Pegylated prodrugs of steroid derivatives and related uses

Abstract

The present disclosure relates to pegylated steroid derivatives (e.g., progesterone derivatives) which may be useful in methods of treatment of the human or animal body. The present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders, such as managing inflammation (e.g., inflammation resulting from traumatic brain injury or stroke).

Description

Attorney Docket No.: NTSS-014 / 001 WO PEGYLATED PRODRUGS OF STEROID DERIVATIVES AND RELATED USESRELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U. S. Provisional Application No.63 / 738,025, filed December 23, 2024, the entire content of which is incorporated herein by reference in its entirety.FIELD OF DISCLOSURE

[0002] The present disclosure relates to pegylated prodrug steroid derivatives which may be useful in methods of treatment of the human or animal body. The present disclosure also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them and to their use in the treatment of disorders, such as managing inflammation (e.g., inflammation resulting from traumatic brain injury or stroke).BACKGROUND

[0003] Brain injuries, including traumatic brain injury (TBI) and stroke, affect over 2 million Americans each year and are a significant health concern worldwide. Traumatic brain injuries result from a blow or jolt to the head or a penetrating head injury that disrupts the function of the brain, with severity ranging from "mild," i.e., a brief change in mental status or consciousness to "severe," i.e., an extended period of unconsciousness or amnesia after the injury. Strokes are a result of diseases that affect the blood vessels that supply blood to the brain. A stroke occurs when a blood vessel that brings oxygen and nutrients to the brain either bursts (hemorrhagic stroke) or is clogged by a blood clot or some other mass (ischemic stroke). The majority of strokes are ischemic, however hemorrhagic strokes typically result in more severe injuries. Despite several decades of effort, scientists have not yet found a pharmacological agent that consistently improves outcomes after stroke or a TBI.

[0004] After a TBI or stroke, inflammation is a principle cause of secondary damage and longterm damage. Following insults to the central nervous system, a cascade of physiological events leads to neuronal loss including, for example, an inflammatory immune response and excitotoxicity resulting from disrupting the glutamate, acetylcholine, cholinergic, GABAA, and NMDA receptor systems. In these cases, a complex cascade of events leads to the delivery of blood-borne leucocytes to sites of injury to kill potential pathogens and promote tissue repair. However, the powerful 312043035 1Attorney Docket No.: NTSS-014 / 001 WOinflammatory response has the capacity to cause damage to normal tissue, and dysregulation of the innate, or acquired immune response is involved in different pathologies.

[0005] The disclosure arises from a need to provide further compounds for the treatment of disorders, including a TBI or stroke. In particular, compounds with improved physicochemical, pharmacological and pharmaceutical properties to existing compounds are desirable.SUMMARY

[0006] In some aspects, the present disclosure provides a compound of Formula I:or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:each Ri and R2 are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-7 cycloalkyl, 3- to 7-membered heterocyclyl, and C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Ria,or Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more Ria;each Ria is independently -OH, -NH2, -CN, halo, C1-6 alkyl, C1-6 alkoxy, -S(Ci-6 alkyl), C3-7 cycloalkyl, or 3- to 7-membered heterocyclyl;R3 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more R3a;each R3a is independently -O(Ra), -OC(O)ORa, -N(Ra)(Rb), -N(Ra)CO(Rb), -N(Ra)CO(ORb), -NHCON(Ra)(Rb), -CN, halo, C1-6 alkyl, -C(O)ORa, -S(C1-6 alkyl), or -C(O)N(Ra)(Rb);Rais H or C1-6 alkyl;Rbis H or C1-6 alkyl; and312043035 2Attorney Docket No.: NTSS-014 / 001 WOn is an integer from 2 to 115.

[0007] In some aspects, the compound is of Formula I, wherein:each Ri and R2 are independently selected from H, C1-6 alkyl, and C2-6 alkenyl,or Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group;R3 is C1-6 alkyl optionally substituted with one or more R3a;each R3a is independently -NH2, -CN, or -C(O)NH2; andn is an integer from 2 to 44.

[0008] In some embodiments, a plurality of compounds of Formula I are homogeneous (i.e., “monodisperse”).

[0009] In some embodiments, a plurality of compounds of Formula I are not heterogeneous (i.e., “polydisperse”).

[0010] In some embodiments, compounds of Formula I are comprised of a polydisperse mixture of PEG units with “n” = 5-115.[Oil] In some embodiments, compounds of Formula I are comprised of a polydisperse mixture of PEG units with “n” = 9-115.

[0012] In some embodiments, compounds of Formula I are “polydisperse” with >50% of isomer “n” content the number of PEG units “n.”

[0013] In some aspects, the present disclosure provides a method of managing inflammation (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0014] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutical composition of the present disclosure.

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed 312043035 3Attorney Docket No.: NTSS-014 / 001 WOinvention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0016] Other features and advantages of the disclosure will be apparent from the fol lowing detailed description and claims.BRIEF DESCRIPTION OF DRAWINGS

[0017] FIG. 1 depicts the asymmetry index after treatment with Compound M-9.15 in rats at varied dosages as compared to vehicle.

[0018] FIG. 2 depicts cortical water content after treatment with Compound M-9.15 in rats at varied dosages as compared to vehicle.

[0019] FIG. 3 depicts hippocampal water content after treatment with Compound M-9.15 in rats at varied dosages as compared to vehicle.

[0020] FIG. 4 depicts the asymmetry index after treatment with Compound M-11.15 in rats at varied dosages as compared to vehicle.

[0021] FIG. 5 depicts cortical water content after treatment with Compound M-11.15 in rats at varied dosages as compared to vehicle.

[0022] FIG. 6 depicts hippocampal water content after treatment with Compound M-11.15 in rats at varied dosages as compared to vehicle.DETAILED DESCRIPTION

[0023] The disclosure relates to pegylated prodrug of steroid derivatives useful for the managing inflammation. In some embodiments, compounds with improved physicochemical, pharmacological and pharmaceutical properties to existing steroid derivatives are desired.

[0024] In some aspects, the present disclosure provides a compound of Formula I:ACH3R.f R2312043035 4Attorney Docket No.: NTSS-014 / 001 WO(Formula I)or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:each Ri and R2 are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cs-7 cycloalkyl, 3- to 7-membered heterocyclyl, and C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Ria,or Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more Ria;each Ria is independently -OH, -NH2, -CN, halo, C1-6 alkyl, C1-6 alkoxy, -S(Ci-6 alkyl), C3-7 cycloalkyl, or 3- to 7-membered heterocyclyl;R3 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more R3a;each R3a is independently -O(Ra), -OC(O)ORa, -N(Ra)(Rb), -N(Ra)CO(Rb), -N(Ra)CO(ORb), -NHCON(Ra)(Rb), -CN, halo, C1-6 alkyl, -C(O)ORa, -S(C1-6 alkyl), or -C(O)N(Ra)(Rb);Rais H or C1-6 alkyl;Rbis H or C1-6 alkyl; andn is an integer from 2 to 115.

[0025] In some aspects, the compound is of Formula I, wherein:each R1 and R2 are independently selected from H, C1-6 alkyl, and C2-6 alkenyl,or Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group;R3 is C1-6 alkyl optionally substituted with one or more R3a;each R3a is independently -NH2, -CN, or -C(O)NH2; andn is an integer from 2 to 44.

[0026] In some aspects, the compound is of Formula I, wherein:each Ri and R2 are independently selected from H, C1-6 alkyl, and C2-6 alkenyl,or Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group;R3 is C1-6 alkyl optionally substituted with one or more R3a;each R3a is independently -NH2, -CN, or -C(O)NH2; and312043035 5Attorney Docket No.: NTSS-014 / 001 WOn is 9.

[0027] In some aspects, the compound is of Formula I, wherein:each Ri and R2 are independently selected from H, C1-6 alkyl, and C2-6 alkenyl, or Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group;R3 is C1-6 alkyl optionally substituted with one or more R3a;each R3a is independently -NH2, -CN, or -C(O)NH2; andn is 11.

[0028] It is understood that, for a compound of Formula I, R1, R2, R1a, R3, R3a, Ra, and Rbcan each be, where applicable, selected from the groups described herein, and any group described herein for any of R1, R2, R1a, R3, R3a, Ra, and Rbcan be combined, where applicable, with any group described herein for one or more of the remainder of R1, R2, R1a, R3, R3a, Ra, and Rb.

[0029] As generally described herein, each R1 and R2 are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, and C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Ria,or Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more Ria.

[0030] In some embodiments, each R1 and R2 are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, and C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Ria.

[0031] In some embodiments, each R1 and R2 are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, and C1-6 alkoxy,

[0032] In some embodiments, each Ri and R2 are independently selected from H, C1-6 alkyl, and C2-6 alkenyl.

[0033] In some embodiments, Ri is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or Cns alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Ria.

[0034] In some embodiments, R1 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy.312043035 6Attorney Docket No.: NTSS-014 / 001 WO

[0035] In some embodiments, Ri is H.

[0036] In some embodiments, Ri is Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Ria.

[0037] In some embodiments, Ri is Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy,

[0038] In some embodiments, Ri is Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more Ria.

[0039] In some embodiments, Ri is Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, or C1-6 alkoxy.

[0040] In some embodiments, Ri is Ci-e alkyl (e.g. linear or branched) optionally substituted with one or more Ria.

[0041] In some embodiments, Ri is C1-6 alkyl (e.g. linear or branched) substituted with one or more Ria.

[0042] In some embodiments, Ri is C1-6 alkyl (e.g. linear or branched).

[0043] In some embodiments, Ri is methyl. In some embodiments, Ri is ethyl. In some embodiments, Ri is propyl. In some embodiments, Ri is butyl. In some embodiments, Ri is pentyl. In some embodiments, Ri is hexyl. In some embodiments, Ri is isopropyl. In some embodiments, Ri is isobutyl. In some embodiments, Ri is isopentyl. In some embodiments, Ri is isohexyl. In some embodiments, Ri is secbutyl. In some embodiments, Ri is secpentyl. In some embodiments, Ri is sechexyl.

[0044] In some embodiments, Ri is methyl optionally substituted with one or more Ria. In some embodiments, Ri is ethyl optionally substituted with one or more Ria. In some embodiments, Ri is propyl optionally substituted with one or more Ria. In some embodiments, Ri is butyl optionally substituted with one or more Ria. In some embodiments, Ri is pentyl optionally substituted with one or more Ria. In some embodiments, Ri is hexyl optionally substituted with one or more Ria. In some embodiments, Ri is isopropyl optionally substituted with one or more Ria. In some embodiments, Ri is isobutyl optionally substituted with one or more Ria. In some embodiments, Ri is isopentyl optionally substituted with one or more Ria. In some embodiments, Ri is isohexyl optionally substituted with one or more Ria. In some embodiments, Ri is secbutyl optionally substituted with one or more Ria. In some embodiments, Ri is secpentyl optionally substituted312043035 7Attorney Docket No.: NTSS-014 / 001 WOwith one or more Ria. In some embodiments, Ri is sechexyl optionally substituted with one or more Ria.

[0045] In some embodiments, Ri is C2-6 alkenyl optionally substituted with one or more Ria.

[0046] In some embodiments, Ri is C2-6 alkenyl substituted with one or more Ria.

[0047] In some embodiments, Ri is C2-6 alkenyl.

[0048] In some embodiments, R1 is C2 alkenyl. In some embodiments, R1 is C3 alkenyl. In some embodiments, R1 is C4 alkenyl. In some embodiments, R1 is C5 alkenyl. In some embodiments, R1 is C6 alkenyl.

[0049] In some embodiments, R1 is C2 alkenyl optionally substituted with one or more R1a. In some embodiments, R1 is C3 alkenyl optionally substituted with one or more R1a. In some embodiments, R1 is C4 alkenyl optionally substituted with one or more R1a. In some embodiments, R1 is C5 alkenyl optionally substituted with one or more R1a. In some embodiments, R1 is C6 alkenyl optionally substituted with one or more R1a.

[0050] In some embodiments, Ri is C2-6 alkynyl optionally substituted with one or more Ria.

[0051] In some embodiments, Ri is C2-6 alkynyl substituted with one or more Ria.

[0052] In some embodiments, Ri is C2-6 alkynyl.

[0053] In some embodiments, Ri is C2 alkynyl. In some embodiments, Ri is C3 alkynyl. In some embodiments, Ri is C4 alkynyl. In some embodiments, R1 is C5 alkynyl. In some embodiments, R1 is C6 alkynyl.

[0054] In some embodiments, Ri is C2 alkynyl optionally substituted with one or more Ria. In some embodiments, Ri is C3 alkynyl optionally substituted with one or more Ria. In some embodiments, Ri is C4 alkynyl optionally substituted with one or more Ria. In some embodiments, Ri is C5 alkynyl optionally substituted with one or more Ria. In some embodiments, Ri is Ce alkynyl optionally substituted with one or more Ria.

[0055] In some embodiments, Ri is Ci-s alkoxy optionally substituted with one or more Ria.

[0056] In some embodiments, Ri is Ci-e alkoxy substituted with one or more Ria.

[0057] In some embodiments, Ri is Ci-s alkoxy.

[0058] In some embodiments, Ri is methoxy. In some embodiments, Ri is ethoxy. In some embodiments, Ri is propoxy. In some embodiments, Ri is butoxy. In some embodiments, Ri is pentoxy. In some embodiments, Ri is hexoxy.

[0059] In some embodiments, Ri is methoxy optionally substituted with one or more Ria. In some embodiments, Ri is ethoxy optionally substituted with one or more Ria. In some embodiments, Ri 312043035 8Attorney Docket No.: NTSS-014 / 001 WOis propoxy optionally substituted with one or more Ria. In some embodiments, Ri is butoxy optionally substituted with one or more Ria. In some embodiments, Ri is pentoxy optionally substituted with one or more Ria. In some embodiments, Ri is hexoxy optionally substituted with one or more Ria.

[0060] In some embodiments, Ri is C3-7 cycloalkyl or 3- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more Ria.

[0061] In some embodiments, Ri is C3-7 cycloalkyl or 3- to 7-membered heterocyclyl.

[0062] In some embodiments, Ri is C3-7 cycloalkyl optionally substituted with one or more Ria.

[0063] In some embodiments, Ri is C3-7 cycloalkyl substituted with one or more Ria.

[0064] In some embodiments, Ri is C3-7 cycloalkyl.

[0065] In some embodiments, Ri is C3 cycloalkyl. In some embodiments, Ri is C4 cycloalkyl. In some embodiments, Ri is Cs cycloalkyl. In some embodiments, Ri is C6 cycloalkyl. In some embodiments, Ri is C7 cycloalkyl.

[0066] In some embodiments, Ri is 3- to 7-membered heterocyclyl optionally substituted with one or more Ria.

[0067] In some embodiments, Ri is 3- to 7-membered heterocyclyl substituted with one or more Ria.

[0068] In some embodiments, Ri is 3- to 7-membered heterocyclyl.

[0069] In some embodiments, Ri is 3-membered heterocyclyl. In some embodiments, Ri is 4-membered heterocyclyl. In some embodiments, Ri is 5-membered heterocyclyl. In some embodiments, Ri is 6-membered heterocyclyl. In some embodiments, Ri is 7-membered heterocyclyl.

[0070] In some embodiments, Ri is 3-membered heterocyclyl optionally substituted with one or more Ria. In some embodiments, Ri is 4-membered heterocyclyl optionally substituted with one or more Ria. In some embodiments, Ri is 5-membered heterocyclyl optionally substituted with one or more Ria. In some embodiments, Ri is 6-membered heterocyclyl optionally substituted with one or more Ria. In some embodiments, Ri is 7-membered heterocyclyl optionally substituted with one or more Ria.

[0071] In some embodiments, R2 is H, C1-6 alkyl, or C2-6 alkenyl.

[0072] In some embodiments, R2 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more R1a.312043035 9Attorney Docket No.: NTSS-014 / 001 WO

[0073] In some embodiments, R2 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy.

[0074] In some embodiments, R2 is H.

[0075] In some embodiments, R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more R1a.

[0076] In some embodiments, R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy.

[0077] In some embodiments, R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more R1a.

[0078] In some embodiments, R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, or C1-6 alkoxy.

[0079] In some embodiments, R2 is C1-6 alkyl (e.g. linear or branched) optionally substituted with one or more R1a.

[0080] In some embodiments, R2 is C1-6 alkyl (e.g. linear or branched) substituted with one or more R1a.

[0081] In some embodiments, R2 is C1-6 alkyl (e.g. linear or branched).

[0082] In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl. In some embodiments, R2 is propyl. In some embodiments, R2 is butyl. In some embodiments, R2 is pentyl. In some embodiments, R2 is hexyl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is isobutyl. In some embodiments, R2 is isopentyl. In some embodiments, R2 is isohexyl. In some embodiments, R2 is secbutyl. In some embodiments, R2 is secpentyl. In some embodiments, R2 is sechexyl.

[0083] In some embodiments, R2 is methyl optionally substituted with one or more R1a. In some embodiments, R2 is ethyl optionally substituted with one or more R1a. In some embodiments, R2 is propyl optionally substituted with one or more R1a. In some embodiments, R2 is butyl optionally substituted with one or more R1a. In some embodiments, R2 is pentyl optionally substituted with one or more R1a. In some embodiments, R2 is hexyl optionally substituted with one or more R1a. In some embodiments, R2 is isopropyl optionally substituted with one or more R1a. In some embodiments, R2 is isobutyl optionally substituted with one or more R1a. In some embodiments, R2 is isopentyl optionally substituted with one or more R1a. In some embodiments, R2 is isohexyl optionally substituted with one or more R1a. In some embodiments, R2 is secbutyl optionally 312043035 10Attorney Docket No.: NTSS-014 / 001 WOsubstituted with one or more Ria. In some embodiments, R2 is secpentyl optionally substituted with one or more Ria. In some embodiments, R2 is sechexyl optionally substituted with one or more Ria.

[0084] In some embodiments, R2 is C2-6 alkenyl optionally substituted with one or more Ria.

[0085] In some embodiments, R2 is C2-6 alkenyl substituted with one or more Ria.

[0086] In some embodiments, R2 is C2-6 alkenyl.

[0087] In some embodiments, R2 is C2 alkenyl. In some embodiments, R2 is Cs alkenyl. In some embodiments, R2 is C4 alkenyl. In some embodiments, R2 is C5 alkenyl. In some embodiments, R2 is C6 alkenyl.

[0088] In some embodiments, R2 is C2 alkenyl optionally substituted with one or more Ria. In some embodiments, R2 is Cs alkenyl optionally substituted with one or more Ria. In some embodiments, R2 is C4 alkenyl optionally substituted with one or more R1a. In some embodiments, R2 is C5 alkenyl optionally substituted with one or more Ria. In some embodiments, R2 is C6 alkenyl optionally substituted with one or more R1a.

[0089] In some embodiments, R2 is C2-6 alkynyl optionally substituted with one or more Ria.

[0090] In some embodiments, R2 is C2-6 alkynyl substituted with one or more R1a.

[0091] In some embodiments, R2 is C2-6 alkynyl.

[0092] In some embodiments, R2 is C2 alkynyl. In some embodiments, R2 is Cs alkynyl. In some embodiments, R2 is C4 alkynyl. In some embodiments, R2 is Cs alkynyl. In some embodiments, R2 is Ce alkynyl.

[0093] In some embodiments, R2 is C2 alkynyl optionally substituted with one or more Ria. In some embodiments, R2 is C3 alkynyl optionally substituted with one or more Ria. In some embodiments, R2 is C4 alkynyl optionally substituted with one or more Ria. In some embodiments, R2 is C5 alkynyl optionally substituted with one or more R1a. In some embodiments, R2 is Ce alkynyl optionally substituted with one or more Ria.

[0094] In some embodiments, R2 is Ci-e alkoxy optionally substituted with one or more Ria.

[0095] In some embodiments, R2 is Ci-e alkoxy substituted with one or more Ria.

[0096] In some embodiments, R2 is Ci-e alkoxy.

[0097] In some embodiments, R2 is methoxy. In some embodiments, R2 is ethoxy. In some embodiments, R2 is propoxy. In some embodiments, R2 is butoxy. In some embodiments, R2 is pentoxy. In some embodiments, R2 is hexoxy.312043035 11Attorney Docket No.: NTSS-014 / 001 WO

[0098] In some embodiments, R2 is methoxy optionally substituted with one or more Ria. In some embodiments, R2 is ethoxy optionally substituted with one or more Ria. In some embodiments, R2 is propoxy optionally substituted with one or more Ria. In some embodiments, R2 is butoxy optionally substituted with one or more Ria. In some embodiments, R2 is pentoxy optionally substituted with one or more Ria. In some embodiments, R2 is hexoxy optionally substituted with one or more Ria.

[0099] In some embodiments, R2 is C3-7 cycloalkyl or 3- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more Ria.

[0100] In some embodiments, R2 is C3-7 cycloalkyl or 3- to 7-membered heterocyclyl.

[0101] In some embodiments, Rz is C3-7 cycloalkyl optionally substituted with one or more Ria.

[0102] In some embodiments, R2 is C3-7 cycloalkyl substituted with one or more Ria.

[0103] In some embodiments, Rz is C3-7 cycloalkyl.

[0104] In some embodiments, R2 is C3 cycloalkyl. In some embodiments, R2 is C4 cycloalkyl. In some embodiments, R2 is C5 cycloalkyl. In some embodiments, R2 is C6 cycloalkyl. In some embodiments, R2 is C7 cycloalkyl.

[0105] In some embodiments, Rz is 3- to 7-membered heterocyclyl optionally substituted with one or more Ria.

[0106] In some embodiments, Rz is 3- to 7-membered heterocyclyl substituted with one or more Ria.

[0107] In some embodiments, Rz is 3- to 7-membered heterocyclyl.

[0108] In some embodiments, Rz is 3-membered heterocyclyl. In some embodiments, Rz is 4- membered heterocyclyl. In some embodiments, Rz is 5-membered heterocyclyl. In some embodiments, Rz is 6-membered heterocyclyl. In some embodiments, Rz is 7-membered heterocyclyl,

[0109] In some embodiments, Rz is 3-membered heterocyclyl optionally substituted with one or more Ria. In some embodiments, Rz is 4-membered heterocyclyl optionally substituted with one or more Ria. In some embodiments, Rz is 5-membered heterocyclyl optionally substituted with one or more Ria. In some embodiments, Rz is 6-membered heterocyclyl optionally substituted with one or more Ria. In some embodiments, Rz is 7-membered heterocyclyl optionally substituted with one or more Ria.

[0110] In some embodiments, R2 is H, C1-6 alkyl, or C2-6 alkenyl.312043035 12Attorney Docket No.: NTSS-014 / 001 WO

[0111] In some embodiments, Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more Ria.

[0112] In some embodiments, Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl optionally substituted with one or more Ria.

[0113] In some embodiments, Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl substituted with one or more Ria.

[0114] In some embodiments, Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl.

[0115] In some embodiments, Ri and R2, together with the atoms to which they are attached, form a C3 cycloalkyl. In some embodiments, Ri and R2, together with the atoms to which they are attached, form a C4 cycloalkyl. In some embodiments, Ri and R2, together with the atoms to which they are attached, form a Cs cycloalkyl. In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C6 cycloalkyl. In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C7 cycloalkyl.

[0116] In some embodiments, Ri and R2, together with the atoms to which they are attached, form a C3 cycloalkyl optionally substituted with one or more Ria. In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C4 cycloalkyl optionally substituted with one or more R1a. In some embodiments, Ri and R2, together with the atoms to which they are attached, form a Cs cycloalkyl optionally substituted with one or more Ria. In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C6 cycloalkyl optionally substituted with one or more R1a. In some embodiments, R1 and R2, together with the atoms to which they are attached, form a C7 cycloalkyl optionally substituted with one or more R1a.

[0117] In some embodiments, Ri and R2, together with the atoms to which they are attached, form a 3- to 7-membered heterocyclyl group optionally substituted with one or more Ria.

[0118] In some embodiments, Ri and R2, together with the atoms to which they are attached, form a 3- to 7-membered heterocyclyl group substituted with one or more Ria.

[0119] In some embodiments, Ri and R2, together with the atoms to which they are attached, form a 3- to 7-membered heterocyclyl group.

[0120] In some embodiments, Ri and R2, together with the atoms to which they are attached, form a 3 -membered heterocyclyl group. In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 4-membered heterocyclyl group. In some embodiments, Ri and 312043035 13Attorney Docket No.: NTSS-014 / 001 WORc, together with the atoms to which they are attached, form a 5-membered heterocyclyl group. In some embodiments, Ri and R2, together with the atoms to which they are attached, form a 6-membered heterocyclyl group. In some embodiments, Ri and R2, together with the atoms to which they are attached, form a 7-membered heterocyclyl group.

[0121] In some embodiments, Ri and R2, together with the atoms to which they are attached, form a 3 -membered heterocyclyl group optionally substituted with one or more Ria. In some embodiments, Ri and R2, together with the atoms to which they are attached, form a 4-membered heterocyclyl group optionally substituted with one or more Ria. In some embodiments, Ri and R2, together with the atoms to which they are attached, form a 5-membered heterocyclyl group optionally substituted with one or more Ria. In some embodiments, Ri and R2, together with the atoms to which they are attached, form a 6-membered heterocyclyl group optionally substituted with one or more Ria. In some embodiments, R1 and R2, together with the atoms to which they are attached, form a 7-membered heterocyclyl group optionally substituted with one or more R1a.

[0122] As generally described herein, each Ria is independently -OH, -NH2, -CN, halo, C1-6 alkyl, C1-6 alkoxy, -S(Ci-6 alkyl), C3-7 cycloalkyl, or 3- to 7-membered heterocyclyl.

[0123] In some embodiments, each Ria is independently -OH.

[0124] In some embodiments, each Ria is independently -NH2.

[0125] In some embodiments, each Ria is independently -CN.

[0126] In some embodiments, each Ria is independently halo.

[0127] In some embodiments, each Ria is independently F, Cl, Br, or I.

[0128] In some embodiments, each Ria is independently F. In some embodiments, each Ria is independently Cl. In some embodiments, each Ria is independently Br. In some embodiments, each Ria is independently I,

[0129] In some embodiments, each Ria is independently C1-6 alkyl.

[0130] In some embodiments, each Ria is independently methyl. In some embodiments, each Ria is independently ethyl. In some embodiments, each Ria is independently propyl. In some embodiments, each Ria is independently butyl. In some embodiments, each Ria is independently pentyl. In some embodiments, each Ria is independently hexyl. In some embodiments, each Ria is independently isopropyl. In some embodiments, each Ria is independently isobutyl. In some embodiments, each Ria is independently isopentyl. In some embodiments, each Ria is independently isohexyl. In some embodiments, each Ria is independently secbutyl. In some312043035 14Attorney Docket No.: NTSS-014 / 001 WOembodiments, each Ria is independently secpentyd. In some embodiments, each Ria is independently sechexyl.

[0131] In some embodiments, each Ria is independently Ci-6 alkoxy.

[0132] In some embodiments, each Ria is independently methoxy. In some embodiments, each Ria is independently ethoxy. In some embodiments, each Ria is independently propoxy. In some embodiments, each Ria is independently butoxy. In some embodiments, each Ria is independently pentoxy. In some embodiments, each Ria is independently hexoxy.

[0133] In some embodiments, each Ria is independently -S(Ci-6 alkyl).

[0134] In some embodiments, each Ria is independently -S(Ci alkyl). In some embodiments, each Ria is independently -S(C2 alkyl). In some embodiments, each Ria is independently -S(Cs alkyl). In some embodiments, each Ria is independently -S(C4 alkyl). In some embodiments, each Ria is independently -S(Cs alkyl). In some embodiments, each Ria is independently -S(C6 alkyl).

[0135] In some embodiments, each Ria is independently C3-7 cycloalkyl.

[0136] In some embodiments, each Ria is independently Cs cycloalkyl. In some embodiments, each Ria is independently C4 cycloalkyl. In some embodiments, each Ria is independently Cs cycloalkyl. In some embodiments, each Ria is independently Ce cycloalkyl. In some embodiments, each Ria is independently C7 cycloalkyl.

[0137] In some embodiments, each Ria is independently 3- to 7-membered heterocyclyl.

[0138] In some embodiments, each Ria is independently 3-membered heterocyclyl. In some embodiments, each Ria is independently 4-membered heterocyclyl. In some embodiments, each Ria is independently 5-membered heterocyclyl. In some embodiments, each Ria is independently 6-membered heterocyclyl. In some embodiments, each Ria is independently 7-membered heterocyclyl.

[0139] As generally described herein, R3 is H, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Rsa.

[0140] In some embodiments, R is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or Ci-e alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Rsa.

[0141] In some embodiments, R3 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy.

[0142] In some embodiments, R3 is H.312043035 15Attorney Docket No.: NTSS-014 / 001 WO

[0143] In some embodiments, Ra is Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Raa.

[0144] In some embodiments, Ra is Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy.

[0145] In some embodiments, Ra is Ci-s alkyl, C2-6 alkenyl, C2-6 alkynyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with one or more Ra.

[0146] In some embodiments, Ra is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, or C1-6 alkoxy.

[0147] In some embodiments, Ra is Ci-s alkyl (e.g. linear or branched) optionally substituted with one or more Raa.

[0148] In some embodiments, Ra is Ci-s alkyl (e.g. linear or branched) substituted with one or more Ria.

[0149] In some embodiments, Ra is Ci-s alkyl (e.g. linear or branched).

[0150] In some embodiments, Ra is methyl. In some embodiments, Ra is ethyl. In some embodiments, Ra is propyl. In some embodiments, Ra is butyl. In some embodiments, Ra is pentyl. In some embodiments, Ra is hexyl. In some embodiments, Ra is isopropyl. In some embodiments, Ra is isobutyl. In some embodiments, Ra is isopentyl. In some embodiments, Ra is isohexyl. In some embodiments, Ra is secbutyl. In some embodiments, Ra is secpentyl. In some embodiments, Ra is sechexyl.

[0151] In some embodiments, Ra is methyl optionally substituted with one or more Raa. In some embodiments, R3 is ethyl optionally substituted with one or more R3a. In some embodiments, Ra is propyl optionally substituted with one or more Ria. In some embodiments, Ra is butyl optionally substituted with one or more Ria. In some embodiments, Ra is pentyl optionally substituted with one or more Raa. In some embodiments, Ra is hexyl optionally substituted with one or more Raa. In some embodiments, R3 is isopropyl optionally substituted with one or more R3a. In some embodiments, Ra is isobutyl optionally substituted with one or more Raa. In some embodiments, R3 is isopentyl optionally substituted with one or more R3a. In some embodiments, Ra is isohexyl optionally substituted with one or more Ra. In some embodiments, R3 is secbutyl optionally substituted with one or more R3a. In some embodiments, Ra is secpentyl optionally substituted with one or more Ra. In some embodiments, Ra is sechexyl optionally substituted with one or more Ra.312043035 16Attorney Docket No.: NTSS-014 / 001 WO

[0152] In some embodiments, Ra is C2-6 alkenyl optionally substituted with one or more Raa.

[0153] In some embodiments, R is C2-6 alkenyl substituted with one or more Raa.

[0154] In some embodiments, Ra is C2-6 alkenyl.

[0155] In some embodiments, R3 is C2 alkenyl. In some embodiments, R3 is C3 alkenyl. In some embodiments, Ra is C4 alkenyl. In some embodiments, R3 is C5 alkenyl. In some embodiments, R3 is C6 alkenyl.

[0156] In some embodiments, R3 is C2 alkenyl optionally substituted with one or more R3a. In some embodiments, R3 is C3 alkenyl optionally substituted with one or more R3a. In some embodiments, R3 is C4 alkenyl optionally substituted with one or more R3a. In some embodiments, R3 is C5 alkenyl optionally substituted with one or more R3a. In some embodiments, R3 is C6 alkenyl optionally substituted with one or more R3a.

[0157] In some embodiments, Ra is C2-6 alkynyl optionally substituted with one or more Raa.

[0158] In some embodiments, R3 is C2-6 alkynyl substituted with one or more R3a.

[0159] In some embodiments, Ra is C2-6 alkynyl.

[0160] In some embodiments, R3 is C2 alkynyl. In some embodiments, R3 is C3 alkynyl. In some embodiments, R3 is C4 alkynyl. In some embodiments, R3 is C5 alkynyl. In some embodiments, R3 is C6 alkynyl.

[0161] In some embodiments, R3 is C2 alkynyl optionally substituted with one or more R3a. In some embodiments, R3 is C3 alkynyl optionally substituted with one or more R3a. In some embodiments, R3 is C4 alkynyl optionally substituted with one or more R3a. In some embodiments, R3 is C5 alkynyl optionally substituted with one or more R3a. In some embodiments, R3 is C6 alkynyl optionally substituted with one or more R3a.

[0162] In some embodiments, R3 is C1-6 alkoxy optionally substituted with one or more R3a.

[0163] In some embodiments, R3 is C1-6 alkoxy substituted with one or more R3a.

[0164] In some embodiments, R3 is C1-6 alkoxy.

[0165] In some embodiments, R3 is methoxy. In some embodiments, R3 is ethoxy. In some embodiments, R3 is propoxy. In some embodiments, R3 is butoxy. In some embodiments, R3 is pentoxy. In some embodiments, R3 is hexoxy.

[0166] In some embodiments, R3 is methoxy optionally substituted with one or more R3a. In some embodiments, R3 is ethoxy optionally substituted with one or more R3a. In some embodiments, R3 is propoxy optionally substituted with one or more R3a. In some embodiments, R3 is butoxy optionally substituted with one or more R3a. In some embodiments, R3 is pentoxy optionally 312043035 17Attorney Docket No.: NTSS-014 / 001 WOsubstituted with one or more R3a. In some embodiments, R3 is hexoxy optionally substituted with one or more R3a.

[0167] In some embodiments, R3 is C3-7 cycloalkyl or 3- to 7-membered heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R3a.

[0168] In some embodiments, R3 is C3-7 cycloalkyl or 3- to 7-membered heterocyclyl.

[0169] In some embodiments, R3 is C3-7 cycloalkyl optionally substituted with one or more Rsa.

[0170] In some embodiments, R3 is C3-7 cycloalkyl substituted with one or more Rsa.

[0171] In some embodiments, R3 is C3-7 cycloalkyl.

[0172] In some embodiments, R3 is C3 cycloalkyl. In some embodiments, R3 is C4 cycloalkyl. In some embodiments, R3 is Cs cycloalkyl. In some embodiments, R3 is Co cycloalkyl. In some embodiments, R3 is C7 cycloalkyl.

[0173] In some embodiments, R3 is 3- to 7-membered heterocyclyl optionally substituted with one or more R3a.

[0174] In some embodiments, R3 is 3- to 7-membered heterocyclyl substituted with one or more Ria.

[0175] In some embodiments, R3 is 3- to 7-membered heterocyclyl.

[0176] In some embodiments, R3 is 3-membered heterocyclyl. In some embodiments, R3 is 4-membered heterocyclyl. In some embodiments, R3 is 5-membered heterocyclyl. In some embodiments, R3 is 6-membered heterocyclyl. In some embodiments, R3 is 7-membered heterocyclyl.

[0177] In some embodiments, R3 is 3-membered heterocyclyl optionally substituted with one or more R3a. In some embodiments, R3 is 4-membered heterocyclyl optionally substituted with one or more R3a. In some embodiments, R3 is 5-membered heterocyclyl optionally substituted with one or more R3a. In some embodiments, R3 is 6-membered heterocyclyl optionally substituted with one or more R3a. In some embodiments, R3 is 7-membered heterocyclyl optionally substituted with one or more R3a.

[0178] As generally described herein, each Rsa is independently -O(Ra), -OC(O)ORa, -N(Ra)(Rb), -N(Ra)CO(Rb), -N(Ra)CO(ORb), -NHCON(Ra)(Rb), -CN, halo, Ci-e alkyl, -C(O)ORa, -S(Ci-6 alkyl), or -C(())N(Ra)(Rb).

[0179] In some embodiments, each Rsa is independently -OH, -NH2, -CN, halo, C1-6 alkyl, -O(Ci- 6 alkyl), -C(O)ORa, -S(C1-6 alkyl), or -C(O)N(Ra)(Rb).

[0180] In some embodiments, each Rsa is independently -O(Ra).312043035 18Attorney Docket No.: NTSS-014 / 001 WO

[0181] In some embodiments, each Rsais independently -OH,

[0182] In some embodiments, each Rsa is independently -O(Ci-6 alkyl).

[0183] In some embodiments, each Rsais independently methoxy. In some embodiments, each Rsa is independently ethoxy. In some embodiments, each Rsa is independently propoxy. In some embodiments, each Rsais independently butoxy. In some embodiments, each Rsa is independently pentoxy. In some embodiments, each Rsa is independently hexoxy.

[0184] In some embodiments, each Rsa is independently -OC(O)ORa.

[0185] In some embodiments, each Rsa is independently -N(Ra)(Rb).

[0186] In some embodiments, each R3a is independently -NH2.

[0187] In some embodiments, each Rsa is independently -N(Ra)CO(Rb).

[0188] In some embodiments, each Rsa is independently -N(Ra)CO(ORb).

[0189] In some embodiments, each R3a is independently -NHCON(Ra)(Rb).

[0190] In some embodiments, each R3a is independently -CN.

[0191] In some embodiments, each R3a is independently halo.

[0192] In some embodiments, each R3a is independently F, Cl, Br, or I.

[0193] In some embodiments, each R3a is independently F. In some embodiments, each R3a is independently Cl. In some embodiments, each R3a is independently Br. In some embodiments, each R3a is independently I.

[0194] In some embodiments, each R3a is independently C1-6 alkyl.

[0195] In some embodiments, each R3a is independently methyl. In some embodiments, each R3a is independently ethyl. In some embodiments, each R3a is independently propyl. In some embodiments, each R3a is independently butyl. In some embodiments, each R3a is independently pentyl. In some embodiments, each R3a is independently hexyl. In some embodiments, each R3a is independently isopropyl. In some embodiments, each R3a is independently isobutyl. In some embodiments, each R3a is independently isopentyl. In some embodiments, each R3a is independently isohexyl. In some embodiments, each R3a is independently secbutyl. In some embodiments, each R3a is independently secpentyl. In some embodiments, each R3a is independently sechexyl.

[0196] In some embodiments, each R3a is independently -C(O)ORa.

[0197] In some embodiments, each R3a is independently -S(C1-6 alkyl).

[0198] In some embodiments, each R3a is independently -S(C1 alkyl). In some embodiments, each R3a is independently -S(C2 alkyl). In some embodiments, each R3a is independently -S(C3 alkyl).312043035 19Attorney Docket No.: NTSS-014 / 001 WOIn some embodiments, each R3a is independently -S(C4 alkyl). In some embodiments, each R3a is independently -S(C5 alkyl). In some embodiments, each R3a is independently -S(C6 alkyl).

[0199] In some embodiments, each R3a is independently -C(O)N(Ra)(Rb).

[0200] In some embodiments, each R3a is independently -NH2, -CN, or -C(O)NH2.

[0201] As generally described herein, Rais H or C1-6 alkyl.

[0202] In some embodiments, Rais H.

[0203] In some embodiments, Rais Ci-e alkyl.

[0204] In some embodiments, Rais methyl. In some embodiments, Rais ethyl. In some embodiments, Rais propyl. In some embodiments, Rais butyl. In some embodiments, Rais pentyl. In some embodiments, Rais hexyl. In some embodiments, Rais isopropyl. In some embodiments, Rais isobutyl. In some embodiments, Rais isopentyl. In some embodiments, Rais isohexyl. In some embodiments, Rais secbutyl. In some embodiments, Rais secpentyl. In some embodiments, Rais sechexyl.

[0205] As generally described herein, Rbis H or C1-6 alkyl.

[0206] In some embodiments, Rbis H.

[0207] In some embodiments, Rbis Ci-s alkyl.

[0208] In some embodiments, Rbis methyl. In some embodiments, Rbis ethyl. In some embodiments, Rbis propyl. In some embodiments, Rbis butyl. In some embodiments, Rbis pentyl. In some embodiments, Rbis hexyl. In some embodiments, Rbis isopropyl. In some embodiments, Rbis isobutyl. In some embodiments, Rbis isopentyl. In some embodiments, Rbis isohexyl. In some embodiments, Rbis secbutyl. In some embodiments, Rbis secpentyl. In some embodiments, Rbis sechexyl.

[0209] In some embodiments, n is an integer from 2 to 115.

[0210] In some embodiments, n is an integer from 2 to 110. In some embodiments, n is an integer from 2 to 105, In some embodiments, n is an integer from 2 to 100. In some embodiments, n is an integer from 2 to 95. In some embodiments, n is an integer from 2 to 90. In some embodiments, n is an integer from 2 to 85. In some embodiments, n is an integer from 2 to 80. In some embodiments, n is an integer from 2 to 75, In some embodiments, n is an integer from 2 to 70. In some embodiments, n is an integer from 2 to 65. In some embodiments, n is an integer from 2 to 60. In some embodiments, n is an integer from 2 to 55. In some embodiments, n is an integer from 2 to 50. In some embodiments, n is an integer from 2 to 45.312043035 20Attorney Docket No.: NTSS-014 / 001 WO

[0211] In some embodiments, n is an integer from 2 to 44. In some embodiments, n is an integer from 2 to 42. In some embodiments, n is an integer from 2 to 40. In some embodiments, n is an integer from 2 to 38. In some embodiments, n is an integer from 2 to 36. In some embodiments, n is an integer from 2 to 34. In some embodiments, n is an integer from 2 to 32. In some embodiments, n is an integer from 2 to 30, In some embodiments, n is an integer from 2 to 28. In some embodiments, n is an integer from 2 to 26. In some embodiments, n is an integer from 2 to 24. In some embodiments, n is an integer from 2 to 22. In some embodiments, n is an integer from 2 to 20. In some embodiments, n is an integer from 2 to 18. In some embodiments, n is an integer from 2 to 16. In some embodiments, n is an integer from 2 to 14. In some embodiments, n is an integer from 2 to 12.

[0212] In some embodiments, n is an integer from 2 to 10. In some embodiments, n is an integer from 2 to 9. In some embodiments, n is an integer from 2 to 8. In some embodiments, n is an integer from 2 to 7. In some embodiments, n is an integer from 2 to 6. In some embodiments, n is an integer from 2 to 5. In some embodiments, n is an integer from 2 to 4. In some embodiments, n is an integer from 2 to 3.

[0213] In some embodiments, n is 9 or 11.

[0214] In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 19. In some embodiments, n is 20. In some embodiments, n is 21. In some embodiments, n is 22. In some embodiments, n is 23. In some embodiments, n is 24. In some embodiments, n is 25, In some embodiments, n is 26. In some embodiments, n is 27. In some embodiments, n is 28. In some embodiments, n is 29. In some embodiments, n is 30. In some embodiments, n is 31, In some embodiments, n is 32, In some embodiments, n is 33. In some embodiments, n is 34. In some embodiments, n is 35. In some embodiments, n is 36. In some embodiments, n is 37. In some embodiments, n is 38. In some embodiments, n is 39. In some embodiments, n is 40. In some embodiments, n is 41. In some embodiments, n is 42. In some embodiments, n is 43. In some embodiments, n is 44.312043035 21Attorney Docket No.: NTSS-014 / 001 WO

[0215] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n,”

[0216] In some embodiments, compounds of Formula I are homogeneous or “monodisperse,” wherein the number of PEG units “n” is from 2 to 22.

[0217] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n” = 2-22 are > 99% homogenous with respect to “n.”

[0218] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n”::::2-22 are > 98% homogenous with respect to “n.”

[0219] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n”::::2-22 are > 97% homogenous with respect to “n.”

[0220] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n”::::2-22 are > 96% homogenous with respect to “n.”

[0221] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n” = 2-22 are > 95% homogenous with respect to “n.”

[0222] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n” = 2-22 are > 90% homogenous with respect to “n.”

[0223] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n” = 2-22 are > 88% homogenous with respect to “n.”

[0224] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n” = 2-22 are > 86% homogenous with respect to “n.”

[0225] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n” = 2-22 are > 84% homogenous with respect to “n.”

[0226] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n” = 2-22 are > 82% homogenous with respect to “n.”

[0227] In some embodiments, compounds of Formula I are homogeneous or “monodisperse” with the number of PEG units “n” = 2-22 are > 80% homogenous with respect to “n.”

[0228] In some embodiments, compounds of Formula I the number of PEG units “n” represents a distribution of isomers comprised of “poly disperse” distribution of PEG units isomers around “n.”

[0229] In some embodiments, compounds of Formula I are comprised of a polydisperse mixture of PEG units with “n”:::9-115.

[0230] In some embodiments, compounds of Formula I are comprised of a polydisperse mixture of PEG units with “n”:::10-18.312043035 22Attorney Docket No.: NTSS-014 / 001 WO

[0231] In some embodiments, compounds of Formula I are comprised of a poly disperse mixture of PEG units with “n” = 9-18.

[0022] In some embodiments, compounds of Formula I are comprised of a poly disperse mixture of PEG units with “n” = 8-18.

[0233] In some embodiments, compounds of Formula I are comprised of a poly disperse mixture of PEG units with “n” = 7-18.

[0234] In some embodiments, compounds of Formula I are comprised of a poly disperse mixture of PEG units with “n” = 6-18.

[0235] In some embodiments, compounds of Formula I are comprised of a poly disperse mixture of PEG units with “n” = 5-18.

[0236] In some embodiments, compounds of Formula I are “polydisperse” with >50% of isomer “n” content the number of PEG units “n.”

[0237] In some embodiments, the compound of Formula I is a prodrug of an oxime derivative of progesterone.

[0238] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is an integer from 2-115.

[0239] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is an integer from 2-44.

[0240] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 2.

[0241] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 3.

[0242] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 4.

[0243] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 5.

[0244] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 6.

[0245] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 7.

[0246] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 8.312043035 23Attorney Docket No.: NTSS-014 / 001 WO

[0247] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 9,

[0248] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 10,

[0249] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 11,

[0250] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 12.

[0251] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 13.

[0252] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 14.

[0253] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 15.

[0254] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 16.

[0255] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 17.

[0256] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 18.

[0257] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 19.

[0258] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 20.

[0259] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 21.

[0260] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 22.

[0261] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 23.

[0262] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 24.312043035 24Attorney Docket No.: NTSS-014 / 001 WO

[0263] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 25,

[0264] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 26,

[0265] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 27,

[0266] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 28.

[0267] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 29.

[0268] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 30.

[0269] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 31.

[0270] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 32.

[0271] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 33.

[0272] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 34.

[0273] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 35.

[0274] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 36.

[0275] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 37.

[0276] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 38.

[0277] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 39.

[0278] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 40.312043035 25Attorney Docket No.: NTSS-014 / 001 WO

[0279] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 41,

[0280] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 42,

[0281] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 43,

[0282] In some embodiments, the compounds of Table 1 are comprised of a monodisperse mixture wherein n is 44.

[0283] In some embodiments, the compounds of Table 1 are comprised of a polydisperse mixture wherein n is an integer from 2-115.

[0284] In some embodiments, the compounds of Table 1 are comprised of a polydisperse mixture wherein n is an integer from 2-44.

[0285] In some embodiments, the compound of Formula I is of Formula IV.

[0286] In some embodiments, the compound of Formula IV is a compound of Table 4.

[0287] In some embodiments, the compound of Formula I is of Formula V.

[0288] In some embodiments, the compound of Formula V is a compound of Table 5.

[0289] In some embodiments, the compound of Formula I is of Formula VI.

[0290] In some embodiments, the compound of Formula VI is a compound of Table 6.

[0291] In some embodiments, the compound of Formula I is of Formula VII.

[0292] In some embodiments, the compound of Formula VII is a compound of Table 7.

[0293] In some embodiments, the compound of Formula I is of Formula VIII.

[0294] In some embodiments, the compound of Formula VIII is a compound of Table 8.

[0295] In some embodiments, the compound of Formula I is of Formula IX.

[0296] In some embodiments, the compound of Formula IX is a compound of Table 9.

[0297] In some embodiments, the compound of Formula I is of Formula X.

[0298] In some embodiments, the compound of Formula X is a compound of Table 10.

[0299] In some embodiments, the compound of Formula I is of Formula XI.

[0300] In some embodiments, the compound of Formula XI is a compound of Table 11.

[0301] In some embodiments, the compound of Formula I is of Formula XII.

[0302] In some embodiments, the compound of Formula XII is a compound of Table 12.

[0303] In some embodiments, the compound of Formula I is of Formula XIII.

[0304] In some embodiments, the compound of Formula XIII is a compound of Table 13.312043035 26Attorney Docket No.: NTSS-014 / 001 WO

[0305] In some embodiments, the compound of Formula I is of Formula XIV.

[0306] In some embodiments, the compound of Formula XIV is a compound of Table 14.

[0307] In some embodiments, the compound of Formula I is of Formula XV.

[0308] In some embodiments, the compound of Formula XV is a compound of Table 15.

[0309] In some embodiments, the compound of Formula I is of Formula XVI.

[0310] In some embodiments, the compound of Formula XVI is a compound of Table 16.

[0311] In some embodiments, the compound of Formula I is of Formula XVII.

[0312] In some embodiments, the compound of Formula XVII is a compound of Table 17.

[0313] In some embodiments, the compound of Formula I is of Formula XVIII.

[0314] In some embodiments, the compound of Formula XVIII is a compound of Table 18.

[0315] In some embodiments, the compound of Formula I is of Formula XXII.

[0316] In some embodiments, the compound of Formula XXII is a compound of Table 22.

[0317] In some embodiments, the compound of Formula I is of Formula XLIV.

[0318] In some embodiments, the compound of Formula XLIV is a compound of Table 44.Table 1. Compounds of Formula ICmpd R1 R2 R3M-10 H H HM-ll Me H HM-12 Me Me HM-13 H H MeM-14 Me H MeM-15 Me Me MeM-16 Et H MeM-17 Et Me MeM-18 Et Et MeM-19 i-Pr H MeM-20 i-Pr Me MeM-21 Allyl H MeM-22 Allyl Me MeM-23 Allyl Allyl MeM-24 Pr H MeM-25 Pr Me MeM-26 Pr Pr MeM-27 i-Butenyl H Me 312043035 27Attorney Docket No.: NTSS-014 / 001 WOCmpd R1 R2 R3M-28 i-Butenyl Me MeM-29 i -Butyl H MeM-30 i-Butyl Me MeM-31 CH2CH=CHCH2MeM-32 CH2CH2CH2CH2 MeM-33 Me Me CH2CNM-34 Me Me CH2CH2CNM-35 Me Me CH₂CO₂Me M-36 Me Me CH2CO2HM-37 Me Me CH2CH2CO2H M-38 Me Me CH₂CONH₂ M-39 Me Me CH2CH2CONH2 M-40 Me Me CONH2M-41 Me Me CONMe₂M-42 Me Me CH2CH2NH2 M-43 Me Me CH2CH2NMe2 M-44 Me Me CH₂CH₂NHC(O)NMe₂M-45 Me Me CH2CH2NHCO2MeTable 4. Compounds of Formula IVCmpd R1 R2 R3M-4.10 H H HM-4.11 Me H HM-4.12 Me Me HM-4.13 H H MeM-4.14 Me H MeM-4.15 Me Me MeM-4.16 Et H MeAttorney Docket No.: NTSS-014 / 001 WO Cmpd Ri R2 RsM-4.17 Et Me MeM-4,18 Et Et MeM-4.19 i-Pr H MeM-4.20 i-Pr Me MeM-4.21 Allyl H MeM-4.22 Allyl Me MeM-4.23 Allyl Allyl MeM-4.24 Pr H MeM-4.25 Pr Me MeM-4.26 Pr Pr MeM-4.27 i-Butenyl H MeM-4.28 i-Butenyl Me MeM-4.29 i -Butyl H MeM-4.30 i-Butyl Me MeM-4.31 CH₂CH=CHCH₂ MeM-4.32 CH₂CH₂CH₂CH₂ MeM-4.33 Me Me CH2CNM-4.34 Me Me CH2CH2CNM-4.35 Me Me CH₂CO₂Me M-4.36 Me Me CH2CO2HM-4.37 Me Me CH2CH2CO2H M-4.38 Me Me CH₂CONH₂ M-4.39 Me Me CH2CH2CONH2 M-4.40 Me Me CONH2M-4.41 Me Me CONMe₂M-4.42 Me Me CH2CH2NH2 M-4.43 Me Me CH2CH2NMe2 M-4.44 Me Me CH₂CH₂NHC(O)NMe₂M-4.45 Me Me CH2CH2NHCO2MeAttorney Docket No.: NTSS-014 / 001 WO(Formula V)Table 5. Compounds of Formula VCmpd R1 R2 R3M-5.10 H H HM-5,11 Me H HM-5.12 Me Me HM-5.13 H H MeM-5.14 Me H MeM-5.15 Me Me MeM-5.16 Et H MeM-5.17 Et Me MeM-5.18 Et Et MeM-5.19 i-Pr H MeM-5.20 i-Pr Me MeM-5.21 Allyl H MeM-5,22 Allyl Me MeM-5.23 Allyl Allyl MeM-5.24 Pr H MeM-5.25 Pr Me MeM-5.26 Pr Pr MeM-5.27 i-Butenyl H MeM-5.28 i-Butenyl Me MeM-5.29 i-Butyl H MeM-5.30 i-Butyl Me MeM-5,31 CH2CH=CHCH2MeM-5.32 CH2CH2CH2CH2 MeM-5.33 Me Me CH2CNM-5.34 Me Me CH2CH2CNM-5.35 Me Me CH2CO2Me M-5.36 Me Me CH2CO2HM-5.37Me Me CH2CH2CO2HAttorney Docket No.: NTSS-014 / 001 WOCmpd Ri R2RsM-5.38 Me Me CH2CONH2 M-5.39 Me Me CH2CH2CONH2 M-5.40 Me Me CONH2M-5.41 Me Me CONMe2M-5.42 Me Me CH2CH2NH2 M-5.43 Me Me CH2CH2NMe2 M-5.44 Me Me CH2CH2NHC(O)NMe2M-5.45 Me Me CH2CH2NHCO2MeTable 6. Compounds of Formula VICmpd Ri R2RsM-6.10 H H HM-6.11 Me H HM-6.12 Me Me HM-6.13 H H MeM-6.14 Me H MeM-6.15 Me Me MeM-6.16 Et H MeM-6.17 Et Me MeM-6.18 Et Et MeM-6.19 i-Pr H MeM-6.20 i-Pr Me MeM-6.21 Allyl H MeM-6.22 Allyl Me MeM-6.23 Allyl Allyl MeM-6.24 Pr H MeM-6.25 Pr Me MeM-6.26 Pr Pr MeAttorney Docket No.: NTSS-014 / 001 WOCmpd R1 R2 R3M-6.27 i-Butenyl H MeM-6.28 i-Butenyl Me MeM-6.29 i-Butyl H MeM-6.30 i-Butyl Me MeM-6.31 CH2CH=CHCH2MeM-6.32 CH2CH2CH2CH2 MeM-6.33 Me Me CH2CNM-6.34 Me Me CH2CH2CNM-6.35 Me Me CH2CO2Me M-6.36 Me Me CH2CO2HM-6.37 Me Me CH2CH2CO2H M-6.38 Me Me CH2CONH2 M-6.39 Me Me CH2CH2CONH2 M-6.40 Me Me CONH2M-6.41 Me Me CONMe2M-6.42 Me Me CH2CH2NH2 M-6.43 Me Me CH2CH2NMe2M-6.44 Me Me CH2CH2NHC(O)NMe2M-6.45 Me Me CH2CH2NHCO2MeTable 7. Compounds of Formula VIICmpd R1R2R3M-7.10 H H HM-7.11 Me H HM-7.12 Me Me HM-7.13 H H MeM-7.14 Me H MeM-7.15 Me Me MeAttorney Docket No.: NTSS-014 / 001 WOCmpd Ri R2 RsM-7.16 Et H MeM-7.17 Et Me MeM-7.18 Et Et MeM-7.19 i-Pr H MeM-7.20 i-Pr Me MeM-7.21 Allyl H MeM-7.22 Allyl Me MeM-7.23 Allyl Allyl MeM-7.24 Pr H MeM-7.25 Pr Me MeM-7.26 Pr Pr MeM-7.27 i-Butenyl H MeM-7.28 i-Butenyl Me MeM-7.29 i-Butyl H MeM-7.30 i -Butyl Me MeM-7.31 CH2CH=CHCH2MeM-7.32 CH2CH2CH2CH2 MeM-7.33 Me Me CH2CNM-7.34 Me Me CH2CH2CNM-7.35 Me Me CH2CO2Me M-7.36 Me Me CH2CO2HM-7.37 Me Me CH2CH2CO2H M-7.38 Me Me CH2CONH2 M-7.39 Me Me CH2CH2CONH2 M-7.40 Me Me CONH2M-7.41 Me Me CONMe2M-7.42 Me Me CH2CH2NH2 M-7.43 Me Me CH2CH2NMe2M-7.44 Me Me CH2CH2NHC(O)NMe2 M-7.45 MeMe CH2CH2NHCO2MeAttorney Docket No.: NTSS-014 / 001 WO(Formula VIII)Table 8. Compounds of Formula VIIICmpd R1 R2 R3M-8.10 H H HM-8.11 Me H HM-8.12 Me Me HM-8.13 H H MeM-8.14 Me H MeM-8.15 Me Me MeM-8.16 Et H MeM-8.17 Et Me MeM-8.18 Et Et MeM-8.19 i-Pr H MeM-8.20 i-Pr Me MeM-8.21 Allyl H MeM-8.22 Allyl Me MeM-8.23 Allyl Allyl MeM-8.24 Pr H MeM-8.25 Pr Me MeM-8.26 Pr Pr MeM-8.27 i-Butenyl H MeM-8.28 i-Butenyl Me MeM-8.29 i-Butyl H MeM-8.30 i-Butyl Me MeM-8.31 CH2CH=CHCH2MeM-8.32 CH2CH2CH2CH2 MeM-8.33 Me Me CH2CNM-8.34 Me Me CH2CH2CNM-8.35 Me Me CH2CO2Me M-8.36 Me Me CH2CO2HM-8.37 Me Me CH2CH2CO2HAttorney Docket No.: NTSS-014 / 001 WOCmpd Ri R2RsM-8.38 Me Me CH2CONH2 XI-8.39 Me Me CH2CH2CONH2 M-8.40 Me Me CONH2M-8.41 Me Me CONMe2M-8.42 Me Me CH2CH2NH2 M-8.43 Me Me CH2CH2NMe2 M-8.44 Me Me CH2CH2NHC(O)NMe2M-8.45 Me Me CH2CH2NHCO2Mevr, R.-5V(Formula IX)Table 9. Compounds of Formula IXCmpd R1 R2 R3M-9.10 H H HM-9.11 Me H HM-9.12 Me Me HM-9.13 H H MeM-9.14 Me H MeM-9.15 Me Me MeM-9.16 Et H MeM-9.17 Et Me MeM-9.18 Et Et MeM-9.19 i-Pr H MeM-9.20 i-Pr Me MeM-9.21 Allyl H MeM-9.22 Allyl Me MeM-9.23 Allyl Allyl MeM-9.24 Pr H MeM-9.25 Pr Me MeM-9.26 Pr Pr MeM-9.27 i-Butenyl H MeAttorney Docket No.: NTSS-014 / 001 WOCmpd R1 R2 R3M-9.28 i-Butenyl Me MeM-9.29 i -Butyl H MeM-9.30 i-Butyl Me MeM-9,31 CH2CH=CHCH2MeM-9.32 CH2CH2CH2CH2 MeM-9.33 Me Me CH2CNM-9.34 Me Me CH2CH2CNM-9.35 Me Me CH2CO2Me M-9.36 Me Me CH2CO2HM-9.37 Me Me CH2CH2CO2H M-9.38 Me Me CH2CONH2M-9.39 Me Me CH2CH2CONH2 M-9.40 Me Me CONH2M-9.41 Me Me CONMe2M-9.42 Me Me CH2CH2NH2 M-9.43 Me Me CH2CH2NMe2 M-9.44 Me Me CH2CH2NHC(O)NMe2M-9.45 Me Me CH2CH2NHCO2Me M-9.46 Me Allyl Me(Formula X)Table 10. Compounds of Formula XCmpd Ri R2 RsM-10.10 H H HM-10.11 Me H HM-10.12 Me Me HM-10.13 H H MeM-10.14 Me H MeM-10.15 Me Me MeAttorney Docket No.: NTSS-014 / 001 WOCmpd Ri R2 RsM-l 0.16 Et H MeM-10.17 Et Me MeM-10.18 Et Et MeM-10.19 i-Pr H MeM-10.20 i-Pr Me MeM-10.21 Allyl H MeM-10.22 Allyl Me MeM-l 0.23 Allyl Allyl MeM-l 0.24 Pr H MeM-10.25 Pr Me MeM-10.26 Pr Pr MeM-10.27 i-Butenyl H MeM-l 0.28 i-Butenyl Me MeM-l 0.29 i-Butyl H MeM-l 0.30 i -Butyl Me MeM-10.31 CH2CH=CHCH2MeM- 10.32 CH2CH2CH2CH2 MeM-l 0.33 Me Me CH2CNM-l 0.34 Me Me CH2CH2CNM-10.35 Me Me CH2CO2Me M-l 0.36 Me Me CH2CO2HM-l 0.37 Me Me CH2CH2CO2H M-l 0.38 Me Me CH2CONH2 M-l 0.39 Me Me CH2CH2CONH2 M-10.40 Me Me CONH2M-l 0.41 Me Me CONMe2M-l 0.42 Me Me CH2CH2NH2 M-l 0.43 Me Me CH2CH2NMe2M-l 0.44 Me Me CH2CH2NHC(O)NMe2 M-l 0.45 MeMe CH2CH2NHCO2MeAttorney Docket No.: NTSS-014 / 001 WOTable 11. Compounds of Formula XICmpd Ri R2 RsM-11.10 H H HM-l l.ll Me H HM-11.12 Me Me HM-11.13 H H MeM-11.14 Me H MeM-11.15 Me Me MeM-11.16 Et H MeM-11.17 Et Me MeM-11.18 Et Et MeM-11.19 i-Pr H MeM-11.20 i-Pr Me MeM-11.21 Allyl H MeM-11.22 Allyl Me MeM-11.23 Allyl Allyl MeM- 11.24 Pr H MeM-11.25 Pr Me MeM-11.26 Pr Pr MeM- 11.27 i-Butenyl H MeM-11.28 i-Butenyl Me MeM- 11.29 i-Butyl H MeM-11.30 i-Butyl Me MeM-11.31 CH2CH=CHCH2MeM-11.32 CH2CH2CH2CH2 MeM-11.33 Me Me CH2CNM- 11.34 Me Me CH2CH2CNM-11.35 Me Me CH2CO2Me M-11.36 Me Me CH2CO2HM-11.37Me Me CH2CH2CO2HAttorney Docket No.: NTSS-014 / 001 WOCmpd Ri R2RsM-11.38 Me Me CH2CONH2M-11.39 Me Me CH2CH2CONH2 M-11.40 Me Me CONH2M-11.41 Me Me CONMe2M- 11.42 Me Me CH2CH2NH2 M-11.43 Me Me CH2CH2NMe2 M- 11.44 Me Me CH2CH2NHC(O)NMe2 M- 11.45 Me ClhCIENIICChMeMeTable 12. Compounds of Formula XIICmpd Ri R2R3M-12.10 H H HM-12.11 Me H HM-12.12 Me Me HM-12.13 H H MeM-12.14 Me H MeM-12.15 Me Me MeM-12.16 Et H MeM-12.17 Et Me MeM-12.18 Et Et MeM-12.19 i-Pr H MeM-12.20 i-Pr Me MeM-12.21 Allyl H MeM-12.22 Allyl Me MeM-12.23 Allyl Allyl MeM-12.24 Pr H MeM-12.25 Pr Me MeM-12.26 Pr Pr MeM-12.27 i-Butenyl H MeM-12.28 i-Butenyl Me MeAttorney Docket No.: NTSS-014 / 001 WOCmpd Ri R2 RsM-12.29 i-Butyl H MeM-12.30 i -Butyl Me MeM-12.31 CH2CH=CHCH2MeM-12.32 CH2CH2CH2CH2 MeM- 12.33 Me Me CH2CNM-12.34 Me Me CH2CH2CNM-12.35 Me Me CH2CO2Me M- 12.36 Me Me CH2CO2HM-12.37 Me Me CH2CH2CO2H M-12.38 Me Me CH2CONH2 M- 12.39 Me Me CH2CH2CONH2 M-12.40 Me Me CONH2M-12.41 Me Me CONMe2M- 12.42 Me Me CH2CH2NH2 M-12.43 Me Me CH2CH2NMe2M-12.44 Me Me CH2CH2NHC(O)NMe2M- 12.45 Me Me CH2CH2NHCO2Me(Formula XIII)Table 13. Compounds of Formula XIIICmpd Ri R2RsM-13.10 H H HM-13.11 Me H HM-13.12 Me Me HM-13.13 H H MeM-13.14 Me H MeM-13.15 Me Me MeM-13.16 Et H MeM-13.17 Et Me MeAttorney Docket No.: NTSS-014 / 001 WOCmpd Ri R2 RsM-13.18 Et Et MeM-13.19 i-Pr H MeM-13.20 i-Pr Me MeM-13.21 Allyl H MeM-13.22 Allyl Me MeM- 13.23 Allyl Allyl MeM-13.24 Pr II MeM-13.25 Pr Me MeM-13.26 Pr Pr MeM-13.27 i-Butenyl H MeM-13.28 i-Butenyl Me MeM-13.29 i-Butyl H MeM-13.30 i -Butyl Me MeM-13.31 CH2CH=CHCH2MeM-13.32 CH2CH2CH2CH2MeM- 13.33 Me Me CH2CNM-13.34 Me Me CH2CH2CNM-13.35 Me Me CH2CO2Me M-13.36 Me Me CH2CO2HM-13.37 Me Me CH2CH2CO2H M-13.38 Me Me CH2CONH2 M-13.39 Me Me CH2CH2CONH2 M-13.40 Me Me CONH2M-13.41 Me Me CONMe2M-13.42 Me Me CH2CH2NH2 M-13.43 Me Me CH2CH2NMe2M-13.44 Me Me CH2CH2NHC(O)NMe2M-13.45 Me Me CH2CH2NHCO2Me(Formula XIV)Attorney Docket No.: NTSS-014 / 001 WO Table 14, Compounds of Formula XIVCmpd R1 R2 R3M-14.10 H H HM-14,11 Me H HM-14.12 Me Me HM-14.13 II II MeM-14.14 Me H MeM-14.15 Me Me MeM-14.16 Et H MeM-14.17 Et Me MeM-14.18 Et Et MeM-14.19 i-Pr H MeM-14.20 i-Pr Me MeM-14.21 Allyl H MeM-14.22 Allyl Me MeM-14.23 Allyl Allyl MeM-14.24 Pr II MeM-14.25 Pr Me MeM-14.26 Pr Pr MeM-14.27 i-Butenyl H MeM-14.28 i-Butenyl Me MeM-14.29 i-Butyl H MeM-14.30 i-Butyl Me MeM-14.31 CH2CH=CHCH2MeM-14.32 CH2CH2CH2CH2MeM-14.33 Me Me CH2CNM-14.34 Me Me CH2CH2CNM-14,35 Me Me CH2CO2Me M-14.36 Me Me CH2CO2HM-14.37 Me Me CH2CH2CO2H M-14,38 Me Me CH2CONH2M-14.39 Me Me CH2CH2CONH2M-14.40 Me Me CONH2M-14,41 Me Me CONMe2M-14.42 Me Me CH2CH2NH2M-14.43 Me Me CH2CH2NMe2M-14.44 Me Me CH2CH2NHC(O)NMe2Attorney Docket No.: NTSS-014 / 001 WO Cmpd Ri R2RsM-14.45 Me Me CH2CH2NHCO2Me(Formula XV)Table 15. Compounds of Formula XVCmpd Ri R2RsM-15.10 H H HM-15.11 Me H HM-15.12 Me Me HM-15.13 H H MeM-15.14 Me II MeM-15.15 Me Me MeM-15.16 Et H MeM-15.17 Et Me MeM-15.18 Et Et MeM-15.19 i-Pr H MeM-15.20 i-Pr Me MeM-15.21 Allyl H MeM-15.22 Allyl Me MeM- 15,23 Allyl Allyl MeM- 15.24 Pr H MeM-15.25 Pr Me MeM- 15.26 Pr Pr MeM- 15.27 i-Butenyl H MeM-15.28 i-Butenyl Me MeM- 15.29 i-Butyl H MeM-15.30 i-Butyl Me MeM-15.31 CH2CH=CHCH2MeM-15.32 CH2CH2CH2CH2MeM-15.33 Me Me CH2CNM-15.34 Me MeCH2CH2CNAttorney Docket No.: NTSS-014 / 001 WOCmpd Ri R2RsM-15.35 Me Me CH2CO2Me M-15.36 Me Me CH2CO2HM-15.37 Me Me CH2CH2CO2H M-15.38 Me Me CH2CONH2M-15.39 Me Me CH2CH2CONH2M-15.40 Me Me CONH2M-15.41 Me Me CONMe2M-15.42 Me Me CH2CH2NH2M-15.43 Me Me CH2CH2NMe2M-15.44 Me Me CH2CH2NHC(O)NMe2M- 15.45 MeMe CH2CH2NHCO2MeTable 16. Compounds of Formula XVICmpd Ri R2RsM-16.10 H H HM-16.11 Me H HM-16.12 Me Me HM-16.13 H H MeM-16.14 Me H MeM-16.15 Me Me MeM-16.16 Et H MeM-16.17 Et Me MeM-16.18 Et Et MeM-16.19 i-Pr II MeM-16.20 i-Pr Me MeM-16.21 Allyl H MeM-16.22 Allyl Me MeM-16.23 Allyl Allyl MeAttorney Docket No.: NTSS-014 / 001 WOCmpd R1 R2 R3M-16.24 Pr H MeM- 16.25 Pr Me MeM-16.26 Pr Pr MeM-16.27 i-Butenyl H MeM-16.28 i-Butenyl Me MeM- 16.29 i -Butyl H MeM-16.30 i-Butyl Me MeM-16.31 CH2CH=CHCH2MeM-16.32 CH2CH2CH2CH2MeM-16.33 Me Me CH2CNM-16.34 Me Me CH2CH2CNM-16.35 Me Me CH2CO2Me M-16.36 Me Me CH2CO2HM- 16.37 Me Me CH2CH2CO2H M-16.38 Me Me CH2CONH2M-16.39 Me Me CH2CH2CONH2M- 16.40 Me Me CONH2M-16.41 Me Me CONMe2M-16.42 Me Me CH2CH2NH2M- 16.43 Me Me CH2CH2NMe2M-16.44 Me Me CH2CH2NHC(O)NMe2M-16.45 Me Me CH2CH2NHCO2Me(Formula XVII)Table 17. Compounds of Formula XVIICmpd R1 R2 R3M-17.10 H H HM-17.11 Me H HM-17.12 Me Me HAttorney Docket No.: NTSS-014 / 001 WOCmpd Ri R2 RsM-17.13 H H MeM-17.14 Me H MeM-17.15 Me Me MeM-17.16 Et H MeM-17.17 Et Me MeM-17.18 Et Et MeM-17.19 i-Pr II MeM-17.20 i-Pr Me MeM-17.21 Allyl H MeM-17.22 Allyl Me MeM-17.23 Allyl Allyl MeM-17.24 Pr H MeM- 17.25 Pr Me MeM-17.26 Pr Pr MeM- 17.27 i-Butenyl H MeM-17.28 i-Butenyl Me MeM- 17.29 i -Butyl H MeM-17.30 i-Butyl Me MeM-17.31 CH2CH=CHCH2MeM-17.32 CH2CH2CH2CH2MeM-17.33 Me Me CH2CNM-17.34 Me Me CH2CH2CNM-17.35 Me Me CH2CO2Me M-17.36 Me Me CH2CO2HM- 17.37 Me Me CH2CH2CO2H M-17.38 Me Me CH2CONH2M-17.39 Me Me CH2CH2CONH2M- 17.40 Me Me CONH2M-17.41 Me Me CONMe2M-17.42 Me Me CH2CH2NH2M- 17.43 Me Me CH2CH2NMe2M-17.44 Me Me CH2CH2NHC(O)NMe2M-17.45Me Me CH2CH2NHCO2MeAttorney Docket No.: NTSS-014 / 001 WOTable 18. Compounds of Formula XVTIICmpd Ri R2 RsM-18.10 H H HM-18.11 Me H HM-18.12 Me Me IIM-18.13 II H MeM-18.14 Me II MeM-18.15 Me Me MeM-18.16 Et H MeM-18.17 Et Me MeM-18.18 Et Et MeM-18.19 i-Pr H MeM-18.20 i-Pr Me MeM-18.21 Allyl H MeM-18.22 Allyl Me MeM- 18.23 Allyl Allyl MeM- 18.24 Pr H MeM-18.25 Pr Me MeM-18.26 Pr Pr MeM- 18.27 i-Butenyl H MeM- 18.28 i-Butenyl Me MeM- 18.29 i-Butyl H MeM-18.30 i-Butyl Me MeM- 18.31 CH2CH=CHCH2MeM-18.32 CH2CH2CH2CH2MeM-18.33 Me Me CH2CNM-18.34 Me Me CH2CH2CNM- 18.35 Me Me CH2CO2Me M-18.36 Me Me CH2CO2HM-18.37Me Me CH2CH2CO2HAttorney Docket No.: NTSS-014 / 001 WOCmpd Ri R2RsM-18.38 Me Me CH2CONH2M-18.39 Me Me CH2CH2CONH2M-18.40 Me Me CONH2M-18.41 Me Me CONMe2M-18.42 Me Me CH2CH2NH2M-18.43 Me Me CH2CH2NMe2M-18.44 Me Me CH2CH2NHC(O)NMe2M-18.45 Me Me CH2CH2NHCO2MeMeTable 22. Polydisperse Compounds of Formula XXII Cmpd R1 R2 R3P-22.10 H H HP-22,11 Me H HP-22.12 Me Me IIP-22.13 II II MeP-22.14 Me H MeP-22.15 Me Me MeP-22.16 Et H MeP-22.17 Et Me MeP-22.18 Et Et MeP-22.19 i-Pr H MeP-22.20 i-Pr Me MeP-22.21 Allyl H MeP-22.22 Allyl Me MeP-22.23 Allyl Allyl MeP-22.24 Pr II MeP-22.25 Pr Me MeP-22.26 Pr Pr MeAttorney Docket No.: NTSS-014 / 001 WOCmpd R1 R2 R3P-22.27 i-Butenyl H MeP-22.28 i-Butenyl Me MeP-22.29 i-Butyl H MeP-22.30 i -Butyl Me MeP-22.31 CH2CH=CHCH2MeP-22.32 CH2CH2CH2CH2MeP-22.33 Me Me CH2CNP-22.34 Me Me CH2CH2CNP-22.35 Me Me CH2CO2Me P-22.36 Me Me CH2CO2HP-22.37 Me Me CH2CH2CO2H P-22.38 Me Me CH2CONH2P-22.39 Me Me CH2CH2CONH2P-22.40 Me Me CONH2P-22.41 Me Me CONMe2P-22.42 Me Me CH2CH2NH2P-22.43 Me Me CH2CH2NMe2P-22.44 Me Me CH2CH2NHC(O)NMe2P-22.45Me Me CH2CH2NHCO2MeTable 44. Polydisperse Compounds of Formula XLIV Cmpd Ri Ri R?P-44.10 H H HP-44,11 Me H HP-44.12 Me Me HP-44.13 II II MeP-44.14 Me H MeAttorney Docket No.: NTSS-014 / 001 WOCmpd Ri R2 RsP-44.15 Me Me MeP-44.16 Et H MeP-44.17 Et Me MeP-44.18 Et Et MeP-44.19 i-Pr II MeP-44.20 i-Pr Me MeP-44.21 Allyl II MeP-44.22 Allyl Me MeP-44.23 Allyl Allyl MeP-44.24 Pr H MeP-44.25 Pr Me MeP-44.26 Pr Pr MeP-44.27 i-Butenyl H MeP-44.28 i-Butenyl Me MeP-44.29 i -Butyl H MeP-44.30 i-Butyl Me MeP-44.31 CH2CH=CHCH2MeP-44.32 CH2CH2CH2CH2MeP-44.33 Me Me CH2CNP-44.34 Me Me CH2CH2CNP-44.35 Me Me CH2CO2Me P-44.36 Me Me CH2CO2HP-44.37 Me Me CH2CH2CO2H P-44.38 Me Me CH2CONH2P-44.39 Me Me CH2CH2CONH2P-44.40 Me Me CONH2P-44.41 Me Me CONMe2P-44.42 Me Me CH2CH2NH2P-44.43 Me Me CH2CH2NMe2P-44.44 Me Me CH2CH2NHC(O)NMe2P-44.45Me Me CH2CH2NHCO2MeAttorney Docket No.: NTSS-014 / 001 WO

[0319] In some embodiments, the compound of Formula I is:

[0320] In some embodiments, the compound of Formula I is:Methods of Synthesis

[0321] Compounds of Formula I may be synthesized as depicted in Scheme 1 by coupling of the intermediate oxime derivative of progesterone, II, with mono or polydisperse PEGylated acylating intermediates of Formula III prepared from the corresponding carboxylic acid precursors. Intermediate II can be readily prepared in 2 steps from commercially available 5-pregnen-3(3-ol-20-one as described in US 2013 / 0210785.Scheme 1

[0322] PEGylated intermediates of Formula III can be prepared as reactive species from the corresponding carboxylic acid intermediates as depicted in Schemes 2 and Scheme 3. Compounds of Formula la, wherein Ri is as defined above for Formula I and Rz is hydrogen, can be synthesized as depicted in Scheme 2. As depicted in Scheme 2 the PEGylated reactive acylating intermediates of Formula Illa can be synthesized starting from PEG compounds of Formula IVa wherein Rs is as defined above for Formula I. In a first step compounds of Formula Via are prepared by alkylation of compounds of Formula IVa with alkylating agents of Formula Va under basic conditions established in the art. One example of a suitable condition involves the deprotonation of the 312043035 51Attorney Docket No.: NTSS-014 / 001 WOhydroxyl group of a compound of Formula IVa with a strong base (e.g, sodium hexamethyl disilazide or sodium hydride) in an aprotic organic solvent (e.g., THE or DMF) at low temperature (e.g, -70°C to 0°C) under inert atmosphere followed by addition of a compound of Formula Va and allowing the reaction mixture to warm to room temperature followed by standard aqueous workup after reaction completion. Alternatively, the alkylation reaction can be accomplished under phase transfer catalysis conditions in aqueous solution using sodium hydroxide as a base in the presence of a phase transfer catalyst such as a tetraalkylammonium salt.

[0323] In a second step carboxylic acid compounds of Formula Vila are prepared by t-butyl ester group cleavage of compounds of Formula Via using suitable acid or base mediated hydrolysis conditions. Examples of suitable acidic conditions include treatment with aqueous solutions together with HCl in an organic solvent (e.g., 4M HC1 in dioxane) in a temperature range of 0°C to 50° or treatment with trifluoroacetic acid in di chloromethane. Suitable basic conditions are treatment with excess NaOH in aqueous or methanol solvent systems in a temperature range of 0°C to 50°.a. b. Step 1 Step 2 IVa Va Via Vilaa. base mediated alkylation conditions (e.g., 1.1 eq. NaH, THF, 0-25 °C) b. t-butylester hydrolysis conditions (e.g., 4M HC1 dioxane, H2O, RT) c. active acylating intermediate formation conditions (e.g., for X = Cl, 2-2.5 eq. oxalylchloride, catalytic DMF, CH₂Cl₂, 0 °C) d. acylation conditions (e.g., Et2N, CH2C12, 0 °C)Scheme 2

[0324] In a third step carboxylic acid compounds of Formula Vila are converted to reactive acylating intermediates of Formula Illa which are not isolated but reacted directly with II under standard acylation conditions (e.g, in the presence of tertiary amine base) to provide compounds of 312043035 52Attorney Docket No.: NTSS-014 / 001 WOFormula la. Examples of reactive acylating intermediates of Formula Illa include, but are not limited to, acid chloride compounds of Formula Illa wherein X = Cl. Acid chloride compounds of Formula Illa wherein X = Cl can be synthesized from the corresponding carboxylic acid compounds of Formula Vila using synthetic methods that are established in the art. A suitable condition for the preparation of acid chloride compounds of Formula Illa is the treatment of carboxylic acid compounds of Formula VII in a solvent (e.g., dichloromethane or toluene) with excess oxalylchloride at 0-25°C. Compounds of Formula la can be prepared by addition of a toluene or dichloromethane solution of an acid chloride compound of Formula Ilia to a solution of II in a suitable aprotic organic solvent e.g., toluene, dichloromethane, isopropylacetate) comprising a suitable tertiary amine base (e.g., tri ethylamine or diisopropylethylamine) at 0-25°C. Other examples of reactive acylating intermediates of Formula Illa include active esters (e.g., pentafluorophenyl esters and hydroxybenzotriazole esters) which can be prepared using standard methods of organic synthesis. Alternatively reactive acylating agents of Formula Illa may be formed in situ and reacted with carboxylic acid compounds of Formula Vila under peptide coupling conditions using reagents that are standard in the art such as carbodiimides (e.g, dicyclohexylcarbodiimide), BOP reagents (e-g-, benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate), or HATU (1-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate).

[0325] Compounds of Formula lb wherein Ri and Rc are independently selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C3-7 cycloalkylalkyl, 3- to 7-membered heterocyclylalkyl, and C1-6 alkoxy can be synthesized as depicted in Scheme 3.312043035 53Docket No.: NTSS-014 / 001 WOa. lithium hexamethyldisilazide, THF, -70 °C, R?-I b. t-butylester hydrolysis conditions (e.g., 4M HC1 dioxane, H₂O, RT) c. active acylating intermediate formation conditions (e.g., for X = Cl, 2-2.5 eq. oxalylchloride, catalytic DMF, CH2CI2, 0 °C) d. acylation conditions (e.g., EtsN, CH2CI2, 0 °C)Scheme 3

[0326] In a first step, compounds of Formula Villa may be prepared by alkylation of compounds of the ester enolate anion of compounds of Formula VI with alkylating agents R2-X where X is a suitable leaving group (e.g., bromide, iodide, methanesulfonate or tnfhiorom ethanesulfonate) (X = Br, I, OSO2CH3, OSO2CF3). The ester enolates of compounds of Formula Via can be generated by treatment with one or more equivalents of a strong non-nucleophilic base (e.g., lithium hexamethyldisilazide, sodium hexamethyldisilazide, or lithium diisopropyamide) in an aprotic organic solvent (e.g., THF) at low temperature ca. -70 °C. Compounds of Formula Villa can be prepared by adding suitable alkylating agents R2-X (e.g., methyliodide for R₂ = Me, or allylbromide for R₂ = allyl) to the enolates of Formula VI at -70 °C and then allowing the solution to warm to room temperature. Compounds of Formula lb can be prepared in subsequent steps analogous to those detailed for the preparation on compounds of Formula la.R3-{o— 4o^c°2tBua. Grubbs catalyst" / (CH2)nCH=CH2b. H2 / Pd-C Villa ”c. HCIScheme 4312043035 54Attorney Docket No.: NTSS-014 / 001 WO

[0327] Compounds of Formula I wherein Ri and R2 together with the atoms to which they are attached, form a cycloalkyl or heterocyclyl group can be synthesized from corresponding intermediates of Formula Vila which can be synthesized by spiroalkylation (e.g, with BrCFhCFhBr to give RI, R2= cyclopropyl or C3) of compounds of Formula Via wherein Ri = H. Alternatively spirocyclic compounds of Formula I can be synthesized from corresponding intermediates of Formula IXa prepared via olefin metathesis methodology and functional group transformations established in the art as exemplified in Scheme 4.

[0328] Monodisperse PEG intermediates of Formula IVa, RsO-PEGn-OH, can be prepared from commercially available monodisperse PEG diols (HO-PEGx-OH) by methods described in the literature. In one exemplary method, a monodisperse PEG diol (HO-PEGx-OH) is first converted to the corresponding cyclic sulfate derivative in two steps: first by treatment with thionylchloride to provid a cyclic sulfite which is then oxidized in a subsequent step to the cyclic sulfate. Ring opening of the cyclic sulfate with the anion of an Rs group end capped monodisperse PEG, RsO-PEGy-OH, followed by hydrolysis of the terminal sulfate group of the product provides intermediates of Formula IVa with formula RsO-PEG(x+y)-OH.

[0329] A range of monomethoxy monodisperse PEG intermediates of Formula IV, MeO-PEGn-OH are commercially available or can be prepared as detailed above or using other methods.

[0330] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0331] In some aspects, the present disclosure provides a method of a compound, comprising one or more steps as described herein.

[0332] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein.

[0333] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.

[0334] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0335] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction312043035 55Attorney Docket No.: NTSS-014 / 001 WOtemperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art,

[0336] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized.Definitions

[0337] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0338] As used herein, “alkyl,” “Ci, Cc, Cs, (' ■. Cs or Ce alkyl” or “Ci-Ce alkyl” is intended to include C₁, C₂, C₃, C₄, C₅ or C₆ straight chain (linear) saturated aliphatic hydrocarbon groups and Cs, C4, Cs or Ce branched saturated aliphatic hydrocarbon groups. For example, C₁-C₆ alkyl is intends to include C₁, C₂, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for straight chain, Cs-Ce for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0339] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0340] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In 312043035 56Attorney Docket No.: NTSS-014 / 001 WOcertain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-Ce” includes alkenyl groups containing two to six carbon atoms. The term “Cs-Cs” includes alkenyl groups containing three to six carbon atoms,

[0341] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, ammo (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, aryl carbonyl amino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0342] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, Cs-Cs for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “Cs-Cs” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C₂, C₃, C₄, C₅ or C₆ chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C₂-C₆ alkenylene linker is intended to include C₂, C₃, C₄, C₅ and C₆ alkenylene linker groups.

[0343] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, aryl carbonyl oxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, 312043035 57Attorney Docket No.: NTSS-014 / 001 WOphosphinate, ammo (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0344] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridmyl.

[0345] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or Cb-Cs). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic.

[0346] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3- 8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g.t1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidmyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridmyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1 Jheptanyl, 2,5-diazabicyclo[2.2.1 ]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3,3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5jdecanyl, l-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-l,l'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-l,5'-furo[3,4-bjpyridin]-yl, 3'H-spiro[cyclohexane-l,r-furo[3,4-c]pyndin]-yl, 3-azabicyclo[3.1,0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, l,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pynmidinyl, 4,5,6,7-tetrahydro-lH-pyrazolo[3,4- 312043035 58Attorney Docket No.: NTSS-014 / 001 WOc]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyI-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyI-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro [3.4] octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0347] The cycloalkyl or heterocycloalkyl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, ammo (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0348] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a RM, and formulation into an efficacious therapeutic agent.

[0349] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.312043035 59Attorney Docket No.: NTSS-014 / 001 WO

[0350] When any variable (e.g, R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0351] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O’.

[0352] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0353] As used herein, the term “alkoxy” or “alkoxy!” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxy! radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and tri chloromethoxy.

[0354] It is understood that the compounds described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted benzene compound. Suitable anions may include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0355] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation 312043035 60Attorney Docket No.: NTSS-014 / 001 WOand a negatively charged group (e.g., carboxylate) on a substituted benzene compound. Suitable cations may include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The substituted benzene compounds also include those salts containing quaternary nitrogen atoms.

[0356] It is to be understood that the present disclosure provides methods for the synthesis of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0357] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0358] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable m certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0359] It is to be understood that compounds of Formula I, or a pharmaceutically acceptable salt thereof, can be prepared in a variety of ways using commercially available starting materials, compounds known m the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; Greene, T. W., Wuts, P G M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fiese ’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic312043035 61Attorney Docket No.: NTSS-014 / 001 WOSynthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art

[0360] One of ordinary' skill in the art will note that, during the reaction sequences and synthetic scheme described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognise that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T. W., Wuts, P G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999.

[0361] It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models.

[0362] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0363] As used herein, the term “subject” refers to a subject having a disease or having an increased risk of developing the disease. A “subject” includes a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human.

[0364] In some embodiments, the term “subject m need thereof” can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (re., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or 312043035 62Attorney Docket No.: NTSS-014 / 001 WOresistant a disease or disorder disclosed herein (i.e,, a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject in need thereof may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy,

[0365] It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0366] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, crystalline form or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model.

[0367] It is to be understood that a compound of Formula I, or a pharmaceutically acceptable salt thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes,

[0368] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0369] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel el al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al.. Current Protocols in Immunology, John Wiley & Sons, N. Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N. Y.; 312043035 63Attorney Docket No.: NTSS-014 / 001 WOFingl et al.. The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0370] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable excipient or carrier.

[0371] As used herein, the term “pharmaceutical composition” is a formulation containing a compound of Formula I, or a pharmaceutically acceptable salt thereof, in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. In some embodiments, routine variations are made to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with one or more pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0372] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, material, compositions, carriers, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0373] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used m the specification and claims may include both one and more than one such excipient.312043035 64Attorney Docket No.: NTSS-014 / 001 WO

[0374] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulphite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0375] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for managing inflammation. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g, a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[0376] As used herein, the term “therapeutically effective amount,” refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.

[0377] As used herein, the term “effective amount,” refers to an amount of a pharmaceutical agent to treat or ameliorate an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.312043035 65Attorney Docket No.: NTSS-014 / 001 WO

[0378] It is to be understood that, for any compound, the therapeutically effective amount or effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, such as rats, mice, rabbits, dogs, or pigs. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans, Therapeutic / prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50(the dose therapeutically effective in 50% of the population) and LD50(the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50 / ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0379] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy.

[0380] The pharmaceutical compositions containing a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable earner comprising excipients and / or auxiliaries that facilitate processing of a compound of Formula I, or a pharmaceutically acceptable salt thereof, into preparations that can be used pharmaceutically. The appropriate formulation is dependent upon the route of administration chosen.

[0381] The compound of Formula I, or a pharmaceutically acceptable salt thereof, can be prepared with one or more pharmaceutically acceptable carrier that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including an implant and microencapsulated delivery system.

[0382] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.312043035 66Attorney Docket No.: NTSS-014 / 001 WO

[0383] It is to be understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure.

[0384] As used herein, the term “pharmaceutically acceptable salts” refers to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making an acid or base salt thereof. Examples of pharmaceutically acceptable salts may include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts may include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts may include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulphonic, acetic, ascorbic, benzene sulphonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulphonic, 1,2-ethane sulphonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsamlic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulphonic, maleic, malic, mandelic, methane sulphonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulphamic, sulphanilic, sulphuric, tannic, tartaric, toluene sulphonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0385] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an argmine salt, or a lysine salt. In some embodiments, the pharmaceutically acceptable salt is a sodium salt.

[0386] Other examples of pharmaceutically acceptable salts may include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulphonic acid, 2-naphthalenesulphonic acid, 4-toluenesul phonic acid, camphorsulphomc acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l -carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood 312043035 67Attorney Docket No.: NTSS-014 / 001 WOthat the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0387] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19thedition, Mack Publishing Co,, Easton, PA (1995), In some embodiments, a compound of Formula I, or a pharmaceutically acceptable salt thereof, is used in pharmaceutical preparations in combination with one or more pharmaceutically acceptable carrier or diluent. A suitable pharmaceutically acceptable carrier includes, but is not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.

[0388] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.

[0389] In the synthetic scheme described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0390] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced m a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.

[0391] As use herein, the phrase “compound of the disclosure” refers to those compounds which are disclosed herein, both generically and specifically.312043035 68Attorney Docket No.: NTSS-014 / 001 WOSolubility Properties

[0392] In some embodiments of a Compound of Formula (I), when n is 2 the compound is water insoluble,

[0393] In some embodiments of a Compound of Formula (I), when n is 3 the compound is water insoluble,

[0394] In some embodiments, water insoluble is less than 0.1 mg / mL in an aqueous solution.Pharmaceutical Compositions

[0395] In some aspects, the present disclosure features pharmaceutical compositions comprising a compound of Formula I, or the pharmaceutically acceptable salt thereof, described herein, and one or more pharmaceutically acceptable carriers or excipients.

[0396] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0397] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, half-normal saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N. J.), dextrose 5% in water (D5 or D5W) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal 312043035 69Attorney Docket No.: NTSS-014 / 001 WOagents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin,

[0398] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.

[0399] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid earner for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0400] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0401] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal 312043035 70Attorney Docket No.: NTSS-014 / 001 WOadministration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art,

[0402] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and poly lactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.

[0403] It may be especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0404] In therapeutic applications, the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, among other factors affecting the selected dosage. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the symptoms of the disease and also causing complete regression of the disease.

[0405] It is understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.Methods of Use

[0406] In some aspects, the present disclosure features a method of preventing or treating a disease in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of Formula I, or the pharmaceutically acceptable salt thereof, described herein.

[0407] In some aspects, the present disclosure features a method of treating a disease in a subject, comprising administering to the subject a pharmaceutically effective amount of a compound of Formula I, or the pharmaceutically acceptable salt thereof, described herein.312043035 71Attorney Docket No.: NTSS-014 / 001 WO

[0408] In some aspects, the present disclosure features a compound of Formula I, or the pharmaceutically acceptable salt thereof, described herein for use in preventing or treating a disease in a subject.

[0409] In some aspects, the present disclosure features a compound of Formula I, or the pharmaceutically acceptable salt thereof, described herein for use in treating a disease in a subject.

[0410] In some aspects, the present disclosure features use of a compound of Formula I, or the pharmaceutically acceptable salt thereof, described herein in the manufacture of a medicament for preventing or treating a disease in a subject.

[0411] In some aspects, the present disclosure features use of a compound of Formula I, or the pharmaceutically acceptable salt thereof, described herein in the manufacture of a medicament for treating a disease in a subject.

[0412] In some aspects, the present disclosure features use of a compound of Formula I, or the pharmaceutically acceptable salt thereof, described herein for preventing or treating a disease in a subject.

[0413] In some aspects, the present disclosure features use of a compound of Formula I, or the pharmaceutically acceptable salt, thereof described herein for treating a disease in a subject.

[0414] In some embodiments, the disease or disorder is inflammation.

[0415] In some embodiments, the inflammation is inflammation resulting from a brain injury.

[0416] In some embodiments, the brain injury is regional cerebral edema.

[0417] In some embodiments, the regional cerebral edema is after CNS injury’.

[0418] In some embodiments, the bram injury’ is brain swelling.

[0419] In some embodiments, the brain injury is a traumatic brain injury (TBI).

[0420] In some embodiments, the inflammation is inflammation resulting from a TBI.

[0421] In some embodiments, the TBI is mild.

[0422] In some embodiments, the TBI is severe,

[0423] In some embodiments, the brain injury is a stroke.

[0424] In some embodiments, the inflammation is inflammation resulting from stroke.

[0425] In some embodiments, after a compound of Formula I, or a pharmaceutically acceptable salt thereof, is administered to the subject, the compound is cleaved to provide an oxime derivative of progesterone.

[0426] In some embodiments, the oxime derivative of progesterone is:312043035 72Attorney Docket No.: NTSS-014 / 001 WO

[0427] In some embodiments, the subject is an animal. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a cell. In some embodiments, the subject is a cell population.Exemplary’ Embodiments

[0428] Exemplary Embodiment 1. A compound of Formula IOFormula Ior a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:each R1 and R2 are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- 7 cycloalkyl, 3- to 7-membered heterocyclyl, and C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Ri a,or Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R;each Ria is independently -OH, -NH2, -CN, halo, Ci-6 alkyl, C1-6 alkoxy, -S(Ci-6 alkyl), C3-7 cycloalkyl, or 3- to 7-membered heterocyclyl;R3 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Rsa;312043035 73Attorney Docket No.: NTSS-014 / 001 WOeach Rsa is independently -0(Ra), -OC(O)ORa-N(Ra)(Rb), -N(Ra)CO(Rb), -N(Ra)CO(ORb), -NHCON(Ra)(Rb), -CN, halo, Ci-6 alkyl, -C(O)ORa, -S(Ci-6 alkyl), or -C(O)N(Ra)(Rb);Rais H or Ci-6 alkyl;Rbis H or C1-6 alkyl; andn is an integer from 2 to 115.

[0429] Exemplary Embodiment 2. The compound of Exemplary Embodiment 1, wherein:each Ri and R2 are independently selected from H, C 1-6 alkyl, and C2-6 alkenyl,or Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group;R3 is C1-6 alkyl optionally substituted with one or more R3a;each R3a is independently -NH2, -CN, or -C(O)NH2; andn is an integer from 2 to 44.

[0430] Exemplary Embodiment 3. The compound of any one of the preceding Exemplary Embodiments, wherein the compounds are monodisperse with the number of PEG units, n.

[0431] Exemplary Embodiment 4. The compound of any one of the preceding Exemplary Embodiments, wherein the compounds are polydisperse with the number of PEG units, n.

[0432] Exemplary Embodiment 5. The compound of any one of the preceding Exemplary Embodiments, wherein Ri is H, methyl, ethyl, isopropyl, isobutenyl, isobutyl, or propenyl.

[0433] Exemplary Embodiment 6. The compound of any one of the preceding Exemplary Embodiments, wherein R2 is H, methyl, or ethyl.

[0434] Exemplary Embodiment 7. The compound of any one of the preceding Exemplary Embodiments, wherein R3 is methyl or ethyl optionally substituted with one or more Ria.

[0435] Exemplary Embodiment 8. The compound of any one of the preceding Exemplary Embodiments, wherein each R3a is independently -NH2, -CN, or -C(O)N(Ra)(Rb)

[0436] Exemplary Embodiment 9. The compound of any one of the preceding Exemplary Embodiments, wherein Rais H.

[0437] Exemplary Embodiment 10. The compound of any one of the preceding Exemplary Embodiments, wherein Rbis H.

[0438] Exemplary Embodiment 11. The compound of any one of the preceding Exemplary Embodiments, wherein n is 9, 11, 12, 17, 22, or 44.

[0439] Exemplary Embodiment 12. The compound of any one of the preceding Exemplary Embodiments, wherein the compound is selected from Table 1 or Table 4-Table 18.312043035 74Attorney Docket No.: NTSS-014 / 001 WO

[0440] Exemplary Embodiment 13. A compound obtainable by, or obtained by, a method described herein.

[0441] Exemplary Embodiment 14. A pharmaceutical composition comprising the compound of any one of Exemplary Embodiments 1-12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0442] Exemplary Embodiment 15. The pharmaceutical composition of Exemplary Embodiment 13, wherein the compound is selected from a compound of Table 1, Table 4- Table 18, Table 22, or Table 44.

[0443] Exemplary Embodiment 16. A method of treating or preventing a disease or disorder in a subject in need thereof, wherein the subject is administered the compound of any one of Exemplary Embodiments 1-13 or the pharmaceutical composition of Exemplary Embodiment 14 or Exemplary Embodiment 15.

[0444] Exemplary Embodiment 17. A compound of any one of Exemplary Embodiments 1-13 or a pharmaceutical composition of Exemplary Embodiment 14 or Exemplary Embodiment 15 for use in treating or preventing a disease or disorder in a subject in need thereof.

[0445] Exemplary Embodiment 18. Use of a compound of any one of Exemplary Embodiments 1-13, or a pharmaceutical composition of Exemplary Embodiment 14 or Exemplary Embodiment 15, for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder in a subject in need thereof.

[0446] Exemplary Embodiment 19. Use of a compound of any one of Exemplary Embodiments 1-13, or a pharmaceutical composition of Exemplary’ Embodiment 14 or Exemplary Embodiment 15, for the treatment or prevention of a disease or disorder in a subject in need thereof.

[0447] Exemplary Embodiment 20. The method, composition, or use of any one of Exemplary- Embodiments 16-19, wherein the disease or disorder is inflammation.

[0448] Exemplary Embodiment 21. The method, composition, or use of any one of Exemplary-Embodiments 16-19, wherein the disease or disorder is a stroke or a traumatic brain injury.

[0449] The disclosure having been described, the following examples are offered by way of illustration and not limitation.312043035 75Attorney Docket No.: NTSS-014 / 001 WOEXAMPLES

[0450] For exemplary purpose, the compounds of Formula (I) are synthesized and tested in the examples. Further, it is understood that the compounds of Formula I may be converted to their corresponding salts using routine techniques in the art.

[0451] !H-NMR spectra of compounds of Formula (I) may not comprise peaks for each indivi dual proton due to masking from the compound and / or solvent. In some embodiments, the proton shielding is due to compounds that are highly water solvated.AbbreviationsCH3I: IodomethaneNaIO4: Sodium periodateRuCl3: Ruthenium ChlorideDCM: DichloromethaneDIPEA: N, N-DiisopropylethylamineDMAP: 4-DimethylaminopyridineEtOAc: Ethyl AcetateHCI: Hydrochloric acidHPLC: High-performance liquid chromatographyLiHMDS: Lithium bis(trimethylsilyl)amideMeOH: MethanolMS: Mass spectrometryNaH: Sodium HydrideNMR: Nuclear magnetic resonanceNaCI: Sodium chloridePyBop: benzotriazol- 1 -y loxytripyrrolidinophosphonium hexafluorophosphateBOP: Benzotriazole- 1 -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate RT: Room temperatureTHE: TetrahydrofuranUV: UltravioletM: MolarityACN: AcetonitrileCCI4: Carbon tetrachlorideH2O: WaterRM: Reaction mixture

[0452] Method A (HPLC Method Conditions): Column: Kinetex EVO, C18 (150x4.6) mm, 5 μm, 100 Å; Mobile phase-A: 0.1 % Formic Acid in (Aq); Mobile phase-B: ACN 100%; Method -T(min) / %B:- 0 / 10, 2 / 10, 6 / 85, 13 / 85, 14 / 10,15 / 10; Flow rate: 1.0 mL / min; Column temp: 30 °C; Diluent: ACN+H2O

[0453] Method B (HPLC Method Conditions): Column: ZORBAX Bonus-RP (150x4.6) mm, 3.5μm; Mobile phase-A:10Mm Ammonium Acetate in (Aq); Mobile phase-B: ACN 100%; Method312043035 76Attorney Docket No.: NTSS-014 / 001 WO-T(min) / %B:- 0 / 5, 2 / 5, 6 / 60, 9 / 100,13 / 100,14 / 5,15 / 5; Flow rate: 1.0 mL / min; Column temp: 30 °C; Diluent: ACN+H2O

[0454] Method C (HPLC Method Conditions): Column: Kinetex EVO C-18 (150x4.6) mm*5μ,100Å; Mobile phase-A:0.01M Ammonium Acetate (Aq); Mobile phase-B: ACN 100%; Method -T(min) / %B:-0 / 10, 2 / 10, 6 / 100, 10 / 100,11 / 10, 12 / 10; Flow rate: 1.0 mL / min; Column temp: 30 °C; Diluent: ACN+H2O

[0455] Method D (HPLC Method Conditions): Column: YMC Triart EXRS C18 (150x4.6) mm, 5μm, 100 Å; Mobile phase-A: 10Mm Ammonium Acetate in (Aq); Mobile phase-B: ACN 100%; Method -T(min) / %B:-0 / 10, 2 / 10, 6 / 100, 13 / 100, 14 / 10, 15 / 10; Flow rate: 1.0 mL / min; Column temp: 30 °C; Diluent: ACN+H2O

[0456] Method E (HPLC Method Conditions): Column: YMC Triart EX RS (150x4.6) mm, 5pm; Mobile phase-A: 0.05 % TFA in Water (100%); Mobile phase-B: Acetonitrile: Water (80:20); Method -T(min) / %B:- 0 / 30,5 / 30,15 / 70, 20 / 80, 30 / 80, 35 / 90, 40 / 100, 41 / 30, 50 / 30; Flow rate: 0.8 mL / min; Column temp: 25 °C; Diluent: Ethanol (100%), Sample Conc: 1.2 mg / mL. CAD Settings: Power function: 1.0, Evaporator Temp: 80 °C, Data rate: 2 Hz, Gas resolution mode: Analytical Filter: 5.0.Monodisperse ExamplesExample 1: (E)-19-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta|a]phenanthren-17-yI)-2, 5, 8, 11, 14, 17-hexaoxa-18-azaicos-18-en-16-oneStep-1: Synthesis of tert-butyl 2, 5, 8, 11, 14-pentaoxahexadecan- 16-oate

[0457] To a solution of monodisperse MeO-PEG4-OH (5.0 g, 24 mmol) in dry THF (60 mL), was added NaH (60% in mineral oil, 1.15 g, 48 mmol) at 0 °C. After hydrogen evolution ceased, tert- 312043035Attorney Docket No.: NTSS-014 / 001 WObutyl bromoacetate (7.03 g, 36 mmol) was added at 0 °C. The reaction mixture was stirred for 10-15 mm at 0 °C and then allowed to stir at room temperature until the reaction was completed based on TLC monitoring. The reaction mixture was quenched with ice at 0 °C, diluted with brine and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated under vacuum. The concentrate was purified by silica gel column chromatography with 2% MeOH-DCM as eluent to give 3.4 g of the title compound as a pale-yellow syrup. HPLC: Method-C (ELSD): 99.91. ESI-MS (calc-322.40, obser-323.2 (M+l)). 1H NMR (CDCl3) 400 MHz: δ ppm 3.78-3.74 (m, 1H), 3.74-3.60 (m, 15H), 3.58-3.52 (m, 2H), 3.37 (s, 3H), 1.47 (s, 9H).Step-2: Synthesis of 2, 5, 8, 11, 14-pentaoxahexadecan- 16-oic acid

[0458] A solution of tert-butyl 2, 5, 8, 11, 14-pentaoxahexadecan-16-oate (0.3 g, 0.9 mmol) in 4M HCl in 1,4-dioxane (3 mL) and H2O (1 mL) was stirred at RT overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3 times with 25 mL of toluene to give 0.23 g of the title compound as pale brown syrup. ESI-MS (calc-266.29, obser.265,15 (M-l)).1H NMR (CDCl3) 400 MHz: δ ppm 7.0-5.9 (bs, 1H), 4.16 (s, 2H), 3.80-3.60 (m, 14H), 3.6-3.52 (m, 2H), 3.39 (s, 3H).Step-3: Synthesis of 2, 5, 8, II, 14-pentaoxahexadecan- 16-oyl chloride

[0459] Oxalyl chloride (0.1 mL, 1.0 mmol) and DMF (0.1 mL) were added at 0 °C to a stirred solution of the 2, 5, 8, 11, 14-pentaoxahexadecan- 16-oic acid (0.23 g, 0.86 mmol) in dry DCM (5 mL). The reaction mixture was allowed to warm to room temperature, stirred 1 h and concentrated to give 0.25 g of the title compound as pale brown gummy syrup which was used directly in the next step.Step-4: (E)-19-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2, 5, 8, 11, 14, 17-hexaoxa-18-azaicos-18-en-16-oneAttorney Docket No.: NTSS-014 / 001 WO

[0460] (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-1-(hydroxyimino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.35 g, 1.05 mmol) was dissolved in 3 mL of dry DCM and then triethylamine (0.6 mL, 4.4 mmol) was added to the reaction mixture. Crude 2, 5, 8, 11, 14-pentaoxahexadecan- 16-oyl chloride (0.25 g) was dissolved in 2 mL of DCM and added at 0 °C. The reaction mixture was allowed to warm to room temperature and the mixture stirred overnight. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with sat. NaHCOs solution and concentrated under reduced pressure. The crude product was purified by Combi-Flash chromatography over silica gel column. The crude concentrate dissolved in a minimum volume DCM was loaded on column and then eluted first with 30-50% EA / hexane gradient to remove non¬ polar impurities. Then the column was eluted using 4% MeOH-DCM solvent gradient to give 0.15 g of the title compound as a pale brown gummy syrup. HPLC: Method-D (UV@ 240 nm): 97%, LC-MS (calc-577.36, obser-(M+H2O): 595.40, HRMS: (M+1): 578.3560, 1H NMR (CDCl3) 400 MHz: δ ppm 5.74 (s, 1H), 4.35 (s, 2H), 3.8-3.6 (m, 15H), 3.60-3.50 (m, 2H), 3.38 (s, 3H), 2.50-2.20 (m, 6H), 2.10-1.82 (m, 7H), 1.80-1.70 (m, 4H), 1.50-1.30 (m, 5H), 1.19 (s, 4H), 1.10-0.9 (m, 3H), 0.71 (s, 3H).Example 2: (E)-19-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-15-methyl-2, 5, 8, 11, 14, 17-hexaoxa-18-azaicos-18-en-16-oneStep-1: Synthesis of tert-butyl 15-methyl-2, 5, 8, 11, 14-pentaoxahexadecan-16-oate

[0461] To a solution of monodisperse MeO-PEG4-OH (5.0 g, 24 mmol) in dry THF (60 mL), NaH (60% in mineral oil, 1.15 g, 48 mmol) was added at 0 °C. After hydrogen evolution ceased, t-butyl 2-bromopropionate (7.53 g, 36 mmol) was added at 0 °C, The mixture was stirred for 10-15 min at 0 °C and then allowed to stir at room temperature until the reaction was completed based on TLC monitoring. The reaction mixture was quenched with ice at 0 °C, diluted with brine and extracted 312043035 79Attorney Docket No.: NTSS-014 / 001 WOwith EtOAc, The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The concentrate was rinsed with pentane, dried under vacuum and then dissolved in water. The aqueous solution containing the crude product was extracted with 30% ether-hexane to remove nonpolar impurities. The aqueous phase was saturated with NaCl and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give 2.4 g of the title compound as a colorless syrup. HPLC: Method-C (ELSD): 99%, ESI-MS (calc-336.43, obser-353.2 (M+H2O)). 1H NMR (CDCl3) 400 MHz: δ ppm 3.89 (q, J1=6.8Hz, J2=13.6Hz, 1H), 3.78-3.71 (m, 1H), 3.70-3.62 (m, 15H), 3.58-3.52 (m, 3H), 3.38 (s, 3H), 1.47 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).Step-2: Synthesis of 15-methyl-2, 5, 8, 11, 14-pentaoxahexadecan- 16-oic acido

[0462] A solution of tert-butyl 15-methyl-2, 5, 8, 11, 14-pentaoxahexadecan-16-oate (2.4 g, 7.1 mmol) in 4M HCl in dioxane (10 mL) and H2O (2 mL) was stirred at RT overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3x with 25 mL of toluene to give 1.9 g of the title compound as pale yellow syrup. HPLC: Method-C (ELSD): 99%. 1H NMR (CDCl3) 400 MHz: δ ppm 12.57 (bs, 1H), 3.93 (q, J1=6.8 Hz, J2=14Hz, 1H), 3.64-3.58 (m, 1H), 3.54-3.49 (m, 14H), 3.48-3.45 (m, 1H), 3.44-3.40 (m, 3H), 3.23 (s, 3H), 1.25 (d, J=6.8Hz, 3H).Step-3: Synthesis of 15-methyl-2, 5, 8, 11,14-pentaoxahexadecan-16-oyl chlorideo

[0463] Oxalyl chloride (0.56 g, 4.5 mmol) and DMF (0.1 mL) were added at 0 °C to a stirred solution of 15-methyl-2, 5, 8, 11, 14-pentaoxahexadecan-16-oic acid (0.5 g, 1.8 mmol) in dry DCM (20 mL). The reaction mixture was allowed to warm to room temperature, stirred overnight, and concentrated to give 0.55 g of the title compound as pale brown syrup which was used directly in the next step.Step-4: Synthesis of (E)-19-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-15-methyl-2, 5, 8, 11, 14, 17-hexaoxa-18-azaicos-18-en-16-one312043035 80Attorney Docket No.: NTSS-014 / 001 WO

[0464] (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.55 g, 1.67 mmol) was dissolved in 10 mL of dry DCM and then triethylamine (0.84 g, 8.35 mmol) was added to the reaction mixture. The crude compound 15-methyl-2, 5, 8, 11, 14-pentaoxahexadecan- 16-oyl chloride was dissolved in 10 mL of DCM and added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with sat. NaHCO3solution and concentrated under reduced pressure to obtain crude product as a brown syrup which was purified by Combi-Flash chromatography over silica gel column that was first preconditioned by elution with 2% TEA-hexane solvent mixture. The crude concentrate dissolved in a minimum volume DCM was loaded on column and then eluted with 30-50% EA / hexane (2% TEA) gradient to remove non-polar impurities. Then the column was eluted using 2-5% MeOH-DCM solvent gradient to give 0.44 g of the title compound as a pale yellow syrup. HPLC: Method-C (UV@ 210 nm): 99%, LC-MS (calc-591.79, observed-(M+H2O): 609.40.1H NMR (CDCh) 400 MHz: d ppm 5.739 (s, IH), 4.19 (q, J1=6.8 Hz, J2=13.6 Hz, 1H), 3.82-3.79 (m, IH), 3.67-3.62 (m, 14H), 3.56-3.54 (m, 2H), 3.39 (s, 3H), 2.50-2.20 (m, 6H), 2.10-2.0 (m, IH), 1.968 (m, 3H), 1.9-1.60 (m, 6H), 1.60-1.50 (m, IH), 1.49 (d, J=6.8, 3H), 1.42-1.25 (m, 4H), 1.19 (s, 3H), 1.10-0.90 (m, 3H), 0.737 (s, 3H).Example 3: (E)-19-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta(a|phenanthren- 17-yl)- 15, 15-dimethyI-2, 5, 8, 11, 14, 17-hexaoxa-18-azaicos-18-en-16-one312043035 81Attorney Docket No.: NTSS-014 / 001 WOStep- 1: Synthesis of tert-butyl 15, 15-dimethyl-2, 5, 8, 11, 14-pentaoxahexadecan- 16-oate

[0465] To a stirred solution of tert-butyl 15-methyl-2, 5, 8, 11, 14-pentaoxahexadecan- 16-oate (1,0 g, 3.0 mmol) in dry THF (20 mL) was added a solution of 2.0 M LDA in THF (15 mL, 30 mmol) at -78 °C under argon atmosphere. The reaction mixture was stirred at -50 °C for 30 min. followed by addition of CH3I (1.85 mL, 30 mmol) at -78 °C. The mixture was stirred for 10 min at -78 °C and then allowed to stir at -20 °C for 2 h. The reaction mixture was quenched by addition of saturated NH4Cl solution at 0 °C. The organic layer was separated, and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. The crude product was purified by Combi Flash chromatography with 3% MeOH-DCM as eluent to give 0.85 g of the title compound as pale-brown syrup. HPLC: Method-C (ELSD): 99%. ’H NAIR (CDCh) 400 MHz: d ppm 3.70-3.60 (m, 13H), 3.57-3.52 (m, 5H), 3.38 (s, 3H), 1.46 (s, 9H), 1.38 (s, 6H).Step-2: Synthesis of 15, 15 -dimethyl- 2, 5, 8, 11, 14-pentaoxahexadecan- 16-oic acidO

[0466] A solution of tert-butyl 15, 15-dimethyl-2, 5, 8, 11, 14-pentaoxahexadecan- 16-oate (0.85 g, 2.42 mmol) in 4M HC1 in 1,4-dioxane (10 mL) and H2O (2 mL) was stirred at RT overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3 times with 25 mL of dry toluene to give 0.55 g of the title compound as pale brown syrup. ESI-MS (calc- 294.34, obser.293.10 (M-l)).NMR (CDCh) 400 MHz: d ppm 12.53 (bs, 1H), 3.52-3.48 (m, 16H), 3.24 (s, 3H), 1.31 (s, 6H).Step-3: Synthesis of 15, 15-dimethyl-2, 5, 8, 11, 14-pentaoxahexadecan- 16-oyl chloride

[0467] Oxalyl chloride (0.80 mL, 9.34 mmol) and DMF (0.1 mL) were added at 0 °C to a stirred solution of 15, 15-dimethyl-2, 5, 8, 11, 14-pentaoxahexadecan- 16-oic acid (0.55 g, 1.86 mmol) in dry DCM (20 mL). The reaction mixture was allowed to warm to room temperature, stirred 2 h and concentrated to give 0.55 g of the title compound as pale brown semi-solid which was used directly in the next step.312043035 82Attorney Docket No.: NTSS-014 / 001 WOStep-4: Synthesis of (E)-19-((8S, 9S, 10R, 13S, 14S. 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-15, 15-dimethyl-2, 5, 8, 11, 14, 17-hexaoxa-18-azaicos-18-en-16-one

[0468] (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13 -dimethyl- 1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.55 g, 1.66 mmol) was dissolved in 10 mL of dry DCM and then triethylamine (1.16 mL, 8.34 mmol) was added. The crude 15, 15, 15-dimethyl-2, 5, 8, 11, 14-pentaoxahexadecan-16-oyl chloride (0.52 g) was dissolved in 10 mL of DCM and added at 0 °C. The reaction mixture was allowed to warm to room temperature and the mixture stirred overnight. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 100 mL) The combined organic layers were washed with sat. NaHCO3 solution and concentrated under reduced pressure to obtain crude product as a brown gummy syrup.

[0469] The crude product was purified by Combi-Flash chromatography over a silica gel column that was first preconditioned by elution with 2% TEA-hexane solvent mixture. The crude concentrate dissolved in a minimum volume DCM was loaded on the column and then eluted first with 30-50% EA / hexane (2% TEA) gradient to remove non-polar impurities. Then the column was eluted using 2-5% MeOH-DCM solvent gradient to give 0.62 g of the title compound as pale brown gummy syrup. HPLC: Method-D (UV@ 240 nm): 97%; HRMS (calc-605.81, obser- 606.3228(M+l)).NMR (CDCh) 400 MHz: d ppm 5.73 (s, 1H), 3.70-3.60 (m, 16H), 3.59-3.52 (m, 2H), 3.37 (s, 3H), 2.50-2.22 (m, 7H), 2.08-1.94 (m, 5H), 1.93-1.68 (m, 5H), 1.56-1.48 (m, 9H), 1.47-1.24 (m, 5H), 1.18 (s, 3H), 1.16-0.92 (m, 3H), 0.73 (s, 3H).Example 4: (E)-22-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cydopenta[a|phenanthren-17-yl)-18, 18-dimethyI-2, 5, 8, 11, 14, 17, 20-heptaoxa-21-azatricos-21-en- 19-one312043035 83Attorney Docket No.: NTSS-014 / 001 WOStep-1: Synthesis of tert-butyl 18-methyl-2, 5, 8, 11, 14, 17-hexaoxanondecan- 19-oateO

[0470] To a stirred solution of Me-PEG5-OH (4.9 g, 19.4 mmol) in dichloromethane (30 mL) at 0 °C was added 50% NaOH solution (30 mL). To the vigorously stirred 2-phase mixture tert-butyl 2- bromopropanoate (16.2 mL, 97.0 mmol) and tetrabutylammonium chloride (1.34 g, 4.86 mmol) were added at 0 °C. The reaction mixture was stirred at RT for 16 h and the reaction progression was monitored by TLC. After reaction completion, dichloromethane (50 mL) was added. The organic layer was separated and washed with brine solution (2 x 100 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum to obtain the crude product as a colorless liquid. This crude compound was dissolved in minimum amount of water (200 mL) and extracted with hexane (2 x 200 mL). The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over Na2SO4 and evaporated under vacuum to obtain the desired compound 6.5 g as colorless gummy mass. HPLC: Method-A (ELSD) 99%, ESI-MS (calc-380.48, obser-397.95 (M+H2O)). Tl NMR (CDCh) 400 MHz: d ppm 3.90 (q, J=6.8Hz, 1H), 3.66-3.63 (m, 18H), 3.56-3.55 (m, 3H), 3.38 (s, 3H), 1.49 (s, 9H), 1.36 (d, J- 6.8 Hz, 3H).Step-2: Synthesis of tert-butyl 18, 18-dimethyl-2, 5, 8, 11, 14, 17- hexaoxanondecan- 19-oateO

[0471] To a stirred solution of tert-butyl 18-methyl-2, 5, 8, 11, 14, 17-undecaoxatetratriacontan-19-oate (6.4g, 16.82 mmol) in dry THF (100 mL) was added 1.0 MLiHMDS in THF (101 mL, 101 mmol) at -78 °C under argon. The mixture was stirred at -78 °C for 30 mm and CH3I (5.24 mL, 84.0 mmol) was added. The mixture was stirred for 10 min at -78 °C, allowed warm to RT and stirred at RT for 16 h. The reaction mixture was quenched with sat. NH4Cl solution (500 mL) at 0 °C and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The concentrate was purified by Combi-Flash 312043035 84Attorney Docket No.: NTSS-014 / 001 WOchromatography over silica gel eluting with 3-4% MeOH-DCM as gradient eluent to give 5.1 g of the title compound as a pale brown gummy syrup. HPLC: Method-A (ELSD) Purity: 99%.1H NMR (CDCl3) 400 MHz : δ ppm 3.72-3.63 (m, 16H), 3.57-3.53 (m, 4H), 3.38 (s, 3H), 1.46 (s, 9H), 1.38 (s, 6H).Step-3: Synthesis of 18. 18-dimethyl-2, 5, 8, 11, 14, 17- hexaoxanondecan- 19-oic acido

[0472] Water (15 mL) was added to a stirred solution of tert-butyl 18, 18-dimethyl-2, 5, 8, 11, 14, 17-undecaoxatetratriacontan-19-oate (5.0 g, 12.67 mmol) in 4M HCl 1,4-dioxane (35.0 mL) at 0 °C. The reaction mixture was allowed to warm to RT, stirred overnight and concentrated under reduced pressure. The concentrate was co-distilled with toluene (3 x 10 mL) to remove residual water. The concentrate was purified by Combi-Flash chromatography using 3-4% MeOH-DCM as gradient eluent to give 2.8 g of the title compound as a pale-yellow gummy syrup. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-338.40, obser-339.35 (M+l)). 'H NMR (CDCh) 400 MHz: d ppm 3.71-3.65 (m, 17H), 3.64-3.55 (m, 4H), 3.38 (s, 3H), 1.47 (s, 6H).Step-4: Synthesis of 18, 18-dimethyl-2, 5, 8, 11, 14, 17- hexaoxanondecan- 19-oyl chlorideO

[0473] To a stirred solution of 18, 18-dimethyl-2, 5, 8, 11, 14, 17- hexaoxanondecan- 19-oic acid (1.5 g, 4.43 mmol) in dry DCM (15 mL) at 0 °C was added oxalyl chloride (0.77 mL, 8.87 mmol) followed by DMF (0.1 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated to give 1.5 g of the title compound as a pale-yellow sticky mass which was used directly in the next step without further purification.Step-5: Synthesis of (E)-22-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-18, 18-dimethyl-2, 5, 8, 11, 14, 17, 20-heptaoxa-2 l-azatricos-21-en- 19-oneAttorney Docket No.: NTSS-014 / 001 WO

[0474] (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimmo)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (1.38 g, 4.20 mmol) was dissolved in 15 mL of dry DCM and then triethylamine (2.93 mL, 21.0 mmol) was added. The crude 18, 18-dimethyl-2, 5, 8, 11, 14, 17-hexaoxanondecan-19-oyl chloride (1.5 g, 4.43 mmol) was dissolved in 15 mL of DCM and added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (1 x 100 mL). The organic layer was concentrated under reduced pressure to yield the crude product (1.7 g) as pale-yellow sticky mass. The crude product was purified by Combi-Flash chromatography over silica gel column that was first preconditioned by elution with 0.1% in TEA-Hexane solvent mixture. The column was then eluted with 200 mL of 50% Ethyl acetate in hexane to remove traces of TEA. The crude concentrate dissolved in a minimum volume of DCM (10 mL), was loaded on column, and which was then eluted with 100% EA / hexane gradient to remove non-polar impurities. Then the column was eluted using 1.5-2% MeOH-DCM as gradient eluent to give 1.4 g of the title compound as a pale-yellow sticky syrup. HPLC: Method-B (UV@240 nm): 98%. LC-MS (calc-649.87, obser-: 667.30 (M+H2O)). ’HNMR (CDCh) 400 MHz: 3 ppm 5.74 (s, 1H), 3.66-3.65 (m, 18H), 3.56-3.54 (m, 2), 3.38 (s, 3H), 2.38-2.30 (m, 6H), 2.00-2.09 (m, 1H), 1.97-1.96 (S, 4H), 1.92-1.71 (m, 6H), 1.60-1.57 (m, 6H), 1.50-1.56 (m, 4H), 1.12-1.19 (m, 4H), 1.18-0.92 (m, 2H), 0.74 (S, 3H).Example 5: (E)-25-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cydopenta[a]phenanthren-17-yl)-2, 5, 8, 11, 14, 17, 20, 23-octaoxa-24-azahexacos-24-en-22-oneStep-1: Synthesis of tert-butyl 2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oateO i

[0475] To a solution of monodisperse MeO-PEG6-OH (1.5 g, 5.1 mmol) in dry THF (30.0 mL), was added NaH (60% in mineral oil, 0.4 g, 10.12 mmol) at 0 °C. After hydrogen evolution ceased,312043035 86Attorney Docket No.: NTSS-014 / 001 WOtert- butyl bromoacetate (1.8 mL, 13 mmol) was added at 0 °C. The mixture was stirred for 10-15 min at 0 °C and then allowed to stir at room temperature until the reaction was completed based on TLC monitoring. The reaction mixture was quenched with ice at 0 °C, diluted with brine and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was dissolved in 100 mL of water and the aqueous layer was extracted with 2 x 30 mL of pentane. The product was extracted from the aqueous layer with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4and concentrated under vacuum to give 1.3 g of the title compound as pale-yellow syrup. HPLC: Method-C (ELSD): 99.6%. ESI¬ MS (calc-410.50, obser-428.3 (M+H2O)).NMR (CDCh) 400 MHz: 3 ppm 4.02 (s, 2H), 3 74-3.62 (m, 24H), 3.58-3.52 (m, 2H), 3.38 (s, 3H), 1.47 (s, 9H).Step-2: Synthesis of 2, 5, 8, II, 14, 17, 20-heptaoxadocosan-22-oic acidOo

[0476] A solution of tert-butyl 2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oate (0.3 g, 0.73 mmol) in 4M HC1 in dioxane (5 mL) and H2O (2 mL) was stirred at RT overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3x with 25 mL of toluene to give 0.24 g of the title compound as a pale brown syrup. ESI-MS (calc-354.4, obser.355.2 (M+1)). 'H NMR (CDCh) 400 MHz: 3 ppm 4.99 (bs, 1H), 4.16 (s, 2H), 3.76-3.60 (m, 23H), 3.59-3.53 (m, 2H), 3.38 (s, 3H).4Step-3: Synthesis of 2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oyl chlorideO6

[0477] Oxalyl chloride (0.1 mL, 0.8 mmol) and DMF (0.1 mL) were added at 0 °C to a stirred solution of 2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oic acid (0.24 g, 0.70 mmol) in diy DCM (5 mL). The reaction mixture was allowed to warm to room temperature, stirred 1 h and concentrated to give 0.26 g of the title compound as pale brown gummy semi solid which was used directly in the next step.Step-4: Synthesis of (E)-25-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2, 5, 8, 11, 14, 17, 20, 23-octaoxa-24-azahexacos-24-en-22-one312043035 87Attorney Docket No.: NTSS-014 / 001 WO

[0478] (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.27 g, 0.83 mmol) was dissolved in 2 mL of dry DCM and triethylamine (0.48 mL, 3.49 mmol) was added to the reaction mixture. The crude 2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oyl chloride (0.26 g) was dissolved in 2 mL of DCM and added at 0 °C. The reaction mixture was allowed to warm to room temperature and the mixture stirred overnight. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2 x 40 mL). The combined organic layers were washed with sat. NaHCOs solution and concentrated under reduced pressure. The crude product was purified by Combi-Flash chromatography using silica gel column chromatography. The crude concentrate was dissolved in a minimum volume DCM and loaded on the column. The column was eluted with 30-50% EA / hexane gradient to remove non-polar impurities and then the column was eluted using 3% MeOH-DCM solvent gradient to give 0.13 g of the title compound as a pale brown gummy syrup. HPLC: Method-D (240 nm): 95%. LC-MS (calc-665.41, obser: 683.65 -(M+H2O), HRMS: 667.4684. NMR (CDCh) 400 MHz: 5 ppm 5.736 (s, 1H), 4.347 (s, 2H), 3.81-3.77 (m, 2H), 3.71- 3.69 (m, 3H), 3.68-3.6 (m, 21H), 3.6-3.53 (m, 2H), 3.4 (s, 3H), 2.5-2.18 (m, 8H), 2.1-1.8 (m, 8H), 1.8-1.7 (m, 5H), 1.55-1.22 (m, 7H), 1.19 (s, 4H), 1.1-0.9 (m, 4H), 0.9-0.8 (m, 1H), 0.671 (s, 3H). Example 6: (E)-25-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cydopenta[a]phenanthren-17-yl)-21-methyl-2, 5, 8, 11, 14, 17, 20, 23-octaoxa-24-azahexacos-24-en-22-oneStep- 1: Synthesis of tert-butyl 2 l-methyl-2,5,8, 11, 14, 17,20-heptaoxadocosan-22-oate312043035 88Attorney Docket No.: NTSS-014 / 001 WO

[0479] To a solution of monodisperse MeO-PEG6-OH (1.0 g, 3.4 mmol) in dry THF (20 mL), was added NaH (60% in mineral oil, 0.16 g, 6.8 mmol) at 0 °C. After hydrogen evolution ceased, t-butyl 2-bromopropanoate (1.1 g, 5.1 mmol) was added at 0 °C. The reaction mixture was stirred for 10-15 mm at 0 °C and then allowed to stir at room temperature until reaction completion based on TLC monitoring. The reaction mixture was quenched with ice at 0 °C, diluted with brine and extracted with EtOAc. The combined organic layers were dried over Na2SO4and concentrated under vacuum. The resulting crude compound was extracted with pentane, dried under vacuum and dissolved in water. The aqueous solution was extracted with 30% ether-hexane to remove nonpolar impurities. The aqueous phase was then saturated with NaCl and extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give 0.6 g of the title compound as a brown syrup. HPLC: Method-C (ELSD): 97%. ESI-MS (calc-424.53, obser-442.3 (M+H2O)). H NMR (CDCh) 400 MHz: 0 ppm 3.89 (q, J1=6.8 Hz, J2=13.6 Hz, 1H), 3.76-3.6 (m, 24H), 3.58-3.52 (m, 4H), 3.38 (s, 3H), 1.47 (s, 9H), 1.37 (d, J 6.8 Hz, 3H).Step-2: Synthesis of 2 l-methyl-2,5,8, 11, 14, 17,20-heptaoxadocosan-22-oic acid

[0480] A solution of tert-butyl 21-methyl-2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oate (0.6 g, 1.4 mmol) in 4M HC1 in dioxane (10 mL) and H2O (2 mL) was stirred at RT for 16 h. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3x with 25 mL of toluene to give 0.4 g of the title compound as pale brown syrup. HPLC: Method-C (ELSD): 98%. ESI-MS (calc-368.42, obser-369.2 (M+I)). ’HNMR (CDCh) 400 MHz: dppm 12.57 (bs, 1H), 3.93 (q, Jl=6.8 Hz, J2=13.6 Hz, HI), 3.64-3.40 (m, 27H), 3.23 (s, 3H), 1.25 (d, J=6.8 Hz, 3H).Step-3: Synthesis of of 2 l-methyl-2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oyl chlorideo

[0481] Oxalyl chloride (0.68 g, 5.4 mmol) and DMF (0.1 mL) were added at 0 °C to a stirred solution of 21-methyl-2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oic acid (0.4 g, 1.1 mmol) in dry DCM (20 mL). The reaction mixture was allowed to warm to room temperature, stirred for 2 h and312043035 89Attorney Docket No.: NTSS-014 / 001 WOconcentrated to give 0.45 g of the crude title compound as a brown semi-solid which was used directly in the next step.Step-4: Synthesis of (E)-25-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-21-methyl-2, 5, 8, 11, 14, 17, 20, 23-octaoxa-24-azahexacos-24-en-22-one

[0482] (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, I I, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.5 g, 1.5 mmol) was dissolved in 10 mL of dry DCM with triethylamine (0.77 g, 7.6 mmol). Crude compound 21-methyl-2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oyl chloride (0.44 g, ca. 1.2mmol) dissolved in 10 mL of DCM, was added at 0 °C and then reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic phases were washed with sat. NaHCOs solution and concentrated under reduced pressure. The crude product was purified by Combi-Flash chromatography over silica gel eluting with a 2% hexane / ethylacetate-50% hexane / ethyl acetate gradient to remove non-polar impurities followed by eluting with a 2-5% MeOH / DCM / 2% TEA gradient to obtain 0.78 g of the title compound as a pale brown syrup. HPLC: Method-D (UV@ 240 nm): 88%, LC-MS (calc-679.89, obser-(M+l): 680.50, HRMS: 680.39,]H NMR (CDCh) 400 MHz: 3 ppm 5.74 (s, 1H), 4.19 (q, J 1=7.2 Hz, <72=12.8 Hz, 1H), 3.82-3.80-3.54 (m, 25H), 3.39 (s, 3H), 3.03-2.96 (m, 1H), 2.50-2.20 (m, 6H), 2.1-1.8 (m, 6H), 1.77-1.70 (m, 3H), 1.55-1.25 (m, 8H), 1.19 (s, 4H), 1.10-0.9 (m, 3H), 0.71 (s, 3H).Example 7: (E)-25-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13- dimethyl -3- oxo- 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-21, 21-dimethyI-2, 5, 8, 11, 14, 17, 20, 23-octaoxa-24-azahexacos-24-en-22-one312043035 90Attorney Docket No.: NTSS-014 / 001 WOStep-1: Synthesis of tert-butyl 21 -methyl-2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oateoO

[0483] To a solution of monodisperse MeO-PEG6-OH (1.0 g, 3.4 mmol) in dry THF (20.0 mL). was added NaH (60% in mineral oil, 0.16 g, 6.74 mmol) at 0 °C. After hydrogen evolution ceased, tert- butyl 2-bromopropanoate (0.8 mL, 5.1 mmol) was added at 0 °C. The mixture was stirred for 10-15 min at 0 °C and then allowed to stir at room temperature until the reaction was completed based on TLC monitoring. The reaction mixture was quenched with ice at 0 °C, diluted with brine and extracted with EtOAc, The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude compound was dissolved in 100 mL of water and the aqueous layer was extracted with 2 x 25 mL of cold pentane. The aqueous layer was separated, saturated with NaCl and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under high vacuum to give 0.65 g of the title compound as pale-brown syrup. HPLC: Method-C (ELSD): 86%. ¹H NMR (CDCl3) 400 MHz: <5 ppm 3.89 (q, Jl=6.8Hz, J2=13.6Hz, III), 3.84-3.62 (m, 24H), 3.60-3.50 (m, 4H), 3.38 (s, 3H), 1.47 (s, 9H), 1.37 (d, J=6.8Hz, 311).Step-2: Synthesis of tert-butyl 21, 21-dimethyl-2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oate

[0484] To a stirred solution of tert-butyl 21-methyl-2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oate (0.45 g, 1.05 mmol) in dry THF (20 mL) was added a solution of 2.0 M LDA in THF (2.6 mL, 5.3 mmol) at -78 °C under argon. The reaction mixture was stirred at -50 °C for 30 min. followed by addition of CH3I (0.65 mL, 10.6 mmol) at -78 °C. The mixture was stirred for 10 min at -78 °C and then allowed to stir at -20 °C for 30 min. The reaction mixture was allowed to warm to RT, stirred for 15 h and quenched by addition of saturated NH4CI solution at 0 °C. The organic layer was separated and the aqueous layer extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was312043035Attorney Docket No.: NTSS-014 / 001 WOpurified by Combi-Flash chromatography over silica gel column that was first preconditioned by eluting with 2% TEA-hexane solvent mixture. This was followed by elution with 3% MeOH-DCM to give 0.4 g of the title compound as pale-brown syrup. HPLC: Method-C (ELSD): 98%,NMR (CDCl3) 400 MHz: δ ppm 3.70-3.60 (m, 23H), 3.58-3.52 (m, 4H), 3.38 (s, 3H), 1.46 (s, 9H), 1.38 (s, 6H).Step-3: Synthesis of 21, 21-dimethyl-2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oic acid

[0485] A solution of tert-butyl 21, 21-dimethyl-2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oate (0.4 g, 0.9 mmol) in 4M HC1 in dioxane (10 mL) and H2O (2 mL) was stirred at RT overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3x with 25 mL of dry toluene to give 0.4 g of the title compound as pale brown syrup. HPLC: Method-C (ELSD): 95%. ESI-MS (calc-382.45, obser.381.20 (M-l)). ¹H NMR (CDCl3) 400 MHz: δ ppm 12.53 (bs, 1H), 3.52-3.48 (m, 24H), 3.23 (s, 3H), 1.26 (s, 6H).Step- 4: Synthesis of 21, 21 -dimethyl- 2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oyl chloride

[0486] Oxalyl chloride (0.9 mL, 11. mmol) and DMF (0.1 mL) were added at 0 °C to a stirred solution of the 21, 21-dimethyl-2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oic acid (0.4 g, 1.0 mmol) in dry DCM (20 mL). The reaction mixture was allowed to warm to room temperature, stirred 16 h and concentrated to give 0.4 g of the title compound as pale brown semi solid which was used directly in the next step.Step-5: (E)-25-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-21, 21-dimethyl-2, 5, 8, 11, 14, 17, 20, 23-octaoxa-24-azahexacos-24-en-22-one

[0487] (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.44 g, 1.33 312043035 92Attorney Docket No.: NTSS-014 / 001 WOmmol) was dissolved in 10 mL of dry DCM and then triethylamine (0.9 mL, 7.0 mmol) was added to the reaction mixture. The crude 21, 21-dimethyl-2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-oyl chloride (0.4 g) was dissolved in 10 mL of DCM and added at 0 °C. The reaction mixture was allowed to room temperature and stirred overnight. The reaction mixture was diluted with water (50 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with sat, NaHCOs solution and concentrated under reduced pressure to obtain the crude product as a brown gummy syrup that was purified by column chromatography and then eluted with 30-50% EA / hexane (2% TEA) gradient to remove non-polar impurities. Then the column was eluted using 2% MeOH-DCM solvent gradient to give 0.3 g of the title compound as a pale brown syrup. HRMS (calc- 693.92, obser-694.3735(M+l))NMR (CDCh) 400 MHz: 3 ppm 5.739 (s, 1H), 3.70-3.60 (m, 24H), 3.59-3.52 (m, 2H), 3.38 (s, 3H), 2.50-2.20 (m, 8H), 2.10-1.90 (m, 5H), 1.90-1.70 (m, 7H), I.55-1.45 (m, 7H), 1.45-1.25 (m, 7H), 1.20 (s, 5H), 1.1-0.9 (m, 3H), 0.74 (s, 3H).Example 8: (E)-28-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyI-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta|a]phenantliren-17-yI)-24,24-dimethyl-2, 5, 8, II, 14, 17, 20, 23, 26-nonaoxa-27-azanonacos-27-en-25-oneStep-1: Synthesis of 1, 3, 6, 9, 12, 15-hexaoxa-2-thiacycloheptadecane 2-oxideo

[0488] To a stirred solution of 3, 6, 9, 12-tetraoxtetradecane-l, 14-diol (10.0 g, 42.0 mmol) in 1.0 L dichloromethane were added DIPEA (36.6 mL, 210 mmol) and DMAP (0.26 g, 2.1 mmol).. The reaction mixture was stirred for 5 minutes at 0 °C and SOCb. (6.1 mL, 84 mmol) dissolved in dry DCM (250 mL) was added dropwise to the reaction mixture over a period of 2 h at 0 °C. After completion of addition the mixture was slowly allowed to warm to RT and stirred for 2 h. The reaction mixture was cooled to 0 °C and quenched with addition of 1.0 L of brine solution. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure.312043035 93Attorney Docket No.: NTSS-014 / 001 WOThe crude product oil was purified by column chromatography over silica gel, using 50% EtOAc-hexane eluent to afford 8.0 g of the title compound as a pale-yellow syrup. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-284.32, obser-302.2 (M+H2O)).1H NMR (CDCl3) 400 MHz: 3 ppm 4.21-4.36 (m, 2H), 4.11-4.26 (m, 2H), 3.77-3.78 (m, 4H), 3.70-3.66 (m, 14H).Step-2: Synthesis of 1, 3, 6, 9, 12, 15-hexaoxa-2-thiacycloheptadecane 2, 2-dioxide

[0489] To a stirred solution of 1, 3, 6, 9, 12, 15 -hexaoxa -2-thiacycloheptadecane 2-oxide (8.0 g, 28.1 mmol) in a mixture of ACN (250 mL), CCI4 (250 mL) and water (400 mL) was added NaIO4 (8.12 g, 28.1 mmol) followed by RuCl3.xH2O (0.41 g, 1.58 mmol ) at 0 °C. The reaction mixture was stirred at RT for 16 h and then was extracted with DCM (2 x 500 mL), The combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel, using EtOAc as eluent to afford 4.5 g of the title compound as a brown liquid. HPLC: Method-B (ELSD): 99%. ESI-MS (calc-300.32, obser-318.1 (M+H2O)). ¹H NMR (CDCl3) 400 MHz: δ ppm 4.45 (t, J=4.8 Hz, 4H), 3.81 (t, J=4.8 Hz, 4H), 3.70-3.65 (m, 12H).Step-3: Synthesis of 2, 5, 8, 11, 14, 17, 20-heptaoxadocosan-22-ol

[0490] To a stirred solution of Me-PEG2-OH (1.8 g, 15 mmol) in THF (20 mL), NaH (0.89 g, 22.5 mmol) was added at 0 °C and the mixture was stirred for 2 h. A solution of 1, 3, 6, 9, 12, 15-hexaoxa-2-thiacycloheptadecane 2, 2-dioxide (4.5 g, 15 mmol) in dry THF (20 mL) was added to the above reaction mixture at 0 °C. The reaction mixture was stirred overnight at RT and was then adjusted to pH = 3 using concentrated H2SO4 (ca. 0.4 mL). The resulting mixture was stirred for 3 h, neutralized with saturated NaHCOs (15.0 mL) solution and then reaction mixture concentrated under vacuum. The concentrate was purified by column chromatography, using 2-3% MeOH m DCM as eluent to afford 3.1g of the title Me-PEG7-OH compound as a pale yellow syrup. HPLC: Method-A (ELSD): 99%, ESI-MS (calc-340.41, obser-358.30 (M+H2O)).1H NMR (CDCh) 400 MHz: 3 ppm 3.67-3.56 (m, 30H), 3.38 (s, 3H), 2.78 (bs, 1H).Step-4: Synthesis of tert-butyl 24-methyl-2, 5, 8, 11, 14, 17, 20, 23-oclaoxapentacosan-25-oate 312043035 94Attorney Docket No.: NTSS-014 / 001 WOo

[0491] To a stirred solution of Me-PEG7-OH (2.9 g, 8.5 mmol) in dichloromethane (18 mL) at 0 °C was added 50% NaOH solution (18 mL). To the vigorously stirred 2-phase mixture tert-butyl 2-bromopropanoate (7.1 mL, 43 mmol) and tetrabutyl ammonium chloride (0,59 g, 2.13 mmol) were added at 0 °C. The reaction mixture was stirred at RT for 16 h and the reaction progression was monitored by TLC. / Xfter completion, dichloromethane (50 mL) was added, and the organic layer was separated and washed with brine solution (2 x 100 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The concentrate was dissolved in minimum amount of water (200 mL) and extracted with hexane (2 x 200 mL). The aqueous layer separated and extracted with ethyl acetate (5 x 100 mL). The combined organic extracts were dried over Na2SO4 and evaporated under vacuum to obtain 2.6 g of the title compound as colorless gummy syrup. HPLC: Method- A (ELSD) 99%. ESLMS (calc-468.58, obser-486.50 (M+H2O)). ¹H NMR (CDCl3) 400 MHz: δ ppm 3.90 (q, J=6.8 Hz, 1H), 3.72-3.63 (m, 25H), 3.58-3.56 (m, 3H), 3.38 (s, 3H), 1.47 (s, 9H), 1.36 (d, J=6.8 Hz, 3H).Step-5: Synthesis of tert-butyl 24, 24-dimethyl-2, 5, 8, 11, 14, 17, 20, 23- octaoxapentacosan-25-oate

[0492] To a stirred solution of tert-butyl 24-methyl-2, 5, 8, 11, 14, 17, 20, 23- octaoxapentacosan -25-oate (2.5 g, 5.34 mmol) m dry THF (40 mL) was added 1.0 M LiHMDS in THF (32 mL, 32 mmol) at -78 °C under argon. The mixture was stirred at -78 °C for 30 min and CH3I (1.7 mL, 27 mmol) was added. The mixture was stirred for 10 min at -78 °C, allowed warm to RT and stirred at RT for 16 h. The reaction mixture was quenched with sat. NH4CI solution (200 mL) at 0 °C and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The concentrate was purified by Combi-Flash chromatography over silica gel eluting with 3-4% MeOH-DCM eluent to give 1.8 g of the title compound as a pale brown gummy syrup. HPLC: Method-A (ELSD) Purity: 99%. ESLMS (calc-482.61, obser-500.75 (M+H2O)). ¹H NMR (CDCl3) 400 MHz: δ ppm 3.62-3.64 (m, 27H), 3.57-3.53 (m, 4H), 3.38 (s, 3H), 1.46 (s, 9H), 1.38 (s, 6H).Step-6: Synthesis of 24, 24-dimethyl-2, 5, 8, 11, 14, 17, 20, 23- octaoxapentacosan -25-oic acid312043035 95Attorney Docket No.: NTSS-014 / 001 WO

[0493] Water (5.1 mL) was added to a stirred solution of tert-butyl 24, 24-dimethyl-2, 5, 8, 11, 14, 17, 20, 23- octaoxapentacosan -25-oate (1.7 g, 3.5 mmol) in 4MHC1 1,4-dioxane (12.0 mL) at 0 °C. The reaction mixture was allowed to warm to RT, stirred overnight and concentrated under reduced pressure. The concentrate was co-distilled with toluene (3 x 10 mL) to remove residual water. The concentrate was purified by Combi-Flash chromatography using 3-4% MeOH-DCM as eluent to give 0.6 g of the title compound as a pale-yellow syrup. HPLC: Method- A (ELSD): 95%. ESI-MS (calc-426.50, obser-427.55 (M+l)). ¹H NMR (CDCl3) 400 MHz: δ ppm 3.71-3.65 (m, 17H), 3.56-3.55 (m, 2H), 3.38 (s, 3H), 1.47 (s, 6H).Step-7: Synthesis of 24. 24-dimethyl-2, 5, 8, / / , 14, 17, 20, 23- octaoxapentacosan-25-oyl chloride

[0494] To a stirred solution of 24, 24-dimethyl-2, 5, 8, 11, 14, 17, 20, 23- octaoxapentacosan 25-oic acid (0.5 g, 1,2 mmol) in dry DCM (5 mL) at 0 °C was added oxalyl chloride (0.2 mL, 2.3 mmol) followed by DMF (0.1 mL), The reaction mixture was stirred at room temperature for 2 h and concentrated to give 0.5 g of the title compound as a pale-yellow sticky mass which was used directly in the next step without further purification.Step-8: Synthesis of (E)-28-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanfhren-17-yl)-24, 24-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxa-27-azanonacos-27-en-25-oneo

[0495] (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13-dimethyl-1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.37 g, 1.12 mmol) was dissolved in 10 mL of dry DCM and then triethylamine (0.78 mL, 5.62 mmol) was added. The crude 24, 24-dimethyl-2, 5, 8, 11, 14, 17, 20, 23- octaoxapentacosan-25-oyl chloride (0.5 g) was dissolved in 10 mL of DCM and added at 0 °C. The reaction mixture was allowed to312043035 96Attorney Docket No.: NTSS-014 / 001 WOwarm to room temperature and stirred overnight. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (1 x 100 mL). The organic layer was concentrated under reduced pressure and the concentrate was purified by Combi-Flash chromatography over silica gel. The crude concentrate dissolved in a minimum volume of DCM (10 mL), was loaded on column, and then eluted with 100% EA / hexane as gradient eluent to remove non-polar impurities. Then the column was eluted using 1.5-2% MeOH-DCM as gradient eluent to give 0.3 g of the title compound as a pale-yellow sticky syrup. HPLC: Method-B (UV@ 240 nm): 97%, LC-MS (calc-737.97, obser-: 755.50 (M+FEO)).NMR (CDCh) 400 MHz: d ppm 5.73 (s, IH), 3.66-3.55 (m, 27H), 3.55- 3.54 (m, 2H), 3.38 (s, 3H), 2.39-2.30 (m, 6H), 2.00-2.09 (m, IH), 1.97-1.96 (S, 4H), 1.92-1.61 (m, 6H), 1.60-1.57 (m, 611), 1.22-1.38(m, 4H), 1.12-1.19(m, 411), 1.18-0.92 (m, 211), 0.74 (S, 3H). Example 9: (E)-31-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cydopenta[a]phenanthren-17-yI)-27, 27-dimethyI-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxa-30-azadotriacont-30-en-28-oneStep-1: Synthesis of 2, 5, 8, 11, 14, 17, 20, 23-octaoxapentacosan-25-ol

[0496] To a stirred solution of monodisperse Me-PEG6-OH (2, 5, 8, 11, 14, 17-hexaoxanonadecan-19-ol) (5.0 g, 16.9 mmol) m THF (30 mL), NaH (1.0 g, 25 mmol) was added at 0 °C under stirring for 2 h at 0 °C. A solution of 1, 3, 6-trioxathiocane 2, 2-dioxide (2.84 g, 16.9 mmol) dissolved in THF (20 mL) was added at 0 °C and the mixture was stirred overnight at RT for 16 h. Water (0.8 mL) was added at 0 °C to quench the reaction mixture and the reaction mixture was adjusted to pH 3 using conc. H2SO4 (0.3 mL). After stirring for 3 h, reaction mixture was neutralized using saturated NaHCOs and concentrated under vacuum. The concentrate was purified by Combi-Flash column chromatography, using 3% MeOH-DCM as eluent to afford 3.9 g of the title compound as a pale brown syrup. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-384.47, obser-385.50 (M+l)). ¹H NMR (CDCl3) 400 MHz: δ ppm 3.83-3.71 (m, 3H), 3.68-3.59 (m, 31H), 3.56-3.54 (m, 2H), 3.38 (s, 3H).312043035 97Attorney Docket No.: NTSS-014 / 001 WOStep-2: Synthesis of tert-butyl 27-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-oate

[0497] To a stirred solution of monodisperse Me-PEG8-OH (2, 5, 8, 11, 14, 17, 20, 23-octaoxapentacosan-25-ol) (3.9 g, 10 mmol) and tert-butyl 2-bromopropanoate (8.5 mL, 50 mmol) in dry DCM (24 mL) was added 50% NaOH solution (24 mL, 10 mmol) at 0° C. TBACl (0.7 g, 2.5 mmol) was added and the mixture was stirred overnight at RT. The mixture was diluted with DCM (100 mL) and water (50 mL). The organic layer was separated, dried over Na2SO4, and concentrated under vacuum. The concentrate was dissolved in a minimum amount of water (50 mL) and the aqueous solution was extracted with hexane (2 x 50 mL). The aqueous layer was saturated with NaCl and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The concentrate was purified by Combi-Flash column chromatography, using 2% MeOH-DCM as eluent to afford 4.5 g of the title compound as a pale yellow syrup. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-512.64, obser-529.90 (M+H2O)). ¹H NMR (CDCl3) 400 MHz: δ ppm 3.89 (q, J1=6.8 Hz, J2=14Hz, 1H), 3.85-3.60 (m, 29H), 3.60-3.40 (m, 3H), 3.38 (s, 3H), 1.48 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).Step-3: Synthesis of tert-butyl 27, 27-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-oate

[0498] To a stirred solution of tert-butyl 27-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-oate (4.5 g, 8.8 mmol) in dry THF (50 mL) was added 1.0 M LiHMDS in THF (52.7 mL, 52.7 mmol) at -78 °C under argon. The mixture was stirred at -78 °C for 30 mm and CH3I (2.7 mL, 449 mmol) was added. The mixture was stirred for 10 min at -78 °C, allowed warm to RT and stirred for 16h. The reaction mixture was quenched with sat. NH4Cl solution at 0 °C and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The concentrate was purified by Combi-Flash chromatography over silica gel eluting with 2.5 % MeOH-DCM to give 3.8 g of the title compound as a pale-yellow liquid. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-526.66, obser-544.60 (M+H2O)). ’H NMR (CDCh) 400 MHz: 3 ppm 3.82-3.61 (m, 29H), 3.57-3.53 (m, 4H), 3.38 (s, 3H), 1.46 (s, 9H), 1.38 (s, 6H).312043035 98Attorney Docket No.: NTSS-014 / 001 WOStep-4: Synthesis of 27, 27 -dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-oic acid

[0499] Water (11 mL) was added to a stirred solution of tert-butyl 27, 27-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-oate (3.7 g, 7.0 mmol) in 4MHC1 1,4-dioxane- (26 mL) at 0 °C. The reaction mixture was allowed to warm to RT, stirred overnight and concentrated under reduced pressure. The concentrate was co-distilled with toluene (3 x 10 mL) to remove residual water. The residue was purified by Combi-Flash chromatography over silica gel using 2% MeOH-DCM as eluent to give 1.7 g of the title compound as a pale brown syrup after drying under high vacuum. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-470.56 obser-471.60 (M+l). ¹H NMR (CDCl3) 400 MHz: δ ppm 3.71-3.63 (m, 29H), 3.60-3.55 (m, 4H), 3.38 (s, 3H), 1.47 (s, 6H). Step-5: Synthesis of 27, 27 -dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-oyl chloride

[0500] Oxalyl chloride (0.22 ml, 2.90 mmol) and DMF (0.05 mL) were added at 0 °C to a stirred solution of the 27, 27-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-oic acid (1.0 g, 2.12 mmol) in dry DCM (10 mL). The reaction mixture was allowed to warm to room temperature, stirred 2 h and concentrated to give 1.1 g of the title compound as pale brown gummy syrup which was used directly in the next step.Step-6: Synthesis of (E)-31-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-27, 27-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxa-30-azadotriacont-30-en-28-one

[0501] (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l -(hydroxyimino)ethyl)-10, 13-dimethyl-1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.74 g, 2.24 mmol) was dissolved in 7 mL of dry DCM and then triethylamine (1.6 mL, 11 mmol) was added to the reaction mixture. The 27, 27-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-oyl chloride (1.1 g,) was dissolved in 7 mL of DCM and added at 0 °C. The reaction mixture was allowed 312043035 99Attorney Docket No.: NTSS-014 / 001 WOto warm to room temperature and stirred overnight. The mixture was diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with sat. NaHCOs solution and concentrated under reduced pressure. The crude product was purified by Combi-Flash chromatography over silica gel column that was first preconditioned by elution with 0.1% TEA-Hexane solvent mixture. The crude concentrate dissolved in a minimum volume DCM was loaded on column and then eluted with 30-50% EA in hexane as a gradient eluent to remove non-polar impurities. Then the column was eluted using 1.5-2% MeOH-DCM as gradient eluent to give 0.9 g of the title compound as a pale yellow syrup. HPLC: Method-B (UV@ 240 nm): 98%, LC-MS (calc- 782.03, obser-: 799.75 (M+H2O)).NMR (CDCh) 400 MHz: 3 ppm 5.73 (s, 1H), 3.67-3.63 (m, 31H), 3.56-3.54 (m, 2H), 3.38 (s, 3H), 2.43-2.27 (m, 6H), 2.02-1.60 (m, 14H), 1.51 (s, 6H), 1.49- I.28 (m, 3H), 1.19 (s, 4H), 1.08-0.94 (m, 2H), 0.74 (s, 3H).Example 10: (E)-34-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-oneStep-1: Synthesis of tert-butyl 30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan- 31-oate

[0502] To a solution of monodisperse MeO-PEG9-OH (7.9 g, 18.4 mmol) in dry THF (80.0 mL), NaH (60% in mineral oil, 1.4 g, 37 mmol) was added at 0 °C. After hydrogen evolution ceased, t-butyl 2-bromopropanoate (6.2 mL, 37 mmol) was added at 0 °C. After then reaction mixture was stirred for 10-15 min at 0 °C and then allowed to stir at room temperature until completed by TLC monitoring. The reaction mixture was quenched with ice at 0 °C, diluted with 500 mL of water and extracted with EtOAc (2x 500 mL). The combined organic layer dried over Na2SO4 and concentrated under vacuum. The concentrate was purified by silica gel column chromatography using 3-4% MeOH-DCM as eluent to give 8.54 g of the title compound as pale-brown syrup. HPLC: Method-B (ELSD): 83%. ESI-MS (calc-556.69, obser-574.85 (M+H2O)). ¹H NMR (CDCl3) 400 MHz: δ 312043035 100Attorney Docket No.: NTSS-014 / 001 WOppm 3.89 (q, Jl=6.8IIz, J2=13.6IIz, 1H), 3.84-3.44 (m, 41H), 3.38 (s, 3H), 1.47 (s, 9H), 1.37 (d. J=6.8Hz, 3H).Step-2: Synthesis of 30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oic acidOH

[0503] Water (5.0 mL) was added to a stirred solution of tert-butyl 30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (5.5 g, 9.9 mol) in 4MHC1 1,4-dioxane solution (20.0 mL) at RT and the mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure and the residue was co-distilled with dry toluene (3 x 10 mL) and dried under high vacuum to obtain 4.7 g of the title compound as a pale brown syrup. HPLC: Method-B (ELSD): 99.90%. ESI-MS (calc-500.58, obser-501.60 (M+l)). ’HNMR (CDCh) 400 MHz: d ppm 3.95 (q, Jl=6.8 Hz, J2=13.6Hz, 1H), 3.70-3.40 (m, 36H), 3.38 (s, 3H), 1.27 (d, J=6.8 Hz, 3H). Step- 3: Synthesis of 30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oyl chlorideCl

[0504] To a stirred solution of 30-methyl-2,5,8, 11, 14, 17,20,23,26,29-decaoxahentriacontan-31 -oic acid (0.8 g, 1.59 mmol) in dry DCM (20 mL), Oxalyl chloride (0.7 mL, 7.995 mmol) and DMF (0.06 mL) were added at 0 °C. After then reaction mixture was allowed to warm to room temperature, stirred for 2 h and concentrated to give 0.75 g of the crude title compound as a pale brown syrup which was used directly in the next step.Step-4: Synthesis of (E)-34-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanlhren-17-yl)-30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-one

[0505] 8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.54 g, 1.64 mmol) was dissolved in 10 mL of dry DCM, to this solution triethylamine (1.1 mL, 8.20 mmol) was 312043035 101Attorney Docket No.: NTSS-014 / 001 WOadded. The crude compound, 30-methyl-2,5,8,ll,14,17,20,23,26,29-decaoxahentriacontan-31-oyl chloride (0,85 g, 1.64 mmol) was dissolved in 10 mL of DCM was added at 0 °C and then reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml.,) and extracted with DCM (2 x 100 mL), The combined organic phase were washed with sat. NaHCO3 solution and concentrated under reduced pressure. The crude compound was dissolved in minimum amount of water (30 ml.,) and then 30% diethyl ether in hexane (50 mL), was added and stir for 10 minutes. The same procedure was repeated 3 times. After then, the aqueous layer was saturated with NaCl and extracted with EtOAc (2 x 100 mL). The organic layer separated and dried over Na2SC>4 and evaporated under vacuum to obtain 0.5 g of the title compound as a pale brown syrup. HPLC: Method-C (UV@ 240 nm): 98%, LC-MS (calc-812.05, obser-828.7 (M+H2O)). NMR (CDCh) 400 MHz: d ppm 5.74 (s, 1H), 4.19 (q, J1=6.8 Hz, J2=13.6 Hz, 1H), 3.88-3.60 (m, 42H), 3.58-3.52 (m, 3H), 3.39 (s, 3H), 2.50-2.20 (m, 6H), 2.1-1.95 (m, 5H), 1.94-1.66 (m, 11H), 1.66-1.22 (m, 10H), 1.22-1.1 (m, 5H), 1.10-0.92 (m, 2H), 0.73 (s, 3H).Example 11: (E)-34-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-30, 30-dimethyl 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-oneStep 1: Synthesis of tert-butyl 30, 30-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29 decaoxahentriacontan-31-oate

[0506] To a stirred solution of tert-butyl 30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29- decaoxahentriacontan-31-oate (13.5 g, 24.3 mmol) in dry THF (100 mL), a solution of 1.0 M LiHMDS in THF (73 mL, 73 mmol) was added at -78 °C under argon atmosphere. The reaction mixture was stirred at -78 °C for 5 min, followed by addition of CH3I (4.5 mL, 73 mmol) dissolved in 50 mL of THF. The mixture was stirred for 10 min at -78° C and then allowed to warm to room temperature. After stirring at RT for 4 h, the reaction mixture was quenched by addition of saturated NH4CI solution at 0 °C. The organic layer was separated, and the aqueous layer extracted with 312043035 102Attorney Docket No.: NTSS-014 / 001 WOEtOAc (2 x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by Combi-Flash chromatography using 3% MeOH-DCM as eluent give 11.2 g of the title compound as pale-brown liquid. HPLC: Method-B (ELSD): 99%. ESI-MS (calc-570.72, obser-588.4 (M+H2O)).1H NMR (CDCh) 400 MHz: d ppm 3.86-3.79 (m, 1H), 3.74-3.60 (m, 34H), 3.59-3.52 (m, 4H), 3.38 (s, 3H), 1.47 (s, 9H), 1.39 (s, 6H). Step 2: Synthesis of 30, 30-dimethyl-2, 5, 8, / / , 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oic acidOH

[0507] To a stirred solution of tert-butyl 30, 30-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (6,0 g, 10.5 mol) in 4MHC1 in 1,4-Dioxane solution (42 mL), water (36 ml,) was added at 0 °C. The reaction mixture was stirred at RT overnight and then concentrated under reduced pressure. The concentrate was co-distilled with toluene (3 x 10 ml.) and the resulting oil was dried under high vacuum to obtain 5.0 g of the crude title compound as pale brown syrup. A 2.5 g fraction of crude product was separated and purified by Combi Flash chromatography using 5% MeOH-DCM as eluent to give 2.0 g of pure title compound as light brown syrup, HPLC: Method-B (ELSD): 99%. ESI-MS (calc-514.61, obser-513.3 (M-l)). 1H NMR (CDCl3) 400 MHz: δ ppm 3.86-3.74 (m, 1H), 3.74-3.60 (m, 35H), 3.60-3.52 (m, 5H), 3.38 (s, 3H), 1.47 (s, 6H).Step-3: Synthesis of (E)-34-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-30, 30-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-one

[0508] To a stirred solution of 30,30-dimethyl-2,5,8,ll,14,17,20,23,26,29-decaoxahentriacontan-31-oic acid (2.0 g, 3.9 mmol) in dry DCM was added 8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-1-(hydroxyimino)ethyl)-10, 13 -dimethyl- 1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (1.28 g, 3.9 mmol) in 20 mL dry DCM, at 0 °C. To this solution PyBOP (2.0 g, 3.9 mmol) was added on and the mixture was stirred at 0 °C for 10 min. DIPEA (3.4 mL, 19 mmol) was added at 0 °C and the reaction mixture was stirred at RT overnight and quenched 312043035 103Attorney Docket No.: NTSS-014 / 001 WOwith ice cold water (50 mL). The organic layer was separated, and the aqueous layer was extracted with 2 x 100 mL of DCM. The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash column chromatography over silica-gel column, which was preconditioned with 0.1% TEA in hexane. The column was first eluted with 0-70% EtOAc / hexane gradient solvent followed by elution with 3-4 % MeOH in DCM to afford 2.0 g of the title compound as colorless syrup. HPLC: Method-B (UV@ 240 nm) 97%). LC-MS (calc-826.08, obser-843.6 (M+H2O)) and HRMS (calc-826.08, obser- 826.6249 (M+1)). 1H NMR (CDCl3) 400 MHz: d ppm: 5.739 (s, 1 H), 3.7-3.6 (m, 38H), 3.56-3.55 (m, 2H), 3.4 (s, 3 H), 2.5 - 2.27 (m, 6 H), 2.09 - 2.0 (m, 1 H), 1.96 (s, 4 H), 1.93 - 1.91 (m, IH), 1.91 - 1.49 (m, 16H), 1.49 - 1.22 (m, 4H), 1.19 (s, 5H), 1.11 - 0.92 (m, 2 H), 0.74 (s, 3H).Example 12: (E)-37-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cydopenta[a]phenanthren-17-yI)-33, 33-dimethyI-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxa-36-azaoctatriacont-36-en-34-one■Nxo'Step-1: Synthesis of 1, 3, 6, 9, 12, 15, 18-heptaoxa-2-thiacycloicosane 2-oxide

[0509] To a stirred solution of 3, 6, 9, 12, 15-pentaoxaheptadecane-l, 17-diol (10.0 g, 35.4 mmol) in dry DCM (2000 mL) were added DIPEA (31 mL) and DMAP (0.22 g, 1.7 mmol) at 0 °C. A solution of SOCI2 (5.2 mL, 71 mmol) in dry DCM (500 mL) was added dropwise to the reaction mixture over a period of 2 h at 0 °C. The reaction mixture was stirred for another 2 h at RT. The reaction mixture was then quenched with saturated NaHCO3 (500 mL) at 0 °C. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The concentrate was purified by column chromatography, using 2% MeOH in DCM as gradient eluent to give 9.8 g of the title compound as a brown liquid. HPLC: Method-A (ELSD): 96%. ESI-MS (calc-328.37, obser-346.35 (M+H2O)).!H NMR (CDCh) 400 MHz: 3 ppm 4.30-4.22 (m, 2H), 4.16-4.11 (m, 2H), 3.81-3.76 (m, 4H), 3.70-3.61 (m, 18H).312043035 104Attomey Docket No.: NTSS-014 / 001 WOStep-2: Synthesis of 1, 3, 6, 9, 12, 15, 18-heptaoxa-2-thiacycloicosane 2, 2-dioxide°" S"°

[0510] To a stirred mixture of 1, 3, 6, 9, 12, 15, 18-heptaoxa-2-thiacycloicosane 2-oxide (9.8 g, 30 mmol) in ACN (294 mL) were added CCl4 (294 mL) and water (441 mL) at 0 °C followed by NaIO4 (7.66 g, 35.8 mmol) and RuCl3.xH2O (0.078 g, 0.298 mmol). The reaction mixture was stirred at RT for 16 h and completion of the reaction was monitored by TLC. The mixture was extracted with DCM (2 x500 mL) and the combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by column chromatography, using 2% MeOH in DCM as eluent to give 5.3 g of the title compound as a pale¬ yellow liquid. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-344.37, obser-345.1 (M+l)).!H NMR (CDCk) 400 MHz: d ppm 4.45 (t, J=4.4 Hz, 4H), 3.84 (t, J=4.4 Hz, 4H), 3.70-3.60 (m, 16H). Step- 3: Synthesis of 2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-ol (Me-PEGio-OH)

[0511] To a stirred solution of monodisperse Me-PEG4-OH (3.1 g, 15 mmol) in THF (30 mL) was added NaH (0.89 g, 22 mmol) at 0 °C. A solution of 1, 3, 6, 9, 12, 15, 18-heptaoxa-2-thiacycloicosane 2, 2-dioxide (5.1 g, 15 mmol) dissolved in DMF (15 mL) was added at 0 °C and the mixture was stirred overnight at RT for 16 h. Water (0.7 mL) was added at 0 °C to quench the reaction mixture. Then, the reaction mixture pH was adjusted to pH = 3 using cone. H2SO4 (0.3 mL). After stirring for 3 h the mixture was neutralized using saturated NaHCOs and concentrated under vacuum. The concentrate was purified by Combi-Flash column chromatography, using 3% MeOH-DCM as eluent to afford 5.1 g of the title compound as a yellow liquid. HPLC: Method-A (ELSD): 99%, ESI-MS (calc-472.57, obser-473.65 (M+l)).1H NMR (CDCl3) 400 MHz: d ppm 3.78-.358 (m, 42H), 3.58-3.52 (m, 2H), 3.38 (s, 3H), 3.10-3.0 (bs, 1H).Step-4: Synthesis of tert-butyl 33-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan-34-oateo

[0512] To a stirred solution of Me-PEGio-OH (5.0 g, 11 mmol) in dichloromethane (30 mL) at 0 °C was added 50% NaOH solution (30 mL). To the vigorously stirred 2-phase mixture tert-butyl 2- 312043035 105Attorney Docket No.: NTSS-014 / 001 WObromopropanoate (8.9 mL, 53 mmol) and tetrabutylammonium chloride (0.74 g, 2.7 mmol) was added at 0 °C. The reaction mixture was stirred at RT for 16 h and the reaction progression was monitored by TLC. After completion, dichloromethane (100 mL) was added, and the organic layer was separated and washed with brine solution (2 x 50 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The concentrate was dissolved in minimum amount of water (200 mL) and extracted with ether (2 x200 mL), The aqueous layer was separated and extracted with ethyl acetate (3 x500 mL). The combined organic extract were dried over Na2SO4 and concentrated under vacuum. The concentrate was purified by Combi-Flash column chromatography, using 3-4% MeOH in DCM as gradient eluent to give 4.7 g of the title compound as a colorless gummy mass. HPLC: Method-A (ELSD) 99%, ESI-MS (calc-600.74, obser-618.80 (M+H2O)). 'll NMR (CDCh) 400 MHz: d ppm 3.89 (q, J=6.8 Hz, III), 3.86-3.44 (m, 41H), 3.38 (s, 3H), 1.48 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).Step-5: Synthesis of tert-butyl 33, 33-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29. 32-undecaoxatetratriacontan-34-oate

[0513] To a stirred solution of tert-butyl 33-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan-34-oate (4.6 g, 7.7 mmol) in dry THF (70 mL) was added 1.0 M LiHMDS in THF (46 mL, 46 mmol) at -78 °C under argon. The mixture was stirred at -78 °C for 30 min and CH3I (3.8 mL, 61 mmol) was added. The mixture was stirred for 10 min at -78 °C, allowed warm to RT and stirred at RT for 16 h. The reaction mixture was quenched with sat. NH4CI solution (50 mL) at 0 °C and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The concentrate was purified by Combi-Flash chromatography over silica gel eluting with 3-4% MeOH-DCM as gradient eluent to give 1.9 g of the title compound as a pale brown syrup. HPLC: Method-A (ELSD) Purity: 99%. ESI-MS (calc-614.77, obser-632.70 (M+H2O)). 'H NMR (CDCh) 400 MHz: 3 ppm 3.72-3.60 (m, 40H), 3.59-3.46 (m, 4H), 3.38 (s, 3H), 1.48 (s, 9H), 1.38 (s, 6H).Step-6: Synthesis of 33, 33-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan- 34-oic acido312043035 106Attorney Docket No.: NTSS-014 / 001 WO

[0514] Water (5 mL) was added to a stirred solution of tert-butyl 33, 33-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan-34-oate (1.7 g, 2.8 mmol) in 4M HC1 1,4-dioxane (12 mL) at 0 °C. The reaction mixture was allowed to warm to RT, stirred overnight and concentrated under reduced pressure. The concentrate was co-distilled with toluene (3 x 10 mL) to remove residual water. The concentrate was purified by Combi-Flash chromatography using 3-4% MeOH-DCM as gradient eluent to give 0.7 g of the title compound as a pale-yellow syrup. HPLC: Method- A (ELSD): 98%. ESI-MS (calc-558.66, obser-559.3 (M+l)).NMR(CDCh) 400 MHz: S ppm 3.78-3.50 (m, 48H), 3.38 (s, 3H), 1.47 (s, 6H).Step-7: Synthesis of 33, 33-dimethyl-2, 5, 8, II, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan-34-oyl chlorideO

[0515] To a stirred solution of 33, 33-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan-34-oic acid (0.5 g, 0.9 mmol) in dry toluene (10 mL) at 0 °C was added oxalyl chloride (0.16 mL, 1.79 mmol) followed by DMF (0.07 mL). The reaction mixture was stirred at room temperature for 4 h and concentrated under vacuum to give 0.5 g of the title compound as a pale-yellow sticky mass which was used directly in the next step without further purification. Step-8: Synthesis of (E)-37-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-33, 33-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxa-36-azaoctatriacont-36-en-34-oneo

[0516] (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.29 g, 0.87 mmol) was dissolved in 5 mL of dry DCM and then triethylamine (0.6 mL) mmol) was added. The crude 33, 33-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan-34-oyl chloride (0.5 g) was dissolved in 5 mL of DCM and added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with water (30 mL)312043035 107Attorney Docket No.: NTSS-014 / 001 WOand extracted with EtOAc (1 x 100 mL). The organic layer was concentrated under reduced pressure and the crude product was purified by Combi-Flash chromatography over silica gel. The silica gel column was first preconditioned by elution with 1.7% TEA in EtOAc-Hexane (1:1) solvent mixture followed by elution with 150 mL EtOAc-Hexane (1:1). The crude concentrate dissolved in a minimum volume of DCM (3 mL), was loaded on the column, followed by elution with a hexane-100% ethylacetate gradient to remove non-polar impurities. Then the column was eluted using 3% IPA-EtOAc to give 0.25 g of the partially purified title compound as a pale-yellow syrup. This product (0.25 g) was re-purified by using Combi-Flash column chromatography to give pure title compound 0.14 g as pale-yellow syrup. HPLC: Method-B (UV@ 240 nm): 99%, LC-MS (calc-870.13, obser-: 887.40 (M+H2O)). NMR (CDCh) 400 MHz: <5 ppm 5.73 (s, 1H), 3.85-3.45 (m, 41H), 3.38 (s, 3H), 2.50-2.20 (m, 6H), 2.10-2.01 (m, 1H), 1.97-1.93 (S, 4H), 1.92-1.71 (m, 4H), 1.69-1.50 (m, 9H), 1.48-1.22 (m, 4H), 1.22-1.12(m, 4H), 1.12-.92 (m, 2H), 0.743 (s, 3H). Example 13: (E)-40-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cydopenta phenanthren-17-yl)-36,36-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38-tridecaoxa-39-azahentetracont-39-en-37-oneStep-1: Synthesis of L 3. 6, 2-trioxathiocane 2-oxide o ii

[0517] To a stirred solution of 2, 2'-oxybis(ethan-l-ol) (10.0 g, 94.2 mmol) in dry DCM (1.0 L) were added DIPEA (82 mL) and DMAP (0.58 g, 4.7 mmol) at 0 °C. A solution of SOCh (22.1 g, 188 mmol) in dry DCM (250 mL) was added dropwise to the mixture over 1 h at 0 °C. The reaction mixture was stirred for another 1 h at RT and quenched with the addition of brine ( 1.5 L). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by Combi-Flash column chromatography using 30-40% EtOAc in hexane as eluent to give 13.1 g of the title compound as a brown liquid which was used directly in the next312043035 108Attorney Docket No.: NTSS-014 / 001 WOstep. 'H NMR (CDCh) 400 MHz; 3 ppm: 4.61-4.55 (m, 2H), 3.96-3.84 (m, 4H), 3.81-3.75 (m, 2 H).Step-2: Synthesis of 1, 3, 6-trioxathiocane 2, 2-dioxideOx ZOO"S" O

[0518] To a stirred mixture of 1, 3, 6, 2-trioxathiocane 2-oxide (13.1 g, 86 mmol) m acetonitrile (500 mL), CCl4 (500 mL) and water (800 mL) at 0 °C was added NalCh (22.1 g, 103 mmol) followed by RuCl3. 3H2O (112 mg, 0.43 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h diluted with water (500 mL) and extracted with DCM (2 x 500 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The concentrated was purified by Combi-flash column chromatography, using 50% EtOAc-hexane as eluent to afford 12.2g of the title compound as a pale brown liquid.!H NMR (CDCh) 400 MHz: 0 ppm: 4.51 (t, J / .4 Hz, 4H), 3.97 (t, J =4.4 Hz, 4H).Step-3: Synthesis of monodisperse Me-PEG11-OH, 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan-34-ol

[0519] To a stirred solution of monodisperse Me-PEG9-OH (2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-ol) (10.0 g, 23.3 mmol) in THF (130 mL) was added NaH (1.4 g, 35 mmol) at 0 °C. The mixture was stirred for 2 h at 0 °C and a solution of 1, 3, 6-trioxathiocane 2, 2-dioxide (4.26 g, 28.0 mmol) dissolved in THF (20 mL) was added at 0 °C. The mixture was stirred overnight at RT for 16 h, water (1 mL) was added at 0 °C to quench the reaction mixture and the reaction mixture pH was adjusted to 3 using cone. H2SO4 (0.6 mL). After stirring for 3 h the mixture was neutralized using saturated NaHCOs and concentrated under vacuum. The concentrate was purified by Combi-Flash column chromatography using 5% MeOH-DCM as eluent to afford 7.0 g of the title compound as a pale brown syrup. HPLC: Method-B (ELSD): 98%. ESI-MS (calc-516.63, obser-517.3(M+1)). H NMR (CDCh) 400 MHz: d ppm 3.83-3.71 (m, 3H), 3.68-3.59 (m, 42H), 3.57-3.52 (m, 2H), 3.38 (s, 3H), 2.85 (bs, 3H).Step-4: Synthesis of tert-butyl 36-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-oateO I 312043035 | Q9Attomey Docket No.: NTSS-014 / 001 WO

[0520] To a stirred solution of monodisperse Me-PEG11-OH, (2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan-34-ol) (4.8 g, 9.3 mmol) in dry THF (75 mL) was added NaH (0.71 g, 19 mmol) at 0 °C. After hydrogen evolution ceased, tert-butyl 2-bromoacetate (4.9 g, 23 mmol) was added and the mixture was stirred overnight at RT. Then, the reaction mixture was cooled to 0 °C and quenched with water followed by addition of NaCl solution (150 mL) and EtOAc (500 mL), The organic layer was separated, dried over Na2SO4, and concentrated under vacuum. The concentrate was dissolved in a minimum amount of water (50 mL) and the aqueous solution was extracted with hexane (2 x 50 mL). The aqueous layer was saturated with NaCl and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to give 4.7 g of the title compound as a pale brown liquid. HPLC: Method-B (ELSD): 97%, ESI-MS (calc: 644.80, obser: 663.00 (M+IhO)).lH NMR (CDCh) 400 MHz: 6 ppm 3.89 (q, J=7.2 Hz, 1H), 3.76-3.6 (m, 44H), 3.58-3.53 (m, 3H), 3.38 (s, 3H), 1.4 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).Step-5: Synthesis of tert-butyl 36, 36-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35- dodecaoxaheptatriacontan-37-oateO I

[0521] To a stirred solution of tert-butyl 36-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-oate (4.7 g, 7.3 mmol) in dry THF (95.0 mL) was added 1.0 M LiHMDS in THF (22 mL, 22 mmol) at -78 °C under argon. The mixture was stirred at -78 °C for 5 min and CH3I (1.4 mL, 22 mmol) dissolved in THF (5 mL) was added. The mixture was stirred for 10 min at -78 °C, allowed warm to RT and stirred for 4 h. The reaction mixture was quenched with sat. NH4Cl solution at 0 °C and extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The concentrate was purified by Combi-Flash chromatography over silica gel eluting with 3% MeOH-DCM to give 3.05 g of the title compound as a pale-brown liquid. HPLC: Method-B (ELSD): 99%. ESI-MS (calc-658.82, obser-676.95 (M+H2O)). ’H NMR (CDCh) 400 MHz: d ppm 3.9-3.8 (m, 1H), 3.7-3.6 (m, 49H), 3.57-3.53 (m, 5H), 3.36 (s, 3H), 1.46 (s, 9H), 1.38 (s, 6H).Step-6: Synthesis of 36, 36-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35- dodecaoxaheptatriacontan-37-oic acid312043035 110Attorney Docket No.: NTSS-014 / 001 WO

[0522] Water (5 mL) was added to a stirred solution of tert-butyl 36, 36-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-oate (2,0 g, 3,0 mmol) in 4M HC1 1,4-dioxane- (20 ml.) at 0 °C. The reaction mixture was allowed to warm to RT, stirred overnight and concentrated under reduced pressure. The concentrate was co-distilled with toluene (3 x 10 mL) to remove residual water. The residue was purified by Combi-Flash chromatography over silica gel using 3-4% MeOH-DCM as eluent to give 1.2 g of the title compound as a pale brown syrup after drying under high vacuum. HPLC: Method-B (ELSD): 97%. ESI-MS (calc-602.72, obser-620.40 (M+H2O)). NMR (CDCl₃) 400 MHz : δ ppm 3.56-3.5 (m, 44H), 3.38 (s, 3H), 1.44 (s, 6H). Step-7: Synthesis of (E)-40-((8S, 9S, 10R, 13S, 14S, 17S) -10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta phenanthren-17-yl)-36, 36-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38-tridecaoxa-39-azahentetracont-39-en-37-one

[0523] BOP (4.3 g, 9,6 mmol) was added to a stirred solution of 36, 36-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-oic acid (5.8 g, 9.6 mmol) and (8S, 9R, 10R, 13S, 14R, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (3,2 g, 9.6 mmol) in dry THF (100 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, DIPEA (5.0 mL, 28.9 mmol) was added at 0 °C and the mixture was stirred overnight at RT. Cold water (200 mL) was added to the reaction mixture followed by extraction with 200 mL of EtOAc. The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The concentrate was purified by Combi-Flash chromatography over a silica gel column that was first preconditioned by elution with 2% TEA-hexane solvent mixture. The crude concentrate dissolved in a minimum volume DCM was loaded on column and then eluted first with 30-50% EA / hexane (2% TEA) gradient to remove non-polar impurities. Then the column was eluted using 2-3% MeOH-DCM solvent gradient to give 5.2 g of the title compound as a pale yellow syrup. HPLC: Method-B (UV@ 240 nm): 98%. LC-MS: calc. 914.18, obser: 931.50 (M+H2O). ¹H NMR (CDCl₃) 400 MHz : δ ppm : 5.73 (s, 1H), 3.7- 3.6 (m, 42H), 3.58-3.52 (m, 2 H), 3.38 (s, 3H), 2.5-2.2 (m, 6H), 2.1-2.0 (m, 1H), 1.96 (s, 4H), 1.93- 1.71 (m, 4H), 1.54-1.48 (m, 8H), 1.42-1.24 (m, 4H), 1.19 (s, 4H), 1.16-0.94 (m, 2H), 0.74 (s, 3H).312043035 111Attorney Docket No.: NTSS-014 / 001 WOExample 14: (E)-43-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-39,39-dimethyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41-tetradecaoxa-42-azatetratetracont-42-en-40-oneStep-1: Synthesis of 1, 3, 6, 9-tetraoxa-2-thiacycloundecane 2-oxide

[0524] To a stirred solution of 2, 2'-(ethane-l, 2-diylbis(oxy))bis(ethan-l-ol) (25 g, 166 mmol) in 1,0 L dry DCM were added DIPEA (145 mL, 832 mmol) and DMAP (1.0 g, 8.3 mmol). The reaction mixture was stirred for 5 minutes at 0 °C and SOCl₂ (24.3 mL, 333 mmol) dissolved in dry DCM (500 mL) was added dropwise to the reaction mixture over a period of 2 h at 0 °C. After completion of addition the mixture was slowly allowed to warm to RT and stirred for 2 h. The reaction mixture was cooled to 0 °C and quenched with addition of 1.0 L of brine solution. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The crude product oil was purified by column chromatography over silica gel, using 50% EtOAc-hexane as eluent to give 23.5 g of the title compound as a pale-brown syrup. ESI-MS (calc-196.22, obser-197.7 (M+l)).NMR (CDCl₃) 400 MHz : δ ppm 4.47-4.42 (m, 2H), 4.09-4.04 (m, 2H), 3.92-3.80 (m, 4H), 3.74-3.62 (m, 4H).Step-2: Synthesis of 1, 3, 6, 9-tetraoxa-2-thiacycloundecane 2, 2-dioxide

[0525] To a stirred solution of 1, 3, 6, 9-tetraoxa-2-thiacycloundecane 2-oxide (23.5 g, 120 mmol) in a mixture of solvents ACN (800 mL), CCl₄ (800 mL) and water (1 L) was added NaIO₄ (30.7 g, 144 mmol) followed by RuCl₃.3H₂O (0.16 g, 0.59 mmol ) at 0 °C, The reaction mixture was stirred at RT for 16 h with reaction completion monitored by TLC. The mixture was diluted with 100 ml. of water, extracted with DCM (2 x 300 mL). The combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column 312043035 112Attorney Docket No.: NTSS-014 / 001 WOchromatography over silica gel using EtOAc as eluent to give 22,7 g of the title compound as a white solid. HPLC: Method- A (ELSD): 98%. ESI-MS (calc-212.22, obser-229.1 (M+H2O)). ¹H NMR (CDCl₃) 400 MHz : δ ppm 4.48-4.46 (m, 4H), 3.89-3.87 (m, 4H), 3.68 (s, 4H).Step-3: Synthesis 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-ol (monodisperse Me-PEG -OH)

[0526] To a stirred solution of monodisperse Me-PEGs>-OH (2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-ol) (10.0 g, 23.3 mmol) in THF (200 mL) was added NaH (60% in mineral oil, 1.40 g, 35 mmol) at 0 °C. The mixture was stirred for 2 h and a solution of 1, 3, 6, 9-tetraoxa-2-thiacycloundecane 2, 2-dioxide (5.45 g, 25.7 mmol) in dry THF (50 mL) was added at 0 °C. The reaction mixture was stirred overnight at RT and adjusted to pH 3 by addition of concentrated H2SO4 (ca. 2.5 ml.). The resulting mixture was stirred for 3 h at RT, neutralized with saturated NaHCO₃ and the concentrated under vacuum. The concentrate was purified by column chromatography using 3-4% MeOH in DCM as eluent to give 11.75 g of the title compound as a syrup. HPLC: Method- A (ELSD): 99%, ESI-MS (calc-560.68, obser-561.60 (M+l)). ¹H NMR (CDCl₃) 400 MHz : δ ppm 3.88-3.44 (m, 54H), 3.39 (s, 3H), 2.80-2.70 (bs, 1H).Step-4: Synthesis of tert-butyl 39-methyl-2, 5, 8, 11, 14. 17, 20, 23, 26, 29, 32, 35, 38- tridecaoxatetracontan-40-oate0

[0527] To a stirred solution of the above Me-PEGi2-OH (11.3 g, 20.1 mmol) in dichloromethane (100 mL) ) was added 50% NaOH solution (60 mL) at 0 °C. To the vigorously stirred 2-phase mixture were added tert- butyl 2-bromopropanoate (16.8 mL, 100 mmol) and tetrabutylammonium chloride (1.39 g, 5.02 mmol) at 0°C. The reaction mixture was stirred at RT for 16 h and the reaction progression was monitored by TLC. After reaction completion, di chloromethane (250 mL) was added, and the organic layer was separated and washed with brine solution (2 x 250 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum.. The concentrate was dissolved in water (200 mL) and extracted with hexane (2 x 200 mL). The aqueous layer was saturated with NaCl and extracted with ethyl acetate (2 x 500 mL). The combined ethyl acetate organic extracts were dried over Na2SO4 and evaporated under vacuum to give 10.5 g of the title compound as a colorless syrup. HPLC: Method-C (ELSD): 98%. ESI-MS (calc-688.85, obser-312043035 113Attorney Docket No.: NTSS-014 / 001 WO706.65 (M+H₂O)). ¹H NMR (CDCl₃) 400 MHz : δ ppm 3.89 (q, J1=6.8 Hz, J2=13.6 Hz, 1H), 3.78-3.60 (m, 46H), 3.58-3.52 (m, 3H), 3.38 (s, 3H), 1.48 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).Step-5: Synthesis of tert-butyl 39, 39-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38-tridecaoxatetracontan-40-oate01

[0528] To a stirred solution of tert-butyl 39-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38-tridecaoxatetracontan-40-oate (4.8 g, 7.0 mmol) in 70 mL of THF was added LiHMDS (56 mL, 1.0 M THF solution, 56 mmol) dropwise under argon atmosphere at -78 °C. The mixture was stirred at -78 °C for 30 min and iodomethane (2.7 mL, 42 mmol) was added at -78 °C. The reaction mixture was allowed to warm to RT and stirred overnight. Saturated NH4Q solution (100 mL) was added to the mixture followed by 100 mL of EtOAc. The organic layer was separated, dried over sodium sulphate, and concentrated under vacuum. The concentrate was dissolved in 100 mL of water and the aqueous solution was extracted with hexane (2 x 50 mL). The aqueous layer was saturated with NaCl and EtOAc (150 mL) was added. The organic layer was separated, dried over Na2SO4 and concentrated under vacuum to give 4.2 g of the title compound as a pale brown syrup. HPLC: Method- A (ELSD): 98%, ESI-MS (calc-702.88, obser-720.90 (M+H2O)). ’H NMR. (CDCh) 400 MHz: 3 ppm 3.90-3.80 (m, 1H), 3.80-3.62 (m, 52H), 3.60-3.52 (m, 5H), 3.39 (s, 3H), 1.47 (s, 9H), 1.39 (s, 6H).Step-6: Synthesis of 39, 39-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38- tridecaoxatetracontan-40-oic acid0

[0529] To a stirred solution of tert-butyl 39, 39-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38-tridecaoxatetracontan-40-oate (8.2 g, 11.7 mmol) in 20 mL of water was added 75 mL of 4M HC1 in 1,4-dioxane at 0 °C. The reaction mixture was stirred at RT for 16 hr and concentrated under vacuum. The concentrate was co-distilled with toluene (3 x 50 mL) and the crude product was purified by flash chromatography over silica gel using 3-4% MeOH-DCM as the eluent to give 6.0 g of the title compound as a pale yellow syrup. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-646.77, obser-647.85 (M+l)). ¹H NMR (CDCl₃) 400 MHz : δ ppm 3.84-3.42 (m, 48H), 3.38 (s, 3H), 1.46 (s, 6H).312043035 114Attorney Docket No.: NTSS-014 / 001 WOStep-7: Synthesis of (E)-43-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-39,39-dimethyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41-tetradecaoxa-42-azatetratetracont-42-en-40-one

[0530] BOP (3.8 g, 8.5 mmol) was added to a stirred solution of 39, 39-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38-tridecaoxatetracontan-40-oic acid (5.5 g, 8.5 mmol) and (8S, 9R, 10R, 13S, 14R, 17S)-17-((E)-1-(hydroxyimino)ethyl)-10, 13-dimethyl-1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (2.80 g, 8.5 mmol) in dry THF (50 mL). DIPEA (4.6 mL) was added at 0 °C to the mixture and the reaction mixture was stirred at RT for 16 h. Water (100 mL) was added and the mixture was extracted with EtOAc. The combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash column chromatography over a column that was first preconditioned with 2% TEA-hexane solvent mixture followed by loading the crude product onto the column in dichloromethane. The column was then eluted with a 30-50% ethyl acetate / hexane gradient to remove non-polar impurities and then with 2-3% MeOH-DCM to give 6.4 g of the title compound as a pale-yellow syrup. HPLC: Method-B (UV@ 240 nm): 99%. ESI-MS (calc-958.20, obser-975.75 (M+H2O)).NMR (CDCl₃) 400 MHz : δ ppm 5.73 (s, 1H), 3.72-3.60 (m, 51H), 3.58-3.52 (m, 2H), 3.38 (s, 3H), 2.47-2.25 (m, 6H), 2.08-1.96 (m, 6H), 1.94-1.68 (m, 6H), 1.62-1.54 (m, 2H), 1.51 (m, 6H), 1.48-1.24 (m, 4H), 1.22-1.14 (m, 4H), 1.12 -0.94(m, 2H), 0.74 (s, 3H). Example 15: (E)-46-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-42,42-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44-pentadecaoxa-45-azaheptatetracont-45-en-43-one312043035 115Attorney Docket No.: NTSS-014 / 001 WOStep-1: Synthesis of 1, 3, 6, 9, 12-pentaoxa-2-thiacyclotetradecane 2-oxide

[0531] To a stirred solution of 2, 2'-((oxybis(ethane-2,l-diyl))bis(oxy))bis(ethan-l-ol) (10.0 g, 51.0 mmol) in dry DCM (1.5 L) were added DIPEA (45 mL) and DMAP (0.31 g, 2.71 mmol) at 0 °C. After stirring for 5 min, a solution of SOCl₂ (7.5 mL, 100 mmol) in DCM (550 mL) was added dropwise to the mixture over a period of 2 h at 0 °C. The mixture was stirred at RT for 2 hrs and brine solution (1000 mL) was added at 0 °C. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The concentrate was purified by column chromatography, using 70% EtOAc in hexane as gradient to afford 10.0 g of the title compound as a pale-yellow liquid. HPLC: Method- A (ELSD): 78%. ESI-MS (calc-240.95, obser-258.1 (M+H2O)). ¹H NMR (CDCl₃) 400 MHz : δ ppm 4.12-4.07 (m, 2H), 3.84-3.78 (m, 4H), 3.72-3.64 (m, 8H).Step-2: Synthesis of 1, 3, 6, 9, 12-pentaoxa-2-thiacyclotetradecane 2,2-dioxide

[0532] To a stirred solution of 1, 3, 6, 9, 12-pentaoxa-2-thiacyclotetradecane 2-oxide (10.0 g, 41.6 mmol) in a solvent mixture of ACN (350 mL), CCI4 (350 mL) and water (525 mL) were added NaIO₄ (10.7 g, 214 mmol) and RuCl₃.xH₂O (0.11 g, 26 mmol) at 0 °C. The mixture was stirred at RT for 16 h. and extracted with DCM (2 x 500 mL), The combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The crude concentrate was purified by column chromatography using 30% EtOAc in hexane as gradient to afford 10 g of the title compound as a brown liquid. HPLC: Method-B (ELSD): 99%. ESI-MS (calc-256.26, obser-274.1 (M+H2O)). ¹H NMR (CDCl₃) 400 MHz : δ ppm 4.47 (t, J=5 Hz, 4H), 3.85 (t, J=5 Hz, 4H), 3.70-3.68 (m, 4H), 3.66-3.64 (m, 4H).Step-3: Synthesis of 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38-tridecaoxatetracontan-40-ol (Me-PEG13-OH)312043035 116Attorney Docket No.: NTSS-014 / 001 WO

[0533] To a stirred solution of monodisperse Me-PEG₉-OH (10.0 g, 23.3 mmol) in THF (100 mL) was added NaH (1.4 g, 35 mmol) at 0 °C. The mixture was stirred for 2 h and 1, 3, 6, 9, 12, 15-hexaoxa-2-thiacycloheptadecane 2, 2-dioxide (7.18 g, 28.0 mmol) dissolved in dry THF (50 mL) was added at 0 °C. The mixture was stirred at RT for 16 h, water (1.0 ml.) added and the pH adjusted to pH = 3 using cone, H2SO4 (0.7 mL). After stirring for 3 h the mixture was neutralized by addition of saturated NaHCOs solution and concentrated under vacuum. The crude product was purified by¬ column chromatography using 2-3% MeOH-DCM gradient to afford 8.2 g of the title compound as pale-yellow solid. HPLC: Method-A (ELSD): 99%, ESI-MS (calc-604.7, obser-605.3 (M+l). ¹H NMR (CDCl₃) 400 MHz : δ ppm 3.68-3.56 (m, 58H), 3.35 (s, 3H), 2.82 (bs, 1H).Step-4: Synthesis of tert-butyl 42-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41- tetradecaoxahexatritetracontan-43-oate

[0534] To a stirred solution of monodisperse Me-PEG₁₃-OH (5.0 g, 8.3 mmol) in di chloromethane (30 m. L) were added 50% NaOH solution (30 ml,), tert-butyl 2-bromopropanoate (6.9 mL, 41 mmol) and TBACl (0,57 g, 2,1 mmol) at 0 °C. The mixture was stirred at RT for 16 hrs and DCM (200 mL) was added. The organic layer was separated, washed with cold brine solution (2 x 200 mL), dried over Na2SO4. and concentrated under vacuum. The concentrate was dissolved in water (200 mL) and the aqueous phase was extracted with hexane (2 x 200 mL). The aqueous layer was saturated with NaCl and extracted with ethyl acetate (2 x 500 mL). The combined organic extracts were dried over Na2SO4 and evaporated under vacuum to give 2.65 g of the title compound as a colorless liquid. HPLC: Method-A (ELSD) 99%. ESI-MS (calc-732.9, obser-750.5 (M+EEO)).’!! NMR (CDCh) 400 MHz: 3 ppm 3.89 (q, J 6.8 Hz, 1H), 3.73-3.71 (m, 2H), 3.67-3.63 (m, 52H), 3.58-3.54 (m, 3H), 3.38 (s, 3H), 1.48 (s, 9H), 1.37 (d, J 6.8 Hz, 3H).Step-5: Synthesis of tert-butyl 42, 42-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41-tetradecaoxahexatetracontan-43-oate

[0535] A solution of tert-butyl 45-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41-tetradecaoxahexatetracontan-43-oate (4.0 g, 5.5 mmol) dissolved in 60 mL of THF was cooled to - 78 °C and 1.0 M LiHMDS in THF (43.7 mL, 43.7 mmol) was added dropwise under argon atmosphere at -78 °C. The mixture was stirred 30 min at -78 °C and iodomethane (2.1 mL, 33 mmol) 312043035 117Attorney Docket No.: NTSS-014 / 001 WOwas added. The reaction mixture was allowed to warm to RT and stirred for 16 hr. The reaction was quenched with saturated NH4CI solution (100 mL) and 100 mL of EtOAc was added. The organic layer was separated, dried over sodium sulphate and evaporated under vacuum. The concentrate was dissolved in 100 mL of water and the aqueous layer was extracted with hexane (2 x 50 mL). The aqueous layer was saturated with NaCl and extracted with EtOAc (100 mL). The organic layer was separated, dried over Na2SO4and concentrated under vacuum to give 1.9 g of the title compound as a pale brown liquid. HPLC: Method-A (ELSD) Purity: 97%. ESI-MS (calc-746.93, obser-764.4 (M+H2O)). NMR (CDCl₃) 400 MHz : δ ppm 3.76-3.83 (m, 1H), 3.62-3.57 (m, 54H), 3.56-3.53 (m, 4H), 3.38 (s, 3H), 1.48 (s, 9H), 1.38 (s, 6H). Step-6: Synthesis of 42. 42-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41-tetradecaoxahexatetracontan-43-oic acid o

[0536] To a solution of tert-butyl 42, 42-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44-pentadecaoxahexatetracontan-46-oate (3.1 g, 4.15 mmol) in 9.3 mL. of water was added 21 mL of 4M 1, 4-dioxane HC1 at 0 °C. The mixture was stirred at RT for 16 hr and concentrated under vacuum. The concentrate was co-distilled with toluene (3 x 50 mL) and crude product was purified by Combi-Flash column chromatography using 3-4% MeOH-DCM as gradient to give 2.2 g of the title compound as a pale brown syrup. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-690.81, obser-708.50 (M+H2O)).NMR (CDCl₃) 400 MHz : δ ppm 3.71-3.62 (m, 52H), 3.60-3.55 (m, 2H), 3.38 (s, 3H), 1.47 (s, 6H).Step-7: Synthesis of 42, 42-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41- tetradecaoxahexatetracontan-43-oyl chlorideo

[0537] Oxalyl chloride (0.25 mL, 2.90 mmol) and DMF (0.1 mL) were added at 0 °C to a stirred solution of the tert-butyl 42, 42-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41-pentadecaoxahexatetracontan-43-acid (1.0 g, 1.5 mmol) in dry toluene (10 mL). The reaction mixture was allowed to warm to room temperature, stirred 2 h and concentrated to give 1.0 g of the title compound as pale brown syrup which was used directly in the next step.Step-8: Synthesis of (E)-46-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-42,42-dimethyl-2, 312043035 118Attorney Docket No.: NTSS-014 / 001 WO5, 8, ll, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44-pentadecaoxa-45-azaheptatetracont-45-en-43-one

[0538] To a stirred solution of (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.7 g, 1.0 mmol) in 7 mL of dry DCM was added triethylamine (0.7 mL, 4.9 mmol). Crude 42, 42- dimethyl- 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41-tetradecaoxatritetracontan-43-oyl chloride (0.7 g) dissolved in 7 mL of DCM was added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with water (10 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with sat. NaHCOs solution and concentrated under reduced pressure. The concentrate was purified by Combi-Flash chromatography over a silica gel column that was first preconditioned by elution with 2% TEA-Hexane solvent mixture. The crude concentrate dissolved in a minimum volume DCM was loaded onto the column and followed by elution with 30-50% EA / hexane (2% TEA) gradient to remove non-polar impurities. Then the column was eluted using 3-4% MeOH-DCM solvent gradient to give 0.74 g of the title compound as a pale brown syrup. HPLC: Method-B (UV@ 240 nm): 97%, LC-MS (calc- 1002.28, obser-: 1019.2 (M+H2O)).NMR (CDCl₃) 400 MHz : δ ppm 5.73 (s, 1H), 3.68-3.53 (m, 58H), 3.38 (s, 3H), 2.43-2.27 (m, 6H), 2.10-1.70 (m, 9H), 1.60-1.50 (m, 8H), 1.50-1.30 (m, 4H), 1.19 (s, 4H), 0.98-1.10 (m, 2H), 0.74 (s, 3H).Example 16: (E)-49-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-45,45-dimethyl-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47-hexadecaoxa-48-azapentacont-48-en-46-oneStep-1: Synthesis of 1, 3, 6, 9, 12, 15-hexaoxa-2-thiacycloheptadecane 2-oxide312043035 119Attorney Docket No.: NTSS-014 / 001 WO

[0539] To a stirred solution of 3,6,9,12-tetraoxtetradecane-1,14-diol (10.0 g, 42.0 mmol) in 1.0 L dichloromethane were added DIPEA (37 mL, 210 mmol) and DMAP (0.26 g, 2.1 mmol). The solution was stirred for 5 minutes at 0 °C and SOCI2 (6.1 mL, 84 mmol) dissolved in dry' DCM (250 mL) was added dropwise over a period of 2 h at 0 °C. The reaction mixture was slowly allowed to warm to RT and stirred for 2 h. The mixture was cooled to 0 °C and quenched with addition of 1.0 L of brine solution). The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure The crude product oil was purified by column chromatography over silica gel, using 70% EtOAc-hexane eluent to afford 9.0 g of the title compound as a pale-yellow syrup. HPLC: Method-A (ELSD): 90%. ESI-MS (calc-284.32, obser-302.2 (M+H2O)). ’HNMR (CDCh) 400 MHz: 3 ppm 4.31-4.26 (m, 2H), 4.17-4.10 (m, 2H), 3.85-3.65 (m, 18H).Step-2: Synthesis of 1, 3, 6, 9, 12, 15-hexaoxa-2-thiacycloheptadecane 2, 2-dioxide

[0540] To a stirred solution of 1, 3, 6, 9, 12, 15-hexaoxa-2-thiacycloheptadecane 2-oxide (9.0 g, 32 mmol) in a mixture of solvents ACN (500 mL), CCl4 (500 mL) and water (800 mL) at 0 °C was added NaIO₄ (8.12 g, 38.0 mmol) followed by RuCl₃.xH₂O (0.41 g, 1.58 mmol ). The reaction mixture was stirred at RT for 16 h. The mixture was extracted with DCM (2 x 500 mL) and the combined organic extracts dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel using EtOAc as eluent to afford 6.5 g of the title compound as a brown liquid. HPLC: Method-B (ELSD): 99%. ESI-MS (calc-300.32, obser-318.1 (M+H2O)). ¹H NMR (CDCl₃) 400 MHz : δ ppm 4.45 (t, J=4.8 Hz, 4H), 3.81 (t, J=4.8 Hz, 4H), 3.70-3.65 (m, 12H).Step-3: Synthesis of 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41-tetradecaoxatritetracontan-43-ol (monodisperse Me-PEGi4-OH)312043035 120Attorney Docket No.: NTSS-014 / 001 WO

[0541] To a stirred solution of monodisperse Me-PEGs>-OH (14.0 g, 32.7 mmol) in THF (150 mL), was added NaH (2.14 g, 49 mmol) at 0 °C. The suspension was stirred for 2 h and a solution of 1, 3, 6, 9, 12, 15-hexaoxa-2-thiacycloheptadecane 2, 2-dioxide (12.8 g, 42.5 mmol) in dry THF (50 mL) was added at 0 °C. The reaction mixture was stirred overnight at RT and the pH was then adjusted to 3 using concentrated H2SO4 (ca. 1.2 ml.). The resulting mixture was stirred for 3 h, neutralized with saturated NaHCO₃ (18,0 mL) solution and concentrated under vacuum. The concentrate was purified by column chromatography using 2-3% MeOH in DCM as eluent to afford 10.7g of the title Me-PEG11-OH compound as a pale-yellow syrup. HPLC: Method- A (ELSD): 99%, ESI -MS (calc-648.78, obser-666.5 (M+H2O)).NMR (CDCI3) 400 MHz: d ppm 4.0-3.5 (m, 69H), 3.39 (s, 3H), 2.81 (bs, 3H).Step-4: Synthesis of tert-butyl 45-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44- pentadecaoxahexatetracontan-46-oate

[0542] To a stirred solution of Me-PEG14-OH (10.7 g, 16.5 mmol) in dichloromethane (60 mL) at 0 °C was added 50% NaOH solution (60 mL, 16.5 mmol). To the vigorously stirred 2-phase mixture were added tert-butyl 2-bromopropanoate (13.8 mL, 82 mmol) and tetrabutylammonium chloride (1.15 g, 4.12 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h and dichloromethane (200 mL) was added. The organic layer was separated and washed with cold brine solution (2 x 200 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The concentrate was dissolved in water (200 mL) and extracted with hexane (2 x 200 mL). The aqueous layer was saturated with NaCl and extracted with ethyl acetate (2 x 500 mL). The combined ethyl acetate organic extracts were dried over Na2SO4 and evaporated under vacuum to yield 8.0 g of the title compound as a colorless liquid.!H NMR (CDCh) 400 MHz: d ppm 3.89 (q, J=6.8 Hz, 1H), 3.78-3.71 (m, 2H), 3.7-3.6 (m, 52H), 3.58-3.52 (m, 3H), 3.38 (s, 3H), 1.48 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).Step-5: Synthesis of tert-butyl 45, 45-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44-pentadecaoxahexatetracontan-46-oate0 I

[0543] To a stirred solution of tert-butyl 45-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44-pentadecaoxahexatetracontan-46-oate (2.5 g, 3.2 mmol) in 20 mL of THF was added 312043035 121Attorney Docket No.: NTSS-014 / 001 WOLiHMDS (32 mL, 1.0 M THF solution, 32 mmol) dropwise under argon atmosphere at -78 °C, The mixture was stirred at -78 °C for 30 min and iodomethane (1.3 mL, 19 mmol) was added at -78 °C. The reaction mixture was allowed to warm to RT and stirred overnight. Saturated NH4Cl solution (100 mL) was added followed by 100 mL of EtOAc. The organic layer was separated, dried over sodium sulphate, and concentrated under vacuum. The concentrate was dissolved in 100 mL of water and the aqueous solution was extracted with hexane (2 x 50 mL) The aqueous layer was saturated with NaCl and EtOAc (100 mL) was added. The organic layer was separated, dried over Na2SO4 and concentrated under vacuum to give 1.9 g of the title compound as a pale brown liquid. ESI-MS (calc-790.98, obser-808.35 (M+H2O)). 1H NMR (CDCl3) 400 MHz: δ ppm 3.83-3.79 (m, 1H), 3.75-3.66 (m, 55H), 3.57-3.53 (m, 5H), 3.38 (s, 3H), 1.48 (s, 9H), 1.38 (s, 6H).Step-6: Synthesis of 45, 45-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44- pentadecaoxahexatetracontan-46-oic acid0

[0544] To a stirred solution of tert-butyl 45, 45-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44-pentadecaoxahexatetracontan-46-oate (3,2 g, 4,1 mmol, 1 eq.) m 10 mL of water was added 50 mL of 4M HC1 in 1,4-dioxane at 0 °C. The reaction mixture was stirred at RT for 16 h. The mixture was concentrated under vacuum and the concentrate was co-distilled with toluene (3 x 50 mL). The crude product was purified by flash chromatography over silica gel using 3-4% MeOH-DCM as the eluent to give 2.45 g of the title compound as a pale brown syrup. HPLC: Method-A (ELSD): 99%. Hl NMR (CDCI3) 400 MHz: d ppm 3.86-3.78 (m, HI), 3.76-3.62 (m, 59H), 3.62- 3.58 (m, 2H), 3.56-3.52 (m, 2H), 3.38 (s, 3H), 1.48 (s, 6H).Step-7: Synthesis of (E)-49-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8,9, 10, 11, 12, 13,14, 15, 16,17-tetradecahydro-IH-cyclopenta[a jphenanthren- 17-yl)-45, 45-dimethyl-2, 5, 8,11, 14, 17, 20, 23, 26,29, 32, 35, 38, 41, 44,47-hexadecaoxa-48-azapentacont-48-en-46-one

[0545] To a stirred solution of 45, 45-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44-pentadecaoxahexatetracontan-46-oic acid (1.8 g, 2.5 mmol) and (8S, 9R, 10R, 13S, 14R, 17S)- 17-((E)-l-(hydroxyimmo)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17- 312043035 122Attorney Docket No.: NTSS-014 / 001 WOtetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.81 g, 2.5 mmol) in dry THF (50 mL) were added BOP reagent (1.1 g, 2.5 mmol) and DIPE A (1.3 mL, 7.4 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h and water (100 mL) was added. The mixture was extracted with EtOAc and the combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash column chromatography over a silica gel column, that was preconditioned with 2% TEA-hexane solvent mixture. The crude compound was loaded on column by dissolving in minimum volume DCM. The column was then eluted with a 30-50% ethyl acetate / hexane gradient to remove non-polar impurities and then with 3% MeOH-DCM solvent gradient to obtain 2.1 g of the title compound as a pale-yellow syrup. HPLC: Method-B (UV@ 240 nm): 98%. ESI-MS (calc- 1046.34, obser-1064.7 (M+H2O)).NMR (CDCh) 400 MHz: d ppm 5.73 (s, 1H), 3.85-3.45 (m, 61H), 3.38 (s, 3H), 2.5-2.20 (m, 6H), 2.1-2.0 (m, 1H), 2.0-1.9 (m, 4H), 1.9-1.7 (m, 4H), 1.55-1.48 (m, 7H), 1.45-1.4 (m, 1H), 1.4-1.25 (m, 3H), 1.20 (s, 4H), l.l-0.9 (m, 2H), 0.74 (s, 3H).Example 17: (E)-52-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,ll,12,13, 14,15,16,17-tetradecahydro-lH-cydopenta|a]phenanthren-17-yI)-48,48-dimethyl-2,5,8,ll,14,17,20,23,26,29,32,35 8,41'>44,47,50-heptadecaoxa-51-azatripentacont-51-en-49-oneStep-1: Synthesis of 1, 3, 6, 9, 12, 15, 18-heptaoxa-2-thiacycloicosane 2-oxide

[0546] To a stirred solution of 3, 6, 9, 12, 15-pentaoxaheptadecane-l, 17-diol (10.0 g, 35.4 mmol) in dry DCM (2.0 L) were added DIPEA (31 mL) and DMAP (0.22 g, 1.8 mmol) at 0 °C. A solution of SOCh (5.2 mL, 71 mmol) in dry DCM (500 mL) was added dropwise to the mixture over a period of 2 h at 0 °C. The reaction mixture was stirred for another Ih at RT. The reaction mixture was quenched with saturated NaHCOs (500 mL) at 0 °C. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by 312043035 123Attorney Docket No.: NTSS-014 / 001 WOcolumn chromatography using 2% MeOH in DCM as eluent to give 9.0 g of the title compound as a brown liquid. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-328.37, obser-346.40 (M+H2O)). 1H NMR (CDCl3) 400 MHz: δ ppm 4.29-4.23 (m, 2H), 4.16-4.11 (m, 2H), 3.79-3.65 (m, 21H). Step-2: Synthesis of 1, 3, 6, 9, 12, 15, 18-heptaoxa-2-thiacycloicosane 2, 2-dioxide%"°crb"o

[0547] To a stirred solution of 1, 3, 6, 9, 12, 15, 18-heptaoxa-2-thiacycloicosane 2-oxide (9.0 g, 27.4 mmol) in ACN (270 mL) were added CCI4 (270 mL) and water (400 mL) at 0 °C followed by NaIO4 (7.0 g, 33 mmol) and RUCI3. XH2O (0.072 g, 0.27 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h and extracted with DCM (2 x 500 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel using 50 % EtOAc in hexane as gradient eluent to give 6.75 g of the title compound as a pale-yellow liquid. HPLC: Method-A (ELSD): 99%. ESIMS (calc-344.37, obser-345.45 (M+l)). ’ H NMR (CDCb) 400 MHz: 3 ppm 4.45 (t, J- =8.4 Hz, 4H), 3.81 (t, J=8.4Hz, 4H), 3.67-3.64 (m, 17H).Step-3: Synthesis of 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44-pentadecaoxahexatetracontan-46-ol (Me-PEGis-OH)15

[0548] To a stirred solution of monodisperse Me-PEGs-OH (5.0 g, 12 mmol) in THF (50 mL) was added NaH (0.7 g, 17.50 mmol) at 0 °C. A solution of 1,3,6,9,12,15,18-heptaoxa-2-thiacycloicosane 2,2-dioxide (4.8 g, 14 mmol) dissolved in THF (25 mL) was added at 0 °C and the mixture was stirred overnight at RT for 16 h. Water (0.5 mL) was added at 0 °C and the pH was adjusted to pH = 3 using cone. H2SO4 (0.5 mL), After stirring for 3 h, the mixture was neutralized using saturated NaHCOs and concentrated under vacuum. The concentrate was purified by Combi-Flash column chromatography using 3% MeOH-DCM as gradient eluent to afford 4.2 g of the title compound as a pale-yellow solid. HPLC: Method-A (ELSD): 93%. ESI-MS (calc-692.83, obser-693.15 (M+l)). 1H NMR (CDCl3) 400 MHz: δ ppm 3.73-3.55 (m, 60H), 3.39 (s, 3H), 2.74 (bs, 1H).Step-4: Synthesis of tert-butyl 48-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47-hexadecaoxanonatetracontan-49-oate312043035 124Attorney Docket No.: NTSS-014 / 001 WO

[0549] To a stirred solution of Me-PEGis-OH (4.2 g, 6.1 mmol) in di chloromethane (25 mL) was added 50% NaOH solution (25 mL) at 0 °C. To the vigorously stirred 2-phase mixture tert-butyl 2-bromopropanoate (5.1 mL, 30 mmol) and tetrabutylammonium chloride (0.42 g, 1.51 mmol) were added at 0 °C. The reaction mixture was stirred at RT for 16 and dichloromethane (100 mL) was added. The organic layer was separated and washed with brine solution (2 x 50 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The concentrate was purified by Combi-Flash column chromatography, using 3% MeOH in DCM as gradient eluent to give 3.8 g of the title compound as a colorless syrup. HPLC: Method- A (ELSD) 99%, ESI-MS (calc-821.00, obser-838.50 (M+H2O)).1H NMR (CDCl3) 400 MHz: δ ppm 3.89 (q, J=6.8 Hz, 1H), 3.74-3.70 (m, 2H), 3.64-3.61 (m, 49H), 3.58-3.53 (m, 3H), 3.38 (s, 3H), 1.48 (s, 9H), 1.37 (d, J= 6.8 Hz, 3H). Step-5: Synthesis of tert-butyl 48, 48-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47-hexadecaoxanonatetracontan-49-oate

[0550] To a stirred solution of tert-butyl 48-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47-hexadecaoxanonatetracontan-49-oate (3.8 g, 4.63 mmol) in dry THF (60 mL) was added 1.0 M LiHMDS in THF (39 mL, 39 mmol) at -78 °C under argon. The mixture was stirred at -78 °C for 30 min and CH3I (1.7 mL, 28 mmol) dissolved in THF (5 mL) was added. The reaction mixture was stirred for 10 min at -78 °C, allowed warm to RT and stirred at RT for 16 h. The mixture was quenched with sat, NH4CI solution at 0 °C and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The concentrate was purified by Combi-Flash chromatography over silica gel eluting with 3% MeOH-DCM as gradient eluent to give 2.28 g of the title compound as a colorless syrup, HPLC: Method-A (ELSD): 97%. ESI-MS (calc-835.03, obser-853.55 (M+H2O)). 1H NMR (CDCl3) 400 MHz: δ ppm 3.83-3.46 (m, 62H), 3.38 (s, 3H), 1.48 (s, 9H), 1.38 (s, 6H).Step-6: Synthesis of 48, 48-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47- hexadecaoxanonatetracontan-49-oic acid

[0551] Water (13 mL) was added to a stirred solution of tert-butyl 48, 48-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47-hexadecaoxanonatetracontan-49-oate (4.2 g, 5.03 mmol) 312043035 125Attorney Docket No.: NTSS-014 / 001 WOin 4M HC1 1,4-dioxane (30 mL) at 0 °C, The reaction mixture was allowed to warm to RT, stirred overnight and concentrated under reduced pressure. The concentrate was co-distilled with toluene (3 x 10 mL) to remove residual water. The crude product was purified by Combi-Flash chromatography over a silica gel column that was first preconditioned by elution with 2% TEA-hexane solvent mixture. The crude concentrate dissolved in a minimum volume DCM was loaded onto the column and then eluted with 3-4% MeOH-DCM as gradient eluent to give 2.4 g of the title compound as a pale-yellow syrup. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-778.92, obser-779.55 (MH )).1H NMR (CDCl3) 400 MHz: δ ppm 3.71-3.63 (m, 63H), 3.60-3.55 (m, 5H), 3.38 (s, 3H), 1.44 (s, 6H).Step-7: Synthesis of 48, 48-dimethyl-2, 5, 8, ll, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47- hexadecaoxanonatetracontan-49-oyl chlorideo

[0552] To a stirred solution of 48, 48-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47-hexadecaoxanonatetracontan-49-oic acid (2.3 g, 3.0 mmol) in dry toluene (10 mL) at 0 °C was added oxalyl chloride (0.51 mL, 5.91 mmol) followed by DMF (0.1 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated to give 2.3 g of the title compound as a pale brown syrup which was used directly m the next step without further purification.Step-8: Synthesis of (E)~52~((8S,9S,10R,13S,14S,17S)~10,13-dimethyl-3-oxo-2,3,6, 7,8,9,10,11,12, 13,14, 15,16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-l 7-yl)-48, 48-dimethyl- 2, 5, 8,11,14,17,20, 23,26, 29, 32, 35, 38, 41, 44,47, 50-heptadecaoxa-5 l-azatripentacont-5 l-en-49-onee

[0553] (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13 -dimethyl- 1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.95 g, 2.88 mmol) was dissolved in 15 mL of dry DCM and then triethylamine (2.0 mL) mmol) was added. Crude 48, 48-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47-hexadecaoxanonatetracontan-49-oyl chloride (2.3 g) was dissolved in 20 mL of DCM and added at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with water (20 mL) and extracted with DCM (1 x 100 mL). The organic 312043035 126Attorney Docket No.: NTSS-014 / 001 WOlayer was washed with sat. NaHCOs solution and concentrated under reduced pressure. The concentrate was purified by Combi-Flash chromatography over a silica gel column that was first preconditioned by elution with 0.1% TEA-hexane solvent mixture. The crude concentrate dissolved in a minimum volume DCM was loaded on the column and then eluted with 30-50% EA / hexane as solvent gradient to remove non-polar impurities. Then the column was eluted using 3-4% MeOH-DCM as solvent gradient to give 1.2 g of the title compound as a pale brown syrup. HPLC: Method-E (CAD): 94.79%, HPLC: Method-B (UV@ 240 nm): 99%, LC-MS (calc-1090.39, obser-1107.30 (M+H2O)). NMR (CDCh) 400 MHz: d ppm 5.73 (s, 1 H), 3.83-3.46 (m, 65H), 3.38 (s, 3H), 2.42- 2.30 (m, 6H), 2.07-2.01 (m, 1H), 1.97-1.92 (m, 4H), 1.92-1.83 (m, 1H), 1.83-1.78 (m, 1H), 1.74-1.68 (m, 1H), 1.68-1.55(m, 2H), 1.54-1.49 (s, 6H), 1.48-1.23 (m, 3H), 1.19 (s, 4H), 1.13-0.95 (m, 2H), 0.743 (s, 3H).Example 18: (E)-61-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cydopenta|a]pheiianthren-17-yI)-57, 57-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59-icosaoxa-60-azadohexacont-60-en-58-oneStep- 1: Synthesis of 1, 3, 6, 9, 12, 15, 18, 21, 24, 27-decaoxa-2-thiacyclononacosane 2-oxide

[0554] To a stirred solution of 3, 6, 9, 12, 15, 18, 21, 24-octaoxahexacosane-l, 26-diol (20.0 g, 48.3 mmol) in dry DCM (2.5 L), were added DIPEA (42 mL, 241 mmol) and DMAP (0.30 g, 2.41 mmol) at 0 °C. SOCb. (7.0 mL, 97 mmol) dissolved in DCM (500 mL) was added dropwise to the reaction mixture over a period of 2 h at 0 °C. The reaction mixture was stirred at RT for 2 h and quenched with sat. NaHCOs (500 mL) solution at 0 °C. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography, eluting with 3-4% MeOH in DCM as eluent to give 15.5 g of the title 312043035 127Attorney Docket No.: NTSS-014 / 001 WOcompound as pale-brown liquid. HPLC: Method-B (ELSD): 99.60% and ESI-MS (calc-460.53, obser-478.30(M+H2O)). 1H NMR (CDCl3) 400 MHz: δ ppm 4.18 (q, J1=4.8 Hz, J2=9.2 Hz, 4H), 3.75-3.73 (m, 4H), 3.7-3.63 (m, 28H).Step-2: Synthesis of 1, 3, 6, 9, 12, 15, 18, 21, 24, 27-decaoxa-2-thiacyclononacosane 2, 2-dioxide

[0555] To a stirred solution of 1, 3, 6, 9, 12, 15, 18, 21, 24, 27- decaoxa -2-thiacyclononacosane 2- oxide (15.5 g, 33.7 mmol) in a solvent mixture comprised of ACN (500 mL), CCL (500 mL) and water (500 mL) was added NalCh (8.64 g, 40.4 mmol) followed by RuCl3. 3H2O (44 mg, 0.16 mmol) at 0 °C. The mixture was allowed to stir at RT for 16 h and extracted with DCM (2 x 500 mL). The combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography using 3-4% MeOH in DCM as eluent to give 13.6 g of the title compound as pale-yellow liquid. HPLC: Method-B (ELSD): 99.79%. ESI-MS (calc-476.53, obser-494.25 (M+H2O)). ^I NMR (CDCh) 400 MHz: d ppm 4.45-4.43 (m, 4H), 3.81-3.79 (m, 4H), 3.69-3.62 (m, 28H).Step-3: Synthesis of 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53- octadecaoxapentapentacontan-55-ol (monodisperse Me-PEG is-OH)

[0556] To a stirred solution of monodisperse Me-PEG9-OH (2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-ol) (10.1 g, 23.6 mmol) in dry THE (200 mL) was added NaH (1.4 g, 35 mmol) at 0 °C. The mixture was stirred for 2 h and 1, 3, 6, 9, 12, 15, 18, 21, 24, 27-decaoxa-2-thiacyclononacosane 2, 2-dioxide (13.5 g, 28.3 mmol) dissolved in dry THF (50 mL) was added at 0 °C. The mixture was allowed to stir at RT for 16 h and quenched with H2O (1.2 mL). The pH of the mixture was adjusted to 3 using cone. H2SO4 (1.2 mL). After stirring for 3 h the mixture was neutralized with saturated NaHCO₃ (18.0 mL) and was concentrated under vacuum. This crude product was purified by column chromatography using 3-4% MeOH in DCM as eluent to give 13.6 g of the title compound as off-white waxy solid. HPLC: Method-A (ELSD): 99.60%. ESI-MS (calc- 824.99, obser-842.50 (M+H2O)).lH NMR (CDCh) 400 MHz: d ppm 3.84-3.60 (m, 76H), 3.56- 3.53 (m, 2H), 3.38 (s, 3H), 2.87 (m, 1H).312043035 128Attorney Docket No.: NTSS-014 / 001 WOStep-4: Synthesis of tert-butyl 57-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56-nonadecaoxaoctapentacontan-58-oate

[0557] To a stirred solution of 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53-octadecaoxapentapentacontan-55-ol (10.6 g, 12.9 mmol) in dichloromethane (70 mL) at 0 °C was added 50% NaOH solution (70 mL, 12.9 mmol) followed by tert-butyl 2-bromopropanoate (10.8 mL, 64.2 mmol) and TBACl (0.89 g, 3.21 mmol). The reaction mixture was stirred at RT for 16 h and DCM (200 mL) was added. The organic layer was separated, washed with cold brine solution (2 x200 mL) and dried over Na₂SO₄. The solvent was evaporated under vacuum and the concentrate was dissolved in water (200 mL). The aqueous phase was extracted with hexane (2 x 200 mL), saturated with NaCl and extracted with ethyl acetate (2 x 500 mL). The combined organic extracts were dried over Na2SO4 and concentrated under vacuum to give 10.3 grams of the crude title compound. Silica gel chromatography of 2.0 g of crude title compound using the Combi-Flash system with 2-3% MeOH-DCM as eluent gave 1.45 g of the pure title compound. HPLC: Method-A (ELSD): 99.64%. ESI-MS (calc-953.16, obser-970.60 (M+H2O)).lH NMR (CDCI3) 400 MHz: ppm 3.91 (q, J1=6.8 Hz, J2=14 Hz, 1H), 3.78-3.71 (m, 2H), 3.76-3.60 (m, 72H), 3.58-3.53 (m, 4H), 3.38 (s, 3H), 1.48 (s, 9H), 1.37 (d, J=6.8 Hz, 3H).Step-5: Synthesis of tert-butyl 57, 57-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56-nonadecaoxaoctapentacontan-58-oate

[0558] To a stirred solution of tert-butyl tert-butyl 57-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56-nonadecaoxaoctapentacontan-58-oate (1.0 g, 1.05 mmol) in 20 mL of dry THF was added 1.0 M LiHMDS in THF (4.2 mL, 4.2 mmol) dropwise at -78 °C under argon atmosphere. The mixture was stirred for 30 min and Iodomethane (0.26 mL, 4.2 mmol) was added at -78 °C. The mixture was allowed to warm to RT and stirred overnight. Saturated NH4CI solution (100 mL) was added followed by 100 mL of EtOAc. The organic layer was separated, dried over sodium sulphate and evaporated under vacuum. The concentrate was dissolved in 100 mL of water, the aqueous phase was extracted with hexane (2 x 50 mL) and saturated with NaCl. The product was extracted from the aqueous phase with EtOAc (100 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum to give 720 mg of the title compound as pale-yellow syrup.312043035 129Attorney Docket No.: NTSS-014 / 001 WOHPLC: Method- A (ELSD): 99%. ESI-MS (calc-967.19, obser-984.60 (M+H2O)).!H NMR (CDCh) 400 MHz: 3 ppm 3.72-3.61 (m, 79H), 3.57-3.54 (m, 5H), 3.38 (s, 3H), 1.46 (s, 9H), 1.38 (s, 6H). Step-6: Synthesis of 57,57-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56-nonadecaoxaoctapentacontan-58-oic acid0

[0559] To a stirred solution of tert-butyl 57, 57-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56-nonadecaoxaoctapentacontan-58-oate (4.25 g, 4.39 mmol) in 20 mL of water was added 50 mL of 4M HC1 in 1,4-Dioxane at 0 °C. The mixture was stirred at RT for 16 h and concentrated under vacuum. The concentrate was co-distilled with toluene (3 x 50 mL) of to remove moisture completely. The obtained crude compound was purified by Combi-Flash column chromatography using 2-3% MeOH-DCM as eluent to obtain 2.1 g of the title compound as a paleyellow syrup. HPLC: Method-A (ELSD): 99.84% and ESI-MS (calc-911.08, obser-928.5 (M+H2O)). ’H NMR (CDCh) 400 MHz: δ ppm 3.71-3.54 (m, 75H), 3.58-3.54 (m, 3H), 3.5-3.42 (m, 1H), 3.38 (s, 3H), 1.46 (s, 6H).Step-7: Synthesis of (E)-61-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-57, 57 -dim ethyl- 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, 59-icosaoxa-60-azadohexacont-60~en~58~one

[0560] To a stirred solution of (8S, 9R, 10R, 13S, 14R, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13 -dimethyl- 1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.74 g, 2.25 mmol) and 57,57-dimethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56-nonadecaoxaoctapentacontan-58-oic acid (2.05 g, 2.25 mmol) in dry THF (50 mL) were added DIPEA (1.2 mL, 6.8 mmol) and BOP reagent (0.99 g, 2.25 mmol) at 0 °C. The reaction mixture was allowed to stir at RT for 16 h and water (100 mL) and EtOAc (200 mL) were added. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to give 3.15 of the crude product as pale-yellow syrup. The crude product was purified by Combi-Flash chromatography over a silica gel column that was first preconditioned by elution with 2% TEA-hexane solvent mixture. The crude concentrate dissolved in a minimum 312043035 130Attorney Docket No.: NTSS-014 / 001 WOvolume DCM was loaded onto the column and then eluted first with 30-50% EA / hexane (2% TEA) gradient to remove non-polar impurities. Then the column was eluted using 3-4% MeOH-DCM solvent gradient to give 1.78 g of the title compound containing BOP reagent related impurities

[0561] To obtain pure product the 1.78 g was dissolved in 200 mL of water followed by ether extraction (2 x 150 ml.), and extraction of the product from the aqueous layer with EtOAc (150 mL). The organic extract phase was dried over Na2SO4 and evaporated under reduced pressure to obtain 1.4 g of the title compound as colorless liquid. HPLC (ELSD): 99%, HPLC: Method-B (UV@ 240 nm): 98%. ESI-MS (calc- 1222.54, obser-1239.8 (M+H2O)).1H NMR (CDCh) 400 MHz: d ppm 5.73 (s, 1H), 3.90-3.46 (m, 77H), 3.38 (s, 3H), 2.5-2.20 (m, 6H), 2.1-1.70 (m, I OH), 1.50 (s, 8H), 1.40-1.25 (m, 3H), 1.19 (s, 4H), 1.10-0.90 (m, 2H), 0.74 (s, 3H).Example 19: (E)-30-alIyl-34-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-oneStep-1: Synthesis o f tert-butyl 30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate

[0562] To a stirred solution of tert-butyl 30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (5.0 g, 9.0 mmol) in dry THF (50 mL) was added LiHMDS (1.0 M solution in THF, 21 mL, 21 mmol) at -78 °C under argon atmosphere. The mixture was stirred at -78 °C for 30 min followed by addition of allyl bromide (1.55 mL, 18 mmol) dissolved in 10 mL of THF. The reaction mixture was stirred for 10 min at -78 °C and then allowed to warm to room temperature. After stirring atRT for 3 h, the reaction mixture was quenched by addition of saturated NaCl solution at 0 °C. The organic layer was separated, and the aqueous layer extracted with EtOAc (200 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The 312043035 131Attorney Docket No.: NTSS-014 / 001 WOcrude product was purified by Combi-Flash chromatography eluting with 4-5% MeOH-DCM to give 3.5 g of the title compound as pale-brown liquid. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-596.75, obser-614.4 (M+H2O)).NMR (CDCh) 400 MHz: 3 ppm 5.90-5.70 (m, 1H), 5.08 (d, J=13.6Hz, 2H), 3.90-3.55 (m, 40H), 3.37 (s, 3H), 2.50-2.40 (m, 2H), 1.46 (s, 9H), 1.33 (s, 3H). Step-2: Synthesis of 30-allyl-30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oic acidO'O' OH

[0563] A solution of tert-butyl 30-allyl-30-metliyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (3.0 g, 5.0 mmol) in 4M HCl in 1,4-dioxane (40 mL) and H2O (10 mL) was stirred at RT for overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3 times with 25 mL of toluene. The concentrate was triturated with 20 mL of hexane and purified by CombiFlash chromatography over silica eluting with 3-4% MeOH-DCM gradient eluent to give 2.8 g of the title compound as pale-brown liquid. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-540.64, obser-558.45 (M+H2O)).1H NMR (CDCl3) 400 MHz: δ ppm 5.83-5.76 (m, 1H), 5.15-5.11 (m, 2H), 3.80-3.50 (m, 41H), 3.38 (s, 3H), 2.60-2.51 (m, 2H), 1.44 (s, 3H).Step-3: Synthesis of (E)-30-allyl-34-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-one

[0564] To a stirred solution of 30-allyl-30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oic acid (2.8 g, 5.2 mmol) in dry THF (50 mL) was added 8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-1-(hydroxyimino)ethyl)-10, 13 -dim ethyl- 1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (1.71 g, 5.18 mmol) at 0 °C. To this solution were added BOP (2.29 g, 5.18 mmol) and DIPEA (2.7 mL, 16 mmol) with stirring at 0 °C. The reaction mixture was stirred at RT overnight and quenched with water (100 mL). The organic layer was separated, and the aqueous layer was extracted with 100 mL of EtOAc. The combined 312043035 132Attorney Docket No.: NTSS-014 / 001 WOorganic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash column chromatography over silica-gel column which was pre-conditioned with 0.1% TEA in hexane. The crude product dissolved in DCM was loaded onto the column followed by elution first with 0-70% EtOAc / hexane gradient solvent, and then with 2-3 % MeOH in EtOAc to afford 3.6 g of purified product as pale-yellow syrup. Repurification of the material by Combi-Flash eluting with 2-3% MeOH-DCM as gradient eluent gave 3.3 g of the title compound as a pale-yellow syrup. HPLC: Method-B (240nm): 99%. LC-MS (calc-852.12, obser-869.60 (M+H2O)),NMR (CDCl3) 400 MHz: δ ppm 5.9-5.76 (m, 1H), 5.73 (s, 1H), 5.13-5.10 (m, 2H), 3.70-3.60 (m, 37H), 3.65-3.5 (m, 2H), 3.36 (s, 3H), 2.7-2.55 (m, 2H), 2.50-2.36 (m, 4H), 2.29-2.17 (m, 3H), 2.10-2.0 (m, 1H), 1.96 (s, 3H), 1.90-1.70 (m, 5H), 1.60-1.50 (m, 2H), 1.46 (s, 3H), 1.40-1.21 (m, 3H), 1.19 (s, 4H), 1.10-0.90 (m, 2H), 0.73 (s, 3H).Example 20: (E)-34-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-30-methyl-30-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-oneStep-1: Synthesis of tert-butyl 30-methyl-30-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate

[0565] A mixture of tert-butyl 30-allyl-30-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (3.9 g, 6.5 mmol) and 10% Pd / 'C (1 g, 0.1 mmol) in MeOH (60 mL), was stirred for 16 hr under hydrogen. The mixture was filtered through celite bed and the solvent was removed under reduced pressure to give 3.8 g of the title compound as pale-brown syrup. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-598.77, obser-616.45 (M+H2O)).1H NMR (CDCl3) 400 MHz: δ ppm 3.74-3.60 (m, 37H), 3.57-3.52 (m, 4H), 3.38 (s, 3H), 1.70-1.64 (m, 2H), 1.46 (s, 9H), 1.33 (s, 3H), 1.31-1.28 (m, 2H), 0.90 (t, J=7.2Hz, 3H).312043035 133Attorney Docket No.: NTSS-014 / 001 WOStep-2: Synthesis of 30-methyl-30-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oic acid

[0566] A solution of tert-butyl 30-methyl-30-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (3.8 g, 6.4 mmol) in 4M HCl in 1,4-dioxane (40 mL) and H2O (5 mL) was stirred at RT for overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3 times with 25 mL of toluene. The concentrate was triturated with 20 mL of hexane and purified by CombiFlash using 2-3% MeOH-DCM as gradient eluent to give 2.75 g of the title compound as pale-brown syrup. HPLC: Method-A (ELSD): 99%. ESI-MS (calc- 542.66, obser-560.50 (M+H2O)).NMR (CDCl3) 400 MHz: δ ppm 3.78-3.44 (m, 34H), 3.38 (s, 3H), 1.80-1.54 (m, 13H), 1.44 (s, 3H), 1.38-1.22 (m, 1H), 0.91 (t, J=7.6Hz, 3H).Step-3: Synthesis of (E)-34-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-30-methyl-30-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-one

[0567] To a stirred mixture of 30-methyl-30-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29- decaoxahentriacontan-31-oic acid (2.75 g, 5.07 mmol and 8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-1- (hydroxyimino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (1.67 g, 5.07 mmol) ) in dry THF (50 mL) were added BOP reagent (2.24 g, 5.07 mmol) and DIPEA (2.7 mL, 15 mmol) at 0 °C. The reaction mixture was stirred at RT for overnight and quenched with ice cold water (100 mL). The organic layer was separated, and the aqueous layer was extracted with 100 mL of EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash column chromatography over silica-gel column, which was preconditioned with 0.1% TEA in hexane. The column was first eluted with 0-70% EtOAc / hexane gradient eluent, and then with 2-3 % MeOH in EtOAc to afford 3.55 g of the title compound as pale-yellow syrup. HPLC: Method-B (240 nm): 96%. LC-MS (calc-854.13, obser-871.55 (M+H2O)).1H NMR (CDCl3) 400 312043035 134Attorney Docket No.: NTSS-014 / 001 WOMHz: d ppm 5.74 (s, 1H), 3.70-3.60 (m, 37H), 3.60-3.50 (m, 2H), 3.38 (s, 3H), 2.50-2.20 (m, 6H), 2.10-2.0 (m, 1H), 2.0-1.93 (m, 4H), 1.90-1.70 (m, 6H), 1.53 (s, 4H), 1.40-1.22 (m, 5H), 1.19 (s, 4H), 1.12-0.95 (m, 1H), 0.91 (t, J=7.2 Hz, 3H), 0.73 (s, 3H).Example 21: (E)-30, 30-diallyl-34-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-oneStep-1: Synthesis of tert-butyl 2. 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate O |\ O / x X / 'YJ''"x. / CX x / / xX.Q / / X\^

[0568] To a stirred solution of Me-PEG9-OH (5.0 g, 12 mmol) in dichloromethane (30 mL) at 0 °C was added 50% NaOH solution (30 mL). To the vigorously stirred 2-phase mixture were added tertbutyl 2-bromoacetate (8.62 mL, 58.3 mmol) and tetrabutylammonium chloride (0.81 g, 2.92 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h and the reaction progression was monitored by TLC. After completion, dichloromethane (250 mL) was added, and the organic layer was separated and washed with brine solution (2 x 250 mL). The organic phase was dried over Na2SO4and concentrated under vacuum. The concentrate was dissolved in water (200 mL) and extracted with hexane (2 x 200 mL). The aqueous layer was saturated with NaCl and extracted with ethyl acetate (2 x 500 mL). The combined ethyl acetate organic extracts were dried over Na2SO4 and evaporated under vacuum to give 10.5 g of the title compound as a colorless syrup. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-542.66, obser-560.4 (M+H2O)).1H NMR (CDCl3) 400 MHz: δ ppm 4.02 (s, 2H), 3.76-3.60 (m, 37H), 3.58-3.52 (m, 2H), 3.38 (s, 3H), 1.47 (s, 9H).Step-2: Synthesis of tert-butyl 2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate312043035 135Attorney Docket No.: NTSS-014 / 001 WO

[0569] To a stirred solution of tert-butyl 2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (2.0 g, 3.7 mmol) in dry THF (35 mL) was added LiHMDS (1.0 M solution in THF, 29.5 mL, 29.5 mmol) at -78 °C under argon atmosphere. The reaction mixture was stirred at -78 °C for 30 min, followed by addition of allyl bromide (3.2 mL, 37 mmol) dissolved in 10 mL of THF. The reaction mixture was stirred for 10 min at -78 °C and then allowed to warm to room temperature. After stirring at RT for 3 h, the reaction mixture was quenched by addition of saturated NaCl solution at 0 °C. The organic layer was separated, and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. The concentrate was dissolved in minimum amount of water (100 mL) and the aqueous layer extracted with hexane (2 x 100 mL). NaCl solution (20 mL) was added, and the product was extracted from the aqueous layer with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over Na2SO4 and evaporated under vacuum to give 1.9 g of the title compound as a pale-yellow oil. HPLC: Method-A (ELSD) 99%. ESI-MS (calc-622.79, obser-640.45 (M+H2O)).1H NMR (CDCl3) 400 MHz: δ ppm 5.84-5.70 (m, 2H), 5.11 (d, J=4 Hz, 2H), 5.08 (s, 2H), 3.74-3.58 (m, 34H), 3.38 (s, 3H), 2.55-2.45 (m, 4H), 1.47 (s, 9H).Step-3: Synthesis of 30, 30-diallyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oic acidO

[0570] A solution of tert-butyl 2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (1.8 g, 2.9 mmol) in 4M HCl in 1,4-dioxane (12 mL) and H2O (5 mL) was stirred at RT overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3 times with 10 mL of toluene. The concentrate was purified by Combi-Flash column chromatography over silica-gel which was preconditioned with 0.1% TEA in hexane. The column was eluted with 0-100% EtOAc-Hexane as gradient followed with 2 % MeOH-DCM to afford 1.35 g of the title compound as a pale-yellow syrup. HPLC: Method-A (ELSD) 99%. ESI-MS (calc-566.68, obser-567.40 (M+l)).1H NMR (CDCl3) 400 MHz: δ ppm 5.82-5.71 (m, 2H), 5.20-5.10 (m, 4H), 3.76-3.60 (m, 38H), 3.58-3.52 (m, 2H), 3.38 (s, 3H), 2.58 (d, J=7.2Hz, 4H).Step-4: Synthesis of (E)-30, 30-diallyl-34-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-one312043035 136Attorney Docket No.: NTSS-014 / 001 WO

[0571] To a stirred mixture of 30, 30-diallyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29- decaoxahentriacontan-31 -oic acid (1.2 g, 2.2 mmol) and 8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-1-(hydroxyimino)ethyl)-10, 13-dimethyl-1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.73 g, 2.2 mmol) in dry THF (20 mL) were added BOP reagent (0.98 g, 2.2 mmol) and DIPEA (1.15 mL) at 0 °C. The reaction mixture was stirred at RT overnight and quenched with ice cold water (50 mL). The organic layer was separated, and the aqueous layer was extracted with 100 mL of EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The concentrate was purified by Combi-Flash column chromatography over silica-gel column, which was preconditioned with 0.1% TEA in hexane. The column was eluted with 0-70% hexane-ethylacetate gradient followed by 2% MeOH in DCM to afford 1.37 g of the title compound as pale yellow syrup. HPLC: Method-B (240 nm): 98%. LC-MS (calc-878.15, obser-895.75 (M+H2O)).1H NMR (CDCl3) 400 MHz: δ ppm 5.83-5.76 (m, 2H), 5.73 (s, 1H), 5.15-5.11 (m, 4H), 3.73-3.67 (m, 35H), 3.56 (m, 2H), 3.38 (s, 3H), 2.67-2.56 (m, 4H), 2.40-2.29 (m, 6H), 2.06-1.87 (m, 6H), 1.77 -1.70 (m, 3H), 1.60-1.55 (m, 2H), 1.50-1.20 (m, 4H), 1.19 (s, 3H), 1.16-0.98 (m, 2H), 0.71 (s, 3H).Example 22: (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(((l-((2, 5, 8, 11, 14, 17, 20, 23, 26 nonaoxaoctacosan-28-yl)oxy)cyclopent-3-ene-1-carbonyl)oxy)imino)ethyl)-10,13-dimethyl-1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one / %•CH3Step-1: Synthesis of tert-butyl l-((2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl)oxy)cyclopent-3-ene-l -carboxylate312043035 137Attorney Docket No.: NTSS-014 / 001 WO

[0572] To a stirred solution of tert-butyl 30, 30-diallyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (3.0 g, 4.82 mmol) in 60 mL of dry DCM, was added Grubb’s G2 catalyst (0.20 g, 0.24 mmol) at 0 °C. Then the mixture was stirred at RT for 16 h, diluted with water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The concentrate was dissolved in minimum amount of water (100 mL) and extracted with hexane (2 xlOO mL) to remove non-polar impurities. The product was extracted from the aqueous layer with EtOAc (2 x 200 mL). The combined organic extracts were dried over Na2SO4 and evaporated under vacuum to give 2.7 g of the title compound as pale-yellow syrup. HPLC: Method-A (ELSD) 99%. ESI-MS (calc-594.74, obser-612.60 (M+H2O)).1H NMR (CDCl3) 400 MHz: δ ppm 5.63 (s, 2H), 3.74-3.60 (m, 34H), 3.60-3.52 (m, 4H), 3.38 (s, 3H), 2.85 (d, J=16Hz, 2H), 2.65 (d, J=16Hz, 2H), 1.47 (s, 9H).Step-2: Synthesis of l-((2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl) oxy) cyclopent-3-ene-1 -carboxylic acid

[0573] A solution of tert-butyl l-((2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl)oxy)cyclopent-3-ene-l -carboxylate (2.1 g, 2.9 mmol) in 4M HC1 in 1,4-dioxane (15 mL) and H2O (7 mL) was stirred at RT for overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3 times with 10 mL of toluene. The concentrate was purified by Combi-Flash column chromatography over silica-gel which was preconditioned with 0.1% TEA in hexane. The column was eluted with 0-100% EtOAc-Hexane as gradient followed by 2 % MeOH-DCM to afford 1.5 g of the title compound as pale yellow syrup. HPLC: Method-A (ELSD) 99%. ESI-MS (calc-538.63, obser-537.3 (M-1)).1H NMR (CDCl3) 400 MHz: δ ppm 5.67 (s, 2H), 3.75-3.60 (m, 33H), 3.58-3.50 (m, 4H), 3.38 (s, 3H), 2.98 (d, J=16.4Hz, 2H), 2.68 (d, J=16.4Hz, 2H). Step-3: Synthesis of (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(((l-((2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl)oxy)cyclopent-3-ene-l-carbonyl)oxy)imino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one312043035 138Attorney Docket No.: NTSS-014 / 001 WO

[0574] To a stirred solution of l-((2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl) oxy) cyclopent-3-ene-l-carboxylic acid (1.4 g, 2.60 mmol) and 8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-1-(hydroxyimino)ethyl)-10, 13 -dimethyl- 1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.85 g, 2.60 mmol) in dry THF (20 mL) were added BOP reagent (1.15 g, 2.60 mmol) and DIPEA (1.4 mL) at 0 °C. The reaction mixture was stirred at RT overnight and quenched with ice cold water (50 mL). The organic layer was separated, and the aqueous layer was extracted with 100 mL of EtOAc. The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash column chromatography over silica-gel which was preconditioned with 0.1% TEA in hexane. The column was eluted with 0-70% EtO Ac / hexane gradient followed by 2% MeOH in DCM to afford 1.6 g of the title compound as pale-yellow syrup, HPLC: Method-B (240 nm) 98%. LC-MS (calc-850.10, obser-867.35 (M+H2O)).1H NMR (CDCl3) 400 MHz: δ ppm 5.73 (s, 1H), 5.67 (s, 2H), 3.76-3.60 (m, 38H), 3.58-3.52 (m, 2H), 3.38 (s, 3H), 2.98 (d, J=16.8 Hz, 2H), 2.76 (d, J=16.8 Hz, 2H), 2.50-2.27 (m, 6H), 2.02-2.01 (m, 1H), 1.94 (s, 3H), 1.93-1.78 (m, 3H), 1.73-1.70 (m, 2H), 1.65-1.48 (m, 2H), 1.47-1.28 (m, 4H), 1.19 (s, 3H), 1.08-0.97 (m, 2H), 0.73 (s, 3H). Example 23: (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(((l-((2, 5, 8, 11, 14, 17, 20, 23, 26- nonaoxaoctacosan-28-yl)oxy)cyclopentane-1-carbonyl)oxy)imino)ethyl)-10, 13-dimethyl-1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-oneStep-1: Synthesis of tert-butyl l-((2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl)oxy)cyclopentane-l-carboxylate312043035 139Attorney Docket No.: NTSS-014 / 001 WO

[0575] To a stirred solution of tert-butyl l-((2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl)oxy)cyclopent-3-ene-l -carboxylate (3.64 g, 5.72 mmol) in EtOH (50 mL), was added 10% Pd / C (1.0 g, 1.6 mmol) at RT under nitrogen atmosphere. The mixture was stirred at RT for 16 h under hydrogen and filtered through celite. The filtrate was dried over Na2SO4 and concentrated under reduced pressure to give 3.0 g of the title compound as pale-brown syrup. HPLC: Method- A (ELSD): 99%. ESI-MS (calc-596.75, obser-614.55 (M+H2O)).1H NMR (CDCl3) 400 MHz: δ ppm 3.78-3.60 (m, 32H), 3.58-3.50 (m, 4H), 3.38 (s, 3H), 2.20-1.84 (m, 5H), 1.82-1.60 (m, 4H), 1.47 (s, 9H).Step-2: Synthesis of 1-((2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl)oxy)cyclopentane-1-carboxylic acid

[0576] A solution of tert-butyl l-((2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl)oxy)cyclopentane-l -carboxylate (3.0 g, 5.0 mmol) in 4MHC1 in 1,4-dioxane (20 mL) and H2O (9 mL) was stirred at RT overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled three times with 8 mL of toluene. The concentrate was purified by Combi-Flash column chromatography over silica-gel column, which was preconditioned with 0.1% TEA in hexane. The column was eluted with 0-100% EtOAc-Hexane gradient followed by 2 % MeOH-DCM to afford 2.2 g of the title compound as a pale-yellow syrup. HPLC: Method-A (ELSD) 99%. ESI-MS (calc-540.65, obser-541.50 (M+l)).1H NMR (CDCl3) 400 MHz: δ ppm 3.78-3.60 (m, 37H), 3.58-3.50 (m, 4H), 3.38 (s, 3H), 2.14-2.04 (m, 2H), 2.02-1.92 (m, 2H), 1.84-1.68 (m, 4H).Step-3: Synthesis of (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(((l-((2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl)oxy)cyclopentane-l-carbonyl)oxy)imino)ethyl)-10,13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one312043035 140Attorney Docket No.: NTSS-014 / 001 WO

[0577] To a stirred mixture of l-((2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxaoctacosan-28-yl)oxy)cyclopentane-l -carboxylic acid (2.1 g, 3.9 mmol) and 8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13 -dimethyl- 1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17- tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (1.3 g, 3.9 mmol) in dry THF (33 mL) were added BOP reagent (1.7 g, 3.9 mmol) and DIPEA (2 mL) at 0 °C. The reaction mixture was stirred at RT for overnight and quenched with ice cold water (40 mL). The organic layer was separated, and the aqueous layer was extracted with 100 mL of EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash column chromatography over silica-gel column which was preconditioned with 0.1% TEA in hexane. The column was eluted with 0-100% EtOAc / hexane followed by 2% MeOH in DCM to afford 1.78 g of the title compound as a pale-yellow syrup. HPLC: Method-B (240 nm): 96%. LC-MS (calc-852.12, obser-869.50 (M+H2O)).1H NMR (CDCl3) 400 MHz: 3 ppm 5.73 (s, 1H), 3.68-3.53 (m, 36H), 3.39 (s, 3H), 2.43-2.27 (m, 6H), 2.15-1.98 (m, 5H), 1.96 (s, 4H), 1.78-1.74 (m, 8H), 1.60-1.58 (m, 2H), 1.47-1.42 (m, 1H), 1.35-1.28 (m, 2H), 1.20 (s, 4H), 1.08-0.98 (m, 2H), 0.74 (s, 3H).Example 24: (E)-34-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yI)-30, 30-diethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-one'3Step-1: Synthesis of tert-butyl 30,30-diethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29- decaoxahentriacontan-31-oate312043035 141Attorney Docket No.: NTSS-014 / 001 WO

[0578] To a stirred solution of tert-butyl 2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (4.0 g, 7.4 mmol) in dry THF (30 mL) was added LiHMDS (1.0 M solution in THF, 59 mL, 59 mmol) at -78 °C under argon atmosphere. The reaction mixture was stirred at -78 °C for 30 min, followed by addition of bromoethane (4.4 mL, 59 mmol) dissolved in 10 mL of THF'. The reaction mixture was stirred for 10 min at -78 °C and then allowed to warm to room temperature. After stirring at RT for 16 h, the reaction mixture was quenched by addition of saturated NaCl solution at 0 °C. The organic layer was separated, and the aqueous layer extracted with EtOAc (2 xlOO mL). The combined organic layers were dried over Na2SO4and concentrated under reduced pressure. The concentrate was purified by CombiFlash column chromatography eluting with 2% MeOH-DCM to give 3.0 g of the title compound as a pale brown syrup. HPLC: Method-A (ELSD) 99%. ESI-MS (calc-598.39, obser-616.4 (M+H2O)).1H NMR (CDCl3) 400 MHz: d ppm 3.69-3.61 (m, 37H), 3.58-3.54 (m, 2H), 3.49 (t, J=7.6 Hz, 2H), 3.38 (s, 3H), 1.73 (q, J=7.6 Hz, 4H), 1.47 (s, 9H), 0.83 (t, J=7.6Hz, 6H).Step-2: Synthesis of 30, 30-diethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oic acid

[0579] A solution of 30, 30-diethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (3.0 g, 5.01 mmol) in H2O (15 mL) and 4M HCl in 1,4-dioxane (20 mL) was stirred at RT overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3 times with 25 mL of toluene. The concentrate was purified by Combi-Flash column chromatography over silica gel eluting with 2% MeOH-DCM to afford 1.8 g of the title compound as pale-yellow syrup. HPLC: Method-A (ELSD) 99%. ESI-MS (calc-542.33, obser-543.1 (M+1)).1H NMR (CDCl3) 400 MHz: δ ppm 3.78-3.60 (m, 33H), 3.58-3.52 (m, 4H), 3.38 (s, 3H), 1.87-1.75 (m, 5H), 0.88 (d, J- 7.2 Hz, 6H).Step-3: Synthesis of (E)-34-((8S, 9S, 10R, 13S, 14S, 17S)-10,13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-30, 30-diethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-one312043035 142Attorney Docket No.: NTSS-014 / 001 WO o

[0580] To a stirred mixture of 30, 30-diethyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31 -oic acid (1.8 g, 3.3 mmol) and 8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-1-(hydroxyimino)ethyl)-10, 13 -dimethyl- 1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (1.1 g, 3.3 mmol) in dry THF (33 mL) were BOP reagent (1.5 g, 3.3 mmol) and DIPEA (1.7 mL) at 0 °C. The reaction mixture was stirred at RT for overnight and quenched with water (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The concentrate was purified by Combi-Flash column chromatography over silica-gel which was preconditioned with 0.1% TEA in hexane. The column eluted with 0-100% EtOAc / hexane gradient eluent followed with 2-3% MeOH in EtO Ac to afford 1,5 g of the title compound as pale brown syrup. HPLC: Method-B (240 nm) 98%. LC-MS (calc-853.56, obser-871.5 (M+H2O)).1H NMR (CDCl3) 400 MHz: <5 ppm 5.73 (s, 1H), 3.72-3.60 (m, 36H), 3.60-3.52 (m, 4H), 3.38 (s, 3H), 2.50-2.24 (m, 7H), 2.08-2.01 (m, 1H), 1.95 (s, 4H), 1.88-1.80 (m, 6H), 1.80-1.66 (m, 4H), 1.58-1.50 (m, 1H), 1.50-1.20 (m, 4H), 1.19 (s, 4H), 1.12-0.94 (m, 2H), 0.91 (t, J=7.6 Hz, 7H), 0.73 (s, 3H).Example 25: (E)-34-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-30, 30-dipropyI-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-oneStep-1: Synthesis of tert-butyl 30, 30-dipropyl-2, 5, 8, II, 14, 17, 20, 23, 26, 29 decaoxahentriacontan-31-oate312043035 143Attorney Docket No.: NTSS-014 / 001 WO

[0581] To a stirred solution of tert-butyl 2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (3.0 g, 5.5 mmol) in dry THF (30 mL) was added LiHMDS (1.0 M solution in THF, 33 mL, 33 mmol) at -78 °C under argon atmosphere. The reaction mixture was stirred at -78 °C for 30 min, followed by addition of 1 -bromopropane (3.0 mL, 33 mmol). The reaction mixture was stirred for 10 min at -78 °C and then allowed to warm to room temperature. After stirring at RT for 16 h, the reaction mixture was quenched by addition of saturated NaCl solution at 0 °C. The organic layer was separated, and the aqueous layer extracted with EtOAc (200 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The concentrate was purified by CombiFlash column chromatography over silica gel eluting with 2% MeOH-DCM to give 2.3 g of the title compound as a pale brown syrup. HPLC: Method-A (ELSD) 99%. ESI-MS (calc-626.42, obser-644.45 (M+H2O)).1H NMR (CDCl3) 400 MHz: δ ppm 3.70-3.60 (m, 36H), 3.58-3.54 (m, 2H), 3.50 (t, J=5.6 Hz, 2H), 3.38 (s, 3H), 1.70-1.62 (m, 4H), 1.45 (s, 9H), 1.40-1.16 (m, 5H), 0.89 (t, J=7.2 Hz, 6H).Step-2: Synthesis of 30, 30-dipropyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oic acid

[0582] A solution of tert-butyl 30,30-dipropyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oate (2.3 g, 3.7 mmol) in 4M HC1 in 1,4-dioxane (12 mL) and H2O (12 mL) was stirred at RT for overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 2 times with 25 mL of toluene. The crude product was purified by Combi-Flash column chromatography over silica gel eluting with 2% MeOH-DCM to afford 1.5 g of the title compound as pale brown syrup. HPLC: Method-A (ELSD) 99%. ESI-MS (calc-570.36, obser-571.5 (M+1)).1H NMR (CDCl3) 400 MHz: δ ppm 3.74-3.60 (m, 37H), 3.58-3.52 (m, 5H), 3.38 (s, 3H), 1.82-1.68 (m, 4H), 1.48-1.32 (m, 2H), 1.30-1.14 (m, 2H), 0.90 (t, J=7.6Hz, 6H). Step-3: Synthesis of (E)-34-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-30, 30-dipropyl-2, 5, 8, 11, 4, 17, 20, 23, 26, 29, 32-undecaoxa-33-azapentatriacont-33-en-31-one312043035 144Attorney Docket No.: NTSS-014 / 001 WOr*N'o^O'^O^O^\iZ'^zO''^O^O'- / XO / x-z°'- / xOZ

[0583] To a stirred mixture of 30, 30-dipropyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29-decaoxahentriacontan-31-oic acid (1.5 g, 2.63 mmol) and 8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l -(hydroxyimino)ethyl)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.86 g, 2.63 mmol) ) in dry THF (50 mL) were added BOP reagent (1.16 g, 2.63 mmol) and DIPEA (1.0 g, 7.9 mmol) at 0 °C. The reaction mixture was stirred at RT overnight and quenched with water (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash column chromatography over silica-gel column which was preconditioned with 0.05% TEA in hexane. The column was eluted with 0-100% EtOAc / hexane gradient followed by 2-3% MeOH in EtOAc to afford 1.3 g of the title compound as pale brown syrup. HPLC: Method-B (240 nm): 98%. LC-MS (calc-882.19, obser-899.60 (M+H2O)),1H NMR (CDCl3) 400 MHz: d ppm 5.73 (s, 1H), 3.65-3.53 (m, 38H), 3.38 (s, 3H), 2.43-2.25 (m, 6H), 1.95-1.93 (m, 5H), 1.80-1.71 (m,9H), 1.37-1.28 (m, 9H), 1.19 (s, 4H), 0.98-0.89 (m, 8H), 0.73 (s, 3H).Example 26: (E)-40-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cycIopenta[a]phenanthren-17-yI)-36-methyI-36-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38-tridecaoxa-39-azahentetracont-39-en-37-oneStep-1: Synthesis of tert-hutyl 36-methyl-36-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35- dodecaoxaheptatriacontan-37-oate312043035 145Attorney Docket No.: NTSS-014 / 001 WO

[0584] To a stirred solution of tert-butyl 36-methyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-oate (1.0 g, 1,6 mmol) in dry THF (20 mL) was added LiHMDS (IM solution in THF, 4.7 mL, 4,7 mmol) at -78 °C under argon atmosphere. The reaction mixture was stirred at -78 °C for 30 min, followed by addition of 1 -bromopropane (0.44 mL, 4,65 mmol). The reaction mixture was stirred for 10 min at -78 °C and then allowed to warm to room temperature. After stirring at RT for 4 h, the reaction mixture was quenched by addition of saturated NH4Cl solution (100 mL) at 0 °C. The organic layer was separated, and the aqueous layer extracted with EtOAc (200 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The concentrate was dissolved in 100 mL of water and the aqueous layer was extracted with hexane (2 x 50 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2SO4 and evaporated to give 0.6 g of the title compound as pale brown syrup. HPLC: Method-A (ELSD) 98%. ESI-MS (calc-686.88, obser-704.65 (M+H2O)).1H NMR (CDCl3) 400 MHz: 3 ppm 3.75-3.60 (m, 46H), 3.60-3.50 (m, 4H), 3.38 (s, 3H), 1.70-1.64 (m, 2H), 1.52-1.40 (m, 16H), 1.36 (s, 3H), 1.29-1.24 (m, 1H), 0.90 (t, J 7.2 Hz, 3H).Step-2: Synthesis of 36-methyl-36-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-oic acidO

[0585] A solution of tert-butyl tert-butyl 36-methyl-36-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-oate (0.6 g, 0.874 mmol) in 4M HCl in 1,4-dioxane (20 mL) and H2O (10 mL) was stirred at RT for overnight. The reaction mixture was concentrated under vacuum and the concentrate was co-distilled 3 times with 25 mL of toluene. The concentrate product was purified by Combi-Flash column chromatography over silica gel eluting with 3-4% MeOH- DCM to afford 0.45 g of the title compound as pale brown syrup. HPLC: Method-A (ELSD): 99%. ESI-MS (calc-630.77, obser-648.4 (M+H2O)).1H NMR (CDCl3) 400 MHz: 3 ppm 3.74-3.60 (m, 40H), 3.58-3.52 (m, 3H), 3.38 (s, 3H), 1.84-1.64 (m, 9H), 1.43 (s, 3H), 1.34-1.22 (m, 2H), 0.91 (t, J 72 Hz, 3H).312043035 146Attorney Docket No.: NTSS-014 / 001 WO Step-3: Synthesis of (E)-40-((8S, 9S, 10R, 13S, 14S, 17S)-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH-cyclopenta[a]phenanthren-17-yl)-36-methyl-36-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38-tridecaoxa-39-azahentetracont-39-en-37-one o

[0586] To a stirred mixture of 36-methyl-36-propyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-oic acid (0.24 g, 0.75 mmol) and 8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13-dimethyl- 1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.43 g, 0.68 mmol) in dry THF (25 mL) were added BOP reagent (0.30 g, 0.68 mmol) and DIPEA (0.35 mL) at 0 °C. The reaction mixture was stirred at RT for overnight and quenched with water (100 mL). The organic layer was separated, and the aqueous layer was extracted with 100 mL of EtOAc. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by Combi-Flash column chromatography over silica-gel which was preconditioned with 0.05% TEA in hexane. The column was eluted with 0-70% EtOAc / hexane followed by 2-3% MeOH in DCM to afford 0.54 g of the title compound as a pale yellow syrup. HPLC: Method- B (240 nm) 97%. LC- MS (calc-942.24, obser-959.6 (M+H2O)).NMR (CDCh) 400 MHz: d ppm 5.73 (s, 1H), 3.70-3.60 (m, 42H), 3.60-3.50 (m, 2H), 3.38 (s, 3H), 2.45-2.36 (m, 4H), 2.35-2.25 (m, 2H), 2.10-2.0 (m, 1H), 1.95 (s, 4H), 1.90-1.70 (m, 7H), 1.60-1.50 (m, 2H), 1.50-1.40 (m, 8H), 1.40-1.20 (m, 4H), 1.19 (s, 3H), 1.10-0.98 (m, 2H), 0.92 (t, J=7.2, 3H), 0.73 (s, 3H).Example 27: (8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-( ((l-((2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-iindecaoxatetratriacontan-34-yl)oxy)cydopent-3-eiie-l-carboiiyl)oxy)iinino)ethyI)-10, 13-dimethyl-l, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopentafa] phenanthren-3-one312043035 147Attorney Docket No.: NTSS-014 / 001 WO oStep-1: Synthesis of tert-butyl 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan- 37-oate

[0587] To a stirred solution of monodisperse Me-PEG11-OH (10.0 g, 19.4 mmol) in dichloromethane (60 mL) at 0 °C was added 50% NaOH solution (60 mL) followed by tert-butyl 2-bromoacetate (14.3 mL, 97 mmol) and TBACl (1.34 g, 4.84 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 hrs and DCM (500 mL) was added. The organic layer was separated, washed with cold brine solution (2 x500 mL), dried over Na2SO4 and concentrated under vacuum. The concentrate was dissolved in water (200 mL) and the aqueous solution was extracted with hexane (2 x 200 mL). The aqueous layer was saturated with NaCl and extracted with ethyl acetate (3 x 500 mL). The combined organic extracts were and dried over Na2SO4and evaporated under vacuum to give 8.0 g of the title compound as a colorless liquid. HPLC: Method-A (ELSD) 99%. ESI-MS (calc-630.79, obser-648.60 (M+H2O)).NMR (CDCh) 400 MHz: 3 ppm 4.02 (s, 2H), 3.74-3.60 (m, 45H), 3.58-3.52 (m, 2H), 3.38 (s, 3H), 1.47 (s, 9H).Step-2: Synthesis of tert-butyl 36, 36-diallyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-oate

[0588] To a stirred solution of tert-butyl 2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-oate (4.0 g, 6.3 mmol) in dry THF (60 mL) was added LiHMDS (IM solution in THF, (51 mL, 51 mmol) at -78 °C under argon atmosphere. The reaction mixture was stirred at -78 °C for 30 min, followed by addition of allylbromide (5.5 mL, 64 mmol). The reaction mixture was stirred for 10 min at -78 °C and then allowed to warm to room temperature. After stirring at RT for 4 h, the reaction mixture was quenched by addition of saturated NH4Cl solution 312043035 148Attorney Docket No.: NTSS-014 / 001 WO(100 mL) at 0 °C. The organic layer was separated, and the aqueous layer extracted with EtOAc (200 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The concentrate was dissolved in 100 mL of water and the aqueous layer extracted with hexane (2 x 50 mL). The aqueous layer was separated and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over Na2SO4 and evaporated under vacuum to give 3.0 g of the title compound as a pale yellow syrup, HPLC: Method-A (ELSD) 99%. ESI-MS (calc-710.90, obser-728.45 (M+H2O)).NMR (CDCh) 400 MHz: <5 ppm 5.80-5.73 (m, 2H), 5.12-5.08 (m, 4H), 3.74-3.58 (m, 44H), 3.58-3.50 (m, 2H), 3.38 (s, 3H), 2.56-2.45 (m, 4H), 1.46 (s, 9H).Step-3: Synthesis of tert-butyl l-((2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan- 34-yl)oxy)cyclopent-3-ene-l-carboxylate

[0589] To a stirred solution of tert-butyl 36, 36-diallyl-2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32, 35-dodecaoxaheptatriacontan-37-oate (2.5 g, 3.52 mmol) in 50 ml, dry DCM was added Grubb’s G2 catalyst (0.15 g, 0, 18 mmol) at 0 °C. The reaction mixture was stirred at RT for 16 h and water (30 mL) was added. The mixture was extracted with ethyl acetate (2 x 80mL), the combined organic extracts were dried over Na2SO4 and concentrated under vacuum. The concentrate was dissolved in a minimum amount of water (50 mL) and the aqueous compound solution was extracted with hexane (2 x 50 mL) to remove non-polar impurities. The product was extracted from the aqueous phase with ethyl acetate (2 x 100 mL). The combined organic layers were dried over Na2SO4 and evaporated under vacuum to give 2.0 g of the title compound as pale yellow syrup. HPLC: Method- A (ELSD) 99%. ESI-MS (calc-682.85, obser-700.50 (M+H2O)).1H NMR (CDCl3) 400 MHz: δ ppm 5.63 (s, 2H), 3.74-3.60 (m, 40H), 3.60-3.50 (m, 4H), 3.38 (s, 3H), 2.85 (d, J=16 Hz, 2H), 2.65 (d, J=16 Hz, 2H), 1.48 (s, 9H).Step-4: Synthesis of l-((2, 5, 8, 11, 14, 17, 20, 23,26, 29, 32-undecaoxatetratriacontan-34-yl) oxy cyclopent- 3-ene- 1 -carboxylic acid

[0590] A solution of tert-butyl l-((2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan- 34-yl)oxy)cyclopent-3-ene-l-carboxylate (2.0 g, 2.9 mmol) in 4M HC1 in 1,4-dioxane (14 mL) and H2O (6 mL) was stirred at RT for overnight. The reaction mixture was concentrated under vacuum 312043035 |49Attorney Docket No.: NTSS-014 / 001 WOand the concentrate was co-distilled 3 times with 10 mL of toluene. The concentrate was purified by Combi-Flash column chromatography over silica-gel which was preconditioned with 0.1 % TEA in hexane. The column was eluted with a 0-100% EtOAc / hexane gradient followed by elution with 2% MeOH in DCM to afford 1.8 g of the title compound as pale yellow syrup. HPLC: Method- A (ELSD) 99%. ESI-MS (calc-626.74, obser-627.45 (M+l)).1H NMR (CDCl3) 400 MHz: δ ppm 5.63 (s, 1H), 3.56-3.47 (m, 43H), 3.45-3.41 (m, 3H), 3.23 (s, 3H), 2.97 (q, J1=6.8 Hz, J2=14 Hz, 4H), 2.78 (d, J=16.4 Hz, 2H), 2.57-2.52 (m, 2H), 1.15 (t, J=6.8 Hz, 7H).Step-5: Synthesis of(8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(((l-((2, 5, 8, 11, 14, 17, 20, 23, 26, 29, 32-undecaoxatetratriacontan-34-yl)oxy)cyclopent-3-ene-l-carbonyl)oxy)imino)ethyl)-10,13- dimethyl-1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H- cyclopenta[a]phenanthren-3-one

[0591] To a stirred mixture of l-((2, 5, 8, 11, 14, 17, 20, 23,26, 29, 32-undecaoxatetratriacontan-34-yl) oxy)cyclopent-3-ene-l-carboxylic acid (1.7 g, 2.7 mmol) and 8S, 9S, 10R, 13S, 14S, 17S)-17-((E)-l-(hydroxyimino)ethyl)-10, 13 -dimethyl-1, 2, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.9 g, 2.7 mmol) in dry THF (30 mL) were added BOP reagent (1.2 g, 2.7 mmol) and DIPEA (1.4 mL) at 0 °C. The reaction mixture was stirred at RT overnight and quenched with water (100 mL). The organic layer was separated, and the aqueous layer was extracted with 100 mL of EtOAc. The...

Claims

1. Attorney Docket No.: NTSS-014 / 001 WO What is claimed is:

1. A compound of F ormula IoFormula Ior a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:each R1 and R2 are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, and C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more R1a,or R1 and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group, wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R1a;each Ria is independently -OH, -NH2, -CN, halo, C1-6 alkyl, C1-6 alkoxy, -S(Ci-6 alkyl), C3-7 cycloalkyl, or 3- to 7-membered heterocyclyl;R3 is H, Ci -6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or C1-6 alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or alkoxy is optionally substituted with one or more Ria;each R3a is independently -O(Ra), -OC(O)ORa, -N(Ra)(Rb), -N(Ra)CO(Rb), -N(Ra)CO(ORb), -NHCON(Ra)(Rb), -CN, halo, C1-6 alkyl, -C(O)ORa, -S(Ci-6 alkyl), or -C(O)N(Ra)(Rb);Rais H or C1-6 alkyl;Rbis H or C1-6 alkyl; andn is an integer from 2 to 115.

2. The compound of claim 1, wherein:each R1 and R2 are independently selected from H, C1-6 alkyl, and C2-6 alkenyl,or Ri and R2, together with the atoms to which they are attached, form a C3-7 cycloalkyl or 3- to 7-membered heterocyclyl group;R3 is C1-6 alkyl optionally substituted with one or more R3a;each R3a is independently -NH2, -CN, or -C(O)NH2; and312043035 167Attorney Docket No.: NTSS-014 / 001 WOn is an integer from 2 to 44.

3. The compound of any one of the preceding claims, wherein the compounds are monodisperse with the number of PEG units, n.

4. The compound of any one of the preceding claims, wherein the compounds are poly disperse with the number of PEG units, n.

5. The compound of any one of the preceding claims, wherein R1 is H, methyl, ethyl, isopropyl, isobutenyl, isobutyl, or propenyl.

6. The compound of any one of the preceding claims, wherein R2 is H, methyl, or ethyl.

7. The compound of any one of the preceding claims, wherein R3 is methyl or ethyl optionally substituted with one or more R3a.

8. The compound of any one of the preceding claims, wherein each R3a is independently -NH2, -CN, or -C(O)N(Ra)(Rb)9. The compound of any one of the preceding claims, wherein Rais H.

10. The compound of any one of the preceding claims, wherein Rbis H11. The compound of any one of the preceding claims, wherein n is 9, 11, 12, 17, 22, or 44,12. The compound of any one of the preceding claims, wherein the compound is selected from Table 1 or Table 4-Table 18.

13. The compound of claim I, wherein the compound is:312043035 168Attorney Docket No.: NTSS-014 / 001 WO14. A compound obtainable by, or obtained by, a method described herein.

15. A pharmaceutical composition comprising the compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

16. The pharmaceutical composition of claim 15, wherein the compound is selected from a compound of Table 1, Table 4-Table 18, Table 22, or Table 44.

17. A method of treating or preventing a disease or disorder in a subject in need thereof, wherein the subject is administered the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15 or claim 16.

18. A compound of any one of claims 1-14 or a pharmaceutical composition of claim 15 or claim 16 for use in treating or preventing a disease or disorder in a subject in need thereof.

19. Use of a compound of any one of claims 1-14 for use in the manufacture of a medicament for the treatment or prevention of a disease or disorder in a subject in need thereof.

20. Use of a compound of any one of claims 1-14, or a pharmaceutical composition of claim 15 or claim 16, for the treatment or prevention of a disease or disorder in a subject in need thereof.

21. The method, composition, or use of any one of claims 17-20, wherein the disease or disorder is inflammation.

22. The method, composition, or use of any one of claims 17-20, wherein the disease or disorder is a traumatic brain injury.312043035 169

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