RU2815064C2 - Pladienolide derivatives as drugs with targeted influence on spliceosome for treatment of cancer - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to pladienolide derivatives or pharmaceutically acceptable salts thereof, represented by the general formula I, where R¹ is selected from (a-m), and each of which may be optionally substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups, C₃-C₈ cycloalkyl groups, and dimethylamino groups; R², R³, R⁴, R⁵, R⁶ and R⁷ are each independently selected from hydrogen, hydroxyl groups and C₁-C₆ alkyl groups; R⁸, R⁹ and R¹³ are each independently selected from hydrogen and C₁-C₆ alkyl groups; R¹⁰, R¹¹ and R¹² are given in the claims; V represents -CH₂-; W is selected from 3-8 membered carbocycles and 3-10 membered heterocycles containing 1-3 heteroatoms selected from nitrogen and oxygen, each of which may be optionally substituted by 1-2 groups independently selected from halogen atoms, groups of -NR⁸R⁹ and C₁-C₆ alkyl groups; X is independently selected from bond, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be optionally substituted by 1-2 groups independently selected from atoms halogen, hydroxyl groups, C₁-C₆ alkyl groups, hydroxy-C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups, methoxy-C₁-C₆ alkyl groups, -SO₂-C₁-C₆ alkyl groups and -NR¹⁴R¹⁵ groups, where each of R¹⁴ and R¹⁵ is independently selected from hydrogen and C₁-C₆ alkyl groups; Y is independently selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be optionally substituted by 1-2 groups independently selected from atoms halogen, hydroxyl groups, C₁-C₆ alkyl groups, hydroxy-C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups, methoxy-C₁-C₆ alkyl groups, -SO₂-C₁-C₆ alkyl groups and -NR¹⁴R¹⁵ groups, where each of R¹⁴ and R¹⁵ is independently selected from hydrogen and C₁-C₆ alkyl groups; each of L¹ and L² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R¹³)-C(O)-, -C(O)- N(R¹³)-, -N(R¹³)-S(O₂)-, -S(O₂)-N(R¹³)-, -S(O₂)- and -N(R¹³)- ; and each n is independently selected from 0-4. The invention also relates to compounds represented by structural formulas IIa, IIb, IIc, IId, IIe, IIIa, IVa and specific compounds (shown in the claims).

EFFECT: compounds used as agents that have a targeted effect on the spliceosome for the treatment of cancer.

43 cl, 24 tbl, 268 ex

Description

This application claims the benefit of priority based on US Provisional Patent Application No. 62/656865, filed April 12, 2018; US Provisional Patent Application No. 62/679658, filed June 1, 2018; US Provisional Patent Application No. 62/814824, filed March 6, 2019; and U.S. Provisional Patent Application No. 62/814828, filed March 6, 2019, all of which are incorporated herein by reference.

Disclosed herein are novel organic compounds and pharmaceutical compositions containing such compounds. These compounds may be useful in the treatment of cancer, in particular types of cancer that are known to benefit from agents that target the spliceosome and mutations therein. These compounds may also be useful in the treatment of cancer when administered in combination with at least one additional therapy.

In eukaryotic organisms, freshly synthesized messenger RNAs typically have several introns that are excised to produce mature mRNA. The spliceosome is a complex of many subunits that performs this task. The spliceosome consists of five small nuclear RNAs (snRNA; U1-6) in combination with various proteins. Mutations in spliceosome genes have been found in various types of cancer.

For example, mutations in splicing factor 3B subunit 1 (SF3B1) of the spliceosome occur in a range of cancers and serve as a target for anticancer drugs. Such cancers include, but are not limited to, myelodysplastic syndrome (MDS), leukemia such as chronic lymphocytic leukemia (CLL), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML), as well as solid tumors such as breast cancer and uveal melanoma .

Compounds isolated from the bacteria 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.), called pladienolides and discovered during a screen for inhibitors of the vascular endothelial growth factor (VEGF) promoter, inhibit the expression of a reporter gene controlled by the human VEGF promoter, however, this inhibition is known to be a useful mechanism of action for anticancer agents.

These compounds also inhibit the proliferation of human U251 glioma cells in vitro . The most effective of these compounds, pladienolide B, inhibits gene expression driven by the VEGF promoter with an IC ₅₀ of 1.8 nM and inhibits glioma cell proliferation with an IC ₅₀ of 3.5 nM. 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 by inhibiting splicing and altering gene expression patterns (Kotake et al. , "Splicing factor SF3b as a target of the antitumor natural product pladienolide", Nature Chemical Biology 2007, 3, 570-575).

Likewise, certain pladienolide B compounds are known, as well as compounds of other pladienolides, disclosed in the following patent applications: 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 pladienolide compound, (8E,12E,14E)-7-((4-cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl -18,19-Epoxytricose-8,12,14-trien-11-olide, also known as E7107, is a semisynthetic derivative of the natural product, pladienolide D, and the results of its phase I study have been published. As another example, the pyridine compound pladienolide , (2S,3S,6S,7R,10R,E)-7,10-dihydroxy-3,7-dimethyl-12-oxo-2-((R,2E,4E)-6-(pyridin-2-yl )hepta-2,4-dien-2-yl)oxacyclododec-4-en-6-yl-4-methylpiperazine-1-carboxylate (also called "(2S,3S,4E,6S,7R,10R)-7, 10-dihydroxy-3,7-dimethyl-12-oxo-2-((2E,4E,6R)-6-(pyridin-2-yl)hepta-2,4-dien-2-yl)oxacyclododec-4- en-6-yl-4-methylpiperazine-1-carboxylate), also known as H3B-8800, has received orphan drug designation for the treatment of certain types of hematological malignancies.

However, additional agents useful in the treatment of cancer are needed, in particular types of cancer that are known to benefit from agents that specifically target the spliceosome and mutations therein.

Recently, immune checkpoint blockade (ICB) has been shown to represent a paradigm shift in the treatment of several different types of cancer. However, not all patients demonstrate durable/long-lasting responses to ICB. See for example Zappasodi, R.et al.Emerging Concepts for Immune Checkpoint Blockade-Based Combination Therapies.Cancer Cell 33, 581-598, doi:10.1016/j.ccell.2018.03.005 (2018); and Wolchok, J.D.et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.N Engl J Med 377, 1345-1356, doi:10.1056/NEJMoa1709684 (2017). Therefore, there is also a need to develop additional therapeutic agents to be administered in combination with ICB or any other therapy to enhance and/or maximize patient response.

Disclosed herein are compounds of Formula I:

I,

and their pharmaceutically acceptable salts,

Where:

R ¹ selected from:

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, C ₃ -C ₈ cycloalkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, dimethylamino groups and methoxy-C ₁ -C ₆ alkyl groups;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen, hydroxyl groups, -OR ¹⁰ groups and C ₁ -C ₆ alkyl groups;

R ⁸ , R ⁹ and R ¹³ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

R ¹⁰ is selected from hydrogen, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ aminoalkyl groups, C ₁ -C ₆ alkylamino groups, C ₁ -C ₆ alkylcarboxylic acid groups, C ₃ -C ₈ cycloalkyl groups, benzyl groups, C ₃ -C ₈ heterocyclyl groups, -CH ₂ -C ₃ -C ₈ heterocyclyl groups, -C(O)-C ₃ -C ₈ heterocyclyl groups, acyl groups, hydroxy-C ₁ -C ₆ alkyl groups, methoxy-C ₁ -C ₆ alkyl groups, -CD ₃ and -C(O)-NR ¹¹ R ¹² groups;

R ¹¹ and R ¹² are independently selected from hydrogen, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ aminoalkyl groups, C ₁ -C ₆ alkylamino groups, C ₃ -C ₈ cycloalkyl groups and C ₃ -C ₈ heterocyclyl groups;

V is selected from -CH ₂ - and -N(R ⁹ )-;

W is selected from 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- ; And

each n is independently selected from 0-4.

Also disclosed herein are pharmaceutical compositions containing at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise at least one pharmaceutically acceptable carrier.

Also disclosed herein are methods of treating a subject with cancer, comprising administering to the subject a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof . In some embodiments, 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, cholangiocarcinoma, 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 a spliceosome gene or protein, such as those listed in Table 1. In some embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts, induces the formation of at least one neoantigen and/or the development of a T-cell response.

Also disclosed herein is the use of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and pharmaceutically acceptable salts thereof, in a method of therapeutic treatment, for example, cancer treatment. In some embodiments, 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, cholangiocarcinoma, 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 a spliceosome gene or protein, such as those listed in Table 1. In some embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts, induces the formation of at least one neoantigen and/or the development of a T-cell response.

Also disclosed herein is at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and pharmaceutically acceptable salts thereof, for use in the preparation of a medicinal product. In some embodiments, the drug is useful for treating cancer. In some embodiments, 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, cholangiocarcinoma, 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 a spliceosome gene or protein, such as those listed in Table 1. In some embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts, induces the formation of at least one neoantigen and/or the development of a T-cell response.

Also disclosed herein are methods of using at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof to target the spliceosome, for example, on spliceosomal subunit 1 SF3B.

Also disclosed herein are methods of inducing the formation of at least one neoantigen, comprising contacting a neoplastic cell with an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and /or pharmaceutically acceptable salts thereof. In some embodiments, such contact may induce the formation of at least one neoantigen.

Also disclosed herein are methods of inducing the formation of at least one neoantigen and/or the development of a T cell response in a subject who has or is suspected of having a neoplastic disorder, comprising administering to the subject an effective amount of at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts.

Also disclosed herein are methods of treating a subject with or suspected of having a neoplastic disorder. In some embodiments, the method includes administering to a subject an effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, wherein administration may result in inducing formation of at least one neoantigen and/or development of a T-cell response. In some embodiments, the method may also include detecting one or more neoantigens and/or T cell response in a subject following administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the method may also include continuous administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof if one or more neoantigens are detected and/or T cell response.

Also provided herein are methods of treating a subject who has or is suspected of having a neoplastic disorder, comprising administering to the subject an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va ) and/or pharmaceutically acceptable salts thereof.

Also provided herein are neoantigen vaccines containing at least one neoantigen peptide. In some embodiments, the at least one neoantigenic peptide comprises a modified or novel neoantigenic sequence induced by contacting a neoplastic cell with an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof.

In some embodiments, the methods and routes of administration provided herein may further provide for the administration of at least one additional therapy. In some embodiments, the methods and routes of administration presented herein may result in lower systemic toxicity and/or improved tolerability.

Also disclosed herein is a method of treating cancer in a subject in need thereof, comprising administering at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof , and at least one additional therapy.

Also disclosed herein is a method of treating a subject who has or is suspected of having a neoplastic disorder, comprising administering at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/ or pharmaceutically acceptable salts thereof, and at least one additional therapy.

Unless otherwise specified, the following definitions will apply throughout this document.

As described herein, compounds may be substituted with one or more substituents, such as those illustrated generally herein or exemplified by specific classes, subclasses and molecules of the present invention. In general, the term "substituted" refers to the replacement of hydrogen radicals in the given structure with a radical of the specified substituent. Unless otherwise specified, a substituted group may have a substituent at each position of the group, and if more than one position in any given structure can be substituted by more than one substituent selected from the specified group, then the substituent at each position may be either the same or different . The combinations of substituents provided in the present invention are those that lead to the formation of stable or chemically feasible compounds.

“Stable” refers to compounds that do not substantially change chemically and/or physically when exposed to conditions allowing them to be produced, detected, and recovered, purified, and used to serve one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is a compound that is substantially unchanged during storage at a temperature of 40° C. or less in the absence of moisture or other chemically active conditions for at least a week.

“Isomers” refer to compounds with the same number and type of atoms, and therefore the same molecular weight, but differing in the arrangement or configuration of the atoms. “Stereoisomers” refer to compounds that are characterized by identical atomic bonds but different arrangements of their atoms in space. "Diastereoisomers" or "diastereomers" refer to stereoisomers that are not enantiomers. "Enantiomers" refer to stereoisomers that are non-matching mirror images of each other when superimposed. "Geometric isomers" refer to cis-trans isomers with different group positions relative to the double bond or ring or central atom.

Enantiomers set forth herein may include "enantiomerically pure" isomers that contain substantially one enantiomer, such as exactly 90%, 92%, 95%, 98% or 99% or more, or exactly 100% of one enantiomer at a particular asymmetric center or centers. An "asymmetric center" or "chiral center" refers to a tetrahedral carbon atom that contains four different substituents.

As used herein, the term “stereomerically pure” means a compound or composition thereof that contains one stereoisomer of the compound and is substantially free of other stereoisomers of the compound. For example, a stereomerically pure composition based on a compound with one chiral center will be substantially free of the opposite enantiomer of the compound. In some embodiments, a stereomerically pure composition based on a compound with two chiral centers will be substantially free of diastereomers and substantially free of the opposite enantiomer of the compound. In some embodiments, a stereomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound, e.g., more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, further, for example, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and further, for example, more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound . See for example US Patent No. 7189715.

"R" and "S" as terms describing isomers are identifiers of the stereochemical configuration at the asymmetric substituted carbon atom. The designation of an asymmetric substituted carbon atom as "R" or "S" is accomplished by applying the Cahn, Ingold, and Prelog rules of precedence, which are well known to those skilled in the art and are described in the Rules of Nomenclature for Organic Chemistry developed by the International Union of Pure and Applied Chemistry (IUPAC). ). Section E, Stereochemistry.

An "amine oxide" or "amine N -oxide" or " N -oxide" is a chemical compound that contains an ^{R3N + -O−} functional group, an NO bond with three additional hydrogens and/or hydrocarbon side chains attached to N. Sometimes it is written as R ³ N→O.

"Ar" or "aryl" refers to an aromatic carbocyclic moiety containing one or more closed rings. Examples include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthracenyl, biphenyl, and pyrenyl. In certain embodiments, aryl groups contain 6 carbon atoms ("C ₆ aryl").

As used herein, “alkyl” or “alkyl group” means a straight-chain, branched-chain or cyclic hydrocarbon that is fully saturated. In certain embodiments, alkyl groups contain 1-8 carbon atoms ("C ₁ -C ₈ alkyl"). In certain embodiments, alkyl groups contain 1-6 carbon atoms ("C ₁ -C ₆ alkyl"). In certain embodiments, alkyl groups contain 1-3 carbon atoms. In yet other embodiments, alkyl groups contain 2-3 carbon atoms, and in other embodiments, alkyl groups contain 1-2 carbon atoms. In certain embodiments, the term "alkyl" or "alkyl group" refers to a cycloalkyl group. In certain embodiments, cycloalkyl groups contain 3-8 carbon atoms ("C ₃ -C ₈ cycloalkyl"). In certain embodiments, cycloalkyl groups contain 3-6 carbon atoms ("C ₃ -C ₆ cycloalkyl"). Non-limiting examples of illustrative alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl and cyclohexyl.

As used herein, the term “alkoxy” refers to an alkyl group, as previously defined, attached to the carbon backbone via an oxygen atom (“alkoxy”).

As used herein, "carbocycle" includes both aromatic (e.g. aryl) and non-aromatic (for example, cycloalkyl) group. In certain embodiments, carbocyclic groups contain 3-10 carbon atoms (“3-10 membered carbocycle”). In certain embodiments, carbocyclic groups contain 3-8 carbon atoms (“3-8 membered carbocycle”). In certain embodiments, carbocyclic groups contain 3-6 carbon atoms (“3-6 membered carbocycle”). In certain embodiments, carbocyclic groups contain 3-5 carbon atoms (“3-5 membered carbocycle”).

"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).

"Heteroatom" refers to O, S or N.

"Heteroaryl" refers to a cyclic moiety containing one or more closed rings with one or more heteroatoms (oxygen, nitrogen or sulfur) in at least one of the rings, where at least one of the rings is aromatic, and where the ring or rings are independently may be condensed and/or bridged. Examples include, but are not limited to, thiophenyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl.

As used herein, “heterocyclyl” or “heterocyclic” means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle containing at least one heteroatom on the ring. The heterocyclyl may be aromatic (for example, heteroaryl) or non-aromatic. In certain embodiments, heterocyclic groups contain 2-10 carbon atoms, 3-10 carbon atoms, 2-8 carbon atoms, 3-8 carbon atoms, 2-6 carbon atoms, 3-6 carbon atoms, 2-4 carbon atoms, 3 -4 carbon atoms or 3 carbon atoms. In certain embodiments, the heterocycle may be a 3-10 membered ring, a 3-8 membered ring, a 3-6 membered ring, a 3-4 membered ring, or a 3-membered ring.

A monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing at least one heteroatom independently selected from O, N, and S. In some embodiments, the heterocycle is a 3- or A 4-membered ring containing one heteroatom selected from O, N, and S. In some embodiments, the heterocycle is a 5-membered ring containing no double bonds or containing one double bond and one, two, or three heteroatoms selected from O, N, and S. In some embodiments, the heterocycle is a 6-, 7-, or 8-membered ring containing no double bonds, containing one or two double bonds, and one, two, or three heteroatoms selected from O, N and S. Representative examples of the monocyclic heterocycle 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, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyraz olidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl (including tetrahydro-2H-pyran-4-yl), tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl and trithianyl.

The bicyclic heterocycles of the present invention are illustrated by 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. Representative examples of bicyclic heterocycles include, but are not limited to, 3,4-dihydro-2H-pyranyl, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxynyl, 2,3-dihydro-1-benzofuranyl , 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl and 1,2,3,4-tetrahydroquinolinyl.

In some embodiments, the bicyclic heterocycle is a spiroheterocycle. As is known in the art, a "spiroheterocycle" is a bicyclic moiety with rings connected by only one atom. The connecting atom is also called a spiroatom, and is most often a quaternary atom such as carbon or nitrogen. Spiro compounds can be designated by using the infix "spiro" followed by square brackets enclosing 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. Examples of such compounds include, but are not limited to, 2,6-diazaspiro[3.3]heptane.

A tricyclic heterocycle is a bicyclic heterocycle fused with an aryl group, or a bicyclic heterocycle fused with a monocyclic cycloalkyl, or a bicyclic heterocycle fused with a monocyclic cycloalkenyl, or a bicyclic heterocycle fused with 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.

The heterocyclic groups of the present invention are attached to the parent molecular moiety by any substituted carbon atom or any substituted nitrogen, oxygen or sulfur atom contained within the group, and they may contain one or two alkylene bridges of 1, 2, 3 or 4 carbon atoms, each of which binds two non-adjacent carbon atoms in groups. 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.

In the above heteroaryl and heterocycles, the nitrogen or sulfur atoms may optionally be oxidized to different oxidation states. In a specific example, the group S(O) _0-2 refers to -S-(sulfide), -S(O)-(sulfoxide) and -SO ₂ -(sulfone), respectively. For convenience, nitrogen atoms, particularly but not exclusively those defined as aromatic ring nitrogen atoms, are meant to include the corresponding N-oxide forms. Thus, it is understood that in the case of a compound of the present invention containing, for example, a pyridyl ring, the corresponding pyridyl-N-oxide is included as another compound of the present invention.

“Treating,” “treating,” or “providing treatment” for cancer refers to reversing the development (e.g. overcoming a block in cell differentiation), relieving symptoms (e.g. relieving one or more symptoms such as fatigue due to anemia, low blood counts, etc.) and/or delaying progression (e.g. delaying the progression of a pathological condition, such as transformation to AML) cancer, as described herein.

As used herein, “subject” means an animal subject, such as a mammalian subject and, in particular, humans.

The term "antibody" is used in its 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 combination thereof, through at least one antigen recognition site within a variable region of the molecule immunoglobulin. The heavy chain of an antibody consists of a heavy chain variable domain (V_H) and heavy chain constant region (C_H). The light chain consists of a light chain variable domain (V_L) and light chain constant domain (C_L). For the purposes of this application, each mature heavy chain and light chain variable domain contains three complementarity determining regions (CDR1, CDR2 and CDR3) within four framework regions (FR1, FR2, FR3 and FR4) located from the N-terminus to the C-terminus. ends: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The "antibody" may be naturally occurring or man-made, such as monoclonal antibodies produced using traditional 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. The antibody may belong to any of the five major immunoglobulin classes: IgA, IgD, IgE, IgG, and IgM, or subclasses thereof (e.g. isotypes IgG1, IgG2, IgG3, IgG4). The term further covers human antibodies, chimeric antibodies, humanized antibodies, and any modified immunoglobulin molecule containing an antigen recognition site, provided that it exhibits the desired biological activity (e.g. binds the target antigen, is internalized into the cell expressing the target antigen).

As used herein, “pharmaceutically acceptable carrier” refers to a non-toxic carrier, excipient or carrier vehicle that does not interfere with the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, excipients or carrier media that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins such as human serum albumin, buffers such as phosphates, glycine , sorbic acid, potassium sorbate, mixtures of partial glycerides 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, polyvinylpyrrolidone, substances based on celluloses, polyethylene glycol, cyclodextrins, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, polyethylene glycol and lanolin.

A "pharmaceutically acceptable salt" is a salt that retains the desired biological activity of the parent compound and does not cause undesirable toxicological effects. Examples of such salts are: (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; and salts formed with organic acids, for example 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 acid, polyglutamic acid, naphthalene sulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, polygalacturonic acid, etc.; and (b) salts formed from elemental anions such as chlorine, bromine and iodine. Cm., for example Hayneset al., "Commentary: Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Structural Database," J. Pharmaceutical Sciences, vol. 94, no. 10 (2005), and Bergeet al., “Pharmaceutical Salts,” J. Pharmaceutical Sciences, vol. 66, no. 1 (1977), which are incorporated herein by reference.

Unless otherwise noted, the nomenclature used herein to describe chemical groups or moieties follows traditional conventions, where the name is read from left to right, with the point of attachment to the rest of the molecule indicated on the right side of the name. For example, the "(C _1-3 alkoxy)C _1-3 alkyl" group is attached to the rest of the molecule at the alkyl end. Additional examples include methoxyethyl, where the attachment point is at the ethyl end, and methylamino, where the attachment point is at the amine end.

Unless otherwise indicated, if a chemical group is described by its chemical formula or structure that has a terminal bond moiety designated as "-", it will be understood that "-" represents the point of attachment.

Unless otherwise indicated, the compounds depicted herein include all enantiomeric, diastereomeric and geometric (or conformational) forms of the structure; for example, R- and S-configurations for each asymmetric center, (Z)- and (E)-isomers at the double bond, and conformational (Z)- and (E)-isomers. Therefore, the individual stereochemical isomers, as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the compounds of the present invention are included within the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. Additionally, unless otherwise indicated, the structures depicted herein include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of the formula disclosed herein are included within the scope of this invention, except for the replacement of hydrogen with deuterium or tritium or the replacement of carbon with ¹³ C- or ¹⁴ C-rich carbon.

In accordance with some embodiments, compounds of formula I are provided herein:

I,

and their pharmaceutically acceptable salts,

Where:

R ¹ selected from:

And

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, C ₃ -C ₈ cycloalkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, dimethylamino groups and methoxy-C ₁ -C ₆ alkyl groups;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen, hydroxyl groups, -OR ¹⁰ groups and C ₁ -C ₆ alkyl groups;

R ⁸ , R ⁹ and R ¹³ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

R ¹⁰ is selected from hydrogen, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ aminoalkyl groups, C ₁ -C ₆ alkylamino groups, C ₁ -C ₆ alkylcarboxylic acid groups, C ₃ -C ₈ cycloalkyl groups, benzyl groups, C ₃ -C ₈ heterocyclyl groups, -CH ₂ -C ₃ -C ₈ heterocyclyl groups, -C(O)-C ₃ -C ₈ heterocyclyl groups, acyl groups, hydroxy-C ₁ -C ₆ alkyl groups, methoxy-C ₁ -C ₆ alkyl groups, -CD ₃ and -C(O)-NR ¹¹ R ¹² groups;

R ¹¹ and R ¹² are independently selected from hydrogen, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ aminoalkyl groups, C ₁ -C ₆ alkylamino groups, C ₃ -C ₈ cycloalkyl groups and C ₃ -C ₈ heterocyclyl groups;

V is selected from -CH ₂ - and -N(R ⁹ )-;

W is selected from 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- ; And

each n is independently selected from 0-4.

In some embodiments, R ¹ in compounds of Formula I is selected from And . In some embodiments, R ¹ in compounds of Formula I is substituted with one or three groups selected from halogen atoms and C ₁ -C ₆ alkyl groups.

In some embodiments, R ¹ in compounds of Formula I is , substituted with 1-3 groups selected from C ₁ -C ₆ alkyl groups, where R ¹⁰ represents methyl. In some embodiments, R ¹ in compounds of Formula I is unsubstituted.

In some embodiments, R ² and R ³ in compounds of Formula I are methyl and hydrogen, respectively.

In some embodiments, R ⁴ and R ⁵ in compounds of Formula I are hydrogen and hydroxyl, respectively.

In some embodiments, R ⁶ and R ⁷ in compounds of Formula I are hydrogen and methyl, respectively

In some embodiments, R ⁸ in compounds of Formula I is methyl.

In some embodiments, V in compounds of Formula I is -CH ₂ -.

In some embodiments, the W in compounds of Formula I is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring, and an imidazopyridine ring, each of which may be substituted with 1-3 groups , independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups.

In some embodiments, W in compounds of formula I is a benzene ring, which may be substituted with 1-3 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups.

In some embodiments, each of X and Y in the compounds of Formula I is independently selected from a bond,

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of Formula I is hydrogen, and X in compounds of Formula I is selected from:

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -S(O ₂ )-C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of Formula I is hydrogen, and X in compounds of Formula I is a bond.

In some embodiments, compounds of formula I are selected from compounds of formula IIa:

IIa,

and their pharmaceutically acceptable salts,

Where:

R ¹⁰ is selected from hydrogen and methyl;

W is selected from 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

In some embodiments, the W in compounds of Formula IIa is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring, and an imidazopyridine ring, each of which may be substituted with 1-3 groups , independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups.

In some embodiments, W in compounds of Formula IIa is a benzene ring, which may be substituted with 1-3 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups.

In some embodiments, each of X and Y in compounds of formula IIa is independently selected from a bond,

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of Formula IIa is hydrogen, and X in compounds of Formula IIa is selected from:

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -S(O ₂ )-C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of Formula IIa is hydrogen and X in compounds of Formula IIa is a bond.

In some embodiments, compounds of formula I are selected from compounds of formula IIb:

IIb,

and their pharmaceutically acceptable salts,

Where:

R ¹⁶ is selected from hydrogen and fluorine;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

In some embodiments, each of X and Y in compounds of Formula IIb is independently selected from a bond,

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of Formula IIb is hydrogen, and X in compounds of Formula IIb is selected from:

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -S(O ₂ )-C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of Formula IIb is hydrogen and X in compounds of Formula IIb is a bond.

In some embodiments, R ¹⁶ in compounds of formula IIb is fluorine.

In some embodiments, compounds of formula I are selected from compounds of formula IIc:

IIc,

and their pharmaceutically acceptable salts,

Where:

R ¹⁶ is selected from hydrogen and fluorine;

Y is selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

L ² selected from the bond, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)-N(R ¹³ )- , -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )-, where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups;

n ³ is 0; And

n ⁴ selected from 0-4.

In some embodiments, Y in compounds of Formula IIc is selected from hydrogen,

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, L2 in compounds of Formula IIc is a bond.

In some embodiments, R ¹⁶ in compounds of Formula IIc is fluorine.

In some embodiments, compounds of formula I are selected from compounds of formula IId:

IId,

and their pharmaceutically acceptable salts,

Where:

R ¹⁶ is selected from hydrogen and fluorine;

X is selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

L ¹ and L ² are independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)-N( R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )-, where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

In some embodiments, X in compounds of formula IId is selected from the relationship,

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, X in compounds of Formula IId is a bond. In some embodiments, X, L ¹ and L ² in compounds of Formula IId are bonds.

In some embodiments, R ¹⁶ in the compound of Formula IId is fluorine.

In some embodiments, compounds of formula I are selected from compounds of formula IIe:

IIe,

and their pharmaceutically acceptable salts,

Where:

R ¹⁶ is selected from hydrogen and fluorine;

X is independently selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy- C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

In some embodiments, X in a compound of formula IIe is selected from the bond

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, X in compounds of Formula IIe is a bond. In some embodiments, X, L ¹ and L ² in compounds of Formula IIe are bonds.

In some embodiments, R ¹⁶ in the compound of Formula IIe is fluorine.

In some embodiments, compounds of formula I are selected from compounds of formula IIIa:

IIIa,

and their pharmaceutically acceptable salts,

Where:

R ¹⁰ is selected from hydrogen and methyl;

W is selected from 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

In some embodiments, the W in compounds of Formula IIIa is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring, and an imidazopyridine ring, each of which may be substituted with 1-3 groups , independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups.

In some embodiments, W in compounds of formula IIIa is a benzene ring, which may be substituted with 1-3 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups.

In some embodiments, each of X and Y in compounds of Formula IIIa is independently selected from a bond,

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of formula IIIa is hydrogen, and X in compounds of formula IIIa is selected from:

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -S(O ₂ )-C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of Formula IIIa is hydrogen and X in compounds of Formula IIIa is a bond. In some embodiments, compounds of formula I are selected from compounds of formula IVa:

IVa,

or a pharmaceutically acceptable salt thereof,

Where:

R ¹⁰ is selected from hydrogen and methyl;

W is selected from 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

In some embodiments, the W in compounds of Formula IVa is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring, and an imidazopyridine ring, each of which may be substituted with 1-3 groups , independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups.

In some embodiments, W in compounds of formula IVa is a benzene ring, which may be substituted with 1-3 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups.

In some embodiments, each of X and Y in compounds of Formula IVa is independently selected from a bond,

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of Formula IVa is hydrogen, and X in compounds of Formula IVa is selected from:

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -S(O ₂ )-C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of Formula IVa is hydrogen and X in compounds of Formula IVa is a bond.

In some embodiments, compounds of formula I are selected from compounds of formula Va:

Va,

or a pharmaceutically acceptable salt thereof,

Where:

R ⁹ is selected from hydrogen and C ₁ -C ₆ alkyl groups;

R ¹⁰ is selected from hydrogen and methyl;

W is selected from 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

In some embodiments, the W in compounds of Formula Va is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring, and an imidazopyridine ring, each of which may be substituted with 1-3 groups , independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups.

In some embodiments, W in compounds of formula Va is a benzene ring, which may be substituted with 1-3 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups.

In some embodiments, each of X and Y in compounds of formula Va is independently selected from a bond,

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of formula Va is hydrogen, and X in compounds of formula Va is selected from:

,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -S(O ₂ )-C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

In some embodiments, Y in compounds of formula Va is hydrogen and X in compounds of formula Va is a bond.

In some embodiments, R ⁹ in compounds of Formula Va is selected from hydrogen and methyl.

Also disclosed herein are compounds selected from:

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperazin-1-ylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-(4-methylpiperazin-1-yl)phenyl]prop- 1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-(1H-indazol-6-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-(1H-indazol-4-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(2-morpholin-4-ylpyridin-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(2-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-fluoro-3-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(3S)-3-(methylamino)pyrrolidine-1 -yl]phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(3S)-3-(methylamino)pyrrolidine-1 -yl]phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(2-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-fluorophenyl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(3-methyl-5-morpholin-4-ylphenyl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-morpholin-4-yl-5-(trifluoromethyl)phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-chloro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2-hydroxyethyl)piperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-4-yl)carbamate;

[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3,4-dimethylpiperazine-1-carboxylate;

[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-propan-2-ylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-tert-butylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclobutylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclopentylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3,5-difluorophenyl)prop-1-en-2-yl]-10-hydroxy-3,7- dimethyl 12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(dimethylamino)-5-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(4-hydroxypiperidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-(1-methylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(1R,5S)-8-oxa-3-azabicyclo[3.2.1] octan-3-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(3-oxopyrrolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(oxan-4-yl)piperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-3-yl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(3-fluoroazetidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-(methylamino)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3-(dimethylamino)piperidine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2R)-2-methylpyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxopyrrolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2S)-2-methylpyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(5-chloropyridin-3-yl)prop-1-en-2-yl]-10-hydroxy-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(pyridin-4-ylmethyl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3,5-dichlorophenyl)prop-1-en-2-yl]-10-hydroxy-3,7- dimethyl 12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxo-1,2-thiazolidin-2-yl)phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(1,3-dimethylindazol-6-yl)prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxo-1,4-thiazinan-4-yl)-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N,N-dimethylcarbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxo-1,4-thiazinan-4-yl)-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-morpholine-4-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-4-yl) carbamate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(1-methylindazol-6-yl)prop-1-ene-2 -yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(3-oxomorpholin-4-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-(cyclopentylsulfamoyl)-2-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(4-methylsulfonylpiperazin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-fluoro-1H-indazol-6-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-imidazol-1-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6S,7R,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6S,7R,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6S,7R,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxoimidazolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[3-(2-fluoroethynyl)-2-oxoimidazolidin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[3-(2-morpholin-4-ylethyl)-2-oxoimidazolidine-1- yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl]-5-fluorophenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(2S)-2-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-(2-methylmorpholin-4-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-[(2S,3R)-3-hydroxy-2-methylpentyl]piperazine -1-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1 -carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-[(2R,3R)-3-hydroxy-2-methylpentanoyl]piperazine -1-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1 -carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-morpholin-4-ylethylsulfonyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4-ethenylsulfonylpiperazin-1-yl)-5-fluorophenyl]prop-1-en-2-yl ]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2R)-2-(hydroxymethyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-(hydroxymethyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(2R)-2-(methylcarbamoyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxo-1,3-diazinan-1-yl)phenyl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[3-(cyclopropylmethyl)-2-oxo-1,3-diazinan-1-yl]-5 -fluorophenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-[(2R)-2-hydroxypropanoyl]piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine -2-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(2-cyclopropyl-2-oxoethyl)piperazin-1-yl]-5-fluorophenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-oxo-2-pyrazin-2-ylethyl)piperazine-1 -yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ;

[(2S,3S,4E,6S,7R,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyclopropylmethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-imidazo[1,2-a]pyridin-6-ylprop-1-en-2-yl] -3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(7-methyl-1H-indazol-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-(cyclopropylsulfamoyl)-3-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-fluoro-5-(4-hydroxypiperidin-1-yl)sulfonylphenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperazin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4-formylpiperazin-1-yl)sulfonylphenyl]prop-1-en-2-yl]-10 -hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-(4-hydroxypiperidin-1-yl)sulfonylphenyl]prop-1-ene-2- yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(6-methyl-1H-indazol-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(1,3-dimethylindazol-4-yl)prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(1-azabicyclo[2.2.2]octan-3-yl)-N-methylcarbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-(cyclopropylmethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(2-hydroxyethyl)indazol-6-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-fluoro-1-methylindazol-6-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-[1-(pyridin-4-ylmethyl)pyrazol- 4-yl]prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(1-methylpyrazol-4-yl)prop-1-ene-2 -yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)-3-oxopiperazin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-methoxyethyl)-3-oxopiperazin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[1-(1-methylpiperidin-4-yl)pyrazol-4- yl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-methoxyacetyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(cyclopropanecarbonyl)piperazin-1-yl]-5-fluorophenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(4-methoxyphenyl)sulfonylpiperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylpyrazol-4-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(4-pyridin-3-ylsulfonylpiperazin-1-yl)phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylimidazol-4-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(cyclohexanecarbonyl)piperazin-1-yl]-5-fluorophenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylindol-6-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(oxan-4-yl)indazol-6-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-2-(oxan-4-yl)indazol-6-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxane-4-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-morpholin-4-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylimidazol-4-carbonyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(2-cyclopropylacetyl)piperazin-1-yl]-5-fluorophenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1,3-oxazol-5-carbonyl)piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethylsulfonyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxetan-3-ylsulfonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(oxetan-3-ylsulfonyl)indazol-6-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-(1-hydroxyisoquinolin-7-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[4-fluoro-1-[2-(methylamino)-2-oxoethyl]indazol-6-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(2-oxo-2-pyrrolidin-1-ylethyl)indazol-6-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(2-morpholin-4-yl-2-oxoethyl)indazol-6-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyanomethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-[2-(dimethylamino)-2-oxoethyl]-4-fluorinazol-6-yl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyclopropylmethyl)-3-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(3-methoxypropanoyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyacetyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(3-hydroxypropyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-(cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(oxan-4-yl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-2-(oxan-4-yl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-(2-methoxyethyl)benzimidazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxolane-3-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4- yl]benzotriazol-5-yl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(4-chlorophenyl)methyl]-7-fluorobenzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-acetylpiperidin-4-yl)-7-fluorobenzimidazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(4-hydroxycyclohexyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(oxan-4-ylmethyl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(2S)-1-hydroxypropan-2-yl]benzotriazol-5-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(2R)-1-hydroxypropan-2-yl]benzotriazol-5-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-[(3S)-oxolan-3-carbonyl]piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-[(3R)-oxolan-3-carbonyl]piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxetane-3-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(3-methyloxetane-3-carbonyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(3-hydroxypropanoyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(4-methyloxan-4-yl)benzotriazol-5-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(1-methylsulfonylpiperidin-4-yl)benzotriazol-5-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxothian-4-yl)-7-fluorobenzotriazol-5-yl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-(2-methoxyethyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-acetylpiperidin-4-yl)-7-fluorobenzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(3R)-oxan-3-yl]benzotriazol-5-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(3S)-oxan-3-yl]benzotriazol-5-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(3R,4S)-3-hydroxyoxan-4-yl]benzotriazol-5- yl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-cyclohexyl-7-fluorobenzotriazol-5-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-(4-methoxyphenyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-[(4-methoxyphenyl)methyl]benzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-chloro-5-fluorophenyl)prop-1-en-2-yl]-10-hydroxy-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl(oxan-4-yl)amino]phenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl(oxetan-3-yl)amino]phenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[methyl(oxan-4-yl)amino]phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[methyl(oxetan-3-yl)amino]phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1,1-dioxothian-4-yl)-methylamino]-5-fluorophenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(1-methylsulfonylpiperidin-4-yl)amino]phenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-(1-methylsulfonylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-[ethyl-(1-methylsulfonylpiperidin-4-yl)amino]-5-fluorophenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(1-methylsulfonylpiperidin-4-yl)-propan-2-ylamino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-acetylpiperidin-4-yl)-methylamino]-5-fluorophenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-(1-propanoylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[[1-(2-methoxyacetyl)piperidin-4-yl]-methylamino]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-benzoylpiperidin-4-yl)-methylamino]-5-fluorophenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(2,2,2-trifluoroacetyl)piperidine-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-(1-propylsulfonylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-cyclopentylsulfonylpiperidin-4-yl)-methylamino]-5-fluorophenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(1-methylimidazol-4-yl)sulfonylpiperidin-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[[1-(benzenesulfonyl)piperidin-4-yl]-methylamino]-5-fluorophenyl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-acetylpiperidin-4-yl)methyl-methylamino]-5-fluorophenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[(1-methylsulfonylpiperidin-4-yl)methyl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(1,3-oxazol-5-carbonyl)piperidin- 4-yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(pyrazin-2-carbonyl)piperidin-4-yl] amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(1-methylimidazol-4-carbonyl)piperidine-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(propan-2-ylcarbamoyl)piperidin-4-yl] amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(propylcarbamoyl)piperidin-4-yl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(phenylcarbamoyl)piperidin-4-yl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(1-methylsulfonylpiperidin-4-yl)oxyphenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(4,4-difluorocyclohexyl)-4-fluorinazol-6-yl]prop-1-ene-2 -yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(1-methylsulfonylpiperidin-4-yl)indazol-6-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-pyrrolidin-1-ylsulfonylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(azetidin-1-ylsulfonyl)phenyl]prop-1-en-2-yl]-10-hydroxy -3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[(3R)-3-hydroxypyrrolidin-1-yl]sulfonylphenyl]prop-1- en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(2S)-2-methylpyrrolidin-1-yl] sulfonylphenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[(1-hydroxy-2-methylpropan-2-yl)sulfamoyl]phenyl]prop -1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4,4-difluoropiperidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(4-methyl-3-pyrrolidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(3,3-difluoropyrrolidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(5-pyrrolidin-1-ylsulfonylpyridin-3-yl )prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(3,3-difluoroazetidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[4-methyl-3-(2-oxopyrrolidin-1-yl) phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(tert-butylsulfamoyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3 ,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-[3-(propan-2-ylsulfamoyl)phenyl] prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-(ethylsulfamoyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-(4-methylpiperazin-1-yl)sulfonylphenyl]prop- 1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-(methylsulfamoyl)phenyl]prop-1-ene-2- yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-pyrrolidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-cyclopropylsulfonylphenyl)prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl- 12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(cyclopropylsulfonylamino)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-(methanesulfonamido)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(3S)-3-[(2-methoxyacetyl)amino]pyrrolidine-1- yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[1-[(2-methylpropan-2-yl)oxycarbonyl]- 3,6-dihydro-2H-pyridin-5-yl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(trideuteriomethyl)piperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(pyridin-4-ylmethyl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(pyrimidin-4-ylmethyl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-morpholine-4-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(dimethylamino)ethyl]carbamate ;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methyl-1,4-diazepan-1 -carboxylate;

[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[(4-methoxyphenyl)methyl]carbamate ;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-(dimethylamino)pyrrolidin- 1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3-(dimethylamino)pyrrolidin- 1-carboxylate;

[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[(2S)-1-hydroxypropan- 2-yl]carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3-oxopiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-fluoropyrrolidine-1-carboxylate ;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,3,4-trimethylpiperazine-1-carboxylate ;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin- 4-yl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2-hydroxyethyl)piperazine-1- carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-piperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cycloheptylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-pyridin-4-ylpiperazin-1-carboxylate ;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclohexylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(4-hydroxyphenyl)ethyl ]-N-methylcarbamate;

(2S,3S,6R,7S,10R,E)-2-((E)-1-(3-fluoro-5-morpholinophenyl)prop-1-en-2-yl)-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl-7-methyl-1,7-diazaspiro[3.5]nonane-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(3-morpholin-4-ylpropyl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(dimethylamino)ethyl]carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-(dimethylamino)pyrrolidine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3-(dimethylamino)pyrrolidine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(2-cyanoethyl)-N-methylcarbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,3,4-trimethylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-fluoropyrrolidine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(dimethylsulfamoylamino)-5-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(2-methoxyacetyl)amino]phenyl]prop-1-en-2-yl ]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(2-cyclopropylacetyl)amino]-5-fluorophenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-[(3-hydroxyphenyl)methyl]piperazine -1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(pyridin-3-ylmethyl)piperazin- 1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-acetylpiperidin-4-yl)-7-fluorobenzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-piperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxymethyl]phenyl]prop -1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[3-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12- oxo-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]methyl-2-oxa-7-azaspiro[3.4]octane-7-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]pyridin-4 -yl]prop-1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[3-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12- oxo-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]methylmorpholine-4-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(dimethylcarbamoyloxymethyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxymethyl] phenyl]prop-1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[[(3R)-3-fluoropyrrolidine-1-carbonyl]oxymethyl]phenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[(4-hydroxypiperidin-1-carbonyl)oxymethyl]phenyl]prop-1-ene -2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

2-[4-[3-fluoro-5-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-6- (piperazin-1-carbonyloxy)-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]piperazin-1-yl]acetic acid;

(2S,3S,6R,7S,10R,E)-2-((E)-1-(3-(dimethylamino)phenyl)prop-1-en-2-yl)-10-hydroxy-3,7- dimethyl 12-oxooxacyclododec-4-en-6-yl-4-methylpiperazine-1-carboxylate;

(2S,3S,6R,7S,10R,E)-2-((E)-1-(3-(dimethylamino)phenyl)prop-1-en-2-yl)-10-hydroxy-3,7- dimethyl 12-oxooxacyclododec-4-en-6-ylpiperazin-1-carboxylate;

(2S,3S,6R,7S,10R,E)-2-((E)-1-(5-chloropyridin-3-yl)prop-1-en-2-yl)-10-hydroxy-3,7 -dimethyl-12-oxooxacyclododec-4-en-6-ylpiperazin-1-carboxylate;

(2S,3S,6R,7S,10R,E)-10-hydroxy-3,7-dimethyl-12-oxo-2-((E)-1-(3-(pyrrolidin-1-ylsulfonyl)phenyl)prop -1-en-2-yl)oxacyclododec-4-en-6-ylpiperazin-1-carboxylate;

and their pharmaceutically acceptable salts.

Disclosed herein are compositions containing at least one compound of the present invention (e.g. compounds of formulas I, IIa-e, IIIa, IVa and Va and/or their pharmaceutically acceptable salts) and at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected in accordance with the particular route of administration for which the composition is intended.

The pharmaceutical compositions of the present invention may be formulated for parenteral administration, oral administration, inhalation spray administration, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration and/or implantable container 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 some embodiments, the compositions are administered intravenously, orally, subcutaneously, or via intramuscular administration. Sterile injectable forms of the compositions of the present invention may be an aqueous or oleaginous suspension. These suspensions can be formulated in accordance with techniques known in the art, using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable carrier media and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils have traditionally been used as a solvent or suspension medium.

Any light, fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylene variants. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifying agents or bioavailability enhancers that are widely used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

If administered orally, the compound (e.g. a compound of formulas I, IIa-e, IIIa, IVa or Va, or a pharmaceutically acceptable salt thereof) may be presented in a dosage form suitable for oral administration, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate can also be added. When administered orally in capsule form, useful diluents include lactose and dried corn starch. If aqueous suspensions are intended for oral administration, the active ingredient is combined with an emulsifying and/or suspending agent. Certain sweeteners, flavors or colors may also be added if necessary.

The compounds and compositions of the present invention can be used to treat various types of cancer, including those that are susceptible to agents that target SF3B1. As noted above, the antitumor activity of pladienolide B is reported to be due to its targeting of the SF3b complex by inhibiting splicing and altering gene expression patterns (Kotake et al. , “Splicing factor SF3b as a target of the antitumor natural product pladienolide,” Nature Chemical Biology 2007, 3, 570-575). Mutations in spliceosomal genes, such as splicing factor 3B subunit 1 (SF3B1) protein, are known to occur in a range 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.

Thus, connections (for example, compounds of formulas I, IIa-e, IIIa, IVa and Va and their pharmaceutically acceptable salts) and compositions of the present invention can be used for the treatment of hematological malignancies, such as, for example, blood cancers (leukemias) and lymph node cancers (lymphomas) ). Leukemias include acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), etc. Lymphomas include Hodgkin's lymphoma and non-Hodgkin's lymphoma. Other hematologic malignancies may include myelodysplastic syndrome (MDS).

Solid tumors include carcinomas such as adenocarcinoma, e.g. breast cancer, pancreatic cancer, prostate cancer, colon or colorectal cancer, lung cancer, stomach cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, glioma, melanoma, etc.

The compounds and compositions of the present invention (for example, a compound of formulas I, IIa-e, IIIa, IVa or Va) may also be used to treat cancers that may be susceptible to agents that target a spliceosomal gene or protein other than SF3B1. The following are non-limiting examples of cancers that may be susceptible to agents that target the spliceosome. Thus, the compounds of the present invention can be administered to subjects for the treatment of a variety of cancers or pathological conditions, such as, for example, patients or subjects suffering from the following.

a)Myelodysplastic syndrome (MDS): see for example "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 ring sideroblasts", Pappaemannuil, E. et al, New England J. Med. 2011, DOI 10.1056/NEJMoa1103283.

b)Chronic lymphocytic leukemia (CLL): see for example "Defects in the spliceosomal machinery: a new pathway of leukaemogenesis", Maciejewski, J.P., Padgett, R.A., 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 leukemia", Quesada et al, Nature Genetics, 2011, 44, 47-52.

c)Chronic myelomonocytic leukemia (CMML): see for example Yoshida et al, Nature 2011; "Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia", Kar S.A. et al, Haematologia, 2012, DOI: 10.3324/haematol.2012.064048; DeBoeveret al., "Transcriptome sequencing reveals a potential mechanism of cryptic 3' splice site selection in SF3B1-mutated cancers", PLOS Computational Biology, 2013, DOI: 10.1371/journal.pcbi.1004105.

d)Acute myeloid leukemia (AML): see for example Malcovatiet al., Blood 2011; Yoshida et al, Nature 2011.

e)Mammary cancer: see for example "Whole genome analysis informs breast cancer response to aromatase inhibition", Elliset al., Nature, 2012, 486, 353-360; DeBoeveret al., "Transcriptome sequencing reveals a potential mechanism of cryptic 3' splice site selection in SF3B1-mutated cancers", PLOS Computational Biology, 2013, DOI: 10.1371/journal.pcbi.1004105; Maguireet al., "SF3B1 mutations constitute a novel therapeutic target in breast cancer", J Pathol 2015, 235, 571-580.

f)Uveal melanoma :see for example "SF3B1 mutations are associated with alternative splicing in uveal melanoma", Furneyet al., Cancer Disc. 2013, 10, 1122-1129; DeBoeveret al., "Transcriptome sequencing reveals a potential mechanism of cryptic 3' splice site selection in SF3B1-mutated cancers", PLOS Computational Biology, 2013, DOI: 10.1371/journal.pcbi.1004105.

g)Endometrial cancer: see for example Tefferiet al., "Myelodysplastic syndromes", N Engl J Med. 2009; 361:1872-85.

h)Stomach cancer: cm., For example, 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", Jeet al. i)Ovarian cancer: cm., For example, 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", Jeet al.

j)Types of bile duct cancer such as cholangiocarcinoma and pancreatic cancer: cm., For example, Biankinet al., "Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes", Nature 2012, 491, 399-405.

k)Lung cancer: cm., For example, "Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia", Quesadaet al., Nature Genetics 44, 47-52 (2012); Scottet al., "Acquired mutations that affect pre-mRNA splicing in hematologic malignancies and solid tumors", JNCI 105, 20, 1540-1549.

Additionally, the Catalog of Somatic Mutations in Cancer (COSMIC) (Wellcome Trust Sanger Institute, Genome Research Limited, England) reports that SF3B1 mutations have been found in samples of various cancer types.

The compound of the present invention (for example, a compound of formulas I, IIa-e, IIIa, IVa or Va) may be administered to a subject in a treatment-effective or therapeutically-effective amount. The amount of a compound of the present invention that can be combined with a carrier material to form a unit dosage form composition will vary depending on the subject being treated and the particular route of administration. In some embodiments, a dose of from 0.01 mg/kg to 100 mg/kg body weight/day of at least one compound disclosed herein is administered. In some embodiments, the dose is from 0.01 mg to 50 mg of at least one compound disclosed herein. In some embodiments, from 0.1 mg to 25 mg of at least one compound disclosed herein is administered. In some embodiments, 5 mg to 40 mg of at least one compound disclosed herein is administered.

It will be appreciated by one of ordinary skill in the art that the specific dosage and treatment schedule for a particular patient will depend on a variety of factors, including the potency of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of elimination, combination of drugs means, the assessment of the attending physician and the severity of the specific disease being treated. The amount of at least one compound disclosed herein will also depend on the particular compound/salt to be used.

In some embodiments, the cancer is tested for and/or tests positive for one or more mutations in a spliceosome gene or protein, wherein the presence of the mutation(s) (a "positive" result) may indicate that the subject's cancer is receptive to a treatment method comprising administration of a compound that targets the protein and/or spliceosome. Examples of such spliceosomal genes include, but are not limited to, the genes presented in Table 1 .

Table 1. Spliceosomal genes and potential diseases associated with them Spliceosome gene Disease(s) Splicing factor 3B subunit 1 (SF3B1) See lists above Accessory factor 1 small nuclear RNA U2 MDS, AML, CMML, LUAD, UCEC (U2AF1) CMML, MDS, PMF, AML High serine/arginine splicing factor 2 (SRSF2) M.D.S. Zinc finger protein 2 (CCCH type), RNA-binding motif, and high serine/arginine content (ZRSR2) Retinal pigmentary dystrophy Splicing factor 8 involved in pre-mRNA processing (PRPF8) Myeloid neoplasia Small nuclear RNA accessory factor 2 U2 (U2AF2) MDS, PRAD, COAD Splicing factor 1 (SF1) Myeloid neoplasia, OV, COAD Splicing factor 3a subunit 1 (SF3A1) M.D.S. Pre-mRNA processing factor 40 homolog B PRP40 (PRPF40B) LUAD RNA binding motif protein 10 (RBM10) COAD Poly(rC) binding protein 1 (PCBP1) SKCM Factor 1 involved in pre-mRNA splicing, crooked neck (CRNKL1) LUSC Helicase 9 with DEAH box (Asp-Glu-Ala-His) (DHX9) STAD Peptidyl-prolyl-cis/trans isomerase-like protein 2 (PPIL2) SKCM RNA binding motif protein 22 (RBM22) LUAD Small nuclear ribonucleoprotein Sm D3 (SNRPD3) GBM, LGG Putative ATP-dependent RNA helicase DDX5 (DDX5) LUAD Factor involved in pre-mRNA splicing with ATP-dependent RNA helicase activity DHX15 (DHX15) DLBCL Polyadenylate binding protein 1 (PABPC1) Myeloid neoplasia

Abbreviations:

MDS=myelodysplastic syndrome

AML=acute myeloid leukemia

CMML=chronic myelomonocytic leukemia

LUAD=lung adenocarcinoma

UCEC=uterine endometrial carcinoma

PMF=progressive massive fibrosis

PRAD=prostate adenocarcinoma

COAD=colon adenocarcinoma

OV=serous cystadenocarcinoma of the ovary

SKCM=cutaneous melanoma

LUSC=lung squamous cell carcinoma

STAD=gastric adenocarcinoma

GBM=glioblastoma multiforme

LGG=low-grade brain glioma

DLBCL=diffuse large B cell lymphoma

In some embodiments, a subject's cancer may be susceptible to a treatment method comprising administration of a compound that targets a given protein and/or spliceosome, even in the absence of such mutations in the spliceosome gene or protein.

Screening or testing for mutations can be carried out using any known methods, such as genotyping, phenotyping, etc., nucleic acid amplification, electrophoresis, microarrays, blotting, functional assays, immunoassays, etc. Screening methods can include, for example, collecting from a specified subject a biological sample containing cancer cells/cancerous tissue.

In some embodiments, a subject with a cancer described herein can be treated with at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof , and at least one additional therapy.

In some embodiments, the at least one additional therapy comprises a cytokine or cytokine analogue therapy, for example, any cytokine or cytokine analog therapy disclosed herein. Cytokines are a broad category of small proteins that have been shown to be involved in autocrine signaling, paracrine signaling, and/or endocrine signaling as immunomodulatory agents. 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 secreted by a cell that influences the function of other cells to mediate an immune response, and the term “cytokine therapy” refers to administering and/or inducing 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 analogue. The terms “cytokine analog” and “cytokine analog therapy” refer to a modified cytokine where one or more amino acid residues of the native cytokine have been replaced by other natural or non-natural amino acid residues and/or where one or more natural or non-natural amino acid residues have been added to native cytokine. In some embodiments, a cytokine or cytokine analogue therapy comprises administering at least one cytokine or cytokine analogue to a patient in need of such treatment.

In some embodiments, the at least one additional therapy comprises one or more engineered T cells that specifically target the tumor (e.g., a tumor-based therapy CAR-T or other cells), for example, any CAR-T therapy disclosed herein. The terms “CAR-T” and “CAR-T therapy” are used interchangeably to refer to a cell or population of cells modified by a CAR (e.g. T cells or T cell populations). In some embodiments, a chimeric T cell receptor (CAR) can be engineered using antigen recognition sequences such that when a CAR is expressed on a cell (e.g., T cell) CAR and/or cell can interact with a target antigen. For example, in some embodiments, a CAR can be constructed by first identifying antibodies that recognize a domain of an antigenic protein expressed on a cell surface. The antigen recognition sequences of such antibodies can then be fused to a T cell receptor domain to achieve selective targeting and activation. In some embodiments, the CAR sequences are cloned into a population of patient-derived T cells and the cells are expanded using currently available protocols. In some embodiments, the engineered T cells are then infused back into the patient's bloodstream prior to treatment with at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically thereof acceptable salts, simultaneously with or after it. In some embodiments, after treatment with at least one compound and/or pharmaceutically acceptable salt, tumor cells may begin to present antigen, for example, an antigen that is targeted by a population of engineered T cells. In some embodiments, a population of engineered T cells can contact and kill antigen-presenting tumor cells.

In some embodiments, the at least one additional therapy comprises a checkpoint inhibitor therapy, e.g. any checkpoint inhibitor therapy disclosed herein. Immune checkpoints are inhibitory pathways that slow or stop immune responses and prevent excess tissue damage due to uncontrolled immune cell activity. As used herein, the terms “checkpoint inhibitor” and “checkpoint inhibitor therapy” are used interchangeably to refer to any therapeutic agent, including any small molecule chemical compound, antibody, nucleic acid molecule or polypeptide, or any fragment thereof, that inhibits one or more inhibitory pathways, resulting in more functional immune activity. In some embodiments, a checkpoint inhibitor therapy comprises administering at least one checkpoint inhibitor to a patient in need of such treatment.

In some embodiments, the at least one additional therapy comprises a neoantigen vaccine. In some embodiments, the treatment comprises administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and administration of a neoantigen vaccine. In some embodiments, the neoantigen vaccine comprises a tumor neoantigen and/or neoantigen induced by at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof . In some embodiments, the treatment further comprises administration of a checkpoint inhibitor therapy. In some embodiments, the checkpoint inhibitor therapy specifically targets PD1/PDL1, CTLA4, OX40, CD40, LAG3, TIM3, GITR, and/or KIR. In some embodiments, the checkpoint inhibitor therapy specifically targets PD1/PDL1 (e.g. is an anti-PD1 antibody or an anti-PDL1 antibody). In some embodiments, the checkpoint inhibitor therapy specifically targets CTLA4 (e.g. is an antibody to CTLA4). In some embodiments, the treatment comprises administering a combination therapy comprising a neoantigen vaccine following an initial (i) administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and (ii) detecting the presence of a neoantigen (e.g. neoantigen from neoantigen vaccine). In some embodiments, neoantigen expression is monitored throughout the course of treatment. In some embodiments, treatment is stopped if no neoantigens are detected.

In some embodiments, also disclosed herein are methods of treating a patient by inducing the production of antigens in tumor cells that can be targeted by the patient's immune system for clearance. Without being limited by theory, in some embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof can produce neoantigens that induce immune response, induce an immune response to double-stranded RNA for example, by re-expression of endogenous retroviruses present in the intron and/or production of neoantigens that induce immunogenic cell death.

As used herein, the term “neoantigen” refers to any antigen to which the immune system has not previously been exposed, which arises as a result of one or more tumor-specific mutations and/or as a result of exposure of the tumor to at least one compound selected from the compounds of formula I ( including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts. Tumor-specific mutations may include missense mutations, frameshifts, translocations and splice variants of mRNA, as well as mutations that affect post-translational processing such as phosphorylation and glycosylation. In some embodiments, such exemplary mutations may result from nonsynonymous changes in the coding sequence and/or mutations that alter mRNA processing (e.g. splicing). In some embodiments, all of these illustrative mutations may result in molecular changes that can be recognized by the corresponding T cell receptor. In various embodiments, an exemplary neoantigen is a neoantigen whose formation is induced by the delivery of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, delivery of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof can induce a new mRNA splice variant, resulting in translation proteins containing one or more new peptide domains to which the immune system has not previously been exposed. In some embodiments, tumor-specific mutations may be mRNA splice variants caused by the delivery or administration of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof .

Without being limited by theory, in some embodiments, delivery of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof can induce a new mRNA splice variant ( For example, exon skipping, intron retention), which leads to 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 new peptide domains that are recognized as foreign by the immune system. In some embodiments, the one or more novel peptide domains do not exist in proteins or in any other part of the human proteome in the absence of treatment with the compound. In some embodiments, proteins containing one or more novel peptide domains can be degraded by the proteasome to generate new peptide fragments that act as substrates for immunopeptide presentation mechanisms, e.g. through a presentation with MHC. In some embodiments, novel peptide fragments representing neoantigens may be presented in the MHC1-linked peptidome, for example, on tumor cells.

In some embodiments, delivery of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof may result in one or more tumor cell-specific events ( For example, cessation of cell growth). In some embodiments, tumor cell-specific event(s) may result in (1) increased contact with phagocytes (Bracciet al. (2014) Cell Death Differ. 21(1):15-25); (2) movement of new peptide fragments into the tumor-draining lymph node for contact with antigen-presenting cells; (3) processing in antigen-presenting cells of new peptide fragments from the phagocytosed tumor cell and presentation of the fragments as neoantigens to populations of circulating naïve T cells; (4) the interaction of new peptide fragments with T cells expressing receptors that recognize the fragments as neoantigens; (5) maturation and activation of effector T cells that mediate responses (e.g. CD4+ and/or CD8+ T cells); and/or (6) contact of T cells with additional tumor cells treated with the compound and presenting new peptide fragments, representing neoantigens, on their surface as part of complexes with MHC1. In some embodiments, tumor cell-specific event(s) may result either directly or indirectly in the recruitment of effector T cells and/or killing of neoantigen-presenting tumor cells.

Also, without being limited by theory, in some embodiments, delivery of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof can cause re-expression of endogenous retroviruses present in the intron, which leads to an immune response to double-stranded RNA.

Moreover, without being limited by theory, in some embodiments, delivery of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof can result in immunogenic cell death triggered by the compound-induced release of neoantigens formed as a result of the mutation. In some embodiments, delivery of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof can induce an immune response to double-stranded RNA. In some embodiments, an immune response to double-stranded RNA may result from re-expression of endogenous retroviruses present in the intron. In some embodiments, the immune response to the double-stranded RNA may result in the death of tumor cells. In some embodiments, delivery of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof can induce immunogenic cell death. In some embodiments, immunogenic cell death may be caused by the release of mutation-derived neoantigens and/or the host immune response to tumor cells.

Accordingly, in some embodiments, methods of treatment are disclosed comprising inducing the formation of neoantigens by administering one or more compounds selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the method includes administering a reduced dosage of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof than would be necessary in the absence of inducing the formation of neoantigens. In some embodiments, the method includes administering one or more initial induction doses to produce neoantigens and induce an immune response (e.g. conversion of naïve T cells to memory cells) followed by a reduction in dosage or frequency of administration (i.e. e. due to the combined effect of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and immune targeting of neoantigens). In some embodiments, treatment may involve administering a combination of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, to induce an immune response based on neoantigens and at least one additional therapy (for example, second anticancer therapy). For example, in some embodiments, treatment may involve administering a combination of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof to induce an immune response based on neoantigens and one or more checkpoint inhibitors. In some embodiments, treatment may involve administering a combination of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, to induce an immune response based on neoantigens and one or more cytokines or cytokine analogues. In some embodiments, treatment may involve administering a combination of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, to induce an immune response based on neoantigens and one or more neoantigen vaccines. In some other embodiments, treatment may involve administering a combination of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, to induce an immune response to based on neoantigens and one or more engineered T cells that specifically target the tumor (e.g. CAR-T).

In some embodiments, neoantigens can be used to monitor the effectiveness of treatment with at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. For example, following administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, a sample may be obtained from a patient (e.g. tumor biopsy) and screen it for neoantigens or markers of immune or inflammatory response. If a neoantigen and/or immune response is detected, additional treatment may be given, e.g. at a reduced dosage.

In some embodiments, methods of treatment are disclosed comprising inducing an immune response to double-stranded RNA by administering one or more compounds selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof.

In some embodiments, methods of treatment are disclosed comprising inducing immunogenic cell death by administering one or more compounds selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof.

In some embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof may be combined with any known anticancer therapy. Examples of current immune activation strategies available for the treatment of cancer include, but are not limited to, treatment with immune checkpoint inhibitor (ICI) molecules, treatment with cytokines or cytokine analogues, vaccination with tumor vaccines, and engineering T- cells that specifically target the tumor (for example, proliferation of tumor-infiltrating lymphocytes or CAR-T). These technologies are primarily aimed at enhancing or inducing an immune response to pre-existing tumor antigens (either mutations or aberrant expression of cell surface proteins). One or more of these strategies may involve one or more mutations that are capable of inducing the development of a T cell response to the antigen. For example, patient responses to checkpoint inhibition may correlate with mutational load with nonsynonymous changes. In addition, cancer vaccine approaches that rely on pre-existing mutations and the antigenicity of those mutations can be used.

Compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts can induce a wide range of changes in the transcriptome that occur in cells of different origins. Translation of these altered mRNAs can produce stable and reproducible altered proteins that produce MHC1-binding neopeptides with high affinity for various isotypes of HLA molecules. Without being limited by theory, due to the large number of changes in the transcriptome and proteome, treatment with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof may increase the number of potentially reactive neoantigens to improve their involvement in the adaptive immune response.

In some embodiments, the present invention provides a method of inducing the formation of at least one neoantigen by contacting a neoplastic cell with an effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va ) and/or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a method of inducing an immune response to double-stranded RNA by contacting a neoplastic cell with an effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides a method of inducing immunogenic cell death by contacting a neoplastic cell with an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/ or pharmaceutically acceptable salts thereof.

In some embodiments, the neoplastic cell is in in vitro cell culture. In some embodiments, the neoplastic cell is obtained from a subject. In some embodiments, the neoplastic cell is in the subject. In some embodiments, the neoplastic cell is derived from a hematologic malignancy or solid tumor. In some embodiments, the hematologic malignancy is selected from B-cell malignancy, leukemia, lymphoma, and myeloma. In some embodiments, the hematologic malignancy is selected from acute myeloid leukemia and multiple myeloma. In some embodiments, the solid tumor is selected from breast cancer (eg, HER2-positive breast cancer), stomach cancer (eg adenocarcinoma of the stomach), prostate cancer, ovarian cancer, lung cancer (for example, adenocarcinoma of the lung), uterine cancer (for example, serous endometrial carcinoma of the uterus), 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.

In some embodiments, the present invention further provides a method of inducing the formation of at least one neoantigen and/or the development of a T cell response in a subject who has or is suspected of having a neoplastic disorder by administering to the subject an effective amount of at least one compound, selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. Also provided herein, in some embodiments, is a method of treating a subject who has or is suspected of having a neoplastic disorder by administering to the subject an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa , IVa and Va) and/or their pharmaceutically acceptable salts, wherein administration of at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts induces formation of at least one neoantigen and/or development of a T cell response.

In various other embodiments, the present invention provides a method of inducing an immune response to double-stranded RNA in a subject who has or is suspected of having a neoplastic disorder by administering to the subject an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. Also provided herein in some embodiments is a method of treating a subject who has or is suspected of having a neoplastic disorder by administering to the subject an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa , IVa and Va) and/or their pharmaceutically acceptable salts, wherein administration of at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts induces immune response to double-stranded RNA.

In still other embodiments, the present invention provides a method of inducing immunogenic cell death in a subject who has or is suspected of having a neoplastic disorder by administering to the subject an effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa -e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. Additionally, in some embodiments, provided herein is a method of treating a subject who has or is suspected of having a neoplastic disorder by administering to the subject an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e , IIIa, IVa and Va) and/or their pharmaceutically acceptable salts, comprising at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts, wherein administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof induces immunogenic cell death.

In some embodiments, the present invention further provides a method of treating a subject who has or is suspected of having a neoplastic disorder by administering to the subject an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa , IVa and Va) and/or their pharmaceutically acceptable salts, wherein administration of at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts induces immunogenic cell death, in combination with one or more additional therapies containing a second agent.

In some embodiments of the therapeutic methods described herein, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, or a second administered agent is reduced due to inducing the formation of at least one neoantigen and/or the development of a T-cell response compared to a standard dosage of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and /or pharmaceutically acceptable salts thereof, or a second agent. In some embodiments, the administered amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, or the second agent is reduced by 10%, 15% , 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% compared to the standard dosage of at least one compound selected from compounds of formula I (including formulas IIa- e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, or a second agent. In some embodiments, the frequency of administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, or the second agent by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% less than a standard dosing regimen of at least one compound selected from compounds of formula I (including including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, or a second agent. In some embodiments, the administered amount and/or dosage of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, or the second agent results in more low systemic toxicity and/or improved tolerability.

As used herein, the term “standard dosage” or “standard administration schedule” refers to any usual or conventional schedule for administering a therapeutic agent, e.g. to a regimen proposed by the manufacturer, approved by regulatory authorities, or otherwise tested in human subjects to meet the needs of the average patient. In some embodiments, the therapeutic agent is at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, with anticancer activity.

For example, a standard dosing regimen for trastuzumab, an exemplary anti-HER2 antibody, may be 8 mg/kg administered intravenously over 90 minutes. (week 1), followed by intravenous administration of 6 mg/kg over 30-90 minutes. every 3 weeks (from week 4 until the end of the treatment cycle) (Herceptin® (trastuzumab), FDA Compliant Labeling Supplement, 2017).

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 4 doses (Yervoy® (ipilimumab), FDA Compliant Labeling Supplement, 2018). Another standard dosing regimen for ipilimumab may be 10 mg/kg administered intravenously over 90 minutes. every 3 weeks for 4 doses, then 10 mg/kg every 12 weeks for up to 3 years (Yervoy® (ipilimumab), FDA Compliant Labeling Supplement, 2018).

As another example, a standard dosing regimen for nivolumab, an exemplary anti-PD1 checkpoint inhibitor antibody, may be 3 mg/kg administered intravenously over 60 minutes. every 2 weeks (Opdivo® (nivolumab), FDA-compliant labeling, 2015).

As another example, a standard dosing regimen for atezolizumab, an exemplary anti-PDL1 checkpoint inhibitor antibody, may be 1200 mg administered intravenously over 60 minutes. every 3 weeks (Tecentriq® (atezolizumab), 2018 FDA Compliant Labeling Supplement).

As another example, a standard dosing regimen for T-DM1, an exemplary anti-HER2 antibody-drug conjugate, may be administered at 3.6 mg/kg intravenously over 90 minutes. every 3 weeks (Kadcyla® (T-DM1), 2016 FDA Compliant Labeling Supplement).

In some embodiments, the methods described herein may further include administering at least one additional therapy (eg, checkpoint inhibitor, neoantigen vaccine, cytokine or cytokine analogue, CAR-T, etc.). In some embodiments, the amount administered of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional therapy reduced due to the induction of the formation of at least one neoantigen and/or the development of a T cell response compared to a standard dosage of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/ or pharmaceutically acceptable salts thereof, and/or at least one additional therapy. In some embodiments, an administered amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional therapy reduced due to the induction of an immune response to double-stranded RNA compared to a standard dosage of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional therapy. In some embodiments, an administered amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional therapy reduced due to induction of immunogenic cell death compared to a standard dosage of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least at least one additional therapy. In some embodiments, an administered amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional therapy reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% compared to the standard dosage of at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional therapy. In some embodiments, the frequency of administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional agent per at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% less than a standard dosing regimen of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional therapy. In some embodiments, the administered amount and/or dosage of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least single additional therapy results in lower systemic toxicity and/or improved tolerability.

In some embodiments, administration of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof is initiated prior to administration of at least one additional therapy. In other embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is initiated after administration of at least one additional therapy. In yet other embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is initiated simultaneously with the administration of at least one additional agent therapy.

In some embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is repeated at least once after the initial administration. In some embodiments, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof used for repeated administration is reduced compared to the amount used for initial administration. In some embodiments, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof used for repeated administration is reduced compared to a standard dosage at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof used for repeated administration is reduced by 10%, 15 %, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% compared to the standard dosage or initial dosage of at least one compound selected from the compounds of formula I (including including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts.

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

In some embodiments, reintroduction of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is carried out simultaneously with reintroduction of at least one additional means of therapy. In some embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is carried out sequentially or spaced out over time with repeated administration of at least at least one additional therapy.

In some embodiments, the at least one additional therapy comprises administering a checkpoint inhibitor, for example, any checkpoint inhibitor disclosed herein. In some embodiments, the subject is intolerant, unresponsive, or deficient in responsiveness to the checkpoint inhibitor when administered alone. In some embodiments, the checkpoint inhibitor specifically targets PD1/PDL1, CTLA4, OX40, CD40, LAG3, TIM3, GITR, and/or KIR. In some embodiments, the checkpoint inhibitor specifically targets CTLA4, OX40, CD40, and/or GITR. In some embodiments, a checkpoint inhibitor is an antibody having inhibitor or agonist activity against its target. In some embodiments, targeting of the checkpoint inhibitor is provided by an inhibitory antibody or other such inhibitory molecule. In other embodiments, targeting of the checkpoint inhibitor is provided by an agonist antibody or other similar agonist molecule.

In some other embodiments, the at least one additional therapy comprises administering a neoantigen vaccine, for example, any neoantigen vaccine disclosed herein. In some embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is administered prior to administration of the neoantigen vaccine. In some embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is administered following administration of the neoantigen vaccine. In some embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is administered concomitantly with administration of the neoantigen vaccine. In some embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is repeated at least once after the initial administration. In some embodiments, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof used for repeated administration is reduced compared to the amount used for initial administration.

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

In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 10 to about 50 amino acids. In some embodiments, the length of the at least one neoantigen peptide ranges from about 10 to about 35 amino acids. In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 15 to about 25 amino acids. In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 10 to about 20 amino acids. In some embodiments, the neoantigenic sequence and/or antigenic moiety does not directly overlap with the canonical peptide sequence (e.g. any of or does not consist of the illustrative canonical peptide sequences underlined in Table 3).

As used herein, the term “antigenic portion” or “antigenic fragment” of a neoantigenic sequence refers to one or more fragments of a neoantigenic sequence that retain the ability to induce a T cell response (e.g. antigen-specific expansion and/or maturation of effector T cell population(s). In some embodiments, the antigenic moiety may also retain the ability to be internalized, processed, and/or presented by antigen presenting cells (e.g. dendritic cells). In some embodiments, the antigenic portion also retains T cell priming function. In some embodiments, the length of the antigenic portion of the neoantigenic sequence ranges from about 10 to about 50 amino acids. In some embodiments, the length of the antigenic portion of the neoantigenic sequence ranges from about 10 to about 35 amino acids. In some embodiments, the length of the antigenic portion of the neoantigenic sequence ranges from about 15 to about 25 amino acids. In some embodiments, the length of the antigenic portion of the neoantigenic sequence ranges from about 10 to about 20 amino acids. In some embodiments, the antigenic portion of the neoantigenic sequence (e.g. the antigenic portion of any one of SEQ ID NO: 30-57) or the mRNA encoding it is formulated as a neoantigen vaccine.

An exemplary embodiment of the antigenic portion is the region(s) flanking amino acids 45-53 of SEQ ID NO: 30. Another exemplary embodiment of the antigenic portion is the region(s) flanking amino acids 82-90 from SEQ ID NO: 30. In some embodiments, the antigenic portion is capable of binding to at least one HLA allele expressed in the subject (e.g. HLA-A*02:01). In some other embodiments, the antigenic moiety 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%, of at least 35%, at least 40%, or at least 45% of subjects in a population of subjects suffering from a neoplastic disorder. In some embodiments, the antigenic portion is capable of eliciting a T cell response against a tumor present in at least 1%, at least 5%, or at least 10% of a population of subjects suffering from a neoplastic disorder.

In some embodiments, the antigenic portion does not directly overlap with or consist of a canonical peptide sequence. As used herein, the term “canonical peptide sequence” refers to any contiguous peptide sequence present in the human proteome in the absence of contact with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va ) and/or pharmaceutically acceptable salts thereof (e.g. in the absence of contact with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof) and/or to which the immune system has previously been exposed. In some embodiments, the canonical peptide sequence is derived from and/or encoded by the open reading frame of the canonical transcript. Exemplary canonical peptide sequences are highlighted in Table 3.

In some embodiments, if a compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is administered, the canonical peptide sequence can be derived from the 24 nucleotides located directly on 5'-end of the frame prior to an aberrant splicing event induced by at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or may be encoded them. Thus, in some embodiments, the canonical peptide sequence contains or consists of 8 amino acids located immediately N-terminal to the neoantigen sequence, the formation of which is induced by at least one compound selected from compounds of formula I (including formulas IIa-e , IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, if the 5' exon sequence ends at the terminal nucleotide of the codon, the canonical peptide sequence ends at the end of the exon. In some other embodiments, if the 5'-terminal exon sequence ends with one or two of the three nucleotides of the codon, the canonical peptide sequence is derived from and/or encoded by the 24 nucleotides preceding the partial codon. In some embodiments, the 3' end of the mRNA sequences in an aberrant splicing event may be translated in the same open reading frame resulting from the 5' end exon until reaching a stop codon, at which point translation may end. In some embodiments, if an aberrant splicing event (eg,exon skipping) results in retention of the open reading frame of the canonical transcript, the C-terminal sequence can be translated into an additional 24 nucleotides encoding the 8 C-terminal amino acids. In some embodiments, in this context, only the region along the aberrant exon junction may encode a neoantigen sequence. In some embodiments, if the open reading frame is shifted (e.g. while retaining the intron), the complete C-terminal sequence (encoded by the 3'-terminal mRNA) may encode a neoantigen sequence.

In some embodiments, the antigenic portion of the neoantigenic sequence is selected by comparing the neoantigenic sequence to a canonical peptide sequence and selecting a portion of the neoantigenic sequence that does not directly overlap with, consist of, and/or align with the canonical peptide sequence. In some embodiments, the antigenic portion of a neoantigen sequence can be screened for antigenicity and/or T cell priming function in the same manner as full-length neoantigen sequences (e.g. neoantigenic sequence from which the antigenic part is derived). In some embodiments, the antigenic portion of the neoantigen sequence is assessed for antigenicity and/or T cell priming function using a T cell priming assay, such as the exemplary T cell priming experiments described herein.

In some embodiments, the neoantigenic sequence is a subject-specific neoantigenic sequence. In some embodiments, the neoantigen sequence is a personalized neoantigen vaccine for the subject. In some embodiments, the neoantigen sequence used to create a personalized neoantigen vaccine for a 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 identifying neoantigens expressed in the subject's tumor, e.g. after administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and selection of a vaccine containing a neoantigen sequence observed in the patient's tumor.

The term "personalized" when used to describe a neoantigen vaccine refers to a vaccine created by identifying one or more neoantigens produced in a patient, preferably a neoantigen identified in the patient after exposure to at least one compound selected from compounds of formula I (in including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and then using one or more of these neoantigens as a vaccine base for the same patient. Accordingly, in some embodiments, the patient is administered at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and is screened for neoantigens produced during treatment. In some embodiments, the selected neoantigen vaccine comprises a neoantigen peptide or mRNA disclosed herein and the presence of which in a patient has been confirmed following exposure to at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va ) and/or pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or a peptide or mRNA vaccine can be administered to a patient alone once or repeatedly. Therefore, in some embodiments, one or more of these neoantigens are used to create a personalized vaccine that is administered to a patient. In some embodiments, one or more neoantigens used to create a 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 one or more neoantigens. Prediction of whether a neoantigen will bind to a specific MHC1 allele can be accomplished using any computational prediction method known in the art. Exemplary methods for computational forecasting are disclosed. for example in Meydanet al. (2013) BMC Bioinformatics 14(Suppl. 2):S13, which is incorporated herein by reference for such methods.

In some other embodiments, the neoantigen sequence is a generic neoantigen sequence. In some embodiments, the neoantigen sequence is a generic neoantigen vaccine.

The term "universal" when used to describe a neoantigen vaccine refers to a vaccine containing a peptide sequence or an mRNA sequence that is based on the common or known neoantigen(s) detected by sequencing neoantigens produced in many patients and/or in patient tissue samples, preferably after exposure to at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable compounds thereof salts The peptide sequence or mRNA sequence used in the vaccine does not need to be present in every patient, but is found in at least a few patients or tissue samples from patients. In some embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or a peptide or mRNA vaccine can be administered to a patient alone once or repeatedly. Therefore, in some embodiments, the peptide sequence or mRNA sequence is used to vaccinate additional patients. In some embodiments, the patient is administered at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and is then administered a peptide or mRNA vaccine based on a known neoantigen for enhancing the immune response to neoantigens produced under the influence of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the patient is administered a generic peptide or mRNA vaccine and is then administered at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, one once or repeatedly. In some embodiments, the neoantigen sequence (or sequences) used to create a universal neoantigen vaccine is selected based on the overall occurrence of the MHC1 allele in a given patient population (Maiers et al. (2007) Hum. Immunol. 68(9):779-88) .

In some embodiments, the neoantigen sequence (e.g. universal neoantigen) 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 the subjects in the population of subjects suffering from a neoplastic disorder. In some embodiments, the neoantigen sequence is capable of inducing a T cell response to a tumor present in at least 1%, at least 5%, or at least 10% of a population of subjects suffering from a neoplastic disorder.

In some embodiments, the neoantigenic sequence has been identified by sequencing at least one neoantigenic peptide or mRNA encoding it, the formation of which is induced in a subject by administration of an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts. In some embodiments, the at least one neoantigenic peptide comprises a neoantigenic sequence the formation of which is induced by contacting a neoplastic cell with an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the neoplastic cell is in in vitro cell culture. In some embodiments, the neoplastic cell is obtained from a subject. In some embodiments, the neoplastic cell is in the subject.

In some embodiments, the neoantigen vaccine comprises at least one neoantigen peptide and a pharmaceutically acceptable carrier (e.g. any of the illustrative media described herein). In some embodiments, the at least one neoantigenic peptide is associated with a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, fisurella hemocyanin, immunoglobulin, thyroglobulin, ovalbumin, toxoid or attenuated toxoid derivative, cytokine, and chemokine. In some embodiments, the neoantigenic peptide and the pharmaceutically acceptable carrier are covalently linked through a linker. In some embodiments, the neoantigenic peptide and the pharmaceutically acceptable carrier are expressed as a fusion protein. In some embodiments, the neoantigen vaccine contains 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.

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.

In some embodiments, the neoantigenic sequence is a subject-specific neoantigenic sequence. 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.

In some other embodiments, the neoantigen sequence is a generic neoantigen sequence. In some embodiments, the neoantigen sequence is a generic neoantigen vaccine. In some embodiments, the 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 at least 35%, at least 40%, or at least 45% of subjects in a population of subjects suffering from a neoplastic disorder. In some embodiments, the neoantigen sequence is capable of inducing a T cell response to a tumor present in at least 1%, at least 5%, or at least 10% of a population of subjects suffering from a neoplastic disorder.

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 that is induced in a subject by administration of an effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the at least one neoantigenic mRNA encodes a neoantigenic sequence, the formation of which is induced by contacting a neoplastic cell with an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the neoplastic cell is in in vitro cell culture. In some embodiments, the neoplastic cell is obtained from a subject. In some embodiments, the neoplastic cell is in the subject.

In some embodiments, the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable carrier (eg, any of the illustrative media described herein). In some embodiments, the at least one neoantigen mRNA is associated with a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, fisurella hemocyanin, immunoglobulin, thyroglobulin, ovalbumin, toxoid or attenuated toxoid derivative, cytokine, and chemokine. In some embodiments, the neoantigen vaccine contains 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 using an encapsulating agent. In some embodiments, the encapsulating agent is a liposome. In some embodiments, the encapsulating agent is a nanoparticle.

In some embodiments, the at least one additional therapy comprises administration of a cytokine or cytokine analog , such as any cytokine or cytokine analog disclosed herein. In some embodiments, the subject is intolerant, unresponsive, or deficient in responsiveness to a cytokine or cytokine analog when administered alone. In some embodiments, the cytokine or cytokine analog provides a T cell enhancer. In some embodiments, the cytokine or cytokine analogue includes IL-2, IL-10, IL-12, IL-15, IFNγ and/or TNFα. In some embodiments, the cytokine or cytokine analogue includes IL-2, IL-10, IL-12 and/or IL-15. In some embodiments, administration of a cytokine or cytokine analog enhances T cell priming following administration of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, due to inducing the formation and presentation of neoantigens.

In some embodiments, the at least one additional therapy comprises the administration of engineered T cells that specifically target the tumor (i.e. e. CAR-T), for example, any CAR-T therapy disclosed herein.

In some embodiments, the methods described herein may further include detecting one or more neoantigens and/or T cell response in a subject following administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and optionally continuing to administer at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof salts if one or more neoantigens and/or T cell response are detected. In some embodiments, detection of one or more neoantigens and/or T cell response in a subject indicates the effectiveness of treatment with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, treatment with an additional therapy along with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is continued if detected one or more neoantigens and/or T cell response. In some embodiments, treatment is continued at a reduced dosage and/or frequency if one or more neoantigens and/or T cell response are detected.

In some embodiments, the methods described herein may further include detecting an immune response to double-stranded RNA in a subject following administration of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, and optionally continuing administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof if an immune response is detected to double-stranded RNA. In some embodiments, detection of an immune response to double-stranded RNA in a subject indicates the effectiveness of treatment with at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable compounds thereof salts In some embodiments, treatment with an additional therapy along with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is continued if detected immune response to double-stranded RNA. In some embodiments, treatment is continued at a reduced dosage and/or frequency if an immune response to the double-stranded RNA is detected.

In some embodiments, the methods described herein may further include detecting immunogenic cell death in a subject following administration of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/ or pharmaceutically acceptable salts thereof, and optionally continuing administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof if immunogenic cell death is detected. In some embodiments, the detection of immunogenic cell death in a subject indicates the effectiveness of treatment with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, treatment with an additional therapy along with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is continued if immunogenic cell death. In some embodiments, treatment is continued at a reduced dosage and/or frequency if immunogenic cell death is detected.

In some embodiments, the subject has a mutational load with nonsynonymous changes of approximately 150 mutations or less. In some embodiments, the subject has a mutational load with nonsynonymous changes of approximately 100 mutations or less. In some embodiments, the subject has a mutational load with nonsynonymous changes of approximately 50 mutations or less. In some embodiments, the subject has a neoplastic disorder, for example, or is suspected of having a hematological malignancy or solid tumor. In some embodiments, the hematologic malignancy is selected from B-cell malignancy, leukemia, lymphoma, and myeloma. In some embodiments, the hematologic 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.

In some embodiments, the present invention further provides a method of treating a subject who has or is suspected of having a neoplastic disorder, comprising: (a) administering to the subject an effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa -e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, wherein administering at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts, induces the formation of at least one neoantigen and/or the development of a T-cell response; (b) detection of one or more neoantigens and/or T-cell response in the subject after administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutical acceptable salts; and (c) continuing to administer at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof if one or more neoantigens and/or T -cellular response. In some embodiments, detection of one or more neoantigens and/or T cell response in a subject indicates the effectiveness of treatment with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the one or more neoantigens comprise the amino acid sequence of any one of SEQ ID NO: 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 of SEQ ID NO: 10-13.

In some embodiments, a patient who has a cancer described herein can be treated with a combination of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and checkpoint inhibitor based therapies.

Treating patients with immune checkpoint inhibition has been shown to have good efficacy in certain clinical indications. The FDA recently approved the use of a checkpoint inhibitor in patients with tumors exhibiting high microsatellite instability, regardless of tissue origin. This registration was based in part on the observation that response rates correlate positively with mutational load (Rizvi et al. (2015) Science 348(6230):124-8; Hellmann et al. (2018) Cancer Cell 33(5): 853-861). Estimates from the literature vary in absolute numbers and by origin, but generally confirm that above a threshold of ~150–250 mutations, the likelihood of response increases. Analysis of TCGA data demonstrates that a large percentage of adult-onset tumors of various origins have a relatively low mutational load with nonsynonymous changes (Vogelstein et al. (2013) Science 339:1549-58). Most lineages are characterized by average nonsynonymous mutation rates of ~30–80 per patient, well below the thresholds required to increase the likelihood of response to checkpoint inhibitors.

For example, HER2-positive breast cancer has been shown to have an average of ~60 nonsynonymous mutations present in a patient sample. However, the threshold for efficacy of checkpoint inhibitor treatment, as mentioned above, is estimated to be in the range of ~150-250 non-synonymous mutations, i.e. i.e. patients with a score above this threshold are more likely to demonstrate complete remission, partial remission and/or stable disease, while patients with a score below this threshold are more likely to exhibit disease progression. Therefore, strategies are required to increase the observed number of nonsynonymous mutations and/or neoantigens present on tumor cells and may increase the overall likelihood of response, e.g. to a checkpoint inhibitor therapy. Because cytokines (and their analogues) act through a similar mechanism of action, such strategies may also increase the overall likelihood of response to cytokine-based therapies.

Currently, response rates for HER2-positive breast cancer are ~15-25% (CTI NCT02129556). In some embodiments disclosed herein, treatment with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, in combination with a control inhibitor points and/or cytokine-based therapy may increase these response rates. In some embodiments, treatment with a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, in combination with a checkpoint inhibitor and/or a cytokine-based therapy can be used against any adult-onset tumor, particularly those with an average frequency of non-synonymous mutations below the calculated threshold of ~150 mutations. In some embodiments, exemplary types of cancer suitable for treatment with a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, alone or in combination with an additional therapy (eg, 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 adenocarcinoma, ovarian cancer, prostate cancer, liver cell cancer, glioblastoma, breast cancer (eg HER2-positive breast cancer), lung cancer (eg non-small cell lung cancer), chronic lymphocytic leukemia and acute myeloid leukemia. Other illustrative suitable types of cancer are identified, for example in Vogelsteinet al. (2013) Science 339:1549–58, which is incorporated herein by reference in its entirety.

Because many checkpoint inhibitor therapies rely on persistent expression of tumor-associated antigens, regular boosters of the treatments are required for effectiveness and to “re-stimulate” reactive T cell populations. The inducible nature of the neoantigens described herein, which are produced by the action of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, provides therapeutic regimens administrations that can be designed to enhance the immune response of neoantigen-reactive T cells while limiting T cell exhaustion often caused by chronic antigen stimulation. For example, in some embodiments, an initial dose of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is administered to a subject to trigger aberrant splicing and production neoantigenic peptides. In some embodiments, after a period of time necessary for protein production and antigen presentation, the subject is then administered an initial dose of a checkpoint inhibitor to stimulate and/or enhance the priming and expansion of effector T cells. In some embodiments, the wait period between doses of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and a checkpoint inhibitor is approximately 2. about 3, about 4, about 5, about 6 or about 7 days. In some embodiments, the waiting period is from about 3 days to about 5 days.

In some embodiments, the checkpoint inhibitor specifically targets CTLA4, OX40, CD40, and/or GITR. In some embodiments, the therapeutic effect of a combination of a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and a checkpoint inhibitor may be additive or superadditive.

In some embodiments, administration of a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof is initiated prior to administration of the checkpoint inhibitor.

In some embodiments, administration of a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof is initiated after administration of the checkpoint inhibitor.

In some embodiments, administration of a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is initiated simultaneously with administration of the checkpoint inhibitor, for example, in a single compounded product or in separate compounded products administered in a single procedure.

In some embodiments, after a period of time necessary for T cell priming and expansion, the subject is then administered a second or subsequent dose of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va ) and/or pharmaceutically acceptable salts thereof, to trigger re-presentation of neoantigenic peptides. In some embodiments, the lag period between the initial dose of the checkpoint inhibitor and the second or subsequent dose containing a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/ or pharmaceutically acceptable salts thereof, is about 2, about 3, about 4, or about 5 weeks. In some embodiments, the waiting period is approximately 3 weeks. In some embodiments, after a second or subsequent dose of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, the immune system may be contacted with neoantigen presenting tumor cells and/or cause the destruction of tumor cells. In some embodiments, the subject is then administered a second or subsequent dose of the checkpoint inhibitor to further expand the effector memory T cell population after secondary priming and expansion of the T cells has been achieved.

In some embodiments, a waiting period between an initial dose containing a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, and a second or a subsequent dose of the checkpoint inhibitor is about 2, about 3, about 4, or about 5 weeks. In some embodiments, the waiting period is approximately 3 weeks.

In some embodiments, administering dosages containing a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, according to this exemplary starting regimen treatment can be “pulsating”, i.e. e. a therapeutically effective amount of at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof can be administered in dosages at long intervals (e.g. approximately every 4 weeks, approximately every 5 weeks, approximately every 6 weeks) to promote antigen presentation, recruitment of T cells, and/or killing of tumor cells, and/or restoration of the memory T cell population. In some embodiments, at later times, treatment with a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof can be combine with one or more checkpoint inhibitors that specifically target by restoring effector function to exhausted T cell populations. For example, in some embodiments, at later times, treatment with at least one compound selected from compounds of Formulas I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof may be combined with one or more checkpoint inhibitors targeting PD1/PDL1, LAG3 and/or TIM3. In some embodiments, the pulsatile nature of neoantigen presentation and priming may provide administration of a checkpoint inhibitor and/or at least one compound selected from Compounds I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable compounds thereof salts, less frequently and/or at lower doses. In some embodiments, the pulsatile nature of neoantigen presentation may provide one or more beneficial treatment effects for a checkpoint inhibitor (e.g. anti-CTLA4 antibodies, such as ipilimumab) compared to a checkpoint inhibitor administered without concomitant administration of a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/ or pharmaceutically acceptable salts thereof, for example, by reducing the potential risk of adverse reactions often observed with standard checkpoint inhibitor administration regimens.

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 negatively regulates immune responses. CTLA4 is constitutively expressed on regulatory T cells, but its expression is increased in conventional T cells only after activation. As used herein, the term “CTLA4 inhibitor” is intended to refer to any inhibitor of CTLA4 and/or the CTLA4 pathway. Exemplary CTLA4 inhibitors include, but are not limited to, anti-CTLA4 antibodies. CTLA4 blocking antibodies for use in humans were developed based on preclinical activity observed in mouse models of antitumor immunity. 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. Cm., for example Phanet al. (2003) Proc Natl Acad Sci USA. 100:8372-7; Ribaset al. (2005) J Clin Oncol. 23:8968-77; Weberet al. (2008) J Clin Oncol. 26:5950-6. In some embodiments, the anti-CTLA4 antibody is ipilimumab.

In certain embodiments, the checkpoint inhibitor is an inhibitor of the programmed cell death protein 1 (PD1) pathway. The programmed cell death protein 1 (PD1) pathway represents a master immune control switch that can be recruited by tumor cells to overcome active T cell immune surveillance. Ligands for PD1 (PDL1 and PDL2) are constitutively expressed or can be induced in various tumors. High levels of PDL1 (and to a lesser extent PDL2) expression on tumor cells have been found to correlate with poor prognosis and poor survival in various other types of solid tumors. Additionally, PD1 has been suggested to control the proliferation of tumor-specific T cells in patients with malignant melanoma. These observations suggest that the PD1/PDL1 pathway plays a critical role in tumor evasion from immune recognition and may be an attractive target for therapeutic intervention. The term “PD1 inhibitor” as used herein is intended to refer to 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, the checkpoint inhibitor is an anti-PD1 antibody. Exemplary anti-PD1 antibodies include, but are not limited to, nivolumab and pemprolizumab (MK-3475). Nivolumab, for example, is a fully human immunoglobulin G4 (IgG4)-based anti-PD1 immune checkpoint inhibitor antibody that disrupts the interaction of the PD1 receptor with its ligands PDL1 and PDL2, thereby providing inhibition of the cellular immune response (Guo et al. (2017) ) J Cancer 8(3):410-6). In some embodiments, the anti-PD1 antibody is nivolumab. Pembrolizumab, for example, is a potent and highly selective humanized IgG4/kappa mAb designed to directly block the interaction between PD1 and its ligands: PDL1 and PDL2. Pembrolizumab significantly increases T cell-mediated immune responses in cultured blood cells from healthy human donors, cancer patients, and nonhuman primates. Pembrolizumab has also been reported to modulate 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. Atezolizumab, for example, is a humanized IgG1 mAb that has been reported to block the PD1/PDL1 interaction by targeting expressed PDL1 on various types of malignant cells. This blockage 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.

In certain embodiments, the checkpoint inhibitor specifically targets PD1/PDL1, CTLA4, OX40, CD40, LAG3, TIM3, GITR, and/or KIR. In certain embodiments, the checkpoint inhibitor specifically targets CTLA4, OX40, CD40, and/or GITR. In certain embodiments, the checkpoint inhibitor is targeted as an inhibitory antibody or other such inhibitory molecule (e.g. inhibitory antibody to CTLA4 or PD1/PDL1). In other certain embodiments, the checkpoint inhibitor has a targeted effect as an agonist for a target; examples from this class include molecules that stimulate OX40, CD40 and/or GITR targets. In some embodiments, a checkpoint inhibitor that targets OX40, CD40, and/or GITR is an agonist antibody. Agonist antibodies directed against OX40 may serve a dual role: inhibiting suppression by regulatory T cells while enhancing the functions of effector T cells. Agonist antibodies to GITR have also been shown to make effector T cells more resistant to inhibition induced by regulatory T cells (Karakiet al. (2016) Vaccines (Basel) 4(4):37). Similarly, agonist antibodies to CD40 demonstrate T cell-dependent antitumor activity. Activation of CD40 on dendritic cells increases the cross-presentation of tumor antigens and hence the number of activated effector T cells directed to the tumor (Ellmarket al. (2015) Oncoimmunol. 4(7):e1011484).

In certain embodiments, the checkpoint inhibitor specifically targets CTLA4 (e.g. is an antibody to CTLA4). In certain embodiments, targeting CTLA4 facilitates the priming and activation of naïve T cells. In certain embodiments, the checkpoint inhibitor specifically targets OX40 (e.g. is an antibody to OX40). In certain embodiments, targeting OX40 enhances the expansion of effector T cells. In certain embodiments, the checkpoint inhibitor specifically targets CD40 (e.g. is an antibody to CD40). In certain embodiments, targeting CD40 inhibits “tolerogenic” T cell priming and/or generation of regulatory T cells. In certain embodiments, the checkpoint inhibitor specifically targets GITR (eg, is an anti-GITR antibody). In certain embodiments, targeting GITR suppresses the activity of regulatory T cells. In certain embodiments, the beneficial effect of combination therapy (e.g. effect on at least one symptom or risk/rate of disease progression), comprising a therapeutically effective amount of at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/ or pharmaceutically acceptable salts thereof, and the agent targeting CTLA4, OX40, CD40 and/or GITR is additive. In some embodiments, the beneficial effect of a combination therapy comprising a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and An agent that specifically targets CTLA4, OX40, CD40 and/or GITR is superadditive (i.e. e. synergistic).

Checkpoint inhibitor-based treatment strategies are based on the hypothesis that treatment facilitates and/or enhances T cell priming in tumor responses that are characterized by weak or insufficient antigenicity (e.g. CTLA4), or that treatment restores and/or enhances T cells that respond to tumor antigens but are “exhausted” due to persistent antigen presentation (eg, PD1, PDL1) (Chen and Mellman (2013) Immunity 39(1):1-10). Examples of suitable therapies and agents for checkpoint inhibition, for example, antibodies to PD1, PDL1 or CTLA4 are known in the art. Cm., for example WO 2001/014424 WO 2013/173223, WO 2016/007235.

Combining these responses by primed T cells following checkpoint inhibitor therapy with treatment to induce the formation of neoantigens in tumor cells (e.g., by administering a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e , IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof) to which the primed immune system can respond may provide beneficial synergy. Since neoantigens formed by the action of compounds selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts have not yet been presented for priming T cells, combination with an inhibitor CTLA4 may be particularly beneficial. In some embodiments, treatment comprises administering a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, to induce the production of neoantigens, and also the initial administration of a CTLA4 inhibitor to stimulate CD8 T cell priming, administered before, concurrently, or after this administration. In some embodiments, the patient is given additional administrations of a CTLA4 inhibitor, for example, to further stimulate the priming and/or activation of neoantigen-reactive CD8 populations. In some embodiments, additional administration to the patient of a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable compounds thereof may be performed to increase neoantigen presentation to the tumor. salts Repeated administrations of a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and the checkpoint inhibitor therapy can occur simultaneously or using time-spaced intervals. In some embodiments, treatment further includes co-treatment with a PD1/PDL1 inhibitor, for example, to restore effector function of exhausted neoantigen-targeting T cells within the tumor microenvironment.

As used herein, the terms “combination” or “combination therapy” refer to the administration of a therapeutically effective amount of at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts, together with an additional agent or therapy (for example, checkpoint inhibitor, cytokine or cytokine analog, neoantigen vaccine, CAR-T), as part of a treatment regimen designed to provide a beneficial (i.e. e. additive or synergistic) effect from the combined action of one or more administered agents. In some embodiments, the combination may also include one or more additional agents, including, but not limited to, chemotherapeutic agents, anti-angiogenesis agents, and agents that reduce immune suppression (eg, second checkpoint inhibitor). The beneficial effect of the combination includes, but is not limited to, the pharmacokinetic or pharmacodynamic synergies provided by the combination of therapeutic agents. Administration of such therapeutic agents in combination is typically carried out over a period of time (eg, minutes, hours, days or weeks depending on the combination chosen).

As used herein, the terms administered “in combination” or “co-administered” mean that two or more different treatments are delivered to a subject over a period of time during which the subject suffers from a medical condition (eg, cancer or neoplastic disorder) in any order. For example, in some embodiments, two or more treatments are delivered after a subject has been diagnosed with a disease or disorder and before the disease or disorder has been treated or eliminated, or when the subject has been identified as being at risk for developing it, but before how the subject developed symptoms of the disease. In some embodiments, one treatment is still being delivered when delivery of the second treatment begins, so that overlap is present. In some embodiments, delivery of the first and second treatments begins at the same time. These types of delivery are sometimes referred to herein as “simultaneous,” “joint,” or “concurrent” delivery. In other embodiments, delivery of one treatment ends before delivery of the second treatment begins. This type of delivery is sometimes referred to herein as “rolling” or “sequential” delivery.

In some embodiments, two treatments (eg, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and a checkpoint inhibitor) are contained in the same composition. Such compositions can be administered in any suitable form and via any suitable route. In other embodiments, two treatments (eg, at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and a checkpoint inhibitor) is administered in separate compositions in any suitable form and by means of any suitable way. For example, in some embodiments, a composition comprising a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and a composition containing checkpoint inhibitor, can be administered simultaneously or sequentially in any order at different time points; in any case, they should be administered close enough in time to provide the desired therapeutic or prophylactic effect.

In embodiments involving either simultaneous or sequential delivery, treatment may be more effective due to combined administration. In some embodiments, the first treatment is more effective for example, an equivalent effect is observed with less of the first treatment (e.g. at a lower dose) than would be observed if the first treatment was administered in the absence of the second treatment. In some embodiments, the first treatment is more effective such that the reduction in the severity of a symptom or other parameter associated with the disease or disorder is greater than would be observed if the first treatment were delivered in the absence of the second treatment. In other embodiments, a similar situation is observed for the second treatment. In some embodiments, the beneficial effect of combination therapy (eg, the effect on at least one symptom or risk/rate of disease progression) is additive. In some embodiments, the benefit of the combination therapy is superadditive.

In some embodiments, the present invention provides a method of treating cancer in a subject in need thereof and/or in a subject who has or is suspected of having a neoplastic disorder by administering to the subject a therapeutically effective amount of at least one compound selected from the compounds formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof; and at least one additional therapy (eg, checkpoint inhibitor, cytokine or cytokine analogue therapies, neoantigen vaccine, CAR-T). In some embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof induces the formation of at least one neoantigen and/or the development T cell response. In some embodiments, administration of a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof induces an immune response to the double-stranded RNA. In some embodiments, administration of a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof induces immunogenic cell death. In some embodiments, the at least one additional therapy may include 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 compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof may be administered in combination with two types checkpoint inhibitor-based therapies, i.e. e. using two different checkpoint inhibitors. In certain other embodiments, at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof may be administered in combination with a control inhibitor therapy. points and neoantigen vaccine.

In some embodiments of the combination therapy, the administered amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional the therapeutic agent is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% relative to the standard dosage of at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional therapy. In some embodiments, the frequency of administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional therapy at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% less than the standard dosing regimen of at least one compound selected from the compounds formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least one additional therapy. In some embodiments, the administered amount and/or dosage of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or at least single additional therapy results in lower systemic toxicity and/or improved tolerability.

In some embodiments, administration of a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof is initiated prior to administration of at least one additional means of therapy. In some embodiments, administration of a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is initiated after administration of at least one additional means of therapy. In some embodiments, administration of a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is initiated simultaneously with administration of at least one additional means of therapy.

In some embodiments, administration of a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is repeated at least once after the initial introduction. In some embodiments, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof used for repeated administration is reduced relative to the amount used for initial introduction. In some embodiments, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof used for repeated administration is reduced relative to the standard dosage by at least at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof used for repeated administration is reduced by 10%, 15 %, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% relative to the unit dosage of at least one compound selected from compounds of formula I (including formulas IIa-e , IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof.

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

In some embodiments, repeated administration of a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is carried out simultaneously with repeated administration of at least at least one additional therapy. In some embodiments, repeated administration of a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is carried out sequentially or spaced out over time. with repeated administration of at least one additional therapy.

In some embodiments, the present invention provides a method of treating cancer in a subject in need thereof and/or in a subject who has or is suspected of having a neoplastic disorder by administering to the subject a therapeutically effective amount of at least one compound selected from the compounds formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof; and checkpoint inhibitor-based therapies. In some embodiments, the checkpoint inhibitor therapy comprises administering at least one checkpoint inhibitor. In some embodiments, a subject is intolerant, unresponsive, or deficient in responsiveness to at least one checkpoint inhibitor when administered alone. In some embodiments, a subject may be considered to be refractory or deficient in receptivity to at least one checkpoint inhibitor, as determined by using, for example, immune-related response criteria to immunotherapy (irRC) and/or immune-related response evaluation criteria to immunotherapy in solid tumors (irRECIST). Cm., for example, Wolchoket al. (2009) Clin Cancer Res. 15(23):7412-20; Bohnsacket al. "Adaptation of the Immune-Related Response Criteria:irRECIST" (Abstract 4958) ESMO 2014. Illustrative criteria may include criteria used in the prior art to determine when tumors in patients with cancer improve ("response") remain the same (“stabilization”) or worsens (“progression”) during treatment if the treatment being evaluated is an immune antineoplastic drug (e.g. checkpoint inhibitor). In some embodiments, a subject may be considered intolerant to at least one checkpoint inhibitor if the subject experiences one or more than one adverse (Grade 2+) event identified for the corresponding checkpoint inhibitor (e.g., ipilimumab). For example, in some embodiments, a subject may be considered intolerant to an ipilimumab-based treatment if the subject experiences one or more adverse events selected from enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy (Yervoy ® (ipilimumab) FDA Compliant Labeling Supplement, 2018).

In some embodiments, the checkpoint inhibitor specifically targets PD1/PDL1, CTLA4, OX40, CD40, LAG3, TIM3, GITR, and/or KIR. In some embodiments, the checkpoint inhibitor specifically targets CTLA4, OX40, CD40, and/or GITR. In some embodiments, targeting of the checkpoint inhibitor is provided by an inhibitory antibody or other such inhibitory molecule. In some other embodiments, the checkpoint inhibitor is targeted as an agonist antibody or other such agonist molecule. In some embodiments, the checkpoint inhibitor comprises an inhibitor of the cytotoxic T lymphocyte-associated antigen 4 (CTLA4) pathway. In some embodiments, the CTLA4 inhibitor is an anti-CTLA4 antibody. In some embodiments, the anti-CTLA4 antibody is ipilimumab. In some embodiments, the checkpoint inhibitor comprises an inhibitor of the programmed cell death protein 1 (PD1) pathway. In some embodiments, the PD1 inhibitor is an anti-PD1 antibody. In some embodiments, the anti-PD1 antibody is nivolumab. In some embodiments, the PD1 inhibitor is an anti-PDL1 antibody. In some embodiments, the anti-PDL1 antibody is atezolizumab. In some embodiments, the checkpoint inhibitor includes a CTLA4 inhibitor and a PD1 inhibitor. In some embodiments, the checkpoint inhibitor specifically targets OX40. In some embodiments, the checkpoint inhibitor specifically targets CD40. In some embodiments, the checkpoint inhibitor specifically targets GITR. In some embodiments, the beneficial effect of combination therapy (eg, effect on at least one symptom or risk/rate of disease progression), comprising a therapeutically effective amount of at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/ or pharmaceutically acceptable salts thereof, and a checkpoint inhibitor (e.g. an antibody or molecule targeting CTLA4, PD1/PDL1, OX40, CD40 and/or GITR) is additive. In some embodiments, the beneficial effect of a combination therapy comprising a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and checkpoint inhibitor (eg. An antibody or molecule that specifically targets CTLA4, PD1/PDL1, OX40, CD40, and/or GITR is superadditive (i.e. e. synergistic).

In some embodiments, the present invention provides a method of treating cancer in a subject in need thereof and/or in a subject who has or is suspected of having a neoplastic disorder by administering to the subject a therapeutically effective amount of at least one compound selected from the compounds formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof; and cytokine or cytokine analogue therapies. In some embodiments, the cytokine or cytokine analogue therapy comprises administering at least one cytokine or cytokine analogue. In some embodiments, a subject is intolerant, unresponsive, or deficient in responsiveness to at least one cytokine or cytokine analog when administered individually.

In some embodiments, the cytokine or cytokine analog provides a T cell enhancer. In some embodiments, the cytokine or cytokine analogue includes IL-2, IL-10, IL-12, IL-15, IFNγ and/or TNFα. In some embodiments, the cytokine or cytokine analogue includes IL-2, IL-10, IL-12 and/or IL-15. In some embodiments, administration of a cytokine or cytokine analog enhances T cell priming following administration of a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically thereof acceptable salts, due to inducing the formation and presentation of neoantigens.

In some embodiments, the cytokine or cytokine analogue comprises IL-2. In some embodiments, IL-2 enhances signals in effector cells to promote their proliferation (Rosenberg (2014) J Immunol. 192(12):5451-8). In some embodiments, the cytokine or cytokine analogue comprises IL-10. In some embodiments, IL-10 enhances the priming and activation of CD8+ T cells (Mumm et al. (2011) Cancer Cell 20(6):781-96). In some embodiments, the cytokine or cytokine analogue comprises IL-12. In some embodiments, IL-12 couples the innate and adaptive immune responses to enhance antigen-specific priming and targeting (Tugues et al. (2015) Cell Death Differ. 22(2):237-46). In some embodiments, the cytokine or cytokine analogue comprises IL-15. In some embodiments, IL-15 enhances the priming and/or activation of effector T cells (CD8). In some embodiments, the cytokine or cytokine analogue comprises IFNγ. In some embodiments, IFNγ complements the secretion of IFNγ by effector T cells. In some embodiments, the cytokine or cytokine analogue comprises TNFα. In some embodiments, TNFα complements the secretion of TNFα by effector T cells.

In some embodiments, an initial dose containing a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof is administered to a subject to trigger an aberrant splicing and production of neoantigenic peptides. In some embodiments, after a period of time necessary for protein production and antigen presentation, the subject is then administered an initial dose of a cytokine or cytokine analog to enhance and/or improve the priming and expansion of effector T cells. In some embodiments, the wait period between doses of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and a cytokine or cytokine analog is approximately 2 , about 3, about 4, about 5, about 6 or about 7 days. In some embodiments, the waiting period is from about 3 days to about 5 days. In some embodiments, the cytokine or cytokine analogue is IL-2, IL-10, IL-12, IL-15, IFNγ and/or TNFα. In some embodiments, the therapeutic benefit of a combination comprising at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and a cytokine or analog cytokine, may be additive or superadditive.

In some embodiments, after a period of time necessary for T cell priming and expansion, the subject is then administered a second or subsequent dose containing a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, to trigger re-presentation of neoantigenic peptides. In some embodiments, the lag period between an initial dose of a cytokine or cytokine analog and a second or subsequent dose containing a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and /or pharmaceutically acceptable salts thereof, is about 2, about 3, about 4 or about 5 weeks. In some embodiments, the waiting period is approximately 3 weeks. In some embodiments, subsequent doses of a cytokine or cytokine analogue may be administered, for example, interspersed with subsequent doses containing a therapeutically effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, following administration of a second or subsequent dose containing a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, immune the system can contact neoantigen-presenting tumor cells and/or cause the destruction of tumor cells. In some embodiments, administering dosages containing a therapeutically effective amount of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, according to this exemplary starting regimen treatment can be “pulsating”, i.e. e. at least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof can be administered in dosages at long intervals (e.g. approximately every 4 weeks, approximately every 5 weeks, approximately every 6 weeks) to promote antigen presentation, recruitment of T cells, and/or killing of tumor cells, and/or restoration of the memory T cell population.

In some embodiments, the subject has a mutational load with nonsynonymous changes of approximately 150 mutations or less. In some embodiments, the subject has a mutational load with nonsynonymous changes of approximately 100 mutations or less. In some embodiments, the subject has a mutational load with nonsynonymous changes of approximately 50 mutations or less. In some embodiments, the subject has a neoplastic disorder, for example, or is suspected of having a hematological malignancy or solid tumor. In some embodiments, the hematologic malignancy is selected from B-cell malignancy, leukemia, lymphoma, and myeloma. In some embodiments, the hematologic 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.

In some embodiments, the subject is in need of a method of treating cancer. In some embodiments, the cancer is a hematologic malignancy or solid tumor. In some embodiments, the hematologic malignancy is selected from B-cell malignancy, leukemia, lymphoma, and myeloma. In some embodiments, the hematologic 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. In some embodiments, a patient who has a cancer described herein can be treated with a combination of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/ or pharmaceutically acceptable salts thereof, and a neoantigen vaccine. Without being limited by theory, vaccines used alone or in combination with immune checkpoint inhibitor (ICI) molecules have shown promise in early phase clinical studies (Ott et al. (2017) Nature 547(7662):217- 21; Sahin et al. (2017) Nature 547(7662):222-6), but usually requires sequencing of mutations in the patient's tumor (Ott et al. (2017) Nature 547(7662):217-21; Aldous and Dong (2018) Bioorg Med Chem 26(10):2842-9). Thus, the effectiveness of vaccines often depends on sufficient numbers of nonsynonymous mutations that are antigenic. In general, tumors with a very low mutational load have a small number of candidate antigens, and in the case of tumors with rapid growth, there is limited time to identify and obtain patient-specific vaccines.

To date, attempts to develop vaccines that have broad immunogenicity coverage for a large percentage of patients have focused on proteins that are either frequently mutated, ectopically overexpressed or amplified, and/or that exist as “self” proteins in the body. In addition, these proteins are often expressed in tissues that are not affected by the immune system (e.g. neuronal markers expressed in neuroendocrine tumor types), while other proteins may be normally expressed during embryogenesis (e.g. cancer embryonic antigens). Thus, the utility of vaccines using such proteins as antigens is often limited to specific tumor lineages or subgroups in which one or more antigens are present. The vaccine's usefulness will also need to be confirmed by sequencing patient tumor samples, which can be time-consuming.

Moreover, if such antigens exist as “self” proteins, the immune system is likely to be primed to recognize such proteins as “self” and thus will not respond. Or, alternatively, if the immune system is able to mount an effector response to such antigens, it may result in target-related side effects in tissues where the antigen may be expressed. In both of these cases, one of the key problems is that most antigenic peptides are derived from passenger genes (i.e. i.e. genes that are mutated or amplified during tumorigenesis, but do not play a critical role in the long-term survival or proliferation of the tumor itself). For this reason, these genes can be silenced without significant consequences for tumor progression and thus may allow the tumor to “escape” the immune response to these antigens. Without wishing to be bound by theory, this mechanism may play a role in tumor evolution, in which random mutations that are highly antigenic are often subject to tumor selection during the early stages of tumorigenesis (Dunnet al. (2004) Annu. Rev. Immunol. 22:329-60).

In addition, some evidence also indicates that constant antigen presentation and immune stimulation can lead to anergy and exhaustion of immune cells (Pardoll (2012) Nat. Rev. Cancer 12(4):252-64). Such phenotypes underlie the therapeutic rationale for currently used ICI-based therapies, as ICIs have been shown to either curb the immune cell exhaustion phenotype (α-PD1/PD-L1) or facilitate additional immune cell responses (α-CTLA4 ). Notably, for the α-CTLA4-based therapy, it was reported that a subset of patients exhibited serious immune-related adverse events, which may be due to the promotion of T-cell activation and disruption of immune tolerance mechanisms that limit autoreactive immune responses.

Both of these approaches (i.e. e. initiation or enhancement of de novo immune responses to neoantigens or reactivation upon anergy or exhaustion of existing immune responses) are associated with persistent activation of the immune system. In this regard, these approaches are sensitive to anergy, editing and other tumor-mediated mechanisms aimed at suppressing immune system involvement.

In contrast, treatment with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof can induce an immune response to novel sequences representing neoantigens. In some embodiments, the presentation of neoantigens provides the adaptive immune system with more diverse targets with which it contacts and is activated. In some embodiments, the ability of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof to clearly induce alternative splicing, and the resulting neoantigens can reduce the risk of immune system fatigue due to chronic exposure to neoantigens caused by mutations and/or limit the ability of tumor cells to adapt to evade therapy. In some embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, in combination with a neoantigen vaccine, enhances the immune response to neoantigens, produced by the action of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is administered before, during or after vaccination. In some embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or the vaccine can be administered once or more than once during the course of treatment. In some embodiments, the vaccine is administered once, and at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is administered more than once during course of treatment. In some embodiments, the vaccine is administered once, followed by one or more booster doses over the course of treatment.

As used herein, the term “neoantigen vaccine” refers to a combined sample of one or more immunogenic neoantigen peptides or mRNA, eg, at least two, at least three, at least four, at least five, or more neoantigen peptides. The term "vaccine" refers to a composition for developing immunity for the prevention and/or treatment of a disease (for example, neoplastic disorder, e.g. hematologic malignancy or solid tumor). Accordingly, vaccines are medicinal preparations that contain immunogenic agents and are intended for use in humans or animals for the development of specific immune defense mechanisms and the formation of protective substances after vaccination. The neoantigen vaccine may further include a pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.

As used herein, the term "immunogenic" refers to any agent or composition that can induce an immune response, for example, T cell response. The immune response may be mediated by an antibody, or a cell, or both.

In some embodiments, the patient is administered at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and is then administered a peptide or mRNA vaccine based on a known neoantigen for enhancing the immune response to neoantigens produced under the influence of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some other embodiments, the patient is administered at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and is screened for neoantigens produced in result of treatment. Therefore, one or more of these neoantigens are used to create a personalized vaccine that is administered to the patient. In any of these embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or a peptide or mRNA vaccine can be administered patient once or several times.

In some embodiments, a suitable neoantigen for a vaccine may be identified by screening a panel of altered splicing and persistently expressed transcripts obtained from one or more patient tissue samples (e.g. from tumor biopsy). In some embodiments, protein variant sequences are identified in a screened sample based on translation along a junction in the aberrantly spliced mRNA, while retaining portions of the protein sequence (no more than 12 amino acids) flanking the amino acid changes spanning the junction. In some embodiments, these compound-spanning peptide fragments are screened for high binding affinity to MHC1 alleles, for example, using a tool such as NetMHC1 (Nielsenet al. (2003) Protein Sci 12(5):1007–17; Andreatta and Neilsen (2016) Bioinformatics 32(4):511-7). These results allow the filtering of neopeptides to neopeptides predicted to bind with high affinity to the HLA allele composition unique to a patient, as well as the collection of pools of neopeptides predicted to bind to a wide range of HLA alleles present at high frequency in different populations (Maierset al. (2007) Hum Immunol 68(9):779–88). In some embodiments, the identified neopeptides are then formulated into a vaccine, for example by association with a suitable carrier or adjuvant (Ottet al. (2017) Nature 547(7662):217-21), or for delivery as mRNA (Sahinet al. (2017) Nature 547(7662):222-6).

In some embodiments, the selected neoantigen is based on a screening result of an individual patient's tumor response to at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, with the identification of one or more treatment-derived neoantigens for use in subsequent vaccination. In other embodiments, the neoantigen is selected for example, based on screening a panel of samples obtained from different patients to identify common neoantigens produced by at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts, and then used as a universal vaccine for future patients.

Without being limited by theory, in some embodiments, the use of a universal neoantigen vaccine will avoid the need to sequence and analyze the unique mutational status of each patient's tumor, since the selected neoantigens are not dependent on the mutation in the tumor, but rather mimic the neoantigen produced by at least one compound, selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and generally recognized by the body as foreign. Additionally, in some embodiments, the use of a neoantigen vaccine may be particularly effective because the patient's tumor cells may be more likely to mutate without producing one or more neoantigens that are dependent on the mutation in the tumor, compared to cells that mimic the neoantigen produced under by the action of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. This may provide the opportunity to formulate a core vaccine that has broad immunogenicity coverage for a large percentage of patients, speeding up initiation of treatment regimens. Patients can be vaccinated according to the schedules set forth herein and, before the next completion of vaccination, can be further treated with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/ or pharmaceutically acceptable salts thereof, for example, to induce the expression of neoantigenic peptides. In some embodiments, patients may be administered at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof, prior to, concurrently with, or subsequent to vaccination. . In some embodiments, patients are administered at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof that have been screened for one or more neoantigens found in a panel of universal neoantigens, and are vaccinated with a universal neoantigen vaccine containing at least one universal neoantigen identified in the subject. In some embodiments, patients may be administered at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof one or more times after vaccination. The compound(s) selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or the vaccine can be administered once or more than once during the course of treatment.

In some embodiments, the vaccine may contain one or more neoantigen peptides or mRNA. In some embodiments, the vaccine contains one or more long neoantigen peptides. In some embodiments, such "long" neoantigen peptides undergo efficient internalization, processing, and cross-presentation in specialized antigen-presenting cells, such as dendritic cells. Likewise, long vaccine peptides have been shown in other contexts to induce cytotoxic T cells in humans (Melief and van der Burg (2008) Nat Rev Cancer 8(5):351-60). In some embodiments, the neoantigenic peptide is extended to include the neoantigenic peptide sequence itself in addition to flanking amino acid sequences. In some embodiments, the extended peptide sequence facilitates uptake of the protein by antigen presenting cells, for example, dendritic cells. In some embodiments, the extended peptide sequence allows for efficient antigen presentation and T cell priming in different HLA isotype models. In some embodiments, a longer neoantigen peptide and/or an extended peptide sequence exhibits increased uptake by antigen presenting cells (e.g. dendritic cells), increased antigen presentation and/or increased T cell priming compared to a shorter neoantigen peptide and/or a shorter peptide sequence (e.g. with a peptide sequence that is less than about 10 or less than about 5 amino acids in length). In some embodiments, the length of the long neoantigen peptide ranges from about 5 to about 50 amino acids. In some embodiments, the length of the long neoantigen peptide ranges from about 10 to about 50 amino acids. In some embodiments, the length of the at least one neoantigen peptide ranges from about 10 to about 35 amino acids. In some embodiments, the length of the long neoantigen peptide ranges from about 15 to about 25 amino acids.

In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 10 to about 35 amino acids. In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 15 to about 25 amino acids. In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 10 to about 20 amino acids. In some embodiments, the neoantigenic sequence and/or antigenic moiety does not directly overlap with the canonical peptide sequence (e.g. any of the illustrative canonical peptide sequences underlined in Table 3) or does not consist of it.

The amino acid sequences of exemplary long neoantigenic peptides are presented in Table 3.

These exemplary neoantigenic peptides are generated following administration of ADCs containing pladienolide-based splicing modulators, however, given a similar mechanism of action (i.e. e. similar splicing modulation mechanisms), similar neoantigenic peptides can be obtained by the action of compounds selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof.

Table 2. Neopeptides Neopeptide SEQ ID NO Connection (HG19) Gene Event type Observed in 1 SPTLPPRSL 1 chr12:49663470-49663610:+ TUBA1C Intron retention H1568 2 HPSIKRGLSSL 2 chr12:42729776-42781257:+ PPHLN1 Exon skipping H1568 3 LLLPHHVL 3 chr12:49663470-49663610:+ TUBA1C Intron retention H1568 4 RTAPGVRPPF 4 chr14:35182767-35183743:- CFL2 Intron retention H1568 5 RPQKSIQAL 5 chr10:28822963-28823162:+ WAC Intron retention H1568 6 APAPPPLPA 6 chr17:80009840-80011149:+ GPS1 Intron retention H1568 7 RPRPSFPVSL 7 chr7:55087058-55134942:+ EGFR Intron retention H1568 8 RPKHGDGFSL 8 chr11:57472287-57472444:- MED19 Intron retention H1568 9 GPAPGKTGL 9 chr7:75932393-75933118:+ HSBP1 Intron retention H1568 10 EAARKGNSL 10 chr1:53480715-53504588:+ SCP2 Exon skipping H1568 eleven RIKEKIEEL eleven chr9:72897499-72912881:+ SMC5 Exon skipping H1568 12 EIKKRFRQF 12 chr1:28531860-28541450:- DNAJC8 Exon skipping H1568 13 HESAAMAET 13 chr11:102272937-102323254:- TMEM123 Exon skipping HCC1954 14 ALKLKQVGV 14 chr1:153610924-153617539:+ CHTOP Exon skipping H1568 15 DLKKRHITF 15 chr13:41323417-41331008:- MRPS31 Exon skipping H1568 16 DVKRNDIAM 16 chr1:41213277-41218822:+ N.F.Y.C. Exon skipping H1568 17 IPSDHILTPA 17 chr6:149718900-149720239:+ TAB2 Exon skipping H1568 18 TVFSTSSLK 18 chr11:61197654-61213412:+ SDHAF2 Exon skipping H1568 19 ITSCLLNF 19 chr5:137892555-137893090:- HSPA9 Intron retention H1568 20 RASPVRGQL 20 chr7:75677544-75677893:+ MDH2 Intron retention H1568 21 VVRKPVIAL 21 chr1:36923582-36929406:- MRPS15 Exon skipping H1568 22 LLSEKKKIS 22 chr6:31750622-31750872:- VARS Intron retention H1568 23 APASKPRPRL 23 chr19:3573798-3574380:+ HMG20B Intron retention H1568 24 RYGQLSEKF 24 chr19:33076813-33078158:+ PDCD5 Exon skipping HCC1954 25 VYISNVSKL 25 chr3:53920961-53925796:- SELK Exon skipping HCC1954 26 LPTKETPSF 26 chr2:85133241-85133394:+ TMSB10 Alternative splice site at the 3' end HCC1954 27 GEAPPPPPA 27 chr17:80223672-80231181:- CSNK1D Intron retention HCC1954 28 LEEISKQEI 28 chr17:27804724-27807385:+ TAOK1 Exon skipping HCC1954 29 IYNHITVKI 29 chr4:2886393-2896308:+ ADD1 Exon skipping HCC1954

The protein sequences of the twenty-nine neopeptides listed in Table 2 may be extended. The extended protein sequence simultaneously includes the neopeptide sequence itself in addition to flanking amino acid sequences. An extended protein sequence better facilitates protein uptake by dendritic cells and promotes antigen presentation and T cell priming in different HLA isotype models. The amino acid sequences of the twenty-nine extended neopeptides are presented in Table 3.

Table 3. Amino acid sequences of extended neopeptides Gene SEQ ID NO Amino acid sequence of extended neopeptide* TUBA1C thirty VDLEPTVI GELTSVTQVRSQGAGTGGLSWGGSAGHSPTLPPRSLSLLLLPHHVLQMKFALALTASSSTLSNSSQARKMLPITMPEGTTPLARRSLTSCWTEFASWLTSAPVFRASWFSTALVGELVLGSPRCSWNVSQLIMARSPSWSSSPFTRRPRFPQL PPHLN1 31 APPRSHPS IKRGLSSL CFL2 32 MVRRARWPGGRGEARKAPRTAPGVRPPF WAC 33 WVNCLFVSGRAAAGGGGGGAVPPYLELAGPPFLLLTLIRIGLGRRSGRAGGRAGTQCGGERGPGFAAFRPLRPFRRLRVCAVCVRGSALGRSVGLPRGGAAGAPFSSSPAPHPRRVLCRCLLFLFFSCHDRRGDSQPYQVPAEAGVEGLEGAGGGREGLLLERRPQKSIQALRCNTSETSTADPLKIPGLVPLALSSKV GPS1 34 MPLPVQVFNLQVTSRGRPGPPRPRAPRHWGRAEVEQGRGACARSRSGTLRAGPPRAARVGGCRAEGASPPWLRAAIGGRRAAPAPPPLPAAHGRGSRPPPRR EGFR 35 QPAQPRTG APARRPRPRPSFPVSLRSAAPPTGTAGGTGRFVLRPGESGAGGGGDAWDTGLQARRGTAAGTSGAPNRSQLSLTFPAQLRRIGVSGRKPGAGGRLGPGSRTCAPRCLPRARRGPGAHPRGGRCPPAETALFREAEEGTQKYSLPSDPAGQAAF MED19 36 FRLHTGPV SPVGGRRQMGRPKHGDGFSLQVCSFIMEQNG HSBP1 37 GVVEITG EPPCSCRGEEEASRAGRAGGVRLKRGSRGPGELNVGPAPGKTGLLIPLLRNWECGSLLRALSAL SCP2 38 KMGFPEA ARKGNSL SMC5 39 LEARIKEK IEELQQALI DNAJC8 40 EIKKRFRQ FKQAVYKQ TMEM123 41 AHESAAMA ETLQHVPS CHTOP 42 NRPSVQAA LKLKQVGV MRPS31 43 KTDDLKKR HITFTLGCGIC N.F.Y.C. 44 MKLDEDVK RNDIAMAI TAB2 45 NSISQIPS DHILTPALFITFMTILDL SDHAF2 46 TVFSTSSL KLNQPQKYLKMKSWPC HSPA9 47 AEEDRRKK VITSCLLNFNLSKAQS MDH2 48 RSFSTSAQ VGQTRGGLQAEAPRPGPRASPVRGQL MRPS15 49 RGYVVRKP VIALSVKI VARS 50 VDMDFGTG GQGAGPVGRGKDWSCTLAVHLLSEKKKISFSQIDRAWGGSQGTVLDKWGPGVVSELHPSAKEVSVGRNSVESLMTWAS HMG20B 51 EKGSHEEE VRVPALSWGRPRAPAPASKPRPRLDLNCLWLRPQPIFLWKLRPRPVPAATPLTGPLPL PDCD5 52 RYGQLSEK FNRRKVMDS SELK 53 MVYISN VSKLCFSKM TMSB10 54 NTLPTKET PSFLLNPHTSWVPRPHREAPRLRVGVAAPLQRPLPALHSH CSNK1D 55 FGDIYLG EAPPPPPAARRPGPCGCQDQARSRKEVVAPAGSPRKSRHRRIVARTQRPLG TAOK1 56 GSASDLLE EISKQEISF ADD1 57 QLIYNHIT VKINLQGD

*Underline indicates amino acids derived from the open reading frame of the canonical transcript (i.e. e. canonical peptide sequence).

As used herein, “neoantigenic peptide” or “mRNA vaccine” includes the use of a fragment of a neoantigenic peptide or the mRNA encoding it, provided that the fragment retains immunogenic potential.

In some embodiments, the neoantigen vaccine contains at least one neoantigen peptide. In some embodiments, the neoantigen vaccine contains 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, the length of the neoantigen peptide(s) ranges from about 5 to about 50 amino acids. In some embodiments, the length of the neoantigen peptide(s) ranges from about 10 to about 50 amino acids. In some embodiments, the length of the at least one neoantigen peptide ranges from about 10 to about 35 amino acids. In some embodiments, the length of the neoantigen peptide(s) ranges from about 15 to about 25 amino acids.

In some embodiments, the present invention provides a method of treating a subject who has or is suspected of having a neoplastic disorder by administering to the subject an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof; and neoantigen vaccine. A neoantigen vaccine may be for example, a peptide neoantigen vaccine or a neoantigen mRNA vaccine. In some embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is administered prior to administration of the neoantigen vaccine. In some embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is administered following administration of the neoantigen vaccine. In some embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is administered concomitantly with administration of the neoantigen vaccine. In some embodiments, administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is repeated at least once after the initial administration. In some embodiments, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof used for repeated administration is reduced compared to the amount used for initial administration.

In some embodiments, the present invention further provides a combination comprising at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof; and neoantigen vaccine (eg universal neoantigen vaccine) for use in the treatment of a subject who has or is suspected of having a neoplastic disorder. In some embodiments, the neoantigen vaccine is a peptide neoantigen vaccine or a neoantigen mRNA vaccine. In some embodiments, the combination further comprises at least one additional therapy. In some embodiments, 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.

In some embodiments, the present invention further provides a method of treating a subject who has or is suspected of having a neoplastic disorder by (a) administering to the subject an effective amount of at least one compound selected from compounds of formula I (including formulas IIa- e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts; (b) detecting one or more neoantigens in a subject after administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof; (c) comparing one or more neoantigens to a panel of universal neoantigens; and (d) administering to the subject a universal neoantigen vaccine comprising at least one universal neoantigen present in the subject. In some embodiments, a generic neoantigen vaccine is administered alone or in combination with at least one additional therapy. In some embodiments, 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.

In some embodiments, the at least one additional therapy comprises repeated administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, repeated administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is initiated prior to administration of the universal neoantigen vaccine. In some embodiments, rechallenge of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof is initiated following administration of a universal neoantigen vaccine. In some embodiments, reintroduction of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof is initiated simultaneously with administration of the universal neoantigen vaccine. In some embodiments, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof used for repeated administration is reduced compared to the amount used for initial administration. In some embodiments, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof used for initial and/or repeated administration is reduced by compared with a standard dosage of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, when administered in the absence of treatment with a vaccine. In some embodiments, the amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof used for initial and/or repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% compared to the standard dosage of at least one compound selected from the compounds of formula I (in including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts.

In some embodiments, the at least one additional therapy comprises administration of a checkpoint inhibitor (eg, any of the exemplary checkpoint inhibitors described herein). In some embodiments, administration of the checkpoint inhibitor is initiated prior to administration of the universal neoantigen vaccine and/or re-administration of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts. In some embodiments, administration of the checkpoint inhibitor is initiated following administration of a universal neoantigen vaccine and/or a boost of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable compounds thereof. salts In some embodiments, administration of the checkpoint inhibitor is initiated concurrently with administration of a generic neoantigen vaccine and/or repeated administration of at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or their pharmaceutically acceptable salts. In some embodiments, administration of the checkpoint inhibitor is repeated at least once after the initial administration. In some embodiments, the amount of checkpoint inhibitor used for reintroduction is reduced compared to the amount used for initial administration. In some embodiments, the amount of checkpoint inhibitor used for re-administration is reduced compared to a standard dosage of the checkpoint inhibitor. In some embodiments, the amount of checkpoint inhibitor used for re-administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% compared to with a standard dosage of a checkpoint inhibitor. In some embodiments, the subject is intolerant, unresponsive, or deficient in responsiveness to the checkpoint inhibitor when administered alone.

In some embodiments, also provided herein are neoantigen vaccines comprising at least one neoantigen peptide or at least one neoantigen mRNA. In some embodiments, the neoantigen vaccine contains at least one neoantigen peptide. In some other embodiments, the neoantigen vaccine comprises at least one neoantigen mRNA.

In some embodiments, also provided herein are kits comprising at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof; and neoantigen vaccine (eg universal neoantigen vaccine). In some embodiments, the neoantigen vaccine is a peptide neoantigen vaccine or a neoantigen mRNA vaccine. In some embodiments, the kit further contains one or more additional components, including, without limitation: instructions for use; other means, for example, one or more additional therapeutic agents; devices, containers or other materials intended for the production of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or a neoantigen vaccine for therapeutic administration; pharmaceutically acceptable carriers and devices, containers or other materials intended for the administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/ or neoantigen vaccine to the patient. Instructions for use may include guidance for therapeutic applications, including suggested dosages and/or modes of administration, for example, for a patient who has or is suspected of having a neoplastic disorder. In some embodiments, the kit further contains instructions for therapeutic use, for example, the use of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and a neoantigen vaccine for the treatment or prevention of a neoplastic disorder in a patient. In some embodiments, the kit further contains at least one additional therapeutic agent (for example, for administration together with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and a neoantigen vaccine, e.g. checkpoint inhibitor). In some embodiments, at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and/or a neoantigen vaccine is formulated as a pharmaceutical composition.

In some embodiments of the methods and compositions disclosed herein, the neoantigen vaccine contains at least one neoantigen peptide. In some embodiments, the length of the at least one neoantigenic peptide ranges from about 10 to about 50 amino acids. In some embodiments, the length of the at least one neoantigen peptide ranges from about 10 to about 35 amino acids. In some embodiments, the length of the at least one neoantigenic peptide ranges from about 15 to about 25 amino acids.

In some embodiments, the at least one neoantigenic peptide contains one or more neoantigenic sequences disclosed herein.

In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 10 to about 35 amino acids. In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 15 to about 25 amino acids. In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 10 to about 20 amino acids. In some embodiments, the neoantigenic sequence and/or antigenic moiety does not directly overlap with the canonical peptide sequence (e.g. any of or does not consist of the illustrative canonical peptide sequences underlined in Table 3).

In some embodiments, the neoantigenic sequence is a subject-specific neoantigenic sequence. 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.

In some other embodiments, the neoantigen sequence is a generic neoantigen sequence. In some embodiments, the neoantigen sequence is a generic neoantigen vaccine. In some embodiments, the 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 at least 35%, at least 40%, or at least 45% of subjects in a population of subjects suffering from a neoplastic disorder. In some embodiments, the neoantigen sequence is capable of inducing a T cell response to a tumor present in at least 1%, at least 5%, or at least 10% of a population of subjects suffering from a neoplastic disorder.

In some embodiments, the neoantigenic sequence has been identified by sequencing at least one neoantigenic peptide that is induced in a subject by administering an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the at least one neoantigenic peptide comprises a neoantigenic sequence the formation of which is induced by contacting a neoplastic cell with an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the neoplastic cell is in in vitro cell culture. In some embodiments, the neoplastic cell is obtained from a subject. In some embodiments, the neoplastic cell is in the subject.

In some embodiments, the neoantigen vaccine comprises at least one neoantigen peptide or mRNA and a pharmaceutically acceptable carrier. In some embodiments, the neoantigen peptide or mRNA may be attached to a suitable carrier to aid in the development of an immune response. Exemplary carriers for binding to immunogenic agents (e.g. neoantigenic peptide or mRNA) include serum albumin, fisurella hemocyanin, immunoglobulin molecules, thyroglobulin, ovalbumin, tetanus toxoid or toxoid from other pathogenic bacteria, such as the bacteria that cause diphtheria,E. coli, bacteria that cause cholera, orH. pylori, or an attenuated derivative of the toxin. Other carriers for stimulating or enhancing the immune response include cytokines such as IL-1, α- and β-peptides IL-1, IL-2, γINF, IL-10, GM-CSF and chemokines such as M1P1α and β and RANTES . Immunogenic agents can also be coupled to peptides that enhance tissue transport, as described, for example in WO 97/17613 and WO 97/17614. In some embodiments, the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, fisurella hemocyanin, immunoglobulin, thyroglobulin, ovalbumin, toxoid or attenuated toxoid derivative, cytokine, and chemokine.

In some embodiments, the neoantigen peptide or mRNA may be attached to a pharmaceutically acceptable carrier. Immunogenic agents can be attached to carriers by chemical crosslinking. Techniques for coupling an immunogenic peptide to a carrier include the formation of disulfide bonds using N-succinimidyl-3-(2-pyridylthio)propionate (SPDP) and succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC) (if the peptide does not contain sulfhydryl group, this can be done by adding a cysteine residue). These reagents form a disulfide bond between themselves and a cysteine in the peptide located on one protein, and an amide bond through an epsilon amino group on a lysine or another free amino group on other amino acids. A number of such disulfide/amide bond forming agents are described in Jansen et al. ((1982) Immun Rev. 62:185). Other bifunctional coupling agents form a thioether bond instead of a disulfide bond. A variety of these thioester linkage forming agents are commercially available and include reactive esters of 6-maleimidocaproic acid, 2-bromoacetic acid and 2-iodoacetic acid, 4-(N-maleimidomethyl)cyclohexane-1-carboxylic acid. Carboxyl groups can be activated by combining them with succinimide or sodium salt of 1-hydroxyl-2-nitro-4-sulfonic acid. In some embodiments, the neoantigenic peptide and the pharmaceutically acceptable carrier are covalently linked through a linker.

Neoantigen and other such immunogenic peptides may also be expressed as carrier fusion proteins. The immunogenic peptide may be attached at the amino terminus, the carboxy terminus, or at any location within the peptide (internal) to the carrier. In some embodiments, multiple repeats of an immunogenic peptide may be present in the fusion protein. In some embodiments, the neoantigen peptide and the pharmaceutically acceptable carrier are expressed as a fusion protein.

In some embodiments, the neoantigen vaccine contains at least one neoantigen peptide or mRNA encoding the same and a pharmaceutically acceptable diluent. In some embodiments, the neoantigen vaccine comprises at least one neoantigen peptide or mRNA encoding the same and a pharmaceutically acceptable adjuvant (e.g. adjuvant described herein).

In some embodiments of the methods and compositions disclosed herein, the neoantigen vaccine comprises at least one neoantigen mRNA. In some embodiments, the at least one neoantigen mRNA encodes one or more neoantigen sequences.

In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 10 to about 50 amino acids. In some embodiments, the length of the at least one neoantigen peptide ranges from about 10 to about 35 amino acids. In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 15 to about 25 amino acids. In some embodiments, the length of the neoantigenic sequence and/or antigenic portion ranges from about 10 to about 20 amino acids. In some embodiments, the neoantigenic sequence and/or antigenic moiety does not directly overlap with the canonical peptide sequence (e.g. any of or does not consist of the illustrative canonical peptide sequences underlined in Table 3).

In some embodiments, the neoantigenic sequence is a subject-specific neoantigenic sequence. 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.

In some other embodiments, the neoantigen sequence is a generic neoantigen sequence. In some embodiments, the neoantigen sequence is a generic neoantigen vaccine. In some embodiments, the 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 at least 35%, at least 40%, or at least 45% of subjects in a population of subjects suffering from a neoplastic disorder. In some embodiments, the neoantigen sequence is capable of inducing a T cell response to a tumor present in at least 1%, at least 5%, or at least 10% of a population of subjects suffering from a neoplastic disorder.

In some embodiments, the neoantigen sequence has been identified by sequencing at least one neoantigen mRNA that is induced in a subject by administration of an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the at least one neoantigenic mRNA encodes a neoantigenic sequence, the formation of which is induced by contacting a neoplastic cell with an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically acceptable salts thereof. In some embodiments, the neoplastic cell is in in vitro cell culture. In some embodiments, the neoplastic cell is obtained from a subject. In some embodiments, the neoplastic cell is in the subject.

In some embodiments, the neoantigen vaccine comprises at least one neoantigen mRNA and a pharmaceutically acceptable carrier. In some embodiments, the at least one neoantigen mRNA is associated with a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, fisurella hemocyanin, immunoglobulin, thyroglobulin, ovalbumin, toxoid or attenuated toxoid derivative, cytokine, and chemokine.

In some embodiments, the neoantigen vaccine contains 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 (e.g. adjuvant described herein).

In some embodiments, the neoantigen mRNA is encapsulated using an encapsulating agent. In some embodiments, the encapsulating agent protects neoantigen mRNA from degradation and improves vaccine delivery (McNamaraet al. (2015) J Immunol Res. 2015:794528). In some embodiments, the encapsulating agent is a liposome. In some embodiments, the liposome is a cationic liposome, such as N-[1-(2,3-dioleoloxy)propyl]-N,N,N-trimethylammonium chloride 1 (DOTAP). In some embodiments, the encapsulating agent is a nanoparticle. In some embodiments, the nanoparticle protects neoantigenic mRNA from nuclease degradation and/or improves cellular uptake and/or delivery efficiency. In some embodiments, the nanoparticle may be designed such that it is completely biodegradable. In some embodiments, the nanoparticle is a biodegradable core-shell nanoparticle comprising a pH-sensitive poly(b-amino ester) (PBAE) core embedded in a phospholipid shell (Suet al. (2011) Mol Pharm. 8(3):774-87). In some embodiments, such nanoparticles are particularly effective in delivering mRNA in vivo and the development of an antitumor immune response.

In some embodiments, the subject has a mutational load with nonsynonymous changes of approximately 150 mutations or less. In some embodiments, the subject has a mutational load with nonsynonymous changes of approximately 100 mutations or less. In some embodiments, the subject has a mutational load with nonsynonymous changes of approximately 50 mutations or less. In some embodiments, the subject has a neoplastic disorder, for example, or is suspected of having a hematological malignancy or solid tumor. In some embodiments, the hematologic malignancy is selected from B-cell malignancy, leukemia, lymphoma, and myeloma. In some embodiments, the hematologic 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.

As used herein, the term “adjuvant” refers to a substance that is capable of increasing, enhancing or modulating the immune response to a concomitant immunogenic agent, e.g. neoantigenic peptide or mRNA. In certain embodiments, the neoantigen of the present invention can be administered in combination with adjuvants, i.e. i.e. substances that do not themselves induce adaptive immune responses, but enhance or modulate the response to an accompanying neoantigen. A number of adjuvants can be used in combination with the disclosed neoantigens to promote the development of an immune response. In some embodiments, the adjuvant(s) are selected to enhance the intrinsic response to the neoantigen without causing conformational changes in the neoantigen that would affect the qualitative form of the response. In some embodiments, the adjuvant(s) are selected to enhance priming and/or activation of effector T cells (e.g. CD8).

In certain embodiments, the adjuvant is an aluminum salt (alum), such as aluminum hydroxide, aluminum phosphate, and aluminum sulfate. Such adjuvants can be used with or without other specific immunostimulatory agents such as 3-O-deacylated monophosphoryl lipid A (MPL) or 3-DMP, polymeric or monomeric amino acids such as polyglutamic acid or polylysine. Such adjuvants may be used with other specific immunostimulatory agents such as muramyl peptides (e.g. N-acetylmuramyl-L-threonyl-D-isoglutamine (thr-MDP), N-acetylnormuramil-L-alanyl-D-isoglutamine (nor-MDP), N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine- 2-(1′-2′-dipalmitoyl-sn-glycero-3-hydroxyphosphoryloxy)-ethylamine (MTP-PE), N-acetylglucosaminyl-N-acetylmuramyl-L-Al-D-isoglu-L-Ala-dipalmitoxypropylamide (DTP -DPP)), or other components of the bacterial cell wall, or without them. Other adjuvants are oil-in-water emulsions and include (a) MF59 (WO 90/14837) containing 5% squalene, 0.5% Tween 80 and 0.5% Span 85 (optionally containing varying amounts of MTP-PE ), formulated into submicron particles using a microfluidizer such as a Model 110Y microfluidizer (Microfluidics), (b) SAF containing 10% squalene, 0.4% Tween 80, 5% Pluronic L121 block polymer and thr-MDP, or microfluidized into a submicron emulsion, or vortexed to form an emulsion with larger particle sizes, and (c) Ribi™ Adjuvant System (RAS), (Ribi ImmunoChem) containing 2% squalene, 0.2% Tween 80 and one or more bacterial components cell wall from the group consisting of monophosphoryl lipid A (MPL), trehalose dimycolate (TDM) and cell wall scaffold (CWS), for example MPL-FCWS (Detox™). In some embodiments, the adjuvant is a saponin, such as Stimulon™ (QS21), or particles derived therefrom, such as ISCOM (immune stimulating complexes) and ISCOMATRIX. Other adjuvants include complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA), cytokines such as interleukins (IL-1, IL-2 and IL-12), macrophage colony stimulating factor (M-CSF) and tumor necrosis factor (TNF). ).

The adjuvant can be administered with an immunogenic agent (for example, neoantigenic peptide or mRNA) as a single composition or it can be administered before, simultaneously with, or after administration of the immunogenic agent. In some embodiments, the immunogenic agent and the adjuvant may be packaged and provided in the same vial or may be packaged in separate vials and mixed prior to use. In some embodiments, the immunogenic agent and adjuvant may be packaged with labeling indicating the intended therapeutic use. In some embodiments, if the immunogenic agent and adjuvant are packaged separately, the package may include instructions for mixing prior to use. The choice of adjuvant and/or carrier depends on the stability of the immunogenic composition containing the adjuvant, the route of administration, the dosage schedule, the effectiveness of the adjuvant for the animal species to be vaccinated and for humans, a pharmaceutically acceptable adjuvant being an adjuvant that has been approved or may be approved by appropriate regulatory authorities for administration to humans. For example, Freund's complete adjuvant is not suitable for administration to humans. However, alum, MPL or Freund's incomplete adjuvant (Changet al. (1998) Adv Drug Deliv Rev. 32:173-186) alone or optionally in combination with any of alum, QS21 and MPL and all combinations thereof are suitable for administration to humans.

In some embodiments, the present invention further provides methods for screening and identifying at least one neoantigen. More specifically, in some embodiments, the present invention provides a method for identifying at least one neoantigen by (a) contacting a neoplastic cell with an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa , IVa and Va) and/or pharmaceutically acceptable salts thereof; (b) detecting at least one alternatively spliced mRNA transcript after contacting the neoplastic cell with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts; (c) predicting the translation of at least one alternatively spliced mRNA transcript into at least one peptide; and (d) comparing the at least one peptide to a reference proteome, wherein at least one neoantigen is identified if the at least one peptide does not match with any peptides in the reference proteome. In some embodiments, the method further includes contacting one or more additional neoplastic cells to identify at least one universal neoantigen. In some embodiments, the method is repeated for one or more additional neoplastic cells or samples (e.g. tissue biopsy) to confirm suitable neoantigens (e.g. for use in a neoantigen vaccine) and/or to identify one or more universal neoantigens.

In various other embodiments, the present invention provides a method for identifying at least one neoantigen by (a) contacting a neoplastic cell with an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof; (b) detecting at least one peptide containing a potential neoantigenic sequence after contacting a neoplastic cell with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts; and (c) comparing at least one peptide to a reference proteome, wherein at least one neoantigen is identified if the at least one peptide does not match any peptide in the reference proteome. In some embodiments, the method further includes contacting one or more additional neoplastic cells to identify at least one universal neoantigen. In some embodiments, the method is repeated for one or more additional neoplastic cells or samples (e.g. tissue biopsy) to confirm suitable neoantigens (e.g. for use in a neoantigen vaccine) and/or to identify one or more universal neoantigens.

In some embodiments of the neoantigen identification methods described herein, detection of at least one alternatively spliced mRNA transcript involves RNAseq. In some embodiments, predicting the translation of at least one alternatively spliced mRNA transcript involves quantifying the change as a percent splicing success rate (dPSI) value for the at least one transcript. In some embodiments, translation prediction of at least one alternatively spliced mRNA transcript involves RiboSeq and/or ribosome profiling.

In some embodiments of the neoantigen identification methods described herein, the methods further include evaluating at least one peptide for predicted binding to major histocompatibility complex (MHC) molecules. In some embodiments, predicted binding to MHC molecules is determined by measuring the initial binding strength predictive affinity for at least one peptide. In some embodiments, a baseline affinity predictive of binding strength that is approximately 500 nM or greater is indicative of binding to MHC molecules. In some embodiments, predicted binding to MHC molecules is determined by identifying a distribution of predicted binding strength values for a series of random peptides and comparing the predicted binding strength of at least one peptide to this distribution. In some embodiments, the predicted binding strength in the top 2% of the distribution indicates weak binding to MHC molecules. In some embodiments, the predicted binding strength in the top 0.5% of the distribution indicates strong binding to MHC molecules.

In some embodiments of the neoantigen identification methods described herein, the neoplastic cell is in in vitro cell culture. In some embodiments, the neoplastic cell is obtained from a subject. In some embodiments, the neoplastic cell is in the subject.

In some embodiments, also provided herein are methods of producing a neoantigen vaccine by (a) identifying at least one neoantigen (e.g. at least one neoantigenic peptide or mRNA encoding it) using any of the exemplary identification methods disclosed herein; and (b) formulating at least one neoantigen together with a pharmaceutically acceptable carrier, diluent or adjuvant (eg, any of the pharmaceutically acceptable carriers, diluents or adjuvants described herein).

In some embodiments, the length of the at least one neoantigen and/or antigenic portion ranges from about 10 to about 50 amino acids. In some embodiments, the length of the at least one neoantigen peptide ranges from about 10 to about 35 amino acids. In some embodiments, the length of the at least one neoantigen and/or antigenic portion ranges from about 15 to about 25 amino acids. In some embodiments, the length of the at least one neoantigen and/or antigenic portion ranges from about 10 to about 20 amino acids. In some embodiments, the at least one neoantigen and/or antigenic moiety does not directly overlap with a canonical peptide sequence (e.g. any of or does not consist of the illustrative canonical peptide sequences underlined in Table 3).

In some embodiments, the at least one neoantigen used in the vaccine is attached to a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is selected from a peptide, serum albumin, fisurella hemocyanin, immunoglobulin, thyroglobulin, ovalbumin, toxoid or attenuated toxoid derivative, cytokine, and chemokine.

In some embodiments, a patient who has a cancer described herein can be treated with a combination of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/ or pharmaceutically acceptable salts thereof, and one or more engineered tumor-targeting T cells (i.e. e., CAR-T). Thus, in some embodiments, the present invention provides a method of treating a subject who has or is suspected of having a neoplastic disorder by administering to the subject an effective amount of at least one compound selected from compounds of formula I (including formulas IIa-e , IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof; and engineered T cells that specifically target the tumor (i.e. e. CAR-T). In some embodiments, a chimeric T cell receptor can be constructed using antigen recognition sequences that react with an identified neoantigen.

For example, in some embodiments, to target changes in the extracellular domains of cell surface proteins induced by at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or thereof pharmaceutically acceptable salts, an antigen-reactive chimeric T-cell receptor (CAR) can be constructed by first identifying antibodies that recognize the neoantigen protein domain expressed on the cell surface. The antigen recognition sequences of such antibodies can then be fused to a T cell receptor domain to achieve selective targeting and activation.

Various other embodiments employ a strategy that combines tumor cell antigen presentation mechanisms together with neoantigens produced by at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or their pharmaceutically acceptable salts. In some embodiments, cells containing known and commonly present HLA alleles (e.g. HLA-A*02:01), can be treated with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, and neoantigens bound MHC1 molecules are identified through ligandomics. In some embodiments, these peptides can be used to prime and/or expand T cells from healthy donors expressing the same HLA allele. In some embodiments, such T cells can be isolated and the T cell receptor (TCR) α and β chains can be sequenced to identify cognate antigen recognition/variable regions. In some embodiments, a cognate CAR can then be constructed.

In some embodiments, the CAR sequences are cloned into a population of patient-derived T cells and the cells are expanded using currently available protocols. In some embodiments, the engineered T cells are then infused back into the patient's bloodstream prior to treatment with at least one compound selected from compounds of Formula I (including Formulas IIa-e, IIIa, IVa, and Va) and/or pharmaceutically thereof acceptable salts, simultaneously with or after it. In some embodiments, following treatment with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, tumor cells may begin to present antigen, e.g. , an antigen that is specifically targeted by a population of engineered T cells. In some embodiments, a population of engineered T cells can contact and kill antigen-presenting tumor cells.

To enable a more complete understanding of the present invention described herein, the following examples are provided below. It should be understood that these examples are presented for illustrative purposes only and should not be construed as limiting the present invention in any way.

EXAMPLES 1-268

General information.

Microwave heating was performed using a Biotage Emrys Liberator or Initiator microwave reactor. Column chromatography was performed using Combiflash Rf200d (Teledyne ISCO). Solvent removal was carried out using either a rotary evaporator from Büchi or a centrifugal evaporator from Genevac. Preparative LC/MS was performed using a Waters autocleaner and a 5-micron XTerra MS C18 19 × 100 mm column under acidic mobile phase conditions. NMR spectra were recorded using a Varian 400 MHz spectrometer.

When the expression "with an inert atmosphere created" is used to describe a reactor (for example, reaction vessel, flask, glass reactor, etc.), this means that the air in the reactor has been replaced by a substantially moisture-free or dry inert gas (such as nitrogen, argon, etc.).

General methods and experimental parts for preparing the compounds of the present invention are set forth below.

The following abbreviations are used in this document:

MeOH: methanol

DMF: Dimethylformamide

LHMDS: lithium hexamethyldisilazide

KHMDS: potassium bis(trimethylsilyl)amide

LCMS: liquid chromatography with mass spectrometry

MS: Mass spectrometry

HPLC: High Pressure Liquid Chromatography

UPLC: Ultra Performance Liquid Chromatography

LC: liquid chromatography

^1H NMR: proton nuclear magnetic resonance

TBSCl: tert-butyldimethylsilyl chloride

THF: tetrahydrofuran

TLC: thin layer chromatography

HBTU: benzotriazoletetramethyluronium hexafluorophosphate

TEA: triethylamine

DCM: dichloromethane

DMSO: dimethyl sulfoxide

ISCO: automated chromatography (Combiflash RF200d)

Hex: hexanes

EtOAc: ethyl acetate

DMAP: Dimethylaminopyridine

NaOH: sodium hydroxide

MgSO ₄ : magnesium sulfate

HCl: hydrochloric acid

AcOH: acetic acid

AIBN: 2,2'-azobisobutyronitrile

NBS: N- bromosuccinimide

Boc: N-tert-butoxycarbonyl

TBDMS: tert-butyldimethylsilyl

TBAF: Tetrabutylammonium fluoride

m CPBA: m -chloroperoxybenzoic acid

Materials. The following compounds are commercially available and/or can be prepared by a number of methods well known to one skilled in the art of organic synthesis. More specifically, the disclosed compounds can be prepared using the reactions and procedures described herein. In the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration and work-up procedures, can be selected as standard conditions for a given reaction unless otherwise indicated. One skilled in the art of organic synthesis will appreciate that the functional groups present in various parts of the molecule must be compatible with the proposed reagents and reactions. Substituents incompatible with the reaction conditions will be obvious to one skilled in the art, and alternative methods are therefore indicated. The starting materials for the examples are either commercially available or easily prepared using standard methods from known materials.

LCMS Information

Mobile phases: A (0.1% formic acid in H ₂ O) and B (0.1% formic acid in acetonitrile).

Gradient: B 5% - 95% in 1.8 minutes.

Column: Acquity BEH C18 column (1.7 µm, 2.1 x 50 mm).

US Pat. Nos. 7,884,128 and 7,816,401, both entitled Process for Total Synthesis of Pladienolide B and Pladienolide D, describe methods for the synthesis of pladienolide B and D. Synthesis of pladienolide B and D can also be performed using methods known in the art and described in Kanada et al. , "Total Synthesis of Potent Antitumor Macrolides Pladienolide B and D", Angew. Chem. Int. Ed. 46:4350–4355 (2007). Canada et al. and PCT publication WO 2003/099813 entitled Novel Physiologically Active Substances describes methods for the synthesis of E7107 (compound 45 of WO '813) from pladienolide D (11107D of WO '813). The corresponding US patent is Patent No. 7550503 issued to Kotake et al.

ILLUSTRATIVE SYNTHESIS OF COMPOUNDS

Exemplary compounds were prepared either according to General Scheme A , including intermediates without a hydroxyl group at the C6 position, or according to General Scheme B , including intermediates with a hydroxyl group at the C6 position.

General scheme A

Step 1. Into a solution of (3S,4S,E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-ol ( 001 , 5.03 g, 19.966 mmol) and (3R,6S)- 3-((tert-butyldimethylsilyl)oxy)-6-methylnon-8-enoic acid ( 002 , 5.0 g, 16.638 mmol) in dry DCM (84 ml, 1297.798 mmol) was added EDC (8.29 g, 43.26 mmol), DMAP (0.407 g, 3.328 mmol) followed by TEA (6.96 ml, 49.915 mmol). The reaction solution was stirred at room temperature overnight. Complete conversion of the acid was shown using LCMS. The reaction mixture was quenched with water and then extracted with DCM (3 x 100 ml). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using ISCO with a gradient of 0 to 20% to give the product - (3R,6S)-(3S,4S,E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-yl -3-((tert-butyldimethylsilyl)oxy)-6-methylnon-8-enoate ( 003 , 7.5 g, 14.03 mmol, yield 84%) - in the form of a colorless oil.

Step 2. The solution of (3R,6S)-(3S,4S, E)-1-iodo-2,4-dimethylhexa-1,5-dien-3-yl-3-((tert-butyldimethylsilyl)oxy)- 6-methylnon-8-enoate ( 002 , 6.5 g, 12.159 mmol) and benzoquinone (0.066 g, 0.608 mmol) in toluene (1296 ml, 9.38 mmol) for 15 minutes. Generation II Hoveyda-Grubbs catalyst (0.762 g, 1.216 mmol) was then added and stirred at 50°C under nitrogen for 6 hours. The reaction mixture was filtered through a pad of celite, washed with excess toluene and then concentrated. The crude reaction mixture was purified by ISCO eluting with 0 to 20% Hex:EtOAc to give the product - (4R,7S,11S,12S, E)-4-((tert-butyldimethylsilyl)oxy)-12-((E) -1-iodoprop-1-en-2-yl)-7,11-dimethyloxacyclododec-9-en-2-one ( 004 , 5.71 g, 11.27 mmol, 93% yield) - as off-white oils

Step 3. Dissolved (4R,7S,11S,12S, E)-4-((tert-butyldimethylsilyl)oxy)-12-((E)-1-iodoprop-1-en-2-yl)-7.11 -dimethyloxacyclododec-9-en-2-one ( 004 , 6.15 g, 11.27 mmol) in dioxane (520 ml) and degassed, add selenium dioxide (4.05 g, 36.477 mmol). The mixture was heated to 80°C and stirred for 5 hours. Completion of the reaction was demonstrated by LCMS. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution. The resulting mixture was dried with Na2SO4, filtered and concentrated in vacuo. The reaction mixture was purified with ISCO, with a gradient of 0 to 30% Hex:EtOAc, to give (4R,7S,8R,11S,12S, E)-4-((tert-butyldimethylsilyl)oxy)-8-hydroxy-12 -((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyloxacyclododec-9-en-2-one ( 005 , 5.5 g, 10.53 mmol).

Step 4. In solution (4R,7S,8R,11S,12S, E)-4-((tert-butyldimethylsilyl)oxy)-8-hydroxy-12-((E)-1-iodoprop-1-ene-2 -yl)-7,11-dimethyloxacyclododec-9-en-2-one ( 005 , 2.5 g, 4.784 mmol) in DCM (0.406 g, 4.784 mmol) added DMAP (0.117 g, 0.957 mmol), triethylamine (2.046 ml, 14.353 mmol) and 4-nitrophenyl chloroformate (1.447 g, 7.177 mmol). The resulting yellowish suspension was stirred for 5 hours. The reaction mixture was concentrated and purified using ISCO with a gradient of 0 to 15% Hex:EtOAc to give the product - (2S,3S,6R,7S,10R, E)-10-((tert -butyldimethylsilyl)oxy)-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl-(4-nitrophenyl)carbonate ( 006 , 3.15 g, 4.58 mmol, 96% yield).

Step 5. Into a solution of (2S,3S,6R,7S,10R, E)-10-((tert-butyldimethylsilyl)oxy)-2-((E)-1-iodoprop-1-en-2-yl)- 3,7-Dimethyl-12-oxooxacyclododec-4-en-6-yl-(4-nitrophenyl)carbonate ( 006 , 2.1 g, 3.054 mmol) in DCM (0.259 g, 3.054 mmol) was added DMAP (0.373 g, 3.054 mmol) and 1-methylpiperazine (0.459 g, 4.581 mmol). The resulting yellowish suspension was stirred for 3 hours. The reaction mixture was concentrated and subjected to ISCO, eluting with 0 to 15% DCM:MeOH, to give the product - (2S,3S,6R,7S,10R, E)-10-((tert- butyldimethylsilyl)oxy)-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl-4-methylpiperazin-1-carboxylate ( 007 , 1.89 g, 2.91 mmol, 95% yield).

Step 6. Into a solution of (2S,3S,6R,7S,10R, E)-10-((tert-butyldimethylsilyl)oxy)-2-((E)-1-iodoprop-1-en-2-yl)- 3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl-4-methylpiperazine-1-carboxylate ( 007 , 1.8 g, 2.775 mmol) in methanol (0.089 g, 2.775 mmol) was added 4-methylbenzenesulfonic acid hydrate acid (0.528 g, 2.775 mmol) at room temperature. After 2 hours, the reaction mixture was quenched with TEA (0.560 g, 5.55 mmol). The reaction mixture was concentrated and diluted with 300 ml DCM, then washed with brine (3 x 50 ml). The organic extract was concentrated and subjected to ISCO eluting with 0 to 15% DCM:MeOH to give the product - (2S,3S,6R,7S,10R, E)-10-hydroxy-2-((E)-1-iodoprop-1 -en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl-4-methylpiperazin-1-carboxylate ( 008 , 1.4 g, 2.62 mmol, 94% yield) .

Step 7. In solution (2S,3S,6R,7S,10R, E)-10-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12 -oxooxacyclododec-4-en-6-yl-4-methylpiperazin-1-carboxylate ( 009 , 15.0 mg, 0.029 mmol) and arylboronic acid ( 010 , 0.035 mmol) added silver oxide (19 mg, 0.086 mmol) and Pd (0) (3.3 mg, 0.003 mmol). The mixture was heated to 60°C for 5 hours. Complete conversion of compound 009 was demonstrated using LCMS. The mixture was cooled, filtered through a thin layer of celite and concentrated. The crude reaction mixture was subjected to ISCO, eluting with 0 to 10% DCM:MeOH to give the products ( 010 , 0.019 mmol, 68.4% yield).

General scheme B

Stages 1-3 correspond to stages 1-3 from scheme 1 , respectively.

Stage 4 . 3.0 eq. was added to a stirred solution of compounds 015 and 016 in a mixture of 1,4-dioxane/water (3:1). Ag ₂ O and 0.1 eq. tetrakis(triphenylphosphine)palladium(0). The mixture was degassed and heated to 100°C for 2 hours. After completion of the reaction as indicated by UPLC, the mixture was cooled to room temperature and filtered to give compound 017 as a mixture of two diastereomers ( isomers A and B ). Isomers A and B were isolated separately by column chromatography using a gradient of 0 to 100% EtOAc/hexanes followed by a gradient of 0 to 20% MeOH/DCM.

Stages 5 and 6 correspond to stages 4 and 5 from scheme 1 , respectively.

Stage 7 . p-toluenesulfonic acid monohydrate was added to a solution of compound 018 in methanol at room temperature. After 2 hours, the reaction mixture was quenched with excess Et ₃ N and concentrated. The solution was extracted with EtOAc, washed with NaHCO ₃ and brine, dried with Na ₂ SO ₄ , filtered and concentrated. The crude product mixture was purified by silica gel column chromatography to give compound 019 .

Compounds 1-85 (Table 4) were prepared using general methods from Procedures 1-10 .

Synthesis of brominated aryl intermediates

Procedure 1

Cs ₂ CO ₃ or Hunig's base (2.5 eq) and amine (1.5 eq) were added to 1-bromo-3,5-difluorobenzene in DMSO. The mixture was heated under microwave radiation in a closed tube at the desired temperature for 1.5 hours. The reaction mixture was diluted with EtOAc, filtered and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography.

Procedure 2

2-bromoethyl ether (1.2 eq.) and Hunig's base (3.0 eq.) were added to a solution of the amine in DMF at room temperature. The mixture was microwaved to 140°C in a sealed tube for 24 hours. The reaction mixture was cooled, quenched with aqueous NaHCO ₃ , extracted with EtOAc, washed with brine, dried with Na2SO4, filtered and concentrated in vacuo with obtaining an unrefined product. The crude product was purified by silica gel column chromatography.

Synthesis of intermediates based on pinacolboronate

Procedure 3

Potassium acetate (2.0 eq.), diborolane (1.2 eq.) and PdCl ₂ ( dppf) ₂ (0.05 eq.). The mixture was refluxed and the reaction was monitored by LC. After 5 hours, aqueous workup yielded the crude product. As a result of column chromatography on silica gel, 1-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine was obtained.

Synthesis of intermediates from the Suzuki coupling reaction

Procedure 4

3.0 eq. was added to a stirred solution of iodide 1 and pinacolboronate in p-dioxane. silver oxide (or K ₂ CO ₃ ) and 0.1 eq. tetrakis(triphenylphosphine)palladium(0). The mixture was degassed and heated to 80°C for 90 minutes. After completion of the reaction, as indicated by UPLC, the reaction mixture was cooled to room temperature, filtered and concentrated. Purification by column chromatography with an elution gradient of 0 to 20% MeOH/DCM yielded the coupling product, aryl-pladienolide .

Procedure 5

2.0 eq. was added to a stirred solution of iodide 1 and pinacolboronate in a mixture of p-dioxane/H ₂ O (3:1). K ₂ CO ₃ and 0.1 eq. Pd(dppf) _Cl2 . The mixture was degassed and heated to 80°C for 1 hour. After completion of the reaction, which was indicated by UPLC, the reaction mixture was cooled to room temperature, filtered and concentrated. Purification by column chromatography with an elution gradient of 0 to 20% MeOH/DCM yielded the coupling product, aryl-pladienolide .

Procedure 6

To a stirred solution of boronate ( for example , boronate 1 above) and bromobenzene 1 in a mixture of 1,4-dioxane/water (3:1) was added 3.0 eq. potassium carbonate (or Ag ₂ O) and 0.1 eq. Pd(PPh ₃ ) ₄ (or PddppfCl ₂ ). The mixture was degassed and heated to 100°C for 2 hours. After completion of the reaction, as indicated by UPLC, the mixture was cooled to room temperature, filtered and purified by column chromatography with an elution gradient of 0 to 100% EtOAc/hexanes, then gradient from 0 to 20% MeOH/DCM, obtaining the coupling reaction product - aryl-pladienolide .

Procedure 7

In a degassed solution 1.5 eq.bromobenzene 1 in 1,4-dioxane, 3.0 eq was added. potassium acetate, 2.0 eq. diborolane and 0.2 eq. Pd(dppf)Cl₂. The mixture was refluxed and the reaction was monitored by LC. After 5 hours, the reaction mixture was cooled. Added 3.0 eq. Ag₂O, 0.2 eq. Pd(PPh₃)₄ and a solution of 1.0 eq.iodide 2. The mixture was degassed and heated to 80°C for 2 hours. The mixture was cooled and subjected to direct column chromatography on silica gel to obtain combination reaction product -aryl-pladienolide.

Synthesis of amidization products

Procedure 8

A solution of carbonate 1 in DCM contained 3.0 eq. triethylamine and 2.0 eq. amine 1 . The resulting yellowish suspension was stirred for 12 hours until carbonate 1 disappeared. The reaction mixture was concentrated to give the crude product and the aryl pladienolide carbamate product was isolated by liquid chromatography.

Procedure 9

HBTU (1.2 eq) and triethylamine (1.5 eq) were added to a solution of amine 2 and carboxylic acid 1 (1.2 eq) in DMSO at room temperature. The solution was stirred for 5 hours at room temperature. Water was added to quench the reaction, then the mixture was extracted with EtOAc, washed with brine and concentrated in vacuo to give the crude product. The resulting product, aryl-pladienolide amide , was purified by silica gel column chromatography.

Procedure 10

1.2 eq. was added to a solution of amine 2 in DCM. sulfonyl chloride 1, 3.0 eq. Hunig's base, and 0.1 eq. DMAP. The mixture was stirred at room temperature until amine 2 was obtained. The reaction mixture was quenched with water, extracted with EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The product, aryl pladienolide sulfonamide , was purified by silica gel column chromatography.

Table 4. Description of characteristics of connections 1-85 and 265-267 Etc. Structure and chemical name according to IUPAC Characteristics 1
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperazin-1-ylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 569.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.04 (t, J=6.53 Hz, 6 H) 1.15-1.29 (m, 2 H) 1.49-1.58 (m, 1 H) 1.80-1.89 (m, 1 H) 1.92 (d, J=1.13 Hz, 3 H) 1.94-2.01 (m, 1 H) 2.34 (s , 3 H) 2.40 (br s, 4 H) 2.55-2.64 (m, 2 H) 2.65-2.73 (m, 1 H) 2.97-3.12 (m, 4 H) 3.14-3.28 (m, 4 H) 3.48-5.28 (m, 5 H) 3.71-3.85 (m, 1 H) 4.90 (t, J= 10.10 Hz, 1 H) 5.29 (d, J=10.67 Hz, 1 H) 5.40 (dd, J=15.00, 9.60 Hz, 1 H) 5.61 (dd, J=14.93, 9.91 Hz, 1 H) 6.57 (s, 1 H) 6.77-6.87 (m, 3 H) 7.24 (t, J=8.09 Hz, 1 H) 2
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-[3-(4-methylpiperazin-1-yl)phenyl]prop- 1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 583.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.92 (d, J=6.78 Hz, 3 H) 0.97 (d, J=6.78 Hz, 3 H) 1.21-1 .39 (m, 2 H) 1.49-1.67 (m, 2 H) 1.81 (d, J=1.13 Hz, 3 H) 1.89-2.02 (m, 1 H) 2.41 (dd, J=14.05, 5.40 Hz, 1 H) 2.52-2.65 (m, 2 H) 2.85 (s, 3 H) 2.91 (s, 3 H ) 3.10-3.28 (m, 12 H) 3.32-3.50 (m, 4 H) 3.70-3.85 (m, 1 H) 4. 78-4.84 (m, 1H), 5.09 (d, J=10.54 Hz, 1 H) 5.39-5.62 (m, 2 H) 6.48-6.56 (m, 1 H) 6.80-6 .93 (m, 3 H) 7.16-7.26 (m, 1 H) 3
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 588.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (d, J=6.90 Hz, 3 H) 0.95 (d, J=6.90 Hz, 3 H) 1.15-1, 29 (m, 2 H) 1.43 (ddd, J=13.52, 9.69, 3.76 Hz, 1 H) 1.74 (br d, J=3.51 Hz, 2 H) 1, 81 (s, 3 H) 1.83-1.92 (m, 1 H) 2.24 (s, 3 H) 2.30 (br s, 4 H) 2.41-2.67 (m, 3 H) 3.00-3.17 (m, 4 H) 3.42 (br s, 4 H) 3.66 (br s, 1 H) 3.77-3.83 (m, 4 H) 4, 82 (t, J=10.04 Hz, 1 H) 5.20 (d, J=10.54 Hz, 1 H) 5.34 (dd, J=14.93, 9.66 Hz, 1 H) 5.53 (dd, J=15.06, 9.91 Hz, 1 H) 6.32-6.60 (m, 4 H) 4
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-(1H-indazol-6-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 525.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.94 (d, J=2.76 Hz, 3 H) 0.96 (d, J=2.76 Hz, 3 H) 1.15-1, 29 (m, 2 H) 1.40-1.50 (m, 1 H) 1.68-1.80 (m, 1 H) 1.83-1.93 (m, 1 H) 1.86 ( d, J=1.13 Hz, 3 H) 2.24 (s, 3 H) 2.27-2.39 (m, 4 H) 2.46-2.64 (m, 3 H) 3.43 (br s, 4 H) 3.60-3.98 (m, 2 H) 4.84 (t, J=10.04 Hz, 1 H) 5.26 (d, J=10.67 Hz, 1 H) 5.31-5.41 (m, 1 H) 5.56 (dd, J=15.06, 9.91 Hz, 1 H) 6.67 (s, 1 H) 7.04 (d, J=8.41 Hz, 1 H) 7.33 (s, 1 H) 7.65 (d, J=8.28 Hz, 1 H) 7.99 (s, 1 H) 9.97-10, 32 (m, 1H) 5
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-(1H-indazol-4-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 525.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.02 (d, J=6.90 Hz, 3 H) 1.06 (d, J=6.78 Hz, 3 H) 1.22-1, 36 (m, 2 H) 1.47-1.56 (m, 1 H) 1.77-1.84 (m, 1 H) 1.87 (d, J=1.13 Hz, 3 H) 1 ,90-2.01 (m, 1 H) 2.30 (s, 3 H) 2.37 (br s, 4 H) 2.53-2.73 (m, 3 H) 3.31-3, 61 (m, 4 H) 3.75 (br s, 2 H) 4.91 (t, J=10.04 Hz, 1 H) 5.38-5.49 (m, 2 H) 5.63 ( dd, J=15.06, 9.91 Hz, 1 H) 6.92 (s, 1 H) 7.06 (d, J=6.65 Hz, 1 H) 7.34 -7.46 (m , 2 H) 8.03 (s, 1 H) 9.95-10.34 (m, 1 H) 6
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-(2-morpholin-4-ylpyridin-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 571.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.00 (t, J=6.84 Hz, 6 H) 1.19-1.31 (m, 2 H) 1.42-1.55 (m , 1 H) 1.74-1.84 (m, 1 H) 1.87 (d, J=1.00 Hz, 3 H) 1.88-1.97 (m, 1 H) 2.31 ( s, 3 H) 2.38 (br s, 4 H) 2.50-2.70 (m, 3 H) 3.40-3.60 (m, 8 H) 3.69-3.78 (m , 1 H) 3.79-3.88 (m, 4 H) 4.88 (t, J=10.10 Hz, 1 H) 5.26 (d, J=10.67 Hz, 1 H) 5 .35-5.46 (m, 1 H) 5.59 (dd, J=15.00, 9.85 Hz, 1 H) 6.46 (s, 2 H) 6.57 (d, J=5 .27 Hz, 1 H) 8.15 (d, J=5.14 Hz, 1 H) 7
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(2-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 588.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.00 (d, J=1.76 Hz, 3 H) 1.02 (d, J=1.76 Hz, 3 H) 1.21-1, 32 (m, 2 H) 1.43-1.55 (m, 1 H) 1.76 (s, 3 H) 1.78-1.86 (m, 1 H) 1.89-1.98 ( m, 1 H) 2.30 (s, 3 H) 2.36 (br s, 4 H) 2.48-2.70 (m, 3 H) 3.02-3.12 (m, 4 H) 3.41-3.56 (m, 5 H) 3.67-3.77 (m, 1 H) 3.84-3.89 (m, 4 H) 4.89 (t, J=10.04 Hz, 1 H) 5.31 (d, J=10.92 Hz, 1 H) 5.40 (dd, J=15.00, 9.72 Hz, 1 H) 5.60 (dd, J=14 .93, 10.04 Hz, 1 H) 6.50 (s, 1 H) 6.73 (dd, J=6.09, 2.95 Hz, 1 H) 6.76-6.82 (m, 1 H) 6.97 (t, J=9.10 Hz, 1 H) 8
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-Fluoro-3-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 588.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.99 (d, J=4.02 Hz, 3 H) 1.01 (d, J=3.89 Hz, 3 H) 1.16-1, 35 (m, 2 H) 1.43-1.55 (m, 1 H) 1.75-1.84 (m, 1 H) 1.86 (s, 3 H) 1.90-2.00 ( m, 2 H) 2.51 (s, 3 H) 2.50-2.88 (m, 3 H) 2.64-2.76 (m, 4 H) 3.05-3.11 (m, 4 H) 3.58-3.76 (m, 5 H) 3.84-3.91 (m, 4 H) 4.89 (t, J=10.10 Hz, 1 H) 5.27 (d , J=10.54 Hz, 1 H) 5.39 (dd, J=14.93, 9.54 Hz, 1 H) 5.61 (dd, J=14.93, 9.91 Hz, 1 H ) 6.52 (s, 1 H) 6.78-6.83 (m, 1 H) 6.85-6.90 (m, 1 H) 6.96-7.04 (m, 1 H) 9
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(3S)-3-(methylamino)pyrrolidine-1 -yl]phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate LCMS (ESI, mass/charge), 583.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.00 (t, J=6.21 Hz, 6 H) 1.20-1.35 (m, 2 H) 1.41-1.57 (m , 1 H) 1.72-1.84 (m, 1 H) 1.88 (d, J=1.25 Hz, 3 H) 1.90-1.98 (m, 1H) 2.23 (td , J=13.11, 6.15 Hz, 2 H) 2.30 (s, 3 H) 2.37 (br s, 4 H) 2.50 (s, 3 H) 2.52-2.70 (m, 3 H) 3.08-3.20 (m, 1 H) 3.23-3.34 (m, 1 H) 3.37-3.45 (m, 2 H) 3.45-3 .57 (m, 5 H) 3.67-3.75 (m, 1 H) 4.89 (t, J=10.04 Hz, 1 H) 5.28 (d, J=10.67 Hz, 1 H) 5.39 (dd, J=15.00, 9.72 Hz, 1 H) 5.61 (dd, J=15.00, 9.98 Hz, 1 H) 6.39-6.49 (m, 2 H) 6.56 (s, 1 H) 6.62 (d, J=7.65 Hz, 1 H) 7.18 (t, J=7.78 Hz, 1H) 10
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(3S)-3-(methylamino)pyrrolidine-1 -yl]phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate LCMS (ESI, mass/charge), 583.6 [M+H] ⁺ eleven
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(2-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate LCMS (ESI, mass/charge), 656.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.99 (d, J=5.02 Hz, 3 H) 1.01 (d, J=5.02 Hz, 3 H) 1.18-1, 36 (m, 2 H) 1.41-1.69 (m, 6 H) 1.76 (s, 3 H) 1.77-1.84 (m, 1 H) 1.85-2.22 ( m, 6 H) 2.45-2.60 (m, 2 H) 2.62-2.69 (m, 1 H) 2.72-3.00 (m, 6 H) 3.02-3, 12 (m, 4 H) 3.34-3.44 (m, 1 H) 3.69-3.77 (m, 1 H) 3.80-3.89 (m, 4 H) 4.20- 4.36 (m, 2 H) 4.86 (t, J=10.10 Hz, 1 H) 5.31 (d, J=10.54 Hz, 1 H) 5.39 (dd, J=15 ,12, 9.72 Hz, 1 H) 5.60 (dd, J=15.06, 9.91 Hz, 1 H) 6.50 (s, 1 H) 6.73 (dd, J=6, 15, 3.01 Hz, 1 H) 6.76-6.83 (m, 1 H) 6.92-7.00 (m, 1 H) 12
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 631.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.98 (d, J=6.65 Hz, 3 H) 1.01 (d, J=6.78 Hz, 3 H) 1.21-1, 46 (m, 2 H) 1.54 -1.70 (m, 2 H) 1.86 (d, J=1.13 Hz, 3 H) 1.89-2.02 (m, 1 H) 2 .30 (s, 3 H) 2.36 -2.43 (m, 4 H) 2.44-2.51 (m, 1 H) 2.56-2.68 (m, 4 H) 2.69 -2.76 (m, 4 H) 3.20-3.26 (m, 4 H) 3.44-3.57 (m, 4 H) 3.73 (t, J=5.90 Hz, 2 H) 3.77-3.84 (m, 1 H) 4.78-4.83 (m, 1H) 5.13 (d, J=10.67 Hz, 1 H) 5.43-5.60 (m, 2 H) 6.48 (br d, J=9.29 Hz, 1 H) 6.52-6.66 (m, 3 H) 13
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate LCMS (ESI, mass/charge), 699.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.98 (d, J=6.78 Hz, 3 H) 1.01 (br d, J=6.78 Hz, 3 H) 1.24-1 .55 (m, 6 H) 1.56-1.72 (m, 6 H) 1.86 (d, J=1.13 Hz, 3 H) 1.87-2.01(m, 3 H) 2.39-2.52 (m, 1 H) 2.54-2.71 (m, 13 H) 2.72-2.88 (m, 2 H) 3.16-3.27 (m, 4 H) 3.72 (t, J=6.02 Hz, 2 H) 3.77-3.87 (m, 1 H) 4.07-4.29 (m, 2 H) 4.76-4, 83 (m, 1 H) 5.13 (d, J=10.67 Hz, 1 H) 5.42-5.64 (m, 2 H) 6.47 (br d, J=9.03 Hz, 1 H) 6.52-6.68 (m, 3 H) 14
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 590.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.99 (d, J=3.89 Hz, 3 H) 1.00 (d, J=3.89 Hz, 3 H) 1.15-1, 33 (m, 2 H) 1.45-1.54 (m, 1 H) 1.75-1.84 (m, 1 H) 1.88 (d, J=1.13 Hz, 3 H) 1 .93 1.90 -1.99 (m, 1 H) 2.07-2.27 (m, 1 H) 2.32-2.44 (m, 4 H) 2.52 (s, 3 H) 2.54-2.60 (m, 2 H) 2.62-2.68 (m, 1 H) 2.73 (br s, 4 H) 3.36-3.63 (m, 5 H) 3 .64-3.76 (m, 5 H) 4.89 (t, J=10.10 Hz, 1 H) 5.27 (d, J=10.67 Hz, 1 H) 5.39 (dd, J=14.93, 9.79 Hz, 1 H) 5.61 (dd, J=15.00, 9.98 Hz, 1 H) 6.12-6.22 (m, 2 H) 6.31 -6.39 (m, 1 H) 6.49-5.54 (m, 1 H) 15
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.90 (d, J=6.65 Hz, 3 H) 1.00 (d, J=6.78 Hz, 3 H) 1.16-1.32 ( m, 2 H) 1.45-1.54 (m, 1 H) 1.70-1.84 (m, 1 H) 1.88 (d, J=1.13 Hz, 3 H) 1.90 -1.96 (m, 1 H) 1.98-2.14 (m, 2 H) 2.31 (s, 3 H) 2.39 (br s, 4 H) 2.50-2.61 ( m, 2 H) 2.62-2.71 (m, 1 H) 3.07-3.22 (m, 1 H) 3.34-3.57 (m, 6 H) 3.58-3, 69 (m, 3 H) 3.69-3.77(m, 1 H) 3.79-3.86 (m, 1 H) 4.89 (t, J=10.10 Hz, 1 H) 5 .26 (d, J=10.67 Hz, 1 H) 5.39 (dd, J=15.06, 9.66 Hz, 1 H) 5.60 (dd, J=15.00, 9.98 Hz, 1 H) 6.24-6.42 (m, 3 H) 6.50 (s, 1 H) 16
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate LCMS (ESI, mass/charge), 684.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=3.39 Hz, 3 H) 1.00 (d, J=3.26 Hz, 3 H) 1.07-1.17 ( m, 1 H) 1.18-1.33 (m, 10 H) 1.42-1.54 (m, 1 H) 1.54-1.71 (m, 5 H) 1.74-1, 83(m,1 H) 1.87 (s, 3 H) 1.89-1.97 (m, 1 H) 1.98-2.12 (m, 2 H) 2.32-2.46 ( m, 2 H) 2.51-2.69 (m, 3 H) 2.70-2.84 (m, 2 H) 2.85-3.18 (m, 5 H) 3.33-3, 44 (m, 2 H) 3.70-3.85 (m, 3 H) 4.22-4.40 (m, 2 H) 4.86 (t, J=10.04 Hz, 1 H) 5 .25 (d, J=10.54 Hz, 1 H) 5.39 (dd, J=15.06, 9.66 Hz, 1 H) 5.59 (dd, J=15.00, 9.85 Hz, 1 H) 6.41-6.54 (m, 4 H) 17
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]-5-fluorophenyl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 615.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.95-1.05 (m, 6 H) 1.18-1.31 (m, 2 H) 1.42-1.54 (m, 1 H) 1 .70-1.84 (m, 1 H) 1.88 (d, J=1.13 Hz, 3 H) 1.90-1.96 (m, 1 H) 2.17-2.25 (m , 2 H) 2.30 (s, 3 H) 2.32 (s, 6 H) 2.33-2.43 (m, 5 H) 2.48-2.70 (m, 3 H) 2, 80-2.97 (m, 1 H) 3.15 (t, J=8.53 Hz, 1 H) 3.29 (td, J=9.44, 6.84 Hz, 1 H) 3.36 -3.44 (m, 2 H) 3.45-3.56 (m, 4 H) 3.67-3.75 (m, 1 H) 4.86 (t, J=10.04 Hz, 1 H) 5.25 (d, J=10.54 Hz, 1 H) 5.39 (dd, J=15.06, 9.66 Hz, 1 H) 5.59 (dd, J=15.00, 9.85 Hz, 1 H) 6.08-6.16 (m, 2 H) 6.32 (br d, J=9.66 Hz, 1 H) 6.47-6.54 (m, 1 H ) 18
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-(3-methyl-5-morpholin-4-ylphenyl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 584.6 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) 0.87-0.92 (m, 6 H) _1.09-1.34 (m, 3 H) 1.40-1.56 (m, 2 H ) 1.80 (s, 3 H) 1.95-2.05 (m, 2 H) 2.14-2.37 (m, 8 H) 2.50 (s, 3 H) 3.05-3 .10 (m, 4 H) 3.30-3.39 (m, 4 H) 3.69-3.75 (m, 5 H) 4.61 (d, J=5.40 Hz, 1 H) 4.66-4.77 (m, 1 H) 4.99 (d, J=10.29 Hz, 1 H) 5.37-5.50 (m, 2 H) 6.45 (s, 1 H ) 6.51-6.71 (m, 3 H) 19
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-[3-morpholin-4-yl-5-(trifluoromethyl)phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 584.6 [M+H] ⁺ 20
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Chloro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 604.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 0.89 (d, J=6.65 Hz, 6 H) 1.16-1.33 (m, 3 H) 1.38-1.55 (m , 2 H) 1.81 (s, 3 H) 2.16 (s, 3 H) 2.20-2.35 (m, 7 H) 3.07-3.17 (m, 4 H) 3, 32-3.53 (m, 4 H) 3.68-3.78 (m, 5 H) 4.64 (d, J=5.14 Hz, 1 H) 4.69 (t, J=9, 47 Hz, 1 H) 4.99 (d, J=10.54 Hz, 1 H) 5.31-5.54 (m, 2 H) 6.46 (s, 1 H) 6.72-6, 80 (m, 2 H) 6.86 (s, 1 H) 21
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2-hydroxyethyl)piperazine-1-carboxylate LCMS (ESI, mass/charge), 618.6 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 0.89 (dd, J=6.59, 2.07 Hz, 6 H) 1.13-1.33 (m, 3 H) 1.40-1 .51 (m, 2 H) 1.82 (s, 3 H) 2.23-2.44 (m, 9 H) 3.08-3.18 (m, 4 H) 3.26-3.56 (m, 6 H) 3.66-3.77 (m, 5 H) 4.40-4.49 (m, 1 H) 4.63 (d, J=5.02 Hz, 1 H) 4, 69 (t, J=9.47 Hz, 1 H) 4.98 (d, J=10.67 Hz, 1 H) 5.34-5.51 (m, 2 H) 6.43-6.56 (m, 2 H) 6.60-6.70 (m, 2 H) 22
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-4-yl)carbamate LCMS (ESI, mass/charge), 616.6 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 0.88 (dd, J=6.53, 2.89 Hz, 6 H) 1.16-1.30 (m, 4 H) 1.38-1 .52 (m, 4 H) 1.63-1.74 (m, 1 H) 1.82 (s, 3 H) 1.90-2.05 (m, 2 H) 2.17 (s, 3 H) 2.25-2.38 (m, 1 H) 2.48-2.52 (m, 3 H) 2.69 (s, 3 H) 2.79-2.87 (m, 2 H) 3.09-3.17 (m, 4 H) 3.66-3.76 (m, 5 H) 4.64 (br s, 1 H) 4.66-4.73 (m, 1 H) 4 .98 (d, J=10.92 Hz, 1 H) 5.42 (dd, J=16.12, 8.47 Hz, 2 H) 6.36-6.57 (m, 2 H) 6, 59-6.74 (m, 2H) 23
[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3,4-dimethylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.6 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 0.88 (dd, J=6.65, 3.89 Hz, 6 H) 0.96 (d, J=6.40 Hz, 3 H) 1, 16-1.30 (m, 3 H) 1.37-1.54 (m, 2 H) 1.81 (s, 3 H) 1.92-2.04 (m, 1 H) 2.22- 2.34 (m, 2 H) 2.35-2.46 (m, 3 H) 2.50 (s, 3 H) 3.06-3.21 (m, 4 H) 3.29-3, 41 (m, 4 H) 3.67-3.80 (m, 5 H) 4.64-4.72 (m, 2 H) 4.97 (d, J=10.29 Hz, 1 H) 5 .32-5.53 (m, 2 H) 6.39-6.56 (m, 2 H) 6.59-6.74 (m, 2 H) 24
[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-propan-2-ylpiperazin-1-carboxylate LCMS (ESI, mass/charge), 616.6 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 0.88 (dd, J=6.40, 3.89 Hz, 6 H) 1.00 (s, 6 H) 1.17-1.32 (m , 3 H) 1.41-1.52 (m, 2 H) 1.81 (s, 3 H) 1.93-2.07 (m, 1 H) 2.20-2.37 (m, 2 H) 2.41-2.47 (m, 5 H) 3.09-3.15 (m, 4 H) 3.27-3.39 (m, 4 H) 3.68-3.77 (m , 5 H) 4.64-4.72 (m, 2 H) 4.97 (d, J=10.54 Hz, 1 H) 5.35-5.51 (m, 2 H) 6.40- 6.59 (m, 2 H) 6.59-6.72 (m, 2 H) 25
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-tert-butylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 630.6 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 0. 08 (s, 9 H) 0.89 (dd, J=6.71, 3.70 Hz, 6 H) 1.17-1.32 (m , 2 H) 1.41-1.52 (m, 2 H) 1.55-1.68 (m, 1 H) 1.81 (s, 3 H) 1.95-2.12 (m, 1 H) 2.24-2.35 (m, 2 H) 2.41-2.48 (m, 4 H) 3.03-3.17 (m, 4 H) 3.24-3.35 (m , 4 H) 3.68-3.82 (m, 5 H) 4.58-4.75 (m, 2 H) 4.98 (d, J=10.04 Hz, 1 H) 5.35- 5.55 (m, 2 H) 6.44-6.55 (s, 2 H) 6.60-6.75 (m, 2 H) 26
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclobutylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 628.6 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6 ) 0.85-0.90 (m, 6 H) _1.14-1.35 (m, 5 H) 1.39-1.51 (m, 4 H ) 1.52-1.63 (m, 1 H) 1.70-1.76 (m, 1 H) 1.80 (s, 3 H) 1.93-2.05 (m, 1 H) 2 .22-2.47 (m, 7 H) 3.08-3.15 (m, 4 H) 3.23-3.38 (m, 4 H) 3.67-3.80 (m, 5 H ) 4.50-4.81 (m, 2 H) 4.97 (d, J =10.67 Hz, 1 H) 5.34-5.54 (m, 2 H) 6.46 (s, 2 H) 6.62 (s, 2 H) 27
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclopentylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 642.7 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- d6 ) 0.85-0.95 (m, 6 H) _1.14-1.33 (m, 4 H) 1.38-1.52 (m, 6 H ) 1.53-1.65 (m, 2 H) 1.67-1.76 (m, 1 H) 1.80 (s, 3 H) 1.89-2.08 (m, 1 H) 2 .19-2.36 (m, 2 H) 2.39-2.50 (m, 5 H) 3.08-3.15 (m, 4 H) 3.36-3.52 (m, 4 H ) 3.68-3.76 (m, 5 H) 4.61-4.77 (m, 2 H) 4.97 (d, J=10.79 Hz, 1 H) 5.35-5.50 (m, 2 H) 6.42-6.56 (m, 2 H) 6.60-6.70 (m, 2 H) 28
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3,5-Difluorophenyl)prop-1-en-2-yl]-10-hydroxy-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 521.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=6.78 Hz, 3 H) 1.01 (d, J=6.78 Hz, 3 H) 1.20-1.32 ( m, 2 H) 1.42-1.56 (m, 1 H) 1.75 -1.84 (m, 1 H) 1.87 (d, J=1.13 Hz, 3 H) 1.89 -1.98 (m, 1 H) 2.30 (s, 3 H) 2.36 (br s, 4 H) 2.49-2.70 (m, 3 H) 3.34 (br s, 1 H) 3.49 (br s, 4 H) 3.71 (s, 1 H) 4.88 (t, J=10.04 Hz, 1 H) 5.25 (d, J=10.54 Hz, 1 H) 5.40 (dd, J=15.06, 9.66 Hz, 1 H) 5.53-5.65 (m, 1 H) 6.49 (s, 1 H) 6.62-6 .73 (m, 1 H) 6.74-6.82 (m, 2 H) 29
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(Dimethylamino)-5-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 546.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.99 (t, J=6.84 Hz, 6 H) 1.21-1.30 (m, 2 H) 1.43-1.55 (m, 1 H) 1.70-1.82 (m, 1 H) 1.88 (br d, J=1.25 Hz, 3 H) 1.90-1.97 (m, 1 H) 2.35 (s , 3 H) 2.46 (br s, 4 H) 2.51-2.68 (m, 3 H) 2.94 (s, 6 H) 3.50-3.61 (m, 4 H) 3 .68-3.78 (m,1 H) 4.88 (t, J=10.04 Hz, 1 H) 5.26 (m, t, J=10.67 Hz, 1 H) 5.39 ( dd, J=14.93, 9.66 Hz, 1 H) 5.60 (dd, J=15.00, 9.85 Hz, 1 H) 6.18-6.43 (m, 3 H) 6 .51 (s.1 H) thirty
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-(4-hydroxypiperidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.99 (t, J=6.71 Hz, 6 H) 1.19-1.31 (m, 2 H) 1.42-1.55 (m, 1 H) 1.59-1.72 (m, 2 H) 1.75 -1.84 (m, 1 H) 1.87 (d, J=1.25 Hz, 3 H) 1.89-2, 02 (m, 3 H) 2.44 (s, 3 H) 2.49-2.70 (m, 8 H) 2.92-3.01 (m, 2 H) 3.50-3.67 ( m, 6 H) 3.67-3.78 (m, 1 H) 3.88 (tt, J=8.56, 4.05 Hz, 1 H) 4.88 (t, J=10.04 Hz , 1 H) 5.25 (d, J=10.54 Hz, 1 H) 5.39 (dd, J=15.00, 9.72 Hz, 1 H) 5.60 (dd, J=15.06 , 9.91 Hz, 1 H) 6.41-6.52 (m, 3 H) 6.54 (s, 1 H) 31
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[methyl-(1-methylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 629.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 1.02 (t, J=6.78 Hz, 6 H) 1.18-1.36 (m, 2 H) 1.46-1.57 (m, 1 H) 1.76-1.92 (m, 6 H) 1.91-2.00 (m, 1 H) 2.22-2.39 (m, 2 H) 2.50 (s, 3 H) 2.54-2.66 (m, 3 H) 2.66-2.77 (m, 8 H) 2.81 (s, 3 H) 3.53-3.89 (m, 9 H) 4, 91 (t, J=10.10 Hz, 1 H) 5.28 (d, J=10.54 Hz, 1 H) 5.42 (dd, J=15.00, 9.72 Hz, 1 H) 5.62 (dd, J=14.81, 9.91 Hz, 1 H) 6.31-6.47 (m, 3 H) 6.52 (s, 1 H) 32
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(1R,5S)-8-oxa-3-azabicyclo[3.2.1] octan-3-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate LCMS (ESI, mass/charge), 614.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.99 (t, J=6.15 Hz, 6 H) 1.18-1.32 (m, 2 H) 1.46-1.57 (m, 1 H) 1.73-1.84 (m, 1 H) 1.86 (s, 3 H) 1.88-2.04 (m, 5 H) 2.45-2.70 (m, 6 H) 2.76-2.93 (m, 4 H) 2.99-3.10 (m, 2 H) 3.16-3.36 (m, 2 H) 3.55-3.77 (m, 5 H) 4.39-4.55 (m, 2 H) 4.88 (t, J=10.10 Hz, 1 H) 5.25 (d, J=10.67 Hz, 1 H) 5.38 (dd, J=14.87, 9.72 Hz, 1 H) 5.60 (dd, J=15.00, 9.98 Hz, 1 H) 6.35-6.42 (m, 2 H) 6.45 (br d, J=9.03 Hz, 1 H) 6.50 (s, 1 H) 33
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 614.5 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) 0.99 (d, J=6.78 Hz, 6 H) 1.19-1.34 (m, 2 H) 1.43-1.55 (m, 1 H) 1.70-1.82 (m, 1 H) 1.88 (br d, J=1.25 Hz, 3 H) 1.91-1.99 (m, 1 H) 2.31 (t , J=6.90 Hz, 2 H) 2.49-2.70 (m, 3 H) 2.78 (s, 3 H) 2.89-3.22 (m, 4 H) 3.30 ( t, J=6.90 Hz, 3 H) 3.53 (s, 2 H) 3.68-3.78 (m, 1 H) 3.80-4.10(m, 4 H) 4.61 -4.67 (m, 2 H) 4.67-4.76 (m, 2 H) 4.89 (t, J=10.16 Hz, 1 H) 5.26 (d, J=10.67 Hz, 1 H) 5.38 (dd, J=15.06, 9.79 Hz, 1 H) 5.61 (dd, J=15.00, 9.98 Hz, 1 H) 6.09-6 .18 (m, 2 H) 6.30-6.37 (m, 1 H) 6.50 (s, 1 H) 34
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 588.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=5.52 Hz, 3 H) 1.00 (d, J=5.52 Hz, 3 H) 1.19-1.34 ( m, 2 H) 1.43-1.55 (m, 1 H) 1.73-1.84 (m, 1 H) 1.87 (d, J=1.25 Hz, 3 H) 1.90 -1.97 (m, 1 H) 2.05-2.19 (m, 2 H) 2.46 (s, 3 H) 2.51-2.59 (m, 3 H) 2.60-2 .68 (m, 4 H) 3.25 (d, J=10.54 Hz, 1 H) 3.34 (td, J=8.91, 3.26 Hz, 1 H) 3.43-3, 53 (m, 2 H) 3.62 (br s, 4 H) 3.70-3.79 (m, 1 H) 4.54-4.66 (m, 1 H) 4.88 (t, J =10.10 Hz, 1 H) 5.26 (d, J=10.67 Hz, 1 H) 5.39 (dd, J=14.93, 9.54 Hz, 1 H) 5.60 (dd , J=14.93, 9.91 Hz, 1 H) 6.10-6.22 (m, 2 H) 6.29-6.37 (m, 1 H) 6.51 (s, 1 H) 35
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-(3-oxopyrrolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 586.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.88-1.06 (m, 6 H) 1.19-1.34 (m, 2 H) 1.41-1.56 (m, 1 H) 1 .73-1.85 (m, 1 H) 1.87 (d, J=1.25 Hz, 3 H) 1.91-2.01 (m, 1 H) 2.49-2.90 (m , 10 H) 3.35-3.56 (m, 2 H) 3.59-3.82 (m, 7 H) 4.10-4.35 (m, 2 H) 4.89 (br t, J=10.10 Hz, 1 H) 5.27 (d, J=10.79 Hz, 1 H) 5.34-5.43 (m, 1 H) 5.62 (br dd, J=14, 56, 9.79 Hz, 1 H) 6.17-6.32 (m, 1 H) 6.47 (br d, J=9.41 Hz, 1 H) 6.53 (s, 1 H) 36
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(oxan-4-yl)piperazine-1-carboxylate LCMS (ESI, mass/charge), 658.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.99 (d, J=6.78 Hz, 6 H) 1.17-1.32 (m, 2 H) 1.41-1.58 (m, 1 H) 1.71-1.85 (m, 3 H) 1.87 (d, J=1.13 Hz, 3 H) 1.89-1.97 (m, 1 H) 1.99-2, 14 (m, 2 H) 2.48-2.60 (m, 3 H) 2.60-2.69 (m, 1 H) 3.02 (br s, 4 H) 3.12-3.24 (m, 5 H) 3.41(br t, J=11.42 Hz, 2 H) 3.63-3.78 (m, 1 H) 3.81 -3.87 (m, 4 H) 3 .92 (br s, 4 H) 4.05-4.16 (m, 2 H) 4.88 (t, J=10.10 Hz, 1 H) 5.25 (d, J=10.67 Hz , 1 H) 5.38 (dd, J=15.00, 9.73 Hz, 1 H) 5.60 (dd, J=15.00, 9.98 Hz, 1 H) 6.44-6, 60 (m, 4 H) 37
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-3-yl)carbamate LCMS (ESI, mass/charge), 616.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.89-1.09 (m, 6 H) 1.17-1.35 (m, 2 H) 1.40 -1.60 (m, 3 H) 1 .71-1.86 (m, 2 H) 1.87 (s, 3 H) 1.88 -2.00 (m, 2 H) 2.25-2.45 (m, 2 H) 2.49 -2.67 (m, 4 H) 2.71 (s, 3 H) 2.82 (s, 3 H) 2.88-3.03 (m, 2 H) 3.13-3.20 (m , 4 H) 3.67-3.77 (m, 1 H) 3.81-3.91 (m, 4 H) 4.21-4.63 (m, 1 H) 4.80-4.93 (m, 1 H) 5.25 (d, J=10.67 Hz, 1 H) 5.35-5.45 (m, 1 H) 5.58 (dd, J=14.93, 10.04 Hz, 1 H) 6.36-6.66 (m, 4 H) 38
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-(3-fluoroazetidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 576.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=6.65 Hz, 3H) 1.01 (d, J=6.78 Hz, 3 H) 1.27-1.47 (m , 2 H) 1.56-1.73 (m, 2 H) 1.86 (d, J=1.00 Hz, 3 H) 1.91-2.03 (m, 1 H) 2.30 ( s, 3 H) 2.36-2.43 (m, 4 H) 2.43-2.53 (m, 1 H) 2.58-2.70 (m, 2 H) 3.38-3, 57 (m, 6 H) 3.73-3.98 (m, 3 H) 4.17 (m, 2 H) 4.82 (m, 1 H) 5.13 (d, J=10.54 Hz , 1 H) 5.43-5.62 (m, 2 H) 6.07-6.19 (m, 2 H) 6.34-6.42 (m, 1 H) 6.49-6.54 (m, 1H) 39
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(3S)-3-(methylamino)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 601.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=6.78 Hz, 3 H) 1.01 (d, J=6.78 Hz, 3 H) 1.27-1.47 ( m, 2 H) 1.64 (br s, 2 H) 1.87 (d, J=1.00 Hz, 3 H) 1.90-2.01 (m, 2 H) 2.02-2, 16 (m, 1 H) 2.31 (s, 3 H) 2.35-2.52 (m, 6 H) 2.56-2.70 (m, 4 H) 3.33-3.38 ( m, 2 H) 3.45-3.59 (m, 6 H) 3.66-3.75 (m, 1 H) 3.76-3.85 (m, 1 H) 479-4.84 ( m, 1 H) 5.13 (d, J=10.67 Hz, 1 H) 5.44-5.62 (m, 2 H) 6.19-6.32 (m, 2 H) 6.33 -6.39 (m, 1 H) 6.53 (s, 1 H) 40
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3-(dimethylamino)piperidine-1-carboxylate LCMS (ESI, mass/charge), 616.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.91-1.05 (m, 6 H) 1.17-1.35 (m, 3 H) 1.42-1.61 (m, 3 H) 1 .73-1.83 (m, 2 H) 1.87 (s, 3 H) 1.86-2.03 (m, 1 H) 2.29-2.46 (m, 1 H) 2.50 -2.68 (m, 3 H) 2.78 (br s, 6 H) 2.87-2.98 (m, 1 H) 3.01-3.11 (m, 1 H) 3.12- 3.21 (m, 4 H) 3.59-3.78 (m, 1 H) 3.80-3.91 (m, 3 H) 3.99-4.23 (m, 1 H) 4, 36-4.66 (m, 1 H) 4.73-5.00 (m, 1 H) 5.25 (d, J=10.67 Hz, 1 H) 5.33-5.47 (m, 1 H) 5.52-5.73 (m, 1 H) 6.31-6.58 (m, 4 H) 41
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(2R)-2-methylpyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 586.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.95-1.03 (m, 6 H) 1.16 (d, J=6.27 Hz, 3 H) 1.21-1.33 (m, 2 H) 1.40-1.56 (m, 1 H) 1.67-1.746 (m, 1 H) 1.74-1.84 (m, 1 H) 1.89 (s, 3 H) 1, 92-1.99 (m, 1 H) 1.99-2.13 (m, 3 H) 2.48-2.60 (m, 2 H) 2.62-2.70 (m, 1 H) 2.76 (s, 3 H) 2.90-3.10 (m, 4 H) 3.10-3.24 (m, 1 H) 3.32-3.44 (m, 1 H) 3, 67-3.77 (m, 1 H) 3.79-3.86 (m, 1 H) 3.86-4.05 (m, 4 H) 4.89 (br t, J=10.10 Hz , 1 H) 5.27 (d, J=10.54 Hz, 1 H) 5.32-5.44 (m, 1 H) 5.55-5.68 (m, 1 H) 6.09- 6.22 (m, 2 H) 6.28 (br d, J=9.54 Hz, 1 H) 6.50 (s, 1 H) 42
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-(2-oxopyrrolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 586.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=6.78 Hz, 3 H) 1.00 (d, J=6.78 Hz, 3 H) 1.16-1.32 ( m, 2 H) 1.40-1.54 (m, 1 H) 1.74-1.82 (m, 1 H) 1.89 (d, J=1.25 Hz, 3 H) 1.90 -1.97 (m, 1 H) 2.09-2.22 (m, 2 H) 2.29 (s, 3 H) 2.24-2.33 (m, 4 H) 2.50-2 .70 (m, 5 H) 3.24-3.35 (m, 1 H) 3.35-3.50 (m, 4 H) 3.60-3.70 (m, 1 H) 3.84 (t, J=7.03 Hz, 2 H) 4.88 (t, J=10.10 Hz, 1 H) 5.26 (d, J=10.67 Hz, 1 H) 5.36-5 .45 (m, 1 H) 5.52 (dd, J=15.00, 9.98 Hz, 1 H) 6.53 (s, 1 H) 6.72 -6.83 (m, 1 H) 7.27-7.30 (m, 1 H) 7.35-7.41 (m, 1 H) 43
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(2S)-2-methylpyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), x586.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.99 (br d, J=5.27 Hz, 6 H) 1.17 (d, J=6.27 Hz, 3 H) 1.21-1.33 (m, 2 H) 1.40-1.56 (m, 1 H) 1.67-1.746 (m, 1 H) 1.74-1.84 (m, 1 H) 1.89 (s, 3 H) 1.92-1.99 (m, 1 H) 1.99-2.13 (m, 3 H) 2.48-2.60 (m, 2 H) 2.62-2.70 (m , 1 H) 2.76 (s, 3 H) 2.90-3.10 (m, 4 H) 3.10-3.24 (m, 1 H) 3.32-3.44 (m, 1 H) 3.67-3.77 (m, 1 H) 3.79-3.86 (m, 1 H) 3.86-4.05 (m, 4 H) 4.89 (br t, J= 10.10 Hz, 1 H) 5.27 (d, J=10.54 Hz, 1 H) 5.39 (dd, J=14.93, 9.54 Hz, 1 H) 5.60 (dd, J=14.93, 9.91 Hz, 1 H) 6.10-6.23 (m, 2 H) 6.28 (br d, J=9.54 Hz, 1 H) 6.50 (s, 1 H) 44
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.99 (d, J=6.65 Hz, 5 H) 1.18-1.35 (m, 2 H) 1.42-1.51 (m, 1 H) 1.72-1.84 (m, 1 H) 1.88 (s, 3 H) 1.91-1.97 (m, 1 H) 1.97-2.19 (m, 4 H) 2.47-2.68 (m, 3 H) 2.71-2.88 (m, 5 H) 3.12-3.22 (m, 1 H) 3.34-3.55 (m, 4 H) 3.62-3.79 (m, 5 H) 3.80-3.90 (m, 1 H) 4.10-4.34 (m, 2 H) 4.89 (br t, J= 10.04 Hz, 1 H) 5.26 (d, J=10.54 Hz, 1 H) 5.38 (br dd, J=14.62, 9.60 Hz, 1 H) 5.61 (dd , J=14.81, 9.91 Hz, 1 H) 6.29-6.44 (m, 3 H) 6.51 (s, 1 H) 45
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 601.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=6.90 Hz, 3 H) 1.00 (d, J=7.03 Hz, 3 H) 1.17-1.32 ( m, 2 H) 1.43-1.55 (m, 1 H) 1.72-1.84 (m, 1 H) 1.87 (d, J=1.13 Hz, 3 H) 1.88 -1.97 (m, 2 H) 2.18-2.28 (m, 1 H) 2.30 (s, 3 H) 2.38 (br s, 4 H) 2.49 (s, 3 H ) 2.51-2.60 (m, 2 H) 2.60-2.69 (m, 1 H) 2.94-3.18 (m, 5 H) 3.24-3.35 (m, 1 H) 3.37-3.59 (m, 5 H) 3.67-3.79 (m, 1 H) 4.88 (t, J=10.10 Hz, 1 H) 5.25 (d , J=10.67 Hz, 1 H) 5.39 (dd, J=15.06, 9.66 Hz, 2 H) 5.59 (dd, J=15.06, 9.91 Hz, 2 H ) 6.06-6.21 (m, 2 H) 6.28-6.37 (m, 1 H) 6.50 (s, 1 H) 46
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(5-Chloropyridin-3-yl)prop-1-en-2-yl]-10-hydroxy-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 520.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.99 (d, J=5.40 Hz, 3 H) 1.01 (d, J=5.27 Hz, 3 H) 1.17-1.33 ( m, 2 H) 1.42-1.55 (m, 1 H) 1.74-1.85 (m, 1 H) 1.89 (s, 3 H) 1.90-1.98 (m, 1 H) 2.32 (s, 3 H) 2.39 (br s, 4 H) 2.50-2.78 (m, 3 H) 3.25-3.37 (m, 1 H) 3, 50 (br s, 4 H) 3.73 (br s, 1 H) 4.88 (t, J=10.04 Hz, 1 H) 5.28 (d, J=10.67 Hz, 1 H) 5.41 (dd, J=15.06, 9.66 Hz, 1 H) 5.59 (dd, J=15.00, 9.85 Hz, 1 H) 6.35-6.64 (m, 1 H) 7.49-7.68 (m, 1 H) 8.40 (d, J=1.38 Hz, 1 H) 8.44 (d, J=2.13 Hz, 1 H) 47
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(pyridin-4-ylmethyl)carbamate LCMS (ESI, mass/charge), 610.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.83-1.11 (m, 6 H) 1.14-1.35 (m, 1 H) 1.35-1.60 (m, 1 H) 1 .67-1.84 (m, 1 H) 1.87 (s, 3 H) 1.94-2.07 (m, 1 H) 2.49-2.75 (m, 3 H) 2.86 -3.05 (m, 3 H) 3.08-3.25 (m, 4 H) 3.63-3.78 (m, 1 H) 3.81-3.94 (m, 4 H) 4 .45-4.69 (m, 2 H) 4.92 (t, J=9.91 Hz, 1 H) 5.19-5.53 (m, 2 H) 5.57 -5.70 (m , 1 H) 6.41-6.59 (m, 4 H) 7.28-7.49 (m, 2 H) 8.49-8.78 (m, 2 H) 48
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3,5-Dichlorophenyl)prop-1-en-2-yl]-10-hydroxy-3,7- dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 553.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=6.78 Hz, 3 H) 1.00 (d, J=6.78 Hz, 3 H) 1.18-1.32 ( m, 2 H) 1.40-1.54 (m, 1 H) 1.74-1.83 (m, 1 H) 1.85 (d, J=1.13 Hz, 3 H) 1.89 -1.97 (m, 1 H) 2.29 (s, 3 H) 2.36 (br s, 4 H) 2.47-2.71 (m, 3 H) 3.26-3.40 ( m, 1 H) 3.48 (br s, 4 H) 3.63-3.80 (m, 1 H) 4.87 (t, J=10.10 Hz, 1 H) 5.40 (dd, J=15.06, 9.66 Hz, 1 H) 5.58 (dd, J=15.00, 9.85 Hz, 1 H) 6.46 (s, 1 H) 7.13 (d, J =1.76 Hz, 2 H) 7.24 (t, J=1.82 Hz, 1 H) 49
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-Dioxo-1,2-thiazolidin-2-yl)phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 604.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 1.00 (t, J=6.71 Hz, 6 H) 1.18 -1.32(m, 2 H) 1.44-1.55 (m, 1 H) 1.73-1.84 (m, 1 H) 1.88 (d, J=1.25 Hz, 3 H) 1.90-2.00 (m, 1 H) 2.30 (s, 3 H) 2.37 (br s, 4 H) 2.49-2.60 (m, 4 H) 2.61-2.74 (m, 1 H) 3.39 (t, J=7.53 Hz, 2 H) 3.49 (br s, 4 H) 3.67-3.75 (m, 1 H) 3.78 (t, J=6.59 Hz, 2 H) 4.89 (t, J=10.04 Hz, 1 H) 5.28 (d, J=10.54 Hz, 1 H) 5.40 (dd, J=15.06, 9.66 Hz, 1 H) 5.60 ( dd, J=15.00, 9.85 Hz, 1 H) 6.56 (s, 1 H) 7.03-7.09 (m, 1 H) 7.12-7.22 (m, 2 H ) 7.29-7.37 (m, 1H) 50
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(1,3-Dimethyl-indazol-6-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 553.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 1.04 (d, J=7.03 Hz, 3 H) 1.06 (d, J=6.90 Hz, 3 H) 1.22-1.36 ( m, 2 H) 1.47-1.55 (m, 1 H) 1.75-1.89 (m, 1 H) 1.93-2.01 (m, 4 H) 2.33 (s, 3 H) 2.39 (br s, 4 H) 2.54-2.74 (m, 6 H) 3.44 (br d, J=10.79 Hz, 1 H) 3.52 (br s, 4 H) 3.69 -3.82 (m, 1 H) 4.01 (s, 3 H) 4.92 (t, J=10.04 Hz, 1 H) 5.35 (d, J=10 .67 Hz, 1 H) 5.44 (dd, J=14.93, 9.66 Hz, 1 H) 5.65 (dd, J=15.06, 9.91 Hz, 1 H) 6.77 (s, 1 H) 7.06 (dd, J=8.41, 1.13 Hz, 1 H) 7.21 (s, 1 H) 7.61 (d, J=8.28 Hz, 1 H ) 51
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-Dioxo-1,4-thiazinan-4-yl)-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N, N-dimethylcarbamate LCMS (ESI, mass/charge), 581.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=6.78 Hz, 3 H) 1.01 (d, J=6.90 Hz, 3 H) 1.15-1.33 ( m, 2 H) 1.40-1.56 (m, 1 H) 1.72-1.84 (m, 1 H) 1.86 (d, J=1.13 Hz, 3 H) 1.89 -2.06 (m, 1 H) 2.48-2.68 (m, 3 H) 2.90 (s, 6 H) 3.02-3.17 (m, 4 H) 3.69-3 .78 (m, 1 H) 3.82-3.95 (m, 4 H) 4.85 (t, J=10.04 Hz, 1 H) 5.24 (d, J=10.54 Hz, 1 H) 5.40 (dd, J=15.06, 9.66 Hz, 1 H) 5.58 (dd, J=15.00, 9.85 Hz, 1 H) 6.43-6.53 (m, 3 H) 6.57 (br d, J=9.29 Hz, 1 H) 52
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-Dioxo-1,4-thiazinan-4-yl)-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 636.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 1.00 (t, J=6.84 Hz, 6 H) 1.21-1.31 (m, 2 H) 1.45-1.55 (m, 1 H) 1.72-1.84 (m, 1 H) 1.87 (s, 3 H) 1.90-1.99 (m, 1 H) 2.40 (s, 3 H) 2.48- 2.70 (m, 7 H) 3.04-3.16 (m, 4 H) 3.50-3.66 (m, 5 H) 3.69-3.79 (m, 1 H) 3, 81-3.88 (m, 4 H) 4.88 (t, J=10.10 Hz, 1 H) 5.25 (d, J=10.29 Hz, 1 H) 5.40 (dd, J=15.06, 9.66 Hz, 1 H) 5.59 (dd, J=14.87, 10.10 Hz, 1 H) 6.46-6.52 (m, 3 H) 6.54 -6.62 (m, 1 H) 53
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]morpholine-4-carboxylate LCMS (ESI, mass/charge), 618.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=6.90 Hz, 3 H) 1.01 (d, J=6.90 Hz, 3 H) 1.17-1.33 ( m, 2 H) 1.41-1.55 (m, 1 H) 1.74-1.84 (m, 1 H) 1.86 (d, J=1.00 Hz, 3 H) 1.90 -2.03 (m, 1 H) 2.49-2.59 (m, 2 H) 2.60-2.66 (m, 3 H) 2.66-2.74 (m, 4 H) 3 .16-3.28 (m, 4 H) 3.39-3.52 (m, 4 H) 3.60-3.78 (m, 7 H) 4.89 (t, J=10.10 Hz , 1 H) 5.25 (d, J=10.67 Hz, 1 H) 5.40 (dd, J=15.06, 9.66 Hz, 1 H) 5.60 (dd, J=15, 06, 9.91 Hz, 1 H) 6.40-6.63 (m, 4 H) 54
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-4-yl) carbamate LCMS (ESI, mass/charge), 659.8 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.97 (d, J=6.78 Hz, 3 H) 1.00 (d, J=6.78 Hz, 3 H) 1.14-1.31 ( m, 2 H) 1.43-1.55 (m, 1 H) 1.56-1.69 (m, 2 H) 1.72-1.84 (m, 3 H) 1.86 (d, J=1.25 Hz, 3 H) 1.89-1.99 (m, 1 H) 2.02 (s, 3H) 2.05-2.17 (m, 2 H) 2.30 (s, 3 H) 2.45-2.58 (m, 2 H) 2.59-2.63 (m, 3 H) 2.64-2.70 (m, 4 H) 2.77 (s, 3 H ) 2.92-3.00 (m, 2 H) 3.16-3.26 (m, 4 H) 3.63-3.69 (m, 2 H) 3.70-3.77 (m, 1 H) 4.88 (t, J=9.98 Hz, 1 H) 5.25 (d, J=10.54 Hz, 1 H) 5.40 (dd, J=15.06, 9.66 Hz, 1 H) 5.58 (dd, J=14.93, 9.91 Hz, 1 H) 6.37-6.58 (m, 4 H) 55
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-(1-methyl-indazol-6-yl)prop-1-ene -2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 539.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 1.01 (d, J=6.78 Hz, 3 H) 1.03-1.06 (m, 3 H) 1.23-1.30 (m, 2 H) 1.46-1.57 (m, 1 H) 1.75-1.86 (m, 2 H) 1.98 -1.98 (m, 4 H) 2.36 (s, 3 H) 2.40-2.51 (m, 4 H) 2.53-2.71 (m, 3 H) 3.44-3.61 (m, 4 H) 3.70-3.78 (m, 1 H) 4.06 (s, 3 H) 4.90 (t, J=10.16 Hz, 1 H) 5.33 (d, J=10.54 Hz, 1 H) 5.41 (dd, J =15.00, 9.72 Hz, 1 H) 5.63 (dd, J=15.06, 9.91 Hz, 1 H) 6.75 (s, 1 H) 7.07 (dd, J= 8.41, 1.13 Hz, 1 H) 7.67 (d, J=8.91 Hz, 1 H) 7.94 (d, J=1.00 Hz, 1 H) 56
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-(3-oxomorpholin-4-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=6.78 Hz, 3 H) 1.00 (d, J=6.90 Hz, 3 H) 1.17-1.32 ( m, 2 H) 1.41-1.52 (m, 1 H) 1.75-1.85 (m, H) 1.88 (d, J=1.38 Hz, 3 H) 1.93 ( br s, 1 H) 2.39 (br s, 3 H) 2.43-2.72 (m, 7 H) 3.50-3.62 (m, 4 H) 3.63-3.68 ( m, 1 H) 3.70-3.80 (m, 3 H) 4.01-4.06 (m, 2 H) 4.54 (s, 2 H) 4.88 (t, J=10, 10 Hz, 1 H) 5.25 (d, J=10.54 Hz, 1 H) 5.40 (dd, J=15.06, 9.66 Hz, 1 H) 5.59 (dd, J= 14.93, 9.91 Hz, 1 H) 6.53 (s, 1 H) 6.87-6.95 (m, 1 H) 6.97-7.02 (m, 1 H) 7.05 (s, 1H) 57
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-(Cyclopentylsulfamoyl)-2-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 650.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.99 (d, J=4.64 Hz, 3 H) 1.01 (d, J=4.64 Hz, 3 H) 1.18-1.31 ( m, 3 H) 1.32-1.43 (m, 2 H) 1.44-1.56 (m, 3 H) 1.57-1.70 (m, 2 H) 1.72-1, 85 (m, 3 H) 1.90 (d, J=1.13 Hz, 3 H) 1.92-1.98 (m, 1 H) 2.40 (s, 3 H) 2.44-2 .73 (m, 7 H) 3.47-3.69 (m, 5 H) 3.69-3.80 (m, 1 H) 4.71 (d, J=7.53 Hz, 1 H) 4.88 (t, J=10.04 Hz, 1 H) 5.26 (d, J=10.54 Hz, 1 H) 5.40 (dd, J=15.06, 9.66 Hz, 1 H) 5.59 (dd, J=15.00, 9.85 Hz, 1 H) 6.56 (s, 1 H) 7.00-7.19 (m, 2 H) 7.86 (s, 1 H) 58
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-(4-methylsulfonylpiperazin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 665.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.99 (t, J=6.71 Hz, 6 H) 1.26 (br t, J=7.15 Hz, 6 H) 1.17-1.32 (m, 2 H) 1.44-1.54 (m, 1 H) 1.71-1.84 (m, 1 H) 1.86 (d, J=1.13 Hz, 3 H) 1, 89-1.99 (m, 1 H) 2.43 (br s, 3 H) 2.49-2.68 (m, 7 H) 2.83 (s, 3 H) 3.23-3.32 (m, 4 H) 3.34-3.45 (m, 4 H) 3.52-3.68 (m, 4 H) 3.68-3.79 (m, 1 H) 4.88 (t , J=10.04 Hz, 1 H) 5.25 (d, J=10.54 Hz, 1 H) 5.39 (dd, J=14.93, 9.66 Hz, 1 H) 5.59 (dd, J=15.06, 9.91 Hz, 1 H) 6.44-6.65 (m, 4 H) 59
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-Fluoro-1H-indazol-6-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 543.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 1.00 (d, J=5.02 Hz, 3 H) 1.02 (br d, J=4.89 Hz, 3 H) 1.19-1.36 (m, 2 H) 1.41-1.59 (m, 1 H) 1.75-1.86 (m, 1 H) 1.92 (d, J=1.13 Hz, 3 H) 1, 93-1.98 (m, 1 H) 2.47-2.87 (m, 10 H) 3.30-3.45 (m, 1 H) 3.62-3.98 (m, 5 H) 4.89 (t, J=10.10 Hz, 1 H) 5.29 (d, J=10.54 Hz, 1 H) 55.39 (dd, J=14.93, 9.66 Hz, 1 H) 5.62 (dd, J=14.93, 9.91 Hz, 1 H) 6.66 (s, 1 H) 6.76 (d, J=10.67 Hz, 1 H) 7.16 (s, 1 H) 8.11 (s, 1 H) 60
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-imidazol-1-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 569.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 1.01 (dd, J=6.84, 1.19 Hz, 6 H) 1.19-1.34 (m, 2 H) 1.44-1.55 (m,1 H) 1.72-1.85 (m, 1 H) 1.91 (d, J=1.25 Hz, 3 H) 1.92-1.98 (m, 1 H) 2, 37 (br s, 3 H) 2.47 (br s, 4 H) 2.53-2.71 (m, 3 H) 3.33 (br s, 1 H) 3.45-3.67 (m , 4 H) 3.73 (br s, 1 H) 4.88 (t, J=10.04 Hz, 1 H) 5.28 (d, J=10.67 Hz, 1 H) 5.41 ( dd, J=14.93, 9.66 Hz, 1 H) 5.60 (dd, J=14.93, 9.91 Hz, 1 H) 6.57 (s, 1 H) 6.96-7 .04 (m, 2 H) 7.06-7.11 (m, 1 H) 7.19-7.24 (m, 1 H) 7.26 (s, 1 H) 7.81-7.92 (m, 1H) 61
[(2S,3S,4E,6S,7R,10S)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 604.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (br d, J=6.78 Hz, 3 H) 1.08-1.18 (m, 2 H) 1.23 (br s, 3 H) 1.41-1.48 (m, 1 H) 1.73-1.79 (m, 1 H) 1.86 (s, 3 H) 2.45-2.69 (m, 7 H) 2, 70-2.93 (m, 3 H) 3.11-3.27 (m, 4 H) 3.63-4.02 (m, 8 H) 4.34-4.52 (m, 1 H) 5.00 (br d, J=9.66 Hz, 1 H) 5.15 (br d, J=10.16 Hz, 1 H) 5.50-5.65 (m, 1 H) 5.69 -5.81 (m, 1 H) 6.39-6.61 (m, 4 H) 62
[(2S,3S,4E,6S,7R,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate LCMS (ESI, mass/charge), 672.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.97 (d, J=6.78 Hz, 3 H) 1.16-1.30 (m, 5 H) 1.32-1.41 (m, 2 H) 1.50-1.61 (m, 1 H) 1.64-1.74 (m, 5 H) 1.81-1.88 (m, 5 H) 2.02-2.08 (m , 2 H) 2.36-2.48 (m, 2 H) 2.52-2.67 (m, 3 H) 2.67-2.92 (m, 2 H) 3.08-3.22 (m, 5 H) 3.36-3.52 (m, 3 H) 3.59-3.68 (m, 1 H) 3.71-3.78 (m, 1 H) 3.80-3 .86 (m, 4 H) 4.31 (s, 1 H) 4.99 (d, J=9.41 Hz, 1 H) 5.25 (d, J=10.79 Hz, 1 H) 5 .56-5.79 (m, 3 H) 6.41-6.57 (m, 4 H) 63
[(2S,3S,4E,6S,7R,10S)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate LCMS (ESI, mass/charge), 672.8 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.95 (d, J=6.78 Hz, 3 H) 1.11-1.30 (m, 5 H) 1.37-1.51 (m, 3 H) 1.55-1.75 (s, 5 H) 1.79-1.82 (m, 1 H) 1.84 (br d, J=1.00 Hz, 3 H) 1.87-1 .92 (m, 1 H) 2.02-2.08 (m, 2 H) 2.46-2.66 (m, 5 H) 2.71-2.91 (m, 3 H) 3.07 -3.18 (m, 4 H) 3.34-3.50 (m, 3 H) 3.78-3.89 (m, 4 H) 4.25-4.43 (m, 2 H) 4 .95 (d, J=9.79 Hz, 1 H) 5.12 (d, J=10.79 Hz, 1 H) 5.55 (dd, J=15.06, 9.91 Hz, 1 H ) 5.74 (dd, J=15.62, 9.98 Hz, 1 H) 6.35-6.56 (m, 4 H) 64
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-(2-oxoimidazolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 587.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.96 (d, J=5.02 Hz, 3 H) 0.98 (d, J=5.02 Hz, 4 H) 1.16-1.29 ( m, 2 H) 1.41-1.54 (m, 1 H) 1.82-1.85 (m, 1 H) 1.87 (d, J=1.25 Hz, 3 H) 1.89 -1.94 (m, 1 H) 2.52 (br s, 3 H) 2.50-2.68 (m, 7 H) 3.52-3.78 (m, 7 H) 3.84- 4.00 (m, 2 H) 4.72 (s, 1 H) 4.86 (t, J=10.10 Hz, 1 H) 5.24 (d, J=10.67 Hz, 1 H) 5.37 (dd, J=15.00, 9.72 Hz, 1 H) 5.57 (dd, J=15.00, 9.85 Hz, 1 H) 6.51 (s, 1 H) 6 ,60-6.70 (m, 1 H) 7.15 (s, 1 H) 7.29-7.32 (m, 1 H) 65
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 631.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.97 (d, J=6.65 Hz, 6 H) 1.16-1.29 (m, 2 H) 1.41-1.56 (m, 1 H) 1.81-1.84 (m, 1 H) 1.87 (br d, J=1.25 Hz, 8 H) 1.89-1.95 (m, 1 H) 2.45-2 .70 (m, 3 H) 2.72-2.84 (m, 7 H) 3.38 -3.47 (m, 4 H) 3.58-3.65 (m, 2 H) 3.66 -3.75 (m, 1 H) 3.77-3.91 (m, 4 H) 4.08-4.30 (m, 2 H) 4.86 (t, J=9.85 Hz, 1 H) 5.24 (d, J=10.79 Hz, 1 H) 5.36 (dd, J=14.68, 9.54 Hz, 1 H) 5.58 (dd, J=14.93, 10.04 Hz, 1 H) 6.50 (s, 1 H) 6.56-6.68 (m, 1 H) 7.14-7.24 (m, 2 H) 66
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[3-(2-fluoroethynyl)-2-oxoimidazolidin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 629.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.96 (d, J=2.64 Hz, 3 H) 0.98 (d, J=2.51 Hz, 3 H) 1.16-1.32 ( m, 2 H) 1.44-1.57(m,1 H) 1.75-1.83 (m, 1 H) 1.87 (br d, J=1.25 Hz, 3 H) 1, 91-1.96 (m, 1 H) 2.48-2.57 (m, 5 H) 2.59-2.69 (m, 2 H) 2.77 (s, 3 H) 3.63- 3.79 (m, 2 H) 3.82-3.90 (m, 4 H) 3.91- 4.00 (m, 4 H) 4.86 (t, J=10.04 Hz, 1 H ) 5.24 (d, J=10.54 Hz, 1 H) 5.37 (dd, J=14.87, 9.72 Hz, 1 H) 5.58 (dd, J=15.00, 9 .98 Hz, 1 H) 6.52 (s, 1 H) 6.71-6.81 (m, 1 H) 7.18 (s, 1 H) 7.27-7.31 (m, 1 H ) 67
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[3-(2-morpholin-4-ylethyl)-2-oxoimidazolidine-1- yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 700.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.97 (t, J=7.09 Hz, 6 H) 1.13-1.28 (m, 2 H) 1.40-1.54 (m, 1 H) 1.81-1.84 (m, 1 H) 1.86 (d, J=1.13 Hz, 3 H) 1.89-1.93 (m, 1 H) 2.37 (br s , 3 H) 2.44-2.67 (m, 13 H) 3.33-3.48 (m, 3 H) 3.50-3.64 (m, 6 H) 3.66-3.74 (m, 5 H) 3.76-3.82 (m, 2 H) 4.86 (t, J=10.04 Hz, 1 H) 5.23 (d, J=10.54 Hz, 1 H ) 5.37 (dd, J=14.87, 9.72 Hz, 1 H) 5.57 (dd, J=15.06, 9.91 Hz, 1 H) 6.50 (s, 1 H) 6.57-6.67 (m, 1 H) 7.19 (s, 1 H) 7.22-7.25 (m, 1 H) 68
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[3-(Cyclopropylmethyl)-2-oxoimidazolidin-1-yl]-5-fluorophenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 641.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.16-0.28 (m, 2 H) 0.48-0.57 (m, 2 H) 0.89-0.94 (m, 1 H) 0 .97 (t, J=7.03 Hz, 6 H) 1.18 -1.29 (m, 2 H) 1.42-1.53 (m, 1 H) 1.73-1.83 (m , 1 H) 1.87 (d, J=1.13 Hz, 3 H) 1.90-1.94 (m, 1 H) 2.37 (s, 3 H) 2.44-2.69 ( m, 7 H) 3.15 (d, J=7.03 Hz, 2 H) 3.49-3.64 (m, 5 H) 3.66-3.74 (m, 1 H) 3.78 (d, J=8.91 Hz, 2 H) 4.86 (t, J=10.10 Hz, 1 H) 5.23 (d, J=10.54 Hz, 1 H) 5.37 (dd , J=14.87, 9.72 Hz, 1 H) 5.57 (dd, J=15.06, 9.91 Hz, 1 H) 6.45-6.54 (m, 1 H) 6, 57-6.67 (m, 1 H) 7.20-7.26 (m, 2 H) 69
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[(2S)-2-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.5 [M+H] ⁺ 70
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-(2-methylmorpholin-4-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.5 [M+H] ⁺ 71
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[4-[(2S,3R)-3-hydroxy-2-methylpentyl]piperazine -1-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1 -carboxylate LCMS (ESI, mass/charge), 687.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.83 (d, J=7.03 Hz, 3 H) 0.91-1.04 (m, 11 H) 1.17-1.28 (m, 2 H) 1.30-1.40 (m, 1 H) 1.42-1.52 (m, 1 H) 1.76-1.80 (m, 1 H) 1.83 (s, 3 H) 1.86-1.91 (m, 1 H) 2.38 (s, 3 H) 2.46-2.72 (m, 7 H) 2.76-2.86 (m, 2 H) 2, 89-3.33 (m, 8 H) 3.46-3.64 (m, 5 H) 3.69 (br s, 1 H) 4.85 (t, J=9.85 Hz, 1 H) 5.22 (d, J=10.67 Hz, 1 H) 5.37 (dd, J=14.87, 9.72 Hz, 1 H) 5.57 (dd, J=15.06, 9, 91 Hz, 1 H) 6.36-6.57 (m, 4 H) 72
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[4-[(2R,3R)-3-hydroxy-2-methylpentanoyl]piperazine -1-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1 -carboxylate LCMS (ESI, mass/charge), 701.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.89-1.03 (m, 9 H) 1.15 (d, J=7.15 Hz, 3 H) 1.20-1.33 (m, 2 H) 1.36-1.63 (m, 3 H) 1.70-1.81 (m, 1H) 1.84 (d, J=1.13 Hz, 3 H) 1.86-1.91 (m, 1 H) 2.30 (s, 3 H) 2.37 (br s, 4 H) 2.48-2.57 (m, 2 H) 2.60-2.71 (m, 2 H ) 3.08-3.26 (m, 4 H) 3.48 (br s, 4 H) 3.57-3.66 (m, 2 H) 3.68-3.75 (m, 2 H) 3.75-3.85 (m, 2 H) 4.12-4.29 (m, 1 H) 4.85 (t, J=10.04 Hz, 1 H) 5.22 (d, J= 10.54 Hz, 1 H) 5.38 (dd, J=15.06, 9.66 Hz, 1 H) 5.56 (dd, J=14.93, 9.91 Hz, 1 H) 6, 22-6.76 (m, 4 H) 73
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-morpholin-4-ylethylsulfonyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 764.8 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.97 (t, J=6.40 Hz, 6 H) 1.15-1.28 (m, 2 H) 1.41-1.55 (m,1 H) 1.72-1.81 (m, 1 H) 1.84 (d, J=1.13 Hz, 3 H) 1.87 -1.95 (m, 1 H) 2.44 (s, 3 H) 2.46-2.68 (m, 11H) 2.80-2.89 (m, 3 H) 3.11-3.18 (m, 2 H) 3.20-3.32 (m , 4 H) 3.39-3.45 (m, 4 H) 3.59 (br s, 4 H) 3.65-3.75 (m, 5 H) 4.85 (t, J=10, 10 Hz, 1 H) 5.22 (d, J=10.67 Hz, 1 H) 5.37 (dd, J=15.00, 9.60 Hz, 1 H) 5.57 (dd, J= 15.00, 9.85 Hz, 1 H) 6.45-6.58 (m, 4 H) 74
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4-ethenylsulfonylpiperazin-1-yl)-5-fluorophenyl]prop-1-en-2-yl ]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 677.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.96 (t, J=6.65 Hz, 6 H) 1.17-1.31 (m, 2 H) 1.40-1.54 (m, 1 H) 1.70-1.81 (m, 1 H) 1.84 (d, J=1.13 Hz, 3 H) 1.88-1.95 (m, 1 H) 2.47 (s, 3 H) 2.49-2.64 (m, 3 H) 2.68 (br s, 4 H) 3.32-3.53 (m, 8 H) 3.55-3.67 (m, 4 H) 3.68-3.76 (m, 1 H) 4.76-4.91 (m, 1 H) 4.85 (t, J=10.10 Hz, 1 H) 5.22 (d, J=10.67 Hz, 1 H) 5.56 (dd, J=15.00, 9.85 Hz, 1 H) 6.07 (d, J=9.91 Hz, 1 H) 6.20- 6.31 (m, 1 H) 6.39-6.58 (m, 5 H) 75
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(3R)-3-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.99 (br t, J=6.71 Hz, 6 H) 1.12 (br d, J=6.40 Hz, 3 H) 1.17-1, 31 (m, 2 H) 1.42-1.56 (m, 1 H) 1.74-1.83 (m, 1 H) 1.87 (s, 3 H) 1.89-1.98 ( m, 1 H) 2.46 (br s, 3 H) 2.51-2.79 (m, 7 H) 3.06-3.24 (m, 2 H) 3.50-3.69 (m , 5 H) 3.70-3.78 (m, 3 H) 3.80-3.87 (m, 1 H) 3.95-4.04 (m, 1 H) 4.88 (br t, J=10.23 Hz, 1 H) 5.39 (dd, J=15.00, 9.60 Hz, 1 H) 5.60 (dd, J=15.00, 9.85 Hz, 1 H) 6.40-6.54 (m, 4 H) 76
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(2R)-2-(hydroxymethyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 618.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=6.78 Hz, 3 H) 1.01 (d, J=6.90 Hz, 3 H) 1.19-1.33 ( m, 2 H) 1.44-1.55 (m, 1 H) 1.75-1.84 (m, 1 H) 1.86 (d, J=1.00 Hz, 3 H) 1.88 -1.98 (m, 1 H) 2.30 (s, 3 H) 2.36 (br s, 4 H) 2.50-2.59 (m, 2 H) 2.60-2.74 ( m, 2 H) 2.86 (td, J=11.92, 3.51 Hz, 1 H) 3.32-3.58 (m, 6H) 3.64-3.88 (m, 5 H) 4.05 (br d, J=2.01 Hz, 1 H) 4.88 (t, J=10.10 Hz, 1 H) 5.25 (d, J=10.67 Hz, 1 H) 5 .40 (dd, J=15.06, 9.66 Hz, 1 H) 5.59 (dd, J=15.06, 9.91 Hz, 1 H) 6.39-6.57 (m, 4 H) 77
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(3S)-3-(hydroxymethyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 618.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.98 (d, J=7.03 Hz, 3 H) 1.01 (d, J=6.78 Hz, 3 H) 1.19-1.33 ( m, 2 H) .44-1.55 (m, 1 H) 1.75-1.84 (m, 1 H) 1.87 (d, J=1.13 Hz, 3H) 1.88-1 .98 (m, 1 H) 2.19-2.43 (m, 7 H) 2.44-2.71 (m, 3 H) 3.12-3.28 (m, 2 H) 3.31 -3.42 (m, 1H) 3.42-3.57 (m, 2 H) 3.59-3.84 (m, 7 H) 3.90-4.04 (m, 2 H) 4, 10-4.17 (m, 1 H) 4.88 (t, J=10.10 Hz, 1 H) 5.25 (d, J=10.67 Hz, 1 H) 5.40 (dd, J =14.93, 9.54 Hz, 1 H) 5.59 (dd, J=14.93, 9.91 Hz, 1 H) 6.28-6.59 (m, 4 H) 78
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[(2R)-2-(methylcarbamoyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 645.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 1.00 (t, J =6.84 Hz, 6 H) 1.21-1.27 (m, 2 H) 1.36-1.54 (m, 1 H) 1.80-1.84 (m, 1 H) 1.86 (br d, J = 1.13 Hz, 3 H) 1.88-1.91 (m, 1 H) 2.37 (s , 3 H) 2.41-2.60 (m, 6 H) 2.62-2.70 (m, 2 H) 2.80-2.91 (m, 4 H) 3.37 -3.45 (m, 1 H) 3.51-3.62 (m, 4 H) 3.68-3.76 (m, 1 H) 3.77-3.87 (m, 1 H) 3.92-4 .01 (m, 1 H) 4.04-4.12 (m, 1 H) 4.89 (t, J =10.04 Hz, 1 H) 5.25 (d, J =10.67 Hz, 1 H) 5.39 (dd, J =15.00, 9.47 Hz, 1 H) 5.60 (dd, J =15.06, 9.79 Hz, 1 H) 6.44-6.64 (m, 5H) 79
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-(2-oxo-1,3-diazinan-1-yl)phenyl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 601.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) 0.98 (d, J=6.78 Hz, 3 H) 1.01 (d, J=6.78 Hz, 3 H) 1.23-1.46 (m, 2 H) 1.61-1.69 (m, 2 H) 1.89 (d, J=1.25 Hz, 3 H) 1.94-2.00 (m, 1 H) 2, 05-2.14 (m, 2 H) 2.36 (s, 3 H) 2.42-2.54 (m, 5 H) 2.55-2.70 (m, 2 H) 3.36- 3.41 (m, 2 H) 3.44-3.59 (m, 4 H) 3.71 (t, J=5.83 Hz, 2 H) 3.79-3.89 (m, 1 H ) 4.90-4.96 (m, 1 H) 5.14 (d, J=10.92 Hz, 2 H) 5.43-5.63 (m, 2 H) 6.56-6.59 (m, 1 H) 6.81-6.92 (m, 1 H) 6.93-7.03 (m, 1 H) 7.04- 7.06 (m, 1 H) 80
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[3-(Cyclopropylmethyl)-2-oxo-1,3-diazinan-1-yl]-5 -fluorophenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 655.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) 0.19-0.30 (m, 2 H) 0.46-0.58 (m, 2 H) 0.91-1.09 (m, 7 H) 1 .19-1.33 (m, 2 H) 1.44-1.53 (m, 1 H) 1.74-1.84 (m, 1 H) 1.87 (d, J = 1.13 Hz , 3 H) 1.89-1.99 (m, 1 H) 2.08-2.20 (m, 2 H) 2.30 (s, 3 H) 2.36 (br s, 4 H) 2 .49-2.58 (m, 2 H) 2.60-2.70 (m, 1 H) 3.29 (d, J =6.90 Hz, 2 H) 3.35-3.42 (m , 1 H) 3.43-3.57 (m, 6 H) 3.63-3.78 (m, 3 H) 4.88 (t, J =10.10 Hz, 1 H) 5.25 ( d, J =10.54 Hz, 1 H) 5.39 (dd, J =15.06, 9.66 Hz, 1 H) 5.59 (dd, J =15.00, 9.85 Hz, 1 H) 6.39-6.57 (m, 1 H) 6.70-6.86 (m, 1 H) 6.92-7.01 (s, 2 H) 81
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[4-[(2R)-2-hydroxypropanoyl]piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 659.5 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) 0.98 (d, J=6.78 Hz, 3 H) 1.01 (d, J=6.78 Hz, 3 H) 1.19-1.31 (m, 2 H) 1.36 (d , J=6.65 Hz, 3 H) 1.43-1.55 (m, 1 H) 1.73-1.84 (m, 1 H) 1.87 (d, J=1.13 Hz, 3 H) 1.89-1.99 (m, 1 H) 2.32 (s, 3 H) 2.39 (br s, 4 H) 2.48-2.68 (m, 3 H) 3, 20 (t, J=5.14 Hz, 4 H) 3.42-3.63 (m, 6 H) 3.68-3.95 (m, 3 H) 4.50 (q, J=6, 65 Hz, 1 H) 4.88 (t, J=10.04 Hz, 1 H) 5.25 (d, J=10.67 Hz, 1 H) 5.40 (dd, J=14.93, 9.66 Hz, 1 H) 5.59 (dd, J=15.06, 9.91 Hz, 1 H) 6.38-6.67 (m, 4 H) 82
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine -2-carboxylate LCMS (ESI, mass/charge), 614.8 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.99 (br d, J =4.39 Hz, 3 H) 1.00 (d, J =4.27 Hz, 3 H) 1.18-1 .35 (m, 4 H) 1.42-1.50 (m, 3 H) 1.75-1.84 (m, 1 H) 1.87 (d, J = 1.00 Hz, 3 H) 1.90-1.99 (m, 1 H) 2.48-2.70 (m, 7 H) 2.95-3.08 (m, 1 H) 3.10-3.18 (m, 4 H) 3.38 (br d, J =10.67 Hz, 2 H) 3.67-3.78 (m, 2 H) 3.80-3.91 (m, 5 H) 4.89 (br t, J =9.79 Hz, 1 H) 5.26 (d, J =10.54 Hz, 1 H) 5.39 (dd, J =15.06, 9.79 Hz, 1 H) 5, 60 (dd, J =15.06, 9.66 Hz, 1 H) 6.43-6.55 (m, 4 H) 83
[(2S,3S,4E,6R,7S,10S)-2-[(E)-1-[3-Fluoro-5-[(3S)-3-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (br t, J =5.90 Hz, 6 H) 1.05 (br d, J =6.53 Hz, 3 H) 1.10- 1.28 (m, 2 H) 1.45-1.56 (m, 1 H) 1.75-1.85 (m, 1 H) 1.80 (s, 3 H) 1.83-1, 93 (m, 1 H) 2.38 (s, 3 H) 2.42-2.70 (m, 7 H) 2.97-3.18 (m, 2 H) 3.40-3.70 ( m, 8 H) 3.71-3.80 (m, 1 H) 3.84-3.97 (m, 1 H) 4.88 (br t, J =10.10 Hz, 1 H) 5, 26 (br d, J =10.54 Hz, 1 H) 5.39 (dd, J =15.00, 9.85 Hz, 1 H) 5.60 (br dd, J =15.12, 9, 85 Hz, 1 H) 6.34-6.56 (m, 4 H) 84
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(2-Cyclopropyl-2-oxoethyl)piperazin-1-yl]-5-fluorophenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 669.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.88-0.95 (m, 2 H) 0.98 (d, J =6.90 Hz, 3 H) 1.00 (d, J =6 .90 Hz, 3 H) 1.04-1.13 (m, 2 H) 1.21-1.31 (m, 2 H) 1.42-1.51 (m, 1 H) 1.73- 1.82 (m, 1 H) 1.83-1.87 (m, 3 H) 1.89-1.96 (m, 1 H) 2.10-2.23 (m, 1 H) 2, 28-2.48 (m, 7 H) 2.49-2.63 (m, 3 H) 2.64-2.76 (m, 4 H) 3.15-3.29 (m, 4 H) 3.40 (s, 2 H) 3.63-3.69 (m, 4 H) 3.69-3.81 (m, 1 H) 4.88 (t, J = 10.10 Hz, 1 H ) 5.25 (d, J =10.79 Hz, 1 H) 5.41 (d, J =9.79 Hz, 1 H) 5.58 (d, J =9.91 Hz, 1 H) 6 .42-6.59 (m, 4 H) 85
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-oxo-2-pyrazin-2-ylethyl)piperazine-1 -yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 707.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.96-1.04 (m, 6 H) 1.20-1.32 (m, 2 H) 1.40-1.54 (m, 1 H ) 1.75-1.84 (m, 1 H) 1.87 (s, 3 H) 1.90-1.98 (m, 1 H) 2.25-2.50 (m, 7 H) 2, 52-2.70 (m, 3 H) 2.78-2.85 (m, 4 H) 3.26-3.34 (m, 4 H) 3.49-3.75 (m, 5 H) 4.19 (s, 2 H) 4.78-4.97 (m, 1 H) 5.26 (d, J =10.54 Hz, 1 H) 5.36-5.45 (m, 1 H ) 5.55-5.64 (m, 1 H) 6.45-6.57 (m, 4 H) 8.50-8.66 (m, 1 H) 8.79 (d, J = 2, 38 Hz, 1 H) 9.25 (d, J =1.51 Hz, 1 H) 265
(2S,3S,6R,7S,10R, E)-2-((E)-1-(3-(Dimethylamino)phenyl)prop-1-en-2-yl)-10-hydroxy-3,7- dimethyl-12-oxooxacyclododec-4-en-6-yl-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 528.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.02 (d, J =6.78 Hz, 6 H) 1.23-1.32 (m, 2 H) 1.45-1.59 (m , 1 H) 1.76-1.86 (m, 1 H) 1.91 (d, J =1.25 Hz, 4 H) 2.50-2.73 (m, 9 H) 2.97 ( s, 6 H) 3.44-3.50 (m, 1 H) 3.65-3.80 (m, 5 H) 4.86-4.95 (m, 1 H) 5.27-5, 33 (m, 1 H) 5.36-5.45 (m, 1 H) 5.58-5.69 (m, 1 H) 6.56-6.71 (m, 4 H) 7.22 ( t, J =7.91 Hz, 1 H). 266
(2S,3S,6R,7S,10R, E)-2-((E)-1-(3-(Dimethylamino)phenyl)prop-1-en-2-yl)-10-hydroxy-3,7- dimethyl 12-oxooxacyclododec-4-en-6-ylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 514.4 [M+H] ⁺ . 267
(2S,3S,6R,7S,10R, E)-2-((E)-1-(5-Chloropyridin-3-yl)prop-1-en-2-yl)-10-hydroxy-3,7 -dimethyl-12-oxooxacyclododec-4-en-6-ylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 506.3 [M+H] ⁺ .

Compounds 86-166 and 264 (Table 5) were prepared using the following procedures 11-19 .

Synthesis of indazole-based intermediates

Procedures 11 and 12 were used to synthesize indazole intermediates characterized by the following general formulas:

, , And .

Procedure 11

To a solution of 6-bromo-4-fluoro-1H-indazole ( 020 , 100 mg, 0.465 mmol) in THF (3.0 ml, 0.15 M) was added cesium carbonate (303 mg, 0.93 mmol) and )cyclopropane ( 021 , 126 mg, 0.93 mmol). At room temperature, the reaction mixture was stirred overnight. The reaction mixture was then diluted with EtOAc (100 ml) and washed with brine. The combined organic layer was concentrated and subjected to ISCO with a gradient of 0 to 30% Hex:EtOAc to give both isomers, 6-bromo-1-(cyclopropylmethyl)-4-fluoro-1H-indazole ( 022 , 62 mg, 0.233 mmol, 50% yield %) and 6-bromo-2-(cyclopropylmethyl)-4-fluoro-1H-indazole ( 023 , 20 mg, 0.078 mmol, 17% yield), which were collected.

( 022 ) LCMS (ESI, mass/charge), 269.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.40-0.50 (m, 2H), 0.57-0.66 (m, 2H), 1.30-1.41 (m, 1H), 1.59 (s, 1H), 4.24 (d, J=6.90 Hz, 2H), 6.96 (dd, J=9.16, 1.25 Hz, 1H), 7.43 (t , J=1.07 Hz, 1H), 8.04 (d, J=0.75 Hz, 1H).

( 023 ) LCMS (ESI, mass/charge), 269.0 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 0.45-0.56 (m, 2H), 0.71-0.80 (m, 2H), 1.38-1.60 (m, 1H), 4.29 (d, J=7.15 Hz, 2H), 6.87 (dd, J=9.54, 1.25 Hz, 1H), 7.70 (t, J=1.13 Hz, 1H ), 8.12 (s, 1H).

Procedure 12

Step 1: NaH (66%, 221 mg, 5.532 mmol) was added to a solution of 6-bromo-1H-indazole ( 024 , 900 mg, 3.688 mmol) in THF (30 mL, 0.12 M). The solution was stirred for 30 minutes and then (bromomethyl)cyclopropane (597 mg, 4.426 mmol) was added. The resulting solution was stirred under N ₂ atmosphere for 12 hours at room temperature. The reaction mixture was diluted with EtOAc (200 ml) and washed with brine. The combined organic layer was concentrated and subjected to a 0 to 20% Hex:EtOAc ISCO gradient to give 1-(cyclopropylmethyl)-6-bromo-1H-indazole ( 025 , 450 mg, 1.509 mmol, 40.9% yield).

Step 2 : Acetic acid ( 200 μL, 3.5 mmol) and SELECTFLUOR (832 mg, 2.348 mmol). The resulting solution was stirred under N2 atmosphere for 12 hours at 50°C. The reaction mixture was then diluted with EtOAc (100 ml) and washed with brine. The combined organic layer was concentrated and subjected to ISCO with a gradient of 0 to 30% Hex:EtOAc to give 1-(cyclopropylmethyl)-3-fluoro-6-bromo-1H-indazole ( 026 , 41 mg, 0.130 mmol, 11.05% yield ).LCMS (ESI, mass/charge), 269.0 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 0.33-0.51 (m, 1H), 0.34-0.39 (m, 2H), 0.45-0.51 (m, 1H), 1.14-1.37 (m, 2H), 1.49 (s, 1H), 4.31 (d, J=7.03 Hz, 2H), 7.16-7.17 (m, 1H) , 7.16-7.20 (m, 1H), 7.30 (dd, J=8.41, 4.89 Hz, 1H), 7.89 (d, J=2.26 Hz, 1H).

Procedure 13

Step 1: Cesium carbonate (303 mg, 0.93 mmol) was added to a solution of 6-bromo-4-fluoro-1H-indazole ( 020 , 100 mg, 0.465 mmol) in THF (3.0 ml, 0.15 M) and methyl 2-bromoacetate (142 mg, 0.93 mmol). At room temperature, the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (100 ml) and washed with brine. The combined organic layer was concentrated and subjected to a 0 to 30% Hex:EtOAc ISCO gradient to give methyl 2-(6-bromo-4-fluoro-1H-indazol-1-yl)acetate ( 027 , 100 mg, 0.349 mmol, yield 75%).

Step 2. In a solution of methyl 2-(6-bromo-4-fluoro-1H-indazol-1-yl) acetate ( 027 , 13 mg, 0.045 mmol) in dichloromethane (0.3 ml, 0.15 M) at At room temperature, pyrrolidine (32.2 mg, 0.453 mmol) was added. The reaction mixture was stirred at room temperature overnight. LCMS showed the complete progress of the reaction. The reaction mixture was diluted with EtOAc (100 ml) and washed with brine. The combined organic layer was concentrated and subjected to a 0 to 30% Hex:EtOAc gradient ISCO to give 2-(6-bromo-4-fluoro-1H-indazol-1-yl)-1-(pyrrolidin-1-yl)ethanone ( 028 , 10 mg, 0.031 mmol, yield 67.7%).

Synthesis of benzotriazole-based intermediates

Procedures 14 and 15 were used to synthesize benzotriazole intermediates characterized by the following general formulas:

, , And .

Procedure 14

Cesium carbonate ( 303 mg, 0.93 mmol) and (bromomethyl)cyclopropane ( 021 , 187 mg, 0.93 mmol). At room temperature, the reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (100 ml) and washed with brine. The combined organic layer was concentrated and subjected to a 0 to 30% Hex:EtOAc ISCO gradient to give 5-bromo-1-(cyclopropylmethyl)-7-fluoro-1H-benzo[d][1,2,3]triazole ( 030 , 40 mg, 0.148 mmol, yield 32%), 6-bromo-2-(cyclopropylmethyl)-4-fluoro-2H-benzo[d][1,2,3]triazole ( 031 , 20 mg, 0.074 mmol, yield 16 %) and 6-bromo-1-(cyclopropylmethyl)-4-fluoro-1H-benzo[d][1,2,3]triazole ( 032 , 16 mg, 0.059 mmol, 12% yield). ( 030 ) LCMS (ESI, mass/charge), 270.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.38-0.61 (m, 4H), 1.31-1.45 (m, 1H), 4.53 (d, J =7.28 Hz, 2H), 7.18-7.27 (m, 1H), 7.95 (d, J =1.38 Hz, 1H). ( 031 ) LCMS (ESI, mass/charge), 270.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.40-0.51 (m, 2H), 0.55-0.67 (m, 2H), 1.48 (quint, J = 7.72, 7 .72, 7.72, 7.72, 4.77, 4.77 Hz, 1H), 4.49 (d, J =7.40 Hz, 2H), 7.08 (dd, J =9.54 , 1.38 Hz, 1H), 7.77 (d, J =1.38 Hz, 1H). ( 032 ) LCMS (ESI, mass/charge), 270.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.45-0.57 (m, 2H), 0.64-0.76 (m, 2H), 1.35-1.46 (m, 1H), 4.49 (d, J =7.15 Hz, 2H), 7.19 (dd, J =9.22, 1.32 Hz, 1H), 7.58 (d, J =1.38 Hz, 1H ).

Procedure 15

Stage 1 . Tetrahydro-2H-pyran-4-amine was added to a solution of 5-bromo-1,3-difluoro-2-nitrobenzene ( 033 , 500 mg, 2.101 mmol) in THF (10 ml, 0.2 M) at room temperature. ( 034 , 202 mg, 1.996 mmol) and triethylamine (0.359 ml, 2.521 mmol). The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated and subjected to ISCO gradient from 0 to 20% Hex:EtOAc to give N-(5-bromo-3-fluoro-2-nitrophenyl)tetrahydro-2H-pyran -4-amine ( 035 , 540 mg, 1.692 mmol, 81% yield).

Stage 2 . Iron was added to a solution of N-(5-bromo-3-fluoro-2-nitrophenyl)tetrahydro-2H-pyran-4-amine ( 035 , 80 mg, 0.251 mmol) in HCl (1 M) MeOH (2.5 ml) (280 mg, 5.014 mmol). Under N2 atmosphere, the reaction mixture was stirred at room temperature for 2 hours. LCMS showed the complete progress of the reaction. Filtered through a layer of silica gel, then evaporated the solvent. The reaction mixture was redissolved in EtOAc (50 ml) and filtered again through a pad of silica gel. The crude product 5-bromo-3-fluoro-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine ( 036 , 60 mg, 0.208 mmol, 83% yield) was used directly in the next step.

Stage 3 . In a solution of 5-bromo-3-fluoro-N1-(tetrahydro-2H-pyran-4-yl)benzene-1,2-diamine ( 036 , 60 mg, 0.208 mmol) in acetic acid (1 ml, 0.2 M ) sodium nitrite (35.8 mg, 0.519 mmol) was added at room temperature. The reaction mixture was stirred at 60°C for 2 hours. Completion of the reaction was demonstrated by LC/MS. The reaction mixture was evacuated and resuspended in EtOAc (50 ml), then washed with brine. The reaction mixture was concentrated and subjected to an ISCO gradient from 0 to 40% Hex:EtOAc to give 6-bromo-4-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d][1,2 ,3]triazole ( 037 , 42 mg, 0.140 mmol, yield 67.4%). LCMS (ESI, mass/charge), 300.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.06-2.13 (m, 2H), 2.42 (qd, J =12.09, 4.39 Hz, 2H), 3.57 (td, J =11.92, 2.01 Hz, 2H), 4.06-4.16 (m, 2H), 4.97 (tt, J =11.50, 4.19 Hz, 1H), 7.19 -7.27 (m, 1H), 7.96 (d, J =1.38 Hz, 1H).

Synthesis of benzimidazole-based intermediates

Procedure 16 was used to synthesize benzotriazole intermediates characterized by the following general formula.

Procedure 16

In a solution of (1r,4r)-4-((2-amino-5-bromo-3-fluorophenyl)amino)cyclohexanol ( 038 , 100 mg, 0.33 mmol) in formic acid (3 ml, 0.11 M) At room temperature, a few drops of concentrated HCl were added. The reaction mixture was stirred at 60°C for 2 hours. Completion of the reaction was demonstrated by LC/MS. The reaction mixture was evacuated and resuspended in EtOAc (50 ml), then washed with brine. The reaction mixture was concentrated and subjected to ISCO with a gradient of 0 to 10% DCM:MeOH to give (1r,4r)-4-(6-bromo-4-fluoro-1H-benzo[d]imidazol-1-yl)cyclohexanol ( 039 , 80 mg, 0.256 mmol, yield 79%). LCMS (ESI, mass/charge), 313.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.55-1.67 (m, 2H), 1.84-1.99 (m, 2H), 2.20-2.30 (m, 4H), 3.84 (tt, J =10.89, 4.05 Hz, 1H), 4.10-4.22 (m, 1H), 7.15 (dd, J =9.66, 1.51 Hz, 1H), 7.39 (d, J =1.51 Hz, 1H).

Synthesis of phenylpiperazine-based intermediates

Procedure 17 was used to synthesize phenylpiperazine intermediates characterized by the following general formula.

Procedure 17

Step 1: To a solution of 1-bromo-3,5-difluorobenzene ( 040 , 218 mg, 1.13 mmol) in DMSO (5.0 ml, 0.23 M) was added K ₂ CO ₃ (187 mg, 1.356 mmol) and piperazine ( 041 , 146 mg, 1.694 mmol). The reaction mixture was heated to 140°C in a sealed tube for 24 hours. The reaction mixture was cooled and diluted with EtOAc (200 ml), then washed with brine and dried with Na ₂ SO ₄ . The organic layer was concentrated and subjected to ISCO with a gradient of 0 to 30% DCM:MeOH to give 1-(3-bromo-5-fluorophenyl)piperazine ( 042 , 234 mg, 0.903 mmol, 80% yield).

Step 2. Into a solution of 1-(3-bromo-5-fluorophenyl)piperazine ( 042 , 45 mg, 0.174 mmol) and 2-(1H-pyrazol-1-yl)acetic acid ( 043 , 32.9 mg, 0. 26 mmol) in DMSO (1 ml, 0.17 M) at room temperature were added HBTU (231 mg, 0.608 mmol) and TEA (0.087 ml, 0.608 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (50 ml) and washed with brine. The combined organic layer was concentrated and subjected to ISCO with a gradient of 0 to 10% DCM:MeOH to give 1-(4-(3-bromo-5-fluorophenyl)piperazin-1-yl)-2-(1H-pyrazol-1-yl) )ethanone ( 044 , 60 mg, 0.163 mmol, yield 94%). LCMS (ESI, mass/charge), 367.0 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 2.80 (s, 2H), 3.08-3.21 (m, 4H), 3.64-3.80 (m, 4H), 5.05 ( s, 2H), 6.27-6.40 (m, 1H), 6.43-6.540 (m, 1H), 6.69-6.82 (m, 2H), 7.45-7.63 ( m, 2H).

Procedure 18

TEA (31.2 mg, 0.309 mmol) was added to a solution of 1-(3-bromo-5-fluorophenyl)piperazine ( 042 , 40 mg, 0.154 mmol) in DCM (1.5 ml, 0.1 mmol) at room temperature. and oxetane-3-sulfonyl chloride ( 045 , 25 mg, 0.15 mmol) and stirred for 5 minutes. DMAP (0.943 mg, 7.718 μmol) was then added. The reaction mixture was stirred for 4 hours. The reaction mixture was diluted in DCM (50 ml) and washed with brine. The combined organic layer was concentrated and subjected to ISCO with a gradient of 0 to 100% Hex:EtOAc to give 1-(3-bromo-5-fluorophenyl)-4-(oxetan-3-ylsulfonyl)piperazine ( 046 , 40 mg, 0.11 mmol, yield 68.3%).

Synthesis of boronate combination products

Procedure 19

Step 1. In solution (2S,3S,6R,7S,10R, E)-10-hydroxy-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12 -oxooxacyclododec-4-en-6-yl-4-methylpiperazin-1-carboxylate ( 008 , 500 mg, 0.936 mmol) in DMSO (9.0 mL, 0.1 M) was added Pd(0) (108 mg, 0.094 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (475 mg, 1.871 mmol) and potassium acetate (184 mg, 1.871 mmol). The reaction mixture was purged with _N2 , then heated to no more than 80°C and stirred for 30 minutes. The reaction mixture was cooled to room temperature and H ₂ O (50 ml) was added. The reaction mixture was extracted with EtOAc (4 x 100 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude reaction mixture was subjected to ISCO eluting with 0 to 10% DCM:MeOH to give (2S,3S,6R,7S,10R, E)-10-hydroxy-3,7-dimethyl-12-oxo-2-((E )-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)oxacyclododec-4-en-6-yl-4-methylpiperazine -1-carboxylate ( boronate 1 , 360 mg, 0.674 mmol, 72.0% yield) as a yellowish solid. LCMS (ESI, mass/charge), 536.4 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ ppm 0.87-1.08 (m, 6H), 1.19-1.35 (m, 3H), 1.28 (s, 12H), 1.42 -1.55 (m, 1H), 1.73-1.85 (m, 1H), 1.88-1.96 (m, 1H), 1.98 (s, 3H), 2.31 (s , 3H), 2.35-2.49 (m, 5H), 2.50-2.65 (m, 2H), 3.39-3.58 (m, 4H), 3.66-3.77 (m, 1H), 4.87 (t, J =10.10 Hz, 1H), 5.14 (d, J =10.54 Hz, 1H), 5.33-5.47 (m, 2H) , 5.56 (dd, J =15.00, 9.98 Hz, 1H).

Stage 2. In solution (2S,3S,6R,7S,10R, E)-10-hydroxy-3,7-dimethyl-12-oxo-2-((E)-1-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)oxacyclododec-4-en-6-yl-4-methylpiperazin-1-carboxylate ( boronate 1 , 15 mg, 0.029 mmol) and aryl bromide ( 047 , 0.035 mmol), silver oxide (19 mg, 0.086 mmol) and Pd(0) (3.3 mg, 0.003 mmol) were added. The reaction mixture was heated to 60°C for 5 hours. Complete conversion of the boronate was demonstrated by LCMS. The mixture was cooled, filtered through a thin layer of celite and concentrated. The crude reaction mixture was subjected to ISCO eluting with 0 to 10% DCM:MeOH to give product 010 .

Table 5. Description of characteristics of connections 86-166 and 264 Etc. Structure and chemical name according to IUPAC Characteristics 86
[(2S,3S,4E,6S,7R,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 604.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.00 (br d, J =6.78 Hz, 3 H) 1.09-1.21 (m, 2 H) 1.26 (br s, 3 H) 1.40-1.48 (m, 1 H) 1.76-1.80 (m, 1 H) 1.87 (s, 3 H) 2.49-2.74 (m, 3 H) 2.82 (s, 3 H) 2.97-3.08 (m, 4 H) 3.12-3.21 (m, 4 H) 3.75-3.82 (m, 1 H) 3, 83-3.91 (m, 8 H) 5.01-5.06 (m, 1 H) 5.27-5.31 (m, 1 H) 5.35 (d, J = 10.29 Hz, 1 H) 5.65-5.75 (m, 1 H) 6.44-6.62 (m, 3 H) 6.66-6.75 (m, 1 H) 87
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(Cyclopropylmethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 597.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.41-0.62 (m, 2H), 0.68-0.91 (m, 2H), 1.03 (d, J =6.78 Hz, 6H), 1.19-1.39 (m, 3H), 1.39-1.87 (m, 4H), 1.93-2.00 (m, 1H), 1.95 (s, 3H) , 2.33-2.42 (m, 3H), 2.42-2.55 (m, 3H), 2.55-2.75 (m, 3H), 3.35-3.50 (m, 1H), 3.50-3.65 (m, 4H), 3.65-3.71 (m, 1H), 3.71-3.82 (m, 1H), 4.23-4.38 ( m, 2H), 4.92 (t, J =10.10 Hz, 1H), 5.30-5.36 (m, 1H), 5.38-5.48 (m, 1H), 5.64 (dd, J =15.00, 9.98 Hz, 1H), 6.61-6.68 (m, 2H), 7.41 (s, 1H), 8.10 (s, 1H) 88
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-imidazo[1,2-a]pyridin-6-ylprop-1-en-2-yl] -3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 525.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.97-1.07 (m, 6H), 1.20-1.35 (m, 3H), 1.45-1.59 (m, 1H), 1.92 (d, J =1.13 Hz, 5H), 2.29-2.35 (m, 3H), 2.35-2.48 (m, 4H), 2.52-2.72 ( m, 3H), 3.41-3.61 (m, 4H), 3.69-3.81 (m, 3H), 4.91 (t, J =10.10 Hz, 1H), 5.23 -5.38 (m, 1H), 5.43 (dd, J =15.00, 9.73 Hz, 1H), 5.62 (dd, J =14.93, 9.91 Hz, 1H), 6.52 (s, 1H), 7.14 (dd, J =9.35, 1.57 Hz, 1H), 7.49-7.73 (m, 1H), 7.63-7.68 ( m, 1H), 7.63-7.67 (m, 1H), 8.07 (s, 1H) 89
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-(7-methyl-1H-indazol-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 539.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.89-1.05 (m, 6H), 1.10-1.29 (m, 5H), 1.34-1.54 (m, 1H), 1.71-1.82 (m, 4H), 1.82-1.91 (m, 1H), 2.25-2.42 (m, 3H), 2.42-2.63 (m, 10H ), 3.51 (br s, 6H), 3.57-3.76 (m, 3H), 4.84 (t, J =10.10 Hz, 1H), 5.29-5.39 (m , 3H), 5.57 (dd, J =15.00, 9.98 Hz, 1H), 6.82 (s, 1H), 6.92 (d, J =7.15 Hz, 1H), 7 .07 (d, J =7.15 Hz, 1H), 7.95 (s, 1H), 8.20 (br s, 1H) 90
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-(Cyclopropylsulfamoyl)-3-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 622.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.57-0.66 (m, 2H), 0.66-0.73 (m, 2H), 0.97-1.07 (m, 6H), 1.20-1.38 (m, 2H), 1.47-1.58 (m, 1H), 1.76-1.87 (m, 1H), 1.87-2.02 (m, 3H ), 2.25-2.32 (m, 1H), 2.39 (s, 3H), 2.42-2.93 (m, 8H), 3.45-3.66 (m, 4H), 3.66-3.79 (m, 1H), 4.90 (t, J =10.04 Hz, 1H), 5.15 (br s, 1H), 5.29 (d, J =10.54 Hz, 1H), 5.43 (dd, J =15.06, 9.66 Hz, 1H), 5.61 (dd, J =14.93, 9.91 Hz, 1H), 6.59 (s , 1H), 7.12-7.22 (m, 1H), 7.18-7.23 (m, 1H), 7.92 (t, J =7.84 Hz, 1H), 8.24- 8.30 (m, 1H) 91
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-Fluoro-5-(4-hydroxypiperidin-1-yl)sulfonylphenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 666.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.87-1.00 (m, 6H), 1.13-1.27 (m, 4H), 1.31-1.49 (m, 2H), 1.54-1.66 (m, 2H), 1.66-1.80 (m, 3H), 1.81-1.93 (m, 3H), 2.23-2.32 (s, 3H ), 2.32-2.44 (m, 3H), 2.44-2.55 (m, 2H), 2.55-2.65 (m, 1H), 2.81-2.92 (m , 2H), 3.16-3.28 (m, 2H), 3.46 (br s, 4H), 3.56-3.70 (m, 2H), 3.71-3.81 (m, 1H), 4.77-4.86 (m, 1H), 5.22-5.28 (m, 1H), 5.29-5.41 (m, 1H), 5.48-5.57 ( m, 1H), 6.47 (s, 1H), 7.10-7.17 (m, 1H), 7.60 (m, 2H) 92
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate LCMS (ESI, mass/charge), 656.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.96-1.06 (m, 6H), 1.18-1.36 (m, 2H), 1.45-1.71 (m, 1H), 1.76-1.86 (m, 1H), 1.90 (s, 3H), 1.91-2.00 (m, 1H), 2.50-2.72 (m, 6H), 2. 95-3.07 (m, 2H), 3.13-3.24 (m, 4H), 3.36-3.45 (m, 1H), 3.45-3.61 (m, 3H), 3.70-3.80 (m, 1H), 3.82-3.91 (m, 4H), 4.86-4.95 (m, 1H), 5.24-5.31 (m, 1H ), 5.37-5.47 (m, 1H), 5.56-5.67 (m, 1H), 5.58-5.62 (m, 1H), 5.62-5.62 (m , 1H), 5.62-5.62 (m, 1H), 6.46-6.57 (m, 4H) 93
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperazin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 633.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.89-0.99 (m, 6H), 1.09-1.30 (m, 6H), 1.66-1.93 (m, 4H), 2.31 (s, 3H), 2.35-2.63 (m, 7H), 2.83-3.07 (m, 6H), 3.19-3.29 (m, 1H), 3, 37-3.73 (m, 6H), 4.77-4.86 (m, 1H), 5.17-5.25 (m, 1H), 5.29-5.39 (m, 1H), 5.47-5.59 (m, 1H), 6.50-6.58 (m, 1H), 7.38-7.61 (m, 4H) 94
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4-Formylpiperazin-1-yl)sulfonylphenyl]prop-1-en-2-yl]-10 -hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 661.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.89-0.99 (m, 6H), 1.12-1.28 (m, 4H), 1.38-1.48 (m, 1H), 1.66-1.78 (m, 2H), 1.81 (d, J =1.25 Hz, 3H), 1.84-1.93 (m, 1H), 2.24-2.63 ( m, 9H), 2.91-3.05 (m, 4H), 3.37-3.62 (m, 7H), 3.63-3.73 (m, 1H), 4.78-4, 86 (m, 1H), 5.18-5.25 (m, 1H), 5.29-5.39 (m, 1H), 5.48-5.59 (m, 1H), 6.51- 6.56 (m, 1H), 7.42-7.49 (m, 2H), 7.51-7.58 (m, 2H), 7.89-7.94 (m, 1H) 95
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-[3-(4-hydroxypiperidin-1-yl)sulfonylphenyl]prop-1-ene-2- yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 648.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.98-1.07 (m, 6H), 1.22-1.35 (m, 2H), 1.46-1.57 (m, 1H), 1.60-1.73 (m, 2H), 1.75-1.86 (m, 1H), 1.86-2.01 (m, 6H), 2.41 (s, 3H), 2, 47-2.73 (m, 7H), 2.84-2.99 (m, 2H), 3.27-3.47 (m, 3H), 3.50-3.86 (m, 7H), 4.86-4.95 (m, 1H), 5.27-5.34 (m, 1H), 5.38-5.47 (m, 1H), 5.57-5.67 (m, 1H ), 6.61-6.66 (m, 1H), 7.47-7.55 (m, 2H), 7.63-7.69 (m, 2H) 96
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-(6-methyl-1H-indazol-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 539.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 0.98-1.08 (m, 7H), 1.30-1.49 (m, 4H), 1.62-1.70 (m, 2H) , 1.82-1.89 (m, 3H), 1.91-2.01 (m, 1H), 2.29-2.35 (m, 3H), 2.38-2.53 (m, 6H), 2.53-2.58 (m, 3H), 2.58-2.75 (m, 2H), 3.42-3.57 (m, 5H), 3.76-3.88 ( m, 1H), 5.22-5.30 (m, 1H), 5.44-5.66 (m, 2H), 6.91 (s, 1H), 6.94-7.02 (m, 1H), 7.10-7.17 (m, 1H), 7.97 (s, 1H) 97
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(1,3-Dimethyl-indazol-4-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 553.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.04 (d, J =6.78 Hz, 3H), 1.06-1.13 (m, 3H), 1.25-1.33 (m, 2H), 1.50-1.61 (m, 1H), 1.73-1.89 (m, 4H), 1.90-2.02 (m, 1H), 2.33-2.38 ( m, 3H), 2.38-2.50 (m, 4H), 2.56-2.71 (m, 7H), 3.44-3.65 (m, 4H), 3.73-3, 81 (m, 2H), 4.02 (s, 3H), 4.88-4.96 (m, 1H), 5.37-5.50 (m, 2H), 5.61-5.70 ( m, 1H), 6.87-6.93 (m, 1H), 7.07-7.11 (m, 1H), 7.21-7.26 (m, 1H), 7.29-7, 36 (m, 1H) 98
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(1-azabicyclo[2.2.2]octan-3-yl)-N-methylcarbamate LCMS (ESI, mass/charge), 628.5 [M+H] ⁺ . ^1H NMR (400 MHz, CD ₃ OD) δ 0.86-0.96 (m, 1H), 0.96-1.02 (m, 3H), 1.02-1.08 (m, 3H) , 1.24-1.46 (m, 6H), 1.60-1.70 (m, 1H), 1.85-1.93 (m, 3H), 1.96-2.08 (m, 3H), 2.10-2.25 (m, 1H), 2.28-2.34 (m, 1H), 2.45-2.55 (m, 1H), 2.60-2.73 ( m, 2H), 3.05 (s, 3H), 3.14-3.20 (m, 3H), 3.20-3.31 (m, 3H), 3.44-3.58 (m, 2H), 3.58-3.72 (m, 1H), 3.80-3.87 (m, 4H), 4.20-4.32 (m, 1H), 5.16 (d, J = 10.54 Hz, 1H), 5.56 (d, J =8.78 Hz, 2H), 6.49-6.66 (m, 3H), 8.42-8.69 (m, 2H) 99
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-(Cyclopropylmethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 597.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.28-0.40 (m, 2H), 0.47-0.67 (m, 2H), 0.67-0.91 (m, 2H), 0.68-0.73 (m, 1H), 0.95 (t, J =6.84 Hz, 6H), 1.09-1.33 (m, 1H), 1.40-1.50 ( m, 1H), 1.68-1.79 (m, 1H), 1.82-1.92 (m, 2H), 2.36-2.45 (m, 3H), 2.45-2, 67 (m, 4H), 2.67-2.99 (m, 4H), 3.51-3.60 (m, 4H), 3.65 (m, 1H), 4.17 (d, J = 6.90 Hz, 2H), 4.82 (t, J =10.10 Hz, 1H), 5.19-5.29 (m, 1H), 5.34 (dd, J =15.00, 9 .72 Hz, 1H), 5.55 (dd, J =14.93, 9.91 Hz, 1H), 6.60-6.68 (m, 2H), 6.99 (s, 1H), 7 .95 (d, J =0.75 Hz, 1H), 8.16 (s, 1H) 100
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-Fluoro-1-(2-hydroxyethyl)indazol-6-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 597.3 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 0.73-0.87 (m, 1H), 0.87-0.97 (m, 6H), 1.11-1.26 (m, 1H), 1.26-1.35 (m, 1H), 1.37-1.50 (m, 1H), 1.67-1.78 (m, 2H), 1.80-1.91 (m, 4H ), 2.34 (s, 3H), 2.37-2.64 (m, 6H), 3.38-3.60 (m, 4H), 3.61-3.77 (m, 1H), 4.01-4.09 (m, 2H), 4.35-4.42 (m, 2H), 4.82 (t, J =10.10 Hz, 1H), 5.23 (d, J = 10.67 Hz, 1H), 5.34 (dd, J =15.00, 9.73 Hz, 1H), 5.54 (dd, J =14.93, 9.91 Hz, 1H), 6, 61 (s, 1H), 6.68 (d, J =10.79 Hz, 1H), 7.02 (s, 2H), 7.97-8.02 (m, 1H) 101
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-Fluoro-1-methyl-indazol-6-yl)prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 557.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.85-0.99 (m, 6H), 1.09-1.30 (m, 2H), 1.44 (br dd, J = 13.30, 9.66 Hz, 2H), 1.57-1.79 (m, 2H), 1.80-1.92 (m, 4H), 2.21-2.30 (m, 3H), 2.33 (br s, 1H), 2.42-2.61 (m, 2H), 3.16-3.57 (m, 6H), 3.60-3.72 (m, 1H), 3.99 ( s, 3H), 4.82 (t, J =10.10 Hz, 1H), 5.24 (d, J =10.54 Hz, 1H), 5.35 (dd, J =15.00, 9 .72 Hz, 1H), 5.55 (dd, J =15.00, 9.98 Hz, 1H), 6.60-6.69 (m, 2H), 6.96 (s, 1H), 7 .93 (s, 1H) 102
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-[1-(pyridin-4-ylmethyl)pyrazol- 4-yl]prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate LCMS (ESI, mass/charge), 566.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.77-0.97 (m, 6H), 1.07-1.28 (m, 3H), 1.32-1.55 (m, 1H), 1.66-1.78 (m, 1H), 1.78-1.82 (m, 3H), 1.82-1.91 (m, 1H), 2.19-2.27 (m, 3H ), 2.27-2.39 (m, 4H), 2.36-2.56 (m, 2H), 3.18-3.55 (m, 5H), 3.64 (br s, 1H) , 4.81 (t, J =10.04 Hz, 1H), 5.13-5.21 (m, 1H), 5.21-5.27 (m, 2H), 5.27-5.38 (m, 1H), 5.45-5.58 (m, 1H), 6.31 (s, 1H), 6.93-7.02 (m, 2H), 7.36-7.42 (m , 1H), 7.56 (s, 1H), 8.47-8.53 (m, 2H) 103
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-(1-methylpyrazol-4-yl)prop-1-ene-2 -yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 489.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78-0.90 (m, 3H), 0.93 (d, J =6.90 Hz, 3H), 1.09-1.29 (m, 2H), 1.35-1.77 (m, 2H), 1.79 (s, 3H), 1.82-1.93 (m, 3H), 2.30-2.37 (m, 1H) , 2.37-2.57 (m, 7H), 3.34 (br d, J =5.27 Hz, 1H), 3.46-3.54 (m, 3H), 3.54-3, 72 (m, 2H), 3.83 (s, 3H), 4.81 (t, J =10.10 Hz, 1H), 5.14-5.23 (m, 1H), 5.31 (dd , J =15.00, 9.73 Hz, 1H), 5.52 (dd, J =15.00, 9.98 Hz, 1H), 6.29 (s, 1H), 7.31 (s, 1H), 7.46 (s, 1H) 104
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-hydroxyethyl)-3-oxopiperazin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 645.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.92-1.01 (m, 6H), 1.11-1.17 (m, 2H), 1.22-1.42 (m, 2H), 1.60 (br s, 2H), 1.81-1.86 (m, 3H), 1.87-1.98 (m, 1H), 2.27 (s, 3H), 2.33-2 .48 (m, 4H), 2.50-2.65 (m, 2H), 3.25-3.31 (m, 3H), 3.48 (br dd, J = 6.59, 4.08 Hz, 2H), 3.52-3.62 (m, 6H), 3.73-3.80 (m, 1H), 3.80-3.85 (m, 2H), 4.74-4, 79 (m, 1H), 5.06-5.15 (m, 1H), 5.48 (dd, J =15.12, 9.10 Hz, 2H), 6.45-6.58 (m, 4H) 105
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[4-(2-methoxyethyl)-3-oxopiperazin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 658.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 0.00 (dd, J =9.54, 6.78 Hz, 6H), 0.25-0.45 (m, 3H), 0.65 (br s, 2H), 0.89 (d, J =1.25 Hz, 4H), 1.31 (s, 3H), 1.36-1.52 (m, 5H), 1.58-1.71 (m, 4H), 2.44-2.70 (m, 11H), 2.71-2.77 (m, 2H), 2.77-2.85 (m, 1H), 2.85-2 .92 (m, 2H), 3.79-3.87 (m, 1H), 4.09-4.19 (m, 1H), 4.45-4.61 (m, 2H), 5.47 -5.66 (m, 4H) 106
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-[1-(1-methylpiperidin-4-yl)pyrazol-4- yl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 572.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.78-0.90 (m, 3H), 0.93 (d, J =6.78 Hz, 3H), 1.08-1.27 (m, 2H), 1.42 (ddd, J =13.87, 9.85, 3.89 Hz, 1H), 1.66-1.77 (m, 1H), 1.80 (s, 3H), 1 .82-1.91 (m, 2H), 1.92-2.13 (m, 6H), 2.19-2.33 (m, 8H), 2.34-2.57 (m, 4H) , 2.91 (br d, J =11.54 Hz, 2H), 3.41 (br s, 4H), 3.49-3.68 (m, 2H), 4.05 (tt, J =11 .26, 4.11 Hz, 1H), 4.81 (t, J =10.10 Hz, 1H), 5.17 (d, J =10.67 Hz, 1H), 5.31 (dd, J =15.06, 9.66 Hz, 1H), 5.51 (dd, J =14.93, 9.91 Hz, 1H), 6.30 (s, 1H), 7.38 (s, 1H) , 7.48 (s, 1H) 107
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 669.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.84-0.94 (m, 6H), 1.44-1.68 (m, 3H), 1.68-2.01 (m, 6H), 2.31-2.37 (m, 3H), 2.37-2.48 (m, 4H), 2.51-2.71 (m, 3H), 2.77-2.90 (m, 4H ), 3.05 (d, J =9.54 Hz, 2H), 3.17-3.29 (m, 4H), 3.46-3.62 (m, 5H), 3.70-3, 80 (m, 1H), 4.90 (s, 1H), 5.24-5.30 (m, 1H), 5.42 (s, 1H), 5.57-5.65 (m, 1H) , 6.47-6.56 (m, 3H) 108
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[4-(2-methoxyacetyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 659.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.02 (dd, J = 8.53, 6.90 Hz, 6H), 1.42-1.60 (m, 1H), 1.76-1, 87 (m, 1H), 1.90 (s, 3H), 1.90-2.00 (m, 2H), 2.30-2.38 (m, 3H), 2.42 (br s, 4H ), 2.48-2.68 (m, 4H), 3.12-3.28 (m, 4H), 3.42-3.47 (m, 4H), 3.47-3.59 (m , 4H), 3.59-3.71 (m, 2H), 3.71-3.84 (m, 3H), 4.15-4.19 (m, 2H), 4.90 (t, J =10.10 Hz, 1H), 5.27 (d, J =10.54 Hz, 1H), 5.42 (dd, J =15.00, 9.73 Hz, 1H), 5.61 (dd , J =15.00, 9.85 Hz, 1H), 6.48-6.59 (m, 4H) 109
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(Cyclopropanecarbonyl)piperazin-1-yl]-5-fluorophenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 655.3 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 0.79-0.92 (m, 2H), 0.94-1.08 (m, 8H), 1.42-1.65 (m, 1H), 1.72-1.86 (m, 2H), 1.89 (s, 3H), 1.90-2.01 (m, 1H), 2.31-2.37 (m, 3H), 2. 37-2.48 (m, 4H), 2.52-2.71 (m, 4H), 3.10-3.33 (m, 5H), 3.53 (br s, 4H), 3.70 -3.89 (m, 5H), 4.90 (t, J =10.10 Hz, 1H), 5.27 (d, J =10.67 Hz, 1H), 5.42 (dd, J = 14.93, 9.66 Hz, 1H), 5.61 (dd, J =15.06, 9.91 Hz, 1H), 6.49-6.57 (m, 4H) 110
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[4-(4-methoxyphenyl)sulfonylpiperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 757.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94-1.07 (m, 6H), 1.40-1.58 (m, 1H), 1.76-1.88 (m, 4H), 1.88-2.00 (m, 1H), 2.32-2.37 (m, 3H), 2.37-2.48 (m, 5H), 2.50-2.70 (m, 4H ), 3.10-3.21 (m, 4H), 3.21-3.32 (m, 4H), 3.40-3.64 (m, 4H), 3.63-3.89 (m , 2H), 3.90 (s, 3H), 4.89 (t, J =10.04 Hz, 1H), 5.25 (d, J =10.67 Hz, 1H), 5.37-5 .46 (m, 1H), 5.60 (dd, J =15.06, 9.91 Hz, 1H), 6.42-6.54 (m, 4H), 7.01-7.06 (m , 2H), 7.72-7.77 (m, 2H) 111
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(1-methylpyrazol-4-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 757.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.88-1.00 (m, 6H), 1.41 (br d, J =9.41 Hz, 2H), 1.78 (d, J =1 ,13 Hz, 4H), 1.80-1.89 (m, 2H), 2.25-2.31 (m, 3H), 2.33-2.43 (m, 3H), 2.43- 2.63 (m, 4H), 2.99-3.15 (m, 4H), 3.16-3.30 (m, 4H), 3.40-3.58 (m, 4H), 3, 61-3.78 (m, 2H), 3.90 (s, 3H), 4.81 (t, J =10.10 Hz, 1H), 5.17 (d, J =10.54 Hz, 1H ), 5.32 (dd, J =15.06, 9.66 Hz, 1H), 5.52 (dd, J =15.00, 9.85 Hz, 1H), 6.34-6.49 ( m, 4H), 7.64-7.68 (m, 1H), 7.68-7.73 (m, 1H) 112
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-(4-pyridin-3-ylsulfonylpiperazin-1-yl)phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 737.3 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 0.95-1.07 (m, 6H), 1.42-1.56 (m, 1H), 1.74-1.88 (m, 5H), 1.88-1.99 (m, 2H), 2.32-2.38 (m, 3H), 2.38-2.49 (m, 4H), 2.49-2.70 (m, 4H ), 3.26 (br dd, J =17.07, 5.52 Hz, 8H), 3.46-3.63 (m, 4H), 3.70-3.86 (m, 1H), 4 .90 (t, J =10.04 Hz, 1H), 5.25 (d, J =10.67 Hz, 1H), 5.41 (dd, J =14.93, 9.66 Hz, 1H) , 5.60 (dd, J =14.93, 9.91 Hz, 1H), 6.43-6.57 (m, 4H), 7.54 (ddd, J =8.00, 4.86, 0.69 Hz, 1H), 8.10 (dt, J =8.03, 2.01 Hz, 1H), 8.88 (dd, J =4.83, 1.44 Hz, 1H), 9, 03-9.06 (m, 1H) 113
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(1-methylimidazol-4-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 757.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.01 (dd, J = 11.54, 6.78 Hz, 6H), 1.44-1.58 (m, 1H), 1.74-1, 90 (m, 4H), 1.90-2.02 (m, 3H), 2.33-2.39 (m, 3H), 2.39-2.50 (m, 4H), 2.52- 2.70 (m, 4H), 3.25-3.32 (m, 4H), 3.32-3.41 (m, 4H), 3.47-3.63 (m, 4H), 3. 70-3.78 (m, 1H), 3.78-3.82 (m, 3H), 4.90 (t, J =10.10 Hz, 1H), 5.26 (d, J =10, 67 Hz, 1H), 5.41 (dd, J =15.06, 9.66 Hz, 1H), 5.61 (dd, J =14.93, 9.91 Hz, 1H), 6.45- 6.56 (m, 4H), 7.46-7.50 (m, 1H), 7.50-7.53 (m, 1H) 114
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(Cyclohexanecarbonyl)piperazin-1-yl]-5-fluorophenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 697.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.02 (dd, J = 8.41, 6.90 Hz, 6H), 1.19-1.37 (m, 4H), 1.44-1, 68 (m, 4H), 1.68-1.87 (m, 6H), 1.89 (d, J =1.00 Hz, 3H), 1.91-2.00 (m, 2H), 2 .32-2.41 (m, 4H), 2.41-2.68 (m, 6H), 3.19 (br s, 4H), 3.55 (br s, 4H), 3.61-3 .70 (m, 2H), 3.75 (br d, J =17.19 Hz, 4H), 4.90 (t, J =10.10 Hz, 1H), 5.27 (d, J =10 .67 Hz, 1H), 5.42 (dd, J =14.93, 9.66 Hz, 1H), 5.61 (dd, J =15.06, 9.91 Hz, 1H), 6.49 -6.57 (m, 4H) 115
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(1-methylindol-6-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 780.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.00 (dd, J = 17.82, 6.78 Hz, 6H), 1.77-1.87 (m, 4H), 1.87-2, 00 (m, 2H), 2.35-2.38 (m, 3H), 2.38-2.50 (m, 5H), 2.50-2.69 (m, 4H), 3.13- 3.21 (m, 4H), 3.21-3.30 (m, 4H), 3.41-3.67 (m, 5H), 3.70-3.79 (m, 1H), 3. 88 (s, 3H), 4.89 (t, J =10.10 Hz, 1H), 5.24 (d, J =10.67 Hz, 1H), 5.36-5.48 (m, 1H ), 5.60 (dd, J =15.00, 9.85 Hz, 1H), 6.39-6.52 (m, 4H), 6.66 (dd, J =3.20, 0.69 Hz, 1H), 7.22 (d, J =3.14 Hz, 1H), 7.45 (d, J =8.66 Hz, 1H), 7.64 (dd, J =8.66, 1 .76 Hz, 1H), 8.14 (d, J =1.38 Hz, 1H) 116
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-Fluoro-1-(oxan-4-yl)indazol-6-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 627.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.89-0.98 (m, 6H), 1.10-1.25 (m, 2H), 1.42 (br d, J =9.41 Hz , 1H), 1.68-1.94 (m, 7H), 2.17-2.41 (m, 9H), 2.44-2.61 (m, 3H), 3.32-3.47 (m, 4H), 3.47-3.59 (m, 3H), 3.66 (br d, J =2.89 Hz, 1H), 4.09 (br s, 2H), 4.47- 4.56 (m, 1H), 4.82 (t, J =10.04 Hz, 1H), 5.22 (d, J =10.54 Hz, 1H), 5.36 (br s, 1H) , 5.54 (dd, J =14.93, 9.91 Hz, 1H), 6.60-6.70 (m, 2H), 7.00 (s, 1H), 7.96 (s, 1H ) 117
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-Fluoro-2-(oxan-4-yl)indazol-6-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 627.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (dd, J =6.78, 1.88 Hz, 6H), 1.18 (br d, J =8.91 Hz, 2H), 1, 32-1.58 (m, 2H), 1.58-1.80 (m, 2H), 1.85 (d, J =1.13 Hz, 3H), 2.10-2.22 (m, 4H), 2.24 (s, 3H), 2.30 (br s, 4H), 2.42-2.61 (m, 4H), 3.33-3.46 (m, 4H), 3, 46-3.58 (m, 3H), 3.65 (br d, J =2.26 Hz, 1H), 4.10 (dt, J =11.67, 3.07 Hz, 2H), 4, 51-4.61 (m, 1H), 4.82 (t, J =10.10 Hz, 1H), 5.23 (d, J =10.54 Hz, 1H), 5.32 (dd, J =15.00, 9.72 Hz, 1H), 5.53 (dd, J =15.00, 9.98 Hz, 1H), 6.51-6.58 (m, 2H), 7.31 ( s, 1H), 7.93 (s, 1H) 118
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(oxane-4-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 699.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.01 (dd, J =9.35, 6.84 Hz, 6H), 1.47-1.56 (m, 1H), 1.60-1, 72 (m, 2H), 1.73-1.87 (m, 2H), 1.89 (s, 3H), 1.90-2.03 (m, 2H), 2.32 (s, 3H) , 2.41 (br s, 4H), 2.52-2.69 (m, 3H), 2.79 (tt, J =11.26, 3.80 Hz, 2H), 3.20 (br s , 4H), 3.39-3.60 (m, 7H), 3.63-3.85 (m, 6H), 4.01-4.10 (m, 2H), 4.90 (t, J =10.10 Hz, 1H), 5.27 (d, J =10.54 Hz, 1H), 5.42 (dd, J =15.06, 9.66 Hz, 1H), 5.61 (dd , J =14.93, 9.91 Hz, 1H), 6.49-6.57 (m, 4H) 119
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-morpholin-4-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 714.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (dd, J = 8.53, 6.90 Hz, 6H), 1.48-1.77 (m, 5H), 1.75-1, 88 (m, 6H), 1.83-1.90 (m, 1H), 2.21-2.29 (m, 4H), 2.33 (br s, 4H), 2.39-2.59 (m, 6H), 3.05-3.22 (m, 5H), 3.31-3.51 (m, 5H), 3.51-3.72 (m, 6H), 4.81 (t , J =10.04 Hz, 1H), 5.18 (d, J =10.67 Hz, 1H), 5.29-5.39 (m, 1H), 5.47-5.58 (m, 1H), 6.39-6.51 (m, 4H) 120
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(1-methyl-imidazol-4-carbonyl)piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 695.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (dd, J = 8.78, 6.90 Hz, 6H), 1.37-1.48 (m, 2H), 1.48-1, 77 (m, 3H), 1.77-1.82 (m, 3H), 1.82-1.92 (m, 1H), 2.20-2.27 (m, 4H), 2.31 ( br s, 4H), 2.42-2.62 (m, 3H), 3.09-3.27 (m, 5H), 3.42 (br s, 5H), 3.56-3.70 ( m, 5H), 4.81 (t, J =10.10 Hz, 1H), 5.19 (d, J =10.67 Hz, 1H), 5.33 (dd, J =15.06, 9 .66 Hz, 1H), 5.52 (dd, J =14.93, 9.91 Hz, 1H), 6.41-6.49 (m, 4H), 7.32 (d, J =1, 25 Hz, 1H), 7.49 (d, J =1.38 Hz, 1H) 121
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(2-Cyclopropylacetyl)piperazin-1-yl]-5-fluorophenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 669.3 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ -0.04-0.02 (m, 2H), 0.35-0.41 (m, 2H), 0.72-0.90 (m, 8H) , 1.20-1.41 (m, 1H), 1.54-1.65 (m, 2H), 1.65-1.68 (m, 3H), 1.68-1.78 (m, 2H), 2.06-2.10 (m, 4H), 2.13-2.21 (m, 4H), 2.24-2.46 (m, 3H), 2.97 (br s, 4H ), 3.15-3.34 (m, 4H), 3.34-3.46 (m, 3H), 3.48-3.61 (m, 3H), 4.68 (t, J =10 ,10 Hz, 1H), 5.00-5.10 (m, 1H), 5.19 (dd, J =14.93, 9.66 Hz, 1H), 5.39 (dd, J =15, 06, 9.91 Hz, 1H), 6.26-6.34 (m, 4H) 122
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 695.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.89-0.93 (m, 3H), 0.94 (br d, J =6.90 Hz, 3H), 1.33-1.54 (m , 1H), 1.63-1.78 (m, 3H), 1.7 (s, 3H), 1.80-1.91 (m, 2H), 2.20-2.26 (m, 5H ), 2.29 (br s, 3H), 2.39-2.59 (m, 3H), 3.00-3.13 (m, 5H), 3.42 (br s, 4H), 3, 61-3.73 (m, 5H), 4.81 (t, J =10.04 Hz, 1H), 4.98 (s, 2H), 5.15-5.23 (m, 1H), 5 .33 (dd, J =15.06, 9.66 Hz, 1H), 5.52 (dd, J =15.00, 9.85 Hz, 1H), 6.26 (t, J =2.13 Hz, 1H), 6.37-6.48 (m, 4H), 7.47 (d, J =2.26 Hz, 2H) 123
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(1,3-oxazol-5-carbonyl)piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 682.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (dd, J =8.91, 6.78 Hz, 6H), 1.38-1.48 (m, 2H), 1.68-1, 78 (m, 2H), 1.78-1.83 (m, 3H), 1.83-1.91 (m, 1H), 2.20-2.24 (m, 3H), 2.24- 2.35 (m, 4H), 2.44-2.59 (m, 3H), 3.16-3.24 (m, 4H), 3.24-3.34 (m, 1H), 3. 34-3.52 (m, 4H), 3.62-3.71 (m, 1H), 3.81-3.92 (m, 4H), 4.81 (t, J = 10.10 Hz, 1H), 5.19 (d, J =10.54 Hz, 1H), 5.33 (dd, J =15.00, 9.60 Hz, 1H), 5.52 (dd, J =14.93 , 9.91 Hz, 1H), 6.41-6.50 (m, 4H), 7.58 (s, 1H), 7.90 (s, 1H) 124
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-hydroxyethylsulfonyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 682.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.97-1.05 (m, 6H), 1.26-1.29 (m, 1H), 1.45-1.57 (m, 1H), 1.77-1.86 (m, 1H), 1.89 (s, 3H), 1.91-2.01 (m, 1H), 2.29-2.34 (m, 3H), 2. 34-2.46 (m, 4H), 2.51-2.72 (m, 3H), 3.18-3.26 (m, 2H), 3.26-3.34 (m, 4H), 3.42-3.56 (m, 8H), 3.71-3.79 (m, 1H), 4.08-4.17 (m, 3H), 4.90 (t, J = 10.04 Hz, 1H), 5.27 (d, J =10.67 Hz, 1H), 5.42 (dd, J =14.93, 9.66 Hz, 1H), 5.61 (dd, J =15 .00, 9.85 Hz, 1H), 6.49-6.59 (m, 4H) 125
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(oxetan-3-ylsulfonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 707.3 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 0.89-0.98 (m, 6H), 1.12-1.25 (m, 2H), 1.37-1.48 (m, 1H), 1.69-1.77 (m, 1H), 1.79 (s, 3H), 1.81-1.91 (m, 1H), 2.20-2.25 (m, 3H), 2. 28 (br s, 4H), 2.39-2.59 (m, 3H), 3.10-3.23 (m, 4H), 3.23-3.32 (m, 1H), 3.33 -3.47 (m, 8H), 3.65 (q, J =6.99 Hz, 1H), 4.38 (tt, J =8.14, 6.48 Hz, 1H), 4.77- 4.85 (m, 3H), 4.86-4.94 (m, 2H), 5.18 (d, J =10.54 Hz, 1H), 5.33 (dd, J =14.93, 9.66 Hz, 1H), 5.52 (dd, J =14.93, 9.91 Hz, 1H), 6.39-6.50 (m, 4H) 126
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-Fluoro-1-(oxetan-3-ylsulfonyl)indazol-6-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 663.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94 (dd, J =6.78, 2.89 Hz, 6H), 1.09-1.26 (m, 2H), 1.38-1, 49 (m, 2H), 1.67-1.78 (m, 2H), 1.85 (d, J =1.13 Hz, 5H), 2.42-2.55 (m, 5H), 2 .55-2.78 (m, 4H), 3.57-3.73 (m, 6H), 4.77-4.90 (m, 4H), 5.18-5.28 (m, 1H) , 5.34 (dd, J =15.00, 9.72 Hz, 1H), 5.55 (dd, J =15.00, 9.98 Hz, 1H), 6.59 (s, 1H), 6.69 (d, J =10.92 Hz, 1H), 7.10 (s, 1H), 8.02-8.06 (m, 1H) 127
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-(1-hydroxyisoquinolin-7-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 552.3 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 0.86-1.03 (m, 6H), 1.38-1.49 (m, 1H), 1.68-1.80 (m, 2H), 1.81-1.93 (m, 5H), 2.18-2.27 (m, 3H), 2.30 (br s, 3H), 2.41-2.62 (m, 4H), 3 .32-3.49 (m, 4H), 3.55-3.72 (m, 2H), 4.83 (t, J =10.10 Hz, 1H), 5.25 (d, J =10 .67 Hz, 1H), 5.30-5.38 (m, 1H), 5.55 (dd, J =15.00, 9.85 Hz, 1H), 6.46 (d, J =7, 15 Hz, 1H), 6.61 (s, 1H), 7.01 (br s, 1H), 7.42-7.53 (m, 2H), 8.26 (s, 1H), 9.91 (br s, 1H) 128
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[4-Fluoro-1-[2-(methylamino)-2-oxoethyl]indazol-6-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 614.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94 (d, J =6.78 Hz, 6H), 1.15-1.24 (m, 1H), 1.34-1.56 (m, 1H), 1.66-1.77 (m, 1H), 1.89 (s, 3H), 2.20-2.26 (m, 3H), 2.26-2.40 (m, 3H) , 2.43-2.62 (m, 2H), 2.69 (d, J =4.77 Hz, 3H), 3.42 (br s, 3H), 3.65 (br s, 1H), 4.81 (t, J =10.04 Hz, 1H), 4.96 (d, J =9.66 Hz, 3H), 5.21 (d, J =10.54 Hz, 1H), 5, 34 (dd, J =15.06, 9.66 Hz, 1H), 5.53 (dd, J =15.00, 9.85 Hz, 1H), 5.76 (br d, J =4.64 Hz, 2H), 6.58 (s, 1H), 6.68-6.75 (m, 1H), 6.75-6.84 (m, 1H), 6.97 (s, 1H), 7 ,12 (d, J =8.41 Hz, 1H), 7.30 (td, J =8.06, 4.96 Hz, 1H), 8.03-8.08 (m, 1H), 8, 08-8.15 (m, 1H) 129
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-Fluoro-1-(2-oxo-2-pyrrolidin-1-ylethyl)indazol-6-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 654.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (d, J =6.78 Hz, 6H), 1.08-1.24 (m, 2H), 1.42 (ddd, J =13, 71, 9.82, 3.95 Hz, 1H), 1.68-1.82 (m, 4H), 1.82-1.85 (m, 2H), 1.89 (s, 3H), 2 ,19-2.28 (m, 3H), 2.32 (br s, 4H), 2.39-2.61 (m, 4H), 3.42 (br t, J =6.90 Hz, 9H ), 3.54-3.70 (m, 1H), 4.81 (t, J =10.04 Hz, 1H), 5.05 (s, 2H), 5.20 (d, J =10, 67 Hz, 1H), 5.33 (dd, J =15.06, 9.66 Hz, 1H), 5.52 (dd, J =14.93, 9.91 Hz, 1H), 6.58 ( s, 1H), 6.67 (d, J =10.92 Hz, 1H), 7.03 (s, 1H), 7.97 (d, J =0.75 Hz, 1H) 130
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-Fluoro-1-(2-morpholin-4-yl-2-oxoethyl)indazol-6-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 670.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (d, J =6.78 Hz, 6H), 1.07-1.29 (m, 2H), 1.34-1.60 (m, 1H), 1.60-1.80 (m, 2H), 1.83 (d, J =1.13 Hz, 3H), 2.20-2.28 (m, 4H), 2.32 (br s, 3H), 2.38-2.63 (m, 3H), 3.31-3.45 (m, 4H), 3.45-3.57 (m, 9H), 3.60-3, 71 (m, 1H), 4.81 (t, J =10.10 Hz, 1H), 5.11 (s, 2H), 5.10-5.23 (m, 2H), 5.33 (dd , J =15.00, 9.72 Hz, 1H), 5.53 (dd, J =15.00, 9.85 Hz, 1H), 6.58 (s, 1H), 6.69 (d, J =10.79 Hz, 1H), 7.05 (s, 1H), 7.96-8.02 (m, 1H) 131
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(Cyanomethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 582.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94 (t, J =6.21 Hz, 6H), 1.19 (br d, J =8.78 Hz, 2H), 1.34-1, 59 (m, 2H), 1.59-1.81 (m, 1H), 1.85 (d, J =1.13 Hz, 4H), 2.18-2.28 (m, 3H), 2 .32 (br s, 4H), 2.44-2.61 (m, 3H), 3.31-3.54 (m, 4H), 3.66 (br d, J =6.27 Hz, 1H ), 4.82 (t, J =10.04 Hz, 1H), 5.20-5.25 (m, 3H), 5.31-5.39 (m, 1H), 5.53 (dd, J =14.93, 9.91 Hz, 1H), 6.62 (s, 1H), 6.76 (d, J =10.67 Hz, 1H), 7.04 (s, 1H), 8, 03 (d, J =0.88 Hz, 1H) 132
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-[2-(Dimethylamino)-2-oxoethyl]-4-fluorinazol-6-yl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 628.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (dd, J =6.78, 0.88 Hz, 6H), 1.07-1.28 (m, 1H), 1.42 (ddd, J =13.71, 9.76, 3.76 Hz, 1H), 1.63-1.78 (m, 1H), 1.80-1.84 (m, 4H), 1.84-1, 91 (m, 1H), 2.19-2.27 (m, 2H), 2.30 (br s, 3H), 2.43-2.62 (m, 4H), 2.80-2.99 (m, 4H), 3.01-3.07 (m, 4H), 3.32-3.51 (m, 3H), 3.61-3.70 (m, 1H), 4.81 (t , J =10.10 Hz, 1H), 5.12 (s, 2H), 5.16-5.24 (m, 1H), 5.33 (dd, J =15.00, 9.72 Hz, 1H), 5.52 (dd, J =15.06, 9.91 Hz, 1H), 6.58 (s, 1H), 6.65-6.74 (m, 2H), 7.00 (s , 1H), 7.96-8.02 (m, 1H) 133
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(Cyclopropylmethyl)-3-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 597.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.32-0.48 (m, 4H), 0.93 (dd, J =6.78, 0.88 Hz, 6H), 1.11-1, 34 (m, 2H), 1.12-1.24 (m, 1H), 1.37-1.65 (m, 2H), 1.65-1.80 (m, 4H), 1.86 ( td, J =6.68, 3.58 Hz, 3H), 2.23 (s, 3H), 2.31 (br s, 4H), 2.40-2.62 (m, 2H), 3, 43 (br s, 3H), 3.55-3.70 (m, 1H), 4.27-4.37 (m, 2H), 4.82 (t, J =10.10 Hz, 1H), 5.27-5.37 (m, 2H), 5.55 (dd, J = 14.93, 9.91 Hz, 1H), 6.58 (s, 1H), 6.87 (dd, J = 8.28, 5.77 Hz, 1H), 7.34 (d, J =8.28 Hz, 1H), 7.88 (d, J =2.38 Hz, 1H) 134
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[4-(3-methoxypropanoyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 673.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.88-0.92 (d, J =6.90, 3H), 0.93 (br d, J =6.90 Hz, 3H), 1.18 (br d, J =8.41 Hz, 2H), 1.33-1.57 (m, 1H), 1.64-1.75 (m, 2H), 1.78 (s, 3H), 1 ,80-1.92 (m, 2H), 2.17-2.27 (m, 4H), 2.30 (br s, 4H), 2.43-2.59 (m, 5H), 3, 03-3.27 (m, 5H), 3.29 (s, 3H), 3.35-3.51 (m, 4H), 3.53-3.60 (m, 2H), 3.62- 3.68 (m, 3H), 3.68-3.76 (m, 2H), 4.80 (t, J =10.10 Hz, 1H), 5.17 (d, J =10.67 Hz , 1H), 5.32 (dd, J =15.06, 9.66 Hz, 1H), 5.51 (dd, J =15.06, 9.91 Hz, 1H), 6.38-6, 47 (m, 4H) 135
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-hydroxyacetyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 645.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.87-0.92 (d, J =6.78 Hz, 3H), 0.93 (d, J =6.78 Hz, 3H), 1.10 -1.24 (m, 2H), 1.34-1.48 (m, 1H), 1.67-1.77 (m, 1H), 1.79 (s, 3H), 1.80-1 .92 (m, 1H), 2.26 (s, 3H), 2.35 (br s, 4H), 2.42-2.60 (m, 4H), 3.07-3.17 (m, 4H), 3.28-3.40 (m, 3H), 3.44 (br s, 4H), 3.55-3.69 (m, 1H), 3.69-3.78 (m, 2H ), 4.13 (s, 2H), 4.80 (t, J =10.04 Hz, 1H), 5.17 (d, J =10.54 Hz, 1H), 5.32 (dd, J =14.93, 9.66 Hz, 1H), 5.51 (dd, J =15.06, 9.91 Hz, 1H), 6.39-6.50 (m, 4H) 136
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(3-hydroxypropyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 645.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.85-0.92 (d, J =6.78 Hz, 3H), 0.93 (d, J =6.78 Hz, 3H), 1.11 -1.37 (m, 3H), 1.37-1.47 (m, 1H), 1.64-1.75 (m, 3H), 1.79 (s, 3H), 1.81-1 .90 (m, 1H), 2.20-2.24 (m, 3H), 2.24-2.34 (m, 4H), 2.40-2.56 (m, 3H), 2.57 -2.67 (m, 5H), 3.03-3.20 (m, 4H), 3.41 (br s, 5H), 3.60-3.69 (m, 1H), 3.61- 3.77 (m, 3H), 4.80 (t, J =9.98 Hz, 1H), 5.17 (d, J =10.67 Hz, 1H), 5.32 (dd, J =15 .06, 9.66 Hz, 1H), 5.51 (dd, J =15.00, 9.85 Hz, 1H), 6.37-6.45 (m, 4H) 137
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(Cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 598.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.37-0.45 (m, 2H), 0.54-0.63 (m, 2H), 0.90-0.94 (m, 3H), 0.95 (br d, J =4.02 Hz, 3H), 1.12-1.24 (m, 2H), 1.24-1.47 (m, 1H), 1.38-1.51 (m, 1H), 1.67-1.78 (m, 1H), 1.78-1.93 (m, 4H), 2.22-2.26 (m, 3H), 2.26-2 .39 (m, 4H), 2.38-2.61 (m, 4H), 3.32-3.52 (m, 4H), 3.66 (br d, J = 3.39 Hz, 1H) , 4.42 (dd, J =7.09, 1.32 Hz, 2H), 4.81 (t, J =10.10 Hz, 1H), 5.23 (d, J =10.67 Hz, 1H), 5.34 (dd, J =14.93, 9.66 Hz, 1H), 5.53 (dd, J =15.00, 9.85 Hz, 1H), 6.62 (s, 1H ), 6.90 (d, J =10.92 Hz, 1H), 7.11 (s, 1H) 138
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-(Cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 598.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.37-0.55 (m, 2H), 0.55-0.64 (m, 2H), 0.90-0.96 (m, 6H), 1.15-1.24 (m, 2H), 1.36-1.56 (m, 2H), 1.68-1.78 (m, 2H), 1.80-1.90 (m, 4H ), 2.21-2.26 (m, 3H), 2.26-2.38 (m, 4H), 2.44-2.64 (m, 3H), 3.34-3.52 (m , 4H), 3.61-3.72 (m, 1H), 4.50 (d, J =7.28 Hz, 2H), 4.82 (t, J =10.04 Hz, 1H), 5 .23 (d, J =10.54 Hz, 1H), 5.33 (dd, J =15.00, 9.72 Hz, 1H), 5.53 (dd, J =14.93, 9.91 Hz, 1H), 6.57 (s, 1H), 6.88 (dd, J =11.42, 0.88 Hz, 1H), 7.46 (s, 1H) 139
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(Cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 598.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.40-0.49 (m, 2H), 0.51-0.61 (m, 2H), 0.94 (d, J =6.65 Hz, 6H), 1.09-1.35 (m, 2H), 1.35-1.49 (m, 2H), 1.67-1.80 (m, 2H), 1.80-1.91 ( m, 4H), 2.22-2.26 (m, 3H), 2.27-2.38 (m, 4H), 2.44-2.63 (m, 3H), 3.35-3, 53 (m, 4H), 3.61-3.72 (m, 1H), 4.53 (d, J =7.28 Hz, 2H), 4.82 (t, J =10.04 Hz, 1H ), 5.23 (d, J =10.67 Hz, 1H), 5.30-5.38 (m, 1H), 5.53 (dd, J =15.00, 9.85 Hz, 1H) , 6.58 (s, 1H), 6.98 (d, J =11.67 Hz, 1H), 7.66 (s, 1H) 140
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-3-(oxan-4-yl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 628.3 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ 0.89-0.98 (m, 6H), 1.13-1.26 (m, 2H), 1.38-1.49 (m, 1H), 1.66-1.79 (m, 2H), 1.79 (s, 3H), 1.96-2.22 (m, 3H), 2.22-2.26 (m, 3H), 2. 26-2.35 (m, 4H), 2.36-2.63 (m, 5H), 3.33-3.50 (m, 4H), 3.57 (br t, J = 11.67 Hz , 2H), 3.63-3.71 (m, 1H), 4.14 (br d, J =11.54 Hz, 2H), 4.77-4.85 (m, 2H), 5.22 (d, J =10.67 Hz, 1H), 5.31-5.39 (m, 1H), 5.53 (dd, J =14.93, 9.91 Hz, 1H), 6.62 ( s, 1H), 6.90 (d, J =10.92 Hz, 1H), 7.11 (s, 1H) 141
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-2-(oxan-4-yl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 628.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94 (d, J =6.78 Hz, 6H), 1.10-1.25 (m, 2H), 1.42 (ddd, J =13, 90, 9.94, 3.76 Hz, 1H), 1.67-1.78 (m, 1H), 1.79-1.91 (m, 4H), 2.17-2.25 (m, 5H), 2.25-2.43 (m, 5H), 2.45-2.62 (m, 3H), 3.33-3.50 (m, 4H), 3.50-3.61 ( m, 2H), 3.61-3.72 (m, 1H), 4.05-4.12 (m, 2H), 4.82 (t, J =10.10 Hz, 1H), 4.87 -4.98 (m, 1H), 5.23 (d, J =10.67 Hz, 1H), 5.33 (dd, J =14.93, 9.66 Hz, 1H), 5.53 ( dd, J =14.93, 9.91 Hz, 1H), 6.56 (s, 1H), 6.88 (dd, J =11.29, 0.88 Hz, 1H), 7.46 (s , 1H) 142
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-Fluoro-3-(2-methoxyethyl)benzimidazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 601.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94 (dd, J =6.78, 1.51 Hz, 6H), 1.08-1.29 (m, 2H), 1.33-1, 60 (m, 1H), 1.60-1.81 (m, 2H), 1.81-1.92 (m, 4H), 2.20-2.29 (m, 4H), 2.33 ( br s, 4H), 2.44-2.62 (m, 3H), 3.24 (s, 3H), 3.34-3.54 (m, 3H), 3.63 (t, J =5 .08 Hz, 3H), 4.22 (t, J =5.02 Hz, 2H), 4.82 (t, J =10.10 Hz, 1H), 5.22 (d, J =10.67 Hz, 1H), 5.33 (dd, J =14.93, 9.66 Hz, 1H), 5.54 (dd, J =14.93, 9.91 Hz, 1H), 6.61 (s , 1H), 6.87 (d, J =11.42 Hz, 1H), 6.99 (s, 1H), 7.86 (s, 1H) 143
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(oxolane-3-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 685.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (dd, J =9.10, 6.84 Hz, 6H), 1.14-1.24 (m, 2H), 1.37-1 .45 (m, 1H), 1.66-1.74 (m, 1H), 1.79 (d, J =1.13 Hz, 3H), 1.82-1.90 (m, 2H), 1.97-2.08 (m, 2H), 2.14-2.21 (m, 1H), 2.23-2.27 (m, 1H), 2.26-2.35 (m, 3H ), 2.42-2.60 (m, 3H), 3.05-3.14 (m, 4H), 3.14-3.24 (m, 1H), 3.35-3.49 (m , 4H), 3.55-3.62 (m, 2H), 3.62-3.67 (m, 1H), 3.67-3.74 (m, 2H), 3.75-3.86 (m, 3H), 3.92-4.00 (m, 1H), 4.76-4.86 (m, 1H), 5.13-5.22 (m, 1H), 5.26-5 .37 (m, 1H), 5.44-5.56 (m, 1H), 6.37-6.48 (m, 4H) 144
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4- yl]benzotriazol-5-yl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate LCMS (ESI, mass/charge), 727.8 [M+H] ⁺ . ^1H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92-0.98 (m, 6H), 1.14-1.21 (m, 2H), 1.42 (s, 10H), 1.69 -1.77 (m, 1H), 1.83 (d, J =1.25 Hz, 4H), 2.04-2.14 (m, 2H), 2.24 (s, 9H), 2, 46-2.61 (m, 3H), 2.89-3.00 (m, 2H), 3.34-3.52 (m, 4H), 3.62-3.70 (m, 1H), 4.19-4.32 (m, 2H), 4.65-4.75 (m, 1H), 4.75-4.86 (m, 1H), 5.18-5.27 (m, 1H ), 5.29-5.41 (m, 1H), 5.48-5.58 (m, 1H), 6.58-6.64 (m, 1H), 6.86-6.94 (m , 1H), 7.07 (s, 1H) 145
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(4-Chlorophenyl)methyl]-7-fluorobenzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 668.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (dd, J = 10.48, 6.84 Hz, 6H), 1.11-1.22 (m, 3H), 1.36-1 .45 (m, 1H), 1.72-1.73 (m, 3H), 1.81-1.87 (m, 2H), 2.27 (s, 3H), 2.30-2.41 (m, 4H), 2.43-2.61 (m, 3H), 3.33-3.53 (m, 4H), 3.60-3.71 (m, 1H), 4.80 (t , J =10.10 Hz, 1H), 5.18 (d, J =10.67 Hz, 1H), 5.27-5.38 (m, 1H), 5.51 (dd, J =15, 00, 9.85 Hz, 1H), 5.71 (d, J =1.00 Hz, 2H), 6.49-6.57 (m, 1H), 6.83-6.92 (m, 2H ), 7.13 (d, J =8.53 Hz, 2H), 7.24-7.28 (m, 2H) 146
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-Acetylpiperidin-4-yl)-7-fluorobenzimidazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 668.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ (m, 3H), 0.95 (br d, J =3.76 Hz, 3H), 1.19 (br d, J =8.66 Hz, 2H) , 1.37-1.51 (m, 1H), 1.67-1.79 (m, 2H), 1.80-2.01 (m, 5H), 2.08-2.12 (m, 1H), 2.08-2.27 (m, 6H), 2.20-2.22 (m, 1H), 2.22-2.27 (m, 1H), 2.32 (s, 3H) , 2.40-2.60 (m, 3H), 2.68 (br t, J =12.99 Hz, 1H), 3.08-3.31 (m, 2H), 3.31-3, 54 (m, 4H), 3.62-3.71 (m, 1H), 3.98 (br d, J =12.67 Hz, 1H), 4.27-4.35 (m, 1H), 4.78-4.88 (m, 2H), 5.22 (d, J =10.67 Hz, 1H), 5.34 (dd, J =14.93, 9.66 Hz, 1H), 5 .53 (dd, J =15.00, 9.85 Hz, 1H), 6.62 (s, 1H), 6.90 (d, J =11.42 Hz, 1H), 6.97 (s, 1H), 7.85 (s, 1H). 147
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-3-(4-hydroxycyclohexyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 642.8 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.91-0.95 (m, 3H), 0.95 (d, J =5.52 Hz, 3H), 1.10-1.26 (m, 2H), 1.36-1.63 (m, 3H), 1.66-1.80 (m, 1H), 1.80-1.89 (m, 4H), 2.11-2.27 ( m, 9H), 2.30 (br s, 4H), 2.43-2.62 (m, 4H), 3.30-3.54 (m, 4H), 3.54-3.71 (m , 1H), 3.77-3.86 (m, 1H), 4.48-4.57 (m, 1H), 4.81 (t, J =10.04 Hz, 1H), 5.22 ( d, J =10.54 Hz, 1H), 5.31-5.40 (m, 1H), 5.53 (dd, J =15.00, 9.85 Hz, 1H), 6.62 (s , 1H), 6.87-6.95 (m, 1H), 7.06-7.11 (m, 1H) 148
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-3-(oxan-4-ylmethyl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 641.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.91-0.94 (m, 3H), 0.95 (d, J =4.89 Hz, 3H), 1.10-1.34 (m, 2H), 1.34-1.49 (m, 6H), 1.68-1.79 (m, 1H), 1.82-1.91 (m, 4H), 2.21-2.28 ( m, 4H), 2.28-2.42 (m, 4H), 2.41-2.60 (m, 3H), 3.18-3.34 (m, 3H), 3.34-3, 55 (m, 4H), 3.66 (br s, 1H), 3.86-3.93 (m, 2H), 4.41 (d, J =7.15 Hz, 2H), 4.81 ( t, J =10.10 Hz, 1H), 5.20-5.25 (m, 1H), 5.35 (dd, J =14.93, 9.66 Hz, 1H), 5.53 (dd , J =14.93, 9.91 Hz, 1H), 6.62 (s, 1H), 6.91 (d, J =10.54 Hz, 1H), 7.04 (s, 1H) 149
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-3-[(2S)-1-hydroxypropan-2-yl]benzotriazol-5-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94 (dd, J =6.78, 3.39 Hz, 6H), 1.13-1.25 (m, 2H), 1.37-1, 51 (m, 1H), 1.59-1.65 (m, 3H), 1.67-1.77 (m, 1H), 1.79-1.91 (m, 5H), 2.20- 2.28 (m, 4H), 2.28-2.42 (m, 4H), 2.45-2.62 (m, 3H), 3.35-3.55 (m, 4H), 3, 62-3.72 (m, 1H), 4.04-4.12 (m, 1H), 4.18 (dd, J =11.86, 7.47 Hz, 1H), 4.78-4, 89 (m, 2H), 5.22 (d, J =10.54 Hz, 1H), 5.34 (dd, J =15.00, 9.72 Hz, 1H), 5.53 (dd, J =15.00, 9.85 Hz, 1H), 6.61 (s, 1H), 6.89 (d, J =11.04 Hz, 1H), 7.13 (s, 1H) 150
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-3-[(2R)-1-hydroxypropan-2-yl]benzotriazol-5-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.6 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.90-0.97 (m, 6H), 1.19 (br d, J =8.03 Hz, 2H), 1.38-1.51 (m , 1H), 1.57-1.68 (m, 3H), 1.68-1.79 (m, 1H), 1.79-1.91 (m, 5H), 2.18-2.26 (m, 4H), 2.26-2.41 (m, 4H), 2.43-2.63 (m, 3H), 3.34-3.53 (m, 4H), 3.61-3 .72 (m, 1H), 4.04-4.10 (m, 1H), 4.14-4.21 (m, 1H), 4.78-4.89 (m, 2H), 5.19 -5.25 (m, 1H), 5.30-5.39 (m, 1H), 5.53 (dd, J =15.00, 9.85 Hz, 1H), 6.61 (s, 1H ), 6.89 (d, J =10.92 Hz, 1H), 7.13 (s, 1H) 151
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-[(3S)-oxolan-3-carbonyl]piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 685.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.88-0.92 (d, J =6.90 Hz, 3H), 0.93 (d, J =6.90 Hz, 3H), 1.06 -1.29 (m, 2H), 1.34-1.49 (m, 1H), 1.68-1.77 (m, 1H), 1.77-1.81 (m, 4H), 1 .81-1.91 (m, 2H), 1.95-2.13 (m, 1H), 2.13-2.22 (m, 1H), 2.22-2.26 (m, 3H) , 2.32 (br s, 4H), 2.37-2.62 (m, 4H), 3.05-3.23 (m, 5H), 3.37-3.52 (m, 4H), 3.67-3.87 (m, 5H), 3.68-3.75 (m, 1H), 3.90-4.00 (m, 1H), 4.80 (t, J =10.04 Hz, 1H), 5.17 (d, J =10.54 Hz, 1H), 5.32 (dd, J =14.93, 9.66 Hz, 1H), 5.51 (dd, J =14 .93, 9.91 Hz, 1H), 6.39-6.48 (m, 4H) 152
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-[(3R)-oxolan-3-carbonyl]piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 685.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.86-0.97 (m, 6H), 1.10-1.24 (m, 2H), 1.34-1.49 (m, 1H), 1.68-1.89 (m, 6H), 1.94-2.12 (m, 1H), 2.12-2.29 (m, 2H), 2.33 (s, 4H), 2. 38-2.61 (m, 7H), 3.05-3.23 (m, 4H), 3.47 (br s, 3H), 3.53-3.62 (m, 2H), 3.62 -3.86 (m, 6H), 3.93-3.98 (m, 1H), 4.80 (t, J =10.10 Hz, 1H), 5.15-5.23 (m, 1H ), 5.32 (dd, J =15.06, 9.66 Hz, 1H), 5.51 (dd, J =14.93, 9.91 Hz, 1H), 6.39-6.51 ( m, 4H) 153
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(oxetane-3-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 671.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.83-0.97 (m, 6H), 1.12-1.22 (m, 2H), 1.34-1.48 (m, 1H), 1.67-1.81 (m, 1H), 1.81-1.96 (m, 4H), 2.19-2.26 (m, 2H), 2.26-2.32 (m, 3H ), 2.32-2.57 (m, 3H), 3.07 (dt, J =18.16, 5.10 Hz, 4H), 3.18-3.33 (m, 3H), 3, 41 (br s, 5H), 3.53-3.67 (m, 2H), 3.67-3.76 (m, 2H), 3.91-4.00 (m, 1H), 4.70 -4.89 (m, 2H), 4.89-5.09 (m, 1H), 5.17 (d, J =10.67 Hz, 1H), 5.23-5.37 (m, 2H ), 5.40-5.55 (m, 2H), 6.37-6.48 (m, 4H) 154
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(3-methyloxetane-3-carbonyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 685.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.90 (br d, J =6.78 Hz, 3H), 0.92-0.95 (m, 3H), 1.06-1.28 (m , 2H), 1.33-1.60 (m, 1H), 1.62 (s, 3H), 1.67-1.77 (m, 1H), 1.77-1.80 (m, 3H ), 1.80-1.90 (m, 1H), 2.20-2.27 (m, 4H), 2.30 (br s, 4H), 2.36-2.61 (m, 4H) , 3.08 (br s, 5H), 3.31-3.53 (m, 4H), 3.53-3.73 (m, 3H), 4.29 (d, J =6.02 Hz, 2H), 4.80 (t, J =10.04 Hz, 1H), 4.93 (d, J =6.02 Hz, 2H), 5.17 (d, J =10.54 Hz, 1H) , 5.32 (dd, J =14.93, 9.66 Hz, 1H), 5.51 (dd, J =15.06, 9.91 Hz, 1H), 6.38-6.49 (m , 4H) 155
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(3-hydroxypropanoyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 659.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.92 (dd, J =9.16, 6.90 Hz, 6H), 1.06-1.28 (m, 2H), 1.33-1, 49 (m, 1H), 1.66-1.76 (m, 1H), 1.76-1.80 (m, 3H), 1.80-1.91 (m, 1H), 2.18- 2.27 (m, 4H), 2.31 (br s, 4H), 2.36-2.58 (m, 5H), 3.03-3.16 (m, 4H), 3.31-3 .47 (m, 4H), 3.47-3.58 (m, 3H), 3.60-3.74 (m, 3H), 3.83 (t, J =5.21 Hz, 2H), 4.80 (t, J =10.10 Hz, 1H), 5.17 (d, J =10.67 Hz, 1H), 5.32 (dd, J =14.93, 9.66 Hz, 1H ), 5.51 (dd, J =15.06, 9.91 Hz, 1H), 6.38-6.48 (m, 4H) 156
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-3-(4-methyloxan-4-yl)benzotriazol-5-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 642.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94 (dd, J =6.71, 3.07 Hz, 6H), 1.10-1.26 (m, 2H), 1.36-1, 64 (m, 2H), 1.64-1.77 (m, 4H), 1.84 (d, J =1.13 Hz, 3H), 2.00-2.21 (m, 3H), 2 ,21-2.28 (m, 4H), 2.32 (br s, 4H), 2.39-2.62 (m, 4H), 2.66-2.91 (m, 2H), 3, 32-3.51 (m, 3H), 3.51-3.70 (m, 2H), 3.74-3.83 (m, 2H), 4.81 (t, J = 10.10 Hz, 1H), 5.22 (d, J =10.67 Hz, 1H), 5.30-5.40 (m, 1H), 5.53 (dd, J =15.06, 9.91 Hz, 1H ), 6.61 (s, 1H), 6.92 (d, J =10.79 Hz, 1H), 7.18 (s, 1H) 157
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-3-(1-methylsulfonylpiperidin-4-yl)benzotriazol-5-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 705.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94 (t, J =6.27 Hz, 6H), 1.08-1.29 (m, 3H), 1.34-1.58 (m, 1H), 1.58-1.80 (m, 3H), 1.84 (d, J =1.25 Hz, 5H), 2.20-2.29 (m, 4H), 2.29-2 .35 (m, 3H), 2.35-2.60 (m, 4H), 2.82 (s, 3H), 2.98-3.14 (m, 2H), 3.31-3.55 (m, 4H), 3.55-3.71 (m, 1H), 3.84-3.92 (m, 2H), 4.73-4.84 (m, 2H), 5.22 (d , J =10.54 Hz, 1H), 5.31-5.39 (m, 1H), 5.53 (dd, J =15.00, 9.85 Hz, 1H), 6.62 (s, 1H), 6.92 (d, J =10.79 Hz, 1H), 7.08 (s, 1H) 158
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-Dioxothian-4-yl)-7-fluorobenzotriazol-5-yl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 676.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.91-0.94 (m, 3H), 0.95 (br d, J =3.51 Hz, 3H), 1.08-1.29 (m , 2H), 1.35-1.60 (m, 1H), 1.61-1.81 (m, 1H), 1.81-1.92 (m, 4H), 2.19-2.29 (m, 4H), 2.33 (br s, 4H), 2.45-2.69 (m, 6H), 2.73-2.95 (m, 3H), 3.12 (td, J = 8.72, 3.26 Hz, 3H), 3.33-3.55 (m, 5H), 3.57-3.76 (m, 1H), 4.81 (t, J =10.04 Hz , 1H), 4.86-5.00 (m, 1H), 5.22 (d, J =10.67 Hz, 1H), 5.35 (dd, J =14.93, 9.66 Hz, 1H), 5.53 (dd, J =15.00, 9.85 Hz, 1H), 6.62 (s, 1H), 6.92-7.04 (m, 1H), 7.08 (s , 1H) 159
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-Fluoro-3-(2-methoxyethyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 602.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94 (dd, J =6.71, 3.07 Hz, 6H), 1.08-1.29 (m, 2H), 1.34-1, 60 (m, 1H), 1.60-1.80 (m, 1H), 1.84 (d, J =1.13 Hz, 4H), 2.20-2.28 (m, 3H), 2 .32 (br s, 4H), 2.39-2.64 (m, 4H), 3.22 (s, 3H), 3.32-3.53 (m, 4H), 3.54-3, 73 (m, 1H), 3.80 (t, J =5.14 Hz, 2H), 4.70 (t, J =5.14 Hz, 2H), 4.81 (t, J =10.10 Hz, 1H), 5.23 (d, J =10.67 Hz, 1H), 5.34 (dd, J =15.06, 9.66 Hz, 1H), 5.53 (dd, J =15 .06, 9.91 Hz, 1H), 6.61 (s, 1H), 6.87 (d, J =10.92 Hz, 1H), 7.17-7.20 (m, 1H) 160
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-Acetylpiperidin-4-yl)-7-fluorobenzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 669.9 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.89-0.99 (m, 6H), 1.10-1.25 (m, 2H), 1.38-1.67 (m, 1H), 1.67-1.90 (m, 6H), 2.09-2.26 (m, 9H), 2.27-2.40 (m, 4H), 2.42-2.63 (m, 4H ), 2.89 (br t, J =10.92 Hz, 1H), 3.24-3.51 (m, 5H), 3.67 (br dd, J =6.90, 3.51 Hz, 1H), 4.01 (br d, J =13.80 Hz, 1H), 4.63-4.84 (m, 3H), 5.22 (d, J =10.54 Hz, 1H), 5 ,29-5.44 (m, 1H), 5.47-5.59 (m, 1H), 6.62 (s, 1H), 6.92 (d, J =10.92 Hz, 1H), 7.07 (s, 1H) 161
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-3-[(3R)-oxan-3-yl]benzotriazol-5-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 628.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.92-0.99 (m, 6H), 1.11-1.27 (m, 5H), 1.34-1.49 (m, 2H), 1.69-1.94 (m, 4H), 2.20-2.25 (m, 4H), 2.25-2.37 (m, 4H), 2.37-2.61 (m, 3H ), 3.25-3.45 (m, 4H), 3.52 (td, J =10.95, 3.83 Hz, 1H), 3.61-3.71 (m, 1H), 3, 79-3.94 (m, 1H), 3.98 (br d, J =11.29 Hz, 1H), 4.07-4.14 (m, 1H), 4.62-4.74 (m , 1H), 4.75-4.85 (m, 2H), 5.23 (br s, 1H), 5.30-5.40 (m, 2H), 5.48-5.59 (m, 1H), 6.61 (s, 1H), 6.90 (d, J =10.92 Hz, 1H), 7.12 (s, 1H) 162
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-3-[(3S)-oxan-3-yl]benzotriazol-5-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 628.7 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.89-0.98 (m, 6H), 1.10-1.38 (m, 2H), 1.38-1.50 (m, 1H), 1.67-1.91 (m, 8H), 2.20-2.27 (m, 4H), 2.30 (br s, 4H), 2.35-2.61 (m, 4H), 3 ,39-3.45 (m, 3H), 3.52 (td, J =10.98, 3.89 Hz, 2H), 3.67 (br dd, J =6.53, 3.39 Hz, 1H), 3.85 (dd, J =11.04, 10.29 Hz, 1H), 3.98 (br d, J =11.54 Hz, 1H), 4.07-4.13 (m, 1H), 4.66 (ddd, J =10.63, 6.31, 4.39 Hz, 1H), 4.81 (t, J =10.04 Hz, 1H), 5.22 (d, J =10.67 Hz, 1H), 5.35 (dd, J =14.93, 9.66 Hz, 1H), 5.53 (dd, J =15.00, 9.85 Hz, 1H), 6 .61 (s, 1H), 6.89 (d, J =10.92 Hz, 1H), 7.12 (s, 1H) 163
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-Fluoro-3-[(3R,4S)-3-hydroxyoxan-4-yl]benzotriazol-5- yl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate LCMS (ESI, mass/charge), 644.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94 (dd, J =6.65, 5.14 Hz, 6H), 1.13-1.24 (m, 2H), 1.39-1, 48 (m, 1H), 1.67-1.97 (m, 4H), 2.06-2.17 (m, 2H), 2.17-2.25 (m, 4H), 2.31 ( br s, 4H), 2.39-2.63 (m, 5H), 3.30-3.60 (m, 6H), 3.61-3.74 (m, 1H), 4.05-4 .26 (m, 2H), 4.35-4.44 (m, 1H), 4.44-4.56 (m, 1H), 4.81 (t, J =10.04 Hz, 1H), 5.22 (d, J =10.54 Hz, 1H), 5.35 (dd, J =15.00, 9.60 Hz, 1H), 5.44-5.58 (m, 1H), 6 .60 (s, 1H), 6.85 (d, J =10.29 Hz, 1H), 7.11-7.17 (m, 1H) 164
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Cyclohexyl-7-fluorobenzotriazol-5-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 626.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.94 (t, J =6.46 Hz, 6H), 1.10-1.26 (m, 2H), 1.26-1.51 (m, 3H), 1.61-1.81 (m, 2H), 1.84 (d, J =1.13 Hz, 4H), 1.94 (br d, J =13.80 Hz, 3H), 2 ,00-2.22 (m, 4H), 2.23-2.32 (m, 3H), 2.37 (br s, 3H), 2.42-2.60 (m, 3H), 3, 37-3.58 (m, 4H), 3.61-3.71 (m, 1H), 4.48-4.57 (m, 1H), 4.81 (t, J = 10.10 Hz, 1H), 5.23 (d, J =10.67 Hz, 1H), 5.34 (dd, J =15.06, 9.66 Hz, 1H), 5.53 (dd, J =15.00 , 9.98 Hz, 1H), 6.62 (s, 1H), 6.89 (d, J =10.92 Hz, 1H), 7.09 (s, 1H) 165
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-Fluoro-3-(4-methoxyphenyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 650.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (d, J =6.65 Hz, 6H), 1.18 (br d, J =8.28 Hz, 2H), 1.38-1, 46 (m, 1H), 1.57-1.91 (m, 3H), 2.18-2.29 (m, 4H), 2.34 (br s, 4H), 2.42-2.59 (m, 4H), 3.31-3.56 (m, 6H), 3.61-3.71 (m, 1H), 3.84 (s, 4H), 4.80 (s, 1H), 5.21 (d, J =10.67 Hz, 1H), 5.35 (br d, J =9.66 Hz, 1H), 5.50 (br d, J =9.91 Hz, 1H), 6.60 (s, 1H), 6.95 (d, J =10.92 Hz, 1H), 7.05 (d, J =8.91 Hz, 2H), 7.55 (d, J =8 .91 Hz, 2H) 166
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-Fluoro-3-[(4-methoxyphenyl)methyl]benzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 664.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.88-0.93 (m, 6H), 1.15-1.22 (m, 2H), 1.37-1.45 (m, 2H), 1.70-1.74 (m, 5H), 1.81-1.91 (m, 2H), 2.22-2.28 (m, 3H), 2.28-2.40 (m, 4H ), 2.41-2.63 (m, 3H), 3.34-3.53 (m, 4H), 3.61-3.68 (m, 1H), 3.70 (s, 4H), 4.80 (s, 1H), 5.14-5.20 (m, 1H), 5.28-5.38 (m, 1H), 5.46-5.55 (m, 1H), 5. 68 (d, J =2.13 Hz, 2H), 6.79 (d, J =8.78 Hz, 2H), 6.83-6.90 (m, 2H), 7.10-7.17 (m, 2H) 264
2-[4-[3-Fluoro-5-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-6- (piperazine-1-carbonyloxy)-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]piperazin-1-yl]acetic acid LC/MS (ESI, mass/charge), 631.4 [M+H] ^{+. 1} H-NMR (400 MHz, CHCl ₃ - d ): δ ppm 0.85-1.16 (m, 2 H) 1.23-1.52 (m, 1 H) 1.57-1.77 ( m, 1 H) 1.87 (s, 1 H) 1.92-2.13 (m, 1 H) 2.35-2.55 (m, 1 H) 2.50-2.74 (m, 1 H) 3.11 (br s, 1 H) 3.36-3.54 (m, 2 H) 3.64 (br d, J =10.42 Hz, 2 H) 3.77-3.90 (m, 1 H) 4.76 (br s, 4 H) 5.07-5.19 (m, 1 H) 5.38-5.68 (m, 1 H) 6.40-6.76 ( m, 1 H) 8.02-8.66 (m, 1 H).

Compounds 167-196 (Tables 5, 6, 8, 10, 12 and 14) and their intermediates (Tables 4, 7, 9, 11 and 13) were prepared using the following general methods from Procedures 20-29 .

Synthesis of boronate-based intermediates

Procedure 20

A solution of 3-fluoro-5-iodoaniline (250 mg, 1.055 mmol) and dihydro-2H-pyran-4(3H)-one (264 mg, 2.637 mmol) in methanol (5 ml) was loaded into a 25 ml round bottom flask with a magnetic stirrer. Acetic acid (0.121 mL, 2.11 mmol) was added and the resulting solution was stirred for 30 minutes at room temperature. Sodium cyanoborohydride (133 mg, 2.11 mmol) was added and the resulting solution was stirred overnight at room temperature. The reaction was quenched with 10 ml of 1 M aqueous NaOH solution and stirred for 15 minutes. The solution was extracted with EtOAc (3 x 15 ml), the combined organic layers were washed with brine (15 ml), dried with MgSO ₄ , filtered and evaporated in vacuo. The dry crude product was loaded onto 3 g of silica and purified by column chromatography (ISCO normal phase, 24 g Gold column, 0 to 60% EtOAc/hexanes gradient) to isolate N-(3-fluoro-5- iodophenyl)tetrahydro-2H-pyran-4-amine ( 047 ) (208 mg, 0.648 mmol, 61%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.41-1.55 (m, 2 H) 1.95-2.09 (m, 2 H) 3.38-3.48 (m, 1 H ) 3.53 (td, J =11.61, 2.13 Hz, 2 H) 3.65-3.80 (m, 1 H) 4.02 (br d, J =11.54 Hz, 2 H ) 6.20-6.30 (m, 1 H) 6.73 (br d, J = 1.76 Hz, 2 H). LCMS: 322.6 [M+H] ⁺ .

Procedure 21

A solution of N-(3-fluoro-5-iodophenyl)tetrahydro-2H-pyran-4-amine ( 047 ) (208 mg, 0.648 mmol) in acetonitrile (4 ml) was loaded into a 10 ml vial with a magnetic stirrer. Cesium carbonate (422 mg, 1.295 mmol) and iodomethane (0.203 mL, 3.239 mmol) were added. The vial was sealed and heated to 80°C with stirring overnight. The reaction mixture was cooled to room temperature. The solids were filtered, washed with 20 ml EtOAc and the solvents were evaporated in vacuo. The crude material was dry loaded onto 3 g of silica and purified by column chromatography (ISCO normal phase, 24 g Gold column, 0 to 60% EtOAc/hexanes gradient) to isolate N-(3-fluoro-5- Iodophenyl)-N-methyltetrahydro-2H-pyran-4-amine ( 048 ) (143 mg, 0.427 mmol, 66%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.62-1.72 (m, 2 H) 1.80-1.94 (m, 2 H) 2.79 (s, 3 H) 3.46 -3.56 (m, 2 H) 3.68-3.78 (m, 1 H) 4.05-4.14 (m, 2 H) 6.38-6.47 (m, 1 H) 6 .74-6.81 (m, 1 H) 6.85-6.90 (m, 1 H). LCMS: 336.1 [M+H] ⁺ .

Procedure 22

Bis(pinacolato)diboron (130 mg, 0.512 mmol), potassium acetate (126 mg, 1.28 mmol) and Pd(dppf)Cl ₂ (38.8 mg, 0.043 mmol) were loaded into a 10 ml vial with a magnetic stirrer. A solution of N-(3-fluoro-5-iodophenyl)-N-methyltetrahydro-2H-pyran-4-amine ( 048 ) (143 mg, 0.427 mmol) in DMF (4 mL) was added. The vial was sealed and heated to 100°C and stirred for 20 hours. The vial was cooled to room temperature, diluted with 5 ml EtOAc, filtered through a pad of celite, washed with 10 ml EtOAc and evaporated in vacuo. The crude material was loaded dry onto a 2 g silica column and purified by column chromatography (ISCO normal phase, 12 g Gold column, 0 to 50% EtOAc/hexanes gradient) to give N-(3-fluoro- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyltetrahydro-2H-pyran-4-amine ( 049 ) (82 mg, 0.245 mmol, 57 %). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.33-1.40 (m, 12 H) 1.64-1.73 (m, 2 H) 1.80-1.94 (m, 2 H ) 2.79-2.85 (m, 3 H) 3.48-3.61 (m, 2 H) 3.79-3.90 (m, 1 H) 4.04-4.13 (m, 2 H) 6.54-6.63 (m, 1 H) 6.82-6.89 (m, 1 H) 6.98-7.04 (m, 1 H). LCMS: 336.3 [M+H] ⁺ .

The following intermediates were also synthesized according to general methods from procedures 20-22 .

Table 6. Description of the characteristics of intermediates synthesized according to procedures 20-22 Intermediate connection Characteristics
N-(3-Fluoro-5-iodophenyl)oxetan-3-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.16-3.21 (m, 1 H) 4.49-4.54 (m, 2 H) 4.81-4.86 (m, 1 H ) 5.01 (t, J =6.53 Hz, 2 H) 6.12-6.18 (m, 1 H) 6.62-6.66 (m, 1 H) 6.81-6.86 (m, 1 H). LCMS: 294.1 [M+H] ⁺ .
N-(3-Iodophenyl)tetrahydro-2H-pyran-4-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.41-1.55 (m, 2 H) 1.98-2.09 (m, 2 H) 3.42-3.62 (m, 4 H ) 3.97-4.07 (m, 2 H) 6.54-6.60 (m, 1 H) 6.85-6.92 (m, 1 H) 6.94-6.99 (m, 1 H) 7.00-7.07 (m, 1 H). LCMS: 304.1 [M+H] ⁺ .
N-(3-Iodophenyl)oxetan-3-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.10-4.24 (m, 1 H) 4.52 (s, 2 H) 4.57-4.65 (m, 1 H) 5.01 (t, J =6.65 Hz, 2 H) 6.43-6.51 (m, 1 H) 6.82-6.87 (m, 1 H) 6.88-6.94 (m, 1 H) 7.08-7.15 (m, 1 H). LCMS: 276.1 [M+H] ⁺ .
4-((3-Fluoro-5-iodophenyl)amino)tetrahydro-2H-thiopyran-1,1-dioxide ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.10-2.26 (m, 2 H) 2.36-2.55 (m, 2 H) 3.04-3.28 (m, 4 H ) 3.46-3.65 (m, 1 H) 3.69-3.89 (m, 1 H) 6.27 (d, J =11.04 Hz, 1 H) 6.74 (s, 1 H) 6.79-6.89 (m, 1 H). LCMS: 370.1 [M+H] ⁺ .
tert-Butyl-4-((3-fluoro-5-iodophenyl)amino)piperidine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.31-1.40 (m, 2 H) 1.49 (s, 9 H) 1.96-2.06 (m, 2 H) 2.87 -3.02 (m, 2 H) 3.31-3.45 (m, 1 H) 3.65-3.80 (m, 1 H) 3.99-4.12 (m, 2 H) 6 .25 (br d, J =11.29 Hz, 1 H) 6.72 (s, 1 H) 6.74-6.79 (m, 1 H).
N-(3-Fluoro-5-iodophenyl)-1-(methylsulfonyl)piperidin-4-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.50-1.66 (m, 2 H) 2.16 (br dd, J = 13.24, 3.45 Hz, 2 H) 2.84 ( s, 3 H) 2.87-2.97 (m, 2 H) 3.30-3.43 (m, 1 H) 3.72 (br d, J = 2.13 Hz, 1 H) 3, 75-3.85 (m, 2 H) 6.25 (dt, J =11.17, 2.13 Hz, 1 H) 6.73 (s, 1 H) 6.75-6.82 (m, 1 H). LCMS: 399.2 [M+H] ⁺ .
tert-Butyl-4-(((3-fluoro-5-iodophenyl)amino)methyl)piperidine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.18 (br dd, J = 12.30, 3.14 Hz, 2 H) 1.48 (s, 9 H) 1.64-1.82 ( m, 3 H) 2.72 (br t, J =12.36 Hz, 2 H) 3.00 (d, J =6.27 Hz, 2 H) 4.15 (q, J =7.07 Hz , 3 H) 6.27 (br d, J =11.17 Hz, 1 H) 6.70-6.80 (m, 2 H).
N-(3-Fluoro-5-iodophenyl)-N-methyloxetan-3-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.97 (s, 3 H) 4.66-4.79 (m, 3 H) 4.88 (d, J = 6.40 Hz, 2 H) 6.23-6.29 (m, 1 H) 6.71-6.76 (m, 1 H) 6.82-6.90 (m, 1 H). LCMS: 308.1 [M+H] ⁺ .
N-(3-Iodophenyl)-N-methyltetrahydro-2H-pyran-4-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.63-1.74 (m, 2 H) 1.80-1.93 (m, 2 H) 2.79 (s, 3 H) 3.44 -4.31 (m, 2 H) 3.51 (d, J =1.88 Hz, 1 H) 3.72-3.84 (m, 1 H) 4.04-4.13 (m, 1 H) 6.74-6.81 (m, 1 H) 6.91-6.99 (m, 1 H) 7.04-7.09 (m, 1 H) 7.10-7.16 (m , 1 H). LCMS: 318.2 [M+H] ⁺ .
N-(3-Iodophenyl)-N-methyloxetan-3-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.94 (s, 3 H) 4.63-4.72 (m, 1 H) 4.72-4.78 (m, 2 H) 4.81 -4.92 (m, 2 H) 6.53-6.64 (m, 1 H) 6.90-7.02 (m, 2 H) 7.12-7.19 (m, 1 H). LCMS: 290.3 [M+H] ⁺ .
4-((3-Fluoro-5-iodophenyl)(methyl)amino)tetrahydro-2H-thiopyran-1,1-dioxide LCMS: 384.1 [M+H] ⁺ .
tert-Butyl-4-((3-fluoro-5-iodophenyl)(methyl)amino)piperidine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.50 (s, 9 H) 1.60-1.78 (m, 4 H) 2.76 (s, 3 H) 2.77-2.88 (m, 2 H) 3.58-3.70 (m, 1 H) 4.18-4.37 (m, 2 H) 6.38-6.47 (m, 1 H) 6.76-6 .82 (m, 1 H) 6.85-6.90 (m, 1 H).
N-(3-Fluoro-5-iodophenyl)-N-methyl-1-(methylsulfonyl)piperidin-4-amine LCMS: 413.2 [M+H] ⁺ .
N-Ethyl-N-(3-fluoro-5-iodophenyl)-1-(methylsulfonyl)piperidin-4-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.18 (t, J =7.03 Hz, 3 H) 1.80-1.98 (m, 4 H) 2.73-2.83 (m , 2 H) 2.85 (s, 3 H) 3.27 (q, J =7.07 Hz, 2 H) 3.54-3.67 (m, 1 H) 3.93-4.03 ( m, 2 H) 6.37 (dt, J =12.89, 2.02 Hz, 1 H) 6.78 (br d, J =7.53 Hz, 1 H) 6.81 (s, 1 H ). LCMS: 427.7 [M+H] ⁺ .
N-(3-Fluoro-5-iodophenyl)-N-isopropyl-1-(methylsulfonyl)piperidin-4-amine LCMS: 441.8 [M+H] ⁺ .
tert-Butyl-4-(((3-fluoro-5-iodophenyl)(methyl)amino)methyl)piperidine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.08-1.24 (m, 2 H) 1.48 (s, 9 H) 1.66 (br d, J = 14.56 Hz, 2 H ) 1.87 (ddd, J =11.45, 7.69, 3.83 Hz, 1 H) 2.67 (br t, J =12.61 Hz, 2 H) 2.96 (s, 3 H ) 3.17 (d, J =7.28 Hz, 2 H) 4.15 (m, 2 H) 6.31 (dt, J =12.67, 2.26 Hz, 1 H) 6.73- 6.80 (m, 2 H).
N-(3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyloxetan-3-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.36 (s, 12 H) 2.95-2.99 (m, 3 H) 4.72-4.82 (m, 3 H) 4.85 -4.95 (m, 2 H) 6.35-6.46 (m, 1 H) 6.84-6.89 (m, 1 H) 6.91-6.97 (m, 1 H). LCMS: 308.3 [M+H] ⁺ .
N-Methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.37 (s, 12 H) 1.64-1.75 (m, 2 H) 1.80-1.94 (m, 2 H) 2.83 (s, 3 H) 3.46-3.61 (m, 2 H) 3.79-3.91 (m, 1 H) 4.04-4.11 (m, 2 H) 6.92-6 .99 (m, 1 H) 7.19-7.28 (m, 2 H) 7.29-7.31 (m, 1 H). LCMS: 318.2 [M+H] ⁺ .
N-Methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.36 (s, 12 H) 2.93-2.96 (m, 3 H) 4.71-4.79 (m, 3 H) 4.86 -4.92 (m, 2 H) 6.73-6.79 (m, 1 H) 7.11-7.17 (m, 1 H) 7.23-7.28 (m, 1 H) 7 .29-7.34 (m, 1 H). LCMS: 290.8 [M+H] ⁺ .

Synthesis of boronate combination products

Procedure 23

A solution of ( 008 ) iodide (39 mg, 0.073 mmol) and (3-chloro-5-fluorophenyl)boronic acid (15.27 mg, 0.088 mmol) in 1,4-dioxane (1.0 ml) was loaded into a 4 ml with a magnetic stirrer. The contents of the vial were degassed using argon for 5 minutes. Silver(I) oxide (50.7 mg, 0.219 mmol) and tetrakis-palladium (8.43 mg, 0.007 mmol) were added, heated to 80°C and stirred for 1 hour. The solution was cooled to room temperature, filtered through a pad of celite, washed with 15 ml EtOAc and concentrated in vacuo. The crude material was dry loaded onto 1 g of silica and purified by column chromatography (ISCO normal phase, 12 g Gold column, 0 to 20% MeOH/DCM gradient) to give the product of Example 167 (15.2 mg , 0.028 mmol, yield 39%).

Procedure 24

Iodide solution was loaded (008) (30 mg, 0.056 mmol) and N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyltetrahydro-2H- pyran-4-amine (049) (28.2 mg, 0.084 mmol) in 1,4-dioxane (1.0 ml) into a 4 ml vial with a magnetic stirrer. The solution was degassed for 5 minutes. Silver(I) oxide (39.0 mg, 0.168 mmol) and tetrakis-palladium (6.49 mg, 0.0056 mmol) were added. The resulting dispersion was heated to 80°C and stirred for 3 hours. The contents of the vial were cooled to room temperature, filtered through a pad of celite, washed with 15 ml EtOAc and concentrated in vacuo. The crude product was purified by reverse phase chromatography (MeCN/H₂O with 0.1% formic acid) and lyophilized to obtain the compound fromexample 168 (2.3 mg, 0.0037 mmol, 7%).

Compounds 167-171 were synthesized according to the general methods from Procedures 23 and 24.

Table 7. Description of characteristics of connections 167-171 Etc. Structure and chemical name according to IUPAC Characteristics 167
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Chloro-5-fluorophenyl)prop-1-en-2-yl]-10-hydroxy-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.02 (dd, J = 10.04, 6.78 Hz, 6 H) 1.30-1.36 (m, 1 H) 1.45-1 .56 (m, 2 H) 1.76-1.87 (m, 1 H) 1.89 (d, J =1.25 Hz, 3 H) 1.95 (br dd, J =7.34, 3.45 Hz, 1 H) 2.32 (s, 3 H) 2.38 (br s, 4 H) 2.51-2.72 (m, 3 H) 3.30-3.40 (m, 1 H) 3.51 (br s, 4 H) 3.76 (br s, 1 H) 4.91 (t, J =10.10 Hz, 1 H) 5.27 (d, J =10.67 Hz, 1 H) 5.43 (dd, J =15.06, 9.66 Hz, 1 H) 5.61 (dd, J =15.00, 9.85 Hz, 1 H) 6.51 (s , 1 H) 6.90 (d, J =9.41 Hz, 1 H) 7.00 (dt, J =8.41, 2.07 Hz, 1 H) 7.07 (s, 1 H). LCMS: 538.5 [M+H] ⁺ 168
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[methyl(oxan-4-yl)amino]phenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.90 (dd, J =6.71, 2.45 Hz, 6 H) 1.19-1.34 (m, 3 H) 1.42 -1.60 (m, 4 H) 1.66-1.78 (m, 2 H) 1.84 (d, J =1.00 Hz, 4 H) 2.17 (s, 3 H) 2, 20-2.38 (m, 5 H) 2.73 (s, 3 H) 3.29 (s, 2 H) 3.34-3.40 (m, 3 H) 3.47 (br t, J =11.11 Hz, 2 H) 3.68-3.78 (m, 1 H) 3.84-3.97 (m, 3 H) 4.61 (d, J =5.02 Hz, 1 H ) 4.70 (t, J =9.41 Hz, 1 H) 5.01 (d, J =10.29 Hz, 1 H) 5.35-5.56 (m, 2 H) 6.34- 6.42 (m, 1 H) 6.45-6.52 (m, 2 H) 6.52-6.58 (m, 1 H). LCMS: 616.6 [M+H] ⁺ 169
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[methyl(oxetan-3-yl)amino]phenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.91 (t, J =6.53 Hz, 6 H) 1.12-1.23 (m, 3 H) 1.37-1.45 (m , 2 H) 1.67-1.76 (m, 3 H) 1.68-1.74 (m, 2 H) 1.78 (d, J = 1.25 Hz, 3 H) 1.81- 1.91 (m, 1 H) 2.43-2.50 (m, 4 H) 2.51-2.60 (m, 2 H) 2.85 (s, 3 H) 3.57-3, 69 (m, 4 H) 4.53-4.63 (m, 1 H) 4.66 (t, J =6.27 Hz, 2 H) 4.73-4.85 (m, 3 H) 5 .17 (d, J =10.54 Hz, 1 H) 5.25-5.36 (m, 1 H) 5.52 (dd, J =14.93, 10.04 Hz, 1 H) 6, 08-6.17 (m, 2 H) 6.36 (d, J =9.03 Hz, 1 H) 6.40 (s, 1 H). LCMS: 588.6 [M+H] ⁺ 170
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-[3-[methyl(oxan-4-yl)amino]phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.83 (d, J =6.65 Hz, 6 H) 1.08-1.29 (m, 3 H) 1.33-1.52 (m, 5 H) 1.63-1.70 (m, 2 H) 1.76 (d, J =1.13 Hz, 4 H) 2.09 (s, 5 H) 2.20-2, 30 (m, 2 H) 2.46-2.56 (m, 2 H) 2.65 (s, 3 H) 3.32-3.43 (m, 3 H) 3.57-3.70 ( m, 1 H) 3.74-3.90 (m, 3 H) 4.53 (d, J =5.15 Hz, 1 H) 4.62 (d, J =9.54 Hz, 1 H) 4.58-4.71 (m, 1 H) 4.93 (d, J =3.01 Hz, 1 H) 5.27-5.45 (m, 3 H) 6.41 (s, 1 H ) 6.55 (d, J =8.03 Hz, 1 H) 6.62 (s, 1 H) 6.68 (dd, J =8.53, 2.26 Hz, 1 H) 7.09 ( t, J =7.91 Hz, 1 H). LCMS: 598.7 [M+H] ⁺ 171
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-[3-[methyl(oxetan-3-yl)amino]phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.02 (t, J = 7.22 Hz, 6 H) 1.24-1.31 (m, 2 H) 1.45-1.55 (m , 3 H) 1.77-1.86 (m, 1 H) 1.90 (d, J =1.13 Hz, 3 H) 1.93-2.00 (m, 1 H) 2.27- 2.46 (m, 6 H) 2.53-2.70 (m, 3 H) 2.92 (s, 3 H) 3.40-3.60 (m, 4 H) 3.67-3, 81 (m, 1 H) 4.60-4.70 (m, 1 H) 4.76 (t, J =6.15 Hz, 2 H) 4.83-5.03 (m, 3 H) 5 .30 (d, J =10.67 Hz, 1 H) 5.42 (dd, J =15.00, 9.85 Hz, 1 H) 5.63 (dd, J =14.81, 10.16 Hz, 1 H) 6.55 (d, J =7.03 Hz, 3 H) 6.79 (d, J =7.65 Hz, 1 H) 7.19-7.26 (m, 1 H) . LCMS: 570.6 [M+H] ⁺

Procedure 25

A solution of boronate 1 (11 mg, 0.021 mmol) and 4-((3-fluoro-5-iodophenyl)(methyl)amino)tetrahydro-2H-thiopyran-1,1-dioxide (11.83 mg, 0.031 mmol)) was loaded. in 1,4-dioxane (1.0 ml) into a 4 ml vial with a magnetic stirrer. The solution was degassed for 5 minutes. Silver(I) oxide (14.31 mg, 0.062 mmol) and tetrakis-palladium (2.38 mg, 0.0021 mmol) were added. The resulting dispersion was heated to 80°C and stirred for 3 hours. The contents of the vial were cooled to room temperature, filtered through a pad of celite, washed with 15 ml EtOAc and concentrated in vacuo. The crude product was purified by reverse phase chromatography (MeCN/H ₂ O with 0.1% formic acid) and lyophilized to give the compound of Example 172 (5.1 mg, 0.0077 mmol, 37%).

Compounds 172-176 were synthesized according to the general methods of procedure 25.

Table 8. Description of characteristics of connections 172-176 Etc. Structure and chemical name according to IUPAC Characteristics 172
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1,1-Dioxothian-4-yl)-methylamino]-5-fluorophenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.96-1.08 (m, 6 H) 1.19-1.34 (m, 2 H) 1.43-1.52 (m, 1 H ) 1.71-1.88 (m, 2 H) 1.90 (d, J = 1.00 Hz, 3 H) 1.92-2.02 (m, 1 H) 2.06-2.18 (m, 2 H) 2.25-2.75 (m, 12 H) 2.82 (s, 3 H) 3.10-3.24 (m, 4 H) 3.28-3.45 (m , 1 H) 3.45-3.68 (m, 3 H) 3.68-3.88 (m, 2 H) 4.83-4.96 (m, 1 H) 5.20-5.34 (m, 1 H) 5.35-5.49 (m, 1 H) 5.54-5.68 (m, 1 H) 6.31-6.59 (m, 4 H). LCMS: 664.6 [M+H] ⁺ 173
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(1-methylsulfonylpiperidin-4-yl)amino]phenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS: 679.6 [M+H] ⁺ 174
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[methyl-(1-methylsulfonylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.02 (t, J = 7.40 Hz, 6 H) 1.24-1.32 (m, 2 H) 1.46-1.53 (m , 2 H) 1.84-1.89 (m, 3 H) 1.90 (s, 4 H) 1.93-1.96 (m, 1 H) 2.30-2.47 (m, 5 H) 2.52-2.72 (m, 5 H) 2.80 (s, 5 H) 2.85 (s, 3 H) 3.33-3.42 (m, 1 H) 3.47- 3.60 (m, 3 H) 3.61-3.81 (m, 3 H) 3.98 (br d, J =10.54 Hz, 2 H) 4.91 (t, J =9.79 Hz, 1 H) 5.28 (d, J =10.54 Hz, 1 H) 5.42 (dd, J =15.18, 9.41 Hz, 1 H) 5.62 (dd, J =14 .74, 9.60 Hz, 1 H) 6.35-6.47 (m, 3 H) 6.53 (s, 1 H). LCMS: 693.7 [M+H] ⁺ 175
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-[Ethyl-(1-methylsulfonylpiperidin-4-yl)amino]-5-fluorophenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.91 (dd, J =8.85, 6.84 Hz, 6 H) 1.08 (t, J =7.03 Hz, 3 H) 1, 13-1.22 (m, 2 H) 1.35-1.46 (m, 2 H) 1.64-1.79 (m, 5 H) 1.79-1.89 (m, 6 H) 2.32 (br dd, J =3.58, 1.57 Hz, 3 H) 2.41-2.61 (m, 5 H) 2.69 (br d, J =11.04 Hz, 2 H ) 2.74 (s, 3 H) 3.18 (q, J =7.07 Hz, 2 H) 3.40-3.59 (m, 5 H) 3.61-3.71 (m, 1 H) 3.82-3.92 (m, 2 H) 4.81 (t, J =10.04 Hz, 1 H) 5.18 (d, J =10.54 Hz, 1 H) 5.31 (dd, J =15.25, 9.47 Hz, 1 H) 5.52 (dd, J =14.93, 10.04 Hz, 1 H) 6.19-6.33 (m, 3 H) 6.41(s, 1H). LCMS: 707.5 [M+H] ⁺ 176
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[(1-methylsulfonylpiperidin-4-yl)-propan-2-ylamino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (t, J =6.46 Hz, 6 H) 1.12 (d, J =6.65 Hz, 6 H) 1.15-1, 22 (m, 2 H) 1.35-1.44 (m, 2 H) 1.65-1.79 (m, 4 H) 1.81 (d, J = 1.13 Hz, 3 H) 1 .82-1.90 (m, 2 H) 2.33-2.60 (m, 8 H) 2.68 (s, 3 H) 2.72 (s, 3 H) 3.23-3.33 (m, 2 H) 3.46-3.71 (m, 6 H) 3.76 (br d, J =11.29 Hz, 2 H) 4.81 (t, J =10.10 Hz, 1 H) 5.18 (d, J =10.79 Hz, 1 H) 5.31 (dd, J =14.93, 9.66 Hz, 1 H) 5.52 (dd, J =15.00, 9.98 Hz, 1 H) 6.34-6.56 (m, 4 H). LCMS: 721.7 [M+H] ⁺

Synthesis of piperidine-based intermediates

Procedure 26

Step 1: Load a solution of tert-butyl-4-((3-fluoro-5-iodophenyl)(methyl)amino)piperidine-1-carboxylate (590 mg, 1.359 mmol) in methanol (15 mL, 370.765 mmol) into a round bottom flask volume 50 ml with magnetic stirrer. HCl (4.0 M in dioxane, 1.698 mL, 6.793 mmol) was added and the resulting solution was stirred overnight at room temperature. The solvents were evaporated in vacuo to give HCl salt and N-(3-fluoro-5-iodophenyl)-N-methylpiperidin-4-amine ( 050 ) (500 mg, 1.349 mmol, 99%). LCMS: 335.1 [M+H] ⁺ .

Step 2. Load a solution of HCl salt and N-(3-fluoro-5-iodophenyl)-N-methylpiperidin-4-amine ( 050 ) (50 mg, 0.135 mmol) in dichloromethane (2 ml) into a 5 ml vial with a magnetic stirrer. N-ethyl-N-isopropylpropan-2-amine (0.059 ml, 0.337 mmol) was added, followed by acetyl chloride (0.014 ml, 0.202 mmol). The resulting solution was stirred overnight at room temperature. The solution was partitioned between water (10 ml) and DCM (10 ml), extracted with DCM (3 x 10 ml) and the combined organic layers were washed with water (10 ml), dried with MgSO4, filtered and evaporated in vacuo. The crude product was dry loaded onto 2 g silica and purified by column chromatography (ISCO normal phase, 24 g Gold column, 0 to 100% EtOAc/hexanes gradient) to give 1-(4-((3- fluoro-5-iodophenyl)(methyl)amino)piperidin-1-yl)ethan-1-one (051) (24 mg, 0.064 mmol, 47%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.61-1.73 (m, 2 H) 1.74-1.90 (m, 2 H) 2.15 (s, 3 H) 2.62 (td, J =12.77, 2.45 Hz, 1 H) 2.75 (s, 3 H) 3.11-3.24 (m, 1 H) 3.63-3.80 (m, 1 H) 3.95 (br dd, J =13.55, 2.38 Hz, 1 H) 4.76-4.87 (m, 1 H) 6.44 (dt, J =12.58, 2, 18 Hz, 1 H) 6.82 (dt, J = 7.53, 1.69 Hz, 1 H) 6.89 (s, 1 H). LCMS: 377.2 [M+H] ⁺ .

The following intermediates were also synthesized according to the general methods from procedure 26.

Table 9. Description of the characteristics of intermediates synthesized according to procedure 26 Intermediate connection Characteristics
3-Fluoro-5-iodo-N-methyl-N-(piperidin-4-ylmethyl)aniline Transferred to the next step without further purification. LCMS: 349.0 [M+H] ⁺ .
1-(4-((3-Fluoro-5-iodophenyl)(methyl)amino)piperidin-1-yl)propan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.19 (t, J = 7.47 Hz, 3 H) 1.59-1.72 (m, 2 H) 1.73-1.89 (m , 2 H) 2.40 (q, J =7.40 Hz, 2 H) 2.52-2.68 (m, 1 H) 2.75 (s, 3 H) 3.13 (br t, J =13.05 Hz, 1 H) 3.62-3.79 (m, 1 H) 3.92-4.10 (m, 1 H) 4.77-4.95 (m, 1 H) 6, 44 (br d, J =12.55 Hz, 1 H) 6.81 (d, J =7.65 Hz, 1 H) 6.89 (s, 1 H). LCMS: 391.2 [M+H] ⁺ .
1-(4-((3-Fluoro-5-iodophenyl)(methyl)amino)piperidin-1-yl)-2-methoxyethan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.69 (qd, J =12.42, 4.39 Hz, 2 H) 1.76-1.88 (m, 2 H) 2.67 (br t, J =12.42 Hz, 1 H) 2.75 (s, 3 H) 3.12 (br s, 1 H) 3.47 (s, 3 H) 3.66-3.81 (m, 1 H) 4.01-4.22 (m, 3 H) 4.78 (br d, J =13.30 Hz, 1 H) 6.43 (dt, J =12.58, 2.24 Hz, 1 H) 6.77-6.84 (m, 1 H) 6.88 (s, 1 H). LCMS: 407.2 [M+H] ⁺ .
(4-((3-Fluoro-5-iodophenyl)(methyl)amino)piperidin-1-yl)(phenyl)methanone ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.64-1.97 (m, 4 H) 2.79 (s, 3 H) 2.83-3.26 (m, 2 H) 3.68 -3.83 (m, 1 H) 3.84-4.05 (m, 1 H) 4.78-5.05 (m, 1 H) 6.46 (br d, J = 12.55 Hz, 1 H) 6.83 (d, J = 7.53 Hz, 1 H) 6.91 (s, 1 H) 7.45 (s, 5 H). LCMS: 439.7 [M+H] ⁺ .
2,2,2-Trifluoro-1-(4-((3-fluoro-5-iodophenyl)(methyl)amino)piperidin-1-yl)ethan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.68-1.83 (m, 2 H) 1.85-1.96 (m, 2 H) 2.76 (s, 3 H) 2.86 (br t, J =12.30 Hz, 1 H) 3.17-3.33 (m, 1 H) 3.73-3.87 (m, 1 H) 4.17 (br dd, J =13 .87, 1.94 Hz, 1 H) 4.74 (ddt, J =13.52, 4.39, 2.34, 2.34 Hz, 1 H) 6.44 (d, J =12.42 Hz, 1 H) 6.79-6.87 (m, 1 H) 6.89 (s, 1 H). LCMS: 431.7 [M+H] ⁺ .
N-(3-Fluoro-5-iodophenyl)-N-methyl-1-(propylsulfonyl)piperidin-4-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.10 (t, J = 7.47 Hz, 3 H) 1.77-1.96 (m, 6 H) 2.78 (s, 3 H) 2.84-2.98 (m, 4 H) 3.56-3.67 (m, 1 H) 3.98 (dt, J = 12.45, 2.12 Hz, 2 H) 6.41 ( dt, J =12.61, 2.16 Hz, 1 H) 6.80 (dt, J =7.53, 1.69 Hz, 1 H) 6.86 (s, 1 H). LCMS: 441.7 [M+H] ⁺ .
1-(Cyclopentylsulfonyl)-N-(3-fluoro-5-iodophenyl)-N-methylpiperidin-4-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.59-1.73 (m, 2 H) 1.77-1.94 (m, 6 H) 1.98-2.08 (m, 4 H ) 2.78 (s, 3 H) 2.88-3.01 (m, 2 H) 3.47 (quin, J =8.16 Hz, 1 H) 3.55-3.68 (m, 1 H) 4.00 (dt, J =12.61, 2.16 Hz, 2 H) 6.42 (dt, J =12.55, 2.26 Hz, 1 H) 6.78-6.83 ( m, 1 H) 6.87 (s, 1 H). LCMS: 467.2 [M+H] ⁺ .
N-(3-Fluoro-5-iodophenyl)-N-methyl-1-((1-methyl-1H-imidazol-4-yl)sulfonyl)piperidin-4-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.72-1.82 (m, 2 H) 1.92 (qd, J = 12.36, 4.20 Hz, 2 H) 2.69-2 .82 (m, 5 H) 3.50 (tt, J =11.75, 3.87 Hz, 1 H) 3.81 (s, 3 H) 4.03 (dt, J =12.20, 2 ,12 Hz, 2 H) 6.36 (dt, J =12.67, 2.26 Hz, 1 H) 6.75-6.79 (m, 1 H) 6.82 (s, 1 H) 7 .48 (d, J =1.38 Hz, 1 H) 7.55 (d, J =1.13 Hz, 1 H). LCMS: 479.2 [M+H] ⁺ .
N-(3-Fluoro-5-iodophenyl)-N-methyl-1-(phenylsulfonyl)piperidin-4-amine ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.73-1.82 (m, 2 H) 1.91 (qd, J = 12.36, 4.33 Hz, 2 H) 2.39 (td , J =12.14, 2.57 Hz, 2 H) 2.75 (s, 3 H) 3.42 (tt, J =11.70, 3.86 Hz, 1 H) 3.99 (dt, J =11.89, 2.15 Hz, 2 H) 6.34 (dt, J =12.55, 2.26 Hz, 1 H) 6.73-6.82 (m, 2 H) 7.55 -7.63 (m, 2 H) 7.64-7.71 (m, 1 H) 7.78-7.85 (m, 2 H). LCMS: 475.1 [M+H] ⁺ .
1-(4-(((3-Fluoro-5-iodophenyl)(methyl)amino)methyl)piperidin-1-yl)ethan-1-one ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.09-1.25 (m, 2 H) 1.74 (br s, 2 H) 1.97 (ddd, J = 11.48, 7.72 , 4.02 Hz, 1 H) 2.11 (s, 3 H) 2.52 (br t, J =11.98 Hz, 1 H) 2.96 (s, 3 H) 2.98-3, 13 (m, 1 H) 3.18 (d, J =7.28 Hz, 2 H) 3.86 (br d, J =13.43 Hz, 1 H) 4.69 (br d, J =12 .42 Hz, 1 H) 6.30 (dt, J = 12.67, 2.26 Hz, 1 H) 6.73-6.81 (m, 2 H). LCMS: 391.0 [M+H] ⁺ .
3-Fluoro-5-iodo-N-methyl-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)aniline ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.33-1.49 (m, 2 H) 1.73-1.92 (m, 3 H) 2.64 (td, J = 12.11, 2.38 Hz, 2 H) 2.79 (s, 3 H) 2.97 (s, 3 H) 3.21 (d, J = 7.03 Hz, 2 H) 3.80-3.94 ( m, 2 H) 6.30 (dt, J = 12.52, 2.21 Hz, 1 H) 6.71-6.80 (m, 2 H). LCMS: 427.0 [M+H] ⁺ .

Compounds 177-187 were prepared from the above intermediates using the general methods of Procedures 23, 24 and 25.

Table 10. Description of characteristics of connections 177-187 Etc. Structure and chemical name according to IUPAC Characteristics 177
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-Acetylpiperidin-4-yl)methylamino]-5-fluorophenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (t, J =6.59 Hz, 6 H) 1.15-1.21 (m, 2 H) 1.37-1.43 (m , 2 H) 1.51-1.65 (m, 4 H) 1.66-1.77 (m, 4 H) 1.80 (d, J =1.00 Hz, 3 H) 1.83- 1.91 (m, 1 H) 2.05 (s, 3 H) 2.21-2.38 (m, 4 H) 2.42-2.60 (m, 6 H) 2.66 (s, 3 H) 3.01-3.14 (m, 1 H) 3.29 (br d, J =10.29 Hz, 1 H) 3.59-3.74 (m, 3 H) 3.80- 3.90 (m, 1 H) 4.71 (br dd, J =14.93, 2.64 Hz, 1 H) 4.81 (t, J =10.16 Hz, 1 H) 5.18 ( d, J =10.67 Hz, 1 H) 5.31 (dd, J =15.06, 9.79 Hz, 1 H) 5.52 (dd, J =15.00, 10.10 Hz, 1 H) 6.24-6.35 (m, 3 H) 6.43 (s, 1 H). LCMS: 657.5 [M+H] ⁺ 178
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[methyl-(1-propanoylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.91 (t, J =6.96 Hz, 6 H) 1.09 (t, J =7.47 Hz, 3 H) 1.13-1, 22 (m, 2 H) 1.34-1.46 (m, 2 H) 1.57-1.63 (m, 2 H) 1.64-1.76 (m, 4 H) 1.80 ( d, J =1.13 Hz, 3 H) 1.82-1.90 (m, 1 H) 2.30 (br d, J =7.40 Hz, 7 H) 2.41-2.60 ( m, 6 H) 2.66 (s, 3 H) 2.97-3.09 (m, 1 H) 3.38-3.58 (m, 3 H) 3.58-3.73 (m, 1 H) 2 H) 3.85-3.95 (m, 1 H) 4.73 (br dd, J =13.18, 2.13 Hz, 1 H) 4.80 (t, J =10.04 Hz, 1 H) 5.18 (d, J =10.67 Hz, 1 H) 5.31 (dd, J =14.93, 9.66 Hz, 1 H) 5.52 (dd, J =14.93 , 10.04 Hz, 1 H) 6.25-6.34 (m, 3 H) 6.42 (s, 1 H). LCMS: 671.6 [M+H] ⁺ 179
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[[1-(2-methoxyacetyl)piperidin-4-yl]methylamino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (t, J =6.90 Hz, 6 H) 1.17 (br s, 2 H) 1.37-1.45 (m, 2 H ) 1.56-1.65 (m, 4 H) 1.67-1.77 (m, 4 H) 1.80 (d, J =1.00 Hz, 3 H) 1.82-1.91 (m, 1 H) 2.29-2.35 (m, 2 H) 2.43-2.61 (m, 6 H) 2.66 (s, 3 H) 2.93-3.10 (m , 1 H) 3.37 (s, 3 H) 3.38-3.59 (m, 3 H) 3.59-3.76 (m, 3 H) 3.87-3.97 (m, 1 H) 3.98-4.13 (m, 2 H) 4.63-4.72 (m, 1 H) 4.81 (t, J =10.10 Hz, 1 H) 5.18 (d, J =10.67 Hz, 1 H) 5.32 (dd, J =15.00, 9.47 Hz, 1 H) 5.52 (dd, J =15.12, 9.98 Hz, 1 H) 6.25-6.34 (m, 3 H) 6.43 (s, 1 H). LCMS: 687.6 [M+H] ⁺ 180
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-Benzoylpiperidin-4-yl)-methylamino]-5-fluorophenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (t, J = 7.47 Hz, 6 H) 1.12-1.23 (m, 2 H) 1.35-1.46 (m , 2 H) 1.55-1.77 (m, 6 H) 1.80 (s, 3 H) 1.82-1.92 (m, 1 H) 2.18-2.41 (m, 6 H) 2.41-2.63 (m, 4 H) 2.70 (s, 3 H) 2.94-3.11 (m, 1 H) 3.20-3.34 (m, 1 H) 3.35-3.55 (m, 3 H) 3.60-3.92 (m, 3 H) 4.81 (t, J =10.04 Hz, 2 H) 5.18 (d, J = 10.54 Hz, 1 H) 5.31 (dd, J =15.12, 9.60 Hz, 1 H) 5.52 (dd, J =15.06, 10.16 Hz, 1 H) 6, 25-6.35 (m, 3 H) 6.43 (s, 1 H) 7.34 (s, 5 H). LCMS: 719.8 [M+H] ⁺ 181
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[methyl-[1-(2,2,2-trifluoroacetyl)piperidine-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (t, J =6.96 Hz, 6 H) 1.14-1.24 (m, 2 H) 1.37-1.46 (m , 1 H) 1.64-1.75 (m, 4 H) 1.80 (d, J =1.25 Hz, 5 H) 1.84-1.89 (m, 1 H) 2.31 ( br s, 3 H) 2.36-2.62 (m, 7 H) 2.67 (s, 3 H) 2.70-2.82 (m, 1 H) 3.14 (br t, J = 12.42 Hz, 1 H) 3.50 (br dd, J =5.83, 2.95 Hz, 4 H) 3.61-3.67 (m, 1 H) 3.68-3.79 ( m, 1 H) 3.99-4.14 (m, 1 H) 4.63 (br d, J =13.55 Hz, 1 H) 4.81 (t, J =10.10 Hz, 1 H ) 5.18 (d, J =10.67 Hz, 1 H) 5.32 (dd, J =14.93, 9.66 Hz, 1 H) 5.52 (dd, J =15.00, 9 .85 Hz, 1 H) 6.26-6.37 (m, 3 H) 6.43 (s, 1 H). LCMS: 711.7 [M+H] ⁺ 182
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[methyl-(1-propylsulfonylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (dd, J =8.34, 6.84 Hz, 6 H) 1.00 (t, J =7.47 Hz, 3 H) 1, 15-1.20 (m, 2 H) 1.37-1.47 (m, 2 H) 1.69-1.78 (m, 7 H) 1.80 (s, 5 H) 1.82- 1.90 (m, 1 H) 2.24-2.30 (m, 1 H) 2.32-2.40 (m, 3 H) 2.44-2.61 (m, 4 H) 2, 69 (s, 3 H) 2.82 (s, 5 H) 3.43-3.51 (m, 3 H) 3.54-3.60 (m, 1 H) 3.61-3.70 ( m, 1 H) 3.87 (br d, J =11.17 Hz, 2 H) 4.81 (t, J =10.10 Hz, 1 H) 5.18 (d, J =10.67 Hz , 1 H) 5.32 (dd, J =15.06, 9.66 Hz, 1 H) 5.52 (dd, J =15.00, 9.98 Hz, 1 H) 6.23-6, 34 (m, 3 H) 6.42 (s, 1 H). LCMS: 721.7 [M+H] ⁺ 183
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-cyclopentylsulfonylpiperidin-4-yl)methylamino]-5-fluorophenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.02 (dd, J =6.59, 5.21 Hz, 6 H) 1.27-1.31 (m, 2 H) 1.44-1 .50 (m, 2 H) 1.78-1.86 (m, 8 H) 1.90 (s, 3 H) 1.93-1.97 (m, 1 H) 2.00-2.07 (m, 4 H) 2.52-2.63 (m, 5 H) 2.64-2.75 (m, 3 H) 2.79 (s, 3 H) 2.88-3.02 (m , 2 H) 3.33-3.56 (m, 4 H) 3.73 (s, 6 H) 3.96-4.05 (m, 2 H) 4.91 (t, J =9.98 Hz, 1 H) 5.29 (d, J =10.67 Hz, 1 H) 5.37-5.46 (m, 1 H) 5.63 (dd, J =15.12, 10.10 Hz , 1 H) 6.34-6.44 (m, 3 H) 6.53 (s, 1 H). LCMS: 747.7 [M+H] ⁺ 184
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[methyl-[1-(1-methylimidazol-4-yl)sulfonylpiperidin-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.91 (dd, J = 10.98, 6.84 Hz, 6 H) 1.12-1.21 (m, 2 H) 1.35-1 .45 (m, 2 H) 1.61-1.75 (m, 4 H) 1.78 (d, J =1.00 Hz, 3 H) 1.80-1.90 (m, 2 H) 2.22-2.38 (m, 3 H) 2.44-2.65 (m, 6 H) 2.68 (s, 3 H) 3.25-3.37 (m, 1 H) 3, 39-3.57 (m, 4 H) 3.39-3.53 (m, 3 H) 3.60-3.66 (m, 1 H) 3.70 (s, 3 H) 3.88- 3.98 (m, 2 H) 4.81 (t, J =10.04 Hz, 1 H) 5.16 (d, J =10.54 Hz, 1 H) 5.31 (dd, J =15 ,12, 9.47 Hz, 1 H) 5.46-5.56 (m, 1 H) 6.19-6.32 (m, 3 H) 6.39 (s, 1 H) 7.37 ( d, J =1.25 Hz, 1 H) 7.45 (s, 1 H). LCMS: 759.5 [M+H] ⁺ 185
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[[1-(Benzenesulfonyl)piperidin-4-yl]methylamino]-5-fluorophenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.90 (dd, J =17.07, 6.78 Hz, 6 H) 1.17 (br d, J =8.41 Hz, 2 H) 1 .35-1.45 (m, 2 H) 1.65-1.73 (m, 4 H) 1.77 (d, J =1.13 Hz, 3 H) 1.78-1.87 (m , 3 H) 2.20-2.38 (m, 7 H) 2.47 (m, 4 H) 2.66 (s, 3 H) 3.31-3.57 (m, 5 H) 3, 59-3.70 (m, 1 H) 3.88 (br d, J =10.54 Hz, 2 H) 4.80 (t, J =9.98 Hz, 1 H) 5.15 (d, J =10.67 Hz, 1 H) 5.30 (dd, J =15.18, 9.66 Hz, 1 H) 5.44-5.57 (m, 1 H) 6.14-6.31 (m, 3 H) 6.37 (s, 1 H) 7.43-7.61 (m, 3 H) 7.67-7.76 (m, 2 H). LCMS: 755.6 [M+H] ⁺ 186
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-Acetylpiperidin-4-yl)methylmethylamino]-5-fluorophenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.91 (t, J =6.27 Hz, 6 H) 1.18 (br d, J =7.91 Hz, 2 H) 1.64-1 .77 (m, 6 H) 1.80 (s, 3 H) 1.85 (br d, J =3.01 Hz, 2 H) 2.01 (s, 3 H) 2.32-2.61 (m, 12 H) 2.87 (s, 3 H) 2.90-2.99 (m, 1 H) 3.10 (br d, J =7.03 Hz, 2 H) 3.48-3 .69 (m, 5 H) 3.70-3.81 (m, 1 H) 4.54-4.63 (m, 1 H) 4.81 (t, J = 9.91 Hz, 1 H) 5.18 (d, J =10.79 Hz, 1 H) 5.31 (dd, J =15.12, 9.60 Hz, 1 H) 5.52 (dd, J =14.87, 9, 98 Hz, 1 H) 6.11-6.20 (m, 2 H) 6.27 (br d, J =8.78 Hz, 1 H) 6.42 (s, 1 H). LCMS: 671.8 [M+H] ⁺ 187
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[methyl-[(1-methylsulfonylpiperidin-4-yl)methyl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS: 707.7 [M+H] ⁺

Synthesis of piperidine-based intermediates

Procedure 27

A solution of piperidine ( 050 ) (50 mg, 0.15 mmol) and oxazole-5-carboxylic acid (25.4 mg, 0.224 mmol) in DMF (2 ml) was loaded into a 4 ml vial with a magnetic stirrer. Hunig's base (0.078 ml, 0.449 mmol), EDC (60.2 mg, 0.314 mmol) and HOBT (48.1 mg, 0.314 mmol) were added. The resulting solution was stirred overnight at room temperature and partitioned between water (10 ml) and EtOAc (10 ml). The solution was extracted with EtOAc (3 x 10 ml), washed with water (10 ml), dried with MgSO ₄ , filtered and evaporated in vacuo. The crude material was dry loaded onto 2 g of silica and purified by column chromatography (ISCO normal phase, 12 g Gold column, 0 to 20% MeOH/DCM gradient) to isolate (4-((3-fluoro- 5-iodophenyl)(methyl)amino)piperidin-1-yl)(oxazol-5-yl)methanone (052) (24 mg, 0.056 mmol, 37%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.68-1.85 (m, 2 H) 1.85-1.96 (m, 2 H) 2.77 (s, 3 H) 2.99 -3.51 (m, 2 H) 3.82 (tt, J =11.56, 4.06 Hz, 1 H) 4.37-5.02 (m, 2 H) 6.45 (dt, J =12.55, 2.26 Hz, 1 H) 6.81-6.87 (m, 1 H) 6.91 (s, 1 H) 7.64 (s, 1 H) 7.96-8, 00 (m, 1 H). LCMS: 430.3 [M+H] ⁺ .

The following intermediates were also synthesized according to the general methods from procedure 27.

Table 11. Description of the characteristics of intermediates synthesized according to procedure 27. Intermediate connection Characteristics
(4-((3-Fluoro-5-iodophenyl)(methyl)amino)piperidin-1-yl)(pyrazin-2-yl)methanone ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.62-1.93 (m, 4 H) 2.70 (s, 3 H) 2.77-2.85 (m, 1 H) 3.04 -3.20 (m, 1 H) 3.64-3.80 (m, 1 H) 4.03-4.16 (m, 1 H) 4.85 (br dd, J = 13.24, 2 .07 Hz, 1 H) 6.36 (dt, J =12.58, 2.24 Hz, 1 H) 6.69-6.75 (m, 1 H) 6.81 (s, 1 H) 8 .49 (dd, J =2.51, 1.51 Hz, 1 H) 8.58 (d, J =2.64 Hz, 1 H) 8.89 (d, J =1.51 Hz, 1 H ). LCMS: 441.3 [M+H] ⁺ .
(4-((3-Fluoro-5-iodophenyl)(methyl)amino)piperidin-1-yl)(1-methyl-1H-imidazol-4-yl)methanone ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.73-1.92 (m, 4 H) 2.76 (s, 3 H) 2.78-2.88 (m, 1 H) 3.01 -3.24 (m, 1 H) 3.76 (s, 3 H) 3.77-3.84 (m, 1 H) 4.78-5.01 (m, 1 H) 5.36-5 .55 (m, 1 H) 6.44 (dt, J =12.77, 2.21 Hz, 1 H) 6.76-6.83 (m, 1 H) 6.89 (s, 1 H) 7.42-7.47 (m, 1 H) 7.55 (d, J = 1.38 Hz, 1 H). LCMS: 443.3 [M+H] ⁺ .

Compounds 188-190 were prepared from the above intermediates using the general methods of Procedure 25.

Table 12. Description of characteristics of connections 188-190 Etc. Structure and chemical name according to IUPAC Characteristics 188
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[methyl-[1-(1,3-oxazol-5-carbonyl)piperidin- 4-yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (t, J =6.65 Hz, 7 H) 1.15-1.21 (m, 2 H) 1.38-1.44 (m , 2 H) 1.65-1.74 (m, 4 H) 1.74-1.83 (m, 6 H) 1.83-1.89 (m, 1 H) 2.25-2.43 (m, 6 H) 2.44-2.65 (m, 5 H) 2.68 (s, 3 H) 3.40-3.57 (m, 4 H) 3.58-3.70 (m , 2 H) 3.71-3.82 (m, 1 H) 4.81 (t, J =9.91 Hz, 1 H) 5.19 (d, J =10.79 Hz, 1 H) 5 .32 (dd, J =15.12, 9.60 Hz, 1 H) 5.44-5.59 (m, 1 H) 6.27-6.36 (m, 3 H) 6.43 (s , 1 H) 7.53 (s, 1 H) 7.88 (s, 1 H). LCMS: 710.6 [M+H] ⁺ 189
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[methyl-[1-(pyrazin-2-carbonyl)piperidin-4-yl] amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (dd, J =6.65, 4.89 Hz, 6 H) 1.14-1.21 (m, 2 H) 1.37-1 .49 (m, 2 H) 1.69-1.77 (m, 4 H) 1.80 (d, J =1.13 Hz, 5 H) 2.34-2.49 (m, 6 H) 2.52-2.63 (m, 4 H) 2.71 (s, 3 H) 2.74-2.86 (m, 1 H) 3.05-3.19 (m, 1 H) 3, 50-3.69 (m, 5 H) 3.76 (s, 1 H) 4.05 (br d, J =13.18 Hz, 1 H) 4.68-4.90 (m, 2 H) 5.18 (d, J =10.67 Hz, 1 H) 5.31 (dd, J =14.87, 9.60 Hz, 1 H) 5.52 (dd, J =15.12, 10, 10 Hz, 1 H) 6.33 (s, 3 H) 6.43 (s, 1 H) 8.48 (dd, J =2.51, 1.51 Hz, 1 H) 8.57 (d, J =2.51 Hz, 1 H) 8.88 (d, J =1.51 Hz, 1 H). LCMS: 721.7 [M+H] ⁺ 190
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[methyl-[1-(1-methylimidazol-4-carbonyl)piperidine-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate LCMS: 723.6 [M+H] ⁺

Synthesis of piperidine-based intermediates

Procedure 28

A solution of HCl salt and N-(3-fluoro-5-iodophenyl)-N-methylpiperidin-4-amine ( 050 ) (50 mg, 0.135 mmol) in dichloromethane (2 ml) was loaded into a 5 ml vial with a magnetic stirrer. N-ethyl-N-isopropylpropan-2-amine (0.035 ml, 0.202 mmol) was added, followed by 2-isocyanatopropane (17.22 mg, 0.202 mmol). The resulting solution was stirred overnight at room temperature and evaporated in vacuo. The dry crude product was loaded onto 2 g of silica and purified by column chromatography (ISCO normal phase, 24 g Gold column, 0 to 100% EtOAc/hexanes gradient) to give 4-((3-fluoro-5 -iodophenyl)(methyl)amino)-N-isopropylpiperidine-1-carboxamide ( 053 ) (45 mg, 0.107 mmol, 80%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.19 (d, J =6.53 Hz, 6 H) 1.66-1.80 (m, 4 H) 2.75 (s, 3 H) 2.81-2.92 (m, 2 H) 3.57-3.73 (m, 1 H) 4.00 (dd, J = 13.49, 6.59 Hz, 1 H) 4.08 ( dt, J =13.40, 2.09 Hz, 2 H) 4.27 (br d, J =7.03 Hz, 1 H) 6.41 (dt, J =12.67, 2.26 Hz, 1 H) 6.75-6.82 (m, 1 H) 6.86 (s, 1 H). LCMS: 420.7 [M+H] ⁺ .

The following intermediates were also synthesized according to the general methods from procedure 28.

Table 13. Description of the characteristics of intermediates synthesized according to procedure 28 Intermediate connection Characteristics
4-((3-Fluoro-5-iodophenyl)(methyl)amino)-N-propylpiperidine-1-carboxamide ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.96 (t, J = 7.40 Hz, 3 H) 1.53-1.60 (m, 2 H) 1.66-1.83 (m , 4 H) 2.75 (s, 3 H) 2.82-2.94 (m, 2 H) 3.19-3.30 (m, 2 H) 3.54-3.75 (m, 1 H) 4.02-4.19 (m, 2 H) 4.50 (br s, 1 H) 6.43 (dt, J = 12.64, 2.21 Hz, 1 H) 6.76-6 .82 (m, 1 H) 6.87 (s, 1 H). LCMS: 420.7 [M+H] ⁺ .
4-((3-Fluoro-5-iodophenyl)(methyl)amino)-N-phenylpiperidine-1-carboxamide ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.70-1.91 (m, 4 H) 2.77 (s, 3 H) 2.95-3.07 (m, 2 H) 3.65 -3.79 (m, 1 H) 4.21-4.30 (m, 2 H) 6.42-6.49 (m, 1 H) 6.79-6.85 (m, 1 H) 6 .90 (s, 1 H) 7.05-7.10 (m, 1 H) 7.30-7.41 (m, 5 H). LCMS: 454.2 [M+H] ⁺ .

Compounds 191-193 were prepared from the above intermediates using the general methods of Procedure 25.

Table 14. Description of characteristics of connections 191-193 Etc. Structure and chemical name according to IUPAC Characteristics 191
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[methyl-[1-(propan-2-ylcarbamoyl)piperidin-4-yl] amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (t, J =7.03 Hz, 6 H) 1.09 (d, J =6.53 Hz, 6 H) 1.14-1, 21 (m, 2 H) 1.33-1.45 (m, 2 H) 1.57-1.76 (m, 6 H) 1.80 (d, J = 1.13 Hz, 3 H) 1 .81-1.89 (m, 1 H) 2.19-2.38 (m, 4 H) 2.44-2.60 (m, 4 H) 2.67 (s, 3 H) 2.71 -2.82 (m, 2 H) 3.24-3.33 (m, 1 H) 3.37-3.53 (m, 3 H) 3.54-3.73 (m, 3 H) 3 .90 (dd, J =13.68, 6.53 Hz, 1 H) 3.98 (br d, J =13.43 Hz, 2 H) 4.15 (br d, J =7.40 Hz, 1 H) 4.81 (t, J =10.10 Hz, 1 H) 5.18 (d, J =10.54 Hz, 1 H) 5.31 (dd, J =15.00, 9.72 Hz, 1 H) 5.52 (dd, J =15.00, 9.98 Hz, 1 H) 6.25-6.34 (m, 3 H) 6.43 (s, 1 H). LCMS: 700.7 [M+H] ⁺ 192
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[methyl-[1-(propylcarbamoyl)piperidin-4-yl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.86 (t, J =7.40 Hz, 3 H) 0.92 (t, J =6.90 Hz, 6 H) 1.18 (br d , J =8.66 Hz, 2 H) 1.46 (br d, J =7.28 Hz, 6 H) 1.61-1.71 (m, 4 H) 1.80 (d, J =1 .25 Hz, 3 H) 1.82-1.90 (m, 1 H) 2.18-2.41 (m, 4 H) 2.45-2.60 (m, 4 H) 2.67 ( s, 3 H) 2.73-2.84 (m, 2 H) 3.09-3.18 (m, 2 H) 3.30 (br d, J =10.92 Hz, 1 H) 3, 36-3.54 (m, 3 H) 3.54-3.70 (m, 3 H) 3.99 (br d, J =13.05 Hz, 2 H) 4.38 (br t, J = 5.46 Hz, 1 H) 4.81 (t, J =10.10 Hz, 1 H) 5.18 (d, J =10.54 Hz, 1 H) 5.31 (dd, J =15, 00, 9.60 Hz, 1 H) 5.52 (dd, J =15.00, 9.98 Hz, 1 H) 6.25-6.33 (m, 3 H) 6.43 (s, 1 H). LCMS: 700.7 [M+H] ⁺ 193
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[methyl-[1-(phenylcarbamoyl)piperidin-4-yl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.92 (dd, J =6.71, 1.44 Hz, 6 H) 1.15-1.23 (m, 2 H) 1.34-1 .42 (m, 2 H) 1.64-1.77 (m, 6 H) 1.81 (d, J = 1.13 Hz, 3 H) 1.83-1.91 (m, 1 H) 2.32-2.66 (m, 8 H) 2.69 (s, 3 H) 2.87-2.98 (m, 2 H) 3.27-3.33 (m, 1 H) 3, 62 (s, 5 H) 4.10-4.20 (m, 2 H) 4.81 (t, J =9.85 Hz, 1 H) 5.19 (d, J =10.42 Hz, 1 H) 5.31 (dd, J =15.12, 9.72 Hz, 1 H) 5.53 (dd, J =14.93, 9.66 Hz, 1 H) 6.25-6.36 ( m, 4 H) 6.44 (s, 1 H) 6.94-7.01 (m, 1 H) 7.20-7.32 (m, 5 H). LCMS: 734.7 [M+H] ⁺

Synthesis of piperidine-based intermediates

Procedure 29

Step 1: Charge a solution of piperidin-4-ol (200 mg, 1.977 mmol) in DCM (5 mL) into a 25 mL round bottom flask equipped with a magnetic stirrer. Hunig's base (1.036 mL, 5.932 mmol) was added followed by methanesulfonyl chloride (0.339 mL, 4.35 mmol). The resulting solution was stirred overnight at room temperature and the reaction was quenched with water (10 ml). The resulting solution was extracted with DCM (3 x 10 ml), washed with brine (10 ml), dried with MgSO ₄ , filtered and evaporated in vacuo to give 1-(methylsulfonyl)piperidin-4-ylmethanesulfonate ( 054 ) (404 mg , 1.571 mmol).

Step 2. Load a solution of 3-bromo-5-fluorophenol (200 mg, 1.047 mmol) and 1-(methylsulfonyl)piperidin-4-ylmethanesulfonate ( 054 ) (404 mg, 1.571 mmol) in DMF (5 ml) into a 10 ml with a magnetic stirrer. Cesium carbonate (682 mg, 2.094 mmol) was added. The resulting dispersion was heated to 70°C and stirred overnight. The reaction mixture was cooled to room temperature and partitioned between EtOAc (10 ml) and water (10 ml). The solution was extracted with EtOAc (3 x 10 ml), washed with brine (10 ml), dried with MgSO ₄ , filtered and evaporated in vacuo. The dry crude product was loaded onto 2 g of silica and purified by column chromatography (ISCO normal phase, 24 g Gold column, 0 to 60% EtOAc/hexanes gradient) to isolate 4-(3-bromo-5- fluorophenoxy)-1-(methylsulfonyl)piperidine ( 055 ) (108 mg, 0.307 mmol, 29%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.97-2.08 (m, 4 H) 2.84 (s, 3 H) 3.36-3.43 (m, 4 H) 4.48 -4.58 (m, 1 H) 6.59 (dt, J = 10.45, 2.24 Hz, 1 H) 6.87-6.93 (m, 2 H). LCMS: 353.1 [M+H] ⁺ .

The following intermediate was also synthesized according to the general methods of procedure 29.

Table 15. Description of the characteristics of the intermediate synthesized according to procedure 29 Intermediate connection Characteristics
6-Bromo-1-(4,4-difluorocyclohexyl)-4-fluoro-1H-indazole ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.91-2.08 (m, 2 H) 2.08-2.18 (m, 2 H) 2.26-2.52 (m, 4 H ) 4.49 (dt, J =10.16, 5.08 Hz, 1 H) 6.99 (dd, J =9.10, 1.19 Hz, 1 H) 7.43 (t, J =1 .00 Hz, 1 H) 8.05 (s, 1 H). LCMS: 334.1 [M+H] ⁺ .

Compounds 194-196 were prepared from the above intermediates using the general methods of Procedure 25.

Table 16. Description of characteristics of connections 194-196 Etc. Structure and chemical name according to IUPAC Characteristics 194
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-(1-methylsulfonylpiperidin-4-yl)oxyphenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.91 (dd, J =6.84, 1.44 Hz, 6 H) 1.15-1.22 (m, 2 H) 1.31-1 .40 (m, 2 H) 1.65-1.77 (m, 2 H) 1.79 (d, J =1.13 Hz, 3 H) 1.83-2.02 (m, 5 H) 2.32-2.72 (m, 8 H) 2.74 (s, 3 H) 3.10-3.38 (m, 7 H) 3.53-3.79 (m, 3 H) 4, 42 (br dd, J =5.71, 2.70 Hz, 1 H) 4.80 (t, J =10.04 Hz, 1 H) 5.17 (d, J =10.42 Hz, 1 H ) 5.30 (dd, J =15.25, 9.85 Hz, 1 H) 5.47-5.58 (m, 1 H) 6.38-6.46 (m, 2 H) 6.49 (s, 1 H) 6.54 (br d, J = 8.91 Hz, 1 H). LCMS: 680.6 [M+H] ⁺ 195
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(4,4-Difluorocyclohexyl)-4-fluorinazol-6-yl]prop-1-ene-2 -yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.94 (dd, J =9.22, 6.84 Hz, 6 H) 1.15-1.21 (m, 2 H) 1.36-1 .45 (m, 2 H) 1.51-1.61 (m, 2 H) 1.66-1.77 (m, 2 H) 1.84 (d, J = 1.13 Hz, 3 H) 1.88-2.12 (m, 4 H) 2.17-2.42 (m, 6 H) 2.43-2.66 (m, 6 H) 3.20-3.39 (m, 1 H) 3.41-3.79 (m, 4 H) 4.43 (br d, J =4.39 Hz, 1 H) 4.82 (t, J =10.16 Hz, 1 H) 5, 23 (d, J =10.79 Hz, 1 H) 5.33 (dd, J =15.12, 9.60 Hz, 1 H) 5.55 (dd, J =15.00, 9.98 Hz , 1 H) 6.61 (s, 1 H) 6.68 (d, J =10.67 Hz, 1 H) 6.96 (s, 1 H) 7.95 (s, 1 H). LCMS: 661.0 [M+H] ⁺ 196
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-Fluoro-1-(1-methylsulfonylpiperidin-4-yl)indazol-6-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.94 (t, J = 7.03 Hz, 6 H) 1.15-1.26 (m, 2 H) 1.33-1.42 (m , 2 H) 1.48-1.58 (m, 2 H) 1.65 (br d, J =5.27 Hz, 1 H) 1.84 (d, J =1.13 Hz, 3 H) 1.86-1.91 (m, 1 H) 2.01-2.16 (m, 2 H) 2.22-2.40 (m, 5 H) 2.42-2.66 (m, 5 H) 2.80 (s, 3 H) 2.99 (br t, J =11.73 Hz, 2 H) 3.22-3.30 (m, 1 H) 3.38-3.57 (m , 2 H) 3.60-3.77 (m, 2 H) 3.82-3.95 (m, 2 H) 4.35-4.52 (m, 1 H) 4.81 (t, J =10.16 Hz, 1 H) 5.16-5.25 (m, 1 H) 5.34 (dd, J =15.06, 9.66 Hz, 1 H) 5.54 (dd, J = 15.00, 9.98 Hz, 1 H) 6.56-6.76 (m, 2 H) 6.96 (s, 1 H) 7.95 (s, 1 H). LCMS: 704.6 [M+H] ⁺

Compounds 197-207 were prepared according to general methods from Procedures 30 and 31 .

Synthesis of a sulfonylpyrrolidine intermediate

Procedure 30

Pyrrolidine (30.2 μL, 0.366 mmol) was added to a stirred solution of 3-bromo-5-fluorobenzene-1-sulfonyl chloride (40 mg, 0.146 mmol) in dichloromethane (471 μL). The reaction solution was stirred at room temperature overnight. The reaction solution was purified by column chromatography using an EtOAc/hexanes gradient from 0 to 100%. The result was 1-((3-bromo-5-fluorophenyl)sulfonyl)pyrrolidine (53.2 mg, 118%) as a white solid. LCMS (ESI, mass/charge), 308.0, 310.0 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.81-1.89 (m, 4H), 3.27-3.34 (m, 4H), 7.50 (tdd, J = 7.53, 7 .53, 2.38, 1.51 Hz, 2H), 7.76-7.83 (m, 1H).

Synthesis of boronate combination products

Procedure 31

Into a stirred solution of boronate 1 (15 mg, 0.028 mmol) and 1-((3-bromo-5-fluorophenyl)sulfonyl)pyrrolidine ( 056 ) (12.11 mg, 0.039 mmol) in 480 μl of 1,4-dioxane and 10 Potassium carbonate (23.27 mg, 0.168 mmol) and tetrakis-triphenylphosphine palladium (16.21 mg, 0.014 mmol) were added to 11 μl of water. The mixture was degassed and heated to 95°C for 2 hours. After completion of the reaction, as indicated by UPLC, the mixture was cooled to room temperature, filtered and purified by column chromatography with an elution gradient of 0 to 100% EtOAc/hexanes, then gradient 0-20% MeOH/DCM. The result was the compound of Example 197 (8.1 mg, 45%) as a colorless oil.

Table 17. Description of characteristics of connections 197-207 Etc. Structure and chemical name according to IUPAC Characteristics 197
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-pyrrolidin-1-ylsulfonylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 636.3 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ): δ 0.84-0.93 (m, 3H), 1.03 (d, J =6.65 Hz, 6H), 1.21-1.32 (m , 11H), 1.47-1.52 (m, 2H), 1.79-1.85 (m, 5H), 1.91 (d, J =1.25 Hz, 3H), 1.94- 2.00 (m, 1H), 2.07 (s, 1H), 2.52-2.74 (m, 7H), 3.27-3.34 (m, 4H), 3.62-3, 82 (m, 4H), 4.15 (q, J =7.15 Hz, 1H), 4.91 (t, J =10.10 Hz, 1H), 5.30 (d, J =10.67 Hz, 1H), 5.43 (dd, J =15.00, 9.60 Hz, 1H), 5.62 (dd, J =15.00, 9.98 Hz, 1H), 6.60 (s , 1H), 7.18-7.23 (m, 1H), 7.44 (dt, J =7.47, 2.04 Hz, 1H), 7.54 (s, 1H). 198
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(Azetidin-1-ylsulfonyl)phenyl]prop-1-en-2-yl]-10-hydroxy -3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 604.6 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.87-0.97 (m, 6H), 1.10-1.25 (m, 3H), 1.29-1.46 (m, 1H), 1.33-1.45 (m, 3H), 1.68-1.78 (m, 1H), 1.78-1.90 (m, 4H), 1.95-2.08 (m, 2H ), 2.43-2.60 (m, 6H), 2.43-2.63 (m, 6H), 3.22-3.31 (m, 1H), 3.60-3.78 (m , 7H), 4.76-4.85 (m, 1H), 5.17-5.26 (m, 1H), 5.28-5.38 (m, 1H), 5.47-5.58 (m, 1H), 6.52-6.59 (m, 1H), 7.40-7.52 (m, 2H), 7.60-7.69 (m, 2H), 7.70-7 .70 (m, 1H) 199
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-[3-[(3R)-3-hydroxypyrrolidin-1-yl]sulfonylphenyl]prop-1- en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 634.5 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (br d, J =6.78 Hz, 6H), 1.13-1.23 (m, 2H), 1.38-1.47 (m , 1H), 1.67-1.77 (m, 2H), 1.80 (s, 4H), 1.84-1.91 (m, 2H), 2.36-2.44 (m, 3H ), 2.44-2.62 (m, 7H), 3.18 (br d, J =11.17 Hz, 1H), 3.28-3.40 (m, 3H), 3.52-3 .70 (m, 5H), 4.29-4.36 (m, 1H), 4.76-4.85 (m, 1H), 5.21 (br d, J =10.67 Hz, 1H) , 5.33 (br dd, J =15.00, 9.72 Hz, 1H), 5.53 (br dd, J =14.87, 9.73 Hz, 1H), 6.54 (s, 1H ), 7.36-7.46 (m, 2H), 7.62-7.69 (m, 2H) 200
[(2S,3S,4E,6R,7R,10S)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(2S)-2-methylpyrrolidin-1-yl] sulfonylphenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate LCMS (ESI, mass/charge), 632.6 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 0.93 (d, J =5.77 Hz, 7H), 1.07-1.21 (m, 3H), 1.24 (d, J =6.40 Hz, 3H), 1.39-1.52 (m, 3H), 1.58-1.77 (m, 4H), 1.80 (s, 4H), 1.83-1.91 (m, 2H), 2.40-2.68 (m, 10H), 2.40-2.67 (m, 9H), 2.53-2.54 (m, 1H), 3.03-3.13 ( m, 1H), 3.33-3.43 (m, 1H), 3.55-3.72 (m, 6H), 4.76-4.86 (m, 1H), 5.16-5, 26 (m, 1H), 5.26-5.37 (m, 1H), 5.47-5.58 (m, 1H), 6.50-6.57 (m, 1H), 7.33- 7.46 (m, 2H), 7.60-7.70 (m, 2H) 201
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-[3-[(1-hydroxy-2-methylpropan-2-yl)sulfamoyl]phenyl]prop -1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 636.6 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.88-0.96 (m, 6H), 1.04-1.10 (m, 6H), 1.15-1.23 (m, 2H), 1.36-1.45 (m, 2H), 1.68-1.77 (m, 2H), 1.77-1.83 (m, 3H), 1.84-1.91 (m, 1H ), 2.44-2.62 (m, 6H), 2.67-2.86 (m, 2H), 3.36-3.43 (m, 2H), 3.62-3.78 (m , 4H), 4.77-4.86 (m, 2H), 5.18-5.23 (m, 1H), 5.27-5.36 (m, 1H), 5.48-5.57 (m, 1H), 6.49-6.57 (m, 1H), 7.32-7.45 (m, 2H), 7.67-7.75 (m, 2H) 202
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4,4-Difluoropiperidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 668.6 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.00-1.06 (m, 6H), 1.20-1.34 (m, 3H), 1.43-1.56 (m, 6H), 1.77-1.86 (m, 1H), 1.86-1.92 (m, 3H), 1.92-2.03 (m, 1H), 2.03-2.17 (m, 4H ), 2.53-2.72 (m, 4H), 2.72-2.83 (m, 3H), 3.20-3.29 (m, 4H), 3.32-3.40 (m , 1H), 3.70-3.81 (m, 2H), 4.87-4.95 (m, 1H), 5.29-5.35 (m, 1H), 5.37-5.47 (m, 1H), 5.59-5.69 (m, 1H), 6.60-6.67 (m, 1H), 7.49-7.59 (m, 2H), 7.63-7 .69 (m, 2H) 203
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-(4-methyl-3-pyrrolidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 632.6 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.92 (dd, J =6.78, 1.88 Hz, 6H), 1.12-1.24 (m, 3H), 1.37-1, 46 (m, 3H), 1.67-1.75 (m, 2H), 1.78-1.89 (m, 8H), 2.44-2.61 (m, 10H), 3.16- 3.27 (m, 5H), 3.27-3.36 (m, 1H), 3.58-3.72 (m, 5H), 4.76-4.85 (m, 1H), 5. 17-5.23 (m, 1H), 5.28-5.36 (m, 1H), 5.48-5.58 (m, 1H), 6.44-6.51 (m, 1H), 7.20-7.27 (m, 2H), 7.77 (d, J =1.51 Hz, 1H) 204
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(3,3-Difluoropyrrolidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 354.6 [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) δ 0.88-0.96 (m, 6H), 1.11-1.29 (m, 5H), 1.64-1.76 (m, 2H), 1.77-1.82 (m, 3H), 1.84-1.94 (m, 1H), 2.14-2.29 (m, 2H), 2.42-2.62 (m, 3H ), 2.65-2.78 (m, 4H), 3.33-3.42 (m, 4H), 3.45-3.57 (m, 2H), 3.59-3.73 (m , 2H), 4.07-4.20 (m, 1H), 4.74-4.87 (m, 1H), 5.17-5.27 (m, 1H), 5.27-5.39 (m, 1H), 5.49-5.61 (m, 1H), 6.51-6.59 (m, 1H), 7.40-7.51 (m, 2H), 7.58-7 .67 (m, 2H), 7.85-7.95 (m, 1H) 205
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(5-pyrrolidin-1-ylsulfonylpyridin-3-yl )prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 619.6 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.82-0.93 (m, 1H), 1.01-1.07 (m, 6H), 1.17-1.38 (m, 5H), 1.46-1.52 (m, 1H), 1.75-1.88 (m, 6H), 1.91-2.03 (m, 4H), 2.53-2.87 (m, 9H ), 3.28-3.37 (m, 5H), 3.41-3.51 (m, 2H), 3.68-3.83 (m, 3H), 4.15-4.32 (m , 2H), 4.86-4.95 (m, 1H), 5.27-5.35 (m, 1H), 5.37-5.49 (m, 1H), 5.57-5.70 (m, 1H), 6.61 (s, 1H), 8.02 (s, 1H), 8.73 (d, J =2.01 Hz, 1H), 8.89-8.98 (m, 1H) 206
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(3,3-Difluoroazetidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 640.6 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (dd, J =9.22, 6.84 Hz, 7H), 0.94-0.95 (m, 1H), 1.03-1, 28 (m, 6H), 1.25-1.39 (m, 4H), 1.51-1.56 (m, 2H), 1.68-1.89 (m, 4H), 2.44- 2.62 (m, 3H), 2.62-2.72 (m, 2H), 2.72-2.76 (m, 3H), 3.34-3.42 (m, 2H), 3. 57-3.72 (m, 3H), 4.04-4.21 (m, 7H), 4.76-4.85 (m, 1H), 5.18-5.26 (m, 1H), 5.26-5.37 (m, 1H), 5.49-5.59 (m, 1H), 6.53-6.58 (m, 1H), 7.45-7.53 (m, 2H ), 7.63-7.70 (m, 2H) 207
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-[4-methyl-3-(2-oxopyrrolidin-1-yl) phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 582.6 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.86-0.95 (m, 6H), 1.10-1.26 (m, 2H), 1.35-1.42 (m, 2H), 1.64-1.76 (m, 1H), 1.76-1.80 (m, 3H), 1.81-1.89 (m, 1H), 2.10-2.20 (m, 5H ),2.41-2.60 (m, 6H),2.62-2.72 (m, 3H), 3.32 (br d, J =10.92 Hz, 1H), 3.59-3 .69 (m, 4H), 4.81 (t, J =10.04 Hz, 1H), 5.18 (d, J =10.54 Hz, 1H), 5.29 (dd, J =14, 93, 9.66 Hz, 1H), 5.53 (dd, J =15.00, 9.98 Hz, 1H), 6.41-6.48 (m, 1H), 6.94-6.99 (m, 1H), 7.03-7.09 (m, 1H), 7.13-7.17 (m, 1H)

Compounds 208-218 were prepared according to general methods from procedure 32 .

Synthesis of boronate combination products

Procedure 32

Into a stirred solution of iodide ( 008 ) (15 mg, 0.028 mmol) and N-(tert-butyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide ( 11.43 mg, 0.034 mmol) silver oxide (19.51 mg, 0.084 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.24 mg, 2.807 μmol) were added to 426 μl of p-dioxane. The mixture was degassed and heated to 80°C for 90 minutes. After completion of the reaction, as indicated by UPLC, the reaction mixture was cooled to room temperature, filtered and concentrated. Purification by column chromatography eluting with a gradient of 0 to 20% MeOH/DCM provided Example 208 (23.3 mg, ~100%) as a colorless oil.

Table 18. Description of characteristics of connections 208-218 and 268 Etc. Structure and chemical name according to IUPAC Characteristics 208
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(tert-Butylsulfamoyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3 ,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 620.8 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ 0.84-0.93 (m, 1H), 0.99-1.05 (m, 6H), 1.22-1.29 (m, 13H), 1 .48-1.56 (m, 1H), 1.79-1.87 (m, 1H), 1.88-1.92 (m, 3H), 1.93-1.99 (m, 1H) , 2.39 (s, 3H), 2.48 (br s, 2H), 2.60 (br d, J =3.14 Hz, 3H), 3.31-3.41 (m, 1H), 3.55-3.59 (m, 2H), 3.71-3.81 (m, 1H), 4.53 (s, 1H), 4.85-4.95 (m, 1H), 5. 32 (s, 2H), 5.38-5.47 (m, 1H), 5.58-5.67 (m, 1H), 6.63 (s, 1H), 7.39-7.52 ( m, 2H), 7.74-7.85 (m, 2H). 209
[(2S,3S,4E,6R,7R,10S)-10-Hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-[3-(propan-2-ylsulfamoyl)phenyl] prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate LCMS (ESI, mass/charge), 606.6 [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) δ 0.89-0.96 (m, 6H), 0.99-1.05 (m, 6H), 1.12-1.23 (m, 2H), 1.37-1.44 (m, 3H), 1.67-1.76 (m, 1H), 1.77-1.83 (m, 3H), 1.83-1.91 (m, 1H ), 2.39-2.50 (m, 1H), 2.43-2.46 (m, 1H), 2.53-2.66 (m, 4H), 3.23-3.30 (m , 1H), 3.27-3.28 (m, 1H), 3.36-3.48 (m, 1H), 3.60-3.70 (m, 2H), 4.17-4.24 (m, 1H), 4.76-4.85 (m, 1H), 5.17-5.24 (m, 1H), 5.28-5.39 (m, 1H), 5.54 (dd , J =15.00, 9.98 Hz, 1H), 6.50-6.56 (m, 1H), 7.32-7.45 (m, 2H), 7.64-7.72 (m , 2H) 210
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-(Ethylsulfamoyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 592.6 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.00-1.06 (m, 6H), 1.13-1.18 (m, 3H), 1.29-1.32 (m, 2H), 1.47-1.56 (m, 2H), 1.74-1.88 (m, 2H), 1.88-1.92 (m, 3H), 1.92-2.00 (m, 1H ), 2.46 (br s, 3H), 2.56-2.70 (m, 5H), 2.99-3.11 (m, 2H), 3.32-3.40 (m, 1H) , 3.54-3.81 (m, 5H), 4.32-4.41 (m, 1H), 4.86-4.96 (m, 1H), 5.27-5.35 (m, 1H), 5.37-5.48 (m, 1H), 5.56-5.68 (m, 1H), 6.60-6.66 (m, 1H), 7.44-7.55 ( m, 2H), 7.73-7.82 (m, 2H) 211
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-[3-(4-methylpiperazin-1-yl)sulfonylphenyl]prop- 1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 647.7 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.72-0.86 (m, 3H), 0.89-0.97 (m, 7H), 1.08-1.26 (m, 12H) , 1.66-1.77 (m, 1H), 1.67-1.78 (m, 1H), 1.78-1.84 (m, 3H), 1.84-1.92 (m, 1H), 1.85-1.95 (m, 1H), 2.44-2.73 (m, 8H), 3.08-3.16 (m, 1H), 3.21-3.30 ( m, 2H), 3.59-3.71 (m, 2H), 4.76 (s, 1H), 5.16-5.25 (m, 1H), 5.27-5.36 (m, 1H), 5.49-5.60 (m, 1H), 6.49-6.57 (m, 1H), 7.40-7.50 (m, 2H), 7.52-7.58 ( m, 2H) 212
[(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-(methylsulfamoyl)phenyl]prop-1-ene-2- yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 578.5 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.93 (dd, J =6.71, 2.07 Hz, 5H), 0.93-0.95 (m, 1H), 1.13-1, 24 (m, 3H), 1.68-1.76 (m, 1H), 1.79-1.84 (m, 4H), 1.84-1.91 (m, 1H), 2.41- 2.64 (m, 12H), 3.06 (s, 1H), 3.22-3.29 (m, 1H), 3.52-3.75 (m, 5H), 4.24-4, 33 (m, 1H), 4.81 (t, J =10.04 Hz, 1H), 5.21 (d, J =10.54 Hz, 1H), 5.34 (d, J =9.66 Hz, 1H), 5.53 (dd, J =15.00, 9.85 Hz, 1H), 6.51-6.55 (m, 1H), 7.36-7.46 (m, 2H) , 7.49-7.53 (m, 1H), 7.64-7.70 (m, 2H) 213
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 632.6 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.03 (dd, J =6.65, 2.89 Hz, 6H), 1.20-1.35 (m, 2H), 1.39-1, 72 (m, 10H), 1.75-1.86 (m, 1H), 1.91 (d, J =1.00 Hz, 3H), 1.93-2.00 (m, 1H), 2 .51-2.82 (m, 7H), 3.02 (br d, J =5.40 Hz, 4H), 3.31-3.42 (m, 1H), 3.59-3.94 ( m, 4H), 4.88-4.98 (m, 1H), 5.26-5.35 (m, 1H), 5.37-5.48 (m, 1H), 5.62 (br d , J =9.91 Hz, 1H), 6.59-6.67 (m, 1H), 7.51 (br d, J =11.67 Hz, 2H), 7.68 (s, 2H) 214
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-pyrrolidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 618.5 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.98-1.08 (m, 6H), 1.21-1.37 (m, 2H), 1.46-1.67 (m, 4H), 1.75-1.86 (m, 5H), 1.89-1.94 (m, 3H), 1.94-2.02 (m, 1H), 2.52-2.82 (m, 7H ), 3.25-3.32 (m, 4H), 3.33-3.42 (m, 1H), 3.66-3.84 (m, 3H), 4.85-4.96 (m , 1H), 5.28-5.35 (m, 1H), 5.37-5.47 (m, 1H), 5.58-5.70 (m, 1H), 6.60-6.68 (m, 1H), 7.44-7.57 (m, 2H), 7.68-7.81 (m, 2H) 215
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Cyclopropylsulfonylphenyl)prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl- 12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 589.5 [M+H]+. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.97-1.10 (m, 9H), 1.21-1.33 (m, 2H), 1.35-1.43 (m, 2H), 1.47-1.57 (m, 2H), 1.77-1.87 (m, 1H), 1.91 (d, J =1.25 Hz, 3H), 1.93-2.02 ( m, 1H), 2.42-2.54 (m, 2H), 2.54-2.85 (m, 7H), 3.32-3.41 (m, 1H), 3.63-3, 92 (m, 4H), 4.86-4.96 (m, 1H), 5.25-5.35 (m, 1H), 5.38-5.49 (m, 1H), 5.58- 5.68 (m, 1H), 6.61-6.68 (m, 1H), 7.54 (br d, J =0.75 Hz, 2H), 7.76-7.87 (m, 2H ) 216
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(Cyclopropylsulfonylamino)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 604.6 [M+H]+. ^1H NMR (400 MHz, CDCl ₃ ) δ 0.93-1.07 (m, 8H), 0.98-0.98 (m, 1H), 1.15-1.22 (m, 2H), 1.23-1.36 (m, 2H), 1.46-1.57 (m, 2H), 1.76-1.87 (m, 1H), 1.88-1.92 (m, 3H ), 1.96 (td, J =6.74, 3.70 Hz, 1H), 2.44-2.73 (m, 8H), 3.41 (d, J =10.79 Hz, 1H) , 3.59-4.00 (m, 3H), 3.67-3.68 (m, 1H), 4.91 (t, J =10.10 Hz, 1H), 5.25-5.34 (m, 1H), 5.35-5.48 (m, 1H), 5.63 (dd, J =15.06, 9.91 Hz, 1H), 6.52-6.62 (m, 2H ), 7.08-7.20 (m, 2H), 7.21-7.26 (m, 1H), 7.30-7.36 (m, 1H) 217
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[(3S)-3-(methanesulfonamido)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 665.5 [M+H]1H NMR (400 MHz, CDCl ₃ ) d ppm 0.97-1.05 (m, 6 H) 1.22-1.31 (m , 2 H) 1.45-1.53 (m, 2 H) 1.75-1.85 (m, 1 H) 1.92-1.99 (m, 1H) 2.04-2.12 ( m, 1 H) 2.31 (br s, 8 H) 2.50-2.69 (m, 3 H) 3.04 (s, 3 H) 3.21-3.29 (m, 1 H) 3.31-3.49 (m, 4 H) 3.58-3.65 (m, 1 H) 3.69-3.77 (m, 1 H) 4.17-4.27 (m, 1 H) 4.36-4.47 (m, 1 H) 4.88-4.94 (m, 1 H) 5.23-5.29 (m, 1 H) 5.37-5.45 (m , 1 H) 5.56-5.65 (m, 1 H) 6.12-6.20 (m, 2 H) 6.34-6.41 (m, 1 H) 6.48-6.53 (m, 1H) 218
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[(3S)-3-[(2-methoxyacetyl)amino]pyrrolidine-1- yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 659.7 [M+H]. 268
(2S,3S,6R,7S,10R, E)-10-Hydroxy-3,7-dimethyl-12-oxo-2-((E)-1-(3-(pyrrolidin-1-ylsulfonyl)phenyl)prop -1-en-2-yl)oxacyclododec-4-en-6-ylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 604.5 [M+H].

Compounds 219 and 220 (Tables 17 and 18) were synthesized according to the general methods from Procedures 33 and 34 .

Procedure 33

Step 1. The vial was loaded with DMAP (0.117 g, 0.957 mmol), DCM (4.78 ml, 0.957 mmol) (4R,7S,8R,11S,12S, E)-4-((tert-butyldimethylsilyl)oxy)- 8-hydroxy-12-((E)-1-iodoprop-1-en-2-yl)-7,11-dimethyloxacyclododec-9-en-2-one ( 005 ) (0.5 g, 0.957 mmol), 4-nitrophenylchloroformate (0.193 g, 0.957 mmol), they were combined and stirred overnight. 1-Methylpiperazine (0.191 mL, 1.722 mmol) was added and then the reaction mixture was stirred for 1 hour. The reaction mixture was directly loaded onto a silica gel column and chromatographed to give (2S,3S,6R,7S,10R,E)- 10-((tert-butyldimethylsilyl)oxy)-2-((E)-1-iodoprop-1-en-2-yl)-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl-4 -methylpiperazine-1-carboxylate ( 007 ) (0.567 g, 0.874 mmol, 91% yield). LCMS (ESI, mass/charge), 649.4 [M+H]+.

Step 2: Combine silver oxide (0.098 g, 0.421 mmol), tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin- 1(2H)-carboxylate (0.052 g, 0.168 mmol), (2S,3S,6R,7S,10R, E)-10-hydroxy-2-((E)-1-iodoprop-1-en-2-yl )-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl-4-methylpiperazin-1-carboxylate ( 007 ) (0.045 g, 0.084 mmol), 1,4-dioxane (0.842 ml, 0.084 mmol) and bubbled with nitrogen for 10 minutes, after which tetrakis(triphenylphosphine)palladium(0) (0.019 g, 0.017 mmol) was added and bubbled with nitrogen for 10 minutes and stirred at 90°C for 1.5 hours. The reaction mixture was filtered, concentrated and chromatographed to give the compound of Example 219 (2S,3S,6R,7S,10R, E)-2-((E)-1-(1-(tert-butoxycarbonyl)-1,2,5,6-tetrahydropyridine -3-yl)prop-1-en-2-yl)-10-hydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl-4-methylpiperazin-1-carboxylate (12 mg, 0.020 mmol, yield 24.16%).

Table 19. Description of connection characteristics 219 Etc. Structure and chemical name according to IUPAC Characteristics 219
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-2-[(E)-1-[1-[(2-methylpropan-2-yl)oxycarbonyl]- 3,6-dihydro-2H-pyridin-5-yl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate LCMS (ESI, mass/charge), 591.7 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 0.87-0.97 (m, 3 H) 1.02 (d, J =6.78 Hz, 3 H) 1.19-1.31 (m, 2 H) 1.42-1.59 (m, 9 H) 1.82 (s, 4 H) 1.86-1.98 (m, 1 H) 2.18-2.27 (m, 2 H) 2.31 (s, 3 H) 2.37 (br s, 4 H) 2.45-2.69 (m, 3 H) 3.50 (br d, J =5.52 Hz, 6 H) 3 .66-3.80 (m, 1 H) 3.81 -4.06 (m, 2 H) 4.82-4.92 (m, 1 H) 5.11-5.19 (m, 1 H ) 5.33-5.43 (m, 1 H) 5.52-5.62 (m, 1 H) 5.73-5.93 (m, 2 H).

Procedure 34

Step 1. To a solution of alcohol ( 057 ) (265 mg, 0.423 mmol, 89% yield) in DCM (2.388 ml, 0.478 mmol) was added DMAP (0.058 g, 0.478 mmol), Hunig's base (0.417 ml, 2.388 mmol), 4 -nitrophenyl chloroformate (0.173 g, 0.86 mmol). The resulting yellowish suspension was stirred for 12 hours until the SM disappeared, the reaction mixture was concentrated and chromatographed to obtain the carbonate. The product was then dissolved in methanol (4.78 ml, 0.478 mmol), tosylic acid (0.182 g, 0.955 mmol) was added and stirred for 1 hour. TEA (1 ml) was added and stirred for 10 minutes. The reaction mixture was then concentrated to dryness and DCM (6 ml) and saturated NaHCO3 solution (2 ml) were added and stirred and extracted. The aqueous layer was then back-extracted with DCM (3×). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to dryness to give ( 058 ) (265 mg, 0.423 mmol, 89% yield). LCMS (ESI, mass/charge), 627.3 [M+H] 1H NMR (400 MHz, CDCl ₃ ) δ ppm 0.06-0.12 (m, 6 H) 0.41-0.42 (m , 1 H) 0.85-0.89 (m, 4 H) 0.91 (s, 10 H) 0.97-1.05 (m, 6 H) 1.09-1.14 (m, 3 H) 1.59-1.66 (m, 2 H) 1.68-1.77 (m, 1 H) 1.84-1.89 (m, 3 H) 1.95-2.02 (m , 1 H) 2.04 (s, 2 H) 2.36-2.44 (m, 1 H) 2.51-2.65 (m, 2 H) 3.10-3.18 (m, 4 H) 3.79-3.88 (m, 4 H) 3.88-3.95 (m, 1 H) 4.79-4.88 (m, 1 H) 5.07-5.14 (m , 1 H) 5.45-5.57 (m, 1 H) 5.63-5.74 (m, 1 H) 6.42-6.55 (m, 4 H) 7.38 (d, J =9.29 Hz, 2 H) 8.24-8.30 (m, 2 H).

Stage 2 . To a solution of carbonate ( 058 ) (50 mg, 0.087 mmol) in DCM (0.434 ml, 0.087 mmol) was added DMAP (10.61 mg, 0.087 mmol), Hunig's base (0.076 ml, 0.434 mmol), 4-nitrophenylchloroformate (0.032 g , 0.156 mmol). The resulting yellowish suspension was stirred for 5 hours and d3-N-methylpiperizine (0.027 g, 0.26 mmol) was added and stirred until the reaction was complete (1 hour). The reaction mixture was concentrated and chromatographed to give ( 059 ) (58 mg, 0.082 mmol, 95% yield). LCMS (ESI, mass/charge), 705.7 [M+H 1H NMR (400 MHz, CDCl ₃ ) d ppm 1.01 (s, 6 H) 1.23-1.32 (m, 2 H) 1 .55 (s, 11 H) 1.75-1.84 (m, 1 H) 1.88 (d, J =1.25 Hz, 3 H) 1.91-2.02 (m, 1 H) 2.02-2.14 (m, 1 H) 2.20-2.46 (m, 8 H) 2.48-2.70 (m, 3 H) 3.19-3.56 (m, 11 H) 3.57-3.66 (m, 1 H) 3.68-3.80 (m, 1 H) 4.16-4.27 (m, 1 H) 4.39-4.49 (m , 1 H) 4.82-4.94 (m, 1 H) 5.24-5.29 (m, 1 H) 5.36-5.46 (m, 1 H) 5.55-5.66 (m, 1 H) 6.10-6.21 (m, 2 H) 6.34-6.42 (m, 1 H) 6.47-6.55 (m, 1 H).

Step 3: Combine carbamate ( 059 ) (58 mg, 0.082 mmol), methanol (823 μL, 0.082 mmol), tosylic acid (46.9 mg, 0.247 mmol) and stir overnight. The reaction mixture was then stirred with TEA (1 ml), concentrated to dryness and extracted with saturated NaHCO3 solution. The organic layer was separated, dried over Na2SO4 and concentrated to dryness and chromatographed (0-10% MeOH in DCM) to give the compound of Example 220 - (2S,3S,6R,7S,10R, E)-2-((E) -1-(3-fluoro-5-morpholinophenyl)prop-1-en-2-yl)-10-hydroxy-3,7-dimethyl-12-oxooxacyclododec-4-en-6-yl-4-(methyl- d3) piperazine-1-carboxylate (17 mg, 0.029 mmol, 35.0% yield).

Table 20. Description of 220 connection characteristics Etc. Structure and chemical name according to IUPAC Characteristics 220
[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(trideuteriomethyl)piperazine-1-carboxylate LCMS (ESI, mass/charge), 591.4 [M+H] ¹ H NMR (400 MHz, CDCl ₃ ) d ppm 0.95-1.05 (m, 6 H) 1.17-1.33 ( m, 2 H) 1.88 (d, J =1.13 Hz, 4 H) 1.91-2.00 (m, 1 H) 2.30-2.43 (m, 4 H) 2.50 -2.68 (m, 3 H) 3.11-3.19 (m, 4 H) 3.31-3.42 (m, 1 H) 3.43-3.58 (m, 4 H) 3 .67-3.79 (m, 1 H) 3.81-3.90 (m, 4 H) 4.84-4.94 (m, 1 H) 5.21-5.29 (m, 1 H ) 5.35-5.46 (m, 1 H) 5.55-5.66 (m, 1 H) 6.43-6.56 (m, 4 H).

Compounds 221-253 were synthesized according to the general methods of procedure 35.

Procedure 35

Step 1: Combine ( 005 ) iodide (0.2 g, 0.393 mmol), 1-(4-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)phenyl)piperazin-1-yl)-2-(1H-pyrazol-1-yl)ethanone (0.179 g, 0.433 mmol), silver oxide (0.456 g, 1.967 mmol), 1,4-dioxane (3, 93 mL, 0.393 mmol) and bubbled with nitrogen for ~5 min. Pd(PPh ₃ ) ₄ (0.068 g, 0.059 mmol) was added and the reaction mixture was bubbled with nitrogen for ~5 min. The reaction mixture was then placed in an oil bath at 80 C and stirred for 3 hours. The reaction mixture was filtered and concentrated, and chromatographed (0 to 100% EtOAc in hexanes) to give compound ( 060 ) (179 mg, 0.268 mmol, 68.0% yield). LCMS (ESI, mass/charge), 683.55 [M+H].

Step 2: To a solution of alcohol ( 060 ) (0.575 g, 0.842 mol) and DCM (4.21 ml, 0.842 mmol), DMAP (0.103 g, 0.842 mmol), Hunig's base (0.735 ml, 4.21 mmol), 4 -nitrophenyl chloroformate (0.305 g, 1.516 mmol). The resulting yellowish suspension was stirred for 12 hours until the starting material disappeared. The reaction mixture was concentrated and chromatographed to give ( 061 ) (0.58 g, 0.684 mmol, 81% yield). LCMS (ESI, mass/charge), 848.5 [M+].

Step 3: Combine ( 061 ) carbonate (580 mg, 0.684 mmol), methanol (6839 μL, 0.684 mmol), tosylic acid (390 mg, 2.052 mmol) and stir for 1 hour. Triethylamine (1 ml) was added and the reaction mixture was stirred for 15 minutes. The reaction mixture was then concentrated to dryness and dissolved in DCM. The crude reaction mixture was stirred with saturated NaHCO ₃ solution for 10 minutes and extracted. The organic phases were combined, dried over anhydrous Na ₂ SO ₄ and concentrated to dryness to give ( 062 ) (410 mg, 0.559 mmol, 82% yield). LCMS (ESI, mass/charge), 734.4 [M+H].

Step 4: Mix carbonate ( 062 ) (0.015 g, 0.020 mmol), DCM (0.204 ml, 0.020 mmol), Hunig's base (7.14 μl, 0.041 mmol) and add amine (0.007 g, 0.061 mmol) and the reaction mixtures are stirred during the night. The reaction mixture was then concentrated to dryness and chromatographed (reverse phase HPLC) to give the product of Example 221 - (2S,3S,6R,7S,10R, E)-2-((E)-1-(3-(4 -(2-(1H-pyrazol-1-yl)acetyl)piperazin-1-yl)-5-fluorophenyl)prop-1-en-2-yl)-10-hydroxy-3,7-dimethyl-12-oxooxacyclododec -4-en-6-yl(pyridin-4-ylmethyl)carbamate (9.4 mg, 0.013 mmol, 65.4% yield).

Table 21. Description of characteristics of connections 221-253 Etc. Structure and chemical name according to IUPAC Characteristics 221
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(pyridin-4-ylmethyl)carbamate LCMS (ESI, mass/charge), 703.4 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 0.92-1.00 (m, 3 H) 1.01-1, 11 (m, 3 H) 1.24-1.46 (m, 2 H) 1.55-1.70 (m, 2 H) 1.87 (s, 3 H) 1.91-1.99 ( m, 1 H) 2.42-2.53 (m, 1 H) 2.57-2.65 (m, 2 H) 3.18-3.29 (m, 4 H) 3.74 (br s , 4 H) 3.77-3.85 (m, 1 H) 4.26-4.37 (m, 2 H) 5.09-5.17 (m, 1 H) 5.20 (s, 2 H) 5.50-5.57 (m, 2 H) 6.33-6.35 (m, 1 H) 6.50-6.54 (m, 1 H) 6.54-6.56 (m , 1 H) 6.60-6.65 (m, 1 H) 6.65-6.67 (m, 1 H) 6.86-6.93 (m, 1 H) 6.89 (d, J =9.29 Hz, 1 H) 7.29-7.38 (m, 2 H) 7.49-7.55 (m, 1 H) 7.62-7.66 (m, 1 H) 8, 09-8.16 (m, 2 H) 8.09-8.15 (m, 1 H) 8.42-8.50 (m, 2 H) 222
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(pyrimidin-4-ylmethyl)carbamate LCMS (ESI, mass/charge), 704.5 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 0.98 (d, J =6.78 Hz, 3 H) 1.06 (br d, J =6.65 Hz, 3 H) 1.24-1.47 (m, 3 H) 1.55-1.69 (m, 2 H) 1.87 (s, 3 H) 1 .91-2.01 (m, 1 H) 2.40-2.52 (m, 1 H) 2.55-2.70 (m, 2 H) 3.16-3.28 (m, 4 H ) 3.67-3.76 (m, 4 H) 3.79 (s, 2 H) 4.39 (s, 2 H) 5.09-5.16 (m, 1 H) 5.20 (s , 2 H) 5.49-5.58 (m, 2 H) 6.30-6.38 (m, 1 H) 6.55 (s, 2 H) 6.59-6.70 (m, 2 H) 7.52 (d, J =1.63 Hz, 1 H) 7.64 (d, J =2.13 Hz, 1 H) 8.71 (d, J =5.27 Hz, 1 H) 9.00-9.11 (m, 1H) 223
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-morpholine-4-carboxylate LCMS (ESI, mass/charge), 682.4 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 1.00 (dd, J =12.05, 6.78 Hz, 6 H ) 1.26-1.45 (m, 2 H) 1.57-1.71 (m, 2 H) 1.87 (d, J = 1.25 Hz, 3 H)
1.91-2.02 (m, 1 H) 2.43-2.52 (m, 1 H) 2.57-2.69 (m, 2 H) 3.18-3.28 (m, 4 H) 3.38-3.50 (m, 4 H) 3.60-3.67 (m, 4 H) 3.71-3.76 (m, 4 H) 3.78-3.84 (m , 1 H) 5.11-5.17 (m, 1 H) 5.18-5.22 (m, 2 H) 5.45-5.60 (m, 3 H) 5.49-5.59 (m, 1 H) 6.29-6.36 (m, 1 H) 6.48-6.58 (m, 2 H) 6.59-6.69 (m, 2 H) 7.51-7 .53 (m, 1 H) 7.63-7.66 (m, 1 H) 224
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(dimethylamino)ethyl]carbamate LCMS (ESI, mass/charge), 683.6 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 0.93-1.10 (m, 6 H) 1.26-1, 47 (m, 2 H) 1.55-1.74 (m, 2 H) 1.82-1.93 (m, 4 H) 2.43-2.54 (m, 6 H) 2.57- 2.66 (m, 2 H) 2.68-2.77 (m, 1 H) 3.18-3.29 (m, 5 H) 3.68-3.75 (m, 3 H) 3, 77-3.84 (m, 1 H) 5.10-5.17 (m, 1 H) 5.19-5.22 (m, 2 H) 5.41-5.58 (m, 3 H) 6.30-6.38 (m, 1 H) 6.47-6.56 (m, 2 H) 6.59-6.70 (m, 2 H) 7.49-7.56 (m, 1 H) 7.60-7.68 (m, 1 H) 225
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methyl-1,4-diazepan-1 -carboxylate LCMS (ESI, mass/charge), 709.5 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 0.95-1.01 (m, 3 H) 1.01-1, 08 (m, 3 H) 1.26-1.49 (m, 3 H) 1.56-1.73 (m, 2 H) 1.87 (d, J = 1.25 Hz, 3 H) 1 .91-2.02 (m, 3 H) 2.42-2.55 (m, 4 H) 2.56-2.70 (m, 2 H) 2.81 (br d, J = 4.27 Hz, 4 H) 3.17-3.29 (m, 5 H) 3.44-3.66 (m, 4 H) 3.67-3.76 (m, 4 H) 3.77-3, 86 (m, 1 H) 5.09-5.17 (m, 1 H) 5.20 (s, 2 H) 5.49 (s, 2 H) 6.31-6.37 (m, 1 H ) 6.46-6.58 (m, 2 H) 6.59-6.69 (m, 2 H) 7.48-7.55 (m, 1 H) 7.61-7.68 (m, 1H) 226
[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[(4-methoxyphenyl)methyl]carbamate LCMS (ESI, mass/charge), 732.5 [M+H] ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.82-1.09 (m, 6 H) 1.17-1.34 ( m, 2 H) 1.40-1.58 (m, 1 H) 1.87 (d, J =1.13 Hz, 5 H) 2.47-2.75 (m, 3 H) 3.08 -3.22 (m, 4 H) 3.67-3.76 (m, 3 H) 3.80 (s, 5 H) 4.30 (br d, J =5.40 Hz, 2 H) 4 .78-4.86 (m, 1 H) 4.87-4.96 (m, 1 H) 5.07 (s, 2 H) 5.23-5.29 (m, 1 H) 5.35 -5.45 (m, 1 H) 5.61 (dd, J =14.93, 9.91 Hz, 1 H) 6.35 (t, J =2.07 Hz, 1 H) 6.47- 6.63 (m, 4 H) 6.82-6.89 (m, 2 H) 7.20 (brd, J =8.41 Hz, 2 H) 7.52-7.59 (m, 2 H ) 227
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-(dimethylamino)pyrrolidin- 1-carboxylate LCMS (ESI, mass/charge), 710.7 [M+H] ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 0.98 (d, J=6.78 Hz, 3 H) 1.00- 1.06 (m, 3 H) 1.26-1.45 (m, 2 H) 1.64 (br s, 2 H) 1.76-1.84 (m, 1 H), 1.87 ( d, J=1.25 Hz, 3 H) 1.90-2.02 (m, 1 H) 2.13-2.24 (m, 1 H) 2.36 (d, J=4.64 Hz , 6 H) 2.42-2.51 (m, 1 H) 2.56-2.67 (m, 2 H) 2.88-2.98 (m, 1 H) 3.11-3.19 (m, 1 H) 3.19-3.28 (m, 4 H) 3.52-3.62 (m, 1 H) 3.64-3.70 (m, 1 H) 3.71-3 .76 (m, 4 H) 3.77-3.85 (m, 1 H) 5.09-5.18 (m, 1 H) 5.20 (s, 2 H) 5.48 (s, 2 H ) 6.34 (s, 1 H) 6.48-6.57 (m, 2 H) 6.59-6.68 (m, 2 H) 7.47-7.55 (m, 1 H) 7 .60-7.66 (m, 1 H) 228
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3-(dimethylamino)pyrrolidin- 1-carboxylate LCMS (ESI, mass/charge), 710.6 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 0.98 (d, J =6.65 Hz, 3 H) 1.00 -1.08 (m, 3 H) 1.26-1.47 (m, 2 H) 1.55-1.71 (m, 2 H) 1.74-1.84 (m, 1 H) 1 .87 (d, J =1.13 Hz, 3 H) 1.91-2.03 (m, 1 H) 2.09-2.24 (m, 1 H) 2.35 (d, J =3 ,64 Hz, 6 H) 2.42-2.50 (m, 1 H) 2.56-2.69 (m, 2 H) 2.82-3.02 (m, 1 H) 3.11- 3.29 (m, 5 H) 3.52-3.70 (m, 2 H) 3.70-3.76 (m, 4 H) 3.78-3.86 (m, 1 H) 5, 10-5.17 (m, 1 H) 5.18-5.23 (m, 2 H) 5.44-5.60 (m, 2 H) 6.31-6.37 (m, 1 H) 6.47-6.58 (m, 2 H) 6.59-6.69 (m, 2 H) 7.49-7.55 (m, 1 H) 7.61-7.67 (m, 1 H) 229
[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[(2S)-1-hydroxypropan- 2-yl]carbamate LCMS (ESI, mass/charge), 670.4 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 1.00 (br dd, J =16.00, 6.71 Hz, 6 H) 1.12 (d, J =6.65 Hz, 4 H) 1.34-1.45 (m, 2 H) 1.56-1.71 (m, 3 H) 1.87 (d, J =1.13 Hz, 4 H) 2.41-2.53 (m, 1 H) 2.56-2.65 (m, 2 H) 3.16-3.26 (m, 3 H) 3 .38-3.50 (m, 2 H) 3.60-3.69 (m, 1 H) 3.69-3.77 (m, 3 H) 3.77-3.86 (m, 1 H ) 5.10-5.17 (m, 1 H) 5.20 (s, 2 H) 6.35 (t, J = 2.13 Hz, 1 H) 6.48-6.69 (m, 3 H) 7.52 (d, J =1.76 Hz, 1 H) 7.64 (d, J =2.26 Hz, 1H) 230
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3-oxopiperazine-1-carboxylate LCMS (ESI, mass/charge), 695.4 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 0.98 (d, J =6.65 Hz, 3 H) 1.03 (d, J =6.90 Hz, 3 H) 1.26-1.46 (m, 2 H) 1.58-1.72 (m, 2 H) 1.87 (d, J =1.13 Hz, 3 H) 1.94-2.05 (m, 1 H) 2.43-2.53 (m, 1 H) 2.58-2.70 (m, 2 H) 3.18-3, 29 (m, 4 H) 3.32-3.36 (m, 2 H) 3.58-3.69 (m, 2 H) 3.69-3.77 (m, 4 H) 3.78- 3.86 (m, 2 H) 3.99-4.14 (m, 2 H) 5.09-5.18 (m, 1 H) 5.20 (s, 2 H) 5.45-5, 63 (m, 2 H) 6.29-6.39 (m, 1 H) 6.45-6.58 (m, 2 H) 6.60-6.70 (m, 2 H) 7.49-7 .54 (m, 1 H) 7.60-7.68 (m, 1 H) 231
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-fluoropyrrolidine-1-carboxylate LCMS (ESI, mass/charge), 684.4 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 0.95-1.07 (m, 6 H) 1.21-1, 31 (m, 2 H) 1.33 (br d, J =8.41 Hz, 2 H) 1.60-1.72 (m, 2 H) 1.87 (d, J =0.75 Hz, 3 H) 1.91-2.07 (m, 2 H) 2.14-2.28 (m, 1 H) 2.42-2.52 (m, 1 H) 2.57-2.69 ( m, 2 H) 3.18-3.28 (m, 4 H) 3.36-3.51 (m, 2 H) 3.52-3.68 (m, 2 H) 3.70-3, 78 (m, 4 H) 3.79-3.86 (m, 1 H) 4.56 (s, 2 H) 5.11-5.17 (m, 2 H) 5.20 (s, 2 H ) 5.51-5.63 (m, 2 H) 6.32-6.37 (m, 1 H) 6.49-6.69 (m, 4 H) 7.49-7.55 (m, 1H) 7.61-7.66 (m, 1H) 232
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,3,4-trimethylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 723.6 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 0.95-1.04 (m, 6 H) 1.06 (s, 6 H) 1.27-1.46 (m, 3 H) 1.54-1.74 (m, 2 H) 1.82-1.90 (m, 3 H) 1.90-2.02 ( m, 1 H) 2.24-2.35 (m, 3 H) 2.41-2.53 (m, 1 H) 2.53-2.69 (m, 4 H) 3.16-3, 29 (m, 7 H) 3.49-3.59 (m, 2 H) 3.68-3.76 (m, 4 H) 3.78-3.86 (m, 1 H) 4.52- 4.60 (m, 1 H) 5.10-5.18 (m, 1 H) 5.18-5.23 (m, 2 H) 5.49 (s, 5 H) 6.30-6, 38 (m, 1 H) 6.47-6.58 (m, 2 H) 6.60-6.70 (m, 2 H) 7.49-7.55 (m, 1 H) 7.62- 7.69 (m, 1H) 233
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin- 4-yl)carbamate LCMS (ESI, mass/charge), 723.5 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 1.00 (dd, J = 14.18, 6.78 Hz, 6 H ) 1.25-1.46 (m, 3 H) 1.60-1.69 (m, 2 H) 1.71-1.78 (m, 2 H) 1.87 (d, J =1, 25 Hz, 3 H) 1.89-2.04 (m, 3 H) 2.43-2.68 (m, 8 H) 2.82 (s, 3 H) 3.18-3.28 (m , 7 H) 3.73 (br d, J =5.27 Hz, 4 H) 3.78-3.86 (m, 1 H) 3.95-4.07 (m, 1 H) 4.53 -4.60 (m, 2 H) 5.11-5.17 (m, 1 H) 5.20 (s, 2 H) 5.50-5.58 (m, 2 H) 6.31-6 .39 (m, 1 H) 6.49-6.68 (m, 4 H) 7.51-7.56 (m, 1 H) 7.63-7.67 (m, 1 H) 234
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2-hydroxyethyl)piperazine-1- carboxylate LCMS (ESI, mass/charge), 725.5 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 1.00 (dd, J = 10.35, 6.71 Hz, 6 H ) 1.22-1.31 (m, 2 H) 1.32-1.45 (m, 2 H) 1.60-1.69 (m, 2 H) 1.87 (d, J =1, 25 Hz, 3 H) 1.92-2.00 (m, 1 H) 2.46-2.51 (m, 4 H) 2.52-2.57 (m, 2 H) 2.58-2 .67 (m, 2 H) 3.19-3.28 (m, 5 H) 3.44-3.53 (m, 4 H) 3.66-3.70 (m, 2 H) 3.72 -3.77 (m, 4 H) 3.78-3.86 (m, 1 H) 4.56 (s, 4 H) 5.10-5.17 (m, 1 H) 5.20 (s , 2 H) 5.46-5.61 (m, 2 H) 6.31-6.37 (m, 1 H) 6.49-6.57 (m, 2 H) 6.60-6.68 (m, 2 H) 7.49-7.54 (m, 1 H) 7.62-7.66 (m, 1 H) 235
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-piperazine-1-carboxylate LCMS (ESI, mass/charge), 681.4 [M+H] ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.93-1.04 (m, 6 H) 1.26 (br s, 3 H) 1.42-1.56 (m, 1 H) 1.75-1.84 (m, 1 H) 1.87 (s, 3 H) 1.89 -2.01 (m, 1 H) 2.42-2.70 (m, 5 H) 3.11 (br s, 5 H) 3.42-3.59 (m, 3 H) 3.74 (s, 8 H) 4.83-4 .99 (m, 1 H) 5.06 (s, 2 H) 5.20-5.31 (m, 1 H) 5.33-5.46 (m, 1 H) 5.54-5.66 (m, 1 H) 6.29-6.37 (m, 1 H) 6.42-6.57 (m, 4 H) 7.55 (d, J = 2.01 Hz, 2 H) 236
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cycloheptylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 778.0 [M+H] ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.99 (br d, J =6.53 Hz, 6 H) 1.16- 1.33 (m, 3 H) 1.42-1.70 (m, 19 H) 1.74-1.84 (m, 3 H) 1.87 (s, 3 H) 1.88-2, 02 (m, 1 H) 2.18-2.33 (m, 2 H) 2.45-2.74 (m, 3 H) 2.81-3.02 (m, 3 H) 3.09- 3.20 (m, 3 H) 3.25-3.50 (m, 4 H) 3.62-3.86 (m, 7 H) 4.04-4.32 (m, 2 H) 4.81 -4.96 237
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-pyridin-4-ylpiperazin-1-carboxylate LCMS (ESI, mass/charge), 758.7 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 0.94-1.06 (m, 6 H) 1.28-1, 46 (m, 2 H) 1.56-1.72 (m, 2 H) 1.87 (d, J =1.13 Hz, 3 H) 1.93-2.05 (m,
1 H) 2.37 (s, 1 H) 2.43-2.52 (m, 1 H) 2.57-2.71 (m, 2 H) 3.18-3.29 (m, 4 H ) 3.53-3.61 (m, 4 H) 3.62-3.69 (m, 4 H) 3.71-3.77 (m, 4 H) 3.77-3.86 (m, 1 H) 4.86-4.91 (m, 1 H) 5.12-5.17 (m, 1 H) 5.20 (s, 2 H) 5.46-5.62 (m, 2 H ) 6.32-6.36 (m, 1 H) 6.48-6.57 (m, 2 H) 6.59-6.69 (m, 2H) 7.20-7.25 (m, 1 H) 7.50-7.55 (m, 1 H) 7.63-7.67 (m, 1 H) 7.68-7.74 (m, 1 H) 238
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclohexylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 763.7 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 0.94-1.07 (m, 6 H) 1.26-1, 46 (m, 2 H) 1.56-1.72 (m, 2 H) 1.87 (d, J =1.25 Hz, 5 H) 1.92-2.02 (m,
1 H) 2.40-2.52 (m, 1 H) 2.58-2.70 (m, 2 H) 2.84-2.98 (m, 3 H) 3.19-3.29 ( m, 4 H) 3.45-3.64 (m, 4 H) 3.70-3.77 (m, 4 H) 3.78-3.86 (m, 1H) 5.11-5.18 (m, 1 H) 5.20 (s, 2 H) 5.44-5.61 (m, 2 H) 6.34 (s, 1 H) 6.49-6.57 (m, 2 H) 6.60-6.68 (m, 2 H) 7.52 (d, J =1.51 Hz, 1 H) 7.64 (d, J =2.01 Hz, 1 H) 239
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(4-hydroxyphenyl)ethyl ]-N-methylcarbamate LCMS (ESI, mass/charge), 746.8 [M+H] 240
(2S,3S,6R,7S,10R, E)-2-((E)-1-(3-Fluoro-5-morpholinophenyl)prop-1-en-2-yl)-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl-7-methyl-1,7-diazaspiro[3.5]nonane-1-carboxylate LCMS (ESI, mass/charge), 628.7 [M+H] 241
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(3-morpholin-4-ylpropyl)carbamate LCMS (ESI, mass/charge), 632.4 [M+H] ¹ H NMR (400 MHz, METHANOL- d 4) δ ppm 0.95-1.07 (m, 6 H) 1.27-1, 49 (m, 4 H) 1.58-1.74 (m, 2 H) 1.78-1.87 (m, 2 H) 1.88-1.91 (m, 3 H)
1.92-2.02 (m, 1 H) 2.42-2.54 (m, 1 H) 2.58-2.67 (m, 2 H) 2.68 (s, 3 H) 3, 04-3.14 (m, 2H) 3.15-3.21 (m, 4H) 3.76-3.79 (m, 1H) 3.81 (s, 2H) 3.81-3 .94 (m, 7 H) 4.76-4.83 (m, 1 H) 5.09-5.21 (m, 1 H) 5.45-5.62 (m, 2 H) 6.47 -6.66 (m, 4 H) 242
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(dimethylamino)ethyl]carbamate LCMS (ESI, mass/charge), 576.6 [M+H] 243
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-(dimethylamino)pyrrolidine-1-carboxylate LCMS (ESI, mass/charge), 602.6 [M+H] 1H NMR (400 MHz, METHANOL- d 4) δ ppm 0.94-1.06 (m, 6 H) 1.24-1.47 (m, 2 H) 1.55-1.70 (m, 2 H) 1.72-1.82 (m, 1 H) 1.87 (d, J = 1.13 Hz, 3 H) 1, 91-2.02 (m, 1 H) 2.09-2.21 (m, 1 H) 2.29 (s, 6 H) 2.39-2.52 (m, 1 H) 2.56- 2.68 (m, 2 H) 2.75-2.88 (m, 1 H) 3.10-3.19 (m, 5 H) 3.52-3.71 (m, 2 H) 3, 76-3.88 (m, 5 H) 4.72-4.82 (m, 1 H) 5.09-5.18 (m, 1 H) 5.42-5.60 (m, 2 H) 6.46-6.65 (m, 4 H) 244
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3-(dimethylamino)pyrrolidine-1-carboxylate LCMS (ESI, mass/charge), 602.6 [M+H 1H NMR (400 MHz, METHANOL- d 4) δ ppm 1.00 (dd, J = 18.89, 6.71 Hz, 6 H) 1 .36 (br d, J =19.58 Hz, 2 H) 1.64 (br t, J =3.01 Hz, 2 H) 1.74-1.85
(m, 1 H) 1.87 (d, J =1.25 Hz, 3 H) 1.90-2.02 (m, 1 H) 2.10-2.21 (m, 1 H) 2, 31 (s, 6 H) 2.40-2.51 (m, 1 H) 2.66 (s, 2 H) 2.76-2.94 (m, 1 H) 3.09-3.19 ( m, 5 H) 3.47-3.73 (m, 2 H) 3.75-3.86 (m, 5 H) 5.08-5.18 (m, 1 H) 5.40-5, 60 (m, 2 H) 6.43-6.68 (m, 4 H) 245
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(2-cyanoethyl)-N-methylcarbamate LCMS (ESI, mass/charge), 572.5 [M+H] 1H NMR (400 MHz, METHANOL- d 4) δ ppm 0.98 (d, J =6.78 Hz, 6 H) 1.24- 1.48 (m, 2 H) 1.56-1.73 (m, 2 H) 1.87 (d, J = 1.13 Hz, 3 H) 1.93-2.05
(m, 1 H) 2.42-2.52 (m, 1 H) 2.57-2.68 (m, 2 H) 2.68-2.76 (m, 2 H) 2.94-3 .03 (m, 3 H) 3.10-3.18 (m, 4 H) 3.47-3.65 (m, 2 H) 3.75-3.86 (m, 5 H) 5.10 -5.18 (m, 1 H) 5.45-5.60 (m, 2 H) 6.45-6.66 (m, 4 H) 246
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,3,4-trimethylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 616.6 [M+H] 1H NMR (400 MHz, METHANOL- d 4) δ ppm 0.89-1.09 (m, 11 H) 1.25-1.48 (m, 2 H) 1.56-1.72 (m, 2 H) 1.87 (d, J = 1.25 Hz, 3 H) 1.91-2.05
(m, 1 H) 2.27 (s, 3 H) 2.42-2.53 (m, 1 H) 2.66 (s, 4 H) 3.10-3.18 (m, 4 H) 3.20-3.28 (m, 2 H) 3.41-3.63 (m, 2 H) 3.81 (dd, J =10.54, 5.65 Hz, 5 H) 5.09- 5.20 (m, 1 H) 5.40-5.62 (m, 2 H) 6.44-6.66 (m, 4 H) 247
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-fluoropyrrolidine-1-carboxylate LCMS (ESI, mass/charge), 577.5 [M+H] 1H NMR (400 MHz, METHANOL- d 4) δ ppm 0.93-1.06 (m, 6 H) 1.25-1.49 (m, 2 H) 1.56-1.74 (m, 2 H) 1.87 (d, J =1.00 Hz, 3 H) 1.96 (br s, 3 H)
2.40-2.51 (m, 1 H) 2.43-2.51 (m, 1 H) 2.57-2.65 (m, 2 H) 2.66 (s, 4 H) 3, 10-3.19 (m, 4 H) 3.37-3.51 (m, 1 H) 3.53-3.73 (m, 2 H) 3.76-3.87 (m, 5 H) 5.09-5.34 (m, 1 H) 5.09-5.16 (m, 1 H) 5.15-5.21 (m, 1 H) 5.28-5.34 (m, 1 H) 5.41-5.62 (m, 2 H) 6.43-6.65 (m, 4 H) 248
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(dimethylsulfamoylamino)-5-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 625.5 [M+H] 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.00 (dd,J=14.31, 6.78 Hz, 6 H) 1.25-1.47 (m, 2 H) 1.56-1.72 (m, 2 H) 1.88 (d,J=1.13 Hz, 3 H) 1.93-2.04 (m, 1 H) 2.39 (s, 3 H) 2.44-2.56 (m, 4 H) 2.57-2.64 (m, 2 H) 2, 80 (s, 7 H) 3.42-3.59 (m, 4 H) 3.76-3.88 (m, 1 H) 5.09-5.19 (m, 1 H) 5.49 (s, 3 H) 6.53 (s, 1 H) 6.68-6.76 (m, 1 H) 6.82-6.90 (m, 1 H) 6.90- 6.98 (m, 1H) 249
[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-Fluoro-5-[(2-methoxyacetyl)amino]phenyl]prop-1-en-2-yl ]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 590.6 [M+H] 1H NMR (400 MHz, METHANOL- d 4) δ ppm 1.00 (dd, J =10.67, 6.78 Hz, 6 H) 1.25-1.45 (m, 2 H) 1.57-1.70 (m, 2 H) 1.89 (d, J =1.25 Hz, 3 H) 1.92-2.00 ( m, 1 H) 2.30 (s, 3 H) 2.35-2.43 (m, 4 H) 2.44-2.51 (m, 1 H) 2.58-2.68 (m, 2 H) 3.48 (s, 6 H) 3.79 (s, 1 H) 4.03 (s, 2 H) 5.14 (d, J =10.54 Hz, 1 H) 5.49 ( s, 2 H) 6.55 (s, 1 H) 6.76-6.81 (m, 1 H) 7.33-7.37 (m, 1 H) 7.41-7.47 (m, 1H) 250
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(2-Cyclopropylacetyl)amino]-5-fluorophenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 600.6 [M+H] 1H NMR (400 MHz, METHANOL- d 4) δ ppm 0.21-0.27 (m, 2 H) 0.54-0.61 (m, 2 H) 1.00 (dd, J =10.79, 6.78 Hz, 6 H) 1.12 (s, 1 H) 1.34 (br s, 2 H) 1.57-1 .73 (m, 2 H) 1.89 (d, J =1.25 Hz, 3 H) 1.92-2.01 (m, 1 H) 2.24-2.29 (m, 2 H) 2.30 (s, 3 H) 2.34-2.43 (m, 4 H) 2.43-2.53 (m, 1 H) 2.57-2.69 (m, 2 H) 3, 39-3.58 (m, 4 H) 3.79 (s, 1 H) 5.14 (d, J =10.67 Hz, 1 H) 5.44-5.61 (m, 3 H) 6 .54 (s, 1 H) 6.71-6.80 (m, 1 H) 7.26 (s, 1 H) 7.36-7.45 (m, 1 H) 251
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-[(3-hydroxyphenyl)methyl]piperazine -1-carboxylate LCMS (ESI, mass/charge), 787.7 [M+H] 252
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-Fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(pyridin-3-ylmethyl)piperazin- 1-carboxylate LCMS (ESI, mass/charge), 772.7 [M+H] 253
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-Acetylpiperidin-4-yl)-7-fluorobenzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]piperazine-1-carboxylate LCMS (ESI, mass/charge), 655.8 [M+H]
¹ H NMR (400 MHz, CDCl ₃ ) d ppm 1.03 (br dd, J = 6.78, 4.14 Hz, 12 H) 1.22-1.36 (m, 2 H) 1.45 - 1.67 (m, 3 H) 1.74-1.87 (m, 1 H) 1.88-1.94 (m, 3 H) 1.94-2.00 (m, 1 H) 2, 20 (s, 3 H) 2.22-2.32 (m, 3 H), 2.35-2.54 (m, 2 H) 2.54-2.72 (m, 3 H) 2.72 -2.90 (m, 4 H) 2.91-3.12 (m, 2 H) 3.31-3.48 (m, 5 H) 3.68 -, 3.81 (m, 1 H) 4.04-4.15 (m, 1 H) 4.68-4.80 (m, 1 H) 4.80-4.93 (m, 2 H) 5.26-5.34 (m, 1 H) 5.39-5.49 (m, v1 H) 5.56-5.68 (m, 1 H) 6.65-6.75 (m, 1 H) 6.92-7.04 (m , 1 H) 7.11-7.18 (m, 1 H)

Compounds 254-261 were synthesized according to the general methods of Procedure 36.

Procedure 36

Step 1: To a stirred solution of iodide ( 008 ) (120 mg, 0.225 mmol) and boronate ( 063 ) (63 mg, 0.269 mmol) in 3.4 ml of p-dioxane, add silver oxide (156 mg, 0.674 mmol) and tetrakis( triphenylphosphine)palladium(0) (25.9 mg, 0.022 mmol). The mixture was degassed and heated to 80°C for 60 minutes. After completion of the reaction, as indicated by UPLC, the reaction mixture was cooled to room temperature, filtered and concentrated. Purification by column chromatography using a 0 to 20% MeOH/DCM gradient provided ( 064 ) (59 mg, 51% yield) as a colorless oil. LCMS (ESI, mass/charge), 515.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) d ppm 1.00 (m, 6 H) 1.14-1.36 (m, 2 H) 1.50 (m, 1H) 1.64-1.84 ( m, 1 H) 1.84-1.94 (m, 4 H) 2.29 (s, 3 H) 2.35 (br s, 4 H) 2.45-2.66 (m, 3 H) 3.48 (br s, 4 H) 3.59-3.76 (m, 1 H) 4.69 (s, 2 H) 4.88 (t, J=10.04 Hz, 1 H) 5, 28 (d, J=10.54 Hz, 1 H) 5.40 (dd, J=14.93, 9.66 Hz, 1 H) 5.60 (dd, J=14.93, 9.91 Hz , 1 H) 6.59 (s, 1 H) 7.18-7.35 (m, 4 H).

Stage 2. Into a stirred solution of the compound (064) (59 mg, 0.115 mmol) in 2 ml 1,2-dichloroethane at At 0°C, 4-nitrophenylcarbonyl chloride (27.7 mg, 0.138 mmol), triethylamine (0.083 ml, 0.573 mmol), then N,N-dimethylpyridin-4-amine (2.8 mg, 0.023 mmol) were added. The mixture was stirred at 0°C for 21 hours. Completion was determined by UPLC.

Step 3: To the mixture from the previous step containing ( 065 ) (approximately 7.8 mg, 0.011 mmol) in 200 μl 1,2-dichloroethane, (R)-pyrrolidin-3-ol ( 066 ) (4 mg, 0.046) was added mmol). The resulting mixture was stirred at room temperature. After completion of the reaction, which was indicated by UPLC, the reaction mixture was concentrated. Purification by HPLC gave the title compound of Example 254 (3.4 mg, 49% yield).

Table 22. Description of characteristics of connections 254-261 Etc. Structure and chemical name according to IUPAC Characteristics 254
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-[3-[[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxymethyl]phenyl]prop -1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 628.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) d ppm 0.89-0.90 (m, J=6.78 Hz, 6 H) 1.15-1.35 (m, 3 H) 1.40- 1.52 (m, 2 H) 1.72-1.90 (m, 6 H) 2.11-2.32 (m, 6 H) 2.54-2.59 (m, 4 H) 3, 27-3.36 (m, 1 H) 3.40-3.49 (m, 7 H) 3.62-3.79 (m, 1 H) 4.30-4.35 (m, 1 H) 4.61-4.72 (m, 2H) 4.94-5.09 (m, 3 H) 5.37-5.50 (m, 2 H) 6.5 (s, 1 H) 7.23 -7.30 (m, 3 H) 7.36 (m, 1 H). 255
[3-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12- oxo-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]methyl-2-oxa-7-azaspiro[3.4]octane-7-carboxylate LCMS (ESI, mass/charge), 254.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 0.89 (d, J=6.65 Hz, 6 H) 1.14-1.36 (m, 3 H) 1.40-1.57 (m , 2 H) 1.76-1.87 (m, 4 H) 2.07-2.19 (m, 2 H) 2.19-2.46 (m, 5H) 2.52-2.59 ( m, 4 H) 3.31-3.57 (m, 8 H) 3.71 (m, 1 H) 4.43 (m, 2 H) 4.48-4.55 (m, 2 H) 4 .61-4.73 (m, 2 H) 4.98-5.09 (m, 3 H) 5.37-5.50 (m, 2 H) 6.54 (br s, 1 H) 7. 22-7.29 (m, 3 H) 7.31-7.43 (m, 1 H) 256
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-[2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]pyridin-4 -yl]prop-1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 630.6 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) d ppm 0.89 (d, J=6.65 Hz, 6 H) 1.14-1.36 (m, 2 H) 1.47 (br d, J= 8.78 Hz, 2 H) 1.81 (br s, 4 H) 1.98-2.19 (m, 2 H) 2.19-2.37 (m, 5 H) 2.52-2, 59 (m, 4 H) 3.29-3.59 (m, 9 H) 3.65-3.92 (m, 1 H) 4.60-4.75 (m, 2 H) 5.0 ( m, 1H) 5.08 (s, 2 H) 5.23 (s, 1 H) 5.37-5.49 (m, 2H) 6.55 (s, 1 H) 7.23-7.30 (m, 3 H) 7.32-7.47 (m, 1 H) 257
[3-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12- oxo-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]methylmorpholine-4-carboxylate LCMS (ESI, mass/charge), 628.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 0.89 (d, J=6.78 Hz, 6H) 1.11-1.36 (m, 3 H) 1.37-1.63 (m, 2 H) 1.73-1.89 (m, 4 H) 2.12-2.31 (m, 5 H) 2.52-2.62 (m, 4 H) 3.28-3.47 ( m, 8 H) 3.53-3.56 (m, 4H), 3.65-3.81 (m, 1 H) 4.58-4.76 (m, 2 H) 4.97-5, 06 (m, 1 H) 5.09 (s, 2 H) 5.33-5.53 (m, 2 H) 6.47-6.58 (m, 1 H) 7.20-7.31 ( m, 3 H) 7.33-7.46 (m, 1 H). 258
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(Dimethylcarbamoyloxymethyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 586.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 0.89 (d, J=6.78 Hz, 6 H) 1.11-1.37 (m, 3 H) 1.40-1.57 (m , 2 H) 1.82 (s, 4 H) 2.23 (m, 5 H) 2.54-2.58 (m, 4 H) 2.85 (m, 6 H) 3.38-3, 49 (m, 4 H) 3.64-3.77 (m, 1 H) 4.59-4.75 (m, 2 H) 5.05 (s, 3 H) 5.34-5.53 ( m, 2 H) 6.49-6.59 (m, 1 H) 7.20-7.30 (m, 3 H) 7.30-7.44 (m, 1 H). 259
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-[3-[[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxymethyl] phenyl]prop-1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 642.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 0.89 (d, J=6.78 Hz, 6 H) 1.14-1.36 (m, 3 H) 1.37-1.52 (m , 2 H) 1.73-1.87 (m, 9 H) 2.20-2.46 (m, 5 H) 2.52-2.61 (m, 4 H) 3.25-3.53 (m, 4 H) 3.52 (m, 2H) 3.63-3.82 (m, 3 H) 4.61-4.73 (m, 2 H) 4.73-4.83 (m, 1 H) 5.05 (s, 3 H) 5.30-5.58 (m, 2 H) 6.42-6.59 (m, 1 H) 7.25 (s, 3 H) 7.31 -7.44 (m, 1 H) 260
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[[(3R)-3-Fluoropyrrolidine-1-carbonyl]oxymethyl]phenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 630.6 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d6) d ppm 0.89 (d, J=6.65 Hz, 6 H) 1.14-1.36 (m, 2 H) 1.47 (br d, J= 8.78 Hz, 2 H) 1.81 (br s, 4 H) 1.98-2.19 (m, 2 H) 2.19-2.37 (m, 5 H) 2.52-2, 59 (m, 4 H) 3.29-3.59 (m, 9 H) 3.65-3.92 (m, 1 H) 4.60-4.75 (m, 2 H) 5.0 ( m, 1H) 5.08 (s, 2 H) 5.23 (s, 1 H) 5.37-5.49 (m, 2H) 6.55 (s, 1 H) 7.23-7.30 (m, 3 H) 7.32-7.47 (m, 1 H). 261
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-[3-[(4-hydroxypiperidin-1-carbonyl)oxymethyl]phenyl]prop-1-ene -2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate LCMS (ESI, mass/charge), 642.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 0.89 (d, J=6.65 Hz, 6 H) 1.13-1.38 (m, 2 H) 1.40-1.57 (m , 1 H) 1.62-1.75 (m, 2 H) 1.78-1.88 (m, 4 H) 2.23-2.46 (m, 5 H) 2.52-2.60 (m, 4 H) 2.91-3.17 (m, 4 H) 3.24-3.45 (m, 4 H) 3.56-3.83 (m, 3 H) 4.56-4 .73 (m, 3 H) 4.78 (d, J=4.02 Hz, 2 H) 4.92-5.15 (m, 3 H) 5.43 (m, 3 H) 6.53 ( s, 1 H) 7.18-7.27 (m, 3 H) 7.30-7.42 (m, 1 H).

Compounds 262 and 263 were synthesized according to the general methods from Procedures 37 and 38.

Procedure 37

Step 1: A solution of DMAP (140 mg, 1.148 mmol), N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (246 mg, 1.148 mmol) and triethylamine (0.667 mL, 4.878 mmol) in 9 mL diethyl ether was stirred within 60 min. at room temperature. To this mixture was added iodide ( 005 ) (500 mg, 0.957 mmol) as a solution in 3 ml of diethyl ether (dropwise over 2 minutes) and stirred at room temperature for 7 hours. After this, 1,4'- bipiperidine ( 066 ) (725 mg, 4.306 mmol) and the mixture was stirred for 19 hours. The mixture was diluted with heptane/MTBE 10:1 and the organic layers were washed several times with saturated sodium bicarbonate/1 M NaOH 1:1. The organic layers were then washed with brine and concentrated. The crude product was purified by MeOH/EtOAc flash silica gel chromatography to isolate compound ( 067 ) (600 mg, 87%). 1H NMR (400 MHz, CDCl ₃ ) d ppm 0.88 (d, J=3.76 Hz, 6 H) 1.68-1.74 (m, 12 H) 1.78 (d, J=6, 78 Hz, 3 H) 2.03 (m, 1H) 2.18-2.42 (m, 12 H) 2.61 (s, 6 H) 3.13-3.35 (m, 8 H) 3 .47-3.62 (m, 2 H) 4.64-4.71 (m, 1 H) 5.01 (m, 1 H) 5.60 (t, J=9.72 Hz, 1 H) 5.90 (d, J=10.67 Hz, 1 H) 6.15-6.33 (m, 2 H) 8.08 (s, 1 H).

Step 2: To a solution of bipiperidine ( 067 ) (600 mg, 0.837 mmol) in 6 ml of methanol, 4-methylbenzenesulfonic acid hydrate (478 mg, 2.51 mmol) was added and stirred for 2 hours. Excess triethylamine was then added and concentrated. Dilute with ethyl acetate, wash with saturated sodium bicarbonate solution, then with saline. The organic layers were dried with sodium sulfate, filtered and concentrated. The crude mixture was purified by flash silica gel chromatography to give compound ( 068 ) (456 mg, 90%). LCMS (ESI, mass/charge), 603.4 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) d ppm 0.90 (d, J=6.65 Hz, 3 H) 0.98 (d, J=6.90 Hz, 3 H) 1.12-1.30 (m, 2 H) 1.34-1.50 (m, 4 H) 1.57 (m, 4 H) 1.74-1.85 (m, 6 H) 1.90 (m, 1 H) 1.99 (s, 1 H) 2.35-2.54 (m, 6 H) 2.57-2.76 (m, 3 H) 3.48 (s, 1 H) 3.71 (br dd , J=6.53, 3.26 Hz, 1 H) 4.16 (br d, J=11.04 Hz, 2 H) 4.83 (t, J=10.04 Hz, 1 H) 5, 25-5.40 (m, 2 H) 5.47-5.55 (m, 1 H) 6.47 (d, J=1.00 Hz, 1 H) 7.26 (s, 1 H).

Step 3: The compound of Example 262 was synthesized according to the procedure described in Procedure 5 by replacing dipiperidine ( 068 ) and 4-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)phenyl)morpholine to prepare the title compound of Example 262 . LCMS (ESI, mass/charge), 656.6 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) d ppm 0.99 (m, 6 H) 1.18-1.31 (m, 3 H) 1.36-1.56 (m, 4 H) 1.59 ( br s, 4 H) 1.82 (m, 4H) 1.86 (s, 3H) 1.91 (m, 1 H) 2.41 (m, 1 H) 2.47-2.65 (m, 6 H) 2.72 (m, 2H) 3.12-3.17 (m, 4 H) 3.37 (br s, 1 H) 3.72 (br s, 1 H) 3.82-3, 87 (m, 4 H) 4.09-4.26 (m, 2 H) 4.86 (t, J=10.04 Hz, 1 H) 5.23-5.26 (m, 1 H) 5 .39 (dd, J=15.06, 9.66 Hz, 1 H) 5.58 (dd, J=14.93, 9.91 Hz, 1 H) 6.45-6.53 (m, 4 H).

Procedure 38

Step 1: The compound was synthesized according to the procedure described in Procedure 5 by replacing dipiperidine ( 068 ) and boronate ( 069 ) (38.7 mg, 0.10 mmol) with dipiperidine ( 070 ). LCMS (ESI, mass/charge), 738.5 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) d ppm 0.99 (t, J=6.27 Hz, 6 H) 1.15-1.36 (m, 2 H) 1.39-1.56 (m, 13 H) 1.64 (br s, 4 H) 1.74-1.95 (m, 7 H) 2.17 (s, 1 H) 2.46-2.66 (m, 8 H) 2.73 (br t, J=12.11 Hz, 2 H) 3.04-3.20 (m, 4 H) 3.53-3.61 (m, 4 H) 3.72 (br s, 1 H) 4.12-4.32 (m, 2 H) 4.87 (t, J=10.04 Hz, 1 H) 5.27 (d, J=10.54 Hz, 1 H) 5.39 (dd , J=14.93, 9.66 Hz, 1 H) 5.59 (dd, J=15.00, 9.98 Hz, 1 H) 6.55 (s, 1 H) 6.78-6, 83 (m, 3 H) 7.21-7.27 (m, 2 H).

Stage 2.In a stirred solution of dipiperidine (070) (19 mg, 0.026 mmol) (example 8, step b) in 7.7 ml DCM at At 0°C, TFA (40 μL, 0.516 mmol) was added. The mixture was warmed to room temperature and stirred for 2 days. The reaction mixture was then diluted in DCM, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on a C-18 acetonitrile/water gradient column to give compound (071) (11 mg, 67%). LCMS (ESI, mass/charge), 328.9 [(M+Na+H)/2]+.

Step 3: To a stirred solution of dipiperidine ( 071 ) (11 mg, 0.017 mmol) in 0.2 ml DCM, add 2-bromoethanol ( 072 ) (2.45 µl, 0.035 mmol) and triethylamine (9.6 µl, 0.069 mmol) . The mixture was stirred until the reaction was complete, which was indicated by LC/MS. The reaction mixture was then diluted in DCM, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash silica gel chromatography to give the title compound of Example 263 (8.4 mg, 71%).

Table 23. Description of characteristics of connections 262-263 Etc. Structure and chemical name according to IUPAC Characteristics 262
[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-Fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- Hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate LCMS (ESI, mass/charge), 656.6 [M+H]+. 1H NMR (400 MHz, CDCl ₃ ) d ppm 0.99 (m, 6 H) 1.18-1.31 (m, 3 H) 1.36-1.56 (m, 4 H) 1.59 ( br s, 4 H) 1.82 (m, 4H) 1.86 (s, 3H) 1.91 (m, 1 H) 2.41 (m, 1 H) 2.47-2.65 (m, 6 H) 2.72 (m, 2H) 3.12-3.17 (m, 4 H) 3.37 (br s, 1 H) 3.72 (br s, 1 H) 3.82-3, 87 (m, 4 H) 4.09-4.26 (m, 2 H) 4.86 (t, J=10.04 Hz, 1 H) 5.23-5.26 (m, 1 H) 5 .39 (dd, J=15.06, 9.66 Hz, 1 H) 5.58 (dd, J=14.93, 9.91 Hz, 1 H) 6.45-6.53 (m, 4 H) 263
[(2S,3S,4E,6R,7S,10R)-10-Hydroxy-2-[(E)-1-[3-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate LCMS (ESI, mass/charge), 681.6 [M+H]+. 1H NMR (400 MHz, METHANOL-d4) d ppm 1.00 (m, 6 H) 1.23-1.51 (m, 3 H) 1.52-1.61 (m, 2 H) 1.65 (br s, 4 H) 1.70 (br s, 1 H) 1.80-2.02 (m, 9 H) 2.06-2.16 (m, 3 H) 2.47 (dd, J= 13.99, 5.33 Hz, 1 H) 2.54-2.72 (m, 2 H) 2.76-2.90 (m, 4 H) 2.90-3.00 (m, 4 H ) 3.06-3.23 (m, 4 H) 3.23-3.28 (m, 4 H) 3.79 (br t, J=5.52 Hz, 3 H) 4.29 (m, 2 H) 5.15 (d, J=10.54 Hz, 1 H) 5.44-5.60 (m, 2 H) 6.57 (s, 1 H) 6.80-6.93 (m , 3 H) 7.24 (t, J=7.91 Hz, 1 H)

BIOLOGICAL METHODS AND MATERIALS

Scintillation Proximity Analysis (SPA) with a probe based on [ ³ H]-labeled pladienolide

Immobilization of a portion of anti-SF3B1 antibodies (MBL) onto anti-mouse Ig-coated scintillation beads from PVT for SPA analysis (PerkinElmer) was carried out as follows: for each 2.5 mg of nuclear extracts, 5 µg of anti-SF3B1 antibody and 1.5 mg of beads were mixed in 150 µl PBS. The antibody-bead mixture was incubated for 30 min. at room temperature and centrifuged at 18,000g within 5 min. 150 μl of PBS was used to resuspend each 1.5 mg of antibody-bead mixture. The beads were suspended and added to the resulting nuclear extracts. The suspension was incubated for 2 hours at 4°C with gentle mixing. The granules were then collected by centrifugation at 18,000g within 5 min. and washed twice with PBS+0.1% Triton X-100. After the final centrifugation step, every 1.5 mg of beads was suspended with 150 μl of PBS. SF3b complexes were tested for binding to a probe based on [³H]-labeled pladienolide ([³H]-PB), synthesized as described previously (Kotakeet al., 2007). 100 μl binding reaction mixtures were prepared using 50 μl bead slurry and by adding different concentrations of PB or PB-OH, and after 30 min. pre-incubation, 2.5 nM was added [³H]-PB. The mixture was incubated for 30 minutes. and luminescence signals were read using a MicroBeta2 plate counter (PerkinElmer). Prism 6 (Graphpad) was used to fit the data to a nonlinear regression curve.

a.

b. Preparation of HeLa cell nuclear extract (for in vitro splicing modulation assay below)

c. Pellets containing HeLa S3 cells were resuspended in hypotonic buffer (10 mM HEPES, pH 7.9, 1.5 mM MgCl ₂ , 10 mM KCl, 0.2 mM PMSF and 0.5 mM DTT) and the suspension was adjusted to a total of 5 Pelleted cell volumes (PCV). After centrifugation, the supernatant was discarded and the cells were adjusted to 3 PCV with hypotonic buffer and incubated on ice for 10 minutes. Cells were lysed using a Dounce homogenizer and then centrifuged. The supernatant was discarded and the pellet was resuspended with ½ volume of pelleted nuclei (PNV) low-salt buffer (20 mM HEPES, pH 7.9, 1.5 mM MgCl ₂ , 20 mM KCl, 0.2 mM EDTA, 25% glycerol, 0.2 mM PMSF, 0.5 mM DTT), then ½ PNV high salt buffer (same as low salt buffer except 1.4 M KCl was used). The nuclei were mixed gently for 30 minutes before centrifugation. The supernatant (nuclear extract) was then dialyzed into storage buffer (20 mM HEPES, pH 7.9, 100 mM KCl, 0.2 mM EDTA, 20% glycerol, 0.2 mM PMSF, 0.5 mM DTT). Protein concentration was determined using a NanoDrop 8000 UV-Vis spectrophotometer (ThermoFisher Scientific).

d. In vitro splicing assay (IVS)

All sequences derived from Ad2 (Pellizzoniet al., 1998) were cloned into the pcDNA3.1(+) vector (Promega) using restriction sites at the 5' end for EcoRI and at the 3' end for XbaI. Plasmids were linearized using XbaI and used as DNA templates in transcription reactionsin vitro. The intronless plasmid FtzΔi (Luo and Reed, 1999) was linearized using EcoRI. All RNA was transcribedin vitro and then cleared using MEGAScript T7 (Invitrogen) and MegaClear (Invitrogen) kits, respectively. For splicing reactions using Ad2 pre-mRNA variants, 1 μl reaction mixture was prepared using 8 μg of nuclear extracts obtained from HeLa S3 cells, 2 ng pre-mRNA, 0.2 ng FTZΔi, and various concentrations of exemplary payloads or DMSO. After a 15-min pre-incubation at 30°C, 1 μl of splicing activation buffer (0.5 mM ATP, 20 mM creatine phosphate, 1.6 mM MgCl) was added₂) and the reaction mixtures were incubated for 90 minutes at 30°C. Reaction mixtures were then quenched with 13 μL DMSO, and 25 nL were used for RT-qPCR. RT-qPCR reactions were prepared using the TaqMan RNA-to-C 1-step kit_T (Life Technologies), RNA from splicing reactions, primer-probe sets for Ad2 mRNA (forward: ACTCTCTTCCGCATCGCTGT; reverse: CCGACGGGTTTCCGATCCAA; probe: CTGTTGGGCTCGCGGTTG) and Ftz (forward: TGGCATCAGATTGCAAAGAC; reverse: ACGCCGGGTGATGTATCTAT; probe: CGAAACGCACCCGTCAGACG). Prism 6 (Graphpad) was used to fit the spliced product data to a nonlinear regression curve and normalized to a control sample (DMSO).

Cell lines

Panc 10.05 (CRL-2547), Panc 05.04 (CRL-2557), NCI-H1568 (CRL-5876), and NCI-H1650 (CRL-5883) cells were purchased from ATCC. Cell lines were maintained in RPMI-1640 (ATCC 30-2001) supplemented with 10% fetal bovine serum (FBS). Panc cell lines were further supplemented with insulin and FBS to a total content of 15%.

Panc 10.05 cells contain WT SF3b, while Panc 05.04 cells contain the K700E mutation in SF3b and exhibit differential sensitivity to SF3b modulators.

NCI-H1568 cells express MCL1 at high levels and undergo apoptosis when treated with an SF3b modulator, whereas NCI-H1650 are MCL1 independent and therefore insensitive to SF3b modulator treatment, showing only cytostasis and not death (Aird et al. , ( 2015). Abstract C8: Targeting MCL1-dependent cancers with SF3B splicing modulators. Molecular Cancer Therapeutics. 14. C8-C8. 10.1158/1535-7163.TARG-15-C8.).

Obtaining compounds and presenting them to cells

Compounds to be analyzed were prepared as stock solutions in 90% dimethyl sulfoxide (DMSO), the purity of which was assessed by LC/MS, and serial dilutions were made in DMSO using a small volume liquid manipulator (VIAFLO ASSIST and a VIAFLO II electronic 16-channel pipette, 0 .5-12.5 µl) at semi-log serial dilutions for 11 points to provide the source for the main dose response (MDR) study used in all tests.

Transfer of compounds from the MDR source plate to cell-ready plates was accomplished directly using low-energy acoustic transfer (ATS100, EDC Biosystems). Once compounds were transferred to the assay plate, the concentration range for dose response studies on cells was typically 10 µM-100 pM (5 log) and the final concentration of DMSO in the assay was consistently 0.1%. Each assay plate had its own cutoff points as it contained vehicle/DMSO as negative controls, vehicle only as positive controls, and a cytotoxic control to examine the dose-dependent effect of bortezomib and staurosporine. Plates ready for analysis were sealed and stored for no more than one month at -20°C before use.

On the day of the assay, cells were harvested, diluted from 37,500 to 25,000 cells per mL, and then 50 μL (750 to 500 cells) were dispensed onto assay-ready plates using a bulk liquid reagent dispenser (using a Multidrop™ Combi reagent dispenser , Thermo Scientific). The DMSO plate was read, which corresponded to time zero (T0), and then all other plates were incubated at 37°C with 5% CO ₂ and 95% relative humidity until the end of the assay. Cell proliferation and viability assays were performed 72 hours after treatment based on cell growth and at least one doubling in number must have occurred.

Measurement of antiproliferative activity of treated cells

Viability and proliferation were assessed by measuring cell ATP using CellTiter-Glo® Luminescent Cell Viability Assay Technical Bulletin Instructions for Use of Product(s) (Promega) according to the manufacturer's instructions. G7570, G7571, G7572, G7573 Literature No. TB288, Revised 3/15) using a microtiter plate reader (Envision, PE).

Cell proliferation was assessed using the signal at time zero (T0) as a positive control and wells with carrier medium within the plate (DMSO) as a negative control. Data were converted to percent inhibition and presented as a range from -100% to 100% growth, with -100% indicating cytotoxic effect and 100% indicating uninhibited or maximal growth. Cell growth at or near 0% is considered a steady-state response.

1. Results

Table 24. Results of biological tests Etc. SPA-ATS,
geometric mean
IC50 (nM)
for SF3B1 (WT) qPCR-IVS-ATS,
geometric mean
IC50 (nM)
for Ad2.1 qPCR-IVS-ATS,
geometric mean
IC50 (nM)
for Ad2.2 Ad2.1/2.2 ratio CTGlo-ATS,
geometric mean
GI50 (nM),
72 hours
PANC0504.1 CTGlo-ATS,
average value
minimum answer, %
72 hours
PANC0504.1 CTGlo-ATS,
geometric mean
GI50 (nM),
72 hours
NCIH1568.1 CTGlo-ATS,
average value
minimum answer, %
72 hours
NCIH1568.1 1 19,803 28,938 18,709 1,547 54,801 -79.550 61,245 -71.582 2 14,700 29,282 24,750 1.183 30,291 -76.626 40,606 -70.665 3 1,744 18,620 10,306 1,807 2.955 -87.809 2.423 -78.460 4 3,796 >25000,000 58,659 426.192 26,904 -27.423 15,481 -46.416 5 6,607 1499.846 94,734 15,832 47.221 -17.631 59,671 -38.293 6 8,853 >25000,000 75,297 332,020 15,693 -88.664 29,143 -17.149 7 2.885 1247.783 25.138 49,637 8,957 -89.436 15,136 -56.359 8 14172.621 42,184 335,973 19,268 -94.207 9 14,917 106,832 26,999 3.957 63,852 -87.085 116.290 -83.308 10 18,088 811.844 39,511 20,547 73,839 -87.077 123.385 -69,020 eleven 9,490 >25000,000 93,381 267,720 54.219 -91.789 84,398 -43.979 12 4,879 14,745 13,542 1,089 7,551 -73.954 3.638 -92.161 13 7,427 19,311 15,877 1.216 32,728 -94,040 20,826 -95.312 14 2,717 584.420 54,679 10,688 19,581 -91.489 14,050 -65.049 15 6,330 21,602 12,286 1.758 6,231 -80.816 7,581 -74.931 16 57,019 100.255 39,239 2.555 41,517 -85.810 59.115 -88.977 17 10,673 46,759 34,009 1.375 57,794 -72.749 53,407 -87.647 18 16,748 77,450 34,312 2,257 19,945 -83.683 26,089 -60.339 19 60,256 353,840 82,303 4,299 40,549 -82.122 67,494 -65.760 20 7,757 61,280 40,259 1.522 14,578 -78.467 17,600 -68.668 21 10.335 1612.616 52.275 30,849 23,638 -90.919 31,212 -50.841 22 5,764 876.293 38,831 22,567 11,553 -84.195 12,792 -69.453 23 4.231 369.160 28,305 13,042 10,429 -90.781 10,847 -64.974 24 5,186 192,475 30,664 6,277 8,286 -89.895 10,866 -67.459 25 4,943 430,092 46,405 9,268 20,469 -88.378 20,618 -49.158 26 11,379 107.167 43,532 2,462 18,968 -88.278 26,479 -68.566 27 10,473 39,853 42,297 0.942 11,911 -84.822 12,297 -71.773 28 10,051 8,549 61,513 0.139 42,924 -41.132 89,619 -39.539 29 5,601 >25000,000 90,701 275.631 34,668 -90.429 53,788 -19.404 thirty 19,063 10,990 1,734 7,020 -75.997 5,890 -78.664 31 43,243 50.141 14,624 3.429 53,037 -90.716 89,383 -98.108 32 3.243 19,498 16,198 1.204 6,528 -69.289 10,016 -74.701 33 5,583 28,419 27,607 1.029 10,030 -77.334 11,999 -73.122 34 3,180 56,541 26,903 2.102 14,046 -85.656 9,461 -55.438 35 4,783 913.307 27,076 33,732 53,186 -87.702 106,908 -46.227 36 3,488 236.343 32,930 7,177 19,014 -84.494 25,362 -54.389 37 2,267 85,797 20,173 4.253 4,612 -86.134 4,748 -82.247 38 3,095 1022.501 25,191 40,589 14,409 -88.672 19,555 -54.093 39 25,961 63,120 31,983 1,974 50,069 -89.747 45,607 -97.412 40 3,984 55,865 28,124 1,986 7,751 -82.881 13,254 -72.259 41 8,256 221.329 39,233 5,641 15,842 -82.009 21,437 -77.375 42 2,924 330.409 12,646 26.129 4,757 -86.319 6,130 -63,030 43 11,951 >25000,000 139.415 179.321 57,498 -88.777 89,062 -36.254 44 8,263 12765.261 86,608 147,392 41,465 -92.314 67,162 -14.871 45 15,877 36,326 18,285 1,987 35,719 -92.006 18,874 -98.435 46 12,199 >25000,000 114,487 218.366 40,026 0.031 78,415 -10.684 47 16947.874 79,628 212,839 78,160 -87.783 66,450 -44.494 48 11,279 >25000,000 187,531 133.311 95.203 -89.415 121,439 -38.837 49 3,039 16254.945 28,331 573,757 9.015 -93.022 11,720 -35.275 50 1.463 17856.646 60.163 296,807 28,290 -82.642 43,578 -65.255 51 19,740 >25000,000 88,061 283,894 80,862 -78.388 111,651 -31.962 52 8,296 39,595 45,397 0.872 13,573 -76.609 23,254 -63.079 53 14.104 1905.683 30,477 62,529 81,130 -92.947 81,762 -59.250 54 4,286 12,450 15,804 0.788 8,658 -94.487 7,806 -96.584 55 2,370 19926.430 45,284 440,028 17,209 -85.478 21,239 -57.557 56 1.937 16,055 15,295 1,050 1,849 -90.320 4.423 -67.625 57 9,161 >25000,000 228.152 109,576 49,719 -71.380 41,349 -47.783 58 6,544 30.122 22,020 1,368 6,969 -91.132 6,998 -70.067 59 2,750 13563.090 46.122 294,071 17,527 -95.512 14,534 -44.526 60 2,987 >25000,000 55,461 450,767 26,744 -87.159 29,909 -42.456 61 13,472 >25000,000 114,387 218,556 41,974 -93.599 46,822 -38.996 62 7,865 586,891 52,933 11,088 40,541 -94.536 54,936 -57.446 63 12,307 18789.671 52,047 361,016 41,172 -96.440 39,304 -50.769 64 3,081 116,017 24.425 4,750 7,959 -92,050 6,499 -66.274 65 2.835 26,222 17,310 1.515 5,742 -88.951 5,878 -68.297 66 2.233 206,385 33,895 6,089 8,224 -89.623 11,718 -64.699 67 1.955 22,653 20,232 1.120 7,272 -87.661 8,603 -75.182 68 3,393 1866.932 35,703 52,291 11,676 -93.925 12,401 -67.270 69 3,830 36,743 20,881 1,760 7,480 -86.274 4.035 -76.018 70 1,550 17,647 16,459 1,072 5,944 -83.969 3.371 -77.042 71 3,713 29,685 18,942 1,567 11,503 -68.599 6,391 -92.527 72 4.659 35,841 13,972 2.565 5,683 -75.581 4,189 -80.730 73 2.423 13,107 13,586 0.965 6,908 -79.201 5,850 -76.720 74 4,880 34,483 20,848 1.654 13,134 -64.747 4,694 -99.528 75 2,154 18,981 15,420 1.231 3,693 -81.995 3,579 -85.064 76 4,197 21,475 17,666 1.216 5,166 -90.504 3,021 -77.948 77 1,784 16.111 13,305 1.211 3,903 -86.524 1,786 -82.189 78 1,760 24,338 13,783 1,766 7,332 -93.916 2,498 -74.454 79 2.139 17,991 12,323 1,460 4,013 -72.802 80 1,590 6,641 8,572 0.775 2.681 -69.196 81 2,591 9,069 4.952 1.831 2,176 -83.963 82 3.795 68,613 28,180 2.435 8,738 -88,044 12,243 -60.656 83 4,567 159,090 49,023 3.245 15,634 -94.723 17,288 -68.447 84 2,749 29,576 22.131 1.336 5,608 -89.010 4,299 -80.428 85 4.735 21,984 27,018 0.814 8,418 -90.914 14.112 -80.438 86 12,173 929.495 89,619 10,372 34,772 -93.814 32,453 -39.164 87 4,984 62,738 26,981 2.325 4,193 -79.550 3.679 -85.463 88 1.021 >25000,000 154,434 161,881 86.265 -5.029 156,578 -20.194 89 3,246 24720.040 95,397 259.128 109,364 -16.694 218,842 -22.815 90 >25000,000 168,183 148,647 141,083 -12.315 106,927 -8.495 91 6,036 14,666 18,860 0.778 4.639 -90.776 6,857 -64.491 92 80,020 >25000,000 664.298 37,634 433.353 -37.359 401,466 -3.918 93 24,701 219.281 41,634 5,267 108,516 -97.726 73,797 -57.108 94 7,481 5565.342 37,521 148,326 30,367 -94.671 35,506 -40.948 95 2,317 10,347 10,014 1.033 2,586 -93.120 2,513 -73.174 96 2.405 >25000,000 108.152 231.155 167,999 -14.554 304,650 -29.687 97 240.267 >25000,000 2894.085 8,638 9144.823 46,987 4369.614 11,801 98 3,447 159,084 35,908 4,430 10,333 -87.759 11,545 -75.954 99 4.138 >25000,000 156,062 160,193 77,983 -69.788 93.243 -73.818 100 1.131 32.113 10,860 2.957 2,888 -91.579 3,696 -68.437 101 1,097 1809.361 4,130 438.113 9,778 -94.474 7,680 -64.073 102 29,757 >25000,000 506,758 49,333 3023.428 24,371 4903.112 31,099 103 258.210 >25000,000 4256.594 5.873 >10000,000 80,958 >10000,000 78,168 104 2.104 31,908 13,892 2,297 4,579 -86.795 5,100 -69,040 105 2,867 68,782 21,791 3.156 5.852 -90.949 6,952 -68.464 106 145,787 21316.281 555.636 38,364 1946,074 25,144 9024.448 49,516 107 8,762 189,979 25,441 7,467 8,464 -83.679 7,274 -87.564 108 2,031 16,802 14,335 1.172 3.313 -82.618 2,470 -79.118 109 2,847 26,481 13,998 1,892 3,546 -84.673 2,001 -84.780 110 42,069 141,880 63,236 2,244 41,768 -74.667 40,946 -93.755 111 27,997 69,785 27,292 2,557 13,896 -71.803 12,823 -81.303 112 12,794 36,638 24.108 1,520 8,289 -80.066 6,234 -86.973 113 8,195 29,264 18,814 1.555 48,965 -80.966 41,765 -73.107 114 18,232 103.149 39.101 2.638 12,323 -82.856 9,346 -87.102 115 144,378 335,063 233,242 1.437 85.228 -97.417 88,916 -93.625 116 4,448 24,986 19,171 1.303 2,203 -76.511 1,547 -90.483 117 9,759 >25000,000 69,572 359.342 50.241 -95.049 79,845 -55.709 118 3.756 21,956 19,869 1.105 4,547 -79.169 3,004 -82.113 119 11,656 31,021 21,652 1.433 8,431 -75.344 8,838 -81.451 120 3,971 25,336 26,526 0.955 9,424 -78,098 11,196 -75.164 121 2,994 25,480 21,964 1,160 3,729 -88.956 2.656 -80.331 122 5.505 18,838 14,314 1.316 2,097 -70.057 1.995 -85.128 123 1,697 16,462 13,079 1.259 2.753 -71.328 2,263 -86.056 124 3,444 12,855 9.437 1,362 5,982 -86.148 3,264 -78.963 125 5.058 17,638 14,945 1,180 6,759 -83.226 4,508 -83.586 126 127 19,133 >25000,000 452.324 55,270 1071.042 11,995 835.105 -18.734 128 8,763 3350.427 18,070 185.417 44.222 -96.227 25,733 -62.651 129 4,376 31,998 15,613 2,049 11,278 -94.183 4,734 -70.909 130 37,142 43,909 30,032 1.462 18,296 -93.452 11,962 -72.458 131 4,040 356.631 45,767 7,792 27,067 -94.995 19,218 -65.430 132 4,913 34.109 12,752 2.675 13,574 -94.673 11,510 -68.423 133 6,986 1671.083 92,470 18,072 25,554 -94.957 17,704 -69.167 134 2.055 26,469 13,270 1.995 4.113 -92.570 3,920 -79.743 135 3.672 14,929 14,858 1.005 2,463 -90.575 2,411 -84.225 136 8,107 8,637 14,479 0.597 7,168 -90.722 137 1,209 27,636 12,146 2.275 1.615 -86.584 1.174 -81.149 138 8,696 >25000,000 57,468 435,028 120.328 -85.916 70,303 -80.330 139 4,318 >25000,000 93.194 268.259 240.142 -21.195 142,072 -61.022 140 1.728 11,563 11,755 0.984 1.631 -80.398 1.251 -82.434 141 12,956 >25000,000 61,283 407,944 72,446 -94.865 48,767 -63.745 142 1,348 12,904 6,986 1.847 2,189 -69.213 143 3,200 19,245 17,177 1.120 3.675 -87.719 1.751 -84.803 144 12,945 22,998 17,838 1,289 4.117 -95.432 145 69,448 688.137 38,070 18,076 24,952 -66.236 146 22,736 11,142 12,673 0.879 2,795 -88.975 147 7,302 9,573 7,431 1,288 1,560 -91.884 148 2,243 12,371 3,566 3,469 1,420 -85.010 149 1.863 9.132 8,715 1,048 1.663 -73.106 150 1.316 8,579 10,968 0.782 2,187 -68,000 151 3,409 17,913 11,423 1,568 2.239 -83.213 152 3.835 16,214 8,392 1.932 1,511 -80.509 153 4,830 14,527 14,848 0.978 2.338 -81.206 154 3.752 20,021 8,724 2,295 1.852 -85.459 155 2,214 8,445 5.877 1.437 1,905 -83.475 156 3,949 8,369 7,912 1.058 1.267 -87.369 157 2,266 8,466 7,491 1.130 1,288 -90.424 158 13,917 18,895 18,193 1.039 6,574 -87.167 159 1.839 88,302 10,196 8,660 3,446 -65.047 160 1,648 4.681 4,688 0.999 1.147 -82.399 0.896 -86.403 161 2,507 8,501 6,311 1,347 0.772 -85.783 162 1.077 9,290 7,400 1.255 1.471 -75.943 163 164 3,594 20,692 27,869 0.742 1.539 -87.159 165 18,724 29,539 15,222 1,941 10,028 -78.159 166 23,795 1509.545 48,288 31,261 17,605 -66.370 167 3,189 >25000,000 46,455 538.154 34,052 -85.316 52,392 -70.414 168 3,049 27,565 16,451 1.676 10,386 -86.930 5,963 -75.760 169 1.429 96,624 19,836 4,871 8,899 -90.232 8,264 -66,086 170 4.926 10988.155 30,980 354,686 23,187 -96.570 25,872 -56.895 171 1,509 18827.426 42,614 441.815 23,552 -92.998 19,645 -50.083 172 5,584 22,596 15,368 1,470 17,920 -88.455 8,722 -74.177 173 20,954 88,062 28,433 3,097 15,154 -79.437 174 3,144 13,142 10,739 1.224 6.035 -80.529 3.858 -92.525 175 5.827 9,503 8.125 1,170 9,488 -99.134 176 38,494 49,735 31,244 1,592 19,031 -88.183 177 2,380 18,243 10,348 1,763 3.618 -80.643 178 2,159 20,409 4,309 4,736 6,847 -77.714 179 6,147 31,411 14,211 2,210 8,698 -82.684 180 42,275 29,896 24,606 1.215 14,432 -86.471 181 8,204 19,659 19,152 1.026 9,736 -85.226 182 86,414 207,933 40,096 5,186 23,384 -69.521 183 66,316 713.164 20,288 35,151 53,565 -66.270 184 14,417 18.135 11,589 1.565 59,779 -85.535 185 186,395 542,957 46,594 11,653 114,397 -99.538 186 12,625 41,845 17,450 2,398 14,473 -70.969 187 43,164 157.172 59,645 2.635 65,000 -54.197 188 2,610 7,414 5.626 1.318 2,767 -79.922 189 6,800 16,928 10,256 1.651 9,532 -76.052 190 6,547 33,521 15,729 2.131 19,847 -69.142 191 3.472 11,620 7,474 1.555 6,329 -83.895 192 3,846 14,134 10,277 1.375 7,490 -75,900 193 126,764 47,796 19,577 2,441 17,220 -89.438 194 10,679 30.128 25,852 1.165 6,729 -75.631 195 69,302 91,936 58,257 1.578 6,595 -95.559 196 13,226 29,980 19,611 1.529 1.829 -90.418 197 2.665 98,532 22,818 4,318 3.526 -91,100 4,693 -69.290 198 7.815 2386.120 43,208 55.224 21,688 -96.773 15,506 -56.095 199 8,992 1822.689 47.173 38,638 33,778 -95.445 22,936 -52.026 200 8,028 8049.493 27,048 297,600 17,434 -94.085 24.228 -51.281 201 5,641 619,579 17,460 35,485 40,947 -91.697 27,494 -48.055 202 14,089 4467.112 25,183 177,387 24,666 -93.824 29,369 -59,083 203 10,093 14444.856 69,732 207.149 44,957 -94.627 47,257 -36.664 204 23,530 >25000,000 113,702 219.873 81,984 -94.081 81,900 -24.924 205 16,221 >25000,000 107,697 232.132 70,845 -91.576 85,857 -28.455 206 1.813 >25000,000 112,801 221,630 62,322 -83.659 72,151 -57.585 207 3.456 22,522 15,523 1.451 15,083 -92.266 16,872 -63.380 208 1,770 1378.136 25,142 54,813 9.265 -94.342 11,644 -47.371 209 4,781 3132.451 30,034 104.297 16,373 -93.368 12,134 -51,998 210 4.353 10999.791 32,727 336.112 27,842 -96.896 17,045 -51.154 211 11,856 651.389 83,449 7,806 47,630 -91.820 60,600 -52.358 212 8,790 >25000,000 93,796 266,536 60.172 -59,089 128,747 -49.302 213 3.227 9.836 7.955 1.236 3,196 -85.603 6,031 -64.116 214 2,297 3924.472 19,217 204.217 3,290 -91.986 6,370 -48.793 215 6,829 20476.683 50,708 403.817 20,031 -81.853 25,032 -42.412 216 3.325 11066.674 35,740 309,648 29,022 -85.005 47.209 -32,014 217 3,180 18,360 16,585 1.107 14,978 -91.288 13,777 -71.339 218 2,795 30,466 5.616 5.425 6,197 -75.420 219 7,958 >25000,000 71,481 349,744 24,575 -91.460 42,396 -42.617 220 3,174 19,337 14,390 1,344 4,362 -90.506 2,012 -76.936 221 9,334 9,597 4,864 1.973 11,415 -66.213 222 23,560 115,933 53,192 2,179 69,418 -58.410 223 15,882 93,895 6,961 13,488 33,076 -62.835 224 3.139 41.136 5,884 6,991 16,428 -61.875 225 18,247 7,559 22,404 0.337 10,999 -73.768 226 1.171 8,742 101,817 0.086 34,694 -64.963 227 3,250 5,848 10,285 0.569 2,367 -81.522 228 3.965 6,310 5,330 1,184 3,287 -77.633 229 17,110 329.387 12,200 27,000 13,389 -65.653 230 12,876 11,748 10,902 1.078 15,854 -69.108 231 26,032 512.816 5,284 97,051 22,694 -59.209 232 5.015 15,326 9,504 1.613 4,674 -78.974 233 2,458 5,872 6,047 0.971 1,984 -87.288 234 3.163 13,069 16,472 0.793 5,202 -81.384 235 5,564 16,010 15,144 1.057 1.937 -84.459 2,347 -84.925 236 84,028 49,935 56,184 0.889 9,924 -90.096 237 8,375 18,550 9.327 1,989 12,024 -78.619 238 18,054 32,210 68.149 0.473 5,789 -88.447 239 149,765 103.261 47,999 2,151 63,497 -77.758 240 241 20,455 >25000,000 130.264 191,917 120.417 -88.873 225,056 -59.521 242 15,329 7146.158 62.113 115,051 68,920 -92.786 180,037 -65.744 243 3,592 98.426 38,548 2,553 10,379 -92.290 10,582 -71.678 244 3,376 3581.722 38,506 93,018 27,607 -95.630 20,195 -65.165 245 17,436 8875.216 64,831 136,897 112,774 -95.548 62,255 -46.475 246 5,802 279,340 36.136 7,730 16,490 -95.467 12,136 -68.331 247 14,431 50,833 34,641 1.467 40,535 -77.509 31,375 -67.545 248 6,624 >25000,000 76,389 327.274 75,840 -92.622 97,040 -46.753 249 5,164 6351.906 33,622 188,921 13,815 -93.297 14,524 -49.016 250 3.626 2185.864 44.144 49,517 23.101 -94.381 15,593 -58.677 251 52,399 49,653 28,136 1.765 13,373 -87.236 252 21,819 22,624 27,410 0.825 10.275 -76.109 253 1.924 10,022 8,586 1.167 12,915 -80.763 2,424 -84.782 254 5.123 22048.355 52,240 422,058 29,045 -77.065 23,704 -41.424 255 7,321 >25000,000 89,728 278,618 65,836 -61.401 67,624 -24.942 256 15,609 >25000,000 112.177 222,862 43,369 -88.839 60,856 -5.090 257 5.745 >25000,000 116.875 213,903 71,477 -75.412 265,710 -4.151 258 11,739 >25000,000 73,832 338,606 28,684 -65.918 29,773 -12.669 259 >25000,000 83,063 300,977 31,491 -86.489 133,009 -43.329 260 0.196 >25000,000 99.444 251,398 39,499 -47.734 42,267 -44.621 261 23290.387 76,557 304.222 32,328 -89.906 57,557 -36.811 262 5.655 4102.465 51,625 79,467 29,341 -91.709 41,697 -65.862 263 37,684 93,581 25,451 3.677 64,532 -88.783 102,396 -67.601 264 35,694 33,402 72,404 0.461 143.328 -21.716 265 5.3 >25000,000 71.6 349.0 36.7 25.1 47.5 -9.0

Administration of at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof

Colon cancer cells CT26 (0.25 × 10⁶; ATCC Cat. No. CRL-2638) was implanted subcutaneously into the right flank of eight-week-old female Balb/c mice (Envigo) in 100 μl of Matrigel without PVS. The CT26 tumor was allowed to grow to an average of ~100 mm³, before animals were included in the efficacy study. Each treatment group contained 12 mice. Mice were treated with at least one compound selected from compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, an anti-CTLA4 antibody, or a combination thereof at various doses and via various routes of administration . At least one compound selected from the compounds of formula I (including formulas IIa-e, IIIa, IVa and Va) and/or pharmaceutically acceptable salts thereof, was formulated in a composition containing 5% ethanol and 95% methylcellulose solution (0 .5% methylcellulose). Anti-CTLA4 antibody was formulated with PBS at pH 7. Tumors were measured 3 times per week for up to 19 days. Tumor volumes were calculated using the formula for an ellipsoid:tumor volume = (length×width ² )/2.

Other embodiments

Embodiment 1. A compound selected from compounds of formula I:

I,

and their pharmaceutically acceptable salts,

Where:

R ¹ selected from:

each of which may be optionally substituted with 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, C ₃ -C ₈ cycloalkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, dimethylamino groups and methoxy-C ₁ -C ₆ alkyl groups;

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen, hydroxyl groups, -OR ¹⁰ groups and C ₁ -C ₆ alkyl groups;

R ⁸ , R ⁹ and R ¹³ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

R ¹⁰ is selected from hydrogen, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ aminoalkyl groups, C ₁ -C ₆ alkylamino groups, C ₁ -C ₆ alkylcarboxylic acid groups, C ₃ -C ₈ cycloalkyl groups, benzyl groups, C ₃ -C ₈ heterocyclyl groups, -CH ₂ -C ₃ -C ₈ heterocyclyl groups, -C(O)-C ₃ -C ₈ heterocyclyl groups, acyl groups, hydroxy-C ₁ -C ₆ alkyl groups, methoxy-C ₁ -C ₆ alkyl groups, -CD ₃ and -C(O)-NR ¹¹ R ¹² groups;

R ¹¹ and R ¹² are independently selected from hydrogen, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ aminoalkyl groups, C ₁ -C ₆ alkylamino groups, C ₃ -C ₈ cycloalkyl groups and C ₃ -C ₈ heterocyclyl groups;

V is selected from -CH ₂ - and -N(R ⁹ )-;

W is selected from 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be optionally substituted with 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be optionally substituted with 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ - C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- ; And

each n is independently selected from 0-4.

Embodiment 2: Connection according to Embodiment 1, wherein R ¹ is selected from And , each of which may be substituted by 1-3 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups.

Embodiment 3: Connection according to Embodiment 1 or Embodiment 2, wherein R ¹ is selected from , which may be substituted by 1-3 groups selected from C ₁ -C ₆ alkyl groups.

Embodiment 4. The compound according to any one of embodiments 1-3, wherein R ¹ is selected from unsubstituted .

Embodiment 5. The compound according to any one of Embodiments 1 to 4, wherein R ² is methyl and R ³ is hydrogen.

Embodiment 6. The compound according to any one of Embodiments 1 to 5, wherein R ⁴ is hydrogen and and R ⁵ is hydroxyl.

Embodiment 7. The compound according to any one of Embodiments 1 to 6, wherein R ⁶ is hydrogen and and R ⁷ is methyl.

Embodiment 8. The compound according to any one of embodiments 1 to 7, wherein R ⁸ is methyl.

Embodiment 9. The compound according to any one of embodiments 1 to 8, wherein V is -CH ₂ -.

Embodiment 10. The compound according to any one of Embodiments 1 to 9, wherein W is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring, and an imidazopyridine ring, each of which may be optionally substituted with 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, and C ₃ -C ₅ cycloalkyl groups.

Embodiment 11. The compound according to any one of Embodiments 1 to 10, wherein W represents a benzene ring which may be optionally substituted with 1 to 3 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups.

Embodiment 12. A connection according to any one of embodiments 1 to 11, wherein each of X and Y is independently selected from a connection,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 13. The compound according to any one of embodiments 1-11, wherein Y is hydrogen and X is selected from:

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 14. A compound selected from compounds of formula IIa:

IIa,

and their pharmaceutically acceptable salts,

Where:

R ¹⁰ is selected from hydrogen and methyl;

W is selected from 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

Embodiment 15. The compound of Embodiment 14, wherein W is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring, and an imidazopyridine ring, each of which may be optionally substituted 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups.

Embodiment 16. The compound of Embodiment 14 or Embodiment 15, wherein W represents a benzene ring which may be optionally substituted with 1 to 3 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups.

Embodiment 17. A connection according to any one of embodiments 14-16, wherein each of X and Y is independently selected from a connection,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 18. The compound according to any one of embodiments 14-17, wherein Y is hydrogen and X is selected from:

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 19. The compound according to any one of embodiments 14 to 17, wherein Y is hydrogen and X is a bond.

Embodiment 20. A compound selected from compounds of formula IIb:

IIb,

and their pharmaceutically acceptable salts,

Where:

R ¹⁶ is selected from hydrogen and fluorine;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

Embodiment 21. The connection according to Embodiment 20, where each of X and Y is independently selected from the connection,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 22. The compound of Embodiment 20 or Embodiment 21, wherein Y is hydrogen and X is selected from:

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 23. The compound according to any one of embodiments 20-22, wherein Y is hydrogen and X is a bond.

Embodiment 24. The compound according to any one of embodiments 20-23, wherein R ¹⁶ is fluorine.

Embodiment 25. A compound selected from compounds of formula IIc:

IIc,

and their pharmaceutically acceptable salts,

Where:

R ¹⁶ is selected from hydrogen and fluorine;

Y is selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

L ² selected from the bond, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)-N(R ¹³ )- , -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )-, where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups;

n ³ is 0; And

n ⁴ selected from 0-4.

Embodiment 26: The compound according to Embodiment 25, wherein Y is selected from hydrogen,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 27: The connection according to Embodiment 25 or Embodiment 26, where L ² represents a link.

Embodiment 28. The compound according to any one of embodiments 25-27, wherein R ¹⁶ is fluorine.

Embodiment 29. A compound selected from compounds of formula IId:

IId,

and their pharmaceutically acceptable salts,

Where:

R ¹⁶ is selected from hydrogen and fluorine;

X is selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

L ¹ and L ² are independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)-N( R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )-, where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

Embodiment 30. Connection according to Embodiment 29, where X is selected from the connection,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 31. The connection according to Embodiment 29 or Embodiment 30, where each of X, L ¹ and L ² is a link.

Embodiment 32. The compound according to any one of embodiments 25-27, wherein R ¹⁶ is fluorine.

Embodiment 33. A compound selected from compounds of formula IIe:

IIe,

and their pharmaceutically acceptable salts,

Where:

R ¹⁶ is selected from hydrogen and fluorine;

X is independently selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy- C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

Embodiment 34. Connection according to Embodiment 33, where X is selected from the connection,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 35. The connection according to Embodiment 33 or Embodiment 34, wherein each of X, L ¹ and L ² is a link.

Embodiment 36. The compound according to any one of embodiments 33-35, wherein R ¹⁶ is fluorine.

Embodiment 37. A compound selected from compounds of formula IIIa:

IIIa,

and their pharmaceutically acceptable salts,

Where:

R ¹⁰ is selected from hydrogen and methyl;

W is selected from 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

Embodiment 38. A compound selected from compounds of formula IVa:

IVa,

or a pharmaceutically acceptable salt thereof,

Where:

R ¹⁰ is selected from hydrogen and methyl;

W is selected from 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

Embodiment 39. The compound of Embodiment 38, wherein W is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring, and an imidazopyridine ring, each of which may be optionally substituted 1-3 groups independently selected from halogen atoms, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups.

Embodiment 40. The compound of Embodiment 38 or Embodiment 39, wherein W represents a benzene ring which may be optionally substituted with 1 to 3 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups.

Embodiment 41. A connection according to any one of embodiments 38-40, wherein each of X and Y is independently selected from a relationship,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 42. The compound according to any one of embodiments 38-41, wherein Y is hydrogen and X is selected from:

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 43. The compound according to any one of embodiments 38 to 42, wherein Y is hydrogen and X is a bond.

Embodiment 44. A compound selected from compounds of formula Va:

Va,

or a pharmaceutically acceptable salt thereof,

Where:

R ⁹ is selected from hydrogen and C ₁ -C ₆ alkyl groups;

R ¹⁰ is selected from hydrogen and methyl;

W is selected from 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups;

each of X and Y is independently selected from bond, hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles, each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups;

each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And

each n is independently selected from 0-4.

Embodiment 45. The compound of Embodiment 44, wherein W is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring, and an imidazopyridine ring, each of which may be optionally substituted 1-3 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups and C ₃ -C ₅ cycloalkyl groups.

Embodiment 46. The compound of Embodiment 44 or Embodiment 45, wherein W represents a benzene ring which may be substituted with 1 to 3 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups.

Embodiment 47. The connection according to any one of embodiments 44-46, wherein each of X and Y is independently selected from the relationship,

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 48. The compound according to any one of embodiments 44-47, wherein Y is hydrogen and X is selected from:

each of which may be substituted by 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups.

Embodiment 49. The compound according to any one of embodiments 44-48, wherein Y is hydrogen and X is a bond.

Embodiment 50. A connection selected from:

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperazin-1-ylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-(4-methylpiperazin-1-yl)phenyl]prop- 1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-(1H-indazol-6-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-(1H-indazol-4-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(2-morpholin-4-ylpyridin-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(2-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-fluoro-3-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(3S)-3-(methylamino)pyrrolidine-1 -yl]phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(3S)-3-(methylamino)pyrrolidine-1 -yl]phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(2-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-fluorophenyl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(3-methyl-5-morpholin-4-ylphenyl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-morpholin-4-yl-5-(trifluoromethyl)phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-chloro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2-hydroxyethyl)piperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-4-yl)carbamate;

[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3,4-dimethylpiperazine-1-carboxylate;

[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-propan-2-ylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-tert-butylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclobutylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclopentylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3,5-difluorophenyl)prop-1-en-2-yl]-10-hydroxy-3,7- dimethyl 12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(dimethylamino)-5-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(4-hydroxypiperidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-(1-methylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(1R,5S)-8-oxa-3-azabicyclo[3.2.1] octan-3-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(3-oxopyrrolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(oxan-4-yl)piperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-3-yl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(3-fluoroazetidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-(methylamino)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3-(dimethylamino)piperidine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2R)-2-methylpyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxopyrrolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2S)-2-methylpyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(5-chloropyridin-3-yl)prop-1-en-2-yl]-10-hydroxy-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(pyridin-4-ylmethyl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3,5-dichlorophenyl)prop-1-en-2-yl]-10-hydroxy-3,7- dimethyl 12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxo-1,2-thiazolidin-2-yl)phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(1,3-dimethylindazol-6-yl)prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxo-1,4-thiazinan-4-yl)-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N,N-dimethylcarbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxo-1,4-thiazinan-4-yl)-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-morpholine-4-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-4-yl) carbamate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(1-methylindazol-6-yl)prop-1-ene-2 -yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(3-oxomorpholin-4-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-(cyclopentylsulfamoyl)-2-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(4-methylsulfonylpiperazin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-fluoro-1H-indazol-6-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-imidazol-1-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6S,7R,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6S,7R,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6S,7R,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxoimidazolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[3-(2-fluoroethynyl)-2-oxoimidazolidin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[3-(2-morpholin-4-ylethyl)-2-oxoimidazolidine-1- yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl]-5-fluorophenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(2S)-2-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-(2-methylmorpholin-4-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-[(2S,3R)-3-hydroxy-2-methylpentyl]piperazine -1-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1 -carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-[(2R,3R)-3-hydroxy-2-methylpentanoyl]piperazine -1-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1 -carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-morpholin-4-ylethylsulfonyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4-ethenylsulfonylpiperazin-1-yl)-5-fluorophenyl]prop-1-en-2-yl ]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2R)-2-(hydroxymethyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-(hydroxymethyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(2R)-2-(methylcarbamoyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxo-1,3-diazinan-1-yl)phenyl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[3-(cyclopropylmethyl)-2-oxo-1,3-diazinan-1-yl]-5 -fluorophenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-[(2R)-2-hydroxypropanoyl]piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine -2-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(2-cyclopropyl-2-oxoethyl)piperazin-1-yl]-5-fluorophenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-oxo-2-pyrazin-2-ylethyl)piperazine-1 -yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ;

[(2S,3S,4E,6S,7R,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyclopropylmethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-imidazo[1,2-a]pyridin-6-ylprop-1-en-2-yl] -3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(7-methyl-1H-indazol-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-(cyclopropylsulfamoyl)-3-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-fluoro-5-(4-hydroxypiperidin-1-yl)sulfonylphenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperazin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4-formylpiperazin-1-yl)sulfonylphenyl]prop-1-en-2-yl]-10 -hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-(4-hydroxypiperidin-1-yl)sulfonylphenyl]prop-1-ene-2- yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(6-methyl-1H-indazol-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(1,3-dimethylindazol-4-yl)prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(1-azabicyclo[2.2.2]octan-3-yl)-N-methylcarbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-(cyclopropylmethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(2-hydroxyethyl)indazol-6-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-fluoro-1-methylindazol-6-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-[1-(pyridin-4-ylmethyl)pyrazol- 4-yl]prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(1-methylpyrazol-4-yl)prop-1-ene-2 -yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)-3-oxopiperazin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-methoxyethyl)-3-oxopiperazin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[1-(1-methylpiperidin-4-yl)pyrazol-4- yl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-methoxyacetyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(cyclopropanecarbonyl)piperazin-1-yl]-5-fluorophenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(4-methoxyphenyl)sulfonylpiperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylpyrazol-4-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(4-pyridin-3-ylsulfonylpiperazin-1-yl)phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylimidazol-4-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(cyclohexanecarbonyl)piperazin-1-yl]-5-fluorophenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylindol-6-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(oxan-4-yl)indazol-6-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-2-(oxan-4-yl)indazol-6-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxane-4-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-morpholin-4-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylimidazol-4-carbonyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(2-cyclopropylacetyl)piperazin-1-yl]-5-fluorophenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1,3-oxazol-5-carbonyl)piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethylsulfonyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxetan-3-ylsulfonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(oxetan-3-ylsulfonyl)indazol-6-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-(1-hydroxyisoquinolin-7-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[4-fluoro-1-[2-(methylamino)-2-oxoethyl]indazol-6-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(2-oxo-2-pyrrolidin-1-ylethyl)indazol-6-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(2-morpholin-4-yl-2-oxoethyl)indazol-6-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyanomethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-[2-(dimethylamino)-2-oxoethyl]-4-fluorinazol-6-yl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyclopropylmethyl)-3-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(3-methoxypropanoyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyacetyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(3-hydroxypropyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-(cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(oxan-4-yl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-2-(oxan-4-yl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-(2-methoxyethyl)benzimidazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxolane-3-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4- yl]benzotriazol-5-yl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(4-chlorophenyl)methyl]-7-fluorobenzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-acetylpiperidin-4-yl)-7-fluorobenzimidazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(4-hydroxycyclohexyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(oxan-4-ylmethyl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(2S)-1-hydroxypropan-2-yl]benzotriazol-5-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(2R)-1-hydroxypropan-2-yl]benzotriazol-5-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-[(3S)-oxolan-3-carbonyl]piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-[(3R)-oxolan-3-carbonyl]piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxetane-3-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(3-methyloxetane-3-carbonyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(3-hydroxypropanoyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(4-methyloxan-4-yl)benzotriazol-5-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(1-methylsulfonylpiperidin-4-yl)benzotriazol-5-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxothian-4-yl)-7-fluorobenzotriazol-5-yl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-(2-methoxyethyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-acetylpiperidin-4-yl)-7-fluorobenzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(3R)-oxan-3-yl]benzotriazol-5-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(3S)-oxan-3-yl]benzotriazol-5-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(3R,4S)-3-hydroxyoxan-4-yl]benzotriazol-5- yl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-cyclohexyl-7-fluorobenzotriazol-5-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-(4-methoxyphenyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-[(4-methoxyphenyl)methyl]benzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-chloro-5-fluorophenyl)prop-1-en-2-yl]-10-hydroxy-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl(oxan-4-yl)amino]phenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl(oxetan-3-yl)amino]phenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[methyl(oxan-4-yl)amino]phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[methyl(oxetan-3-yl)amino]phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1,1-dioxothian-4-yl)-methylamino]-5-fluorophenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(1-methylsulfonylpiperidin-4-yl)amino]phenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-(1-methylsulfonylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-[ethyl-(1-methylsulfonylpiperidin-4-yl)amino]-5-fluorophenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(1-methylsulfonylpiperidin-4-yl)-propan-2-ylamino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-acetylpiperidin-4-yl)-methylamino]-5-fluorophenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-(1-propanoylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[[1-(2-methoxyacetyl)piperidin-4-yl]-methylamino]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-benzoylpiperidin-4-yl)-methylamino]-5-fluorophenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(2,2,2-trifluoroacetyl)piperidine-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-(1-propylsulfonylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-cyclopentylsulfonylpiperidin-4-yl)-methylamino]-5-fluorophenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(1-methylimidazol-4-yl)sulfonylpiperidin-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[[1-(benzenesulfonyl)piperidin-4-yl]-methylamino]-5-fluorophenyl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-acetylpiperidin-4-yl)methyl-methylamino]-5-fluorophenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[(1-methylsulfonylpiperidin-4-yl)methyl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(1,3-oxazol-5-carbonyl)piperidin- 4-yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(pyrazin-2-carbonyl)piperidin-4-yl] amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(1-methylimidazol-4-carbonyl)piperidine-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(propan-2-ylcarbamoyl)piperidin-4-yl] amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(propylcarbamoyl)piperidin-4-yl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(phenylcarbamoyl)piperidin-4-yl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(1-methylsulfonylpiperidin-4-yl)oxyphenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(4,4-difluorocyclohexyl)-4-fluorinazol-6-yl]prop-1-ene-2 -yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(1-methylsulfonylpiperidin-4-yl)indazol-6-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-pyrrolidin-1-ylsulfonylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(azetidin-1-ylsulfonyl)phenyl]prop-1-en-2-yl]-10-hydroxy -3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[(3R)-3-hydroxypyrrolidin-1-yl]sulfonylphenyl]prop-1- en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(2S)-2-methylpyrrolidin-1-yl] sulfonylphenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[(1-hydroxy-2-methylpropan-2-yl)sulfamoyl]phenyl]prop -1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4,4-difluoropiperidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(4-methyl-3-pyrrolidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(3,3-difluoropyrrolidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(5-pyrrolidin-1-ylsulfonylpyridin-3-yl )prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(3,3-difluoroazetidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[4-methyl-3-(2-oxopyrrolidin-1-yl) phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(tert-butylsulfamoyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3 ,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-[3-(propan-2-ylsulfamoyl)phenyl] prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-(ethylsulfamoyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-(4-methylpiperazin-1-yl)sulfonylphenyl]prop- 1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-(methylsulfamoyl)phenyl]prop-1-ene-2- yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-pyrrolidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-cyclopropylsulfonylphenyl)prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl- 12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(cyclopropylsulfonylamino)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-(methanesulfonamido)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(3S)-3-[(2-methoxyacetyl)amino]pyrrolidine-1- yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[1-[(2-methylpropan-2-yl)oxycarbonyl]- 3,6-dihydro-2H-pyridin-5-yl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate;

[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(trideuteriomethyl)piperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(pyridin-4-ylmethyl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(pyrimidin-4-ylmethyl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-morpholine-4-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(dimethylamino)ethyl]carbamate ;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methyl-1,4-diazepan-1 -carboxylate;

[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[(4-methoxyphenyl)methyl]carbamate ;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-(dimethylamino)pyrrolidin- 1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3-(dimethylamino)pyrrolidin- 1-carboxylate;

[(2R,3R,4E,6R,7S,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[(2S)-1-hydroxypropan- 2-yl]carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3-oxopiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-fluoropyrrolidine-1-carboxylate ;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,3,4-trimethylpiperazine-1-carboxylate ;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin- 4-yl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2-hydroxyethyl)piperazine-1- carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-piperazin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cycloheptylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-pyridin-4-ylpiperazin-1-carboxylate ;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclohexylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(4-hydroxyphenyl)ethyl ]-N-methylcarbamate;

(2S,3S,6R,7S,10R,E)-2-((E)-1-(3-fluoro-5-morpholinophenyl)prop-1-en-2-yl)-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl-7-methyl-1,7-diazaspiro[3.5]nonane-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(3-morpholin-4-ylpropyl)carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(dimethylamino)ethyl]carbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-(dimethylamino)pyrrolidine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3-(dimethylamino)pyrrolidine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(2-cyanoethyl)-N-methylcarbamate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,3,4-trimethylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-fluoropyrrolidine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(dimethylsulfamoylamino)-5-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(2-methoxyacetyl)amino]phenyl]prop-1-en-2-yl ]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(2-cyclopropylacetyl)amino]-5-fluorophenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-[(3-hydroxyphenyl)methyl]piperazine -1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(pyridin-3-ylmethyl)piperazin- 1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-acetylpiperidin-4-yl)-7-fluorobenzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-piperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxymethyl]phenyl]prop -1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[3-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12- oxo-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]methyl-2-oxa-7-azaspiro[3.4]octane-7-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]pyridin-4 -yl]prop-1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[3-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12- oxo-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]methylmorpholine-4-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(dimethylcarbamoyloxymethyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxymethyl] phenyl]prop-1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[[(3R)-3-fluoropyrrolidine-1-carbonyl]oxymethyl]phenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[(4-hydroxypiperidin-1-carbonyl)oxymethyl]phenyl]prop-1-ene -2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

[(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate;

2-[4-[3-fluoro-5-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-6- (piperazin-1-carbonyloxy)-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]piperazin-1-yl]acetic acid;

(2S,3S,6R,7S,10R,E)-2-((E)-1-(3-(dimethylamino)phenyl)prop-1-en-2-yl)-10-hydroxy-3,7- dimethyl 12-oxooxacyclododec-4-en-6-yl-4-methylpiperazine-1-carboxylate;

(2S,3S,6R,7S,10R,E)-2-((E)-1-(3-(dimethylamino)phenyl)prop-1-en-2-yl)-10-hydroxy-3,7- dimethyl 12-oxooxacyclododec-4-en-6-ylpiperazin-1-carboxylate;

(2S,3S,6R,7S,10R,E)-2-((E)-1-(5-chloropyridin-3-yl)prop-1-en-2-yl)-10-hydroxy-3,7 -dimethyl-12-oxooxacyclododec-4-en-6-ylpiperazin-1-carboxylate;

(2S,3S,6R,7S,10R,E)-10-hydroxy-3,7-dimethyl-12-oxo-2-((E)-1-(3-(pyrrolidin-1-ylsulfonyl)phenyl)prop -1-en-2-yl)oxacyclododec-4-en-6-ylpiperazin-1-carboxylate;

and their pharmaceutically acceptable salts.

Embodiment 51. The compound of any one of embodiments 1-50, wherein the compound contains more than about 80% by weight of one stereoisomer of the compound.

Embodiment 52. The compound of an embodiment of any one of Embodiments 1-50, wherein the compound contains more than about 90% by weight of one stereoisomer of the compound.

Embodiment 53. The compound of any one of embodiments 1-50, wherein the compound contains more than about 95% by weight of one stereoisomer of the compound.

Embodiment 54. The compound of any one of embodiments 1-50, wherein the compound contains more than about 97% by weight of one stereoisomer of the compound.

Embodiment 55. A pharmaceutical composition containing at least one compound selected from the compounds and/or their pharmaceutically acceptable salts according to any one of paragraphs. 1-54.

Embodiment 56. The pharmaceutical composition according to Embodiment 55, wherein the composition is formulated for intravenous, oral, subcutaneous or intramuscular administration.

Embodiment 57. The pharmaceutical composition according to Embodiment 56, wherein the composition is formulated for oral administration.

Embodiment 58. A method of treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any of Embodiments 1-54, or a pharmaceutical composition according to any of embodiments 55-57, wherein the cancer is selected from myelodysplastic syndrome, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer, breast cancer, uveal melanoma, gastric cancer, cholangiocarcinoma and lung cancer.

Embodiment 59. The method of Embodiment 58, wherein said cancer is selected from myelodysplastic syndrome, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia, and acute myeloid leukemia.

Embodiment 60. The method of Embodiment 58, wherein said cancer is a myelodysplastic syndrome.

Embodiment 61. The method of Embodiment 58, wherein the cancer is chronic myelomonocytic leukemia.

Embodiment 62. The method of Embodiment 58, wherein the cancer is acute myeloid leukemia.

Embodiment 63. The method of Embodiment 58, wherein said cancer is chronic lymphocytic leukemia.

Embodiment 64. The method of Embodiment 58, wherein the cancer is acute lymphoblastic leukemia.

Embodiment 65. The method of Embodiment 58, wherein said cancer is endometrial cancer.

Embodiment 66. The method of Embodiment 58, wherein said cancer is ovarian cancer.

Embodiment 67. The method of Embodiment 58, wherein said cancer is breast cancer.

Embodiment 68. The method of Embodiment 58, wherein said cancer is uveal melanoma.

Embodiment 69. The method of Embodiment 58, wherein said cancer is gastric cancer.

Embodiment 70. The method of Embodiment 58, wherein said cancer is cholangiocarcinoma.

Embodiment 71. The method of Embodiment 58, wherein said cancer is lung cancer.

Embodiment 72. The method of Embodiment 58, wherein said cancer is colon cancer.

Embodiment 73. The method of Embodiment 58, wherein said cancer is pancreatic cancer.

Embodiment 74. The method of any one of embodiments 58-73, wherein the cancer is positive for one or more mutations in a spliceosome gene or protein.

Embodiment 75. The method of Embodiment 74, wherein said spliceosomal gene or protein is selected from splicing factor 3B subunit 1 (SF3B1), small nuclear RNA accessory factor 1 U2 (U2AF1), high serine/arginine splicing factor 2 (SRSF2) , zinc finger protein 2 (CCCH type), RNA-binding motif and high serine/arginine content (ZRSR2), pre-mRNA processing splicing factor 8 (PRPF8), small nuclear RNA accessory factor 2 U2 (U2AF2 ), splicing factor 1 (SF1), splicing factor 3a subunit 1 (SF3A1), pre-mRNA processing factor 40 homolog B PRP40 (PRPF40B), RNA binding motif protein 10 (RBM10), poly(rC) binding protein 1 (PCBP1), pre-mRNA splicing factor 1, crooked neck (CRNKL1), DEAH-box helicase 9 (Asp-Glu-Ala-His) (DHX9), peptidyl-prolyl-cis-like protein 2 -trans isomerase (PPIL2), RNA binding motif protein 22 (RBM22), small nuclear ribonucleoprotein Sm D3 (SNRPD3), putative ATP-dependent RNA helicase DDX5 (DDX5), a factor involved in pre-mRNA splicing, with activity of ATP-dependent RNA helicase DHX15 (DHX15) and polyadenylate binding protein 1 (PABPC1).

Embodiment 76. The method of Embodiment 75, wherein the spliceosomal gene or protein is splicing factor 3B subunit 1.

Embodiment 77. A method of treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any of Embodiments 1-54, or a pharmaceutical composition according to any of embodiments 55-57 and at least one additional therapy.

Embodiment 78. The method of Embodiment 77, 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.

Embodiment 79. The method of Embodiment 77, wherein a therapeutically effective amount of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof of any one of Embodiments 1-54, or a pharmaceutical composition of any of Embodiments 55-57 , 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 dosage of the compound of formula I or a pharmaceutically acceptable salt thereof and/or at least one additional therapy.

Embodiment 80. The method according to any of embodiments 77-79, wherein the frequency of administration of at least one compound selected from compounds and/or pharmaceutically acceptable salts thereof according to any of embodiments 1-54, or a pharmaceutical composition according to any one of embodiments 55-57 and/or at least one additional therapy by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 90% less than the standard dosage regimen of at least one compound selected from the compounds and/or their pharmaceutically acceptable salts according to any of embodiments 1-54, or the pharmaceutical composition according to any of embodiments 55-57, and/or at least one additional means of therapy.

Embodiment 81. The method according to any of embodiments 77-80, wherein the administered amount and/or dose of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any of embodiments 1-54, or the pharmaceutical composition according to any of embodiments 55-57, and/or at least one additional therapy result in lower systemic toxicity and/or improved tolerability.

Embodiment 82. The method of Embodiment 77, wherein administration of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any of Embodiments 1-54, or the pharmaceutical composition according to any of Embodiments 55-57 is started before administering at least one additional therapy.

Embodiment 83. The method of Embodiment 77, wherein administration of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any of Embodiments 1-54, or the pharmaceutical composition according to any of Embodiments 55-57 is started after administering at least one additional therapy.

Embodiment 84. The method of Embodiment 77, wherein administration of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any one of Embodiments 1-54, or the pharmaceutical composition according to any one of Embodiments 55-57 is started simultaneously with the introduction of at least one additional therapy.

Embodiment 85. The method according to any of embodiments 77-84, wherein administering at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any of embodiments 1-54, or a pharmaceutical composition according to any of embodiments 55 -57 is repeated at least once after the initial administration.

Embodiment 86. The method of Embodiment 85, wherein the amount of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any of Embodiments 1-54, or the pharmaceutical composition according to any of Embodiments 55-57, used for repeated administration, reduced relative to the amount used for initial administration.

Embodiment 87. The method of Embodiment 85, wherein the amount of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any of Embodiments 1-54, or the pharmaceutical composition according to any of Embodiments 55-57, used for repeated administration, reduced relative to the standard dosage of at least one compound selected from the compounds and/or their pharmaceutically acceptable salts according to any of embodiments 1-54, or the pharmaceutical composition according to any of embodiments 55-57.

Embodiment 88. The method of Embodiment 85, wherein the amount of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any of Embodiments 1-54, or the pharmaceutical composition according to any of Embodiments 55-57, used for repeated administration, reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% relative to the standard dosage of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any of embodiments 1-54, or a pharmaceutical composition according to any of embodiments 55-57.

Embodiment 89. The method of any one of embodiments 77-88, wherein administration of the at least one additional therapy is repeated at least once after the initial administration.

Embodiment 90. The method of Embodiment 89, wherein the amount of at least one additional therapy used for repeated administration is reduced relative to the amount used for initial administration.

Embodiment 91. The method of Embodiment 89, wherein the amount of the at least one additional therapy used for repeated administration is reduced relative to the standard dosage of the at least one additional therapy.

Embodiment 92. The method of Embodiment 89, wherein the amount of at least one additional therapy used for repeated administration is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% , 50%, 75% or 90% relative to the standard dosage of at least one additional therapy.

Embodiment 93. The method according to any one of embodiments 77-92, wherein re-administering at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any one of embodiments 1-54, or a pharmaceutical composition according to any one of embodiments 55-57 is carried out simultaneously with repeated administration of at least one additional therapy.

Embodiment 94. The method according to any one of embodiments 77-92, wherein re-administering at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any one of embodiments 1-54, or a pharmaceutical composition according to any one of embodiments 55-57 are carried out sequentially or spaced in time with repeated administration of at least one additional therapy.

Embodiment 95. The method of any one of embodiments 77-94, wherein the at least one additional therapy comprises administering a checkpoint inhibitor.

Embodiment 96. The method of Embodiment 95, wherein the subject is intolerant, unresponsive, or insufficiently responsive to the checkpoint inhibitor when administered alone.

Embodiment 97. The method of Embodiment 95, wherein the checkpoint inhibitor specifically targets CTLA4, PD1, PDL1, OX40, CD40, GITR, LAG3, TIM3, and/or KIR.

Embodiment 98. The method of Embodiment 95, wherein the checkpoint inhibitor specifically targets CTLA4, OX40, CD40, and/or GITR.

Embodiment 99. The method of Embodiment 97 or Embodiment 98, wherein the checkpoint inhibitor comprises an inhibitor of the cytotoxic T lymphocyte-associated antigen 4 (CTLA4) pathway.

Embodiment 100. The method of Embodiment 99, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

Embodiment 101. The method of Embodiment 100, wherein the anti-CTLA4 antibody is ipilimumab.

Embodiment 102. The method of Embodiment 97 or Embodiment 98, wherein the checkpoint inhibitor comprises an inhibitor of the programmed cell death protein 1 (PD1) pathway.

Embodiment 103. The method of Embodiment 102, wherein the PD1 inhibitor is an anti-PD1 antibody.

Embodiment 104. The method of Embodiment 103, wherein the anti-PD1 antibody is nivolumab.

Embodiment 105. The method of Embodiment 102, wherein the PD1 inhibitor is an anti-PDL1 antibody.

Embodiment 106. The method of Embodiment 105, wherein the anti-PDL1 antibody is atezolizumab.

Embodiment 107. The method of Embodiment 97 or Embodiment 98, wherein the checkpoint inhibitor comprises a CTLA4 inhibitor and a PD1 inhibitor.

Embodiment 108. The method of Embodiment 107, wherein the CTLA4 inhibitor is an anti-CTLA4 antibody.

Embodiment 109. The method of Embodiment 108, wherein the anti-CTLA4 antibody is ipilimumab.

Embodiment 110. The method of Embodiment 107 or Embodiment 108, wherein the PD1 inhibitor is an anti-PD1 antibody.

Embodiment 111. The method of Embodiment 110, wherein the anti-PD1 antibody is nivolumab.

Embodiment 112. The method of Embodiment 107 or Embodiment 108, wherein the PD1 inhibitor is an anti-PDL1 antibody.

Embodiment 113. The method of Embodiment 112, wherein the anti-PDL1 antibody is atezolizumab.

Embodiment 114. The method of any one of embodiments 77-94, wherein the at least one additional therapy comprises administering a cytokine or cytokine analogue.

Embodiment 115. The method of Embodiment 114, wherein the subject is intolerant, unresponsive, or deficient in responsiveness to the cytokine or cytokine analog when administered alone.

Embodiment 116. The method of Embodiment 114, wherein the cytokine or cytokine analogue provides a T cell enhancer.

Embodiment 117. The method of Embodiment 114, wherein the cytokine or cytokine analogue comprises IL-2, IL-10, IL-12, IL-15, IFNγ and/or TNFα.

Embodiment 118. The method of any one of embodiments 77-94, wherein the at least one additional therapy comprises engineered T cells that specifically target the tumor.

Embodiment 119. The method of any one of embodiments 77-118, wherein the subject has a mutational load with nonsynonymous changes of approximately 150 mutations or less.

Embodiment 120. The method of any one of embodiments 77-119, wherein the subject has a mutational load with non-synonymous changes of approximately 100 mutations or less.

Embodiment 121. The method of any one of embodiments 77-120, wherein the subject has a mutational load with nonsynonymous changes of 50 mutations or less.

Embodiment 122. The method of any one of embodiments 77-121, wherein the cancer is a hematologic malignancy or a solid tumor. The method of embodiment 122, wherein the hematologic malignancy is selected from B-cell malignancy, leukemia, lymphoma, and myeloma.

Embodiment 123. The method of Embodiment 122 or Embodiment 123, wherein the hematologic malignancy is selected from acute myeloid leukemia and multiple myeloma.

Embodiment 124. The method of Embodiment 122, 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.

Embodiment 125. The method according to any one of embodiments 77-121, wherein the cancer is selected from myelodysplastic syndrome, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, colon cancer, pancreatic cancer, endometrial cancer, ovarian cancer , breast cancer, uveal melanoma, gastric cancer, cholangiocarcinoma and lung cancer.

Embodiment 126. A method of inducing the formation of at least one neoantigen, comprising contacting a neoplastic cell with a therapeutically effective amount of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof according to any of embodiments 1-54, or pharmaceutical the composition according to any one of embodiments 55-57, thereby inducing the production of at least one neoantigen.

Embodiment 127. The method of Embodiment 126, wherein the neoplastic cell is in an in vitro cell culture.

Embodiment 128. The method of Embodiment 126 or Embodiment 127, wherein the neoplastic cell is obtained from a subject.

Embodiment 129. The method of Embodiment 126, wherein the neoplastic cell is in the subject.

Embodiment 130. The method of any one of embodiments 126-129, wherein the neoplastic cell is derived from a hematologic malignancy or solid tumor.

Embodiment 131. The method of Embodiment 130, wherein the hematologic malignancy is selected from B-cell malignancy, leukemia, lymphoma, and myeloma.

Embodiment 132. The method of Embodiment 130 or Embodiment 131, wherein the hematologic malignancy is selected from acute myeloid leukemia and multiple myeloma.

Embodiment 133. The method of Embodiment 130, 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.

Embodiment 134. A method of inducing the formation of at least one neoantigen and/or the development of a T cell response in a subject with or suspected of having a neoplastic disorder, comprising administering to the subject a therapeutically effective amount of at least one compound selected from the compounds and/or pharmaceutically acceptable salts according to any of embodiments 1-54, or a pharmaceutical composition according to any one of embodiments 55-57.

Embodiment 135. A method of treating a subject with or suspected of having a neoplastic disorder, comprising administering to the subject a therapeutically effective amount of at least one compound selected from the compounds and/or pharmaceutically acceptable salts thereof of any of Embodiments 1-54, or a pharmaceutical composition according to any one of embodiments 55-57, wherein administration of at least one compound or pharmaceutical composition induces the formation of at least one neoantigen and/or the development of a T cell response.

Embodiment 136. The method of Embodiment 135, wherein the administered amount of at least one compound or pharmaceutical composition is reduced due to inducing the formation of at least one neoantigen and/or the development of a T cell response relative to a standard dosage of the at least one compound or pharmaceutical composition.

Embodiment 137. The method of Embodiment 136, wherein the administered amount of at least one compound or pharmaceutical composition is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% relative to the unit dosage of at least one compound or pharmaceutical composition.

Embodiment 138. The method according to any one of embodiments 135-137, wherein the frequency of administration of the at least one compound or pharmaceutical composition is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75% or 90% less than the standard dosage regimen of at least one compound or pharmaceutical composition.

Embodiment 139. The method of any one of embodiments 135-137, wherein the administered amount and/or dosage of at least one compound or pharmaceutical composition results in lower systemic toxicity and/or improved tolerability.

Embodiment 140. The method of any one of embodiments 134-119, further comprising administering at least one additional therapy.

Claims (405)

1. A compound selected from compounds of formula I I and their pharmaceutically acceptable salts, where R ¹ is selected from: each of which may be optionally substituted with 1-3 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, C ₃ -C ₈ cycloalkyl groups and dimethylamino groups; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from hydrogen, hydroxyl groups and C ₁ -C ₆ alkyl groups; R ⁸ , R ⁹ and R ¹³ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups; R ¹⁰ selected from hydrogen, C ₁ -C ₆ alkyl groups, C ₃ -C ₈ cycloalkyl groups, benzyl groups, C ₃ -C ₈ heterocyclyl groups containing 1-2 heteroatoms selected from nitrogen and oxygen, -CH ₂ -C ₃ -C ₈ heterocyclyl groups containing 1-2 heteroatoms selected from nitrogen and oxygen, hydroxy-C ₁ -C ₆ alkyl groups and -CD ₃ groups; R ¹¹ and R ¹² are independently selected from hydrogen, C ₁ -C ₆ alkyl groups, C ₁ -C ₆ aminoalkyl groups, C ₁ -C ₆ alkylamino groups and C ₃ -C ₈ heterocyclyl groups containing 1-2 heteroatoms selected from nitrogen and oxygen; V represents -CH ₂ -; W is selected from 3-8 membered carbocycles and 3-10 membered heterocycles containing 1-3 heteroatoms selected from nitrogen and oxygen, each of which may be optionally substituted by 1-2 groups independently selected from halogen atoms, -NR groups ⁸ R ⁹ and C ₁ -C ₆ alkyl groups; X is independently selected from bond, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be optionally substituted by 1-2 groups independently selected from atoms halogen, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; Y is independently selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be optionally substituted by 1-2 groups independently selected from atoms halogen, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- ; And each n is independently selected from 0-4. 2. Connection according to claim 1, where R ¹ is selected from And , each of which may be substituted by 1-3 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups. 3. Connection according to claim 1 or 2, where R ¹ is selected from which may be substituted by 1-3 groups selected from C ₁ -C ₆ alkyl groups. 4. Connection according to any one of paragraphs. 1-3, where R ¹ is selected from unsubstituted . 5. Connection according to any one of paragraphs. 1-4, where R ² represents methyl and R ³ represents hydrogen. 6. Connection according to any one of paragraphs. 1-5, where R ⁴ represents hydrogen and R ⁵ represents hydroxyl. 7. Connection according to any one of paragraphs. 1-6, where R ⁶ represents hydrogen and R ⁷ represents methyl. 8. Connection according to any one of paragraphs. 1-7, where R ⁸ represents methyl. 9. Connection according to any one of paragraphs. 1-8, wherein W is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring and an imidazopyridine ring, each of which may be optionally substituted with 1-2 groups, independently selected from halogen atoms, -NR ⁸ R ⁹ groups and C ₁ -C ₆ alkyl groups. 10. Connection according to any one of paragraphs. 1-9, where W represents a benzene ring, which may be optionally substituted with 1-2 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups. 11. Connection according to any one of paragraphs. 1-10, where each of X and Y is independently selected from: each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups. 12. Connection according to any one of paragraphs. 1-10 where Y is hydrogen and X is selected from: each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups. 13. A compound selected from compounds of formula IIa IIa and their pharmaceutically acceptable salts, where R ¹⁰ is selected from hydrogen and methyl; R ⁸ and R ⁹ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups; W is selected from 3-8 membered carbocycles and 3-10 membered heterocycles containing 1-3 heteroatoms selected from nitrogen and oxygen, each of which may be substituted by 1-2 groups independently selected from halogen atoms, -NR ⁸ groups R ⁹ and C ₁ -C ₆ alkyl groups; X is selected from bonds, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and groups -NR ¹⁴ R ¹⁵ , where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; Y is independently selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-2 groups independently selected from halogen atoms , hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C 1 -C ₆ alkyl groups, -SO _{2 -C 1} -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And each n is independently selected from 0-4. 14. The compound of claim 13, wherein W is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring and an imidazopyridine ring, each of which may be optionally substituted with 1- 2 groups independently selected from halogen atoms, -NR ⁸ R ⁹ groups and C ₁ -C ₆ alkyl groups. 15. The compound according to claim 13 or 14, where W represents a benzene ring, which may be optionally substituted with 1-2 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups. 16. Connection according to any one of paragraphs. 13-15, where each of X and Y is independently selected from: communications, each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups. 17. Connection according to any one of paragraphs. 13-15 where Y is hydrogen and X is selected from: each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups. 18. Connection according to any one of paragraphs. 13-15, where Y represents hydrogen and X represents a bond. 19. A compound selected from compounds of formula IIb IIb and their pharmaceutically acceptable salts, where R ¹⁶ is selected from hydrogen and fluorine; X is independently selected from bond, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-2 groups independently selected from halogen atoms , hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C 1 -C ₆ alkyl groups, -SO _{2 -C 1} -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; Y is independently selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-2 groups independently selected from halogen atoms , hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C 1 -C ₆ alkyl groups, -SO _{2 -C 1} -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And each n is independently selected from 0-4. 20. The connection of claim 19, wherein each of X and Y is independently selected from: each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups. 21. A compound according to claim 19, where Y is hydrogen and X is selected from: each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups. 22. The compound of claim 19, wherein Y is hydrogen and X is a bond. 23. Connection according to any one of paragraphs. 19-22, where R ¹⁶ represents fluorine. 24. A compound selected from compounds of formula IIc IIc and their pharmaceutically acceptable salts, where R ¹⁶ is selected from hydrogen and fluorine; Y is selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and groups -NR ¹⁴ R ¹⁵ , where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; L ² selected from the bond, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)-N(R ¹³ )- , -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )-, where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; n ³ is 0; And n ⁴ selected from 0-4. 25. The connection according to claim 24, where Y is selected from: hydrogen, each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups. 26. The connection according to claim 24 or 25, where L ² represents a bond. 27. The connection according to any one of paragraphs. 24-26, where R ¹⁶ represents fluorine. 28. A compound selected from compounds of formula IId IId and their pharmaceutically acceptable salts, where R ¹⁶ is selected from hydrogen and fluorine; X is selected from 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups , C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and groups - NR ¹⁴ R ¹⁵ where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; L ¹ and L ² are independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)-N( R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )-, where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And each n is independently selected from 0-4. 29. The connection according to claim 28, where X is selected from: each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups. 30. The connection of claim 28 or 29, wherein each of L ¹ and L ² is a link. 31. The connection according to any one of paragraphs. 28-30, where R ¹⁶ represents fluorine. 32. A compound selected from compounds of formula IIe IIe and their pharmaceutically acceptable salts, where R ¹⁶ is selected from hydrogen and fluorine; X is independently selected from 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ -C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and groups -NR ¹⁴ R ¹⁵ where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And each n is independently selected from 0-4. 33. The connection according to claim 32, where X is selected from: each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups. 34. The connection of claim 32 or 33, wherein L ¹ and L ² are each a bond. 35. The connection according to any one of paragraphs. 32-34, where R ¹⁶ represents fluorine. 36. A compound selected from compounds of formula IIIa IIIa and their pharmaceutically acceptable salts, where R ¹⁰ is selected from hydrogen and methyl; R ⁸ and R ⁹ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups; W is selected from 3-8 membered carbocycles and 3-10 membered heterocycles containing 1-3 heteroatoms selected from nitrogen and oxygen, each of which may be substituted by 1-2 groups independently selected from halogen atoms, -NR ⁸ groups R ⁹ and C ₁ -C ₆ alkyl groups; X is independently selected from bond, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-3 groups independently selected from halogen atoms , hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C 1 -C ₆ alkyl groups, -SO _{2 -C 1} -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; Y is independently selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-3 groups independently selected from halogen atoms , hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C 1 -C ₆ alkyl groups, -SO _{2 -C 1} -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And each n is independently selected from 0-4. 37. A compound selected from compounds of formula IVa IVa or pharmaceutically acceptable salts thereof, where R ¹⁰ is selected from hydrogen and methyl; R ⁸ and R ⁹ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups; W is selected from 3-8 membered carbocycles and 3-10 membered heterocycles containing 1-3 heteroatoms selected from nitrogen and oxygen, each of which may be substituted by 1-3 groups independently selected from halogen atoms, -NR ⁸ groups R ⁹ and C ₁ -C ₆ alkyl groups; X is independently selected from bond, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-3 groups independently selected from halogen atoms , hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C 1 -C ₆ alkyl groups, -SO _{2 -C 1} -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; Y is independently selected from hydrogen, 3-8 membered carbocycles and 3-8 membered heterocycles containing 1-2 heteroatoms selected from nitrogen, sulfur and oxygen, each of which may be substituted by 1-3 groups independently selected from halogen atoms , hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C 1 -C ₆ alkyl groups, -SO _{2 -C 1} -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, where each of R ¹⁴ and R ¹⁵ is independently selected from hydrogen and C ₁ -C ₆ alkyl groups; each of L ¹ and L ² is independently selected from the relationship, -O-, -C(O)-, -C(O)O-, -N(R ¹³ )-C(O)-, -C(O)- N(R ¹³ )-, -N(R ¹³ )-S(O ₂ )-, -S(O ₂ )-N(R ¹³ )-, -S(O ₂ )- and -N(R ¹³ )- where R ¹³ is selected from hydrogen and C ₁ -C ₆ alkyl groups; And each n is independently selected from 0-4. 38. The compound of claim 37, wherein W is selected from a benzene ring, a pyridine ring, a benzimidazole ring, a benzotriazole ring, an indazole ring, a 1,2,3,6-tetrahydropyridine ring and an imidazopyridine ring, each of which may be optionally substituted with 1- 2 groups independently selected from halogen atoms and C ₁ -C ₆ alkyl groups. 39. The compound according to claim 37 or 38, where W represents a benzene ring, which may be optionally substituted with 1-2 groups selected from halogen atoms and C ₁ -C ₆ alkyl groups. 40. The connection according to any one of paragraphs. 37-39, where each of X and Y is independently selected from: each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups. 41. The connection according to any one of paragraphs. 37-39 where Y is hydrogen and X is selected from: each of which may be substituted by 1-2 groups independently selected from halogen atoms, hydroxyl groups, C ₁ -C ₆ alkyl groups, hydroxy-C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, methoxy-C ₁ - C ₆ alkyl groups, -SO ₂ -C ₁ -C ₆ alkyl groups and -NR ¹⁴ R ¹⁵ groups, wherein R ¹⁴ and R ¹⁵ are each independently selected from hydrogen and C ₁ -C ₆ alkyl groups. 42. The connection according to any one of paragraphs. 37-39 where Y represents hydrogen and X represents a bond. 43. Connection selected from: [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperazin-1-ylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-(4-methylpiperazin-1-yl)phenyl]prop- 1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-(1H-indazol-6-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-(1H-indazol-4-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(2-morpholin-4-ylpyridin-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(2-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-fluoro-3-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(3R)-3-(methylamino)pyrrolidine-1 -yl]phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(3S)-3-(methylamino)pyrrolidine-1 -yl]phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(2-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-fluoropyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-fluorophenyl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(3-methyl-5-morpholin-4-ylphenyl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-morpholin-4-yl-5-(trifluoromethyl)phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-chloro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2-hydroxyethyl)piperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-4-yl)carbamate; [(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3,4-dimethylpiperazine-1-carboxylate; [(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-propan-2-ylpiperazin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-tert-butylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclobutylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclopentylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3,5-difluorophenyl)prop-1-en-2-yl]-10-hydroxy-3,7- dimethyl 12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(dimethylamino)-5-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(4-hydroxypiperidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-(1-methylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(1R,5S)-8-oxa-3-azabicyclo[3.2.1] octan-3-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-hydroxypyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(3-oxopyrrolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(oxan-4-yl)piperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-3-yl)carbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(3-fluoroazetidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7SR,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-(methylamino)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3-(dimethylamino)piperidine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2R)-2-methylpyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxopyrrolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2S)-2-methylpyrrolidin-1-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-(methylamino)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(5-chloropyridin-3-yl)prop-1-en-2-yl]-10-hydroxy-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(pyridin-4-ylmethyl)carbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3,5-dichlorophenyl)prop-1-en-2-yl]-10-hydroxy-3,7- dimethyl 12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxo-1,2-thiazolidin-2-yl)phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(1,3-dimethylindazol-6-yl)prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxo-1,4-thiazinan-4-yl)-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N,N-dimethylcarbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxo-1,4-thiazinan-4-yl)-5-fluorophenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-morpholine-4-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin-4-yl) carbamate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(1-methylindazol-6-yl)prop-1-ene-2 -yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(3-oxomorpholin-4-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-(cyclopentylsulfamoyl)-2-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(4-methylsulfonylpiperazin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-fluoro-1H-indazol-6-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-imidazol-1-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7R,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6S,7R,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate; [(2S,3S,4E,6S,7R,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxoimidazolidin-1-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[3-(2-hydroxyethyl)-2-oxoimidazolidin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[3-(2-fluoroethynyl)-2-oxoimidazolidin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[3-(2-morpholin-4-ylethyl)-2-oxoimidazolidine-1- yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl]-5-fluorophenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(2S)-2-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-(2-methylmorpholin-4-yl)phenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-[(2S,3R)-3-hydroxy-2-methylpentyl]piperazine -1-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1 -carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-[(2R,3R)-3-hydroxy-2-methylpentanoyl]piperazine -1-yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1 -carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-morpholin-4-ylethylsulfonyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4-ethenylsulfonylpiperazin-1-yl)-5-fluorophenyl]prop-1-en-2-yl ]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3R)-3-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(2R)-2-(hydroxymethyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-(hydroxymethyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(2R)-2-(methylcarbamoyl)morpholin-4-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(2-oxo-1,3-diazinan-1-yl)phenyl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[3-(cyclopropylmethyl)-2-oxo-1,3-diazinan-1-yl]-5 -fluorophenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-[(2R)-2-hydroxypropanoyl]piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine -2-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-methylmorpholin-4-yl]phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(2-cyclopropyl-2-oxoethyl)piperazin-1-yl]-5-fluorophenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-oxo-2-pyrazin-2-ylethyl)piperazine-1 -yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate ; [(2S,3S,4E,6S,7R,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-7, 10-dihydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyclopropylmethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-imidazo[1,2-a]pyridin-6-ylprop-1-en-2-yl] -3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(7-methyl-1H-indazol-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-(cyclopropylsulfamoyl)-3-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-fluoro-5-(4-hydroxypiperidin-1-yl)sulfonylphenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2,2,2-trifluoroethyl)piperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperazin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4-formylpiperazin-1-yl)sulfonylphenyl]prop-1-en-2-yl]-10 -hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-(4-hydroxypiperidin-1-yl)sulfonylphenyl]prop-1-ene-2- yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(6-methyl-1H-indazol-4-yl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(1,3-dimethylindazol-4-yl)prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(1-azabicyclo[2.2.2]octan-3-yl)-N-methylcarbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-(cyclopropylmethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(2-hydroxyethyl)indazol-6-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(4-fluoro-1-methylindazol-6-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-[1-(pyridin-4-ylmethyl)pyrazol- 4-yl]prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(1-methylpyrazol-4-yl)prop-1-ene-2 -yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethyl)-3-oxopiperazin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-methoxyethyl)-3-oxopiperazin-1-yl]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[1-(1-methylpiperidin-4-yl)pyrazol-4- yl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-methoxyacetyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(cyclopropanecarbonyl)piperazin-1-yl]-5-fluorophenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(4-methoxyphenyl)sulfonylpiperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylpyrazol-4-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(4-pyridin-3-ylsulfonylpiperazin-1-yl)phenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylimidazol-4-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(cyclohexanecarbonyl)piperazin-1-yl]-5-fluorophenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylindol-6-yl)sulfonylpiperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(oxan-4-yl)indazol-6-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-2-(oxan-4-yl)indazol-6-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxane-4-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-morpholin-4-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1-methylimidazol-4-carbonyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[4-(2-cyclopropylacetyl)piperazin-1-yl]-5-fluorophenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(1,3-oxazol-5-carbonyl)piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyethylsulfonyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxetan-3-ylsulfonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-(1-hydroxyisoquinolin-7-yl)prop-1-en-2-yl]-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[4-fluoro-1-[2-(methylamino)-2-oxoethyl]indazol-6-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(2-oxo-2-pyrrolidin-1-ylethyl)indazol-6-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(2-morpholin-4-yl-2-oxoethyl)indazol-6-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyanomethyl)-4-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-[2-(dimethylamino)-2-oxoethyl]-4-fluorinazol-6-yl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyclopropylmethyl)-3-fluorinazol-6-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[4-(3-methoxypropanoyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-hydroxyacetyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(3-hydroxypropyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[2-(cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(cyclopropylmethyl)-7-fluorobenzotriazol-5-yl]prop-1-en-2-yl]- 10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(oxan-4-yl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-2-(oxan-4-yl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-(2-methoxyethyl)benzimidazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxolane-3-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4- yl]benzotriazol-5-yl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(4-chlorophenyl)methyl]-7-fluorobenzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-acetylpiperidin-4-yl)-7-fluorobenzimidazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(4-hydroxycyclohexyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(oxan-4-ylmethyl)benzotriazol-5-yl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(2S)-1-hydroxypropan-2-yl]benzotriazol-5-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(2R)-1-hydroxypropan-2-yl]benzotriazol-5-yl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-[(3S)-oxolan-3-carbonyl]piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-[(3R)-oxolan-3-carbonyl]piperazin-1-yl ]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(oxetane-3-carbonyl)piperazin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(3-methyloxetane-3-carbonyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(3-hydroxypropanoyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(4-methyloxan-4-yl)benzotriazol-5-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-(1-methylsulfonylpiperidin-4-yl)benzotriazol-5-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1,1-dioxothian-4-yl)-7-fluorobenzotriazol-5-yl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-(2-methoxyethyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-acetylpiperidin-4-yl)-7-fluorobenzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(3R)-oxan-3-yl]benzotriazol-5-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[7-fluoro-3-[(3S)-oxan-3-yl]benzotriazol-5-yl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-cyclohexyl-7-fluorobenzotriazol-5-yl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-(4-methoxyphenyl)benzotriazol-5-yl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[7-fluoro-3-[(4-methoxyphenyl)methyl]benzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-chloro-5-fluorophenyl)prop-1-en-2-yl]-10-hydroxy-3, 7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl(oxan-4-yl)amino]phenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl(oxetan-3-yl)amino]phenyl]prop-1-ene- 2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[methyl(oxan-4-yl)amino]phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[methyl(oxetan-3-yl)amino]phenyl] prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1,1-dioxothian-4-yl)-methylamino]-5-fluorophenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(1-methylsulfonylpiperidin-4-yl)amino]phenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-(1-methylsulfonylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-[ethyl-(1-methylsulfonylpiperidin-4-yl)amino]-5-fluorophenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(1-methylsulfonylpiperidin-4-yl)-propan-2-ylamino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-acetylpiperidin-4-yl)-methylamino]-5-fluorophenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-(1-propanoylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[[1-(2-methoxyacetyl)piperidin-4-yl]-methylamino]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-benzoylpiperidin-4-yl)-methylamino]-5-fluorophenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(2,2,2-trifluoroacetyl)piperidine-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-(1-propylsulfonylpiperidin-4-yl)amino]phenyl]prop-1 -en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-cyclopentylsulfonylpiperidin-4-yl)-methylamino]-5-fluorophenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(1-methylimidazol-4-yl)sulfonylpiperidin-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[[1-(benzenesulfonyl)piperidin-4-yl]-methylamino]-5-fluorophenyl]prop- 1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(1-acetylpiperidin-4-yl)methyl-methylamino]-5-fluorophenyl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[(1-methylsulfonylpiperidin-4-yl)methyl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(1,3-oxazol-5-carbonyl)piperidin- 4-yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin- 1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(pyrazin-2-carbonyl)piperidin-4-yl] amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(1-methylimidazol-4-carbonyl)piperidine-4- yl]amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1- carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(propan-2-ylcarbamoyl)piperidin-4-yl] amino]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(propylcarbamoyl)piperidin-4-yl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[methyl-[1-(phenylcarbamoyl)piperidin-4-yl]amino]phenyl] prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-(1-methylsulfonylpiperidin-4-yl)oxyphenyl]prop-1-ene-2- yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[1-(4,4-difluorocyclohexyl)-4-fluorinazol-6-yl]prop-1-ene-2 -yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[4-fluoro-1-(1-methylsulfonylpiperidin-4-yl)indazol-6-yl]prop-1- en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-pyrrolidin-1-ylsulfonylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(azetidin-1-ylsulfonyl)phenyl]prop-1-en-2-yl]-10-hydroxy -3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[(3R)-3-hydroxypyrrolidin-1-yl]sulfonylphenyl]prop-1- en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-[(2S)-2-methylpyrrolidin-1-yl] sulfonylphenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[(1-hydroxy-2-methylpropan-2-yl)sulfamoyl]phenyl]prop -1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(4,4-difluoropiperidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-(4-methyl-3-pyrrolidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(3,3-difluoropyrrolidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(5-pyrrolidin-1-ylsulfonylpyridin-3-yl )prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(3,3-difluoroazetidin-1-yl)sulfonylphenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[4-methyl-3-(2-oxopyrrolidin-1-yl) phenyl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(tert-butylsulfamoyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3 ,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-[3-(propan-2-ylsulfamoyl)phenyl] prop-1-en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-(ethylsulfamoyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-(4-methylpiperazin-1-yl)sulfonylphenyl]prop- 1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[3-(methylsulfamoyl)phenyl]prop-1-ene-2- yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-piperidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-2-[(E)-1-(3-pyrrolidin-1-ylsulfonylphenyl)prop-1 -en-2-yl]-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-cyclopropylsulfonylphenyl)prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl- 12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(cyclopropylsulfonylamino)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[(3S)-3-(methanesulfonamido)pyrrolidin-1-yl]phenyl]prop -1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(3S)-3-[(2-methoxyacetyl)amino]pyrrolidine-1- yl]phenyl]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-2-[(E)-1-[1-[(2-methylpropan-2-yl)oxycarbonyl]- 3,6-dihydro-2H-pyridin-5-yl]prop-1-en-2-yl]-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazin-1-carboxylate; [(2R,3R,4E,6R,7S,10S)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(trideuteriomethyl)piperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(pyridin-4-ylmethyl)carbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(pyrimidin-4-ylmethyl)carbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-morpholine-4-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(dimethylamino)ethyl]carbamate ; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methyl-1,4-diazepan-1 -carboxylate; [(2R,3R,4E,6R,7S,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[(4-methoxyphenyl)methyl]carbamate ; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-(dimethylamino)pyrrolidin- 1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3-(dimethylamino)pyrrolidin- 1-carboxylate; [(2R,3R,4E,6R,7S,10S)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[(2S)-1-hydroxypropan- 2-yl]carbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3-oxopiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-fluoropyrrolidine-1-carboxylate ; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,3,4-trimethylpiperazine-1-carboxylate ; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-methyl-N-(1-methylpiperidin- 4-yl)carbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(2-hydroxyethyl)piperazine-1- carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-piperazin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cycloheptylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-pyridin-4-ylpiperazin-1-carboxylate ; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-cyclohexylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(4-hydroxyphenyl)ethyl ]-N-methylcarbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(3-morpholin-4-ylpropyl)carbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-[2-(dimethylamino)ethyl]carbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-(dimethylamino)pyrrolidine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3S)-3-(dimethylamino)pyrrolidine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-N-(2-cyanoethyl)-N-methylcarbamate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-3,3,4-trimethylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-(3R)-3-fluoropyrrolidine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(dimethylsulfamoylamino)-5-fluorophenyl]prop-1-en-2-yl]-10-hydroxy- 3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7R,10S)-2-[(E)-1-[3-fluoro-5-[(2-methoxyacetyl)amino]phenyl]prop-1-en-2-yl ]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[(2-cyclopropylacetyl)amino]-5-fluorophenyl]prop-1-en-2-yl] -10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-[(3-hydroxyphenyl)methyl]piperazine -1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-fluoro-5-[4-(2-pyrazol-1-ylacetyl)piperazin-1-yl]phenyl ]prop-1-en-2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-(pyridin-3-ylmethyl)piperazin- 1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(1-acetylpiperidin-4-yl)-7-fluorobenzotriazol-5-yl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-piperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[[(3R)-3-hydroxypyrrolidine-1-carbonyl]oxymethyl]phenyl]prop -1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [3-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12- oxo-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]methyl-2-oxa-7-azaspiro[3.4]octane-7-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]pyridin-4 -yl]prop-1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [3-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-6-(4-methylpiperazine-1-carbonyl)oxy-12- oxo-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]methylmorpholine-4-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-(dimethylcarbamoyloxymethyl)phenyl]prop-1-en-2-yl]-10-hydroxy-3,7 -dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]oxymethyl] phenyl]prop-1-en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-[3-[[(3R)-3-fluoropyrrolidine-1-carbonyl]oxymethyl]phenyl]prop-1-ene -2-yl]-10-hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[(4-hydroxypiperidin-1-carbonyl)oxymethyl]phenyl]prop-1-ene -2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-methylpiperazine-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-2-[(E)-1-(3-fluoro-5-morpholin-4-ylphenyl)prop-1-en-2-yl]-10- hydroxy-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate; [(2S,3S,4E,6R,7S,10R)-10-hydroxy-2-[(E)-1-[3-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]prop-1 -en-2-yl]-3,7-dimethyl-12-oxo-1-oxacyclododec-4-en-6-yl]-4-piperidin-1-ylpiperidin-1-carboxylate; 2-[4-[3-fluoro-5-[(E)-2-[(2S,3S,4E,6R,7S,10R)-10-hydroxy-3,7-dimethyl-12-oxo-6- (piperazin-1-carbonyloxy)-1-oxacyclododec-4-en-2-yl]prop-1-enyl]phenyl]piperazin-1-yl]acetic acid; (2S,3S,6R,7S,10R,E)-2-((E)-1-(3-(dimethylamino)phenyl)prop-1-en-2-yl)-10-hydroxy-3,7- dimethyl 12-oxooxacyclododec-4-en-6-yl-4-methylpiperazine-1-carboxylate; and pharmaceutically acceptable salts thereof.