogen, hydroxyl, C1-C6 alkoxy group, and C1-C6 alkyl group; and

[0084] Y is selected from phenyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, wherein Y may be unsubstituted or independently selected from oxo, C1-C6 alkyl, C3-C5 cycloalkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, methoxy C1-C6 alkyl, -NR 11 R 12 Group, as well as The group is substituted 1-3 times, wherein R 11 and R 12 are each independently selected from hydrogen and a C1-C6 alkyl group.

[0085] Item 2. The compound according to Item 1, wherein Y is

[0086] Item 3. The compound according to Item 1, wherein Y is an optionally substituted phenyl group.

[0087] Item 4. The compound according to Item 1, wherein R 1 Selected from methyl, Group, Group, Group, Group, Group, Group, Groups, and group.

[0088] Item 5. A compound selected from compounds having Formula II:

[0089]

[0090] and pharmaceutically acceptable salts thereof,

[0091] in:

[0092] X is selected from O, NR' groups, and CH2, wherein R' is selected from hydrogen and C1-C6 alkyl groups;

[0093] R 1 Selected from methyl, -NR 11 R 12 Group, Groups, and Group,

[0094] R 10 is selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and halogenated C1-C6 alkyl groups, wherein these C3-C8 cycloalkyl groups may be unsubstituted or substituted 1-3 times by groups independently selected from C1-C6 alkyl groups, hydroxyl groups, halogen groups, and C1-C6 alkoxy groups;

[0095] R 11 and R 12 Each independently selected from C1-C6 alkyl groups;

[0096] R 2 or R 3 One of the following is selected from hydrogen and a C1-C6 alkyl group, and the other is selected from hydrogen, a hydroxyl group, and a C1-C6 alkyl group;

[0097] R 4 or R 5 One of is hydrogen, and the other is selected from hydrogen, hydroxyl, and

[0098] R 6 and R 7 Each independently selected from C1-C6 alkyl groups;

[0099] R 8 and R 9 are each independently selected from hydrogen and a C1-C6 alkyl group; or R 8 and R 9 together form a cyclopropyl ring; and

[0100] Y is selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, methoxy groups, and -NR 13 R 14 Group, where R 13 and R 14 are each independently selected from hydrogen, a C1-C6 alkyl group, and a methoxy C1-C6 alkyl group; or R 13 and R 14 Together with N, it can form a group selected from the following

[0101] morpholine, piperidine, thiazolidine, indole, indoline, and isoindoline rings;

[0102] wherein Y may be unsubstituted or independently selected from C1-C6 alkyl groups, hydroxyl, hydroxy C1-C6 alkyl groups, methoxy, methoxy C1-C6 alkyl groups, halogen, halogenated C1-C6 alkyl groups, -C(O)NH2, -NHCOO-C1-C6 alkyl groups, -COOH, and -NR 15 R 16 The group is substituted 1-3 times, wherein R 15 and R 16 are each independently selected from hydrogen and a C1-C6 alkyl group.

[0103] Item 6. A compound selected from compounds having Formula III:

[0104]

[0105] and pharmaceutically acceptable salts thereof,

[0106] in:

[0107] n is selected from 0, 1 and 2;

[0108] m is selected from 1, 2 and 3;

[0109] R 1 Selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, -NR 11 R 12 Group, Group, Group, Group, Group, Group, Group, Group, Groups, and Group,

[0110] R 11 Selected from hydrogen, -NR 16 R 17 Group, C1-C6 alkyl group, -(C1-C6 alkyl)-CO2H group, -(C1-C6 alkyl)-CO2R 12 Group, -(C1-C6 alkyl)-NR 16 R 17 Groups, C3-C8 cycloalkyl groups, and C3-C8 heterocyclyl groups, wherein these -NR 11 R 12 Groups, C1-C6 alkyl groups, C3-C8 cycloalkyl groups and C3-C8 heterocyclyl groups may be unsubstituted or substituted 1-3 times by groups independently selected from C1-C6 alkyl groups, -(C1-C6 alkyl)-CO2H groups, hydroxyl groups, halogen groups and C1-C6 alkoxy groups;

[0111] R 12 is selected from hydrogen and C1-C6 alkyl groups;

[0112] R 2 or R 3 One of them is selected from hydrogen and C1-C6 alkyl groups, and the other is selected from hydrogen, -OR 10 、-OC(O)R 10 、-OC(O)R 1 , and C1-C6 alkyl groups;

[0113] R 4 is hydrogen or hydroxyl;

[0114] R 5 and R 6 Each independently selected from C1-C6 alkyl groups;

[0115] R7 and R8 are each independently selected from hydrogen, hydroxyl, C1-C6 alkoxy group, and C1-C6 alkyl group; and

[0116] R 9 and R 10 are each independently selected from hydrogen, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group; or, R 9 or R 10 One of the is oxo and the other is absent;

[0117] Z is selected from C1-C6 alkyl groups, -C(O)-C1-C6 alkyl groups, -OR 13 , and -NR 14 R 15 Group,

[0118] where R13 is selected from hydrogen, a C1-C6 alkyl group, and a -C(O)-C1-C6 alkyl group,

[0119] where R 14 and R 15 are each independently selected from hydrogen, a C1-C6 alkyl group, and a methoxy C1-C6 alkyl group; or R 14 and R 15 Together with N, it can form a group selected from the following

[0120] morpholine, piperidine, thiazolidine, indole, indoline, and isoindoline rings;

[0121] wherein Z may be unsubstituted or independently selected from C1-C6 alkyl groups, C3-C5 cycloalkyl groups, hydroxy C1-C6 alkyl groups, C1-C6 alkoxy groups, methoxy C1-C6 alkyl groups, -NR 16 R 17 Group, as well as The group is substituted 1-3 times, wherein R 16 and R 17 are each independently selected from hydrogen and a C1-C6 alkyl group.

[0122] Item 7. The compound according to Item 6, wherein R 1 Selected from methyl, Group, Group, Group, Group, Group, Group, Group, Groups, and group.

[0123] Item 8. A compound selected from:

[0124] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-9-oxo-9-pyrrolidin-1-ylnona-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0125] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[[(2R,3R)-3-hydroxypentan-2-yl]carbamoyloxy]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0126] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-(propylcarbamoyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0127] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propyl)carbamoyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0128] Pyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0129] 4-Cycloheptyl-4-oxopiperazin-4-ium-1-carboxylate [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propyl)carbamoyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0130] [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(dimethylcarbamoyloxy)-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0131] [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-(diethylcarbamoyloxy)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0132] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propan-2-yl)carbamoyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0133] [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[butyl(methyl)carbamoyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0134] [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[but-2-yl(methyl)carbamoyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0135] (2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-carbamoyloxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0136] (2R)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid [(2S,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0137] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[2-methoxyethyl(methyl)carbamoyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0138] Azetidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0139] (2S)-2-methylpyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0140] (2S)-2-methylpyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0141] Piperidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0142] (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0143] (2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] (3R)-3-hydroxypyrrolidine-1-carboxylate;

[0144] Morpholine-4-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0145] 4-Methylpiperazine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0146] 3-Thiazolidinecarboxylic acid [(2R,3E,5E)-6-[(2R,3S,4E,6R,7R,10R)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0147] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0148] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0149] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0150] 1,3-Dihydroisoindole-2-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0151] Indole-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0152] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[2-(1-hydroxyethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0153] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,2-dimethylpyrrolidin-1-carbonyl)oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0154] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2S,5S)-2,5-dimethylpyrrolidin-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0155] 2,3-Dihydroindole-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0156] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0157] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0158] 2-Oxa-5-azaspiro[3.4]octane-5-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0159] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0160] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0161] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-6-[6-[(2R)-1-hydroxypropan-2-yl]pyridin-2-yl]hept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl]acetate;

[0162] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E)-6-[2-(dimethylamino)pyrimidin-4-yl]hept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0163] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0164] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridazin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0165] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrimidin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0166] 4-Propan-2-ylpiperazine-1-carboxylic acid [(2R,3R,4E,6S,7R,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6R)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0167] 4-tert-Butylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0168] 4-Cyclopentylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0169] 4-(oxan-4-yl)piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0170] 6-cycloheptyl-2,6-diazaspiro[3.3]heptane-2-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0171] 4-Cycloheptyl-3-methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0172] 4-Cyclobutylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0173] N-Methyl-N-(1-methylpiperidin-4-yl)carbamic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0174] Morpholine-4-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0175] (1S,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid [(2R,3R,4E,6S,7R,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6R)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0176] 8-cycloheptyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0177] 4-Methyl-1,4-diazepane-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0178] 4-Cyclohexylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0179] Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0180] 4-Cycloheptyl-1,4-diazacycloheptane-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0181] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-hydroxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0182] 4-(Azepan-1-yl)piperidine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0183] 4-(8,8-Difluoro-3-azabicyclo[3.2.1]octan-3-yl)piperidine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0184] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-9-oxo-9-pyrrolidin-1-ylnona-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0185] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propyl)carbamoyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0186] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0187] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0188] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0189] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10R)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-10-(pyrrolidin-1-carbonyloxy)-1-oxacyclododecan-4-en-6-yl] ester;

[0190] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(2S)-2-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0191] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3R)-3-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0192] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3R)-3-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0193] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-carbamoylpyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0194] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[(2R)-2-(methoxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0195] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2S,5S)-2,5-dimethylpyrrolidin-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0196] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0197] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0198] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,2-dimethylpyrrolidin-1-carbonyl)oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0199] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10R)-2-[(2E,4E)-6,6-dimethyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0200] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E)-6,6-dimethyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-7-hydroxy-3,7-dimethyl-12-oxo-10-(pyrrolidin-1-carbonyloxy)-1-oxacyclododecan-4-en-6-yl] ester;

[0201] (2R)-1-[(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyloxy]carbonylpyrrolidine-2-carboxylic acid;

[0202] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(3-oxopyrrolidin-1-carbonyl)oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0203] 2-Oxa-7-azaspiro[3.4]octane-7-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0204] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0205] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-5-[1-(pyrrolidin-1-carbonyloxymethyl)cyclopropyl]penta-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0206] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3S,4R)-3,4-dihydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0207] (3S)-1-[(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyloxy]carbonylpyrrolidine-3-carboxylic acid;

[0208] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3S)-3-(dimethylamino)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0209] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,5-dihydropyrrole-1-carbonyloxy)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0210] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0211] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3S)-3-[(2-methylprop-2-yl)oxycarbonylamino]pyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0212] 3-Azabicyclo[3.1.0]hexane-3-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0213] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0214] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0215] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-2-ylhexa-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0216] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-(2-pyrrolidin-1-ylpyrimidin-4-yl)hept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0217] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrazin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0218] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E)-6-[2-(dimethylamino)pyrimidin-4-yl]hept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0219] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-(3-methylpyridin-2-yl)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0220] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-(4-methylpyridin-2-yl)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0221] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrimidin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0222] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridazin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0223] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrimidin-4-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0224] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyrimidin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0225] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyrimidin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0226] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-(4-methylpyrimidin-2-yl)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0227] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-(6-pyrrolidin-1-ylpyridin-2-yl)hept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0228] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0229] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0230] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0231] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0232] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0233] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0234] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0235] (2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0236] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0237] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0238] N,N-Dimethylcarbamic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0239] [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0240] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0241] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0242] Pyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6R)-6-(dimethylcarbamoyloxy)-3-methyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0243] (3R)-3-Hydroxypyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6R)-6-(dimethylcarbamoyloxy)-3-methyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0244] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0245] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-[(2S)-2-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0246] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0247] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0248] 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0249] [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0250] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0251] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0252] N,N-Dimethylcarbamic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0253] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E)-6-[2-(dimethylamino)pyrimidin-4-yl]hept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0254] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-(2-pyrrolidin-1-ylpyrimidin-4-yl)hept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0255] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-[2-[(3S)-3-triethylsilyloxypyrrolidin-1-yl]pyrimidin-4-yl]hept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0256] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E)-6-[2-[(3R)-3-hydroxypyrrolidin-1-yl]pyrimidin-4-yl]hept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0257] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-pyrimidin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0258] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0259] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0260] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0261] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3S)-3-(1-phenyltetrazol-5-yl)oxypyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0262] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0263] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0264] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0265] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0266] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonylamino)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0267] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]amino]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0268] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonylamino)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0269] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[methyl(pyrrolidine-1-carbonyl)amino]hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0270] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(4-cyclopropyltriazol-1-yl)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0271] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-methoxycarbonyloxy-6-methylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0272] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-9-methoxy-6-methyl-9-oxona-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0273] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(cyclopentanecarbonylamino)-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0274] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(cyclopentanecarbonylamino)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0275] 4-Cycloheptyl-1-piperazinecarboxylic acid [(2R,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-7-[oxo(1-pyrrolidinyl)methoxy]hept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0276] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0277] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-azacyclododecan-4-en-6-yl] ester;

[0278] Pyrrolidine-1-carboxylic acid [(2R,3E,5E)-2-methyl-6-[(2S,3S,4E,6R)-3-methyl-6-[(4-methylpiperazine-1-carbonyl)amino]-12-oxo-1-oxacyclododecan-4-en-2-yl]hept-3,5-dienyl] ester;

[0279] (2R,3R)-3-hydroxy-2-methylpentanoate [(2S,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0280] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-hydroxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0281] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-4-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0282] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0283] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0284] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-7-methyl-6-pyridin-2-yloct-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0285] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[(2R,3R)-3-[(2R,3R)-3-acetyloxypentan-2-yl]oxiran-2-yl]-6-hydroxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0286] [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-6-methyl-8-phenyloct-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0287] [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-6-phenylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0288] [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-6-thiophen-2-ylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0289] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-phenylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0290] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-6-(6-methoxypyridin-2-yl)hept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0291] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-[6-(2-methylpropyloxy)pyridin-2-yl]hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl]acetate;

[0292] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-methyl-8-pyridin-2-yloct-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0293] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-methyl-7-pyridin-2-ylhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0294] (2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E,6R)-6-hydroxy-6-methyl-8-phenyloct-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0295] (2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-2-ylhexa-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0296] (2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhexa-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0297] (2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-4-ylhexa-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0298] [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-8-(4-hydroxyphenyl)-6-methyloct-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0299] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-methyl-8-phenyloct-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0300] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-8-[2-(methoxymethyl)phenyl]-6-methylocta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0301] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-8-[4-(methoxymethyl)phenyl]-6-methylocta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0302] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-8-[3-(methoxymethyl)phenyl]-6-methylocta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0303] [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6S)-6-hydroxy-6-methyl-7-[(2R,3R)-3-[(2S)-3-oxopentan-2-yl]oxiran-2-yl]hept-2,4-dien-2-yl]-3,7-dimethyl-10,12-dioxo-1-oxacyclododecan-4-en-6-yl]acetate;

[0304] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6E,8S)-8-pyridin-2-ylnon-2,4,6-trien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0305] 4-Methyl-4-oxopiperazin-4-ium-1-carboxylate [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0306] 4-(4-Fluoropiperidin-1-yl)piperidine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0307] 4-(4,4-Difluoropiperidin-1-yl)piperidine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0308] (4S,7S,8S,9E,11S,12S)-4,7,8-trihydroxy-7,11-dimethyl-12-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-9-en-2-one;

[0309] Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7-acetyloxy-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0310] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl piperazine-1-carboxylate;

[0311] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((S,2E,4E)-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxadodec-4-en-6-yl piperazine-1-carboxylate; Piperazine-1-carboxylate (2S,3S,4E,6S,7S,10S)-6-acetyloxy-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-7-yl] ester;

[0312] Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7-acetyloxy-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0313] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7R,10R)-7-ethoxy-10-hydroxy-2-[(2E,4E,6R)-6-hydroxy-7-[(2R,3R)-3-[(2S,3S)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0314] Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-6-acetyloxy-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-7-yl] ester;

[0315] Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0316] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0317] N-Methyl-N-[2-(methylamino)ethyl]carbamate [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl]

[0318] N-Methyl-N-[2-(dimethylamino)ethyl]carbamate [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl]

[0319] 3-[4-[[(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl]oxycarbonyl]piperazin-2-yl]propanoic acid;

[0320] 4-[4-[[(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl]oxycarbonyl]piperazin-1-yl]butanoic acid;

[0321] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;

[0322] (2S,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-7-yl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;

[0323] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl)-4-propylpiperazine-1-carboxylate;

[0324] (2R,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((2S,6R,E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-4-en-2-yl)-3,7-dimethyl-12-oxooxadodec-4-en-7-yl 4-(2-hydroxyethyl)piperazine-1-carboxylate;

[0325] (2S,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-7-yl 4-methylpiperazine-1-carboxylate;

[0326] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl)-4-(2-aminoethyl)piperazine-1-carboxylate;

[0327] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl)-4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate;

[0328] (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl 4-methylpiperazine-1-carboxylate;

[0329] (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl piperazine-1-carboxylate;

[0330] and pharmaceutically acceptable salts thereof.

[0331] Item 9. The compound of any one of Items 1-8, wherein the compound is stereomerically pure.

[0332] Item 10. A pharmaceutical composition comprising the compound and / or pharmaceutically acceptable salt according to any one of Items 1 to 9.

[0333] Item 11. The pharmaceutical compound of Item 10, wherein the composition is formulated for intravenous, oral, subcutaneous or intramuscular administration.

[0334] Item 12. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound and / or pharmaceutically acceptable salt as described in any one of Items 1-9, or a pharmaceutical composition as described in Item 10 or Item 11.

[0335] Item 13. The method of Item 12, wherein the cancer is selected from myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer, breast cancer, uveal melanoma, gastric cancer, bile duct cancer, and lung cancer.

[0336] Item 14. The method of Item 13, wherein the cancer is selected from myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, and acute myeloid leukemia.

[0337] Item 15. The method of Item 13, wherein the cancer is myelodysplastic syndrome.

[0338] Item 16. The method of Item 13, wherein the cancer is chronic lymphocytic leukemia.

[0339] Item 17. The method of Item 13, wherein the cancer is chronic myelomonocytic leukemia.

[0340] Item 18. The method of Item 13, wherein the cancer is acute myeloid leukemia.

[0341] Item 19. The method of Item 13, wherein the cancer is colon cancer.

[0342] Item 20. The method of Item 13, wherein the cancer is pancreatic cancer.

[0343] Item 21. The method of Item 13, wherein the cancer is endometrial cancer.

[0344] Item 22. The method of Item 13, wherein the cancer is ovarian cancer.

[0345] Item 23. The method of Item 13, wherein the cancer is breast cancer.

[0346] Item 24. The method of Item 13, wherein the cancer is uveal melanoma.

[0347] Item 25. The method of Item 13, wherein the cancer is gastric cancer.

[0348] Item 26. The method of Item 13, wherein the cancer is bile duct cancer.

[0349] Item 27. The method of Item 13, wherein the cancer is lung cancer.

[0350] Item 28. The method of any one of Items 12-27, wherein the cancer is positive for one or more mutations in a spliceosomal gene or protein.

[0351] Item 29. A method as described in Item 28, wherein the spliceosomal gene or protein is selected from splicing factor 3B subunit 1 (SF3B1), U2 small nuclear RNA auxiliary factor 1 (U2AF1), serine / arginine-rich splicing factor 2 (SRSF2), zinc finger (CCCH type) RNA binding motif and serine / arginine-rich 2 (ZRSR2), pre-mRNA processing splicing factor 8 (PRPF8), U2 small nuclear RNA auxiliary factor 2 (U2AF2), splicing factor 1 (SF1), splicing factor 3a subunit 1 (SF3B1), U2 small nuclear RNA auxiliary factor 1 (U2AF ... The genes encoding the mitochondrial splicing factor 1 (M1), mitochondrial splicing factor 1 (M1), mitochondrial splicing factor 2 (M2), mitochondrial splicing factor 3 (M3), mitochondrial splicing factor 4 (M4), mitochondrial splicing factor 5 (M5), mitochondrial splicing factor 6 (M6), mitochondrial splicing factor 7 (M7), mitochondrial splicing factor 1 (M8), mitochondrial splicing factor 2 (M9), mitochondrial splicing factor 3 (M1), mitochondrial splicing factor 5 (M1), mitochondrial splicing factor 6 (M1), mitochondrial splicing factor 1 (M1), mitochondrial splicing factor 1 (M2), mitochondrial splicing factor 2 (M1), mitochondrial splicing factor 3 ...1), mitochondrial splicing factor 2 (M2), mitochondrial splicing factor 1 (M1), mitochondrial splicing factor 1 (M1), mitochondrial splicing factor 1 (

[0352] Item 30. The method of Item 29, wherein the spliceosomal gene or protein is splicing factor 3B subunit 1 (SF3B1).

[0353] Item 31. Use of the compound and / or pharmaceutically acceptable salt described in any one of Items 1 to 9, or the pharmaceutical composition described in Item 10 or Item 11, in the preparation of a medicament for treating cancer.

[0354] Item 32. The use as described in Item 31, wherein the cancer is selected from myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer, breast cancer, uveal melanoma, gastric cancer, bile duct cancer, and lung cancer.

[0355] Item 33. The use according to Item 32, wherein the cancer is selected from myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, and acute myeloid leukemia.

[0356] Item 34. The use according to Item 32, wherein the cancer is myelodysplastic syndrome.

[0357] Item 35. The use according to Item 32, wherein the cancer is chronic lymphocytic leukemia.

[0358] Item 36. The use according to Item 32, wherein the cancer is chronic myelomonocytic leukemia.

[0359] Item 37. The use according to Item 32, wherein the cancer is acute myeloid leukemia.

[0360] Item 38. The use according to Item 32, wherein the cancer is colon cancer.

[0361] Item 39. The use according to Item 32, wherein the cancer is pancreatic cancer.

[0362] Item 40. The use according to Item 32, wherein the cancer is endometrial cancer.

[0363] Item 41. The use according to Item 32, wherein the cancer is ovarian cancer.

[0364] Item 42. The use according to Item 32, wherein the cancer is breast cancer.

[0365] Item 43. The use of Item 32, wherein the cancer is uveal melanoma.

[0366] Item 44. The use according to Item 32, wherein the cancer is gastric cancer.

[0367] Item 45. The use according to Item 32, wherein the cancer is bile duct cancer.

[0368] Item 46. The use according to Item 32, wherein the cancer is lung cancer.

[0369] Item 47. The use of any one of Items 31-46, wherein the cancer is positive for one or more mutations in a spliceosomal gene or protein.

[0370] Item 48. The use according to Item 47, wherein the spliceosomal gene or protein is selected from splicing factor 3B subunit 1 (SF3B1), U2 small nuclear RNA auxiliary factor 1 (U2AF1), serine / arginine-rich splicing factor 2 (SRSF2), zinc finger (CCCH type) RNA binding motif and serine / arginine-rich 2 (ZRSR2), pre-mRNA processing splicing factor 8 (PRPF8), U2 small nuclear RNA auxiliary factor 2 (U2AF2), splicing factor 1 (SF1), splicing factor 3a subunit 1 (SF3B1), U2 small nuclear RNA auxiliary factor 1 (U2AF ... The genes encoding the mitochondrial splicing factor 1 (M1), mitochondrial splicing factor 1 (M1), mitochondrial splicing factor 2 (M2), mitochondrial splicing factor 3 (M3), mitochondrial splicing factor 4 (M4), mitochondrial splicing factor 5 (M5), mitochondrial splicing factor 6 (M6), mitochondrial splicing factor 7 (M7), mitochondrial splicing factor 1 (M8), mitochondrial splicing factor 2 (M9), mitochondrial splicing factor 3 (M1), mitochondrial splicing factor 5 (M1), mitochondrial splicing factor 6 (M1), mitochondrial splicing factor 1 (M1), mitochondrial splicing factor 1 (M2), mitochondrial splicing factor 2 (M1), mitochondrial splicing factor 3 ...1), mitochondrial splicing factor 2 (M2), mitochondrial splicing factor 1 (M1), mitochondrial splicing factor 1 (M1), mitochondrial splicing factor 1 (

[0371] Item 49. The use according to Item 48, wherein the spliceosomal gene or protein is splicing factor 3B subunit 1 (SF3B1).

[0372] Item 50. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or a pharmaceutical composition of Item 10 or Item 11; and

[0373] At least one additional therapy.

[0374] Item 51. The method of Item 50, wherein the at least one additional therapy comprises at least one, at least two, at least three, at least four, or at least five additional therapies.

[0375] Item 52. The method of Item 50, wherein the amount of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11, and / or the at least one additional therapy administered is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% relative to the standard dose of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11, and / or the at least one additional therapy.

[0376] Item 53. A method as described in any of Items 50 to 52, wherein the compound as described in any of Items 1-9 and / or the pharmaceutically acceptable salt, or the pharmaceutical composition as described in Item 10 or Item 11, and / or the at least one additional therapy is administered at a frequency that is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% less than the standard dosing regimen of the compound as described in any of Items 1-9 and / or the pharmaceutical composition as described in Item 10 or Item 11, and / or the at least one additional therapy.

[0377] Item 54. The method of any one of Items 50 to 53, wherein the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11, and / or the at least one additional therapy is administered in an amount and / or dose that results in lower systemic toxicity and / or improved tolerability.

[0378] Item 55. The method of Item 50, wherein administration of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11, is initiated prior to administration of the at least one additional therapy.

[0379] Item 56. The method of Item 50, wherein administration of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11 is initiated after administration of the at least one additional therapy.

[0380] Item 57. The method of Item 50, wherein administration of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11, is initiated simultaneously with administration of the at least one additional therapy.

[0381] Item 58. The method of any one of Items 50 to 57, wherein, after the initial administration, the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11 is repeatedly administered at least once.

[0382] Item 59. The method of Item 58, wherein the amount of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11 for repeated administration is reduced relative to the amount for initial administration.

[0383] Item 60. The method of Item 58, wherein the amount of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11 for repeated administration is reduced relative to a standard dose of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11.

[0384] Item 61. The method of Item 58, wherein the amount of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11 for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% relative to the standard dose of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11.

[0385] Item 62. The method of any one of Items 50 to 61, wherein, after the initial administration, the at least one additional therapy is repeated at least once.

[0386] Item 63. The method of Item 62, wherein the amount of the at least one additional therapy for repeated administration is reduced relative to the amount for initial administration.

[0387] Item 64. The method of Item 62, wherein the amount of the at least one additional therapy for repeated administration is reduced relative to a standard dose of the at least one additional therapy.

[0388] Item 65. A method as described in Item 62, wherein the amount of the at least one additional therapy for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% relative to the standard dose of the at least one additional therapy.

[0389] Item 66. The method of any one of Items 50 to 65, wherein repeated administration of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11 is concurrent with repeated administration of the at least one additional therapy.

[0390] Item 67. The method of any one of Items 50 to 65, wherein repeated administration of the compound and / or pharmaceutically acceptable salt of any one of Items 1-9, or the pharmaceutical composition of Item 10 or Item 11 is continuous or interleaved with repeated administration of the at least one additional therapy.

[0391] Item 68. The method of any one of Items 50 to 67, wherein the at least one additional therapy comprises administration of a checkpoint inhibitor.

[0392] Item 69. The method of Item 68, wherein the subject is intolerant, unresponsive, or poorly responsive to the checkpoint inhibitor when administered alone.

[0393] Item 70. The method of Item 68, wherein the checkpoint inhibitor targets CTLA4, PD1, PDL1, OX40, CD40, GITR, LAG3, TIM3, and / or KIR.

[0394] Item 71. The method of Item 68, wherein the checkpoint inhibitor targets CTLA4, OX40, CD40, and / or GITR.

[0395] Item 72. The method of Item 70 or Item 71, wherein the checkpoint inhibitor comprises a cytotoxic T lymphocyte-associated antigen 4 pathway (CTLA4) inhibitor.

[0396] Item 73. The method of Item 72, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

[0397] Item 74. The method of Item 73, wherein the anti-CTLA4 antibody is ipilimumab.

[0398] Item 75. The method of Item 70 or Item 71, wherein the checkpoint inhibitor comprises a programmed death-1 pathway (PD1) inhibitor.

[0399] Item 76. The method of Item 75, wherein the PD1 inhibitor is an anti-PD1 antibody.

[0400] Item 77. The method of Item 76, wherein the anti-PD1 antibody is nivolumab.

[0401] Item 78. The method of Item 75, wherein the PD1 inhibitor is an anti-PDL1 antibody.

[0402] Item 79. The method of Item 78, wherein the anti-PDL1 antibody is atezolizumab.

[0403] Item 80. The method of Item 70 or Item 71, wherein the checkpoint inhibitor comprises a CTLA4 inhibitor and a PD1 inhibitor.

[0404] Item 81. The method of Item 80, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

[0405] Item 82. The method of Item 81, wherein the anti-CTLA4 antibody is ipilimumab.

[0406] Item 83. The method of Item 80 or Item 81, wherein the PD1 inhibitor is an anti-PD1 antibody.

[0407] Item 84. The method of Item 83, wherein the anti-PD1 antibody is nivolumab.

[0408] Item 85. The method of Item 80 or Item 81, wherein the PD1 inhibitor is an anti-PDL1 antibody.

[0409] Item 86. The method of Item 85, wherein the anti-PDL1 antibody is atezolizumab.

[0410] Item 87. The method of any one of Items 50 to 67, wherein the at least one additional therapy comprises administration of a cytokine or a cytokine analog.

[0411] Item 88. The method of Item 87, wherein the subject is intolerant to, unresponsive to, or poorly responsive to the cytokine or cytokine analog when administered alone.

[0412] Item 89. The method of Item 87, wherein the cytokine or cytokine analog comprises a T cell enhancer.

[0413] Item 90. The method of Item 87, wherein the cytokine or cytokine analog comprises IL-2, IL-10, IL-12, IL-15, IFNγ, and / or TNFα.

[0414] Item 91. The method of any one of Items 50 to 67, wherein the at least one additional therapy comprises administration of engineered tumor-targeting T cells.

[0415] Item 92. The method of any one of Items 50 to 91, wherein the subject has a non-synonymous mutation burden of approximately 150 mutations or fewer.

[0416] Item 93. The method of any one of Items 50 to 92, wherein the subject has a non-synonymous mutation burden of approximately 100 mutations or fewer.

[0417] Item 94. The method of any one of Items 50 to 93, wherein the subject has a non-synonymous mutation burden of approximately 50 mutations or fewer.

[0418] Item 95. The method of any one of Items 50 to 94, wherein the cancer is a hematological malignancy or a solid tumor.

[0419] Item 96. The method of Item 95, wherein the hematological malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myeloma.

[0420] Item 97. The method of Item 95 or Item 96, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma.

[0421] Item 98. The method of Item 95, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, and esophageal cancer.

[0422] Item 99. A method as described in any one of Items 50 to 94, wherein the cancer is selected from myelodysplastic syndrome, chronic lymphocytic leukemia, acute lymphocytic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer, breast cancer, uveal melanoma, gastric cancer, bile duct cancer, and lung cancer.

[0423] Item 100. A method for inducing at least one new antigen, the method comprising contacting tumor cells with a therapeutically effective amount of a compound and / or a pharmaceutically acceptable salt as described in any one of Items 1-9, or a pharmaceutical composition as described in Item 10 or Item 11, thereby inducing the production of at least one new antigen.

[0424] Item 101. The method of Item 100, wherein the tumor cells are present in an in vitro cell culture.

[0425] Item 102. The method of Item 100 or Item 101, wherein the tumor cells are obtained from a subject.

[0426] Item 103. The method of Item 100, wherein the tumor cell is present in a subject.

[0427] Item 104. The method of any one of Items 100 to 103, wherein the tumor cell is derived from a hematological malignancy or a solid tumor.

[0428] Item 105. The method of Item 104, wherein the hematological malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myeloma.

[0429] Item 106. The method of Item 104 or Item 105, wherein the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma.

[0430] Item 107. The method of Item 104, wherein the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, and esophageal cancer.

[0431] Item 108. A method for inducing at least one neoantigen and / or T cell response in a subject having or suspected of having a neoplastic disease, the method comprising administering to the subject a therapeutically effective amount of a compound and / or pharmaceutically acceptable salt as described in any one of Items 1-9, or a pharmaceutical composition as described in Item 10 or Item 11.

[0432] Item 109. A method for treating a subject having or suspected of having a neoplastic disease, the method comprising administering to the subject a therapeutically effective amount of a compound and / or pharmaceutically acceptable salt as described in any one of Items 1-9, or a pharmaceutical composition as described in Item 10 or Item 11, wherein administration of the compound and / or pharmaceutically acceptable salt, or pharmaceutical composition induces at least one neoantigen and / or T cell response.

[0433] Item 110. The method of Item 109, wherein the amount of the compound and / or pharmaceutically acceptable salt, or pharmaceutical composition administered is reduced relative to a standard dose of the compound and / or pharmaceutically acceptable salt, or pharmaceutical composition due to the induction of at least one neoantigen and / or T cell response.

[0434] Item 111. The method of Item 110, wherein the amount of the compound and / or pharmaceutically acceptable salt, or pharmaceutical composition administered is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% relative to a standard dose of the compound and / or pharmaceutically acceptable salt, or pharmaceutical composition.

[0435] Item 112. The method of any one of Items 109 to 111, wherein the compound and / or pharmaceutically acceptable salt, or pharmaceutical composition is administered at a frequency that is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% less relative to the standard dosing regimen of the compound and / or pharmaceutically acceptable salt, or pharmaceutical composition.

[0436] Item 113. The method of any one of Items 109 to 111, wherein the amount and / or dosage of the compound and / or pharmaceutically acceptable salt, or pharmaceutical composition administered results in lower systemic toxicity and / or improved tolerability.

[0437] Item 114. The method of any one of Items 108 to 113, further comprising administering at least one additional therapy.

[0438] As described herein, the compounds of the present disclosure may be substituted with one or more substituents, such as those generally described herein, or as exemplified by the specific classes, subclasses, and species of the present disclosure. Typically, the term "substituted" refers to the replacement of hydrogen radicals in a given structure with the free radicals of specific substituents. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group, and when one or more positions in any given structure may be substituted by one or more substituents selected from a specified group, the substituent may be the same or different at each position. The combination of substituents contemplated by the present disclosure is that which results in the formation of stable or chemically feasible compounds.

[0439] "Stable" refers to compounds that do not substantially alter chemically and / or physically when subjected to conditions that allow their production, detection, recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that does not substantially alter when kept at a temperature of 40° C. or below, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0440] "Isomers" refer to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ in the arrangement or configuration of the atoms. "Stereoisomers" refer to compounds that have the same atomic connectivity but differ in the arrangement of their atoms in space. "Diastereomers" or "diastereomers" refer to stereoisomers that are not enantiomers. "Enantiomers" refer to stereoisomers that are non-superimposable mirror images of one another.

[0441] Enantiomers as taught herein can include "enantiomerically pure" isomers, which contain substantially a single enantiomer at one or more particular asymmetric centers, for example, greater than or equal to 90%, 92%, 95%, 98%, or 99%, or equal to 100% of a single enantiomer. An "asymmetric center" or "chiral center" refers to a tetrahedral carbon atom containing four different substituents.

[0442] As used herein, "stereomerically pure" refers to a compound or composition thereof that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of the compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. In some embodiments, a stereomerically pure composition of a compound having two chiral centers will be substantially free of diastereomers of the compound and substantially free of the opposite enantiomer. In some embodiments, a stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, such as greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, further such as greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, and further such as greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. See, e.g., U.S. Patent No. 7,189,715.

[0443] "R" and "S," as terms describing isomers, are descriptors of the stereochemical configuration at an asymmetrically substituted carbon atom. Designation of an asymmetrically substituted carbon atom as "R" or "S" is accomplished by applying the Cahn-Ingold-Prelog priority rules, as is well known to those skilled in the art and as described in the International Union of Pure and Applied Chemistry (IUPAC) Rules of Organic Nomenclature, Part E, Stereochemistry.

[0444] "Amine oxides" or "amine-N-oxides" or "N-oxides" are compounds containing the functional group R 3 N + -O - (having three additional hydrogens and / or hydrocarbon side chains attached to the N-O bonds). Sometimes written as R 3 N→O.

[0445] "Ar" or "aryl" refers to an aromatic carbocyclic moiety having one or more closed rings. Examples include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, biphenyl, and pyrenyl.

[0446] "Heteroaryl" refers to a cyclic moiety having one or more closed rings, one or more heteroatoms (oxygen, nitrogen, or sulfur) in at least one of these rings, wherein at least one of these rings is aromatic, and wherein the ring(s) can independently be fused and / or bridged. Examples include, but are not limited to, phenyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl.

[0447] As used herein, "alkyl" or "alkyl group" means a fully saturated straight chain (i.e., unbranched), branched or cyclic hydrocarbon chain. In certain embodiments, the alkyl group contains 1-8 carbon atoms. In certain embodiments, the alkyl group contains 1-6 carbon atoms ("C1-C6 alkyl group"). In certain embodiments, the alkyl group contains 1-3 carbon atoms. In other embodiments, the alkyl group contains 2-3 carbon atoms, and in certain embodiments, the alkyl group contains 1-2 carbon atoms. In certain embodiments, the term "alkyl" or "alkyl group" refers to a cycloalkyl group, also referred to as a carbocycle. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl and cyclohexyl.

[0448] As used herein, "alkoxy" refers to an alkyl group as previously defined attached to the main carbon chain through an oxygen ("alkoxy") atom.

[0449] "Haloalkyl" refers to an alkyl group substituted with one or more halogen atoms (F, Cl, Br, I). For example, "fluoromethyl" refers to a methyl group substituted with one or more fluorine atoms (e.g., monofluoromethyl, difluoromethyl, or trifluoromethyl).

[0450] "Heteroatom" refers to O, S or N.

[0451] As used herein, "heterocyclyl" or "heterocyclic" means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle containing at least one heteroatom in the ring.

[0452] Monocyclic heterocycles are 3-, 4-, 5-, 6-, 7-, or 8-membered rings containing at least one heteroatom independently selected from O, N, and S. In some embodiments, heterocycles are 3- or 4-membered rings containing one heteroatom selected from O, N, and S. In some embodiments, heterocycles are 5-membered rings containing zero or one double bond and one, two, or three heteroatoms selected from O, N, and S. In some embodiments, heterocycles are 6-, 7-, or 8-membered rings containing zero, one, or two double bonds and one, two, or three heteroatoms selected from O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, dihydropyranyl (including 3,4-dihydro-2H-pyran-6-yl), 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, Diazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl (including tetrahydro-2H-pyran-4-yl), tetrahydrothiophenyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl.

[0453] The bicyclic heterocycle of the present disclosure includes a monocyclic heterocycle fused to an aryl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle. Examples of bicyclic heterocycles include, but are not limited to, 3,4-dihydro-2H-pyranyl, 1,3-benzodioxolyl, 1,3-benzodithiolene, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl.

[0454] In some embodiments, the bicyclic heterocycle is a spiroheterocycle. As is known in the art, a "spiro" heterocycle is a bicyclic moiety in which the rings are connected by only one atom. The connecting atom is also called a spiro atom and is most commonly a quaternary atom, such as carbon or nitrogen. Spirocyclic compounds can be named using the infix spiro followed by square brackets containing the number of atoms in the smaller ring and the number of atoms in the larger ring, excluding the spiro atom itself; the numbers are separated by a dot. A non-limiting example of such a compound is 2,6-diazaspiro[3.3]heptane.

[0455] A tricyclic heterocycle is a bicyclic heterocycle fused to an aryl group, a bicyclic heterocycle fused to a monocyclic cycloalkyl group, a bicyclic heterocycle fused to a monocyclic cycloalkenyl group, or a bicyclic heterocycle fused to a monocyclic heterocycle. Representative examples of tricyclic heterocycles include, but are not limited to, 2,3,4,4a,9,9a-hexahydro-1H-carbazolyl, 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl, and 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl.

[0456] The heterocyclic groups disclosed herein are attached to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen, oxygen, or sulfur atom contained within the group, and may contain one or two alkylene bridges having 1, 2, 3, or 4 carbon atoms, each connecting two non-adjacent carbon atoms of the group. Examples of such "bridged" heterocyclic groups include, but are not limited to, oxatricyclo[3.3.1.1 3,7 ]Decyl (including 2-oxatricyclo[3.3.1].1 3,7] decyl), 2,4-dioxabicyclo[4.2.1]nonyl, oxabicyclo[2.2.1]heptyl (including 2-oxabicyclo[2.2.1]heptyl), and 2,5-diazabicyclo[2.2.1]heptane.

[0457] In the above heteroaryl and heterocyclic groups, the nitrogen or sulfur atoms may be optionally oxidized to various oxidation states. In a specific embodiment, the group S(O) 0-2 refers to -S- (sulfide), -S(O)- (sulfoxide), and -SO2- (sulfone), respectively. For convenience, nitrogen, particularly but not exclusively, those defined as cyclic aromatic nitrogens, are meant to include those corresponding N-oxide forms. Thus, for a compound of the disclosure having, for example, a pyridyl ring; the corresponding pyridyl-N-oxide is meant to be included as another compound of the disclosure.

[0458] "Treatment," "treat," or "treating" cancer refers to reversing (e.g., overcoming a differentiation block in a cell), alleviating (e.g., alleviating one or more symptoms, such as fatigue caused by anemia, low blood counts, etc.), and / or delaying the progression of a cancer as described herein (e.g., delaying the progression of a condition, such as transformation to AML).

[0459] As used herein, "subject" means an animal subject, such as a mammalian subject, and particularly a human.

[0460] The term "antibody" is used in the broadest sense to refer to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or a combination of the foregoing, through at least one antigen recognition site within the variable region of the immunoglobulin molecule. The heavy chain of an antibody consists of a heavy chain variable domain (VH ) and heavy chain constant region (C H ). The light chain is composed of the light chain variable domain (V L ) and the light chain constant domain (C L ) composition. For the purposes of this application, mature heavy and light chain variable domains each comprise three complementary determining regions (CDR1, CDR2, and CDR3) within four framework regions (FR1, FR2, FR3, and FR4) arranged from N-terminus to C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. An "antibody" can be naturally occurring or artificial, such as a monoclonal antibody produced by conventional hybridoma technology. The term "antibody" includes full-length monoclonal antibodies and full-length polyclonal antibodies, as well as antibody fragments such as Fab, Fab', F(ab')2, Fv, and single-chain antibodies. An antibody can be any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or a subclass thereof (e.g., isotype IgG1, IgG2, IgG3, IgG4). The term further encompasses human antibodies, chimeric antibodies, humanized antibodies, and any modified immunoglobulin molecule that contains an antigen recognition site so long as it exhibits the desired biological activity (e.g., binding to target antigen, internalization in target antigen-expressing cells).

[0461] As used herein, "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, cyclodextrin, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0462] "Pharmaceutically acceptable salts" are salts that retain the desired biological activity of the parent compound and do not impart undesirable toxicological effects. Examples of such salts are: (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (b) salts formed with elemental anions such as chloride, bromide, and iodide. See, e.g., Haynes et al., "Commentary: Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Structural Database," J. Pharmaceutical Sciences, Vol. 94, No. 10 (2005), and Berge et al., "Pharmaceutical Salts," J. Pharmaceutical Sciences, Vol. 66, No. 1 (1977), incorporated herein by reference.

[0463] Unless otherwise indicated, the nomenclature used herein to describe chemical groups or moieties follows the convention that the name is read from left to right, with the point of attachment to the rest of the molecule to the right of the name. For example, the group "(C 1-3 Alkoxy) C 1-3 The "alkyl" group is attached to the remainder of the molecule at the alkyl terminus. Further examples include methoxyethyl, where the point of attachment is at the ethyl terminus, and methylamino, where the point of attachment is at the amine terminus.

[0464] Unless otherwise indicated, when a chemical group is described by a chemical formula or structure having a terminal bond moiety indicated by a "-", it is understood that the "-" indicates the point of attachment.

[0465] Unless otherwise stated, the compounds depicted herein include all enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure. In addition, unless otherwise stated, the structures depicted herein include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a compound having a formula disclosed herein, except for the replacement of hydrogen with deuterium or tritium, or with an enriched 13 C or 14 Such compounds are useful as analytical tools or probes in, for example, biological assays.

[0466] According to some embodiments, provided herein are compounds having Formula I:

[0467]

[0468] and pharmaceutically acceptable salts thereof,

[0469] in:

[0470] n is selected from 0, 1, 2 or 3;

[0471] R 1 Selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, -NR 9 R 10 Group, Group, Group, Group, Group, Group, Group, Groups, and group;

[0472] R 9 Selected from hydrogen, -NR 11 R 12 Groups, C1-C6 alkyl groups, -(C1-C6 alkyl)-CO2H groups, C3-C8 cycloalkyl groups, and C3-C8 heterocyclyl groups, wherein these -NR 11 R 12Groups, C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and C3-C8 heterocyclyl groups may be unsubstituted or substituted 1-3 times by groups independently selected from C1-C6 alkyl groups, -(C1-C6 alkyl)-CO2H groups, hydroxyl groups, halogen groups, and C1-C6 alkoxy groups;

[0473] R 10 is selected from hydrogen and C1-C6 alkyl groups;

[0474] R 2 or R 3 One of them is selected from hydrogen and C1-C6 alkyl groups, and the other is selected from hydrogen, -OR 10 、-OC(O)R 10 、-OC(O)R 1 , and C1-C6 alkyl groups;

[0475] R 4 selected from hydrogen and hydroxyl;

[0476] R 5 and R 6 Each independently selected from C1-C6 alkyl groups;

[0477] R7 and R8 are each independently selected from hydrogen, hydroxyl, C1-C6 alkoxy group, and C1-C6 alkyl group; and

[0478] Y is selected from phenyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, wherein Y may be unsubstituted or independently selected from oxo, C1-C6 alkyl, C3-C5 cycloalkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, methoxy C1-C6 alkyl, -NR 11 R 12 Group, as well as The group is substituted 1-3 times, wherein R 11 and R 12 are each independently selected from hydrogen and a C1-C6 alkyl group.

[0479] In some embodiments, in Formula I, Y is

[0480] In some embodiments, in Formula I, Y is selected from an optionally substituted phenyl group.

[0481] In some embodiments, in Formula I, R 1 Selected from methyl, Group, Group, Group, Group, Group, Group, Groups, and Group, where R 9 、R 10 、R 11 and R 12 As defined above.

[0482] Also provided herein are compounds having Formula II:

[0483]

[0484] and pharmaceutically acceptable salts thereof,

[0485] in:

[0486] X is selected from O, NR' groups, and CH2, wherein R' is selected from hydrogen and C1-C6 alkyl groups;

[0487] R 1 Selected from methyl, NR 11 R 12 Group, Groups, and group;

[0488] R 10 is selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and halogenated C1-C6 alkyl groups, wherein these C3-C8 cycloalkyl groups may be unsubstituted or substituted 1-3 times by groups independently selected from C1-C6 alkyl groups, hydroxyl groups, halogen groups, and C1-C6 alkoxy groups;

[0489] R 11 and R 12 Each independently selected from C1-C6 alkyl groups;

[0490] R 2 or R 3 One of the following is selected from hydrogen and a C1-C6 alkyl group, and the other is selected from hydrogen, a hydroxyl group, and a C1-C6 alkyl group;

[0491] R 4 or R 5 One of is hydrogen, and the other is selected from hydrogen, hydroxyl, and

[0492] R 6 and R 7 Each independently selected from C1-C6 alkyl groups;

[0493] R 8 and R 9 are each independently selected from hydrogen and a C1-C6 alkyl group; or R8 and R 9 together form a cyclopropyl ring; and

[0494] Y is selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, methoxy groups, and -NR 13 R 14 Group, where R 13 and R 14 are each independently selected from hydrogen, a C1-C6 alkyl group, and a methoxy C1-C6 alkyl group; or R 13 and R 14 Together with N, it can form a group selected from the following

[0495] morpholine, piperidine, thiazolidine, indole, indoline, and isoindoline rings;

[0496] wherein Y may be unsubstituted or independently selected from C1-C6 alkyl groups, hydroxyl, hydroxy C1-C6 alkyl groups, methoxy, methoxy C1-C6 alkyl groups, halogen, halogenated C1-C6 alkyl groups, -C(O)NH2, -NHCOO-C1-C6 alkyl groups, -COOH, and -NR 15 R 16 The group is substituted 1-3 times, wherein R 15 and R 16 are each independently selected from hydrogen and a C1-C6 alkyl group.

[0497] Also disclosed herein are compounds having the formula III:

[0498]

[0499] and pharmaceutically acceptable salts thereof,

[0500] in:

[0501] n is selected from 0, 1 and 2;

[0502] m is selected from 1, 2 and 3;

[0503] R 1 Selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, -NR 11 R 12 Group, Group, Group, Group, Group, Group, Group, Group, Groups, and Group,

[0504] R 11 Selected from hydrogen, -NR 16 R 17 Group, C1-C6 alkyl group, -(C1-C6 alkyl)-CO2H group, -(C1-C6 alkyl)-CO2R 12 Group, -(C1-C6 alkyl)-NR 16 R 17 Groups, C3-C8 cycloalkyl groups, and C3-C8 heterocyclyl groups, wherein these -NR 16 R 17 Groups, C1-C6 alkyl groups, C3-C8 cycloalkyl groups and C3-C8 heterocyclyl groups may be unsubstituted or substituted 1-3 times by groups independently selected from C1-C6 alkyl groups, -(C1-C6 alkyl)-CO2H groups, hydroxyl groups, halogen groups and C1-C6 alkoxy groups;

[0505] R 12 is selected from hydrogen and C1-C6 alkyl groups;

[0506] R 2 or R 3 One of them is selected from hydrogen and C1-C6 alkyl groups, and the other is selected from hydrogen, -OR 10 、-OC(O)R 10 、-OC(O)R 1 , and C1-C6 alkyl groups;

[0507] R 4 is hydrogen or hydroxyl;

[0508] R 5 and R 6 Each independently selected from C1-C6 alkyl groups;

[0509] R7 and R8 are each independently selected from hydrogen, hydroxyl, C1-C6 alkoxy group, and C1-C6 alkyl group; and

[0510] R 9 and R 10 are each independently selected from hydrogen, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group; or, R 9 or R 10 One of the is oxo and the other is absent;

[0511] Z is selected from C1-C6 alkyl groups, -C(O)-C1-C6 alkyl groups, -OR 13 , and -NR 14 R 15 Group,

[0512] where R 13 is selected from hydrogen, a C1-C6 alkyl group, and a -C(O)-C1-C6 alkyl group,

[0513] where R 14 and R 15 are each independently selected from hydrogen, a C1-C6 alkyl group, and a methoxy C1-C6 alkyl group; or R 14 and R 15 Together with N, it can form a group selected from the following

[0514] morpholine, piperidine, thiazolidine, indole, indoline, and isoindoline rings;

[0515] wherein Z may be unsubstituted or independently selected from C1-C6 alkyl groups, C3-C5 cycloalkyl groups, hydroxy C1-C6 alkyl groups, C1-C6 alkoxy groups, methoxy C1-C6 alkyl groups, -NR 16 R 17 Group, as well as The group is substituted 1-3 times, wherein R 16 and R 17 are each independently selected from hydrogen and a C1-C6 alkyl group.

[0516] In some embodiments, in Formula III, R 1 Selected from methyl, Group, Group, Group, Group, Group, Group, Group, Groups, and Group, where R 11 、R 12 、R 16 、R 17 As defined above.

[0517] Also disclosed herein are compounds selected from the group consisting of:

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536] and pharmaceutically acceptable salts thereof.

[0537] Also disclosed herein are compounds selected from the group consisting of:

[0538] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-9-oxo-9-pyrrolidin-1-ylnona-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0539] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[[(2R,3R)-3-hydroxypentan-2-yl]carbamoyloxy]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0540] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-(propylcarbamoyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0541] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propyl)carbamoyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0542] Pyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0543] 4-Cycloheptyl-4-oxopiperazin-4-ium-1-carboxylate [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propyl)carbamoyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0544] [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(dimethylcarbamoyloxy)-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0545] [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-(diethylcarbamoyloxy)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0546] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propan-2-yl)carbamoyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0547] [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[butyl(methyl)carbamoyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0548] [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[but-2-yl(methyl)carbamoyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0549] (2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-carbamoyloxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0550] (2R)-2-(methoxymethyl)pyrrolidine-1-carboxylic acid [(2S,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0551] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[2-methoxyethyl(methyl)carbamoyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0552] Azetidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0553] (2S)-2-methylpyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0554] (2S)-2-methylpyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0555] Piperidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0556] (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0557] (2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] (3R)-3-hydroxypyrrolidine-1-carboxylate;

[0558] Morpholine-4-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0559] 4-Methylpiperazine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0560] 3-Thiazolidinecarboxylic acid [(2R,3E,5E)-6-[(2R,3S,4E,6R,7R,10R)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0561] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0562] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0563] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0564] 1,3-Dihydroisoindole-2-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0565] Indole-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0566] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[2-(1-hydroxyethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0567] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,2-dimethylpyrrolidin-1-carbonyl)oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0568] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2S,5S)-2,5-dimethylpyrrolidin-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0569] 2,3-Dihydroindole-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0570] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0571] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0572] 2-Oxa-5-azaspiro[3.4]octane-5-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0573] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0574] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0575] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-6-[6-[(2R)-1-hydroxypropan-2-yl]pyridin-2-yl]hept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl]acetate;

[0576] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E)-6-[2-(dimethylamino)pyrimidin-4-yl]hept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0577] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0578] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridazin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0579] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrimidin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0580] 4-Propan-2-ylpiperazine-1-carboxylic acid [(2R,3R,4E,6S,7R,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6R)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0581] 4-tert-Butylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0582] 4-Cyclopentylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0583] 4-(oxan-4-yl)piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0584] 6-cycloheptyl-2,6-diazaspiro[3.3]heptane-2-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0585] 4-Cycloheptyl-3-methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0586] 4-Cyclobutylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0587] N-Methyl-N-(1-methylpiperidin-4-yl)carbamic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0588] Morpholine-4-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0589] (1S,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid [(2R,3R,4E,6S,7R,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6R)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0590] 8-cycloheptyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0591] 4-Methyl-1,4-diazepane-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0592] 4-Cyclohexylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0593] Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0594] 4-Cycloheptyl-1,4-diazacycloheptane-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0595] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-hydroxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0596] 4-(Azepan-1-yl)piperidine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0597] 4-(8,8-Difluoro-3-azabicyclo[3.2.1]octan-3-yl)piperidine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0598] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-9-oxo-9-pyrrolidin-1-ylnona-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0599] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propyl)carbamoyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0600] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0601] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0602] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0603] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10R)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-10-(pyrrolidin-1-carbonyloxy)-1-oxacyclododecan-4-en-6-yl] ester;

[0604] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(2S)-2-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0605] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3R)-3-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0606] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3R)-3-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0607] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-carbamoylpyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0608] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[(2R)-2-(methoxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0609] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2S,5S)-2,5-dimethylpyrrolidin-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0610] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0611] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0612] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,2-dimethylpyrrolidin-1-carbonyl)oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0613] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10R)-2-[(2E,4E)-6,6-dimethyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0614] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E)-6,6-dimethyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-7-hydroxy-3,7-dimethyl-12-oxo-10-(pyrrolidin-1-carbonyloxy)-1-oxacyclododecan-4-en-6-yl] ester;

[0615] (2R)-1-[(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyloxy]carbonylpyrrolidine-2-carboxylic acid;

[0616] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(3-oxopyrrolidin-1-carbonyl)oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0617] 2-Oxa-7-azaspiro[3.4]octane-7-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0618] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0619] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-5-[1-(pyrrolidin-1-carbonyloxymethyl)cyclopropyl]penta-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0620] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3S,4R)-3,4-dihydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0621] (3S)-1-[(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyloxy]carbonylpyrrolidine-3-carboxylic acid;

[0622] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3S)-3-(dimethylamino)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0623] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,5-dihydropyrrole-1-carbonyloxy)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0624] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0625] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3S)-3-[(2-methylprop-2-yl)oxycarbonylamino]pyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0626] 3-Azabicyclo[3.1.0]hexane-3-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0627] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0628] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0629] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-2-ylhexa-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0630] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-(2-pyrrolidin-1-ylpyrimidin-4-yl)hept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0631] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrazin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0632] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E)-6-[2-(dimethylamino)pyrimidin-4-yl]hept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0633] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-(3-methylpyridin-2-yl)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0634] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-(4-methylpyridin-2-yl)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0635] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrimidin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0636] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridazin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0637] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyrimidin-4-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0638] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyrimidin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0639] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyrimidin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0640] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-(4-methylpyrimidin-2-yl)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0641] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-(6-pyrrolidin-1-ylpyridin-2-yl)hept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0642] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0643] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0644] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0645] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0646] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0647] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0648] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0649] (2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0650] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0651] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0652] N,N-Dimethylcarbamic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0653] [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0654] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0655] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0656] Pyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6R)-6-(dimethylcarbamoyloxy)-3-methyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0657] (3R)-3-Hydroxypyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6R)-6-(dimethylcarbamoyloxy)-3-methyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0658] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0659] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-[(2S)-2-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0660] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0661] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0662] 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0663] [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0664] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0665] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0666] N,N-Dimethylcarbamic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0667] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E)-6-[2-(dimethylamino)pyrimidin-4-yl]hept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0668] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-(2-pyrrolidin-1-ylpyrimidin-4-yl)hept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0669] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-[2-[(3S)-3-triethylsilyloxypyrrolidin-1-yl]pyrimidin-4-yl]hept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0670] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E)-6-[2-[(3R)-3-hydroxypyrrolidin-1-yl]pyrimidin-4-yl]hept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0671] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-12-oxo-2-[(2E,4E)-6-pyrimidin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0672] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0673] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0674] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0675] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3S)-3-(1-phenyltetrazol-5-yl)oxypyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0676] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0677] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0678] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0679] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0680] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonylamino)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0681] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]amino]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0682] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonylamino)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0683] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[methyl(pyrrolidine-1-carbonyl)amino]hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0684] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(4-cyclopropyltriazol-1-yl)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0685] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-methoxycarbonyloxy-6-methylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0686] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-9-methoxy-6-methyl-9-oxona-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0687] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(cyclopentanecarbonylamino)-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0688] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(cyclopentanecarbonylamino)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0689] 4-Cycloheptyl-1-piperazinecarboxylic acid [(2R,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-7-[oxo(1-pyrrolidinyl)methoxy]hept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0690] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0691] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3-methyl-12-oxo-1-azacyclododecan-4-en-6-yl] ester;

[0692] Pyrrolidine-1-carboxylic acid [(2R,3E,5E)-2-methyl-6-[(2S,3S,4E,6R)-3-methyl-6-[(4-methylpiperazine-1-carbonyl)amino]-12-oxo-1-oxacyclododecan-4-en-2-yl]hept-3,5-dienyl] ester;

[0693] (2R,3R)-3-hydroxy-2-methylpentanoate [(2S,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester;

[0694] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-hydroxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0695] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-4-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0696] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0697] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0698] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-7-methyl-6-pyridin-2-yloct-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0699] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[(2R,3R)-3-[(2R,3R)-3-acetyloxypentan-2-yl]oxiran-2-yl]-6-hydroxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0700] [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-6-methyl-8-phenyloct-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0701] [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-6-phenylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0702] [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-6-thiophen-2-ylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0703] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-phenylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0704] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-6-(6-methoxypyridin-2-yl)hept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0705] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-[6-(2-methylpropyloxy)pyridin-2-yl]hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl]acetate;

[0706] (2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-methyl-8-pyridin-2-yloct-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0707] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-methyl-7-pyridin-2-ylhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0708] (2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E,6R)-6-hydroxy-6-methyl-8-phenyloct-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0709] (2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-2-ylhexa-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0710] (2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhexa-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0711] (2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-4-ylhexa-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] acetate;

[0712] [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-2-[(2E,4E)-6-hydroxy-8-(4-hydroxyphenyl)-6-methyloct-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0713] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E)-6-methyl-8-phenyloct-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0714] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-8-[2-(methoxymethyl)phenyl]-6-methylocta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0715] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-8-[4-(methoxymethyl)phenyl]-6-methylocta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0716] [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E)-8-[3-(methoxymethyl)phenyl]-6-methylocta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] acetate;

[0717] [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6S)-6-hydroxy-6-methyl-7-[(2R,3R)-3-[(2S)-3-oxopentan-2-yl]oxiran-2-yl]hept-2,4-dien-2-yl]-3,7-dimethyl-10,12-dioxo-1-oxacyclododecan-4-en-6-yl]acetate;

[0718] 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6E,8S)-8-pyridin-2-ylnon-2,4,6-trien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0719] 4-Methyl-4-oxopiperazin-4-ium-1-carboxylate [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0720] 4-(4-Fluoropiperidin-1-yl)piperidine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0721] 4-(4,4-Difluoropiperidin-1-yl)piperidine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-6-pyridin-3-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester;

[0722] (4S,7S,8S,9E,11S,12S)-4,7,8-trihydroxy-7,11-dimethyl-12-[(2E,4E,6S)-6-pyridin-2-ylhept-2,4-dien-2-yl]-1-oxacyclododecan-9-en-2-one;

[0723] Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7-acetyloxy-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0724] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl piperazine-1-carboxylate;

[0725] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((S,2E,4E)-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl piperazine-1-carboxylate;

[0726] Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-6-acetyloxy-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-7-yl] ester;

[0727] Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7-acetyloxy-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0728] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7R,10R)-7-ethoxy-10-hydroxy-2-[(2E,4E,6R)-6-hydroxy-7-[(2R,3R)-3-[(2S,3S)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0729] Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-6-acetyloxy-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-7-yl] ester;

[0730] Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0731] 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester;

[0732] N-Methyl-N-[2-(methylamino)ethyl]carbamate [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl]

[0733] N-Methyl-N-[2-(dimethylamino)ethyl]carbamate [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl]

[0734] 3-[4-[[(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl]oxycarbonyl]piperazin-2-yl]propanoic acid;

[0735] 4-[4-[[(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl]oxycarbonyl]piperazin-1-yl]butanoic acid;

[0736] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;

[0737] (2S,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-7-yl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;

[0738] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl)-4-propylpiperazine-1-carboxylate;

[0739] (2R,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((2S,6R,E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-4-en-2-yl)-3,7-dimethyl-12-oxooxadodec-4-en-7-yl 4-(2-hydroxyethyl)piperazine-1-carboxylate;

[0740] (2S,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-7-yl 4-methylpiperazine-1-carboxylate;

[0741] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl)-4-(2-aminoethyl)piperazine-1-carboxylate;

[0742] (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl)-4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate;

[0743] (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl 4-methylpiperazine-1-carboxylate;

[0744] (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododecan-4-en-6-yl piperazine-1-carboxylate;

[0745] and pharmaceutically acceptable salts thereof.

[0746] Disclosed herein are compositions comprising at least one compound of the disclosure (e.g., a compound of Formula I, II, and III) and / or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier can be selected based on the specific route of administration contemplated for the composition.

[0747] The pharmaceutical compositions of the present disclosure can be formulated for parenteral, oral, inhalation spray, topical, rectal, nasal, buccal, vaginal or implantable drug reservoir administration, etc. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In certain embodiments, the composition is administered intravenously, orally, subcutaneously or by intramuscular administration. The sterile injectable form of the composition of the present disclosure can be an aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Water, Ringer's solution and isotonic sodium chloride solution can be used in acceptable vehicles and solvents. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0748] Any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and glyceride derivatives thereof can be used to prepare injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants that are generally used to prepare pharmaceutically acceptable dosage forms (including emulsions and suspensions). For the purpose of preparation, other conventional surfactants can also be used, such as Tweens, Spans and other emulsifiers or bioavailability enhancers, which are generally used to make pharmaceutically acceptable solids, liquids or other dosage forms.

[0749] For oral administration, the compound of the present disclosure (e.g., Formula I, II or III) and / or its pharmaceutically acceptable salt can be provided in an acceptable oral dosage form (including but not limited to capsules, tablets, aqueous suspensions or solutions). In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate can also be added. For oral administration in the form of capsules, useful diluents include lactose and dry corn starch. When oral use of aqueous suspensions is required, the active ingredient can be combined with an emulsifier and / or a suspending agent. If desired, certain sweeteners, flavorings or coloring agents can also be added.

[0750] The compounds and compositions disclosed herein can be used to treat various types of cancer, including those that respond to agents that target the spliceosome, including SF3B1. As noted above, the antitumor activity of pladienolide B has been reported to be related to its targeting of the SF3b complex, inhibiting splicing and altering gene expression patterns (Kotake et al., "Splicing factor SF3bas a target of the antitumor natural product pladienolide," Nature Chemical Biology 2007, 3, 570-575). Mutations in the splicing factor 3B subunit 1 (SF3B1) protein are known to be associated with a variety of cancers, such as hematologic malignancies and solid tumors. Scott et al., "Acquired mutations that affect pre-mRNA splicing in hematologic malignancies and solid tumors," JNCI 105, 20, 1540-1549.

[0751] Therefore, the compounds of the present disclosure (e.g., compounds with Formula I, II, and III and the aforementioned pharmaceutically acceptable salts) and compositions can be used to treat hematological malignancies, such as blood cancers (leukemias) and lymph node cancers (lymphomas). Leukemias include acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), etc. Lymphomas include Hodgkin's lymphoma and non-Hodgkin's lymphoma. Other hematological malignancies may include myelodysplastic syndrome (MDS).

[0752] Solid tumors include malignancies such as adenocarcinomas, for example breast cancer, pancreatic cancer, prostate cancer, colon or colorectal cancer, lung cancer, stomach cancer, cervical cancer, endometrial cancer, ovarian cancer, bile duct cancer, glioma, melanoma, and the like.

[0753] The compounds of the present disclosure (e.g., compounds of Formula I, II, and III) and pharmaceutically acceptable salts and compositions thereof can also be used to treat cancers that may respond to agents targeting spliceosome genes or proteins other than SF3B1. The following are non-limiting examples of cancers that respond to agents targeting the spliceosome. Thus, the compounds of the present disclosure can be administered to subjects to treat a variety of such cancers or conditions, particularly patients or subjects suffering from the following diseases:

[0754] a) Myelodysplastic syndrome (MDS) : See, e.g., “SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications,” Damm F. et al. Leukemia, 2011, 1-4; “Frequent pathway mutations in splicing machinery in myelodysplasia,” Yoshida K. et al. Nature, 2011, 478, 64-69; “Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic / myeloproliferative neoplasms,” Malcovati L. et al., Blood, 2011, 118, 24, 6239-6246; "Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis," Makishima et al., Blood, 2012, 119, 3203-3210; "Somatic SF3B1 mutation in myelodysplasia with ringsideroblasts," Pappaemannuil, E. et al., New England J. Med. 2011, DOI 10.1056 / NEJMoa1103283.

[0755] b) Chronic lymphocytic leukemia (CLL): See, e.g., “Defects in the spliceosomal machinery: a new pathway of leukaemogenesis,” Maciejewski, JP, Padgett, RA, Br. J. Haematology, 2012, 1-9; “Mutations in the SF3B1 splicing factor in chronic lymphocytic leukemia: associations with progression and fludarabine-refractoriness,” Rossi et al., Blood, 2011, 118, 6904-6908; “Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic Exome sequencing identifies recurrent mutations in the splicing factor SF3B1 gene in chronic lymphocytic leukemia," Quesada et al., Nature Genetics, 2011, 44, 47-52.

[0756] c) Chronic myelomonocytic leukemia (CMML) ): See, e.g., Yoshida et al., Nature 2011; “Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenilemyelomonocytic leukemia,” Kar SA et al., Haematologia, 2012, DOI: 10.3324 / haematol.2012.064048.

[0757] d) Acute myeloid leukemia (AML): See, for example, Malcovati et al., Blood 2011; Yoshida et al., Nature 2011.

[0758] e) Breast cancer : See, e.g., “Whole genome analysis informs breast cancer response to aromatase inhibition,” Ellis et al., Nature, 2012, 486, 353-360.

[0759] f) Uveal melanoma : See, e.g., “SF3B1 mutations are associated with alternative splicing in uveal melanoma”, Furney et al., Cancer Disc. 2013, 10, 1122-1129.

[0760] g) Endometrial cancer : See, e.g., Tefferi et al., "Myelodysplastic syndromes." N Engl J Med. 2009; 361: 1872-85.

[0761] h) Gastric cancer : See, e.g., Int J Cancer. 2013 Jul;133(1):260-5, "Mutational analysis of splicing machinery genes SF3B1, U2AF1 and SRSF2 in myelodysplasia and other common tumors." Je et al.

[0762] i) Ovarian cancer: See, e.g., Int J Cancer. 2013 Jul;133(1):260-5, "Mutational analysis of splicing machinery genes SF3B1, U2AF1 and SRSF2 in myelodysplasia and other common tumors." Je et al.

[0763] j) Biliary tract cancers such as bile duct cancer and pancreatic cancer See, e.g., Biankin et al., "Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes," Nature 2012, 491, 399-405.

[0764] k) lung cancer : See, e.g., “Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia,” Quesada et al., Nature Genetics 44, 47-52 (2012); Scott et al., “Acquired mutations that affect pre-mRNA splicing in hematologic malignancies and solid tumors,” JNCI 105, 20, 1540-1549.

[0765] In addition, the Catalogue of Somatic Mutations in Cancer (COSMIC) (Wellcome Trust Sanger Institute, Genome Research Ltd, UK) reported that SF3B1 mutations have been found in various types of cancer samples.

[0766] The compound of the present disclosure (for example, a compound with Formula I, II or III) can be administered to a subject in a therapeutically effective or therapeutically effective amount. The amount of the compound of the present disclosure that can be combined with a carrier material to produce a composition of a single dosage form will vary depending on the subject being treated and the specific route of administration. In certain embodiments, at least one compound disclosed herein is administered at a dosage of 0.01mg / kg-100mg / kg body weight / day. In certain embodiments, the dosage is at least one compound disclosed herein from 0.01mg to 50mg. In certain embodiments, at least one compound disclosed herein is provided from 0.1mg to 25mg. In certain embodiments, at least one compound disclosed herein is provided from 5mg to 40mg.

[0767] It will be understood by those skilled in the art that the specific dosage and treatment regimen for a particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of at least one compound disclosed herein will also depend on the specific compound / salt used.

[0768] In some embodiments, the cancer is tested for and / or is positive for one or more mutations in the splicing factor 3B subunit 1 (SF3B1) gene or protein, wherein the presence of the one or more mutations ("positive") indicates that the subject's cancer is responsive to treatment comprising administering at least one compound disclosed herein that targets the protein and / or the spliceosome. Examples of such spliceosomal genes include, but are not limited to, those presented in Table 1.

[0769] Table 1: Spliceosome genes and possible diseases

[0770]

[0771]

[0772] Keywords:

[0773] MDS = myelodysplastic syndrome

[0774] AML = acute myeloid leukemia

[0775] CMML = chronic myelomonocytic leukemia

[0776] LUAD = lung adenocarcinoma

[0777] UCEC = uterine corpus endometrial carcinoma

[0778] PMF = progressive massive fibrosis

[0779] PRAD = prostate adenocarcinoma

[0780] COAD = colon adenocarcinoma

[0781] OV = ovarian serous cystadenocarcinoma

[0782] SKCM = cutaneous melanoma

[0783] LUSC = lung squamous cell carcinoma

[0784] STAD = Gastric Adenocarcinoma

[0785] GBM = glioblastoma multiforme

[0786] LGG = low-grade glioma

[0787] DLBCL = diffuse large B-cell lymphoma

[0788] In some embodiments, a subject's cancer may be responsive to treatment methods comprising administering a compound targeted to such protein and / or the spliceosome even in the absence of such mutations in the spliceosomal gene or protein.

[0789] Screening or testing for mutations can be performed by any known means, such as genotyping, phenotyping, etc., by nucleic acid amplification, electrophoresis, microarray, blotting, functional assays, immunoassays, etc. Screening methods can include, for example, collecting a biological sample from the subject containing cancer cells / tissue.

[0790] In some embodiments, a subject having cancer as described herein can be treated with at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and pharmaceutically acceptable salts of any of the foregoing, and at least one additional therapy.

[0791] In some embodiments, at least one additional therapy includes a cytokine or cytokine analog therapy, such as any cytokine or cytokine analog therapy disclosed herein. Cytokines are a broad class of small proteins that have been shown to participate in autocrine signaling, paracrine signaling, and / or endocrine signaling as immunomodulators. Exemplary cytokines are disclosed herein and include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors. As used herein, the term "cytokine" refers to a polypeptide that is secreted from a cell and affects the function of other cells to mediate an immune response, and the term "cytokine therapy" refers to the administration of such a peptide and / or the induction of the secretion of such a peptide. In some embodiments, the cytokine is a recombinant cytokine or an analog thereof. In some embodiments, the cytokine is a cytokine analog. The terms "cytokine analog" and "cytokine analog therapy" refer to modified cytokines in which one or more amino acid residues of a natural cytokine have been replaced by other natural or non-natural amino acid residues and / or one or more natural or non-natural amino acid residues have been added to a natural cytokine. In some embodiments, a cytokine or cytokine analog therapy includes administering at least one cytokine or cytokine analog to a patient in need of such treatment.

[0792] In some embodiments, at least one additional therapy includes one or more engineered targeted tumor T cells (e.g., CAR-T or other cell-based therapies), for example, any CAR-T therapy disclosed herein. The terms "CAR-T" and "CAR-T therapy" are used interchangeably and refer to cells or cell groups (e.g., T cells or T cell groups) modified by CAR. In some embodiments, an antigen recognition sequence can be used to engineer a chimeric T cell receptor (CAR) so that when CAR is expressed on a cell (e.g., T cell), CAR and / or cells react with the target antigen. For example, in some embodiments, CAR can be engineered by first identifying antibodies that recognize antigen protein domains expressed on the surface of the cell. The antigen recognition sequences of such antibodies can then be fused with T cell receptor domains for selective targeting and activation. In some embodiments, the CAR sequence is cloned into a patient-derived T cell group and amplified using currently available protocols. In some embodiments, the engineered T cells are then returned to the patient's circulation before, simultaneously, or after treatment with at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. After treatment with at least one compound and / or pharmaceutically acceptable salt, in some embodiments, tumor cells can begin to present antigens, e.g., antigens targeted by engineered T cell populations. In some embodiments, engineered T cell populations can engage with and kill tumor cells presenting the antigen.

[0793] In some embodiments, at least one additional therapy includes a checkpoint inhibitor therapy, such as any checkpoint inhibitor therapy disclosed herein. Immune checkpoints are inhibitory pathways that slow down or terminate the immune response and prevent the uncontrolled activity of immune cells from causing excessive tissue damage. As used herein, the terms "checkpoint inhibitor" and "checkpoint inhibitor therapy" are used interchangeably and refer to any therapeutic agent that inhibits one or more inhibitory pathways, including any small molecule compound, antibody, nucleic acid molecule, or polypeptide, or any fragment thereof, thereby allowing for a wider range of immune activity. In some embodiments, checkpoint inhibitor therapy includes administering at least one checkpoint inhibitor to a patient in need of such treatment.

[0794] In some embodiments, at least one additional therapy comprises a neoantigen vaccine. In some embodiments, treatment includes administering at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing, and administering a neoantigen vaccine. In some embodiments, the neoantigen vaccine comprises tumor neoantigens and / or neoantigens induced by at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, treatment further comprises administering a checkpoint inhibitor therapy. In some embodiments, the checkpoint inhibitor therapy targets PD1 / PDL1, CTLA4, OX40, CD40, LAG3, TIM3, GITR, and / or KIR. In some embodiments, the checkpoint inhibitor therapy targets PD1 / PDL1 (e.g., anti-PD1 antibody or anti-PDL1 antibody). In some embodiments, the checkpoint inhibitor therapy targets CTLA4 (e.g., anti-CTLA4 antibody). In some embodiments, treatment comprises first (i) administering at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing; and (ii) detecting the presence of a neoantigen (e.g., a neoantigen from a neoantigen vaccine), followed by administering a combination therapy comprising a neoantigen vaccine. In some embodiments, the expression of the neoantigen is monitored during the course of treatment. In some embodiments, treatment is interrupted if no neoantigen is detected.

[0795] In some embodiments, methods of treating a patient by inducing neoantigens in tumor cells are also disclosed herein, which tumor cells can be targeted for elimination by the patient's immune system. Without being bound by theory, in some embodiments, administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing can produce neoantigens that induce an immune response, for example, a double-stranded RNA immune response due to re-expressed intron-resident endogenous retroviruses, and / or produce neoantigens that induce immunogenic cell death.

[0796] As used herein, the term "neoantigen" refers to any antigen that has not been previously exposed to the immune system, which is derived from one or more tumor-specific mutations and / or exposing the tumor to at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. Tumor-specific mutations may include missense mutations, frameshifts, translocations, and mRNA splice variants, as well as mutations that affect post-translational processing (such as phosphorylation and glycosylation). In some embodiments, these exemplary mutations may be derived from non-synonymous coding changes and / or mutations that change mRNA processing (e.g., splicing). In some embodiments, all of these exemplary mutations may result in molecular changes that can be distinguished by appropriate T cell receptors. In some embodiments, exemplary neoantigens are neoantigens induced by delivering at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, delivery of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing can induce novel mRNA splicing, which results in the translation of proteins containing one or more novel peptide domains that have not been previously exposed to the immune system. In some embodiments, tumor-specific mutations can be mRNA splice variants resulting from delivery or administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing.

[0797] Without being bound by theory, in some embodiments, delivery of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing can induce novel mRNA splicing (e.g., exon skipping, intron retention), which results in changes in the open reading frames and / or coding sequences of various genes. In some embodiments, these altered genes are translated into proteins containing one or more novel peptide domains that are recognized as exogenous by the immune system. In some embodiments, in the absence of compound treatment, the one or more novel peptide domains are not present in proteins or any other part of the human proteome. In some embodiments, proteins containing one or more novel peptide domains can be degraded by the proteasome to produce novel peptide fragments that serve as substrates for immune peptide presentation mechanisms, such as via MHC presentation. In some embodiments, novel peptide fragments representing new antigens can be presented in MHC1-bound peptide groups, such as on tumor cells.

[0798] In some embodiments, delivery of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing can result in one or more tumor cell intrinsic events (e.g., cell growth arrest). In some embodiments, the one or more tumor cell intrinsic events can result in (1) enhanced engagement of phagocytes (Bracci et al. (2014) Cell Death Differ [Cell Death and Differentiation]. 21(1):15-25); (2) transport of novel peptide fragments to tumor-draining lymph nodes for engagement with antigen-presenting cells; (3) antigen-presenting cells processing the novel peptide fragments from phagocytosed tumor cells and presenting these fragments as neoantigens to circulating naive T cell populations; (4) interaction of the novel peptide fragments with T cells expressing receptors that recognize these fragments as neoantigens; (5) maturation and activation of effector T cell responses (e.g., CD4+ and / or CD8+ T cells); and / or (6) engagement of T cells with additional tumor cells exposed to compound treatment and presentation of the novel peptide fragments representing the neoantigens on their surface MHC1 complexes. In some embodiments, one or more tumor cell intrinsic events can directly or indirectly lead to T cell engagement and / or killing of neoantigen-presenting tumor cells with effector function.

[0799] Additionally, without being bound by theory, in some embodiments, delivery of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing can cause re-expression of intron-residing endogenous retroviruses, resulting in a double-stranded RNA immune response.

[0800] Further, without being bound by theory, in some embodiments, delivery of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing may result in immunogenic cell death triggered by the release of new antigens derived from mutations induced by the compound. In some embodiments, delivery of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing may induce a double-stranded RNA immune response. In some embodiments, the double-stranded RNA immune response may be caused by the re-expression of endogenous retroviruses in which introns reside. In some embodiments, the double-stranded RNA immune response may result in tumor cell death. In some embodiments, delivery of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing may induce immunogenic cell death. In some embodiments, immunogenic cell death may be caused by the release of new antigens derived from mutations and / or a host immune response against tumor cells.

[0801] Thus, in some embodiments, methods of treatment are disclosed that include inducing neoantigens by administering at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the method includes administering a reduced dose of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing compared to the dose required in the absence of induced neoantigens. In some embodiments, the method includes administering one or more initial induction doses to produce neoantigens and induce an immune response (e.g., converting naive T cells into memory cells), followed by a reduction in dose or frequency of administration (i.e., due to the combined effect of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing and the immune targeting of the neoantigen). In some embodiments, treatment may include administering a combination of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing to induce an immune response based on the neoantigen and at least one additional therapy (e.g., a second anticancer therapy). For example, in some embodiments, treatment may include administering at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing to induce an immune response based on a neoantigen and a combination of one or more checkpoint inhibitors. In some embodiments, treatment may include administering at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing to induce an immune response based on a neoantigen and a combination of one or more cytokines or cytokine analogs. In some embodiments, treatment may include administering at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing to induce an immune response based on a neoantigen and a combination of one or more neoantigen vaccines. In some other embodiments, treatment may include administering at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing to induce an immune response based on a neoantigen and a combination of one or more engineered tumor-targeting T cells (e.g., CAR-T).

[0802] In some embodiments, the new antigens can be used to monitor the effectiveness of treatment with at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. For example, after administering at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing, a patient sample (e.g., a tumor biopsy) can be obtained and screened for new antigens or identifiers of immune or inflammatory responses. If new antigens and / or immune responses are detected, further treatment can be provided, for example, at a reduced dose.

[0803] In some embodiments, treatment methods are disclosed that comprise inducing a double-stranded RNA immune response by administering at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and pharmaceutically acceptable salts of any of the foregoing.

[0804] In some embodiments, treatment methods are disclosed that comprise inducing immunogenic cell death by administering at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and pharmaceutically acceptable salts of any of the foregoing.

[0805] In some embodiments, at least one compound selected from a compound having formula I, a compound having formula II, a compound having formula III, and a pharmaceutically acceptable salt of any of the foregoing can be combined with any known anticancer therapy. Examples of immune activation strategies currently available for oncology treatment include, but are not limited to, treatment with immune checkpoint inhibitors (ICI) molecules, treatment with cytokines or cytokine analogs, vaccination with tumor-associated vaccines, and engineered targeted tumor T cells (e.g., tumor infiltrating lymphocytes or CAR-T amplification). These technologies primarily focus on enhancing or inducing immune responses to existing tumor antigens (mutations or abnormal expression of cell surface proteins). One or more of these strategies may involve one or more mutations capable of inducing antigenic T cell responses. For example, a patient's response to checkpoint inhibition may be associated with a non-synonymous mutation burden. Additionally, a cancer vaccine method that relies on the antigenicity of pre-existing mutations and these mutations can be used.

[0806] Compounds of Formula I, compounds of Formula II, compounds of Formula III, and pharmaceutically acceptable salts of any of the foregoing can induce extensive changes in the transcriptome that occur across multiple lineages. The translation of these mRNA changes can produce robust and reproducible protein changes that generate new MHC1 binding peptides with high affinity across multiple HLA isotypes. Without being bound by theory, due to the extensive changes in the transcriptome and proteome, treatment with at least one compound selected from compounds of Formula I, compounds of Formula II, compounds of Formula III, and pharmaceutically acceptable salts of any of the foregoing can increase the number of potentially reactive neoantigens to enhance engagement of the adaptive immune response.

[0807] In some embodiments, the present disclosure provides a method of inducing at least one neoantigen by contacting tumor cells with a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the present disclosure provides a method of inducing a double-stranded RNA immune response by contacting tumor cells with a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the present disclosure provides a method of inducing immunogenic cell death by contacting tumor cells with a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing.

[0808] In certain embodiments, the tumor cell is present in an in vitro cell culture. In certain embodiments, the tumor cell is obtained from a subject. In certain embodiments, the tumor cell is present in a subject. In certain embodiments, the tumor cell is derived from a hematological malignancy or a solid tumor. In certain embodiments, the hematological malignancy is selected from B cell malignancies, leukemia, lymphoma and myeloma. In certain embodiments, the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma. In certain embodiments, the solid tumor is selected from breast cancer (e.g., HER2 positive breast cancer), gastric cancer (e.g., gastric adenocarcinoma), prostate cancer, ovarian cancer, lung cancer (e.g., lung adenocarcinoma), uterine cancer (e.g., uterine serous endometrial cancer), salivary duct carcinoma, melanoma, colon cancer and esophageal cancer. In certain embodiments, the solid tumor is selected from HER2 positive breast cancer, gastric adenocarcinoma and prostate cancer.

[0809] In some embodiments, the present disclosure further provides a method of inducing at least one neoantigen and / or T cell response in a subject having or suspected of having a neoplastic disease, by administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing. In some embodiments, the present disclosure further provides a method of treating a subject having or suspected of having a neoplastic disease, by administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing, wherein administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing induces at least one neoantigen and / or T cell response.

[0810] In various other embodiments, the present disclosure provides a method of inducing a double-stranded RNA immune response in a subject having or suspected of having a neoplastic disease, by administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing. In some embodiments, the present disclosure also provides a method of treating a subject having or suspected of having a neoplastic disease, by administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing, wherein administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing induces a double-stranded RNA immune response.

[0811] In yet other embodiments, the present disclosure provides a method of inducing immunogenic cell death in a subject having or suspected of having a neoplastic disease, by administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing. In some embodiments, further provided herein is a method of treating a subject having or suspected of having a neoplastic disease, by administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing, comprising at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing, wherein administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing induces immunogenic cell death.

[0812] In some embodiments, the present disclosure further provides a method of treating a subject having or suspected of having a neoplastic disease by administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing in combination with one or more additional therapies comprising a second agent, wherein administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing induces immunogenic cell death.

[0813] In some embodiments of the methods of treatment described herein, the amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, or a second agent administered is reduced due to the induction of at least one neoantigen and / or T cell response, compared to a standard dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, or a second agent. In some embodiments, the amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, or a second agent administered is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% compared to a standard dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, or a second agent. In some embodiments, the at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, or the second agent, is administered at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% less frequently than the standard dosing regimen of the at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, or the second agent. In some embodiments, the amount and / or dosage of the at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, or the second agent, results in lower systemic toxicity and / or improved tolerability.

[0814] As used herein, the term "standard dose" or "standard dosing regimen" refers to any common or conventional dosing regimen for a therapeutic agent, such as a regimen proposed by a manufacturer, approved by a regulatory agency, or otherwise tested in human subjects that meets the needs of the average patient. In some embodiments, the therapeutic agent is at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, which has anti-cancer activity.

[0815] For example, a standard dosing regimen for trastuzumab (an exemplary anti-HER2 antibody) may be 8 mg / kg intravenously administered over 90 minutes (week 1), followed by 6 mg / kg intravenously administered over 30-90 minutes every 3 weeks (week 4 through the end of the treatment cycle). (Trastuzumab) FDA label supplement, 2017).

[0816] As another example, a standard dosing regimen for ipilimumab (an exemplary anti-CTLA4 checkpoint inhibitor antibody) may be 3 mg / kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses ( (Ipilimumab) FDA Label Supplement, 2018). Another standard dosing regimen for ipilimumab may be 10 mg / kg administered intravenously over 90 minutes every 3 weeks for 4 doses, followed by 10 mg / kg every 12 weeks for up to 3 years ( (Ipilimumab) FDA label supplement, 2018).

[0817] As another example, a standard dosing regimen for nivolumab (an exemplary anti-PD1 checkpoint inhibitor antibody) may be 3 mg / kg (400 mg / kg) administered intravenously over 60 minutes every 2 weeks. (Nivolumab) FDA label supplement, 2015).

[0818] As another example, a standard dosing regimen for atezolizumab (an exemplary anti-PDL1 checkpoint inhibitor antibody) may be 1200 mg / kg (400 mg / kg) administered intravenously over 60 minutes every 3 weeks. (Atezolizumab) FDA label supplement, 2018).

[0819] As yet another example, a standard dosing regimen for T-DM1 (an exemplary anti-HER2 antibody-drug conjugate) may be 3.6 mg / kg (400 mg / kg) administered intravenously over 90 minutes every 3 weeks. (T-DM1) FDA label supplement, 2016).

[0820] In some embodiments, the methods described herein may further comprise administering at least one additional therapy (e.g., a checkpoint inhibitor, a neoantigen vaccine, a cytokine or cytokine analog, a CAR-T, etc.). In some embodiments, the amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy administered is reduced due to the induction of at least one neoantigen and / or T cell response. In some embodiments, the amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy administered is reduced due to the induction of a double-stranded RNA immune response compared to the standard dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy. In some embodiments, the amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy administered is reduced due to induction of immunogenic cell death compared to a standard dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy. In some embodiments, the amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy administered is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% compared to a standard dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy.In some embodiments, the compound of formula I, the compound of formula II, the compound of formula III, and the pharmaceutically acceptable salts of any of the foregoing, and / or at least one additional therapy is administered at a frequency that is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% less than the standard dosing regimen of the compound of formula I, the compound of formula II, the compound of formula III, and the pharmaceutically acceptable salts of any of the foregoing, and / or at least one additional therapy. In some embodiments, the amount and / or dosage of the compound of formula I, the compound of formula II, the compound of formula III, and the pharmaceutically acceptable salts of any of the foregoing, and / or at least one additional therapy administered results in lower systemic toxicity and / or improved tolerability.

[0821] In some embodiments, administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is initiated prior to administration of at least one additional therapy. In other embodiments, administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is initiated after administration of at least one additional therapy. In yet other embodiments, administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is initiated simultaneously with administration of at least one additional therapy.

[0822] In some embodiments, after the initial administration, at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing is administered repeatedly at least once. In some embodiments, the amount of at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing for repeated administration is reduced compared to the amount used for the initial administration. In some embodiments, the amount of at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing for repeated administration is reduced compared to the standard dose of at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing. In some embodiments, the amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% compared to the standard dose or initial dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing.

[0823] In some embodiments, after the initial administration, the at least one additional therapy is repeated at least once. In some embodiments, the amount of the at least one additional therapy for repeated administration is reduced compared to the amount used for the initial administration. In some embodiments, the amount of the at least one additional therapy for repeated administration is reduced compared to a standard dose of the at least one additional therapy. In some embodiments, the amount of the at least one additional therapy for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% compared to a standard dose or initial dose of the at least one additional therapy.

[0824] In some embodiments, repeated administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is concurrent with repeated administration of at least one additional therapy. In some embodiments, administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is continuous or staggered with repeated administration of at least one additional therapy.

[0825] In some embodiments, at least one additional therapy comprises administering a checkpoint inhibitor, such as any checkpoint inhibitor disclosed herein. In some embodiments, when administered alone, the subject is intolerant, unresponsive, or poorly responsive to the checkpoint inhibitor. In some embodiments, the checkpoint inhibitor targets PD1 / PDL1, CTLA4, OX40, CD40, LAG3, TIM3, GITR, and / or KIR. In some embodiments, the checkpoint inhibitor targets CTLA4, OX40, CD40, and / or GITR. In some embodiments, the checkpoint inhibitor is an antibody that has inhibitory or agonist activity against its target. In some embodiments, the checkpoint inhibitor targets an inhibitory antibody or other similar inhibitory molecule. In other embodiments, the checkpoint inhibitor targets an agonist antibody or other similar agonist molecule.

[0826] In some other embodiments, at least one additional therapy comprises administering a neoantigen vaccine, such as any of the neoantigen vaccines disclosed herein. In some embodiments, at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is administered prior to administering the neoantigen vaccine. In some embodiments, at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is administered after administering the neoantigen vaccine. In some embodiments, at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is administered simultaneously with the administration of the neoantigen vaccine. In some embodiments, after the initial administration, at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is administered repeatedly at least once. In some embodiments, the amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing for repeated administration is reduced compared to the amount used for the initial administration.

[0827] In some embodiments, the neoantigen vaccine comprises at least one neoantigenic peptide. In some embodiments, the at least one neoantigenic peptide ranges from about 10 to about 50 amino acids in length. In some embodiments, the at least one neoantigenic peptide ranges from about 10 to about 35 amino acids in length. In some embodiments, the at least one neoantigenic peptide ranges from about 15 to about 25 amino acids in length. In some embodiments, the at least one neoantigenic peptide comprises one or more neoantigenic sequences.

[0828] In some embodiments, the neoantigen sequence and / or antigen portion ranges in length from about 10 to about 50 amino acids. In some embodiments, at least one neoantigen peptide ranges in length from about 10 to about 35 amino acids. In some embodiments, the neoantigen sequence and / or antigen portion ranges in length from about 15 to about 25 amino acids. In some embodiments, the neoantigen sequence and / or antigen portion ranges in length from about 10 to about 20 amino acids. In some embodiments, the neoantigen sequence and / or antigen portion does not exclusively overlap with or consist of a typical peptide sequence (e.g., any exemplary typical peptide sequence underlined in Table 13).

[0829] As used herein, the term "antigen portion" or "antigen fragment" of a neoantigen sequence refers to one or more fragments of a neoantigen sequence that retain the ability to induce T cell responses (e.g., antigen-specific amplification and / or maturation of one or more effector T cell populations). In some embodiments, the antigen portion can also retain the ability to be internalized, processed, and / or presented by antigen-presenting cells (e.g., dendritic cells). In some embodiments, the antigen portion also retains T cell priming function. In some embodiments, the antigen portion of the neoantigen sequence ranges in length from about 10 to about 50 amino acids. In some embodiments, the antigen portion of the neoantigen sequence ranges in length from about 10 to about 35 amino acids. In some embodiments, the antigen portion of the neoantigen sequence ranges in length from about 15 to about 25 amino acids. In some embodiments, the antigen portion of the neoantigen sequence ranges in length from about 10 to about 20 amino acids. In some embodiments, the antigen portion of the neoantigen sequence (e.g., the antigen portion of any one of SEQ ID NO: 30-57) or its encoding mRNA is formulated into a neoantigen vaccine.

[0830] An exemplary embodiment of an antigenic portion is one or more regions flanking amino acids 45-53 of SEQ ID NO: 30. Another exemplary embodiment of an antigenic portion is one or more regions flanking amino acids 82-90 of SEQ ID NO: 30. In some embodiments, the antigenic portion is capable of binding to at least one HLA allele (e.g., HLA-A*02:01) expressed in a subject. In some other embodiments, the antigenic portion is capable of binding to at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% of a subject population having a neoplastic disease. In some embodiments, the antigenic portion is capable of eliciting a T cell response against tumors present in at least 1%, at least 5%, or at least 10% of a subject population having a neoplastic disease.

[0831] In certain embodiments, antigenic moieties do not exclusively overlap with typical peptide sequences or consist of typical peptide sequences. As used herein, term "typical peptide sequence" refers to when not contacting at least one compound selected from a compound with formula I, a compound with formula II, a compound with formula III, and a pharmaceutically acceptable salt of any of the foregoing (e.g., when not contacting at least one compound selected from a compound with formula I, a compound with formula II, a compound with formula III, and a pharmaceutically acceptable salt of any of the foregoing), and / or when previously exposed to immunity, any continuous peptide sequence present in the human proteome. In certain embodiments, typical peptide sequences are derived from typical transcript open reading frames and / or are encoded by typical transcript open reading frames. Exemplary typical peptide sequences are underlined in Table 13.

[0832] In some embodiments, when at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing is administered, the typical peptide sequence may be derived from and / or encoded by the 24 nucleotides in the 5' frame immediately preceding the abnormal splicing event induced by at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. Thus, in some embodiments, the typical peptide sequence comprises or consists of the 8 amino acids immediately preceding the N-terminus of the neoantigen sequence induced by at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, when the 5' exon sequence terminates at the terminal nucleotide of a codon, the typical peptide sequence terminates at the end of the exon. In some other embodiments, when the 5' exon sequence terminates at one or two of the three nucleotides of a codon, the typical peptide sequence is derived from and / or encoded by the 24 nucleotides preceding the incomplete codon. In some embodiments, the mRNA sequence 3' of the abnormal splicing event can be translated in the same open reading frame derived from the 5' exon until the stop codon is reached, thereby terminating translation. In some embodiments, when the abnormal splicing event (e.g., exon skipping) causes the typical transcript open reading frame to be conserved, the C-terminal sequence can translate another 24 nucleotides, encoding 8 C-terminal amino acids. In this context, in some embodiments, only the region spanning the abnormal exon junction can encode the neoantigen sequence. In some embodiments, when the open reading frame is shifted (e.g., intron retention), the complete C-terminal sequence (encoded by 3'mRNA) can encode the neoantigen sequence.

[0833] In some embodiments, the antigen portion of the neoantigen sequence is selected by comparing the neoantigen sequence with a typical peptide sequence; and selecting a portion of the neoantigen sequence that does not exclusively overlap with the typical peptide sequence, consists of the typical peptide sequence, and / or is aligned with the typical peptide sequence. In some embodiments, the antigenicity and / or T cell priming function of the antigen portion of the neoantigen sequence can be screened in the same manner as the full-length neoantigen sequence (e.g., the neoantigen sequence of the derived antigen portion). In some embodiments, the antigenicity and / or T cell priming function of the antigen portion of the neoantigen sequence are assessed using T cell priming analysis, such as the exemplary T cell priming experiments described herein.

[0834] In some embodiments, the neoantigen sequence is a neoantigen sequence specific to the subject. In some embodiments, the neoantigen sequence is a personalized neoantigen vaccine for the subject. In some embodiments, the neoantigen sequence used to generate a personalized neoantigen vaccine for the subject is capable of binding to at least one HLA allele expressed in the subject. In some embodiments, the personalized neoantigen vaccine is selected by, for example, identifying neoantigens expressed in the subject's tumor after administering at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and selecting a vaccine comprising the neoantigen sequence observed in the patient's tumor.

[0835] When used to describe a neoantigen vaccine, the term "personalized" refers to a vaccine produced by identifying one or more neoantigens produced in a patient after exposure to at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, preferably a neoantigen identified in the patient, and then using one or more of those neoantigens as the basis for a vaccine for the same patient. Thus, in some embodiments, a patient is administered at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and screened for neoantigens produced by treatment. In some embodiments, the selected neoantigen vaccine comprises a neoantigen peptide or mRNA disclosed herein and demonstrated to be present in the patient after exposure to at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, at least one compound and / or peptide or mRNA vaccine selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing can be administered to the patient once or repeatedly. Subsequently, in some embodiments, one or more of those new antigens are used to generate a personalized vaccine for administration to the patient. In some embodiments, the one or more new antigens used to generate the personalized vaccine have binding affinity for one or more patient-specific HLA alleles. In some embodiments, the patient expresses one or more MHC1 alleles that bind to the one or more new antigens. Any computational prediction method known in the art can be used to determine the prediction of whether a given new antigen will bind to a specific MHC1 allele. Exemplary computational prediction methods are disclosed, for example, in Meydan et al. (2013) BMC Bioinformatics 14 (Suppl. 2): S13 [BMC Bioinformatics 14 (Suppl. 2): S13], which are incorporated herein by reference.

[0836] In some other embodiments, the neoantigen sequence is a universal neoantigen sequence. In some embodiments, the neoantigen sequence is a universal neoantigen vaccine.

[0837] When used to describe a neoantigen vaccine, the term "universal" refers to a vaccine having a peptide or mRNA sequence based on one or more common or known neoantigens observed by sequencing neoantigens produced in multiple patients and / or patient tissue samples, preferably after exposure to at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. The peptide or mRNA sequence used in the vaccine does not need to be present in every patient, but rather is observed in at least several patients or patient tissue samples. In some embodiments, at least one compound and / or peptide or mRNA vaccine selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing can be administered to a patient once or repeatedly. Subsequently, in some embodiments, the peptide or mRNA sequence is used to vaccinate other patients. In some embodiments, a patient is administered at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and then administered a peptide or mRNA vaccine of a known neoantigen to enhance the immune response to a neoantigen produced by at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, a patient is administered a universal peptide or mRNA vaccine and then administered at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the neoantigen sequence (or sequences) used to generate a universal neoantigen vaccine is selected based on the overall MHC1 allele frequency in a given patient population (Maiers et al. (2007) Hum. Immunol. 68(9):779-88).

[0838] In some embodiments, the neoantigen (e.g., universal neoantigen) sequence is capable of binding to at least one HLA allele expressed in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% of a population of subjects with a neoplastic disease. In some embodiments, the neoantigen sequence is capable of eliciting a T cell response against tumors present in at least 1%, at least 5%, or at least 10% of a population of subjects with a neoplastic disease.

[0839] In some embodiments, the neoantigen sequence is identified by sequencing at least one neoantigenic peptide induced in a subject or its encoding mRNA by administering a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the at least one neoantigenic peptide comprises a neoantigen sequence induced by contacting a tumor cell with a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the tumor cell is present in an in vitro cell culture. In some embodiments, the tumor cell is obtained from a subject. In some embodiments, the tumor cell is present in a subject.

[0840] In some embodiments, the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable carrier (e.g., any exemplary carrier described herein). In some embodiments, at least one neoantigen peptide is connected to a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is selected from peptides, serum albumin, keyhole limpet hemocyanin, immunoglobulin, thyroglobulin, ovalbumin, toxoid or attenuated toxoid derivatives, cytokines and chemokines. In some embodiments, the neoantigen peptide and the pharmaceutically acceptable carrier are covalently linked via a connector. In some embodiments, the neoantigen peptide and the pharmaceutically acceptable carrier are expressed as a fusion protein. In some embodiments, the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable diluent. In some embodiments, the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable adjuvant.

[0841] In some embodiments, the neoantigen vaccine comprises at least one neoantigen mRNA. In some embodiments, the at least one neoantigen mRNA encodes one or more neoantigen sequences.

[0842] In some embodiments, the neoantigen sequence is a neoantigen sequence specific to the subject. In some embodiments, the neoantigen sequence is a personalized neoantigen vaccine for the subject. In some embodiments, the neoantigen sequence is capable of binding to at least one HLA allele expressed in the subject.

[0843] In some other embodiments, the neoantigen sequence is a universal neoantigen sequence. In some embodiments, the neoantigen sequence is a universal neoantigen vaccine. In some embodiments, the neoantigen sequence is capable of binding to at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% of the subjects in the subject population with a neoplastic disease. In some embodiments, the neoantigen sequence is capable of eliciting a T cell response against tumors present in at least 1%, at least 5%, or at least 10% of the subject population with a neoplastic disease.

[0844] In some embodiments, the neoantigen sequence has been identified by sequencing the protein sequence of at least one neoantigen. In some embodiments, the neoantigen sequence has been identified by sequencing at least one mRNA encoding a neoantigen induced in a subject by administering a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, at least one neoantigen mRNA encodes a neoantigen sequence induced by contacting tumor cells with a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the tumor cells are present in in vitro cell cultures. In some embodiments, the tumor cells are obtained from a subject. In some embodiments, the tumor cells are present in a subject.

[0845] In some embodiments, the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable carrier (e.g., any exemplary carrier described herein). In some embodiments, at least one neoantigen mRNA is connected to a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is selected from peptides, serum albumin, keyhole limpet hemocyanin, immunoglobulin, thyroglobulin, ovalbumin, toxoid or attenuated toxoid derivatives, cytokines and chemokines. In some embodiments, the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable diluent. In some embodiments, the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable adjuvant. In some embodiments, the neoantigen mRNA is encapsulated by an encapsulating agent. In some embodiments, the encapsulating agent is a liposome. In some embodiments, the encapsulating agent is a nanoparticle.

[0846] In some embodiments, at least one additional therapy comprises administering a cytokine or cytokine analog, such as any cytokine or cytokine analog disclosed herein. In some embodiments, when administered alone, the subject is intolerant, unresponsive, or poorly responsive to the cytokine or cytokine analog. In some embodiments, the cytokine or cytokine analog comprises a T cell enhancer. In some embodiments, the cytokine or cytokine analog comprises IL-2, IL-10, IL-12, IL-15, IFNγ, and / or TNFα. In some embodiments, the cytokine or cytokine analog comprises IL-2, IL-10, IL-12, and / or IL-15. In some embodiments, after administering at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, administering a cytokine or cytokine analog enhances T cell priming due to the induction and presentation of new antigens.

[0847] In some embodiments, at least one additional therapy comprises administration of engineered tumor-targeting T cells (ie, CAR-T), e.g., any CAR-T therapy disclosed herein.

[0848] In some embodiments, the methods described herein may further comprise detecting one or more neoantigens and / or T cell responses in the subject after administering at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and optionally continuing to administer at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing if one or more neoantigens and / or T cell responses are detected. In some embodiments, detecting one or more neoantigens and / or T cell responses in the subject indicates the efficacy of treatment with at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, if one or more neoantigens and / or T cell responses are detected, treatment with additional therapy and at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is continued. In some embodiments, if one or more neoantigens and / or T cell responses are detected, treatment is continued at a reduced dose and / or frequency.

[0849] In some embodiments, the methods described herein may further comprise detecting a double-stranded RNA immune response in the subject after administering at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and optionally continuing to administer at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing if a double-stranded RNA immune response is detected. In some embodiments, detecting a double-stranded RNA immune response in the subject indicates efficacy of treatment with at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, if a double-stranded RNA immune response is detected, treatment is continued with additional therapy and at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, if a double-stranded RNA immune response is detected, treatment is continued at a reduced dose and / or frequency.

[0850] In some embodiments, the methods described herein may further comprise detecting immunogenic cell death in the subject after administering at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and optionally continuing to administer at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing if immunogenic cell death is detected. In some embodiments, detecting immunogenic cell death in the subject indicates efficacy of treatment with at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, if immunogenic cell death is detected, treatment is continued with additional therapy and at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, if immunogenic cell death is detected, treatment is continued at a reduced dose and / or frequency.

[0851] In some embodiments, the subject has a non-synonymous mutation burden of about 150 mutations or less. In some embodiments, the subject has a non-synonymous mutation burden of about 100 mutations or less. In some embodiments, the subject has a non-synonymous mutation burden of about 50 mutations or less. In some embodiments, the subject suffers from or is suspected of suffering from a neoplastic disease, such as a hematological malignancy or a solid tumor. In some embodiments, the hematological malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myelomas. In some embodiments, the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma. In some embodiments, the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, and esophageal cancer. In some embodiments, the solid tumor is selected from HER2-positive breast cancer, gastric adenocarcinoma, and prostate cancer.

[0852] In some embodiments, the present disclosure further provides a method of treating a subject having or suspected of having a neoplastic disease, comprising: (a) administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing, wherein administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing induces at least one neoantigen and / or T cell response; (b) detecting one or more neoantigens and / or T cell responses in the subject after administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing; and (c) continuing to administer at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing if one or more neoantigens and / or T cell responses are detected. In some embodiments, detection of one or more neoantigens and / or T cell responses in a subject indicates efficacy of treatment with at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the one or more neoantigens comprise the amino acid sequence of any one of SEQ ID NOs: 1-29. In some embodiments, the one or more neoantigens comprise the amino acid sequence of SEQ ID NO: 1. In some embodiments, the one or more neoantigens comprise the amino acid sequence of SEQ ID NO: 3. In some embodiments, the one or more neoantigens comprise the amino acid sequence of any one of SEQ ID NOs: 10-13.

[0853] In some embodiments, patients suffering from cancer as described herein can be treated with a combination of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and pharmaceutically acceptable salts of any of the foregoing and a checkpoint inhibitor therapy.

[0854] It has been shown that treating patients with immune checkpoint inhibition has robust efficacy in certain clinical indications. Recently, the FDA approved the use of checkpoint inhibitors in patients with tumors that exhibit high microsatellite instability and are agnostic to tissue lineage. This approval is based in part on the observation that response rate is positively correlated with mutation burden (Rizvi et al. (2015) Science [Science] 348 (6230): 124-8; Hellmann et al. (2018) Cancer Cell [Cancer Cell] 33 (5): 853-861). Estimates from the literature vary in absolute numbers and lineages, but generally support a threshold of more than about 150-250 mutations, with an increased probability of response. Analysis of TCGA data shows that a large percentage of adult-onset tumor lineages have a relatively low burden of non-synonymous mutations (Vogelstein et al. (2013) Science [Science] 339: 1549-58). The median nonsynonymous mutation rate in most pedigrees was approximately 30–80 per patient, well below the threshold that increases the chance of response to checkpoint inhibitors.

[0855] For example, it has been shown that HER2 positive breast cancer has a median of about 60 non-synonymous mutations per patient sample. However, as mentioned above, the threshold value of checkpoint inhibitor treatment efficacy is estimated to be within the range of about 150-250 non-synonymous mutations, that is, patients above this threshold are more likely to show complete remission, partial remission, and / or stable disease, while patients below this threshold are more likely to show progressive disease. Therefore, it is desirable to enhance the strategy of the apparent number of non-synonymous mutations and / or neoantigens presented on tumor cells, and it is possible to enhance the total response probability of, for example, checkpoint inhibitor therapy. Since cytokines (and their analogs) work by similar mechanisms of action, such strategies can also enhance the total response probability of cytokine-based therapy.

[0856] The current response rate for HER2-positive breast cancer is about 15%-25% (CTI NCT02129556). In some embodiments disclosed herein, treatment with at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing in combination with a checkpoint inhibitor and / or cytokine therapy can improve such response rates. In some embodiments, treatment with a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing in combination with a checkpoint inhibitor and / or cytokine therapy can be applied to any adult-onset tumor, particularly those with a median non-synonymous mutation rate below an estimated threshold of about 150 mutations. In certain embodiments, the exemplary cancer types suitable for treatment with a therapeutically effective amount of a compound selected from a compound with Formula I, a compound with Formula II, a compound with Formula III, and a pharmaceutically acceptable salt of any of the foregoing, alone or in combination with other therapies (e.g., checkpoint inhibitor therapy, cytokine therapy) include, but are not limited to, esophageal cancer, non-Hodgkin's lymphoma, colorectal cancer, head and neck cancer, gastric cancer, endometrial cancer, pancreatic cancer, ovarian cancer, prostate cancer, hepatocellular carcinoma, glioblastoma, breast cancer (e.g., HER2 positive breast cancer), lung cancer (e.g., non-small cell lung cancer), chronic lymphocytic leukemia, and acute myeloid leukemia. Other exemplary suitable cancer types are, for example, identified in Vogelstein et al. (2013) Science [science] 339: 1549-58, which are incorporated herein by reference in their entirety.

[0857] Since many checkpoint inhibitor therapies are based on the chronic expression of tumor-associated antigens, regular treatment is required to enhance efficacy and "re-enhance" reactive T cell populations. The inductive properties of the neoantigens described herein derived from at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing provide therapeutic dosing regimens that can be designed to enhance the immune response of neoantigen-reactive T cells while limiting T cell exhaustion typically caused by chronic antigen stimulation. For example, in some embodiments, an initial dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is administered to a subject to trigger abnormal splicing and production of neoantigen peptides. After allowing protein production and antigen presentation for a period of time, in some embodiments, an initial dose of a checkpoint inhibitor is then administered to the subject to strengthen and / or enhance effector T cell priming and expansion. In some embodiments, the waiting period between the dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing and the checkpoint inhibitor is about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In some embodiments, the waiting period is between about 3 days and about 5 days.

[0858] In some embodiments, the checkpoint inhibitor targets CTLA4, OX40, CD40, and / or GITR. In some embodiments, the combined therapeutic benefit of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing and a checkpoint inhibitor may be additive or super-additive.

[0859] In some embodiments, administration of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is initiated prior to administration of a checkpoint inhibitor.

[0860] In some embodiments, administration of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing is initiated after administration of a checkpoint inhibitor.

[0861] In some embodiments, administration of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is initiated simultaneously with administration of the checkpoint inhibitor, for example, in a single formulated product or in separate formulated products administered in a single procedure.

[0862] In some embodiments, after allowing T cells to initiate and expand for a period of time, a second or subsequent dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is then administered to the subject to trigger the re-presentation of the neoantigen peptide. In some embodiments, the waiting period between the initial dose of the checkpoint inhibitor and the second or subsequent dose of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is about 2 weeks, about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the waiting period is about 3 weeks. After the second or subsequent dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, in some embodiments, the immune system may engage with neoantigen-presenting tumor cells and / or trigger tumor cell killing. In some embodiments, a second or subsequent dose of a checkpoint inhibitor is then administered to the subject to further expand the memory effector T cell population after allowing secondary T cells to initiate and expand.

[0863] In some embodiments, the waiting period between an initial dose of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing and a second or subsequent dose of a checkpoint inhibitor is about 2 weeks, about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the waiting period is about 3 weeks.

[0864] In some embodiments, after this exemplary initial treatment regimen, the administration of a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any one of the foregoing can be pulsed, i.e., a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any one of the foregoing can be administered at extended intervals (e.g., about every 4 weeks, about every 5 weeks, about every 6 weeks) to allow for antigen presentation, T cell engagement and / or tumor cell killing, and / or restoration of memory T cell populations. At a later time point, in some embodiments, treatment with a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any one of the foregoing can be combined with one or more checkpoint inhibitors whose goal is to restore effector function to exhausted T cell populations. For example, in some embodiments, at a later time point, treatment with at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing may be combined with one or more checkpoint inhibitors targeting PD1 / PDL1, LAG3, and / or TIM3. In some embodiments, the pulsed nature of neoantigen presentation and priming allows checkpoint inhibitors and / or at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing to be administered less frequently and / or at a lower dose. In some embodiments, the pulsed nature of neoantigen presentation can provide one or more therapeutic benefits of a checkpoint inhibitor (e.g., an anti-CTLA4 antibody, such as ipilimumab), for example, by reducing the potential risk of adverse reactions typically observed with standard dosing regimens of checkpoint inhibitors, relative to checkpoint inhibitors administered without concurrent administration of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing.

[0865] In certain embodiments, the checkpoint inhibitor is an inhibitor of the cytotoxic T lymphocyte-associated antigen (CTLA4) pathway. CTLA4, also known as CD152, is a protein receptor that downregulates immune responses. CTLA4 is constitutively expressed in regulatory T cells, but is only upregulated in conventional T cells after activation. As used herein, the term "CTLA4 inhibitor" means any inhibitor of CTLA4 and / or the CTLA4 pathway. Exemplary CTLA4 inhibitors include, but are not limited to, anti-CTLA4 antibodies. Based on preclinical activity seen in mouse models of anti-tumor immunity, CTLA4 blocking antibodies for humans have been developed. Exemplary anti-CTLA4 antibodies include, but are not limited to, ipilimumab (MDX-010) and tremelimumab (CP-675,206), both of which are fully human. Ipilimumab is an IgG1 with a plasma half-life of approximately 12-14 days; tremelimumab is an IgG2 with a plasma half-life of approximately 22 days. See, e.g., Phan et al. (2003) Proc Natl Acad Sci USA 100:8372-7; Ribas et al. (2005) J Clin Oncol 23:8968-77; Weber et al. (2008) J Clin Oncol 26:5950-6. In some embodiments, the anti-CTLA4 antibody is ipilimumab.

[0866] In certain embodiments, checkpoint inhibitors are inhibitors of the programmed cell death-1 (PD1) pathway. The programmed cell death 1 (PD1) pathway represents a major immune control switch that can engage tumor cells to overcome active T cell immune surveillance. PD1's ligands (PDL1 and PDL2) are constitutively expressed or can be induced in various tumors. It has been found that high expression of PDL1 on tumor cells (and to a lesser extent PDL2) is associated with poor prognosis and survival in various other solid tumor types. In addition, it has been proposed that PD1 regulates tumor-specific T cell expansion in patients with malignant melanoma. These observations suggest that the PD1 / PDL1 pathway plays a key role in tumor immune evasion and can be considered an attractive target for therapeutic intervention. As used herein, the term "PD1 inhibitor" means any inhibitor of PD1 and / or the PD1 pathway. Exemplary PD1 inhibitors include, but are not limited to, anti-PD1 and anti-PDL1 antibodies. In certain embodiments, checkpoint inhibitors are anti-PD1 antibodies. Exemplary anti-PD1 antibodies include, but are not limited to, nivolumab and pembrolizumab (MK-3475). For example, nivolumab is a fully human immunoglobulin G4 (IgG4) PD1 immune checkpoint inhibitor antibody that disrupts the interaction between the PD1 receptor and its ligands PDL1 and PDL2, thereby inhibiting cellular immune responses (Guo et al. (2017) J Cancer 8(3):410-6). In some embodiments, the anti-PD1 antibody is nivolumab. For example, pembrolizumab is a potent and highly selective humanized mAb of the IgG4 / κ isotype that is designed to directly block the interaction between PD1 and its ligands PDL1 and PDL2. Pembrolizumab strongly enhances T lymphocyte immune responses in cultured blood cells from healthy human donors, cancer patients, and primates. It has also been reported that pembrolizumab regulates the levels of interleukin 2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and other cytokines. Exemplary anti-PDL1 antibodies include, but are not limited to, atezolizumab, avelumab, and durvalumab. For example, atezolizumab is an IgG1 humanized mAb that has been reported to block the PD1 / PDL1 interaction by targeting PDL1 expressed on a variety of malignant cells. This blockade of the PD1 / PDL1 pathway may stimulate immune defense mechanisms against tumors (Abdin et al. (2018) Cancers (Basel) 10(2):32). In some embodiments, the anti-PDL1 antibody is atezolizumab.

[0867] In certain embodiments, the check point inhibitor targets PD1 / PDL1, CTLA4, OX40, CD40, LAG3, TIM3, GITR, and / or KIR. In certain embodiments, the check point inhibitor targets CTLA4, OX40, CD40, and / or GITR. In certain embodiments, the check point inhibitor targets inhibitory antibodies or other similar inhibitory molecules (e.g., inhibitory anti-CTLA4 or anti-PD1 / PDL1 antibodies). In certain other embodiments, the check point inhibitor targets agonists of the target; examples of this category include stimulatory targets OX40, CD40, and / or GITR. In some embodiments, the check point inhibitor targeting OX40, CD40, and / or GITR is an agonist antibody. Agonist antibodies for OX40 can have a dual effect, inhibiting regulatory T cell suppression while enhancing effector T cell function. Agonist anti-GITR antibodies have also been shown to render effector T cells more resistant to suppression induced by regulatory T cells (Karaki et al. (2016) Vaccines (Basel) 4(4):37). Similarly, agonist CD40 antibodies exhibit T cell-dependent anti-tumor activity. Activation of CD40 on dendritic cells increases cross-presentation of tumor antigens and, therefore, increases the number of activated tumor-directed effector T cells (Ellmark et al. (2015) Oncoimmunol 4(7):e1011484).

[0868] In certain embodiments, check point inhibitors target CTLA4 (e.g., anti-CTLA4 antibodies). In certain embodiments, targeting CTLA4 promotes the initiation and activation of initial T cells. In certain embodiments, check point inhibitors target OX40 (e.g., anti-OX40 antibodies). In certain embodiments, targeting OX40 enhances the expansion of effector T cells. In certain embodiments, check point inhibitors target CD40 (e.g., anti-CD40 antibodies). In certain embodiments, targeting CD40 inhibits the "tolerogenic" initiation of T cells and / or the formation of regulatory T cells. In certain embodiments, check point inhibitors target GITR (e.g., anti-GITR antibodies). In certain embodiments, targeting GITR inhibits the activity of regulatory T cells. In certain embodiments, the benefits of the combination therapy using a therapeutically effective amount of a compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing and a medicament targeting CTLA4, OX40, CD40 and / or GITR are cumulative (e.g., the effect on the risk / rate of at least one symptom or disease progression). In some embodiments, the benefit of combination therapy with a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and pharmaceutically acceptable salts of any of the foregoing, and an agent that targets CTLA4, OX40, CD40, and / or GITR is supra-additive (i.e., synergistic).

[0869] Checkpoint inhibitor treatment strategies are based on the following assumptions: treatment promotes and / or enhances the initiation of T cell responses against weak or poorly antigenic tumors (e.g., CTLA4), or treatment restores and / or reactivates T cells that react to tumor antigens but have become "exhausted" due to the chronic nature of antigen presentation (e.g., PD1, PDL1) (Chen and Mellman (2013) Immunity 39 (1): 1-10). Examples of suitable checkpoint inhibitor therapies and agents, such as anti-PD1, anti-PDL1 or anti-CTLA4 antibodies, are known in the art. See, for example, WO 2001 / 014424, WO 2013 / 173223, WO 2016 / 007235.

[0870] Combining these activated T cell responses after checkpoint inhibitor therapy with treatment that induces new antigens in tumor cells that can react with the activated immune system (e.g., by administering a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing) can provide a beneficial synergistic effect. Since the new antigens derived from the compound selected from the compound of formula I, the compound of formula II, the compound of formula III, and the pharmaceutically acceptable salt of any of the foregoing have not yet been presented for T cell priming, the combination with a CTLA4 inhibitor can be particularly beneficial. In some embodiments, the treatment includes administering a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing to induce the production of new antigens before, simultaneously with, or after the initial administration of a CTLA4 inhibitor to stimulate CD8 T cell priming. In some embodiments, the patient is provided with additional administration of a CTLA4 inhibitor, for example, to further stimulate the priming and / or activation of the new antigen-reactive CD8 population. In some embodiments, the patient may be given an additional administration of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing to increase neoantigen presentation by the tumor. Repeated administration of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing and checkpoint inhibitor therapy may occur simultaneously or at staggered time intervals. In some embodiments, treatment further comprises co-treatment with a PD1 / PDL1 inhibitor, for example to restore the effector function of T cells targeting neoantigens that are exhausted within the tumor microenvironment.

[0871] As used herein, the term "combination" or "combination therapy" refers to a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing, administered together with another agent or therapy (e.g., checkpoint inhibitors, cytokines or cytokine analogs, neoantigen vaccines, CAR-T) as part of a treatment regimen intended to provide a beneficial (i.e., additive or synergistic) effect from the combined action of one or more administered agents. In some embodiments, the combination may further include one or more additional agents, including but not limited to chemotherapeutic agents, anti-angiogenic agents, and agents that reduce immunosuppression (e.g., a second checkpoint inhibitor). The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-actions resulting from the combination of therapeutic agents. The combined administration of these therapeutic agents is typically performed within a defined time period (e.g., minutes, hours, days, or weeks, depending on the combination selected).

[0872] As used herein, "combination" administration or "co-administration" means delivering two or more different treatments to a subject in any order while the subject is suffering from a medical condition (e.g., cancer or a neoplastic disease). For example, in some embodiments, two or more treatments are delivered after the subject has been diagnosed with a disease or condition and before the disease or condition has been cured or eliminated, or before the subject has developed symptoms of the disease, after the subject has been identified as being in danger. In some embodiments, the delivery of the first treatment is still ongoing when the delivery of the second treatment begins, so there is overlap. In some embodiments, the first and second treatments begin simultaneously. These types of delivery are sometimes referred to herein as "simultaneous," "parallel," or "concomitant" delivery. In other embodiments, the delivery of the first treatment ends before the delivery of the second treatment begins. This type of delivery is sometimes referred to as "continuous" or "sequential" delivery.

[0873] In some embodiments, two treatments (e.g., a compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and at least one compound of a pharmaceutically acceptable salt of any of the foregoing, and a checkpoint inhibitor) are included in the same composition. Such compositions can be administered in any appropriate form and by any suitable route. In other embodiments, two treatments (e.g., a compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and at least one compound of a pharmaceutically acceptable salt of any of the foregoing, and a checkpoint inhibitor) are administered in separate compositions, in any appropriate form, and by any suitable route. For example, in some embodiments, a composition comprising a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing, and a composition comprising a checkpoint inhibitor can be administered sequentially in any order in parallel or at different time points; in either case, they should be administered sufficiently close in time to provide the desired therapeutic or preventive effect.

[0874] In embodiments delivered simultaneously or sequentially, due to combined administration, treatment may be more effective. In certain embodiments, the first treatment is more effective, for example, compared to what is observed when the first treatment is administered in the absence of the second treatment, an equivalent effect is observed when the first treatment is less (e.g., with a lower dose). In certain embodiments, the first treatment is more effective, such that the reduction in symptoms or other parameters associated with the disease or condition is greater than what is observed when the first treatment is delivered in the absence of the second treatment. In other embodiments, a similar situation is observed with the second treatment. In certain embodiments, the benefits of the combination therapy (e.g., the effect on the risk / rate of at least one symptom or disease progression) are cumulative. In certain embodiments, the benefits of the combination therapy are super-cumulative.

[0875] In some embodiments, the present disclosure provides a method for treating cancer in a subject in need thereof and / or a subject suffering from or suspected of having a neoplastic disease, the method comprising administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing; and at least one additional therapy (e.g., checkpoint inhibitor therapy, cytokine or cytokine analog, new antigen vaccine, CAR-T). In some embodiments, administration of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing induces at least one new antigen and / or T cell response. In some embodiments, administration of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing induces a double-stranded RNA immune response. In some embodiments, administration of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing induces immunogenic cell death. In some embodiments, the at least one additional therapy may comprise at least one, at least two, at least three, at least four, or at least five additional therapies. For example, in some embodiments, a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing may be administered in combination with two checkpoint therapies (i.e., using two different checkpoint inhibitors). In some embodiments, at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing may be administered in combination with a checkpoint inhibitor therapy and a neoantigen vaccine.

[0876] In some embodiments of the combination therapy, the administered amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% relative to the standard dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy. In some embodiments, the compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy is administered at a frequency that is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% less than the standard dosing regimen of the compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy. In some embodiments, the amount and / or dosage of the compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and / or at least one additional therapy results in lower systemic toxicity and / or improved tolerability.

[0877] In some embodiments, administration of a therapeutically effective amount of at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing is initiated prior to administration of at least one additional therapy. In some embodiments, administration of a therapeutically effective amount of at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing is initiated after administration of at least one additional therapy. In some embodiments, administration of a therapeutically effective amount of at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing is initiated simultaneously with administration of at least one additional therapy.

[0878] In some embodiments, after the initial administration, a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing is repeatedly administered at least once. In some embodiments, the amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing for repeated administration is reduced relative to the amount used for the initial administration. In some embodiments, the amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing for repeated administration is reduced relative to the standard dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any one of the foregoing. In some embodiments, the amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% relative to a standard dose of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing.

[0879] In some embodiments, after the initial administration, the at least one additional therapy is repeated at least once. In some embodiments, the amount of the at least one additional therapy for repeated administration is reduced relative to the amount used for the initial administration. In some embodiments, the amount of the at least one additional therapy for repeated administration is reduced relative to a standard dose of the at least one additional therapy. In some embodiments, the amount of the at least one additional therapy for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% relative to a standard dose of the at least one additional therapy.

[0880] In some embodiments, repeated administration of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is concurrent with repeated administration of at least one additional therapy. In some embodiments, repeated administration of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is sequential or staggered with repeated administration of at least one additional therapy.

[0881] In some embodiments, the present disclosure provides a method for treating a subject in need thereof and / or a subject suffering from or suspected of having a neoplastic disease, the method being by administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing; and checkpoint inhibitor therapy. In some embodiments, checkpoint inhibitor therapy includes administering at least one checkpoint inhibitor. In some embodiments, when administered alone, the subject is intolerant, unresponsive, or poorly responsive to at least one checkpoint inhibitor. In some embodiments, the subject may be considered to be unresponsive or poorly responsive to at least one checkpoint inhibitor, as determined using, for example, immune-related response criteria (irRC) and / or immune-related response evaluation criteria (irRECIST) in solid tumors. See, e.g., Wolchok et al. (2009) Clin Cancer Res. 15(23):7412-20; Bohnsack et al. "Adaptation of the Immune-Related Response Criteria: irRECIST" (Abstract 4958) ESMO 2014. Exemplary criteria may include criteria used in the art to define when a tumor in a cancer patient improves ("responds"), remains the same ("stable"), or worsens ("progresses") during treatment when the treatment being evaluated is an immuno-oncology drug (e.g., a checkpoint inhibitor). In some embodiments, a subject may be considered intolerant to at least one checkpoint inhibitor if the subject exhibits one or more adverse (grade 2+) events identified for the corresponding checkpoint inhibitor (e.g., ipilimumab). In some embodiments, a subject may be considered intolerant to ipilimumab treatment, for example, if the subject exhibits one or more adverse events selected from enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathies. (Ipilimumab) FDA label supplement, 2018).

[0882] In some embodiments, checkpoint inhibitors target PD1 / PDL1, CTLA4, OX40, CD40, LAG3, TIM3, GITR, and / or KIR. In some embodiments, checkpoint inhibitors target CTLA4, OX40, CD40, and / or GITR. In some embodiments, checkpoint inhibitors are targeted with inhibitory antibodies or other similar inhibitory molecules. In some other embodiments, checkpoint inhibitors are targeted with agonist antibodies or other similar agonist molecules. In some embodiments, checkpoint inhibitors include cytotoxic T lymphocyte-associated antigen 4 pathway (CTLA4) inhibitors. In some embodiments, CTLA4 inhibitors are anti-CTLA4 antibodies. In some embodiments, anti-CTLA4 antibodies are ipilimumab. In some embodiments, checkpoint inhibitors include programmed death-1 pathway (PD1) inhibitors. In some embodiments, PD1 inhibitors are anti-PD1 antibodies. In some embodiments, anti-PD1 antibodies are nivolumab. In some embodiments, PD1 inhibitors are anti-PDL1 antibodies. In some embodiments, anti-PDL1 antibodies are atezolizumab. In some embodiments, checkpoint inhibitors include CTLA4 inhibitors and PD1 inhibitors. In some embodiments, checkpoint inhibitors target OX40. In some embodiments, checkpoint inhibitors target CD40. In some embodiments, checkpoint inhibitors target GITR. In some embodiments, the benefits of a combination therapy using a therapeutically effective amount of a compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing and a checkpoint inhibitor (e.g., an antibody or molecule targeting CTLA4, PD1 / PDL1, OX40, CD40, and / or GITR) are cumulative. In some embodiments, the benefits of a combination therapy using a therapeutically effective amount of a compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing and a checkpoint inhibitor (e.g., an antibody or molecule targeting CTLA4, PD1 / PDL1, OX40, CD40, and / or GITR) are super-additive (i.e., synergistic).

[0883] In some embodiments, the present disclosure provides a method for treating cancer in a subject in need thereof and / or a subject suffering from or suspected of having a neoplastic disease, the method comprising administering to the subject a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing; and cytokine or cytokine analog therapy. In some embodiments, cytokine or cytokine analog therapy comprises administering at least one cytokine or cytokine analog. In some embodiments, when administered alone, the subject is intolerant, unresponsive, or poorly responsive to at least one cytokine or cytokine analog.

[0884] In some embodiments, the cytokine or cytokine analog comprises a T cell enhancer. In some embodiments, the cytokine or cytokine analog comprises IL-2, IL-10, IL-12, IL-15, IFNγ, and / or TNFα. In some embodiments, the cytokine or cytokine analog comprises IL-2, IL-10, IL-12, and / or IL-15. In some embodiments, after administering a therapeutically effective amount of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing, administration of a cytokine or cytokine analog enhances T cell priming due to the induction and presentation of new antigens.

[0885] In some embodiments, the cytokine or cytokine analog comprises IL-2. In some embodiments, IL-2 strengthens signals directed to effector cells to promote their expansion (Rosenberg (2014) J Immunol. [Journal of Immunology] 192 (12): 5451-8). In some embodiments, the cytokine or cytokine analog comprises IL-10. In some embodiments, IL-10 strengthens CD8+ T cell priming and activation (Mumm et al. (2011) Cancer Cell [Cancer Cell] 20 (6): 781-96). In some embodiments, the cytokine or cytokine analog comprises IL-12. In some embodiments, IL-12 connects innate and adaptive immune responses to strengthen antigen-specific priming and targeting (Tugues et al. (2015) Cell Death Differ [Cell Death and Differentiation]. 22 (2): 237-46). In some embodiments, the cytokine or cytokine analog comprises IL-15. In some embodiments, IL-15 strengthens T-effector (CD8) cell priming and / or activation. In some embodiments, the cytokine or cytokine analog comprises IFNγ. In some embodiments, IFNγ supplements T effector cell secretion of IFNγ. In some embodiments, the cytokine or cytokine analog comprises TNFα. In some embodiments, TNFα supplements T effector cell secretion of TNFα.

[0886] In some embodiments, a therapeutically effective amount of an initial dose of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing is administered to the subject to trigger abnormal splicing and production of new antigenic peptides. After allowing protein production and antigen presentation for a period of time, in some embodiments, an initial dose of a cytokine or cytokine analog is then administered to the subject to strengthen and / or enhance effector T cell priming and expansion. In some embodiments, the waiting period between the dose of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing and the cytokine or cytokine analog is about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days. In some embodiments, the waiting period is between about 3 days and about 5 days. In some embodiments, the cytokine or cytokine analog is IL-2, IL-10, IL-12, IL-15, IFNγ, and / or TNFα. In some embodiments, the combined therapeutic benefit of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and pharmaceutically acceptable salts of any of the foregoing and a cytokine or cytokine analog may be additive or supra-additive.

[0887] In some embodiments, after allowing T cells to initiate and expand for a period of time, a second or subsequent dose of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is then administered to the subject to trigger the re-presentation of the neoantigenic peptide. In some embodiments, the waiting period between the initial dose of the cytokine or cytokine analog and the second or subsequent dose of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing is about 2 weeks, about 3 weeks, about 4 weeks, or about 5 weeks. In some embodiments, the waiting period is about 3 weeks. In some embodiments, subsequent doses of the cytokine or cytokine analog may be administered, for example, interspersed between subsequent doses of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. After the second or subsequent dose of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, in some embodiments, the immune system can engage with neoantigen-presenting tumor cells and / or initiate tumor cell killing. In some embodiments, after this exemplary initial treatment regimen, the administration of a therapeutically effective amount of at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing can be pulsed, i.e., at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing can be administered at extended intervals (e.g., about every 4 weeks, about every 5 weeks, about every 6 weeks) to allow for antigen presentation, T cell engagement and / or tumor cell killing, and / or recovery of memory T cell populations.

[0888] In some embodiments, the subject has a non-synonymous mutation burden of about 150 mutations or less. In some embodiments, the subject has a non-synonymous mutation burden of about 100 mutations or less. In some embodiments, the subject has a non-synonymous mutation burden of about 50 mutations or less. In some embodiments, the subject suffers from or is suspected of suffering from a neoplastic disease, such as a hematological malignancy or a solid tumor. In some embodiments, the hematological malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myelomas. In some embodiments, the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma. In some embodiments, the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, and esophageal cancer. In some embodiments, the solid tumor is selected from HER2-positive breast cancer, gastric adenocarcinoma, and prostate cancer.

[0889] In some embodiments, the subject is in need of a method for treating cancer. In some embodiments, the cancer is a hematological malignancy or a solid tumor. In some embodiments, the hematological malignancy is selected from B-cell malignancies, leukemias, lymphomas, and myelomas. In some embodiments, the hematological malignancy is selected from acute myeloid leukemia and multiple myeloma. In some embodiments, the solid tumor is selected from breast cancer, gastric cancer, prostate cancer, ovarian cancer, lung cancer, uterine cancer, salivary duct carcinoma, melanoma, colon cancer, and esophageal cancer. In some embodiments, the solid tumor is selected from HER2-positive breast cancer, gastric adenocarcinoma, and prostate cancer.

[0890] In some embodiments, a patient with cancer as described herein can be treated with a combination of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing and a neoantigen vaccine. Without being bound by theory, vaccines used alone or in combination with immune checkpoint inhibitor (ICI) molecules have shown promise in early trials (Ott et al. (2017) Nature [Nature] 547 (7662): 217-21; Sahin et al. (2017) Nature [Nature] 547 (7662): 222-6), but generally require sequencing of patient tumor mutations (Ott et al. (2017) Nature [Nature] 547 (7662): 217-21; Aldous and Dong (2018) Bioorg. Med. Chem. [Biological Organic Chemistry and Medicinal Chemistry Communications] 26 (10): 2842-9). Therefore, vaccines generally depend on a sufficient number of antigenic non-synonymous mutations. Typically, tumors with very low mutational burdens provide few candidate antigens, and rapidly growing tumors provide limited time to identify and generate patient-specific vaccines.

[0891] So far, the attempt of developing a vaccine with broad immunogenicity in a large percentage of patients has focused on proteins that are frequently mutated, overexpressed or amplified in ectopic locations and / or proteins that exist in the form of "self" proteins in vivo. In addition, these proteins are typically expressed in immune-restricted tissues (e.g., neuronal markers expressed in neuroendocrine tumor types), while other proteins can be normally expressed during embryogenesis (e.g., carcinoembryonic antigens). Therefore, the effectiveness of vaccines using such proteins as antigens is typically limited to specific tumor lineages or one or more subgroups presenting the antigen therein. It is also necessary to confirm vaccine effectiveness by sequencing patient tumor samples, which may be time-consuming.

[0892] In addition, if these antigens exist in the form of "self" proteins, the immune system may be activated to identify these as "self" and therefore unresponsive. Alternatively, if the immune system can produce effector responses to these antigens, it may result in on-target side effects in tissues that can express antigens. In both cases, one of key challenges is that most antigen peptides are derived from "passenger" genes (i.e., mutations or amplifications during tumorigenesis, but not playing a key role in the continued survival or proliferation of the tumor itself). In this way, these genes can be silenced and the progress of the tumor will not be significantly affected, and therefore the tumor will be allowed to "escape" the immune response for these antigens. It is not desirable to be bound by theory, this mechanism may work in tumor evolution, wherein during the early stages of tumorigenesis, random mutations with strong antigenicity are often "selected" (Dunn et al. (2004) Annu. Rev. Immunol. [Annual Review of Immunology] 22:329-60) through tumor.

[0893] In addition, some evidence also suggests that chronic antigen presentation and immune stimulation may lead to immune cell anergy and exhaustion (Pardoll (2012) Nat. Rev. Cancer [Natural Review - Cancer] 12 (4): 252-64). These phenotypes form the basis of the therapeutic principle behind current ICI treatment, as ICI has been shown to inhibit exhausted immune cell phenotypes (α-PD1 / PD-L1) or promote additional immune cell responses (α-CTLA4). Notably, for α-CTLA4 therapy, it has been reported that certain subgroups of patients exhibit severe immune-related adverse events, which may be attributed to promoting T cell activation and breaking immune tolerance mechanisms that limit autoreactive immune responses.

[0894] Both approaches (i.e., triggering or enhancing a de novo immune response to a new antigen or disabling or exhausting an existing immune response) are associated with chronic immune activation. As such, these approaches are susceptible to disabling, editing, and other tumor-mediated mechanisms designed to suppress immune engagement.

[0895] In contrast, treatment with at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing can induce an immune response to novel sequences representing new antigens. In some embodiments, the presentation of new antigens provides more different targets for the adaptive immune system to engage and activate. In some embodiments, the ability of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing to sharply induce alternative splicing and the resulting new antigens can reduce the risk of immune system fatigue caused by long-term exposure to mutation-driven new antigens and / or limit the ability of tumor cells to adapt to escape therapy. In some embodiments, administration of at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing is combined with a new antigen vaccine to enhance the immune response to new antigens produced by at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing is administered before, during, or after vaccination. In some embodiments, at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing and / or the vaccine may be administered once or more than once during the course of treatment. In some embodiments, the vaccine is administered once during the course of treatment and at least one compound selected from a compound of formula I, a compound of formula II, a compound of formula III, and a pharmaceutically acceptable salt of any of the foregoing is administered more than once. In some embodiments, the vaccine is administered once during the course of treatment and is followed by one or more boosters.

[0896] As used herein, the term "neoantigen vaccine" refers to a pooled sample of one or more immunogenic neoantigenic peptides or mRNAs, such as at least two, at least three, at least four, at least five or more neoantigenic peptides. The term "vaccine" refers to a composition for producing immunity for the prevention and / or treatment of a disease (e.g., a neoplastic disease, such as a hematological malignancy or a solid tumor). Thus, a vaccine is a drug that contains an immunogenic agent and is intended for use in humans or animals to produce specific immune defenses and protective substances after vaccination. The neoantigen vaccine may additionally include a pharmaceutically acceptable carrier, diluent, excipient, and / or adjuvant.

[0897] As used herein, the term "immunogenic" refers to any agent or composition that can elicit an immune response, such as a T cell response. The immune response can be antibody-mediated or cell-mediated, or both.

[0898] In some embodiments, a patient is administered at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and then a peptide or mRNA vaccine of a known neoantigen is administered to enhance the immune response to the neoantigen produced by at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. In some other embodiments, a patient is administered at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and screened for neoantigens produced by treatment. Subsequently, one or more of those neoantigens are used to generate a personalized vaccine for administration to the patient. In any of these embodiments, at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing and / or a peptide or mRNA vaccine can be administered to the patient once or repeatedly.

[0899] In some embodiments, suitable neoantigens for vaccines can be identified by screening a panel of transcripts with altered splicing and robust expression from one or more tissue samples from a patient (e.g., from a tumor biopsy). In some embodiments, variant protein sequences are identified in the screened samples based on translation across aberrantly spliced ​​mRNA junctions, while retaining the portion of the protein sequence (up to 12 amino acids) flanking the amino acid changes across the junction. In some embodiments, these junction-spanning peptide fragments are scanned for high-affinity binding to MHC1 alleles, for example, using tools such as NetMHC1 (Nielsen et al. (2003) Protein Sci 12(5):1007-17; Andreatta and Neilsen (2016) Bioinformatics 32(4):511-7). These results allow filtering of novel peptides to those predicted to be high affinity binders for unique patient HLA allele compositions and assembling a library of novel peptides predicted to bind broadly to HLA alleles present at high frequencies in different populations (Maiers et al. (2007) Hum Immunol [Human Immunology] 68(9): 779-88). In some embodiments, the identified novel peptides are then formulated into vaccines, for example by combining with a suitable carrier or adjuvant (Ott et al. (2017) Nature [Nature] 547(7662): 217-21), or delivered as mRNA (Sahin et al. (2017) Nature [Nature] 547(7662): 222-6).

[0900] In some embodiments, the neoantigens selected are based on screening of individual patients' tumor responses to at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, to identify one or more neoantigens generated by treatment for subsequent vaccination. In other embodiments, neoantigens are selected, for example, based on screening a panel of samples from different patients to identify common neoantigens generated by at least one compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, and then used as a universal vaccine for future patients.

[0901] Without being bound by theory, in some embodiments, the use of universal neoantigen vaccines will avoid the need to sequence and analyze the unique mutational status of each patient's tumor because the neoantigens selected do not depend on tumor mutations, but rather mimic neoantigens produced by at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing and generally recognized by the body as foreign. In addition, in some embodiments, the use of neoantigen vaccines can be particularly effective because a patient's tumor cells may be more likely to mutate and not produce one or more neoantigens that depend on tumor mutations than those that mimic neoantigens produced by at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing. This may allow the formulation of a stock vaccine that is broadly immunogenic in a large percentage of patients, thereby accelerating the start of treatment regimens. Patients can be vaccinated according to the protocols outlined herein, and then, after vaccination, can be further treated with at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, for example, to induce expression of a neoantigenic peptide. In some embodiments, the patient can be administered at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, before, simultaneously with, or after vaccination. In some embodiments, the patient is administered at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, screened for one or more neoantigens found in a panel of universal neoantigens, and vaccinated with a universal neoantigen vaccine comprising at least one universal neoantigen identified in the subject. In some embodiments, the patient can be administered at least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and a pharmaceutically acceptable salt of any of the foregoing, one or more times after vaccination. At least one compound selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and pharmaceutically acceptable salts of any of the foregoing and / or a vaccine may be administered once or more than once during the course of treatment.

[0902] In some embodiments, the vaccine may comprise one or more than one neoantigenic peptide or mRNA. In some embodiments, the vaccine may comprise one or more than one long neoantigenic peptide. In some embodiments, such "long" neoantigenic peptides are effectively internalized, processed, and cross-presented in professional antigen-presenting cells (such as dendritic cells). Similarly, in other cases, long vaccine peptides have been shown to induce cytotoxic T cells in humans (Melief and van der Burg (2008) Nat Rev Cancer [Cancer Nature Reviews] 8 (5): 351-60). In some embodiments, in addition to the flanking amino acid sequence, the neoantigenic peptide extends to include the neoantigenic peptide sequence itself. In some embodiments, the extended peptide sequence promotes the uptake of proteins by antigen-presenting cells (e.g., dendritic cells). In some embodiments, the extended peptide sequence enables effective antigen presentation and T cell priming to be achieved in models with different HLA isotypes. In some embodiments, compared to shorter neoantigen peptides and / or shorter peptide sequences (e.g., peptide sequences less than about 10 or less than about 5 amino acids in length), longer neoantigen peptides and / or extended peptide sequences show increased uptake by antigen-presenting cells (e.g., dendritic cells), increased antigen presentation, and / or increased T cell priming. In some embodiments, long neoantigen peptides range in length from about 5 to about 50 amino acids. In some embodiments, long neoantigen peptides range in length from about 10 to about 50 amino acids. In some embodiments, at least one neoantigen peptide ranges in length from about 10 to about 35 amino acids. In some embodiments, long neoantigen peptides range in length from about 15 to about 25 amino acids.

[0903] In some embodiments, the neoantigen sequence and / or antigen portion ranges in length from about 10 to about 35 amino acids. In some embodiments, the neoantigen sequence and / or antigen portion ranges in length from about 15 to about 25 amino acids. In some embodiments, the neoantigen sequence and / or antigen portion ranges in length from about 10 to about 20 amino acids. In some embodiments, the neoantigen sequence and / or antigen portion does not exclusively overlap with or consist of a typical peptide sequence (e.g., any exemplary typical peptide sequence underlined in Table 13).

[0904] Table 13 lists the amino acid sequences of exemplary long neoantigenic peptides.

[0905] These exemplary neoantigenic peptides are produced following administration of an ADC containing a praldiolactone splicing modulator, however, given similar mechanisms of action (i.e., similar splicing modulation mechanisms), similar neoantigenic peptides can be produced by compounds selected from a compound of Formula I, a compound of Formula II, a compound of Formula III, and pharmaceutically acceptable salts of any of the foregoing.

[0906] Table 12. New peptides

[0907]

[0908]

[0909] The protein sequences of the twenty-nine novel peptides listed in Table 12 can be extended. In addition to flanking amino acid sequences, the extended protein sequence also incorporates the novel peptide sequence itself. The extended protein sequence better promotes protein uptake by dendritic cells and enables antigen presentation and T cell priming in models with different HLA isotypes. Table 13 lists the amino acid sequences of the twenty-nine extended novel peptides.

[0910] Table 13. Amino acid sequences of extended novel peptides

[0911]

[0912]

[0913]

[0914] * Underline The amino acids derived from the reading open frame of a typical transcript (ie, a typical peptide sequence) are indicated.

[0915] As used herein, neoantigenic peptide or mRNA vaccine encompasses the use of fragments of the neoantigenic peptide or its encoding mRNA, as long as the fragment retains immunogenic potential.

[0916] In some embodiments, the neoantigen vaccine comprises at least one neoantigenic peptide. In some embodiments, the neoantigen vaccine comprises at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 15, or at least 20 neoantigenic peptides. In some embodiments, one or more neoantigenic peptides range in length from about 5 to about 50 amino acids. In some embodiments, one or more neoantigenic peptides range in length from about 10 to about 50 amino acids. In some embodiments, at least one neoantigenic peptide ranges in length from about 10 to about 35 amino acids. In some embodiments, one or more neoantigenic peptides range in length from about 15 to about 25 amino acids.

[0917] In some embodiments, the present disclosure provides a method for treating a subject having or suspected of having a neoplastic disease by ad...

Claims

1. A compound selected from compounds having formula II: and pharmaceutically acceptable salts thereof, in: X is selected from O, NR' groups, and CH2, wherein R' is selected from hydrogen and C1-C6 alkyl groups; R 1 Selected from methyl, -NR 11 R 12 Group, Groups, and Group, R 10 Selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and halogenated C1-C6 alkyl groups, wherein these C3-C8 cycloalkyl groups may be unsubstituted or substituted 1-3 times by groups independently selected from C1-C6 alkyl groups, hydroxyl groups, halogen groups, and C1-C6 alkoxy groups; R 11 and R 12 Each is independently selected from a C1-C6 alkyl group; R 2 or R 3 One of the following is selected from hydrogen and a C1-C6 alkyl group, and the other is selected from hydrogen, a hydroxyl group, and a C1-C6 alkyl group; R 4 or R 5 One of is hydrogen, and the other is selected from hydrogen, hydroxyl, and R 6 and R 7 Each is independently selected from a C1-C6 alkyl group; R 8 and R 9 are each independently selected from hydrogen and a C1-C6 alkyl group; or R 8 and R 9 together form a cyclopropyl ring; and Y is selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, methoxy groups, and -NR 13 R 14 Group, where R 13 and R 14 are each independently selected from hydrogen, a C1-C6 alkyl group, and a methoxy C1-C6 alkyl group; or R 13 and R 14 Together with N, it can form a group selected from the following morpholine, piperidine, thiazolidine, indole, indoline, and isoindoline rings; Wherein Y can be unsubstituted or be independently selected from C1-C6 alkyl group, hydroxyl, hydroxy C1-C6 alkyl group, methoxy, methoxy C1-C6 alkyl group, halogen, halogenated C1-C6 alkyl group, -C(O)NH2, -NHCOO-C1-C6 alkyl group, -COOH, and -NR 15 R 16 The group is substituted 1-3 times, where R 15 and R 16 are each independently selected from hydrogen and a C1-C6 alkyl group, Among them, when X is O, Y is -NR 13 R 14 , R 1 for R 2 is hydroxyl group, R 3 is methyl, R 4 is hydrogen, R 5 is hydroxyl group, R 6 and R 7 is methyl, R 8 and R 9 are independently hydrogen or methyl, R 10 is cycloheptyl, then R 13 and R 14 Not independently methyl and propyl.

2. A compound selected from compounds having formula III: and pharmaceutically acceptable salts thereof, in: n is selected from 0, 1 and 2; m is selected from 1, 2 and 3; R 1 Selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, -NR 11 R 12 Group, Group, Group, Group, Group, Group, Group, Group, Group, Groups, and Group, R 11 Selected from hydrogen, -NR 16 R 17 group, C1-C6 alkyl group, -(C1-C6 alkyl)-CO2H group, -(C1-C6 alkyl)-CO2R 12 Group, -(C1-C6 alkyl)-NR 16 R 17 Groups, C3-C8 cycloalkyl groups, and C3-C8 heterocyclyl groups, wherein these -NR 16 R 17 The C1-C6 alkyl group, the C3-C8 cycloalkyl group and the C3-C8 heterocyclyl group may be unsubstituted or substituted 1 to 3 times by a group independently selected from the group consisting of a C1-C6 alkyl group, a -(C1-C6 alkyl)-CO2H group, a hydroxyl group, a halogen group and a C1-C6 alkoxy group; R 12 is selected from hydrogen and a C1-C6 alkyl group; R 2 or R 3 One of them is selected from hydrogen and C1-C6 alkyl groups, and the other is selected from hydrogen, -OR 10 、-OC(O)R 10 、-OC(O)R 1 , and C1-C6 alkyl groups; R 4 is hydrogen or hydroxyl; R 5 and R 6 Each is independently selected from a C1-C6 alkyl group; R 7 and R 8 are each independently selected from hydrogen, hydroxyl, C1-C6 alkoxy group, and C1-C6 alkyl group; and R 9 and R 10 are each independently selected from hydrogen, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group; or, R 9 or R 10 One of them is oxo and the other is absent; Z is selected from a C1-C6 alkyl group, a -C(O)-C1-C6 alkyl group, a -OR 13 , and -NR 14 R 15 Group, Where R 13 is selected from hydrogen, a C1-C6 alkyl group, and a -C(O)-C1-C6 alkyl group, Where R 14 and R 15 are each independently selected from hydrogen, a C1-C6 alkyl group, and a methoxy C1-C6 alkyl group; or R 14 and R 15 Together with N, it can form a group selected from the following morpholine, piperidine, thiazolidine, indole, indoline, and isoindoline rings; Wherein Z can be unsubstituted or be independently selected from C1-C6 alkyl group, C3-C5 cycloalkyl group, hydroxy C1-C6 alkyl group, C1-C6 alkoxy group, methoxy C1-C6 alkyl group, -NR 16 R 17 Group, as well as The group is substituted 1-3 times, wherein R 16 and R 17 are each independently selected from hydrogen and a C1-C6 alkyl group, When n=1, m is 2, R 9 and R 10 are independently hydroxy, methyl and C1-C6 alkoxy, R 2 and R 3 are independently selected from hydrogen, methyl, hydroxy, and C1-C6 alkoxy, R 1 Selected from C1-C6 alkyl, C3-C8 cycloalkyl, -NR 11 R 12 base, Group, Group, Group, Group, Group and group, then Z is not ethyl.

3. The compound according to claim 2, wherein R 1 Selected from methyl, Group, Group, Group, Group, Group, Group, Group, Groups, and Group.

4. A compound selected from: 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-9-oxo-9-pyrrolidin-1-ylnona-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[[(2R,3R)-3-hydroxypentan-2-yl]carbamoyloxy]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-(propylcarbamoyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propyl)carbamoyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; Pyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(dimethylcarbamoyloxy)-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-(diethylcarbamoyloxy)-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-7-[methyl(propan-2-yl)carbamoyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[butyl(methyl)carbamoyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[butan-2-yl(methyl)carbamoyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-carbamoyloxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; (2R)-2-(Methoxymethyl)pyrrolidine-1-carboxylic acid [(2S,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[2-methoxyethyl(methyl)carbamoyl]oxy-6-methylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]acetate; Azetidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; (2S)-2-methylpyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; (2S)-2-methylpyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; Piperidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; (2R)-2-(Hydroxymethyl)pyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; (3R)-3-Hydroxypyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; Morpholine-4-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; 4-Methylpiperazine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; 3-Thiazolidinecarboxylic acid [(2R,3E,5E)-6-[(2R,3S,4E,6R,7R,10R)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 1,3-Dihydroisoindole-2-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; Indole-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[2-(1-hydroxyethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,2-dimethylpyrrolidine-1-carbonyl)oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2S,5S)-2,5-dimethylpyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 2,3-Dihydroindole-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 2-Oxa-5-azaspiro[3.4]octane-5-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6S)-6-methyl-9-oxo-9-pyrrolidin-1-ylnona-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10R)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-10-(pyrrolidine-1-carbonyloxy)-1-oxacyclododecan-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(2S)-2-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3R)-3-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3R)-3-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-carbamoylpyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-[(2R)-2-(methoxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2S,5S)-2,5-dimethylpyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3R)-3-fluoropyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,2-dimethylpyrrolidine-1-carbonyl)oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10R)-2-[(2E,4E)-6,6-dimethyl-7-(pyrrolidine-1-carbonyloxy)hept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E)-6,6-dimethyl-7-(pyrrolidine-1-carbonyloxy)hept-2,4-dien-2-yl]-7-hydroxy-3,7-dimethyl-12-oxo-10-(pyrrolidine-1-carbonyloxy)-1-oxacyclododecan-4-en-6-yl] ester; (2R)-1-[(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyloxy]carbonylpyrrolidine-2-carboxylic acid; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(3-oxopyrrolidine-1-carbonyl)oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 2-Oxa-7-azaspiro[3.4]octane-7-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-5-[1-(pyrrolidine-1-carbonyloxymethyl)cyclopropyl]penta-2,4-dien-2-yl]-1-oxacyclododecan-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3S,4R)-3,4-dihydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; (3S)-1-[(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyloxy]carbonylpyrrolidine-3-carboxylic acid; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(3S)-3-(dimethylamino)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(2,5-dihydropyrrole-1-carbonyloxy)-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3S)-3-[(2-methylpropan-2-yl)oxycarbonylamino]pyrrolidine-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 3-Azabicyclo[3.1.0]hexane-3-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-(4-cycloheptylpiperazine-1-carbonyl)oxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidin-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-2-[(2E,4E,6R)-7-[(2R)-2-(fluoromethyl)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] acetate; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; Pyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6R)-6-(dimethylcarbamoyloxy)-3-methyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; (3R)-3-Hydroxypyrrolidine-1-carboxylic acid [(2R,3E,5E)-6-[(2S,3S,4E,6R)-6-(dimethylcarbamoyloxy)-3-methyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-3-methyl-2-[(2E,4E,6R)-6-methyl-7-[(2S)-2-methylpyrrolidin-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododecan-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-(2,2,2-trifluoroethyl)piperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3-methyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6R)-7-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S)-7-hydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[(3S)-3-(1-phenyltetrazol-5-yl)oxypyrrolidine-1-carbonyl]oxyhept-2,4-dien-2-yl]-12-oxo-1-oxacyclododecan-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonyloxy)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonylamino)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-7-[[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]amino]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-(pyrrolidine-1-carbonylamino)hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-3,7-dimethyl-2-[(2E,4E,6R)-6-methyl-7-[methyl(pyrrolidine-1-carbonyl)amino]hept-2,4-dien-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6S)-7-methoxycarbonyloxy-6-methylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7,10-dihydroxy-2-[(2E,4E,6R)-9-methoxy-6-methyl-9-oxona-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(cyclopentanecarbonylamino)-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6R)-7-(cyclopentanecarbonylamino)-6-methylhept-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Cycloheptyl-1-piperazinecarboxylic acid [(2R,3S,4E,6R,7R,10R)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-[(2E,4E)-7-[oxo(1-pyrrolidinyl)methoxy]hept-2,4-dien-2-yl]-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R,7R,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6R)-2-[(2E,4E,6R)-7-[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxy-6-methylhept-2,4-dien-2-yl]-3-methyl-12-oxo-1-azacyclododecan-4-en-6-yl] ester; Pyrrolidine-1-carboxylic acid [(2R,3E,5E)-2-methyl-6-[(2S,3S,4E,6R)-3-methyl-6-[(4-methylpiperazine-1-carbonyl)amino]-12-oxo-1-oxacyclododecan-4-en-2-yl]hept-3,5-dienyl] ester; (2R,3R)-3-hydroxy-2-methylpentanoic acid [(2S,3E,5E)-6-[(2S,3S,4E,6S,7S,10S)-6-acetyloxy-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-2-yl]-2-methylhepta-3,5-dienyl] ester; 4-Cycloheptylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-2-[(2E,4E,6S)-7-[(2R,3R)-3-[(2R,3R)-3-acetyloxypentan-2-yl]oxiran-2-yl]-6-hydroxy-6-methylhepta-2,4-dien-2-yl]-7,10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; [(2S,3S,4E,6S,7S)-7-hydroxy-2-[(2E,4E,6S)-6-hydroxy-6-methyl-7-[(2R,3R)-3-[(2S)-3-oxopentan-2-yl]oxiran-2-yl]hept-2,4-dien-2-yl]-3,7-dimethyl-10,12-dioxo-1-oxacyclododec-4-en-6-yl]acetate; Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7-acetyloxy-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((S,2E,4E)-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate; Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-6-acetyloxy-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-7-yl] ester; Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-7-acetyloxy-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-6-acetyloxy-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-7-yl] ester; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (2S,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-7-yl ester; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl 4-propylpiperazine-1-carboxylate; (2R,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((2S,6R,E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-4-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-7-yl 4-(2-hydroxyethyl)piperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-6-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-7-yl 4-methylpiperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl 4-(2-aminoethyl)piperazine-1-carboxylate; 4-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylic acid (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7R,10R)-7-ethoxy-10-hydroxy-2-[(2E,4E,6R)-6-hydroxy-7-[(2R,3R)-3-[(2S,3S)-3-hydroxypentan-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; Piperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 4-Methylpiperazine-1-carboxylic acid [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6R)-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhepta-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; N-methyl-N-[2-(methylamino)ethyl]carbamic acid [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; N-methyl-N-[2-(dimethylamino)ethyl]carbamic acid [(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl] ester; 3-[4-[[(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododecan-4-en-6-yl]oxycarbonyl]piperazin-2-yl]propanoic acid; 4-[4-[[(2S,3S,4E,6S,7S,10S)-10-hydroxy-2-[(2E,4E,6S)-6-hydroxy-7-[(2R,3R)-3-[(2R,3R)-3-hydroxypent-2-yl]oxiran-2-yl]-6-methylhept-2,4-dien-2-yl]-7-methoxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]oxycarbonyl]piperazin-1-yl]butanoic acid; (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl 4-methylpiperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((R,2E,4E)-6-hydroxy-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhepta-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate; (2S,3S,6S,7R,10R,E)-7-acetoxy-10-hydroxy-2-((S,2E,4E)-7-((2R,3R)-3-((2R,3S)-3-hydroxypentan-2-yl)oxiran-2-yl)-6-methylhept-2,4-dien-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl piperazine-1-carboxylate; and pharmaceutically acceptable salts thereof.

5. The compound according to any one of claims 1 to 4, wherein The compounds are stereomerically pure.

6. A pharmaceutical composition comprising the compound and / or pharmaceutically acceptable salt according to any one of claims 1 to 5.

7. The pharmaceutical compound according to claim 6, wherein The compositions are formulated for intravenous, oral, subcutaneous or intramuscular administration.

8. Use of the compound and / or pharmaceutically acceptable salt according to any one of claims 1 to 5, or the pharmaceutical composition according to claim 6 or claim 7, in the preparation of a medicament for treating cancer.

9. The use according to claim 8, wherein The cancer is selected from the group consisting of myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer, breast cancer, uveal melanoma, gastric cancer, bile duct cancer, and lung cancer.

10. The use according to claim 9, wherein The cancer is selected from the group consisting of myelodysplastic syndrome, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, and acute myeloid leukemia.

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