WITHAFERIN ANALOGIES, PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS, AND METHODS OF PREPARING THEM.

Abstract

The invention relates to compounds, pharmaceutical preparations containing compounds, and methods of preparing compounds. Compounds with the formula (I): and pharmaceutical salts, or derivatives thereof, are useful for the treatment of a variety of diseases and medical conditions.

Description

WITHAFERIN A ANALOG AND METHOD FOR TREATMENT USING THE SAMECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority and benefit of U.S. Provisional Patent Application No. 63 / 587,721 filed on October 03, 2023. The contents of this application are incorporated herein by reference in their entirety for all purposes.TECHNICAL FIELD

[0002] The present disclosure relates generally to compounds, compositions, and methods for treating a variety of diseases and conditions, and more specifically, for treating inflammatory-related diseases.BACKGROUND

[0003] Inflammation plays a crucial role in the immune response to injury and infection, but excessive or chronic inflammation can be detrimental, leading to a variety of diseases. Inflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn's disease, are characterized by chronic inflammation in the gastrointestinal tract and can lead to debilitating symptoms and complications, including severe pain, weight loss, and malnutrition. In addition, alcoholic hepatitis is a significant inflammatory condition resulting from prolonged excessive alcohol intake. Its symptoms can range from mild, including jaundice and malaise, to severe, leading to liver failure and potential death. The current treatment regimens for alcoholic hepatitis and other liver diseases are limited and often not wholly effective, necessitating the exploration for more targeted and potent therapeutic agents.

[0004] TNF-a, a pro-inflammatory cytokine, has been extensively identified as a crucial player in the pathogenesis of IBD. Overproduction of TNF-a results in enhanced inflammatory responses, tissue damage, and promotes the chronicity of intestinal inflammation observed in IBD patients. Consequently, therapies aimed at neutralizing TNF-a, such as monoclonal antibodies, have demonstrated efficacy in the treatment of IBD. However, despite their therapeutic benefits, anti-TNF-a therapies can also lead to potential adverse effects, such as infections, malignancies, and the development of anti-drug antibodies. Furthermore, a significant subset of IBD patients are non-responsive or lose their responsiveness to anti-TNF-a treatments over time. Therefore, there exists a dire need for alternative or complementary strategies to target the TNF-a pathway.

[0005] The NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome, a multiprotein complex, has been identified as a key player in the initiation and progression of inflammation. It is involved in the activation of inflammatory responses, including the release of pro-inflammatory cytokines like IL-ip and IL- 18, which further aggravate liver damage. It has been shown that dysregulated NLRP3 inflammasome activation is associated with the pathogenesis of both IBD and alcoholic hepatitis, thus presenting an appealing target for therapeutic intervention. Current IBD treatments primarily focus on reducing inflammation and maintaining remission but do not directly target the pathophysiological processes underlying the disease.

[0006] HSP90, a heat shock protein, is a molecular chaperone involved in the folding and function of various proteins. HSP90 operates as a homodimer, and each monomer consists of three distinct domains: an N-terminal domain (N-domain), a middle domain, and a C-terminal domain. Each of these domains has specific functions and characteristics. The N-domain is known for its ATP / ADP -binding pocket, and is the main site for most of the HSP90 inhibitors known today. Examples of HSP90 inhibitors that target the N-domain of HSP90 include Geldanamycin and its derivative 17-AAG (Tanespimycin), Ganetespib (STA-9090), and PU- H71.

[0007] Interestingly, HSP90 has been found to regulate the stability of both TNF-a and the NLRP3 inflammasome. Specifically, the C-terminal domain of HSP90 binds to TNF-a and NLRP3, aiding in its stability and proper function. However, uncontrolled activation of TNF- a or NLRP3, often due to constant interaction with HSP90, can lead to persistent inflammation seen in diseases like IBD and alcoholic hepatitis.

[0008] Accordingly, there is an ongoing need in the art for compounds, compositions and methods for treating inflammatory -related diseases, such as IBD and alcoholic hepatitis, along with a variety of other diseases and conditions.BRIEF SUMMARY

[0009] Embodiments described herein relate to compounds, compositions, and methods for treating, reducing, or ameliorating a variety of diseases, disorders, or conditions in a subject inneed thereof. Even though inflammation is a host's protective reaction to infections, it can be harmful and destructive in excess. In various circumstances, inflammation is regarded as a disease-modifying mechanism, prompting substantial efforts to address detrimental inflammatory reactions observed in conditions such as inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, and other diseases.

[0010] A compound of Formula (I) is provided herein. The compound of Formula (I) is as follows:(I), or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen,R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl,wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;R3is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, -(NR9R10Rn)+, or -OC(=O)NH-(C2-Cealkynyl), wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NH, NR12, or N -O’;R4, R5, R6, R7, R8, R9, R10, and R11are each, independently, hydrogen, deuterium, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, deuterium, halogen, =0, -OR9, -SR9, -NR9R10, -COOR9, - COHR9R10, -CR9R10RU, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, or -O- (heterocyclyl); with the proviso:(1) when R1is hydrogen, then R2is a halogen;(2) wheneach of T, U, V, W, and X is CH or CR12, then only one of T, U, V, W, and X is CR12, whereinthe remaining T, U, V, W, and X are CH; and(3) whenare CH, one of W or U is nitrogen, and the other of W or U is CH, then V is not C(-OCH3).

[0011] These compounds and pharmaceutically acceptable compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, inflammatory diseases, such as Inflammatory Bowel Disease (IBD), Crohn’s Disease (CD), and alcoholic hepatitis; and cancer, such as colorectal cancer. In various embodiments, the compounds of Formula (I) and pharmaceutically acceptable compositions are inhibitors, or modulators of one or more of the following therapeutic targets: heat shock protein 90 (HSP90), NLR family pyrin domain containing 3 (NLRP3) inflammasome, tumor necrosis factor alpha (TNF- a), and transforming growth factor beta (TGF-P), and thus areuseful for treating or lessening the severity of the variety of diseases, disorders, or conditions described herein.

[0012] Also provided herein is a method of treating, ameliorating, or preventing an NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome-mediated condition or disease, or for comprising administering a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen,R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl,wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;R3is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, -(NR9R10Rn)+, or -OC(=O)NH-(C2-Ce alkynyl), wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NH, NR12, orN -0’;R4, R5, R6, R7, R8, R9, R10, and R11are each, independently, hydrogen, deuterium, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, deuterium, halogen, =0, -OR9, -SR9, -NR9R10, -C00R9, - COHR9R10, -CR9R10RU, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, or -O- (heterocyclyl). In some embodiments, the compound of Formula (I) is administered in a therapeutically effective amount.

[0013] In another aspect, provided herein is a method of treating, ameliorating, or preventing a tumor necrosis factor alpha (TNF-a)-mediated condition or disease, comprising administering a compound of Formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen,R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl,wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;R3is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, -(NR9R10Rn)+, or -OC(=O)NH-(C2-Ce alkynyl), wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NH, NR12, or N -O’;R4, R5, R6, R7, R8, R9, R10, and R11are each, independently, hydrogen, deuterium, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, deuterium, halogen, =0, -OR9, -SR9, -NR9R10, -COOR9, - COHR9R10, -CR9R10RU, -CN, -N3, Ci-Ce alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, or -O- (heterocyclyl). In some embodiments, the compound of Formula (I) is administered in a therapeutically effective amount.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0015] FIGS. 1A and IB are charts and graphs illustrating experimental results of nonlimiting embodiments of a compound of Formula I inhibiting the NLRP3 pathway in human primary cells.

[0016] FIGS. 2A and 2B represent pictorial and graphical representation of NLRP3 stability regulation by a compound of Formula I in accordance with one or more exemplary embodiments of the present disclosure.

[0017] FIGS. 3A and 3B represent dose dependent NLRP3 protein degradation by a compound of Formula I in accordance with one or more exemplary embodiments of the present disclosure. While FIG. 3C represents proteasome rescue of NLRP3 protein by a compound of Formula I in accordance with one or more exemplary embodiments of the present disclosure.

[0018] FIG. 4 illustrates dose dependent in-vitro target engagement of a compound of Formula I in accordance with one or more exemplary embodiments of the present disclosure.

[0019] FIGS. 5A-5D illustrate dose-dependent reduction in Disease Activity Index and combined histopathology score in dextran sodium sulfate (DSS) induced Colitis Murine model of a compound of Formula I in accordance with one or more exemplary embodiments of the present disclosure.

[0020] FIGS. 6A-6F depict reduction of disease Activity Index in Chronic dextran sodium sulfate (DSS) induced IBD Murine model by a compound of Formula I in accordance with one or more exemplary embodiments of the present disclosure.

[0021] FIGS. 7A and 7B depict dose responsive efficacy of a compound of Formula I in a dextran sodium sulfate (DSS) induced Colitis Murine model (Prophylactic mode) in accordance with one or more exemplary embodiments of the present disclosure.

[0022] FIGS. 8A-8D illustrates reduced DSS-induced DAI score on day 8 in dextran sodium sulfate (DSS) induced Colitis Murine model by a compound of Formula I in accordance with one or more exemplary embodiments of the present disclosure.

[0023] FIGS. 9A and 9B illustrate reduced DSS-induced colon shortening in dextran sodium sulfate (DSS) induced Colitis Murine model by a compound of Formula I in accordance with one or more exemplary embodiments of the present disclosure.

[0024] FIGS. 10A-10D demonstrate the prevention of DSS-induced intestinal permeability in dextran sodium sulfate (DSS) induced Colitis Murine model by a compound of Formula I in accordance with one or more exemplary embodiments of the present disclosure.

[0025] FIGS. 11A-11C depict reduction of DSS-induced clinically relevant markers in dextran sodium sulfate (DSS) induced Murine model by a compound of Formula I in accordance with one or more exemplary embodiments of the present disclosure.

[0026] FIGS. 12A-12C depict the effect of a compound of Formula I in DSS-induced proinflammatory markers in colon in accordance with one or more exemplary embodiments of the present disclosure.

[0027] FIGS. 13A-13C depict the effect of a compound of Formula I on DSS-induced systemic inflammation in accordance with one or more exemplary embodiments of the present disclosure.

[0028] FIGS. 14A and 14B depict the effect of a compound of Formula I on DSS-induced proinflammatory markers in serum in accordance with one or more exemplary embodiments of the present disclosure.

[0029] FIG. 15 depicts the effect of a compound of Formula I in DSS-induced systemic inflammation in accordance with one or more exemplary embodiments of the present disclosure.

[0030] FIG. 16 depicts the effect of a compound of Formula I in inhibiting IL-ip release from differentiated THP1 cells in accordance with one or more exemplary embodiments of the present disclosure.

[0031] FIG. 17 depicts the effect of a compound of Formula I on pyroptosis in differentiated THP1 cells in accordance with one or more exemplary embodiments of the present disclosure.

[0032] FIGS. 18A-18D depict the effect of a compound of Formula I in alcohol-induced liver injury mouse model in accordance with one or more exemplary embodiments of the present disclosure.DETAILED DESCRIPTION

[0033] Provided herein are compounds, compositions, and methods for treating, reducing, or ameliorating a variety of diseases, disorders, or conditions in a subject in need thereof. Even though inflammation is a host's protective reaction to infections, it can be harmful and destructive in excess. In various circumstances, inflammation is regarded as a diseasemodifying mechanism, prompting substantial efforts to address detrimental inflammatory reactions observed in conditions such as inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis and other diseases.

[0034] As used herein, the term “subject” refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats and mice. In certain embodiments, the subject is a primate. In yet another embodiment, the subject is a human.

[0035] As used herein, a subject is “in need of’ or “in need thereof’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

[0036] As an essential part of the innate immune system, NLRP3 (NACHT, LRR and PYD domain-containing protein 3) functions as a pattern recognition receptor (PRR) in cells like macrophages. The NLRP3 protein, a multimolecular complex, plays a central role in the pathogenesis of various diseases characterized by harmful inflammatory responses. The NLRP3 protein detects cellular stress caused by pathogens or damage, and it forms a complex with an adaptor protein called ASC (apoptosis-associated speck-like protein containing a CARD). This complex, known as the inflammasome, is responsible for activating the protease caspase- 1. Caspase- 1 then cleaves precursor forms of the pro-inflammatory cytokines interleukin (IL)- 1 (3 and IL-18, converting them into their active forms, which are subsequently released. Caspase-1 is responsible for the proteolytic cleavage of gasdermin D, resulting in the formation of pores in the cellular membrane and subsequent pyroptotic cell death. This process enables the release of inflammasome complexes into the extracellular space, thereby amplifying the inflammatory response. In the context of Alzheimer's disease models, extracellular ASC specks have been observed to initiate the seeding of amyloid deposition and aggregation.

[0037] As used herein, the term “NLRP3” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and anti-sense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0038] Consequently, there exists a significant level of interest in the development of inhibitors targeting the NLRP3 inflammasome. Heat-shock protein 90 (HSP90) is a highly abundant protein that plays a crucial role in numerous cellular signaling pathways, including inflammation. This is achieved through its ability to interact with and modulate the activity of various client proteins within the cellular environment. It has been proposed that HSP90 has the ability to interact with NLRP3, thereby exerting control over the activation of inflammasomes and the secretion of IL-ip. To this end, the compounds and compositions as contemplated herein are HSP90 inhibitors that inhibit NLRP3 -dependent inflammation.

[0039] In certain embodiments, the present disclosure relates to compounds and compositions that modulate NLRP3 stability by inhibiting the interaction of NLRP3 by the C- terminal domain of HSP90 to modulate the NLRP3 inflammasome's activity. By preventing HSP90's stabilizing action, the compounds and composition described herein may reduce overactivation of the inflammasome, thereby mitigating the inflammatory response.

[0040] TNF-a, or tumor necrosis factor-alpha, is a pro-inflammatory cytokine produced by various cell types, primarily macrophages and T-cells, in response to infection, injury, or other stimuli. It plays a pivotal role in the body's immune response by promoting inflammation, mediating apoptosis (cell death), regulating cell proliferation, and coordinating a wide range of cellular activities that are essential for host defense against pathogens. However, overproduction or chronic presence of TNF-a can lead to pathological inflammation and is implicated in various diseases, including alcoholic liver disease, inflammatory bowel disease, and psoriasis.

[0041] As used herein, the term “TNF-a” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and anti-sense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous TNF-a, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0042] Consequently, there exists a significant level of interest in the development of inhibitors targeting TNF-a. It has been proposed that HSP90 has the ability to interact with TNF-a. To this end, the compounds and compositions as contemplated herein are HSP90 inhibitors that inhibit TNF-a-dependent inflammation.

[0043] In certain embodiments, the present disclosure relates to compounds and compositions that modulate TNF-a stability by inhibiting the interaction of TNF-a by the C- terminal domain of HSP90 to modulate TNF-a activity. By preventing HSP90's stabilizing action, the compounds and composition described herein may reduce overactivation of TNF- a, thereby mitigating the inflammatory response.

[0044] In other embodiments, HSP90 as a molecular chaperone, plays a vital role in stabilizing and assisting the conformational maturation of various proteins are involved in signaling pathways that can, directly or indirectly, influence the production, stability, oractivity of cytokines. Non-limiting examples of cytokines or cytokine pathways that are influenced by proteins regulated by HSP90, include:(1) NF-KB pathway: HSP90 regulates the stability of IKB kinase (IKK). IKK plays a role in the degradation of IKB, leading to the activation of NF-KB. Activated NF-KB then translocates to the nucleus and can induce the expression of various cytokines including TNF-a, IL-ip, IL-6, and IL-8.(2) STAT proteins wherein HSP90 is involved in stabilizing Signal Transducer and Activator of Transcription (STAT) proteins. STATs, once activated, can induce the expression of various cytokines and growth factors.(3) HIF-la: Under hypoxic conditions, the stabilization of Hypoxia-Inducible Factor 1-alpha (HIF-la) by HSP90 can lead to the expression of VEGF and other cytokines.(4) Toll-like receptors (TLRs): HSP90 is involved in the maturation and stability of some TLRs, which play a significant role in innate immunity and can induce the production of various cytokines upon activation.(5) Receptor tyrosine kinases: HSP90 stabilizes various receptor tyrosine kinases. These receptors, upon activation, can activate downstream pathways leading to the production of various growth factors and cytokines.(6) IL-1 receptor-associated kinase (IRAK): HSP90 stabilizes IRAK, which is involved in IL- 1 signaling and can influence the production of cytokines downstream.

[0045] It should be noted that HSP90 may not directly regulate cytokines but rather stabilizes and assists in the function of many client proteins that, in turn, influence cytokine production, stability, or activity.

[0046] The compounds and compositions described herein are used to treat, prevent, or ameliorate (reduce the severity of) one or more symptoms associated with diseases and conditions characterized by aberrant NLRP3 inflammasome activity, aberrant TNF-a activity, or both. Such diseases and conditions include inflammatory bowel diseases, systemic inflammatory diseases, inflammatory skin diseases, gastrointestinal diseases, kidney diseases, cardiovascular diseases, liver diseases, autoimmune diseases, and respiratory diseases. The pharmaceutical compositions include a compound described herein and a pharmaceuticallyacceptable carrier. The present disclosure further includes kits containing the pharmaceutical composition. The present disclosure further includes methods of treating a pathological state in a mammal through the administration of any compounds or composition described herein.Compounds

[0047] A compound of Formula (I) is provided herein. The compound of Formula (I) is as follows:(I), or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen,R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl,wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;R3is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, -(NR9R10Rn)+, or -0C(=0)NH-(C2-Cealkynyl), wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NH, NR12, or N -O’;R4, R5, R6, R7, R8, R9, R10, and R11are each, independently, hydrogen, deuterium, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, deuterium, halogen, =0, -OR9, -SR9, -NR9R10, -COOR9, - COHR9R10, -CR9R10RU, -CN, -N3, Ci-Ce alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, or -O- (heterocyclyl); with the proviso:(1) when R1is hydrogen, then R2is a halogen;(2) wheneach of T, U, V, W, and X is CH or CR12, then only one of T, U, V, W, and X is CR12, whereinthe remaining T, U, V, W, and X are CH; and(3) whenare CH, one of W or U is nitrogen, and the other of W or U is CH, then V is not C(-OCH3).

[0048] In some variations of the foregoing,R1is hydrogen,R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl,aralkyl, heteroaryl, cycloalkyl ring, heterocycloalkyl,wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloalkyl ring, or heterocycloalkyl are unsubstituted or substituted with one or more R12;R3is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloalkyl ring, heterocycloalkyl, -(NR9R10Rn)+, or -0C(=0)NH-(C2-Ce alkynyl), wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloalkyl ring, or heterocycloalkyl are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NH, NR12, or N -O-;R4, R5, R6, R7, R8, R9, R10, and R11are each, independently, hydrogen, deuterium, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, deuterium, halogen, =0, -OR9, -SR9, -NR9R10, -COOR9, - COHR9R10, -CR9R10RU, -CN, -N3, Ci-Ce alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloalkyl ring, heterocycloalkyl, or -O- (heterocy cl oalky 1) .

[0049] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0050] As described herein, compounds of the disclosure can optionally be substituted with one or more substituents, such as are illustrated generally herein, or as exemplified by particular classes, subclasses, and species of the disclosure. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds.

[0051] The phrase “optionally substituted” may be used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. A ring substituent, such as a heterocyclyl, can be bound to another ring, such as a cycloaliphatic ring, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds.

[0052] The term “alkyl” or “alkyl group” as used herein, means a straight-chain (i.e. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In some embodiments, alkyl groups contain 1-10 carbon atoms. In other embodiments, groups contain 1-8 carbon atoms. In still other embodiments, groups contain 1-6 carbon atoms, and in yet other embodiments groups contain 1-4 carbon atoms. Suitable alkyl groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl groups.

[0053] The term “alkenyl” or “alkenyl group” as used herein, means an unsaturated linear straight-chain (i.e. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that contains at least one moiety of the formula (C=C). Unless otherwise specified, alkenyl groups contain 2-20 carbon atoms. In some embodiments, alkenyl groups contain 2-10 carbon atoms. In other embodiments, alkenyl groups contain 2-8 carbon atoms. In still other embodiments, alkenyl groups contain 2-6 carbon atoms, and in yet other embodiments alkenyl groups contain 2-4 carbon atoms. Suitable alkenyl groups include, but are not limited to, linear or branched, substituted or unsubstituted alkenyl groups.

[0054] The term “alkynyl” or “alkynyl group” as used herein, means an unsaturated linear straight-chain (i.e. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that contains at least carbon-carbon triple bond. Unless otherwise specified, alkynyl groups contain 2-20 carbon atoms. In some embodiments, alkynyl groups contain 2-10 carbon atoms. In other embodiments, alkynyl groups contain 2-8 carbon atoms. In still other embodiments, alkynyl groups contain 2-6 carbon atoms, and in yet other embodiments alkynyl groups contain2-4 carbon atoms. Suitable alkynyl groups include, but are not limited to, linear or branched, substituted or unsubstituted alkynyl groups.

[0055] The term “cycloaliphatic ring” mean a monocyclic hydrocarbon ring, or a polycyclic hydrocarbon ring system containing no heteroatoms, that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic and that has a single point of attachment to the rest of the molecule. The term “polycyclic ring system,” as used herein, includes bicyclic and tricyclic 4- to 12-membered structures that form at least two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common) including fused, bridged, or spirocyclic ring systems. Particular cycloaliphatic ring groups include those having 3 to 12 carbon atoms (C3-C12 cycloaliphatic ring), those having 3 to 6 carbon atoms (C3-C6 cycloaliphatic ring), and those having 5 to 6 carbon atoms (Cs-Ce cycloaliphatic ring). Additional exemplary cycloaliphatic ring groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0056] The term “halogen” or “halo” as used herein, means F, Cl, Br or I.

[0057] Unless otherwise specified, the term “heterocyclyl” as used herein means nonaromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring atoms in one or more ring members is an independently selected heteroatom. Heterocyclic ring can be saturated or can contain one or more unsaturated bonds. In some embodiments, the “heterocyclyl” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring system contains 3 to 7 ring members. Particular heterocyclyl groups include 3- to 12-membered heterocyclyl; 4- to 6-membered heterocyclyl; 5- to 6-membered heterocyclyl; 5- to 6-membered heterocyclyl containing one or more heteroatoms selected from N, O, or S; and 5- to 6-membered heterocyclyl, containing 1-2 heteroatoms selected from N or O.

[0058] The term “heteroatom” means oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)). In some embodiments, a heteroatom may be oxygen, sulfur, or nitrogen.

[0059] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation but is not aromatic.

[0060] The term “alkoxy,” or “thioalkyl,” as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

[0061] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring carbon atoms and containing no heteroatoms, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring carbon atoms. The term “aryl” may be used interchangeably with the term “aryl ring.” Particular aryl groups include those having 6 to 12 carbon atoms (C6-C12 aryl) or those having 6 to 10 carbon atoms (Ce-Cio aryl). Additional exemplary aryl groups include phenyl and napthyl.

[0062] The term “heteroaryl,” used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy,” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. In some embodiments, the one or more heteroatoms are selected from oxygen, sulfur, and nitrogen. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic.” Particular heteroaryl groups include 5- to 12-membered heteroaryl, 5- to 10-membered heteroaryl, and 5- to 6-membered heteroaryl.

[0063] “D” and “d” both refer to deuterium.

[0064] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of Formula (I) of the disclosure are within the scope of the disclosure. Thus, included within the scope of the disclosure are tautomers of compounds of Formula (I). The structures also include zwitterioinc forms of the compounds or salts of Formula (I) where appropriate.

[0065] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched orisotopically-labeled atoms. The isotopically-labeled compounds may have one or more atoms replaced by an atom having an atomic mass or mass number usually found in nature. Examples of isotopes present in compounds of Formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to,2H,3H,13C,14C,15N,18O,17O,35S and18F. Certain isotopically-labeled compounds of Formula (I), in addition to being useful as therapeutic agents, are also useful in drug and / or substrate tissue distribution assays, as analytical tools or as probes in other biological assays. In one aspect of the present disclosure, tritiated (e.g.,3H) and carbon-14 (e.g.,14C) isotopes are useful given their ease of detectability. In another aspect of the present disclosure, replacement of one or more hydrogen atoms with heavier isotopes such as deuterium, (e.g.,2H) can afford certain therapeutic advantages.

[0066] In some embodiments, the compound of Formula (I) is Formula (la):pharmaceutically acceptable salt thereof, and wherein:R1is hydrogen,R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl,wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;R3is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, -(NR9R10Rn)+, or -0C(=0)NH-(C2-Ce alkynyl), wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NH, NR12, or N -O’;R4, R5, R6, R7, R8, R9, R10, and R11are each, independently, hydrogen, deuterium, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, deuterium, halogen, =0, -OR9, -SR9, -NR9R10, -C00R9, - COHR9R10, -CR9R10RU, -CN, -N3, Ci-Ce alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, or -O- (heterocyclyl); with the proviso:(1) when R1is hydrogen, then R2is a halogen;(2) wheneach of T, U, V, W, and X is CH or CR12, then only one of T, U, V, W, and X is CR12, whereinthe remaining T, U, V, W, and X are CH; and(3) whenare CH, one of W or U is nitrogen, and the other of W or U is CH, then V is not C(-OCH3).

[0067] In some embodiments, the compound of Formula (la) is a compound of formula (la-1):(Ia-1), or a pharmaceutically acceptable salt thereof.

[0068] In certain embodiments, R1of Formula (these and other embodiments, the compound of Formula (la) may be Formula (laa):pharmaceutically acceptable salt thereof, and wherein:R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl,wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;R3is hydrogen, halogen, -OR9, -SR9, -NR9R10, -C00R9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, -(NR9R10Rn)+, or -0C(=0)NH-(C2-Ce alkynyl), wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NH, NR12, or N -O’;R9, R10, and R11are each, independently, hydrogen, deuterium, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, deuterium, halogen, =0, -OR9, -SR9, -NR9R10, -C00R9, - COHR9R10, -CR9R10RU, -CN, -N3, Ci-Ce alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, or -O- (heterocyclyl); with the proviso:(1) when R1is hydrogen, then R2is a halogen;(2) wheneach of T, U, V, W, and X is CH or CR12, then only one of T, U, V, W, and X is CR12, whereinthe remaining T, U, V, W, and X are CH; and(3) whenare CH, one of W or U is nitrogen, and the other of W or U is CH, then V is not C(-0CH3).

[0069] In some embodiments,each of T, U, V, W, and X areCH or CR12. In these and other embodiments, the compound of Formula (laa) is selected from the group of:acceptable salt or stereoisomer thereof.

[0070] In some embodiments,only one of T, U, V, W, and X is sulfur, nitrogen, NH, NR12, or N+-O', and the remainder of T, U, V, W, and X are CH or CR12.In these and other embodiments, the compound of Formula (laa) is selected from the group of:or a pharmaceutically acceptable salt or stereoisomer thereof.

[0071] In some embodiments,least two of T, U, V, W, and X are sulfur, nitrogen, NH, NR12, or N+-0‘, and the remaining of T, U, V, W, and X are CH or CR12. In these and other embodiments, the compound of Formula (laa) is selected from the group of:or a pharmaceutically acceptable salt or stereoisomer thereof.

[0072] In certain embodiments, R1of Formulathese and other embodiments, the compound of Formula (la) may be Formula (lab):(lab), or a pharmaceutically acceptable salt thereof, and wherein:R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl,wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;R3is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, -(NR9R10Rn)+, or -OC(=O)NH-(C2-Ce alkynyl), wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;T, U, V, and W are each, independently, CH, CR12, sulfur, nitrogen, NH, NR12, or N -O’;R9, R10, and R11are each, independently, hydrogen, deuterium, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, deuterium, halogen, =0, -OR9, -SR9, -NR9R10, -COOR9, - COHR9R10, -CR9R10RU, -CN, -N3, Ci-Ce alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, or -O-(heterocyclyl).

[0073] In exemplary embodiments, the compound of Formula (lab) is selected from the group of:or a pharmaceutically acceptable salt or stereoisomer thereof.

[0074] In some embodiments, R1of Formula (I) or (la) is hydrogen. In these embodiments when R1is hydrogen, the compound of Formula (la) may be Formula (lac):(lac), or a pharmaceutically acceptable salt thereof, wherein:R2is halogen;R3is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, -(NR9R10Rn)+, or -OC(=O)NH-(C2-Ce alkynyl), wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;R9, R10, and R11are each, independently, hydrogen, deuterium, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, deuterium, halogen, =0, -OR9, -SR9, -NR9R10, -COOR9, - COHR9R10, -CR9R10RU, -CN, -N3, Ci-Ce alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, or -O-(heterocyclyl).

[0075] In exemplary embodiments, the compound of Formula (lac) is:or a pharmaceutically acceptable salt or stereoisomer thereof.

[0076] In some embodiments,wherein m is 0, 1, 2, 3, 4,5, or 6.wherein p is 0, 1, 2, or 3.

[0079] In some embodiments,wherein q is 0, 1, or 2. In some embodiments,wherein p is 0, 1, 2, or 3. In some, wherein q is 0, 1, or 2.

[0080] In some embodiments, R2is halogen, -OR9, -NR9R10, 5-membered heterocyclyl, or, wherein R9and R10are each independently hydrogen or Ci-Ce alkyl. In some embodiments,

[0081] In some embodiments, R3is hydrogen, halogen, -OR9, -NR9R10, Ci-Ce alkoxy, 5- to 6-membered heterocyclyl optionally substituted by one or more Ci-Ce alkyl, -(NR9R10Rn)+,-OC(=O)NH-(C2-Ce alkynyl), or, wherein R9, R10, and R11are each independently hydrogen or Ci-Ce alkyl. In some embodiments, R3is hydrogen, -OH,

[0082] In some embodiments, R12is deuterium, halogen, =0, -NR9R10, -CN, Ci-Ce alkyl,Ci-Ce alkoxy, 4-membered heterocyclyl, or -O-(heterocyclyl), wherein R9and R10are each independently hydrogen or Ci-Ce alkyl. In some embodiments, R12is deuterium, -F, -CN, =0,

[0083] Non-limiting examples of suitable compounds include any of the following compounds, or pharmaceutically acceptable salts thereof.Pharmaceutically Acceptable Salts, Prodrugs, and Compositions

[0084] As described herein, the compounds of Formula (I) are provided as inhibitors or modulators of one or more of the following therapeutic targets: HSP90, NLRP3 inflammasome and TGF-p. In relation to, or independent of, this inhibitory or modulatory activity, the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to inflammatory bowel diseases, systemic inflammatory diseases, inflammatory skin diseases, gastrointestinal diseases, kidney diseases, cardiovascular diseases, liver diseases, autoimmune diseases, and respiratory diseases. Accordingly, in another aspect of the disclosure, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds of Formula (I) as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

[0085] It will also be appreciated that certain compounds of this disclosure can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the disclosure, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a subject in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.Furthermore, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs which upon administration to a subject in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0086] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitory active metabolite or residue thereof. As used herein, the term “inhibitory active metabolite or residue thereof’ means that a metabolite or residue thereof is also an inhibitor or modulator of one or more of the therapeutic targets.

[0087] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference in its entirety. Pharmaceutically acceptable salts of the compounds of Formula (I) of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, di gluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy- ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(CI-4 alkyl)4 salts. This disclosure also envisions the quaternizationof any basic nitrogen-containing groups of the compounds of Formula (I) disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quatemization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0088] The term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the disclosure. The term “prodrug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood, such an ester. A thorough discussion is provided in Higuchi, T., and V. Stella, “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series 14, and in “Bioreversible Carriers in Drug Design,” in Edward B. Roche (ed.), American Pharmaceutical Association, Pergam on Press, 1987, both of which are incorporated herein by reference.

[0089] As described herein, the pharmaceutically acceptable compositions of the disclosure additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of Formula (I) of the disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure. Some examples of materials which can serve as pharmaceutically acceptablecarriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0090] In another aspect, the disclosure features a pharmaceutical composition comprising the compound of Formula (I) of the disclosure and a pharmaceutically acceptable carrier.

[0091] In another aspect, the disclosure features a pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0092] The compound of Formula (I), or a pharmaceutically acceptable salt thereof used in the compositions administered may be obtained from any commercially available sources, or any methods or techniques known in the art. For example, in some variations, the compound of Formula (I) may be isolated from a natural source. In other variations, the compound of Formula (I) may be synthesized according to any methods known in the art.

[0093] Compositions for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known in the art, for example by conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes. It willbe appreciated that the unit content of the compound of Formula (I) contained in an individual dose of each dosage form need not in itself constitute a therapeutically effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units.

[0094] In various embodiments, the composition includes the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and optionally consists essentially of the compound of Formula (I), or a pharmaceutically acceptable salt thereof. As used herein, the phrase “consisting essentially of’ generally encompasses the specifically recited elements / components for a particular embodiment. Further, the phrase “consisting essentially of’ generally encompasses and allows for the presence of additional or optional elements / components that do not materially impact the basic and / or novel characteristics of that particular embodiment. In certain embodiments, “consisting essentially of’ allows for the presence of <10, <5, or <1, weight percent (wt. %) of additional or optional components based on the total weight of the composition.

[0095] In various embodiments, the composition includes one or more pharmaceutically acceptable additives that are inactive ingredients. Examples of inactive ingredients include, but are not limited to, excipients, such as diluents and binders, granulating agents, glidants (or flow aids), fillers, lubricants, preservatives, stabilizers, coatings, disintegrants, fragrances, pigments, preservatives, solvents (e.g., alcohols), and combinations thereof. If utilized to form the composition, the inactive ingredient(s) can be used in various amounts and combined with the compound, or a pharmaceutically acceptable salt thereof, of Formula (I) to form a composition that is suitable for oral administration to humans or animals. It is to be further appreciated that the amounts of actives described herein can be normalized with respect to 100 parts by weight of the composition to account for the presence of inactive ingredients (if utilized).

[0096] Optionally, the composition may include one or more additional components such as additives. Suitable additives include those understood in the art, including but not limited to, moisturizers, emollients, emulsifiers, surfactants, oils, extracts, skin protectants, disinfectants, antiseptics, drugs and drug substances, analgesic compounds, anti-neuralgic compound, anti-oxidants, blood circulation promoters, antidepressant compounds, anti-anxiety compounds, anti-stress compounds, sunscreens, insect repellants, preservatives, exfoliants, fragrances, colors, fillers, solvents, vehicles, carriers, other types of additives known to those of skill in the art, and combinations thereof. Such additives may be utilized alone or incombination. In general, the optional additives may be of any type used in pharmaceuticals, nutraceuticals, personal care products and cosmetic products.

[0097] Examples of such carrier components are oils, fats, waxes, surfactants, humectants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, dyestuffs, lower alkanols, and the like. If desired, further ingredients may be incorporated in the compositions, e.g., anti-inflammatory agents, antibacterials, antifungals, disinfectants, vitamins, sunscreens, antibiotics, skin bleaching agents, healing enhancers / fibroblast proliferation compounds, neuromuscular blocking agents, sunscreens, or other anti-acne agents.

[0098] Examples of oils as a carrier agent comprises fats and oils such as olive oil and hydrogenated oils; waxes such as beeswax and lanolin; hydrocarbons such as liquid paraffin, ceresin, and squalene; fatty acids such as stearic acid and oleic acid; alcohols such as cetyl alcohol, stearyl alcohol, lanolin alcohol, and hexadecanol; and esters such as isopropyl myristate, isopropyl palmitate and butyl stearate. As examples of surfactants as carrier agents, there may be cited anionic surfactants such as sodium stearate, sodium cetylsulfate, polyoxyethylene laurylether phosphate, sodium N-acyl glutamate; cationic surfactants such as stearyldimethylbenzylammonium chloride and stearyltrimethylammonium chloride; ampholytic surfactants such as alkylaminoethylglycine hydrocloride solutions and lecithin; and nonionic surfactants such as glycerin monostearate, sorbitan monostearate, sucrose fatty acid esters, propylene glycol monostearate, polyoxyethylene oleylether, polyethylene glycol monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene coconut fatty acid monoethanolarnide, polyoxypropylene glycol (such as the materials sold under the trademark “Pluronic”), polyoxyethylene castor oil, and polyoxyethylene lanolin. Examples of humectants as carrier agents include glycerin, 1,3-butylene glycol, and propylene glycol; examples of lower alcohols include ethanol and isopropanol; examples of thickening agents include xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol and, sodium carboxymethyl cellulose. Examples of antioxidants comprise butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, citric acid, ethoxyquin, alpha lipoic acid, vitamin C, vitamin E, co-enzyme Q-10, and idebenone; botanical anti-oxidants include carotenoids such as lycopene; flavonoids such as silymarin (milk thistle), silybin, silydianin, sily christine; soybeans (isoflavins), grape seed extract; polyphenols such as green tea extract, rosmarinic acid (rosemary), hypercin (Saint John's wort), oleuropein (olive leaf), curcurmin (tumeric root),tetrahydrocurcumin, and pycogenol (marine bark pine). Examples of anti-inflammatory agents include anti-inflammatory botanicals such as allantoin, aloe vera, ginkgo biloba, green tea (also considered an antioxidant). Examples of skin bleaching agents are hydroquinone or kojic acid. Examples of healing enhancers / fibroblast proliferation compounds include copper peptides or palmitoyl-pentapetide (pal-KTTKS). Examples of neuromuscular blocking agents such as acetyl hexapeptide 3 (argircline) or dimethylaminoethanol. Examples of chelating agents include disodium edetate and ethanehydroxy diphosphate. Examples of buffers as carrier agents comprise citric acid, sodium citrate, boric acid, borax, and disodium hydrogen phosphate; and examples of preservatives are methyl parahydroxybenzoate, ethyl parahydroxybenzoate, dehydroacetic acid, salicylic acid and benzoic acid.

[0099] It is to be appreciated that certain components or additives may be classified under different terms of art and just because a component or additive is classified under such a term does not mean that they are limited to that function. If utilized, the additive or additives may be present in the composition in various amounts. Additional ingredients for optional use in the composition are described in U.S. Pat. No. 5,747,006 to Domoff et al., U.S. Pat. Nos. 5,980,904, 6,994,874, 7,060,304, 7,247,321, and 7,364,759 to Leverett et al., and U.S. Publication No. 2017 / 0252293 to Brumbaugh et al., the disclosures of which are hereby incorporated by reference in their entirety.

[0100] The composition can be prepared using various methods. For example, actives of the composition, and optionally one or more inactives, can be mixed or blended and compressed or compounded utilizing various techniques understood in the art. The composition of this disclosure is not limited to a particular order of manufacturing steps or method of manufacture.

[0101] The composition may comprise at least about 0.375% w / w, at least about 0.75% w / w, at least about 1% w / w, at least about 1.5% w / w, at least about 3% w / w, at least 4% w / w, at least 5% w / w, at least 6% w / w, at least 7% w / w, at least 8% w / w, at least 9% w / w, at least 10% w / w, at least 11% w / w, at least 12% w / w, at least 13% w / w, at least 14% w / w, at least 15% w / w, at least 16% w / w, at least 17% w / w, at least 18% w / w, at least 19% w / w, at least 20% w / w, or even more of the compound, or a pharmaceutically acceptable salt thereof, of Formula (I). In certain variations, the composition comprises about 0.375%, about 0.75%, about 1%, about 1.5%, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w,about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, or even more of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0102] In certain variations, the composition comprises between about 0.1% and about 20% w / w, between about 0.1% and about 15% w / w, between about 0.1% and about 5% w / w, between about 0.1% and about 3% w / w, between about 0.1% and about 1.5% w / w, between about 0.1% and about 1% w / w, between about 0.1% and about 0.75% w / w, between about 0.1% and about 0.375% w / w, between about 0.375% and about 5% w / w, between about 0.375% and about 3% w / w, between about 0.375% and about 1.5% w / w, between about 0.375% and about 1% w / w, between about 0.375% and about 0.75% w / w, between about 0.75% and about 5% w / w, between about 0.75% and about 3% w / w, between about 0.75% and about 1.5% w / w, between about 0.75% and about 1% w / w, between about 1% and about 5% w / w, between about 1% and about 3% w / w, between about 1% and about 1.5% w / w, between about 1.5% and about 5% w / w, between about 1.5% and about 3% w / w, between about 3% and about 5% w / w, between about 1% and about 15% w / w, between about 2% and about 10% w / w, between about 4% and about 8% w / w, between about 5% and about 15% w / w, or between about 8% and about 12% w / w of the compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0103] In other embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is present in the composition has a purity of at least about 50% w / w, at least about 60% w / w, at least about 70% w / w, at least about 75% w / w, at least about 80% w / w, at least about 90% w / w, at least about 95% w / w, at least about 96% w / w, at least about 97% w / w, at least about 98% w / w, at least about 99% w / w, at least about 99.9% w / w, at least about 99.99% w / w, or at least about 99.999% w / w; or a purity of about 100% w / w.

[0104] In other variations of the foregoing, the composition further comprises one or more additional components, including for example, fragrants, colorants, and / or excipients.Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

[0105] In one aspect, provided herein is a method of treating, ameliorating, or preventing a condition or disease in a subject in need thereof, comprising administering a compound of formula (I):(I), or a pharmaceutically acceptable salt thereof, wherein:R1is hydrogen,R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -C00R9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl,wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;R3is hydrogen, halogen, -OR9, -SR9, -NR9R10, -C00R9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, -(NR^^R11)*, or -0C(=0)NH-(C2-Ce alkynyl), wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NH, NR12, or N -0’;R4, R5, R6, R7, R8, R9, R10, and R11are each, independently, hydrogen, deuterium, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, deuterium, halogen, =0, -OR9, -SR9, -NR9R10, -C00R9, - COHR9R10, -CR9R10RU, -CN, -N3, Ci-Ce alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, or -O-(heterocyclyl). In some embodiments, the compound of Formula (I) is administered in a therapeutically effective amount. In some embodiments, the condition or disease is mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome. In some embodiments, the condition or disease is mediated by tumor necrosis factor alpha (TNF-a).

[0106] In another aspect, provided herein is a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in treating, ameliorating, or preventing a condition or disease. In some embodiments, the condition or disease is mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome. In some embodiments, the condition or disease is mediated by tumor necrosis factor alpha (TNF-a).

[0107] In another aspect, provided herein is a use of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating, ameliorating, or preventing a condition or disease. In some embodiments, the condition or disease is mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome. In some embodiments, the condition or disease is mediated by tumor necrosis factor alpha (TNF-a).

[0108] In some embodiments, the condition or disease is selected from the group consisting of inflammatory bowel diseases such as ulcerative colitis (UC), and Crohn's disease; systemic inflammatory diseases such as autoinflammatory disorders, Cryopyrin-associated periodic syndromes, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurologic cutaneous articular (CINCA) syndrome, and neonatal onset multi-system inflammatory disease (NOMID); inflammatory skin diseases such as acne vulgaris, hidradenitis suppurativa, and psoriasis; gastrointestinal diseases such as colorectal cancer; kidney diseases such as acute kidney injury, chronic kidney disease, and diabetic kidney disease; cardiovascular diseases such as coronary atherosclerotic heart disease, cardiomyopathy, myocardial infarction, cardiac hypertrophy, and ischaemia-reperfusion injury; liver diseases such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic steatohepatitis, chronic hepatitis C virus infection, paracetamol-induced liver injury, and alcoholic liver injury; autoimmune diseases such as gout, pseudo gout, rheumatoid arthritis (RA), multiple sclerosis (MS), Addison's disease, celiac disease, systemic lupus erythematous (SLE), and vitiligo; and respiratory diseases such as chronic pulmonary diseases, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and asthma. Invarious embodiments, the compounds of Formula (I) and pharmaceutically acceptable compositions are inhibitors or modulators of one or more of the following therapeutic targets: HSP90, NLRP3 inflammasome and TGF-P, and thus are useful for treating or lessening the severity of the variety of diseases, disorders, or conditions described herein.

[0109] In some embodiments, the condition or disease is a tumor necrosis factor alpha (TNF-a)-mediated condition or disease. In some embodiments, the condition or disease is an NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome-mediated condition or disease. In some embodiments, the condition or disease is selected from the group of inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof. In some embodiments, the condition or disease is selected from the group of inflammatory bowel disease (IBD), Crohn’s disease, or a combination thereof. In some embodiments, the condition or disease is selected from the group of colorectal cancer, alcoholic hepatitis, or a combination thereof.

[0110] In some embodiments, the compound of Formula (I) is, or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, provided herein is a method of treating, ameliorating, or preventing inflammatory bowel disease (IBD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of, or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments. the compound of Formula (I) is, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, provided herein is a method of treating, ameliorating, or preventing alcoholic hepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount ofthereof.

[0114] In various embodiments, the terms “inhibits” and “modulates” are used interchangeably to refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. Specifically, in some embodiment, inhibiting NLRP3 or inhibiting NLRP3 inflammasome pathway comprises reducing the ability of NLRP3 or NLRP3 inflammasome pathway to induce the production of IL-1 beta and / or IL-18. This can be achieved by mechanisms, including, but not limited to, inactivating, destabilizing, and / or altering distribution of NLRP3. This can be achieved by mechanisms, including, but not limited to, inactivating, destabilizing, and / or altering distribution of NLRP3. In other embodiments, inhibiting HSP90 or inhibiting HSP90 pathway comprises reducing the ability of HSP90 to stabilize NLRP3 and therefore reduce the ability of NLRP3 to induce the production of IL-1 beta and / or IL-18. This can be achieved by mechanisms, including, but not limited to, inactivating, destabilizing, and / or altering distribution of HSP90.

[0115] In certain embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, inhibits or modulated one or more of the therapeutic targets with an ICso less than 50 micromolar (pM), optionally less than 40 pM, optionally less than 30 pM, optionally less than 20 pM, optionally less than 10 pM, or optionally less than 1 pM. Alternatively, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, inhibits or modulated one or more of the therapeutic targets with an ICso from about 0.01 pM to about 100 pM, optionally from about 0.1 pM to about 75 pM, optionally from about 1 pM to about 50 pM, optionally from about 1 pM to about 25 pM, or optionally from about 1 pM to about 10 pM.

[0116] In some embodiments, “treating” or “treatment” refers to both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. In these and other embodiments, “treating” or “treatment” refers to obtaining beneficial or desired results, for example clinical results, in a subject, including: (1) alleviating one or more symptoms caused by or associated with a disease, disorder, or condition; (2) reducing the extent of the disease, disorder, or condition; (3) slowing or stopping the development or progression of one or more symptoms caused by or associated with the disease, disorder, or condition (for example, stabilizing the disease, disorder, or condition); and (4) relieving the disease, for example, by causing the regression of one or more clinical symptoms (e.g., ameliorating the disease state, enhancing the effect of another medication, delaying or stopping the progression of the disease, and / or increasing the quality of life).

[0117] In some aspects, the disclosure features a method of treating or lessening the severity in a subject of variety of diseases, disorders, or conditions comprising administering a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compound, or a pharmaceutically acceptable salt thereof.

[0118] The term “a therapeutically effective amount” of a compound of the present disclosure refers to an amount of the compound of the present disclosure that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay diseaseprogression, or prevent a disease, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present disclosure that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and / or ameliorate a condition, or a disorder or a disease (i) mediated by NLRP3, or (ii) associated with NLRP3 activity, or (iii) characterized by activity (normal or abnormal) of NLRP3; (2) reduce or inhibit the activity of NLRP3 (e.g., by binding to the C-terminal of HSP90 for preventing stabilization of NLRP3 by HSP90); or (3) reduce or inhibit the expression of NLRP3. In another non-limiting embodiment, the term “a therapeutically effective amount” of a compound of the present disclosure refers to the amount that when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit the activity of NLRP3; or at least partially reduce or inhibit the expression of NLRP3. The therapeutically effective amount may be ascertained experimentally.

[0119] In some embodiments, the method comprises administering to the subject the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an excipient to form a composition. The composition may comprise between 10-500 mg, or between 10-800 mg, or between 20-1,000 mg, or between 30-1,200 mg, or between 50-1,500 mg, or between 100- 2,000 mg or even more of the compound of Formula (I), or a pharmaceutically acceptable salt thereof in a single dosage unit. Viewed from a different perspective, at least 20 wt%, or at least 30 wt%, or at least 40 wt%, or at least 50 wt%, or at least 60 wt%, or at least 70 wt%, or at least 80 wt%, or at least 90 wt% of the composition will be the compound of Formula (I), or a pharmaceutically acceptable salt thereof. Consequently, preferred oral single dosage units (or recommended daily uptake) will be between 20-200 mg, or between 40-400 mg, or between 60-600 mg, or between 80-800 mg, or between 100-1,000 mg, or between 200-2,000 mg, and in some cases even higher.

[0120] As used herein, the term “administering” a pharmaceutical composition or drug refers to both direct and indirect administration of the pharmaceutical composition or drug, wherein direct administration of the pharmaceutical composition or drug is typically performed by a health care professional (e.g., physician, nurse, etc.), and wherein indirect administration includes a step of providing or making available the pharmaceutical composition or drug to the health care professional for direct administration (e.g., via injection, infusion, oral delivery, topical delivery, etc.).

[0121] In some variations, the method comprises administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in a petroleum-based vehicle, such as petroleum jelly to form a composition. The composition comprises at least about 0.375% w / w, at least about 0.75% w / w, at least about 1% w / w, at least about 1.5% w / w, at least about 3% w / w, at least 4% w / w, at least 5% w / w, at least 6% w / w, at least 7% w / w, at least 8% w / w, at least 9% w / w, at least 10% w / w, at least 11% w / w, at least 12% w / w, at least 13% w / w, at least 14% w / w, at least 15% w / w, at least 16% w / w, at least 17% w / w, at least 18% w / w, at least 19% w / w, at least 20% w / w, or even more of Formula (I) or a pharmaceutically acceptable salt thereof. In certain variations, the composition comprises about 0.375%, about 0.75%, about 1%, about 1.5%, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, or even more of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0122] In various embodiments, the amount of composition administered to the subject is based on the amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in milligrams (mg) per area of skin in centimeters-squared (cm2). The composition may be administered to the subject in an amount of at least 0.01 mg / cm2(mg of the compound per cm2of skin), at least 0.02 mg / cm2. at least 0.03 mg / cm2. at least 0.04 mg / cm2. at least 0.05 mg / cm2. at least 0.06 mg / cm2. at least 0.07 mg / cm2. at least 0.08 mg / cm2. at least 0.09 mg / cm2. at least 0.1 mg / cm2. at least 0.12 mg / cm2. at least 0.14 mg / cm2. at least 0.16 mg / cm2. at least 0.18 mg / cm2. at least 0.2 mg / cm2. at least 0.22 mg / cm2. at least 0.24 mg / cm2. at least 0.26 mg / cm2. at least 0.28 mg / cm2. at least 0.3 mg / cm2. at least 0.32 mg / cm2. at least 0.34 mg / cm2. at least 0.36 mg / cm2. at least 0.3 8mg / cm2. at least 0.4 mg / cm2, or even more. The composition may be administered to the subject in an amount of between about 0.01 mg / cm2and about 0.4 mg / cm2, between about 0.05 mg / cm2and about 0.3 mg / cm2, between about 0.1 mg / cm2and about 3 mg / cm2, or between about 0.15 mg / cm2and about 0.25 mg / cm2.

[0123] The composition may be applied as needed, daily, several times per day or in any suitable regimen such that the desired outcome is achieved. In the method of this disclosure, the frequency of administration (e.g., oral application) can depend on several factors, including the severity of the condition or symptoms of the same or the desired level of relief from the symptoms. Generally, a regimen includes application of the composition once or twice daily toinclude an administration in the morning and / or an administration in the evening. The amount and / or frequency of application of the composition may depend on several factors, including the level of desired results and the specific composition. In some embodiments, the composition is administered once per day. In other embodiments, the composition is administered twice per day. In still other embodiments, the composition is administered three times per day. In yet other embodiments, the composition is administered four times per day. However, it is to be appreciated that the composition may be administered more than four times per day.

[0124] In some variations, the composition is administered for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, at least about 16 weeks, at least about 24 weeks, at least about 32 weeks, at least about 40 weeks, at least about 48 weeks, or at least about 1 year. In certain variations, the composition is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 24 weeks, about 32 weeks, about 40 weeks, about 48 weeks, or about 1 year. In one variation, the composition is administered for between about 1 week and about 1 year, between about 4 weeks and about 8 weeks, between about 4 weeks and about 12 weeks, between about 4 weeks and about 16 weeks, between about 4 weeks and about 24 weeks, between about 4 weeks and about 32 weeks, between about 4 weeks and about 40 weeks, between about 4 weeks and about 48 weeks, or between about 4 weeks and about 1 year.

[0125] The compound of Formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, may be administered as described herein. In some embodiments, the composition is topically administered to the subject. In other embodiments, the composition is orally administered.

[0126] In another aspect, the disclosure features a method of inhibiting a therapeutic target, such as at least one of HSP90, NLRP3 inflammasome and TGF-P, in a subject comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0127] In some exemplary embodiments, the disclosure features a method of treating or lessening the severity in a subject of inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease comprising administering a therapeutically effective amount of acompound of Formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compound, or a pharmaceutically acceptable salt thereof.

[0128] In other exemplary embodiments, the disclosure features a method of treating or lessening the severity in a subject of gastrointestinal diseases, such as colorectal cancer comprising administering a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the compound, or a pharmaceutically acceptable salt thereof.

[0129] In some variations of the foregoing, the subject is formally diagnosed or clinically diagnosed with an inflammatory bowel disease, such as ulcerative colitis and Crohn's disease, or a gastrointestinal disease, such as colorectal cancer.Manufacture of Medicaments

[0130] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the disclosure and does not impose a limitation on the scope of the disclosure otherwise claimed.

[0131] Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present disclosure can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration.

[0132] Accordingly, as used herein a compound of the present disclosure can be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (antipodes), racemates, or mixtures thereof.

[0133] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometricor optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0134] Any resulting racemates of compounds of the present disclosure or of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present disclosure into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor- 10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.

[0135] A method of making a compound (e.g., a compound of Formula (I)) is provided. In various embodiments, the compound is of Formula (laa). The method comprises the step of providing a pyrazine as a first intermediate. The method further comprises the step of combining a 2-pyranone and the first intermediate to form a second intermediate. The method may further comprise purification of the second intermediate in ammonium bicarbonate to form the compound of Formula (laa).

[0136] In certain embodiments, the method may further comprise the step of providing a solvent, salt, a ligand, a catalyst, or combinations thereof. Other components may be provided, including, but not limited to, bases, acids, oxidizing agents, reducing agents, halogenating agents, coupling agents, protecting groups, and the like.

[0137] In these and other embodiment, the step of providing a pyrazine as a first intermediate is further defined as combining (i) the solvent, the salt, the ligand, the catalyst, or combinations thereof, and (ii) the pyrazine to form the first intermediate. In some aspects, the pyrazine is 2-chloro-5-isopropoxypyrazine.

[0138] In these and other embodiment, the step of combining a 2-pyranone and the first intermediate to form a second intermediate is further defined as combining (i) the solvent, the salt, the ligand, the catalyst, or combinations thereof, and (ii) the 2-pyranone and the first intermediate to form the second intermediate. In some aspects, the 2-pyranone is 2-pyranone is (4S,4aR,5aR,6aS,6bS,9R,9aS,l laS,l lbR)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-iodo-9a,l Ib-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10,11,1 la,l lb-dodecahydrocyclopenta[l,2]phenanthro[8a,9-b]oxiren- l(4H)-one.

[0139] The solvent may be selected from the group of 1,4-di oxane, tetrahydrofuran, ethyl acetate, heptane, water, or combinations thereof. The salt may be selected from the group of lithium chloride, sodium sulphate, ammonium bicarbonate, or combinations thereof.

[0140] The ligand may be selected from the group of hexabutyl distannane, tributyl(5- isopropoxy-2-pyrazinyl) stannane, tricyclohexyl phosphine, triphenylarsane and combinations thereof. The catalyst may be selected from the group of palladium — (lE,4E)-l,5-diphenyl-l,4- pentadien-3-one (2 / 3), Tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium [Pd2(dba)3], Copper Iodide [Cui], Triphenylarsane [AsPh3], Tetrakis (triphenylphosphine)palladium(O) [Pd(PPh3)4], Bis(triphenylphosphine)palladium(II) dichloride [PdC12(PPh3)2], and combinations thereof.

[0141] The base may be selected from the group of sodium hydride, potassium carbonate, triethylamine, sodium hydroxide, lithium diisopropylamide, and combinations thereof. The acid may be selected from the group of hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and combinations thereof.

[0142] The oxidizing agent may be selected from the group of hydrogen peroxide, metachloroperoxybenzoic acid, potassium permanganate, pyridinium chlorochromate, and combinations thereof. The reducing agent may be selected from the group of sodium borohydride, lithium aluminum hydride, hydrogen gas with palladium catalyst, diisobutylaluminum hydride, and combinations thereof.

[0143] The halogenating agent may be selected from the group of thionyl chloride, phosphorus tribromide, iodine monochloride, and combinations thereof. The coupling agent may be selected from the group of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), and combinations thereof. The protecting group may be selected from the group of tert-butyldimethylsilyl chloride (TBSC1), di-tert-butyl dicarbonate (Boc anhydride), benzyl bromide, and combinations thereof.

[0144] The compounds of the present disclosure may be prepared in accordance with the compound of Formula (I), or a pharmaceutically acceptable salt thereof, by the routes described in the following Schemes or the Examples. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the disclosure otherwise claimed. In the following general methods, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, T, U, V, W, and X are as previously defined in the above embodiments, or limited to designations in the Schemes. Unless otherwise stated, starting materials are either commercially available or are prepared by known methods.

[0145] In some embodiments, compounds of the present disclosure, as described herein, may be prepared by a reaction sequence shown in Scheme 1 below and described below to provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0146] Step-1: Synthesis of (4S,4aR,5aR,6aS,6bS,9R,9aS,llaS,llbR)-4-hydroxy-9- ((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-iodo- 9a,llb-dimethyl-5a,6,6a,6b,7,8,9,9a,10,ll,lla,llb- dodecahydrocyclopenta[l,2]phenanthro[8a,9-b]oxiren-l(4H)-one:

[0147] To the stirred solution of withaferin-A (3 g, 1 eq; 6.37 mmol) in dichloromethane (30 mL) was added N,N-dimethyl pyridin-4-amine (1.17 g, 1.5 eq., 9.56 mmol) at inert atmosphere. After 10 minutes, iodine (1.94 g, 1.2 eq., 7.65 mmol) was added to the reaction mixture and the resultant reaction mixture was allowed to stir at room temperature for 3 hours. The reaction mixture was quenched by saturated aqueous sodium thiosulfate solution (50 mL). The aqueous layer was extracted with dichloromethane (3 x 45 mL). Collected organics, dried over sodium sulphate and concentrated under reduced pressure to obtain crude. The crude was purified by combi-flash chromatography (using 5% methanol in dichloromethane) afforded (4S,4aR,5aR,6aS,6bS,9R,9aS,l laS,l lbR)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4- methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-iodo-9a,l Ib-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10,11,1 la,l lb-dodecahydrocyclopenta[l,2]phenanthro[8a,9-b]oxiren- l(4H)-one (2.1 g, 55%) as a white solid.Analytical data:LCMS: 90.55% (m / z: 595.18, [M-H]+, observed 595.18, [M+H]+, 2.29 min (4 min run).’H-NMR (400 MHz, DMSO-6): d 7.78 (d, J= 6.4 Hz, 1H), 5.87 (d, J = 3.6 Hz, 1H), 5.87 (d, J = 3.6 Hz, 1H), 4.58 (t, J = 5.2 Hz, 1H), 4.30-4.27 (m, 1H), 4.18-4.08 (m, 2H), 3.51-3.48 (m, 1H), 3.19 (s, 1H), 2.35-2.43 (m, 1H), 2.00-2.12 (m, 5H), 1.86-1.89 (m, 1H), 1.73-1.80 (m, 2H), 1.55-1.58 (m, 1H), 1.24-1.38 (m, 9H), 0.95-1.10 (m, 4H), 0.91 (d, J = 6.4 Hz, 3H), 0.64-0.71 (m, 4H)Step-2:

[0148] Method A: To a stirring solution of (4S,4aR,5aR,6aS,6bS,9R,9aS,l laS,l lbR)-4- hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)- 2-iodo-9a,l lb-dimethyl-5a,6,6a,6b,7,8,9,9a,10,l 1,1 la,l 1b- dodecahydrocyclopenta[l,2]phenanthro[8a,9-b]oxiren-l(4H)-one (1 eq; 1.02 mmol) in 1,4 dioxane and water were added dipotassium carbonate (2 eq., 2.04 mmol) and potassio-X6- borane (1.5 eq., 1.53 mmol). The resulting reaction mixture was degassed by purging with nitrogen for 30 minutes. After that, [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.2 eq., 204 pmol) was added to the above mixture and resultant mixture was heated at 85oC for 5 hours. Reaction was monitored by TLC (5% methanol in dichloromethane). After completion of the reaction, reaction mass was quenched by citric acid solution followed by extraction with dichloromethane (2 x 40 mL).Collected organics, dried over sodium sulphate and concentrated under reduced pressure to obtain crude. The crude was purified by combi-flash chromatography (5-10% methanol in dichloromethane) to furnish the corresponding compound

[0149] Method B: To a stirred solution of (lS,2R,6S,7R,9R,HS,12S,15R,16S)-6- hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2- yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16]octadec-4-en-3-one (1 eq; 2.35 mmol) in tetrahydrofuran (14 mL) were added X’-copper -i-) iodide (0.1 eq., 235 pmol), triphenylarsane (71.9 mg, 0.1 eq., 235 pmol), and (tributyl stannyl)reagent (2 eq., 4.69 mmol). Reaction mixture was purged with continuous flow of nitrogen for 30 minutes. After that, tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (0.01 eq., 23.5 pmol) was added and gain reaction mixture was degassed using nitrogen for 5 minutes. Resultant reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction (monitored by TLC: 5% methanol in dichloromethane), reaction mixture was filtered through celite bed and filtrate was diluted by water (30 mL) followed by extraction with dichloromethane (2 x 50 mL). Collected organics, dried over sodium sulphate and then concentrated under reduced pressure to get crude, which was purified by prep HPLC to afford the compound.

[0150] The processes can be extended to prepare any of the compounds of Formula (I), any of its sub-formulas, or a pharmaceutically acceptable salt thereof, as described herein. Depending on the starting materials and the selected route, as mentioned in Scheme 1 above, a skilled person in the art would know how to prepare compound of Formula (I), or a pharmaceutically acceptable salt thereof. Certain variants or alternative processes are described herein below in the experimental section.

[0151] The disclosure further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure material. Compounds of the disclosure and intermediates can also be converted into each other according to methods generally known to those skilled in the art.

[0152] In one aspect, the disclosure provides the use of a compound of Formula (I) or pharmaceutical composition described herein for the manufacture of a medicament for use ininhibiting a therapeutic target, such as at least one of HSP90, NLRP3 inflammasome and TGF- P-Administration of Pharmaceutically Acceptable Salts and Compositions

[0153] The compounds of Formula (I) and compositions, according to the method of the disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the pain or non-pain diseases recited herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of Formula (I) of the disclosure may be formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds of Formula (I) and compositions of the disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0154] The pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intraci stemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. In certain embodiments, the compounds of Formula (I) of the disclosure may beadministered orally or parenterally at dosage levels of about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg and optionally from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0155] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0156] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0157] It is known that sterols, such as cholesterol, will form complexes with cyclodextrins. Thus, in certain embodiments, where the inhibitor is a steroidal alkaloid, it may be formulated with cyclodextrins, such as a-, P- and y-cyclodextrin, dimethyl-P cyclodextrin and 2- hydroxypropyl-P-cyclodextrin.

[0158] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0159] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, by autoclave sterilization, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In various embodiments, a first portion of the formulation may be sterilized by filtration (e.g., the compound) and the second portion may be sterilized by autoclave sterilization (e.g., the excipient).

[0160] In order to prolong the effect of a compound of the disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0161] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0162] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0163] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0164] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present disclosure, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0165] Formulations of the pharmaceutical compositions of the disclosure for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0166] Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0167] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0168] The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0169] Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0170] Dosage forms for the topical or transdermal administration of a compound include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. Theactive compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0171] The ointments, pastes, creams and gels may contain, in addition to an active compound of this disclosure, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0172] Powders and sprays can contain, in addition to a compound of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0173] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0174] Ophthalmic formulation, eye ointments, eye drops, and eardrops are also contemplated as being within the scope of this disclosure. Pharmaceutical compositions suitable for parenteral administration comprise one or more compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0175] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0176] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0177] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0178] When the compounds of Formula (I) are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0179] The addition of the active compound to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in a therapeutically effective amount and incorporating the premix into the complete ration.

[0180] Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as “Applied Animal Nutrition”, W.H. Freedman and CO., San Francisco, U.S.A., 1969 or “Livestock Feeds and Feeding” O and B books, Corvallis, Ore., U.S.A., 1977).

[0181] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow-release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable andnon-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0182] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0183] The selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0184] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of Formula (I) employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0185] In general, a suitable daily dose of a compound will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous, intracerebroventricular and subcutaneous doses of the compounds of Formula (I) for a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day.

[0186] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.

[0187] The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep, and poultry and pets in general.

[0188] The compound can be administered as such or in admixtures with pharmaceutically acceptable and / or sterile carriers and can also be administered in conjunction with other antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Conjunctive therapy thus includes sequential, simultaneous and separate administration of the active compound in a way that the therapeutic effects of the first administered one are still detectable when the subsequent therapy is administered.

[0189] The present disclosure contemplates formulation of the subject compounds in any of the aforementioned pharmaceutical compositions and preparations. Furthermore, the present disclosure contemplates administration via any of the foregoing routes of administration. One of skill in the art can select the appropriate formulation and route of administration based on the condition being treated and the overall health, age, and size of the patient being treated.

[0190] The activity of a compound utilized in this disclosure as an inhibitor of the therapeutic targets may be assayed according to methods described generally in the Examples herein, or according to methods available to one of ordinary skill in the art.Combination Product and Combination Therapy

[0191] It will also be appreciated that the compounds of Formula (I) and pharmaceutically acceptable compositions of the disclosure can be employed in combination therapies, that is, the compounds of Formula (I) and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, the compound of Formula (I) may be administered concurrently with an additional therapeutic agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

[0192] Combination” refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of the present disclosure and a combination partner (e.g. another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g. powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term “pharmaceutical combination” as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents. The term “pharmaceutical combination” as used herein refers to either a fixed combination in one dosage unit form, or non-fixed combination or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. The term “fixed combination” means that the therapeutic agents, e.g. a compound of the present disclosure and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the therapeutic agents, e.g. a compound of the present disclosure and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more therapeutic agents.

[0193] The term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple, or in separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and / or liquids may be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times. In either case,the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0194] The compound of the present disclosure may be administered either simultaneously with, or before or after, one or more additional therapeutic agents. The compound of the present disclosure may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the disclosure.

[0195] In one embodiment, a product is provided herein comprising a compound of Formula (I), or a pharmaceutical acceptable salt thereof, and at least one additional therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by NLRP3. Products provided as a combined preparation include a composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent(s) together in the same pharmaceutical composition, or the compound of any one of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent(s) in separate form, e.g. in the form of a kit.

[0196] In one embodiment, the disclosure provides a pharmaceutical combination comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and additional therapeutic agent(s). Optionally, the pharmaceutical combination may comprise a pharmaceutically acceptable carrier, as described above.

[0197] In one embodiment, a kit is provided herein comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, the kit is configured to separately retain the compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.

[0198] The compound of the present disclosure may be administered either simultaneously with, or before or after, one or more additional therapeutic agents. The compound of the present disclosure may be administered separately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the additional therapeutic agent(s). A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment or nucleic acid, which is therapeutically active or enhances the therapeutic activity when administered to a patient in combination with a compound of the present disclosure.

[0199] In one embodiment, the present disclosure provides a product comprising a compound of Formula (I), or a pharmaceutical acceptable salt thereof, and at least one additional therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by NLRP3. Products provided as a combined preparation include a composition comprising the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent(s) together in the same pharmaceutical composition, or the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent(s) in separate form, e.g., in the form of a kit.

[0200] In some embodiments, the present disclosure provides a pharmaceutical combination comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and additional therapeutic agent(s). Optionally, the pharmaceutical combination may comprise a pharmaceutically acceptable carrier, as described above.

[0201] In various embodiments, the present disclosure provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, the kit is configured for separately retaining the compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, typically used for the packaging of tablets, capsules and the like.

[0202] The kit of the disclosure may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the disclosure typically comprises directions for administration.

[0203] In some embodiments, the present disclosure relates to a kit that includes the pharmaceutical composition and specific instructions that explain how to use the pharmaceutical composition for treating, ameliorating, or preventing one or more conditions and diseases (e.g., a disease or condition mediated by NLRP3) in a subject in need thereof.

[0204] In the combination therapies of the present disclosure, the compound of Formula (I) and the additional therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Moreover, the compound of Formula (I) and the additional therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g., in the case of a kit comprising the compound of Formula (I) and the additional therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g., during sequential administration of the compound of the Formula (I) and the additional therapeutic agent.

[0205] Accordingly, the present disclosure provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for treating a disease or condition mediated by NLRP3, wherein the medicament is prepared for administration with additional therapeutic agent. The present disclosure also provides the use of additional therapeutic agents for treating a disease or condition mediated by NLRP3 wherein the medicament is administered with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0206] The present disclosure also provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by NLRP3, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is prepared for administration with additional therapeutic agent. The present disclosure also provides additional therapeutic agent for use in a method of treating a disease or condition mediated by NLRP3, wherein the additional therapeutic agent is prepared for administration with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. The present disclosure also provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition mediated by NLRP3, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered with additional therapeutic agent. The present disclosure also provides additional therapeutic agents for use in a method of treating a disease or condition mediated by NLRP3, wherein the additional therapeutic agent is administered with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0207] The present disclosure also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for treating a disease or condition mediated by NLRP3, wherein the patient has previously (e.g., within 24 hours) been treated with the additional therapeutic agent. The present disclosure also provides the use of the additionaltherapeutic agent for treating a disease or condition mediated by NLRP3 inflammasome pathway, wherein the patient has previously (e.g., within 24 hours) been treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the additional therapeutic agent is a therapeutic agent useful in the treatment of inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, auto-immune diseases, auto-inflammatory diseases, or cancer, as disclosed herein.

[0209] In various embodiment, the additional therapeutic agent useful in the combination therapy is selected from famesoid X receptor (FXR) agonists; anti-steatotics; anti-fibrotics; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiation therapy and surgical procedures; urate-lowering therapies; anabolics and cartilage regenerative therapy; blockade of IL-17; complement inhibitors; Bruton's tyrosine Kinase inhibitors (BTK inhibitors); Toll Like receptor inhibitors (TLR7 / 8 inhibitors); CAR-T therapy; anti-hypertensive agents; cholesterol lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; P2-agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs (“NSAIDs”); acetylsalicylic acid drugs (ASA) including aspirin; paracetamol; regenerative therapy treatments; cystic fibrosis treatments; and atherosclerotic treatment.

[0210] The amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions will range from about 10% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0211] The compounds of Formula (I) of this disclosure or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the disclosure, in another aspect, includes a composition for coating an implantable device comprising a compound of the disclosure as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the disclosure includes an implantable device coated with a composition comprising a compound of the disclosure as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

[0212] Another aspect of the disclosure relates to inhibiting a therapeutic target activity in a biological sample or a subject, which method comprises administering to the subject, or contacting the biological sample with a compound of Formula (I) or a composition comprising the compound. The term “biological sample,” as used herein, includes, without limitation, cell cultures or extracts thereof, biopsied material obtained from a mammal or extracts thereof, and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0213] Inhibition of a therapeutic target activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of therapeutic targets in biological and pathological phenomena; and the comparative evaluation of new therapeutic target inhibitors.

[0214] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of + / - 10%, 5%, 2%, or 1%.

[0215] Reference to “between” two values or parameters herein includes (and describes) embodiments that include those two values or parameters per se. For example, description referring to “between x and y” includes description of “x” and “y” per se.ENUMERATED EMBODIMENTS

[0216] The following enumerated embodiments are representative of some aspects of the invention.Embodiment 1. A compound of Formula (I):pharmaceutically acceptable salt thereof, wherein:R1is hydrogen,R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, - s, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl group selected from the groupwherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloalkane, or heterocycloalkane are unsubstituted or substituted with one or more R12;R3is, independently, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, - CR9R10RH, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, aryl, aralkyl, heteroaryl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl group selected from the groupwherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloalkane, or heterocycloalkane are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NR12, or N+R12;R4to R11are each, independently, hydrogen, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, halogen, =0, -OR9, -SR9, -NR9R10, -C00R9, -COHR9R10, -CR9R10Rn, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, aryl, aralkyl, heteroaryl, isopropyl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl group selected from the groupwith the proviso:R2is a halogen when R1is hydrogen;R12of CR12of only onewhen R1Embodiment 2. The compound of embodiment 1, wherein the compound of Formula (I) is Formula (la):pharmaceutically acceptable salt thereof, and wherein:R1is hydrogen,R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl group selected from the groupwherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloalkane, or heterocycloalkane are unsubstituted or substituted with one or more R12;R3is, independently, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, - CR9R10RH, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, aryl, aralkyl, heteroaryl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl groupheteroaryl, cycloalkane, or heterocycloalkane are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NR12, or N+R12;R9to R11are each, independently, hydrogen, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, halogen, =0, -OR9, -SR9, -NR9R10, -C00R9, -COHR9R10, -CR9R10Rn, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, aryl, aralkyl, heteroaryl, isopropyl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl group selected from the groupwith the proviso that:R12of CR12of only onewhen R1Embodiment 3. The compound of embodiment 2, wherein R1is:Embodiment 4. The compound of embodiment 3, wherein the compound of Formula (la) is Formula (laa):(laa) or a pharmaceutically acceptable salt thereof, and wherein:R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl group selected from the groupwherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloalkane, or heterocycloalkane are unsubstituted or substituted with one or more R12;R3is, independently, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, - CR9R10RH, -CN, -N3, Ci-Ce alkyl, Ci-C6haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-C6alkoxy, aryl, aralkyl, heteroaryl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl groupheteroaryl, cycloalkane, or heterocycloalkane are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NR12, or N+R12;R9to R11are each, independently, hydrogen, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, halogen, =0, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, aryl, aralkyl, heteroaryl, isopropyl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl group selected from the groupwith the proviso:R12of CR12of only onewhenEmbodiment 5. The compound of embodiment 4, wherein T, U, V, W, and X are CR12.Embodiment 6. The compound of embodiment 5, wherein the compound of Formula(laa) is selected from the group of:or a pharmaceutically acceptable salt or stereoisomer thereof.Embodiment 7. The compound of embodiment 4, wherein one of T or X is sulfur, nitrogen, NR12, or N+R12, the other of T or X is CR12, and U, V, W, and X are CR12.Embodiment 8. The compound of embodiment 7, wherein the compound of Formula(laa) is selected from the group of:or a pharmaceutically acceptable salt or stereoisomer thereof.Embodiment 9. The compound of embodiment 4, wherein at least two of T, U, V, W, and X are sulfur, nitrogen, NR12, or N+R12, the remaining of T, U, V, W, and X are CR12.Embodiment 10. The compound of embodiment 9, wherein the compound of Formula (laa) is selected from the group of:or a pharmaceutically acceptable salt or stereoisomer thereof.Embodiment 11. The compound of embodiment 2, wherein R1is:Embodiment 12. The compound of embodiment 11, wherein the compound of Formula(la) is Formula (lab):(lab), or a pharmaceutically acceptable salt thereof, and wherein:R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl group selected from the groupwherein the Ci-Ce alkyl, the aryl, theheteroaryl, cycloalkane, or heterocycloalkane are unsubstituted or substituted with one or more R12;R3is, independently, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10RH, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, aryl, aralkyl, heteroaryl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl groupheteroaryl, cycloalkane, or heterocycloalkane are unsubstituted or substituted with one or more R12;T, U, V, and W are each, independently, CH, CR12, sulfur, nitrogen, NR12, or N+R12;R9to R11are each, independently, hydrogen, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, halogen, =0, -OR9, -SR9, -NR9R10, -C00R9, -COHR9R10, -CR9R10Rn, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, aryl, aralkyl, heteroaryl, isopropyl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl group selected from the groupEmbodiment 13. The compound of embodiment 11, wherein the compound of Formula (lab) is selected from the group of:or a pharmaceutically acceptable salt or stereoisomer thereof.Embodiment 14. The compound of embodiment 2, wherein R1is hydrogen.Embodiment 15. The compound of embodiment 14, wherein the compound of Formula(la) is Formula (lac):(lac), or a pharmaceutically acceptable salt thereof, wherein:R2is halogen;R3is, independently, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, aryl, aralkyl, heteroaryl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl groupheteroaryl, cycloalkane, or heterocycloalkane are unsubstituted or substituted with one or more R12;R9to R11are each, independently, hydrogen, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, halogen, =0, -OR9, -SR9, -NR9R10, -C00R9, -COHR9R10, -CR9R10Rn, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6alkoxy, aryl, aralkyl, heteroaryl, isopropyl, cycloalkane, heterocycloalkane, or a hetero(aryl)alkyl group selected from the groupEmbodiment 16. The compound of embodiment 15, wherein the compound of FormulaEmbodiment 17. A pharmaceutical composition comprising the compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.Embodiment 18. A method of treating, ameliorating, or preventing an NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome-mediated condition or disease, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1 to 16.I l lEmbodiment 19. The method of embodiment 18, wherein the condition or disease is selected from the group of inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.Embodiment 20. A method of treating, ameliorating, or preventing a tumor necrosis factor alpha (TNF-a)-mediated condition or disease, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1 to 16.Embodiment 21. The method of embodiment 20, wherein the condition or disease is selected from the group of inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.Embodiment 22. A method of treating, ameliorating, or preventing an NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome-mediated condition or disease, comprising administering a therapeutically effective amount of a pharmaceutical composition according to any one of embodiment 17.Embodiment 23. The method of embodiment 22, wherein the condition or disease is selected from the group of cardiovascular condition or disease, an endocrine condition or disease, a neurological condition or disease, a gastrointestinal condition or disease, or a combination thereof.Embodiment 24. A method of treating, ameliorating, or preventing tumor necrosis factor alpha (TNF-a)-mediated condition or disease, comprising administering a therapeutically effective amount of a pharmaceutical composition according to any one of embodiment 17.Embodiment 25. The method of embodiment 24, wherein the condition or disease is selected from the group of cardiovascular condition or disease, an endocrine condition or disease, a neurological condition or disease, a gastrointestinal condition or disease, or a combination thereof.Embodiment 26. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in a method of treating, ameliorating, or preventing an NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome-mediated condition or disease.Embodiment 27. The pharmaceutical composition of embodiment 26, wherein the condition or disease is selected from the group of inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.Embodiment 28. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in a method of treating, ameliorating, or preventing a tumor necrosis factor alpha (TNF-a)- mediated condition or disease.Embodiment 29. The pharmaceutical composition of embodiment 28, wherein the condition or disease is selected from the group of inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.Embodiment 30. Use of a compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a medicament for use in treating, ameliorating, or preventing an NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome-mediated condition or disease.Embodiment 31. The use of embodiment 30, wherein the condition or disease is selected from the group of inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.Embodiment 32. Use of a compound of any one of embodiments 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a medicament for use in treating, ameliorating, or preventing a tumor necrosis factor alpha (TNF-a)-mediated condition or disease.Embodiment 33. The use of embodiment 32, wherein the condition or disease is selected from the group of inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.Embodiment 34. A method of treating, ameliorating, or preventing an NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome-mediated condition or disease, comprising administering an inhibitor of the C-terminal domain of heat shock protein 90 (hsp90).Embodiment 35. The method of embodiment 34, wherein the condition or disease is selected from the group of inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.Embodiment 36. A method of treating, ameliorating, or preventing a tumor necrosis factor alpha (TNF-a)-mediated condition or disease, comprising administering an inhibitor of the C- terminal domain of heat shock protein 90 (hsp90).Embodiment 37. The method of embodiment 36, wherein the condition or disease is selected from the group of inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.EXAMPLES

[0217] The presently disclosed subject matter will be better understood by reference to the following examples, which are provided as exemplary embodiments of the disclosure, and not by way of limitation.

[0218] Compounds of the present disclosure may be prepared by methods known in the art of organic synthesis. In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

[0219] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers.

[0220] The chemical names were generated using ChemBioDraw Ultra vl4 from CambridgeSoft.

[0221] Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

[0222] LC-MS: System: Waters Acquity UPLC with Waters SQ detector. Column: Acquity HSS T3 1.8 pm 2.1*50 mm, column temperature: 60° C. Gradient: from 5 to 98% B in 1.4 min, A=water+0.05% formic acid+3.75 mM ammonium acetate, B=acetonitrile+0.04% formic acid, flow: 1.0 mL / min. Mass spectrometry results are reported as the ratio of mass over charge.

[0223] HPLC: System: Shimadzu LH-40 Auto sampler with PDA detector Column: X- Bridge PREP C18 (19*250)mm, 10pm Mobile phase: Acetonitrile: 5mM Ammonium Bicarbonate in H2O

[0224] NMR: Measurements were performed on a Bruker Ultrashield™ 400 (400 MHz) or Bruker Ascend™ (400 MHz) or Bruker cryo system (600 MHz) spectrometer using or not tetramethylsilane (TMS) as an internal standard. Chemical shifts (5) are reported in ppm downfield from TMS, spectra splitting pattern are designated as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), septet (sept), multiplet, unresolved or overlapping signals (m), broad signal (bf). Deuterated solvents are given in parentheses and have chemical shifts of dimethyl sulfoxide (5 2.50 ppm), methanol (5 3.31 ppm), chloroform (5 7.26 ppm), or other solvents as indicated in NMR spectral data.Synthesis of Exemplary Embodiments of the Compound of Formula (I)

[0225] Synthesis of Compound 1

[0226] Step-1: Synthesis of (4S,4aR,5aR,6aS,6bS,9R,9aS,llaS,HbR)-4-hydroxy-9- ((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-iodo- 9a,llb-dimethyl-5a,6,6a,6b,7,8,9,9a,10,ll,Ha,llb- dodecahydrocyclopenta[l,2]phenanthro[8a,9-b]oxiren-l(4H)-one:To the stirred solution of withaferin-A (3 g, 1 eq; 6.37 mmol) in di chloromethane (30 mL) was added N, -di methyl pyridin-4-amine (1.17 g, 1.5 eq., 9.56 mmol) at inert atmosphere. After 10 minutes, iodine (1.94 g, 1.2 eq., 7.65 mmol) was added to the reaction mixture and the resultant reaction mixture was allowed to stir at room temperature for 3 hours. The reactionmixture was quenched by saturated aqueous sodium thiosulfate solution (50 mL). The aqueous layer was extracted with dichloromethane (3 x 45 mL). Collected organics, dried over sodium sulphate and concentrated under reduced pressure to obtain crude. The crude was purified by combi-flash chromatography (using 5% methanol in dichloromethane) afforded (45, 4a / , 5a / ?, 6a5, 6b5, 9R, 9aS, l la5, l lb / ?)-4-hydroxy-9-((5)-l-(( / ?)-5-(hydroxymethyl)-4-methyl-6-oxo- 3,6-dihydro-2H-pyran-2-yl)ethyl)-2-iodo-9a,l lb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1,2] phenanthrol [8a, 9-b]oxiren-l(4H)-one (2.1 g, 55%) as a white solid.Analytical data:LCMS: 90.55% (m / z: 595.18, [M-H]+, observed 595.18, [M+H]+, 2.29 min (4 min run).’H-NMR (400 MHz, DMSO-< / 6): d 7.78 (d, J= 6.4 Hz, 1H), 5.87 (d, J = 3.6 Hz, 1H), 5.87 (d, J = 3.6 Hz, 1H), 4.58 (t, J = 5.2 Hz, 1H), 4.30-4.27 (m, 1H), 4.18-4.08 (m, 2H), 3.51-3.48 (m, 1H), 3.19 (s, 1H), 2.35-2.43 (m, 1H), 2.00-2.12 (m, 5H), 1.86-1.89 (m, 1H), 1.73-1.80 (m, 2H), 1.55-1.58 (m, 1H), 1.24-1.38 (m, 9H), 0.95-1.10 (m, 4H), 0.91 (d, J = 6.4 Hz, 3H), 0.64-0.71 (m, 4H)

[0227] Step-2: Synthesis of (45',4al?,5al?,6a5,6b5',9a5,lla5,llbl?)-4-hydroxy-9-((5)-l- ((7?)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,llb- dimethyl-2-phenyl-5a,6,6a,6b,7,8,9,9a,10,ll,lla,llb- dodecahydrocyclopenta[l,2]phenanthro[8a,9-b]oxiren-l(4H)-one:To a stirring solution of (4S,4aR,5aR,6aS,6bS,9R,9aS,l laS,l lbR)-4-hydroxy-9-((S)-l-((R)-5- (hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-iodo-9a,l Ib-dimethyl- 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10,11,1 la,l lb-dodecahydrocyclopenta[l,2]phenanthro[8a,9-b]oxiren- l(4H)-one (609 mg, 1 eq; 1.02 mmol) in 1,4 dioxane (9.74 mL) and water (2.44 mL) were added dipotassium carbonate (282 mg, 2 eq., 2.04 mmol) and trifluoro(phenyl) potassio-X6- borane (282 mg, 1.5 eq., 1.53 mmol). The resulting reaction mixture was degassed by purging with nitrogen for 30 minutes. After that, [l,l'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (149 mg, 0.2 eq., 204 pmol) was added to the above mixture and resultant mixture was heated at 85oC for 5 hours. Reaction was monitored by TLC (5% methanol in dichloromethane). After completion of the reaction, reaction mass was quenched by citric acid solution followed by extraction with dichloromethane (2 x 40 mL). Collected organics, dried over sodium sulphate and concentrated under reduced pressure to obtain crude.The crude was purified by combi-flash chromatography (5-10% methanol in dichloromethane) to furnish (4S, 4aR, 5aR, 6aS, 6bS, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l-((R)-5- (hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,l lb-dimethyl-2- phenyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 lb-dodecahydrocyclopenta[l,2] phenanthrol [8a,9-b]oxiren-l(4H)-one (20 mg, 6%) as a white solid.

[0228] Analytical data:LCMS: 99.10% (m / z: 547.45, [M+l]+, 569.45 [M+23]+, 6.12 min (10 min run).’H-NMR (400 MHz, DMSO-< / 6): 8 7.40-7.35 (m, 5H), 7.03 (d, J = 6.40 Hz, 1H), 4.45-4.33 (m, 3H), 3.92 (d, J = 6.40 Hz, 1H), 3.20 (s, 1H), 2.54-2.45 (m, 1H), 2.21 (dd, J= 2.40, 14.80 Hz, 1H), 2.03-1.94 (m, 6H), 1.67-1.45 (m, 7H), 1.43-1.26 (m, 3H), 1.22-1.05 (m, 4H), 1.02- 0.92 (m, 4H), 0.72 (s, 3H).

[0229] Synthesis of Compound 2

[0230] Step-1: Synthesis of ((45, 4a / ?, 5a / ?, 6a.S'. 6b.S. 9 / ?, 9a.S'. 11 aS. llb / ?)-2-(4- fluorophenyl)-4-hydroxy-9-((5)-l-(( / ?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro- 2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthrol [8a, 9-b]oxiren-l(4H)-one:To a stirred solution of (4S,4aR,5aR,6aS,6bS,9R,9aS,l laS,l lbR)-4-hydroxy-9-((S)-l-((R)-5- (hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-iodo-9a,l Ib-dimethyl- 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10,11,1 la,l lb-dodecahydrocyclopenta[l,2]phenanthro[8a,9-b]oxiren- l(4H)-one (450 mg, 1 eq; 754 pmol) in DME / Water (1 / 1) (90 mL) were added 2-(4- fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (335 mg, 2 eq., 1.51 mmol) and disodium carbonate (160 mg, 2 eq., 1.51 mmol) The resultant mixture was degassed using nitrogen for 15 minutes. After that, 10% palladium on carbon (0.1 g, 0.12 eq., 94 pmol) was added to the above mixture and continued stirring for 16 hours at room temperature. Aftercompletion of the reaction (monitored by TLC: 5% methanol in di chloromethane), reaction mixture was passed through hy-flow celite and obtained filtrate was extracted with dichloromethane (3 x 25 mL). Collected organics, dried over sodium sulfate and concentrated under reduced pressure to obtain crude. Crude was further purified using preparative HPLC (using AA Method) to furnish ((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-2-(4- fluorophenyl)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H- pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 11b- dodecahydrocyclopenta[l,2] phenanthrol [8a, 9-b]oxiren-l(4H)-one (239 mg, 56%) as a white solid.

[0231] Analytical data:LCMS: 99.44% (m / z: 565.40, [M+l]+, 587.40 [M+23]+, 6.16 min (10 min run).’H-NMR (400 MHz, DMSO-< / 6): 8 7.36-7.33 (m, 2H), 7.28-7.22 (m, 3H), 5.69 (d, J = 3.60 Hz, 1H), 4.57 (t, J = 5.60 Hz, 1H), 4.30-4.26 (m, 1H), 4.18-4.08 (m, 2H), 3.70 (dd, J= 3.60, 6.60 Hz, 1H), 3.16 (s, 1H), 2.43-2.35 (m, 1H), 2.09 (dd, = 2.40, 18.40 Hz, 1H), 2.00-2.03 (m, 4H), 1.90-1.93 (m, 1H), 1.84-1.56 (m, 3H), 1.38-1.24 (m, 8H), 1.17-1.05 (m, 3H), 1.00-0.84 (m, 5H), 0.67 (s, 3H).

[0232] Synthesis of Compound 3

[0233] Step-1: Synthesis of (45, 4al?, 5aR, 6aS, 6b5. 9R, 9aS, 1 la5. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-2-(4- methoxyphenyl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthrol [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (15, 2R, 6S, 7R, 9R, 115, 125, 157?, 165)-6-hydroxy-15-[(15)-l-[(27?)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl] ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (250 mg, 1 eq; 419 pmol)in dimethoxyethane and water (1 : 1 ratio; 5 mL) were added (4-methoxyphenyl) boronic acid (127 mg, 2 eq., 838 pmol), and disodium carbonate (88.8 mg, 2 eq., 838 pmol) and then the reaction mixture was purged with N2 gas for 15 minutes. After that, 10% palladium on carbon (70 mg) was added to the above mixture and reaction is again purged with N2 gas for 5 minutes. The reaction mixture was further stirred overnight at room temperature. The reaction mixture further passed through the celite bed and then the filtrate was washed with dichloromethane (30 mL). The collected organics was dried over sodium sulphate and concentrated under reduced pressure to obtain the crude. The crude was purified by preparative-HPLC (AA method) to afford (15, 2R, 6S, 7R, 9R, 115, 125, 15A, 165)-6-hydroxy-15-[(15)-l-[(2A)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl] ethyl] -4-(4-methoxyphenyl)- 2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (62 mg, 26%) as a white solid.

[0234] Analytical details:LCMS: 99.55% (m / z: 577.40, [M+l]+, 6.07 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 7.25 (d, J= 8.80 Hz, 2H), 7.16 (d, J= 6.80 Hz, 1H), 6.96 (d, J = 8.80 Hz, 2H), 5.62 (d, J= 3.60 Hz, 1H), 4.57 (t, J = 5.20 Hz, 1H), 4.30-4.27 (m, 1H), 4.18-4.08 (m, 2H), 3.77 (s, 3H), 3.68 (dd, J = 3.60, 6.60 Hz, 1H), 3.15 (s, 1H), 2.43-2.35 (m, 1H), 2.12-2.03 (m, 2H), 2.00 (s, 3H), 1.91-1.94 (m, 1H), 1.83-1.56 (m, 3H), 1.40-1.20 (m, 8H), 1.22-1.00 (m, 3H), 0.93-0.96 (m, 4H), 0.84 (m, 1H), 0.67 (s, 3H).

[0235] Synthesis of Compound 4

[0236] Step-1: Synthesis of (45, 4al?, 5al?, 6a5. 6b5. 91?, 9a5. 1 la5. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl) ethyl)-9a,llb-dimethyl-2-(2-(trifluoromethyl) phenyl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthrol [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of 2-iodo withaferin-A (450 mg, 754 pmol) in DME-Water (7.89 mL) were added [2-(trifluoromethyl) phenyl] boronic acid (287 mg, 2 eq., 1.51 mmol), disodium carbonate (160 mg, 2 eq., 1.51 mmol). Resultant reaction mixture was degassed for 15 minutes. After that, 10% palladium on carbon (0.1 g, 940 pmol) was heated at 50oC for 16 hours. Progress of reaction was monitored by TLC (5% methanol in dichloromethane) which showed formation of new spot. After completion of the reaction, the reaction mixture was passed through hy-flow celite and then the filtrate was extracted with dichloromethane (3 x 25 mL). The collected organics was dried over sodium sulphate and then concentrated under reduced pressure to obtain crude. The crude was purified by preparative HPLC (AA method) to furnish (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((5)-l-((7?)-5-(hydroxymethyl)-4- methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl) ethyl)-9a, 1 lb-dimethyl-2-(2-(trifluoromethyl) phenyl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 lb-dodecahydrocyclopenta[l, 2] phenanthrol [8a, 9-b]oxiren-l(4H)-one (15 mg, 3%) as a white solid.

[0237] Analytical data:LCMS: 98.45% (m / z: 615.45, [M+l]+, 637.40 [M+23]+, 6.37 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 7.76 (d, J= 7.60 Hz, 1H), 7.70 (t, J= 7.60 Hz, 1H), 7.59 (t, J= 7.60 Hz, 1H), 7.28 (d, J= 7.20 Hz, 1H), 7.00 (d, J= 6.40 Hz, 1H), 5.79 (d, J= 4.00 Hz, 1H), 4.58 (t, J= 5.60 Hz, 1H), 4.27-4.30 (m, 1H), 4.18-4.08 (m, 2H), 3.69 (dd, J= 4.40, 6.40 Hz, 1H), 3.26 (s, 1H), 2.39-2.42 (m, 1H), 2.16-2.08 (m, 2H), 2.00 (s, 3H), 1.85-1.60 (m, 4H), 1.44-1.05 (m, 10H), 0.98-0.88 (m, 6H), 0.66 (s, 3H).

[0238] Synthesis of Compound 5

[0239] Step-1: Synthesis of (45, 4al?, 5aR, 6aS, 6b.S. 9R, 9aS, 1 la.S. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl) ethyl)-9a, llb-dimethyl-2-(pyridin-3-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta[l, 2] phenanthro[8a, 9-b]oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (1.4 g, 1 eq; 2.35 mmol) in tetrahydrofuran (14 mL) were added X1-copper(l+) iodide (44.7 mg, 0.1 eq., 235 pmol), triphenylarsane (71.9 mg, 0.1 eq., 235 pmol), and 3 -(tributyl stannyl) pyridine (1.73 g, 2 eq., 4.69 mmol). Reaction mixture was purged with continuous flow of nitrogen for 30 minutes. After that, tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (21.5 mg, 0.01 eq., 23.5 pmol) was added and gain reaction mixture was degassed using nitrogen for 5 minutes. Resultant reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction (monitored by TLC: 5% methanol in di chloromethane), reaction mixture was filtered through celite bed and filtrate was diluted by water (30 mL) followed by extraction with dichloromethane (2 x 50 mL). Collected organics, dried over sodium sulphate and then concentrated under reduced pressure to get crude.Note: The crude from different batches was mixed together and enriched by combi-flash chromatography (4-10% of methanol in di chloromethane) to obtain crude with 47 g with 93% by LCMS. This was further purified by SFC (0.1 % of NFLOH) to furnish 20.7 g of 99% pure (45, 4a / , 5aR, 6aS, 6b5, 9R, 9aS, l la5, l lbA)-4-hydroxy-9-((5)-l-((A)-5-(hydroxymethyl)-4- methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a,l lb-dimethyl-2-(pyridin-3-yl) 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthrol [8a, 9-b] oxiren- l(4H)-one (20.7 g) as a white solid.

[0240] Analytical data:LCMS: 99.47% (m / z: 548.45, [M+l]+, 5.14 min (10 min run).’H-NMR (400 MHz, DMSO-< / 6): d 8.55 (d, J= 3.60 Hz, 1H), 8.50 (s, 1H), 7.73-7.70 (m, 1H), 7.46-7.43 (m, 2H), 5.78 (d, J= 3.60 Hz, 1H), 4.59 (t, J = 5.20 Hz, 1H), 4.31-4.26 (m, 1H), 4.18-4.08 (m, 1H), 3.72 (dd, J= 3.60, 6.40 Hz, 1H), 3.19 (s, 1H), 2.50-2.35 (m, 1H), 2.11-2.07 (m, 2H), 1.99 (s, 3H), 1.93-1.56 (m, 4H), 1.41-1.28 (m, 8H), 1.16-1.00 (m, 5H), 0.88-0.90 (m, 4H), 0.67 (s, 3H).13C-NMR (400 MHz, DMSO-6): 200.81, 165.32, 154.66, 149.22, 148.05, 139.54, 138.96, 134.82, 131.30, 125.44, 123.61, 77.51, 68.53, 63.31, 57.74, 55.26, 54.52, 51.05, 47.71, 42.29, 42.00, 38.40, 30.68, 29.33, 29.03, 26.51, 23.96, 20.48, 19.90, 15.43, 13.03, 11.26.

[0241] Synthesis of Compound 6

[0242] Step-1: Synthesis of (45, 4al?, 5aR, 6aS, 6b.S, 9R, 9aS, 1 la.S. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthrol [8a, 9-b]oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.4 g, 1 eq; 671 pmol) in DME / Water (1 / 1, 10 mL), were added (l-methyl-lH-pyrazol-4-yl)boronic acid (169 mg, 2 eq., 1.34 mmol) and disodium carbonate (142 mg, 2 eq., 1.34 mmol). Reaction mixture was degassed for 15 minutes suing nitrogen and then 10% palladium on carbon (101 mg) was added. Resultant reaction mixture was stirred at 50oC for 16 hours. After completion of the reaction (5% methanol in dichloromethane), reaction mixture was passed through hy-flow celite and filtrate was quenched with saturated NaHCCh (40 mL) followed by extraction from dichloromethane (3 x 50 mL). The collected organics was dried over sodium sulfate and then concentrated under reduced pressure to obtain crude. The crude was purified by prep-HPLC (using AA method) afforded (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 1 laS, 1 lbR)-4-hydroxy-9-((S)- l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,l 1b- dimethyl-2-(l-methyl-lH-pyrazol-4-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 11b- dodecahydrocyclopenta [1, 2] phenanthrol [8a, 9-b] oxiren-l(4H)-one (106 mg, 29%) as a white solid.

[0243] Analytical data:LCMS: 98.31% (m / z: 551.45, [M+l]+, 573.40 [M+23]+, 5.42 min (10 min run).’H-NMR (400 MHz, DMSO-< / 6): 8 7.88 (s, 1H), 7.69 (s, 1H), 7.11 (d, J= 6.80 Hz, 1H), 5.56 (d, J= 3.60 Hz, 1H), 4.57 (t, J= 5.60 Hz, 1H), 4.26-4.28 (m, 1H), 4.18-4.07 (m, 2H), 3.82 (s, 3H), 3.63 (dd, 7= 3.60, 6.80 Hz, lH), 3.15 (s, 1H), 2.41-2.33 (m, 1H), 2.10-1.99 (m, 5H), 1.91- 1.54 (m, 5H), 1.38-0.99 (m, 10H), 0.94-0.90 (m, 4H), 0.72-0.69 (m, 1H), 0.65 (s, 3H).

[0244] Synthesis of Compound 7

[0245] Step-1: Synthesis of (45, 4al?, 5al?, 6a5. 6b5. 91?, 9a5. 11:15. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(pyrimidin-5-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthrol [8a, 9-b]oxiren-l(4H)-one:To a stirred solution of (15, 27?, 65, 77?, 97?, 115, 125, 165)-6-hydroxy-15-[(15)-l-[(27?)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (1 g, 1 eq; 1.68 mmol) in 1,4- dioxane: water (12 mL, 5: 1) were added (pyrimidin-5-yl)boronic acid (312 mg, 1.5 eq., 2.51 mmol) and caesium carbonate (1.64 g, 3 eq., 5.03 mmol). The reaction mixture was degassed by N2 for 30 minutes and after that palladium (2+) bis(triphenylphosphane) dichloride (118 mg, 0.1 eq., 168 pmol) was added. The reaction mixture was allowed to stir for 16 hours at 90°C. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL) and then extracted with dichloromethane (3 x 50 mL). Collected organics, dried with Na2SO4 and concentrated under reduced pressure to obtain crude. The crude residue was purified by combi-flash chromatography (using 10% methanol in dichloromethane) to furnish crude. Crude was purified by preparative HPLC (Method: AA) afforded (45, 4a7?, 5a7?, 6a5, 6b5, 97?, 9a5, l la5, l lb7?)-4-hydroxy-9-((5)-l-((7?)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl) ethyl)-9a, 1 lb-dimethyl-2-(pyrimidin-5-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthrol [8a,9-b] oxiren-l(4H)-one (119 mg; 13%) as a white solid.

[0246] Analytical data:LCMS: 95.51% (m / z: 549.40, [M+l]+, 5.61 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 9.18 (s, 1H), 8.77 (s, 2H), 7.61 (d, J= 6.80 Hz, 1H), 4.31- 4.26 (m, 1H), 4.17-4.04 (m, 2H), 3.74 (d, J = 6.80 Hz, 1H), 3.21 (s, 1H), 2.39-2.42 (m, 1H), 2.10-2.06 (m, 2H), 2.00 (s, 3H), 1.88-1.91 (m, 1H), 1.83-1.56 (m, 3H), 1.42-1.22 (m, 9H), 1.20- 1.06 (m, 3H), 1.05-0.95 (m, 2H), 0.91-0.93 (m, 4H), 0.66 (s, 3H).13C-NMR (400 MHz, DMSO-6): d 200.45, 165.31, 157.80, 155.37, 154.65, 154.65, 135.85, 129.26, 125.44, 77.51, 68.37, 63.10, 57.94, 55.12, 54.51, 51.11, 47.71, 42.23, 41.98, 38.33, 30.60, 29.36, 29.03, 26.49, 23.96, 20.50, 19.89, 15.60, 13.05, 11.26.

[0247] Synthesis of Compound 8

[0248] Step-1: Synthesis of (45, 4al?, 5al?, 6a.S'. 6b.S. 91?, 9a.S'. 1 la.S. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(pyridin-4-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthrol [8a, 9-b]oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (1.2 g, 1 eq; 2.01 mmol) in tetrahydrofuran (24 mL) were added X1-copper(l+) iodide (38.3 mg, 0.1 eq., 201 pmol), triphenylarsane (61.6 mg, 0.1 eq., 201 pmol), and 4-(tributylstannyl) pyridine (1.48 g, 2 eq., 4.02 mmol). Resultant reaction mixture is degassed using nitrogen gas for 30 minutes. After that, tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (92.1 mg, 0.05 eq., 101 pmol) was added to the above reaction mixture and allowed to stir at 80°C for 16 hours. Aftercompletion of the reaction (reaction was monitored by TLC), mixture was filtered by using celite bed and filtrate was extracted by di chloromethane (3 x 30 mL). Collected organics, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude. Crude was purified by using preparative-HPLC (ABC method) afforded. (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-2-(pyridin-4-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthrol [8a, 9-b] oxiren-l(4H)-one (112 mg, 10%) as a white solid.Analytical data:LCMS: 93.94% (m / z: 548.35, [M+l]+, 5.10 min (10 min run).’H-NMR (400 MHz, DMSO-< / 6): d 8.61 (s, 1H), 7.55 (d, J = 6.80 Hz, 1H), 7.33 (d, J = 4.40 Hz, 2H), 5.83 (d, J= 3.60 Hz, 1H), 4.59 (t, J= 5.60 Hz, 1H), 4.29-4.27 (m, 1H), 4.17-4.08 (m, 2H), 3.74 (dd, 7= 3.60, 6.80 Hz, 1H), 3.18 (s, 1H), 2.43-2.32 (m, 1H), 2.09 (dd, J= 2.40, 18.20 Hz, 1H), 1.99-2.03 (m, 4H), 1.90-1.93 (m, 1H), 1.81-1.56 (m, 3H), 1.45-1.23 (m, 8H), 1.16- 0.97 (m, 5H), 0.92 (d, J= 6.40 Hz, 3H), 0.84-0.86 (m, 1H), 0.67 (s, 3H).13C-NMR (400 MHz, DMSO-< / 6): 200.34, 165.29, 154.64, 150.05, 150.05, 140.74, 139.38, 125.43, 77.49, 68.42, 63.25, 57.60, 55.26, 54.50, 51.02, 47.74, 42.20, 41.98, 30.63, 29.26, 29.01, 26.50, 23.93, 20.45, 19.88, 15.30, 13.01, 11.24

[0249] Synthesis of Compound 9

[0250] Step-1: Synthesis of (45, 4a / ?, 5a / ?, 6a.S'. 6b.S. 9 / ?, 9a.S'. 11 aS. llb / ?)-2-(3- fluoropyridin-4-yl)-4-hydroxy-9-((5)-l-(( / ?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.5 g, 1 eq; 838 pmol) in water (0.5 mL) and 1,4-dioxane (5 mL) were added (3-fluoropyridin-4-yl)boronic acid (177 mg, 1.5 eq., 1.26 mmol) and dicaesium(l+)carbonate (819 mg, 3 eq., 2.51 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 35 minutes and then palladium(2+)bis (triphenylphosphane) dichloride (58.8 mg, 0.1 eq., 83.8 pmol) was added to the reaction mixture. The reaction mixture was again purged with nitrogen gas for 5 minutes. The reaction vessel was sealed and stirred at 85°C for 16 hours. After completion of the reaction (monitored by TLC: 5% methanol in di chloromethane), the reaction mixture was quenched with water (10 mL) and then extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulphate and then concentrated under reduced pressure to get crude. The crude residue was purified by combi-flash chromatography (using 5% methanol in dichloromethane) followed by preparative-HPLC (TFA method) purification (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-2-(3-fluoropyridin-4-yl)-4-hydroxy-9-((S)-l- ((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 11b- dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b]oxiren-l(4H)-one (16 mg, 3%) as a white solid.

[0251] Analytical data:LCMS: 98.88% (m / z: 566.35, [M+l]+, 5.78 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.59 (d, J= 2.00 Hz, 1H), 8.49 (d, J= 4.80 Hz, 1H), 7.48 (d, J = 6.80 Hz, 1H), 7.43-7.40 (m, 1H), 5.88 (d, J = 3.60 Hz, 1H), 4.57 (t, J = 5.60 Hz, 1H), 4.31-4.28 (m, 1H), 4.19-4.08 (m, 2H), 3.74 (dd, J= 4.00, 6.60 Hz, 1H), 3.21 (s, 1H), 2.50-2.37 (m, 1H), 2.15-2.06 (m, 2H), 2.00 (s, 3H), 1.90-1.94 (m, 1H), 1.84-1.58 (m, 3H), 1.43-1.46 (m, 1H), 1.38-1.18 (m, 7H), 1.16-0.90 (m, 8H), 0.60 (s, 3H).

[0252] Synthesis of Compound 10

[0253] Step-1: Synthesis of (45, 4al?, 5aR, 6aS, 6b.S. 9R, 9aS, 1 la.S. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(thiazol-5-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a ,9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl] ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.5 g, 1 eq; 838 pmol) in 1, 4-dioxane (5 mL) and water (1 mL) were added 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)- 1,3 -thiazole (265 mg, 1.5 eq., 1.26 mmol) and dipotassium carbonate (348 mg, 3 eq., 2.51 mmol) at room temperature. The reaction mixture was purged with nitrogen gas for 35 minutes and then [l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (68.6 mg, 0.1 eq., 83.8 pmol) was added to it The reaction mixture was again purged with nitrogen gas for 5 minutes. The reaction vessel was sealed, and the reaction was stirred at 100°C for 16 hours. After completion of the reaction (monitoring by LCMS), reaction mixture was passed through celite, and filtrate was concentrated to get crude. The crude was enriched by combi-flash chromatography (5% methanol in dichloromethane) followed by purification by preparative HPLC (ABC method) 4S,4aR,5aR,6aS,6bS,9R,9aS,l laS,l lbR)-4-hydroxy-9-((S)-l-((R)-5- (hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,l lb-dimethyl-2- (thiazol-5-yl)-5a,6,6a,6b,7,8,9,9a,10,l l,l la,l lb- dodecahydrocyclopenta[l,2]phenanthro[8a,9-b]oxiren-l(4H)-on (18 mg, 4%) as a white solid.

[0254] Analytical data:LCMS: 95.19% (m / z: 554.30, [M+l]+, 5.82 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 9.08 (s, 1H), 8.20 (s, 1H), 7.48 (d, J= 6.40 Hz, 1H), 5.80 (s, 1H), 4.29-4.25 (m, 1H), 4.17-4.08 (m, 2H), 3.72 (d, J= 6.8 Hz, 1H), 3.20 (s, 1H), 2.40-2.33 (m, 1H), 2.09-2.02 (m, 2H), 1.99 (s, 3H), 1.89-1.54 (m, 4H), 1.35-1.21 (m, 8H), 1.11-0.89 (m, 8H), 0.76-0.72 (m, 1H), 0.65 (s, 3H).

[0255] Synthesis of Compound 11

[0256] Step-1: Synthesis of (45, 4al?, 5al?, 6a.S'. 6b.S. 91?, 9a.S'. 1 la.S. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(pyrazin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To the stirred solution of (IS, 2R, 6S,7R, 9R, I IS, 12S, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl] ethyl]-4-iodo-2, 16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.4 g, 1 eq; 671 pmol) in N, N- dimethyl formamide (4 mL) were added to diiodocopper (31.9 mg, 0.15 eq., 101 pmol) and 2- (tributylstannyl) pyrazine (248 mg, 671 pmol). The reaction mixture was degassed by N2 for 30 minutes and then after, l,l'-Bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane (27.4 mg, 0.05 eq., 33.5 pmol) was added. The reaction mixture was allowed to stir for 4 hours at 60°C. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water (15 mL) and then extracted with di chloromethane (3 x 55 mL). Collected organics, dried over Na2SO4 and concentrated under reduced pressure to obtain crude. The crude residue was purified by combi-flash chromatography (eluted at 10% methanol in dichloromethane) to obtain crude. Crude was further purified by preparative HPLC (Method: AA) afforded 4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l- ((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 11b- dimethyl-2-(pyrazin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (111 mg; 30%) as a white solid.

[0257] Analytical data:LCMS: 99.41% (m / z: 549.40, [M+l]+, 5.80 min (10 min run).’H-NMR (400 MHz, DMSO-< / 6): 3 8.70-8.69 (m, 1H), 8.65 (d, J = 1.20 Hz, 1H), 8.63 (d, J = 2.40 Hz, 1H), 7.77 (d, J = 6.80 Hz, 1H), 5.85 (d, J = 3.60 Hz, 1H), 4.58 (t, J = 5.20 Hz, 1H), 4.31-4.26 (m, 1H), 4.18-4.08 (m, 2H), 3.79 (dd, J = 3.60, 6.80 Hz, 1H), 3.18 (s, 1H), 2.42-2.33 (m, 1H), 2.09 (dd, J= 3.20, 18.20 Hz, 1H), 2.02-2.03 (m, 1H), 1.99 (s, 3H), 1.92 (s, 1H), 1.83- 1.70 (m, 2H), 1.60-1.39 (m, 2H), 1.37-1.23 (m, 7H), 1.17-1.03 (m, 3H), 0.99-0.92 (m, 5H), 0.67 (s, 3H).

[0258] Synthesis of Compound 12

[0259] Step-1: Synthesis of 3-((45. 4a / ?, 5a / ?, 6a5. 6b.S. 9 / ?, 9a5. 11 aS. llb / ?)-4- hydroxy-9-((5)-l-(( / ?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-9a, llb-dimethyl-l-oxo-1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-2-yl) benzonitrileTo a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.5 g, 1 eq; 838 pmol) in 1,4-dioxane (1 mL, 11.7 mmol) were added 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzonitrile (192 mg, 838 pmol) and sodium hydrogen carbonate (42.2 mg, 3 eq., 503 pmol). The resultant solution was purged with nitrogen for 40 minutes. After that, [1, 1 '-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane (27.4 mg, 0.2 eq., 33.5 pmol) was added and again it was purged with nitrogen for 5 minutes. The reaction mixture was warmed to 60°C and was allowed to stir for 16 hours. After completion of the reaction, thereaction mixture was filtered through celite, and filtrate was extracted with di chloromethane (3 x 40 mL). Collected organics, dried over sodium sulphate and then concentrated under reduced pressure to obtain crude. The crude residue was enriched by Combi-flash (eluting at 60% of ethyl acetate in n-heptane) and then purified preparative HPLC (ABC method) afforded and was afforded 3-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l-((R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-1-oxo- 1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-tetradecahydrocyclopenta [1, 2] phenanthro [8a ,9-b] oxiren-2-yl) benzonitrile (18 mg, 4%) as a white solid.

[0260] Analytical data:LCMS: 95.30% (m / z: 572.45, [M+l]+, 594.35, [M+23], 6.33 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 7.84 (d, J= 6.00 Hz, 1H), 7.79 (s, 1H), 7.61-7.63 (m, 2H), 7.46 (d, J= 6.40 Hz, 1H), 5.72-5.79 (m, 1H), 4.59-4.56 (m, 1H), 4.27-4.30 (m, 1H), 4.17-4.08 (m, 2H), 3.72 (d, J= 5.60 Hz, 1H), 3.18 (s, 1H), 2.43-2.33 (m, 1H), 2.06-2.10 (m, 2H), 1.99 (s, 3H), 1.90-1.93 (m, 1H), 1.90-1.85 (m, 3H), 1.65-1.47 (m, 1H), 1.38-1.20 (m, 7H), 1.18-0.87 (m, 8H), 0.66 (s, 3H).

[0261] Synthesis of Compound 13

[0262] Step-1: Synthesis of (45, 4al?, 5al?, 6a.S'. 6b.S. 91?, 9a.S'. IlaA, llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (5 g, 8.38 mmol) in dimethylformamide (50 mL, 646 mmol) were added diiodocopper (399 mg, 0.15 eq., 1.26mmol), 2-(tributylstannyl) pyridine (6.17 g, 2 eq., 16.8 mmol) under inert atmosphere at room temperature. The above reaction mixture was purged with nitrogen for 40 minutes and then, l,l'-Bis (diphenylphosphino) ferrocene]palladium (II) Dichloride Dichloromethane adduct (342 mg, 0.05 eq., 419 pmol) was added to the reaction mixture. After that, reaction mixture was purged for another 5 minutes with nitrogen. The reaction mixture was heated at 65 °C for 4 hours. After completion of the reaction, (monitored by TLC: 5% methanol in dichloromethane), reaction mixture was quenched with ice-cold (60 mL) water and extracted with di chloromethane (3 X 15 mL). The combined organics was dried over sodium sulphate and evaporated under reduced pressure to obtain crude. Crude was enriched by combi-flash chromatography (eluted at: 4-10% methanol in di chloromethane) followed by purification using preparative HPLC afforded 4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, 1 lbR)-4-hydroxy-9- ((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl) ethyl)-9a, 11b- dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (1.1 g, 24%) as a white solid.

[0263] Analytical data:LCMS: 96.60% (m / z: 548.60, [M+l]+, 546.7 [M-l]+, 5.36 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.60 (d, J= 4.00 Hz, 1H), 7.83 (t, J= 7.60 Hz, 1H), 7.68 (d, J = 6.80 Hz, 1H), 7.39-7.34 (m, 2H), 5.75 (d, J = 3.20 Hz, 1H), 4.59 (t, J = 5.20 Hz, 1H), 4.42-4.32 (m, 1H), 4.30-4.07 (m, 2H), 3.77-3.74 (m, lH), 3.16 (s, 1H), 2.42-2.33 (m, 1H), 2.11- 2.02 (m, 2H), 1.99 (s, 3H), 1.90-1.93 (m, 1H), 1.80-1.90 (m, 1H), 1.70-1.72 (m, 1H), 1.55-1.57 (m, 1H), 1.38-1.41 (m, 2H), 1.28-1.35 (m, 4H), 1.22-1.25 (m, 2H), 1.05-1.15 (m, 3H), 0.86- 0.98 (m, 5H), 0.66 (s, 3H).13C-NMR (400 MHz, DMSO-6): 200.56, 165.29, 154.62, 152.47, 149.57, 141.12, 139.79, 136.90, 125.43, 123.38, 122.14, 77.50, 68.50, 63.50, 57.54, 55.30, 54.51, 51.01, 47.89, 42.08, 30.75, 29.22, 29.01, 26.49, 23.94, 20.47, 19.86, 15.10, 13.00, 11.23.

[0264] Synthesis of Compound 14

[0265] Step-1: Synthesis of (45, 4al?, 5aR, 6aS, 6b.S. 9R, 9aS, 1 la.S. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(pyridazin-4-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (1 g, 1 eq; 1.68 mmol) in N, N’- dimethylformamide (10 mL, 129 mmol) were added 4-(tributylstannyl) pyridazine (743 mg, 1.2 eq., 2.01 mmol) and diiodocopper (79.8 mg, 0.15 eq., 251 pmol). The reaction mixture was purged with nitrogen gas for 35 minutes and then l,l'-Bis (diphenylphosphino) ferrocene] palladium (II) Dichloride dichloromethane adduct (68.4 mg, 0.05 eq., 83.8 pmol) was added to it . The reaction mixture was again purged with nitrogen gas for 5 minutes. The reaction vessel was sealed and stirred at 60°C for 16 hours. After completion of reaction (monitored by LCMS), it was quenched by adding sodium chloride solution (30 mL) followed by extraction with ethyl acetate (3 x 20 mL). Collected organics, dried over sodium sulfate and concentrated under reduced pressure to obtain crude. Crude was purified by preparative HPLC (ABC method) to get (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-4- (pyridazin-4-yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (75 mg, 2%) as a white solid.

[0266] Analytical data:LCMS: 95.11% (m / z: 549.40, [M+l]+, 571.40, [M+23]+, 5.45 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 9.26 (dd, J = 1.20, 5.60 Hz, 1H), 9.23 (dd, J= 1.20, 2.40 Hz, 1H), 7.78 (d, J = 6.80 Hz, 1H), 7.65 (dd, J= 2.40, 5.60 Hz, 1H), 5.93 (d, J= 4.00 Hz, 1H),4.59 (t, J= 5.60 Hz, 1H), 4.31-4.26 (m, 1H), 4.18-4.07 (m, 2H), 3.76 (dd, J = 3.60, 6.60 Hz, 1H), 3.20 (s, 1H), 2.42-2.32 (m, 1H), 2.11-2.02 (m, 2H), 1.99 (s, 3H), 1.89-1.92 (m, 1H), 1.83- 1.71 (m, 2H), 1.57-1.53 (m, 1H), 1.39-1.25 (m, 8H), 1.16-0.96 (m, 4H), 0.87-0.89 (m, 4H), 0.66 (s, 3H).

[0267] Synthesis of Compound 15

[0268] Step-1: Synthesis of (45, 4al?, 5al?, 6a.S'. 6b.S. 91?, 9a.S'. 1 la.S. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(6-methylpyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.5 g, 1 eq; 838 pmol) N, N’- dimethylformamide (2.62 mL) was added 2-methyl-6- (tributyl stannyl) pyridine (961 mg, 3 eq., 2.51 mmol) and diiodocopper (39.9 mg, 0.15 eq., 126 pmol).The reaction mixture was purged with nitrogen for 35 minutes and then l,l'-Bis (diphenylphosphino) ferrocene]palladium(II) Dichloride dichloromethane Adduct (34.2 mg, 0.05 eq., 41.9 pmol) was added to it . The reaction mixture was again purged with nitrogen for 5 minutes. The reaction vessel was sealed and stirred at 60°C for 16 hours. After completion of the reaction (monitored by LCMS), it was quenched with sodium chloride solution (30 mL). Further it was extracted using ethyl acetate (2 x 40 mL). Collected organics, dried over by sodium sulfate and then concentrated under reduced pressure to obtain crude. Crude was purified by preparative HPLC (ABC method) to obtain (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, 1 lbR)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 11b- dimethyl-2-(6-methylpyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (89 mg, 19%) as a white solid.

[0269] Analytical data:LCMS: 98.56% (m / z: 562.6, [M+l]+, 560.6, [M-l]+, 5.21 min (10 min run).’H-NMR (400 MHz, DMSO-< / 6): 8 7.71 (t, J= 8.00 Hz, 1H), 7.64 (d, J= 6.80 Hz, 1H), 7.21 (t, J = 8.40 Hz, 2H), 5.71 (d, J= 3.60 Hz, 1H), 4.59 (t, J= 5.20 Hz, 1H), 4.31-4.26 (m, 1H), 3.75 (dd, J = 3.60, 6.80 Hz, 1H), 3.15 (s, 1H), 2.47 (s, 3H), 2.44-2.31 (m, 1H), 2.11-2.02 (m, 2H), 1.99 (s, 3H), 1.90-1.93 (m, 1H), 1.83-1.67 (m, 2H), 1.57-1.33 (m, 4H), 1.30-1.21 (m, 6H), 1.15-1.04 (m, 4H), 0.97-0.84 (m, 5H), 0.66 (s, 3H).13C-NMR (400 MHz, DMSO-< / 6): 200.72, 165.30, 157.75, 154.65, 151.66, 141.23, 139.19, 137.11, 125.43, 122.73, 119.07, 77.51, 68.52, 63.59, 57.45, 55.34, 54.51, 51.02, 47.91, 42.06, 38.38, 30.80, 29.20, 29.01, 26.50, 24.21, 23.96, 20.49, 19.86, 14.98, 13.03, 11.23.

[0270] Synthesis of Compound 16

[0271] Step-1: Synthesis of (45, 4a / ?, 5a / ?, 6a.S'. 6b.S. 9 / ?, 9a.S'. 11 aS. llb / ?)-2-(5- fluoropyridin-2-yl)-4-hydroxy-9-((5)-l-(( / ?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7S, 9R, 11 S, 12S, 16S)-15-[(lS)-l-[(2R)-5-{[(tert- butyldimethylsilyl) oxy] methyl }-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl] ethyl]-4-iodo- 2, 16-dimethyl-3-oxo-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-6-yl acetate (0.5 g, 1 eq; 664 pmol) in tetrahydrofuran (6 mL, 73.7 mmol) were added 5-fluoro-2-(tributylstannyl) pyridine (282 mg, 1.1 eq., 731 pmol), triphenylarsane (20.3 mg, 0.1 eq., 66.4 pmol) anddiiodocopper (21.1 mg, 0.1 eq., 66.4 pmol). The reaction mixture was purged with nitrogen gas for 35 minutes and then added tris (l,5-diphenylpenta-l,4-dien-3-one) dipalladium (30.4 mg, 0.05 eq., 33.2 pmol). The reaction mixture was again purged with nitrogen gas for 10 minutes. The reaction vessel was sealed and stirred at 85°C for 3 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with 10% citric acid solution (20 mL). Reaction mass was extracted with ethyl acetate (3 x 45 mL). The collected organics was dried over Na2SO4 and concentrated under reduced pressure to obtain crude. The crude was purified by preparative HPLC (ABC method) afforded (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 1 laS, 1 lbR)-2-(5-fluoropyridin-2-yl)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4- methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (100 mg, 27%) as a white solid.

[0272] Analytical data:LCMS: 99.20% (m / z: 566.6, [M+l]+, 5.63 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.61 (d, J= 2.80 Hz, 1H), 7.77 (dt, J= 2.80, 12.67 Hz, 1H), 7.64 (d, J= 6.40 Hz, 1H), 7.47 (dd, = 4.80, 8.80 Hz, 1H), 5.76 (d, J= 3.60 Hz, 1H), 4.59 (t, J= 5.60 Hz, 1H), 4.27-4.30 (m, 1H), 4.18-4.08 (m, 2H), 3.75 (dd, J= 3.60, 6.60 Hz, 1H), 3.16 (s, 1H), 2.50-2.33 (m, 1H), 2.11-2.02 (m, 2H), 1.99 (s, 3H), 1.93-1.52 (m, 5H), 1.45-1.22 (m, 7H), 1.15-1.04 (m, 3H), 0.98-0.82 (m, 5H), 0.66 (s, 3H).13C-NMR (400 MHz, DMSO-6): 200.47, 165.29, 165.29, 157.33, 154.63, 149.05, 140.04, 137.94, 137.70, 125.43, 123.55, 77.50, 68.43, 63.43, 57.57, 55.28, 54.51, 51.03, 47.89, 42.11, 41.98, 30.72, 29.24, 29.01, 26.49, 23.94, 20.46, 19.87, 15.14, 13.59, 13.01, 11.23.

[0273] Synthesis of Compound 17

[0274] Step-1: (R)-6-[(S)-l-{(lS, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-4-(5-fluoro-3- pyridyl)-6-hydroxy-2, 16-dimethyl-3-oxo-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4- en-15-yl}ethyl]-3-(hydroxymethyl)-4-methyl-5 ,6-dihydro-2H-pyran-2-oneTo a stirred solution of (R)-6-[(S)-l-{(lS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-4- iodo-2, 16-dimethyl-3-oxo-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-15-yl}ethyl]-3- (hydroxymethyl)-4-methyl-5, 6-dihydro-2H-pyran-2-one (4 g, 6.71 mmol) in 1,4-di oxane (40 mL) were added 2-(5-fluoro-3-pyridyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2.24 g, 1.5 eq., 10.1 mmol) and dicaesium(l+) carbonate (6.55 g, 3 eq., 20.1 mmol) dissolved in water (8 mL) at room temperature. The reaction mixture was purged with N2 for 30 min then added palladium (2+) bis (triphenylphosphane) dichloride (471 mg, 0.1 eq., 671 pmol) followed by further purging with N2 for 5min.The reaction vessel was sealed and stirred at 90°C for 4 hours. After completion of the reaction (monitored by LCMS), mixture was filtered through celite bed and washed with DCM (50 mL). Diluted the filtrate by water (50 mL) and extracted with DCM (2 x 70 mL). Collected organics, dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. The crude was purified by Prep-HPLC (ABC method) (R)-6-[(S)-l- {(1S, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-4-(5-fhioro-3-pyridyl)-6-hydroxy-2, 16-dimethyl- 3-oxo-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en- 15-yl }ethyl]-3-(hy droxymethyl)-4- methyl-5, 6-dihydro-2H-pyran-2-one (1 g, 25.8%) as a white solid.

[0275] Analytical data:LCMS: 98.01% (m / z: 566.4, [M+l]+, 5.44 min (10 min run).’H-NMR (400 MHz, DMSO-6): 3 8.59 (d, J = 2.40 Hz, 1H), 8.38 (s, 1H), 7.70-7.74 (m, 1H), 7.55 (d, J = 6.80 Hz, 1H), 5.84 (d, J = 3.60 Hz, 1H), 4.59 (t, J = 5.60 Hz, 1H), 4.26-4.30 (m, 1H), 4.07-4.18 (m, 2H), 3.72-3.75 (m, 1H), 3.20 (s, 1H), 2.34-2.42 (m, 1H), 2.03-2.07 (m, 2H), 1.99 (s, 3H), 1.56-1.92 (m, 4H), 1.25-1.38 (m, 8H), 0.87-1.15 (m, 8H), 0.66 (s, 3H).19F-NMR (400 MHz, DMSO-6): 3 -127 0813C-NMR (400 MHz, DMSO-d6): 3200 47, 165.32, 160.11, 157.58, 154.66, 144.43, 144.40, 141.21, 137.45, 137.22, 132.86, 132.82, 125.44, 121.61, 121.42, 77.51, 68.41, 63.19, 57.80, 55.15, 54.51, 51.06, 47.76, 42.20, 41.99, 30.62, 29.33, 29.03, 26.51, 23.96, 20.50, 19.90, 15.49, 13.04, 11.25.

[0276] Synthesis of Compound 18

[0277] Step-1: Synthesis of (( / ?)-6-((5)-l-((45, 4a / ?, 5a / ?, 6a.S'. 6b.S. 9 / ?, 9a.S'. 11 aS. llb / ?)-4-hydroxy-9a, llb-dimethyl-l-oxo-2-(pyridin-4-yl)-l, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, llb-tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-9-yl) ethyl)-4- methyl-2-oxo-5, 6-dihydro-2H-pyran-3-yl) methyl prop-2-yn-l-ylcarbamate:To a stirred solution of (1S, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-4- (pyridin-4-yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.2 g, 1 eq; 365 pmol) in dichloromethane (2 mL) were added 3-isocyanatoprop-l-yne (35 mg, 1.2 eq., 438 pmol) and tri ethylamine (102 pL, 2 eq., 730 pmol) drop wisely at OoC. Resultant reaction mixture was allowed to stir at room temperature for 45 minutes. After completion of the reaction (monitored by TLC: 5% methanol in di chloromethane), the reaction mass was diluted with water (30 mL) and then extracted with dichloromethane (2 x 40 mL). Collected organics, dried over sodium sulphate and concentrated reduced pressure to get crude. Crude was purified by preparative HPLC (ABC method) afforded ((R)-6-((S)-l-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, 1 lbR)-4-hydroxy-9a, 1 lb-dimethyl-l-oxo-2-(pyridin-4-yl)-l, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, l lb-tetradecahydrocyclopenta [1,2] phenanthro [8a, 9-b] oxiren-9-yl)ethyl)-4- methyl-2-oxo-5, 6-dihydro-2H-pyran-3-yl)m ethyl prop-2-yn-l-ylcarbamate (3 mg, 1.3%) as a white solid.

[0278] Analytical data:LCMS: 97.07% (m / z: 629.15, [M+l]+, 2.35 min (6 min run).’H-NMR (400 MHz, DMSO-< / 6): d 8.60 (d, J= 5.60 Hz, 2H), 7.53-7.55 (m, 2H), 7.32 (d, J= 6.00 Hz, 2H), 5.80 (d, J= 3.60 Hz, 1H), 4.72-4.71 (m, 2H), 4.29-4.32 (m, 1H), 3.75-3.73 (m,3H), 3.18 (s, 1H), 3.07 (s, 1H), 2.33-2.41 (m, 1H), 2.16-2.20 (m, 1H), 2.03-2.06 (m, 4H), 1.74 (s, 4H), 1.45-1.20 (m, 7H), 1.19-1.00 (m, 4H), 0.99-0.80 (m, 5H), 0.67 (s, 3H).

[0279] Synthesis of Compound 19

[0280] Step-1: Synthesis of (( / ?)-6-((5)-l-((45, 4a / ?, 5a / ?, 6a.S'. 6b.S. 9 / ?, 9a.S'. 11 aS. llb / ?)-4-hydroxy-9a, llb-dimethyl-l-oxo-2-(pyridin-3-yl)-l, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, llb-tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-9-yl)ethyl)-4- methyl-2-oxo-5, 6-dihydro-2H-pyran-3-yl)methyl prop-2-yn-l-ylcarbamate:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-4- (pyri din-3 -yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (56.6 mg, 1 eq; 103 pmol) in dichloromethane (10 mL) were added triethylamine (41.8 mg, 4 eq., 413 pmol) and 4-nitrophenyl N-(prop-2-yn-l-yl)carbamate (45.5 mg, 2 eq., 207 pmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC: 60% ethyl acetate in n-hexane), reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (2 x 30 mL). Collected organics, dried over sodium sulphate and concentrated under reduced pressure to obtain crude. The crude was purified by preparative-HPLC (ABC method) afforded ((R)-6- ((S)-1-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, 1 lbR)-4-hydroxy-9a, 1 lb-dimethyl-l-oxo-2- (pyridin-3-yl)-l, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, l lb-tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-9-yl)ethyl)-4-methyl-2-oxo-5, 6-dihydro-2H-pyran-3-yl)methyl prop-2-yn-l-ylcarbamate (21 mg, 32%) as a white solid.

[0281] Analytical data:LCMS: 99.44% (m / z: 629.30, [M+l]+, 2.35 min (6 min run).’H-NMR (400 MHz, DMSO-< / 6): d 8.56-8.54 (m, 1H), 8.50 (d, J= 1.60 Hz, 1H), 7.71 (d, J= 8.00 Hz, 1H), 7.60-7.56 (m, 1H), 7.46-7.43 (m, 2H), 5.77 (d, J= 3.60 Hz, 1H), 4.74-4.68 (m,2H), 4.29-4.32 (m, 1H), 3.75-3.71 (m, 2H), 3.19 (s, 1H), 3.08 (s, 1H), 2.33-2.50 (m, 2H), 2.16- 2.20 (m, 1H), 2.03-2.07 (m, 4H), 1.93-1.56 (m, 4H), 1.39-1.25 (m, 8H), 1.15-0.80 (m, 8H), 0.65 (s, 3H).

[0282] Synthesis of Compound 20

[0283] Step-1: Synthesis of 4-((4.S'. 4a / ?, 5a / ?, 6a5, 6b.S. 9 / ?, 9a5, l laS. llb / ?)-4- hydroxy-9-((5)-l-(( / ?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-9a, llb-dimethyl-l-oxo-1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-2-yl)benzonitrile:To a stirred solution of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l- ((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-2-iodo-9a, 11b- dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (0.6 g, 1 eq; 1.01 mmol) in 1,4-dioxane (10 mL) were added 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) benzonitrile (346 mg, 1.5 eq., 1.51 mmol) and dicaesium (1+) carbonate (983 mg, 3 eq., 3.02 mmol). The reaction mixture was purged with N2 gas for 35 minutes and then palladium (II) bis (triphenylphosphane) di chloride (70.6 mg, 0.1 eq., 101 pmol) was added to it. The reaction mixture was again purged with N2 gas for 5 minutes. The reaction vessel was sealed and stirred at 80°C for 16 hours. After completion of the reaction (monitored by LCMS), reaction mixture was passed through celite. Collected filtrate, diluted by addition of water (30 mL) and then extracted with ethyl acetate (3 x 55 mL). Collected organics, dried over sodium sulphate and then concentrated under reduced pressure to obtain crude. The crude residue was purified by preparative HPLC (method: Ammonium Acetate) to afford 4-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l-((R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-1- oxo-1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 1 la,l Ib-tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-2-yl)benzonitrile (29 mg, 5%) as a white solid.

[0284] Analytical data:LCMS: 99.58% (m / z: 572.50, [M+l]+, 5.63 min (10 min run).’H-NMR (400 MHz, DMSO-r / D2O): <5 7.88 (d, J= 8.40 Hz, 2H), 7.49 (dd, J= 6.80, 10.00 Hz, 3H), 5.80 (d, J= 3.60 Hz, 1H), 4.58 (t, J= 5.20 Hz, 1H), 4.30-4.26 (m, 1H), 4.18-4.08 (m, 2H), 3.73 (dd, J = 3.60, 6.80 Hz, 1H), 3.18 (s, 1H), 2.39-2.43 (m, 1H), 2.12-2.06 (m, 2H), 2.00 (s, 3H), 1.95-1.50 (m, 4H), 1.45-1.20 (m, 8H), 1.14-1.00 (m, 3H), 0.99-0.80 (m, 5H), 0.67 (s, 3H).

[0285] Synthesis of Compound 21

[0286] Step-1: Synthesis of (45, 4al?, 5al?, 6a.S'. 6b.S. 91?, 9a.S'. 1 la.S. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(pyrimidin-4-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.5 g, 1 eq; 838 pmol) in tetrahydrofuran (5 mL, 61.4 mmol) were added 4-(tributylstannyl) pyrimidine (340 mg, 1.1 eq., 922 pmol) and X’-copper (1+) iodide (47.9 mg, 0.3 eq., 251 pmol). The reaction mixture was degassed using nitrogen gas for 30 minutes. After that, tris ((lE,4E)-l,5-diphenylpenta- l,4-dien-3-one) dipalladium (38.4 mg, 0.05 eq., 41.9 pmol) was added. The reaction mixture was degassed using nitrogen for 5 minutes and reaction was refluxed at 90°C for 16 hours. After the reaction was completed (monitored by TLC and LCMS), the reaction mixture was filtered through celite bed, filtrate was evaporated under vacuum to obtain crude. Crude was purified by Prep. HPLC (ABC method) afforded (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6- hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-4-(pyrimidin-4-yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16]octadec-4- en-3-one (68 mg, 26%) as a white solid.

[0287] Analytical data:LCMS: 89.13% (m / z: 549.60, [M+l]+, 4.98 min (10 min run).’H-NMR (400 MHz, DMSO-6): 3 9.21 (s, 1H), 8.85 (d, J= 5.20 Hz, 1H), 7.95 (d, J= 6.80 Hz, 1H), 7.52 (dd, J= 1.20, 5.40 Hz, 1H), 5.90 (d, J = 3.60 Hz, 1H), 4.59 (t, J = 5.20 Hz, 1H), 4.31-4.22 (m, 1H), 4.18-4.07 (m, 2H), 3.80 (dd, J= 3.60, 6.80 Hz, 1H), 3.18 (s, 1H), 2.42-2.33 (m, 1H), 2.11-1.92 (m, 6H), 1.95-1.70 (m, 3H), 1.62-1.50 (m, 1H), 1.43-1.22 (m, 9H), 1.20- 1.00 (m, 6H), 0.66 (s, 3H).

[0288] Synthesis of Compound 22

[0289] Step-1: Synthesis of (45, 4a.S. 5aR, 6aS, 6b.S. 9R, 9aS, 1 la.S. llbl?)-2-iodo-4- methoxy-9-((5)-l-((l?)-5-(methoxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b]oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8- oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (2 g, 4.25 mmol) in dichloromethane (20 mL, 312 mmol) was added silver oxide (3.97 g, 4 eq., 17 mmol) under inert atmosphere. Then iodomethane (9.05 g, 15 eq., 63.7 mmol) was added to it and reaction continued stirring at room temperature for 4 days. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through celite bed and filtrate was extracted with dichloromethane(3 x 30 mL). Collected organics, dried over sodium sulphate and concentrated under reduced pressure to obtain crude. Crude was purified by combi-flash chromatography using (70% ethyl acetate in n-hexane) afforded (IS, 2R, 6S, 7S, 9R, 11 S, 12S, 16S)-6-methoxy-15-[(lS)-l- [(2R)-5-(methoxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (1.2 g, 57%) as a white solid.

[0290] Analytical data:LCMS: 95.60% (m / z: 499.19, [M+l]+, 2.55 min (4 min run).

[0291] Step-2: Synthesis of (45, 4a5, 5aR, 6a5, 6b5, 9R, 9a5, lla5, llb / ?)-4-methoxy-9-((5)-l-(( / ?)-5-(methoxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(pyridin-4-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7S, 9R, 11 S, 12S, 16S)-6-methoxy-15-[(lS)-l-[(2R)-5- (methoxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8- oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.4 g, 802 pmol) in dichloromethane (5 mL) were added N, N-dimethylpyridin-4-amine (294 mg, 3 eq., 2.41 mmol), iodine (285 mg, 2.8 eq., 2.25 mmol) and reaction stirred at room temperature for 2 hours. After completion of reaction (monitored by TLC and by LCMS), quenched by adding sodium thiosulfate solution (20 mL) and then extracted using dichloromethane (2 x 35 mL). Collected organics, dried over sodium sulphate and then concentrated under reduced pressure to obtain crude. Crude was purified by combi-flash chromatography (5% methanol and dichloromethane) to yield (IS, 2R, 6S, 7S, 9R, 11 S, 12S, 16S)-4-iodo-6-methoxy-15-[(lS)-l-[(2R)-5-(methoxymethyl)-4-methyl- 6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16] octadec-4-en-3-one. (340 mg, 68%) as a white solid.

[0292] Analytical data:LCMS: 72.21% (m / z: 625.09, [M+l]+, 2.71 min (4 min run).

[0293] Step-3: Synthesis of (45, 4a5, 5a / ?, 6a5, 6b5, 9R, 9a5, lla5, llb / ?)-2-iodo-4- methoxy-9-((5)-l-(( / ?)-5-(methoxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2- yl)ethyl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b]oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7S, 9R, 11 S, 12S, 16S)-4-iodo-6-methoxy-15-[(lS)-l- [(2R)-5-(methoxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (337 mg, 1 eq; 540 pmol) in N,N- dimethylformamide (3.37 mL) were added 4-(tributylstannyl)pyridine (397 mg, 2 eq., 1.08 mmol) and diiodocopper (25.7 mg, 0.15 eq., 80.9 pmol). The resultant reaction mixture was purged with nitrogen gas for 35 minutes and then l,l'-Bis (diphenylphosphino) ferrocene] palladium(II) dichloride dichloromethane adduct (22 mg, 0.05 eq., 27 pmol) was added to it . The reaction mixture was again purged with nitrogen gas for 5 minutes. The reaction vessel was sealed and stirred at 60°C for 16 hours. After completion of the reaction (monitored by TLC and LCMS), it was quenched by adding ice cold water (30 mL) and brine solution (30 mL). It was then extracted using ethyl acetate (3 x 35 mL). Collected organics, dried over sodium sulphate and concentrated under reduced pressure to obtain crude. Crude product was purified by preparative HPLC (ABC method) afforded (IS, 2R, 6S, 7S, 9R, 1 IS, 12S, 16S)-6- methoxy-15-[(lS)-l-[(2R)-5-(methoxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl]ethyl]-2, 16-dimethyl-4-(pyridin-4-yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en- 3 -one (22 mg, 7%) as a white solid.

[0294] Analytical data:LCMS: 95.01% (m / z: 576.60, [M+l]+, 6.28 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.62 (d, J= 4.00 Hz, 2H), 7.62 (d, J= 6.40 Hz, 2H), 7.34 (d, J= 6.00 Hz, 2H), 4.32-4.29 (m, 1H), 4.12-4.02 (m, 2H), 3.55 (d, J= 6.40 Hz, 1H), 3.34 (s, 3H), 3.20 (s, 3H), 3.18 (s, 1H), 2.43-2.39 (m, 1H), 2.13 (dd, J= 3.20, 18.40 Hz, 1H), 2.04-2.07 (m, 1H), 2.00 (s, 3H), 1.90-1.93 (m, 1H), 1.89-1.50 (m, 3H), 1.45-1.20 (m, 8H), 1.15-1.04 (m, 3H), 0.97-1.00 (m, 1H), 0.92 (d, J= 6.80 Hz, 3H), 0.87-0.83 (m, 1H), 0.66 (s, 3H).

[0295] Synthesis of Compound 23

[0296] Step-1: Synthesis of 3-((4.S'. 4a / ?, 5a / ?, 6a.S'. 6b.S. 9 / ?, 9a.S'. 11 aS. llb / ?)-4- hydroxy-9-((5)-l-(( / ?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-9a, llb-dimethyl-l-oxo-1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-2-yl) pyridine 1-oxide:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-4- (pyri din-3 -yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.5 g, 1 eq; 913 pmol) in di chloromethane (10 mL) was added 3 -chlorobenzene- 1-carboperoxoic acid (236 mg, 1.5 eq., 1.37 mmol) at -20°C and resultant reaction mixture was stirred for 16 hours at -20°C. After completion of the reaction (reaction was monitored by TLC), excess of solvent was evaporated under reduced pressure to get crude. Obtained crude was purified by prep HPLC (AA method) afforded 3-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l- ((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 11b- dimethyl-1 -oxo-1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-2-yl) pyridine 1-oxide (82 mg, 16%) as an off white solid.

[0297] Analytical data:LCMS: 99.02% (m / z: 564.50, [M+l]+, 4.42 min (10 min run).’H-NMR (400 MHz, DMSO-< / 6): 8 8.22 (d, J= 6.40 Hz, 1H), 8.16 (d, J= 1.20 Hz, 1H), 7.54 (d, J= 6.40 Hz, 1H), 7.46 (t, J= 6.80 Hz, 1H), 7.30 (d, J= 8.00 Hz, 1H), 5.83 (d, J= 3.60 Hz, 1H), 4.59 (t, J= 5.20 Hz, 1H), 4.31-4.26 (m, 1H), 4.18-4.08 (m, 2H), 3.71 (dd, J= 3.60, 6.60 Hz, 1H), 3.19 (s, 1H), 2.42-2.32 (m, 1H), 2.11-2.02 (m, 2H), 1.99 (s, 3H), 1.91-1.71 (m, 3H), 1.56-1.58 (m, 1H), 1.40-1.20 (m, 8H), 1.15-0.97 (m, 4H), 0.92-0.84 (m, 4H), 0.66 (s, 3H).13C-NMR (400 MHz, DMSO-< / 6): 200.16, 165.31, 154.66, 141.60, 138.22, 136.99, 136.67, 134.42, 126.44, 125.44, 124.06, 77.51, 68.347, 63.08, 57.75, 55.16, 54.52, 51.083, 47.77, 42.17, 41.99, 38.37, 30.56, 29.33, 29.03, 26.50, 23.95, 20.48, 19.89, 15.43, 13.036, 11.24.

[0298] Synthesis of Compound 24

[0299] Step-1: Synthesis of (45, 4al?, 5al?, 6a.S'. 6b.S. 91?, 9a.S'. 1 la.S. llbl?)-4-hydroxy- 9-((5)-l-((7?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-2-(5- methoxypyridin-2-yl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b]oxiren-l(4H)-one:To a stirred solution of (2R, 6S, 7R, 9R, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.8 g, 1 eq; 1.34 mmol) in tetrahydrofuran (15 mL, 184 mmol) was added 5-methoxy-2-(tributylstannyl) pyridine (534 mg, 1.34 mmol), triphenylarsane (41.1 mg, 0.1 eq., 134 pmol) and diiodocopper (42.6 mg, 0.1 eq., 134 pmol). The resultant reaction mixture was purged with nitrogen gas for 35 minutes and then added tris(l,5-diphenylpenta-l,4-dien-3-one) dipalladium (12.3 mg, 0.01 eq., 13.4 pmol). The reaction mixture was again purged with nitrogen gas for 10 minutes. The reaction vessel was sealed and stirred at 85°C for 16 hours. After completion of reaction (monitored by LCMS), it was diluted with water (90 mL) and then it was extracted with di chloromethane (3 x 45 mL). Collected organics, dried over sodium sulphate and concentrated under reduced pressure to afford the crude. Crude was purified by preparative HPLC (ABC method) to afford (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)- 4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl) ethyl)-2-(5-methoxypyridin-2-yl)-9a, 11b- dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (113 mg, 15%) as a white solid.

[0300] Analytical data:LCMS: 97.28% (m / z: 578.60, [M+l]+, 5.32 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.32 (d, J= 2.80 Hz, 1H), 7.55 (d, J= 6.80 Hz, 1H), 7.42 (dd, J= 2.80, 8.80 Hz, 1H), 7.35 (d, J = 8.80 Hz, 1H), 5.68 (d, J = 3.60 Hz, 1H), 4.58 (t, J = 5.60 Hz, 1H), 4.31-4.26 (m, 1H), 4.18-4.07 (m, 2H), 3.84 (s, 3H), 3.73 (dd, J= 3.60, 6.80 Hz, 1H), 3.15 (s, 1H), 2.42-2.49 (m, 1H), 2.11-2.06 (m, 2H), 1.99 (s, 3H), 1.93-1.55 (m, 4H), 1.34-1.40 (m, 3H), 1.31 (s, 3H), 1.21-1.24 (m, 2H), 1.15-1.02 (m, 3H), 0.96-0.81 (m, 5H), 0.66 (s, 3H).13C-NMR (400 MHz, DMSO-6): 200.77, 165.30, 155.10, 154.64, 144.72, 140.63, 137.63, 125.43, 122.62, 120.53, 77.50, 68.54, 63.57, 57.53, 55.66, 55.32, 54.50, 51.03, 47.90, 42.13, 38.89, 30.78, 29.24, 29.01, 26.49, 23.95, 20.52, 19.87, 15.09, 13.02, 11.24.

[0301] Synthesis of Compound 25

[0302] Step-1: Synthesis of (45, 4al?, 5aR, 6aS, 6b.S. 9R, 9aS, 1 la.S. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(5-methylpyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.2 g, 1 eq; 335 pmol) in tetrahydrofuran (2 mL) were added X1-copper(l+) iodide (6.39 mg, 0.1 eq., 33.5 pmol), triphenylarsane (10.3 mg, 0.1 eq., 33.5 pmol) and 5-methyl-2-(tributylstannyl) pyridine (256 mg, 2 eq., 671 pmol). After that, the reaction mixture was degassed using nitrogen gas for 30 minutes. To this stirring solution, tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (3.07 mg, 0.01 eq., 3.35 pmol) was added followed by further degassing by nitrogen for 5 minutes. Finally, the reaction mixture was heated at 80°C for 16 hours. After completion of the reaction (monitored by TLC: 5% methanol in di chloromethane) mixture was filtered through celite bed and filtrate was diluted by water (20 mL) and then extracted using dichloromethane (3 x 45 mL). Collected organics, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude. Crude was purified using prep-HPLC (ABC method) (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-2-(5-methylpyridin-2-yl)-5a, 6, 6a,6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren- l(4H)-one (160 mg, 85%) as a white solid.

[0303] Analytical data:LCMS: 98.96% (m / z: 562.60, [M+l]+, 5.44 min (10 min run).’H-NMR (400 MHz, DMSO-6): 3 8.44 (s, 1H), 7.63 (d, J= 6.80 Hz, 2H), 7.29 (d, J= 8.00 Hz, 1H), 5.71 (d, J= 3.20 Hz, 1H), 4.59 (t, J= 5.20 Hz, 1H), 4.26-4.30 (m, 1H), 4.16-4.09 (m, 2H), 3.74 (dd, 7= 3.20, 6.40 Hz, 1H), 3.15 (s, 1H), 2.31 (s, 3H), 2.11-2.02 (m, 5H), 1.93-1.99 (m, 1H), 1.90-1.55 (m, 3H), 1.41-1.23 (m, 8H), 1.12-1.06 (m, 3H), 0.96-0.84 (m, 5H), 0.66 (s, 3H).

[0304] Synthesis of Compound 26

[0305] Step-1: Synthesis of (45, 4al?, 5aR, 6aS, 6b.S. 9R, 9aS, 1 la.S. llbl?)-4-hydroxy- 9-((5)-l-((l?)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(4-methylpyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.2 g, 1 eq. 335 pmol) in tetrahydrofuran (2 mL) were added X1-copper(l+) iodide (6.39 mg, 0.1 eq., 33.5 pmol), 4- methyl-2-(tributylstannyl) pyridine (247 mg, 2 eq; 671 pmol) and then reaction was degassed using nitrogen gas for 30 minutes. After that, tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (3.07 mg, 0.01 eq., 3.35 pmol) was added and again it was degassed by nitrogen for 5 minutes. Finally, the reaction mixture was heated 80°C for 16 hours. After completion of the reaction (monitored by TLC: 5% methanol in di chloromethane), reaction mixture was filtered through celite bed and filtrate was diluted by water (20 mL) and then extracted usingdichloromethane (3 x 45 mL). Collected organics, dried over anhydrous sodium sulphate and then concentrated under reduced pressure to get crude. Crude was purified by using preparative-HPLC (ABC method) afforded (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4- hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-9a, 1 lb-dimethyl-2-(4-methylpyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 11b- dodecahydrocyclopenta [1,2] phenanthro [8a, 9-b] oxiren-l(4H)-one (115 mg, 61%) as a white solid.

[0306] Analytical data:LCMS: 97.47% (m / z: 562.60, [M+l]+, 5.40 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.45 (d, J= 5.20 Hz, 1H), 7.63 (d, J= 6.40 Hz, 1H), 7.21- 7.18 (m, 2H), 5.73 (s, 1H), 4.59 (t, J= 5.20 Hz, 1H), 4.30-4.27 (m, 1H), 4.15-4.10 (m, 2H), 3.74 (d, J = 6.80 Hz, 1H), 3.16 (s, 1H), 2.12-1.91 (m, 6H), 1.88-1.62 (m, 2H), 1.60-1.19 (m, 9H), 1.13-1.05 (m, 3H), 0.93-0.86 (m, 5H), 0.66 (s, 3H).

[0307] Synthesis of Compound 27Compound 27

[0308] Step-1: Synthesis of 6-(tributylstannyl) picolinonitrile:To a stirred solution 6-bromopyridine-2-carbonitrile (1 g, 5.46 mmol) in N, N-dimethylform amide (1 mL) and 1,2-dimethoxy ethane (8 mL) was added bi s(tributyl stannane) (4.77 g, 1.5 eq., 8.2 mmol). Purged with nitrogen gas for 30 min. Added tetrakis(triphenylphosphine)palladium (0) (0.505g, 0.08 eq, 0.436 mmol) and purged with nitrogen for 5 min. The reaction mixture was stirred at 100°C for 16h. The reaction mixture was quenched with chilled water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with saturated brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified through combi flash using 25-30% ethyl acetate in hexane to get desired product 6-(tributylstannyl) picolinonitrile (0.26 g, 12.1%) as colour less liquid.

[0309] Analytical data:’H-NMR (400 MHz, DMSO-6): d 7.87-7.82 (m, 2H), 7.80-7.78 (m, 1H), 1.61-1.44 (m, 6H), 1.32-1.23 (m, 6H), 1.20 -1.13 (m, 6H), 0.87-0.89 (m, 9H).

[0310] Step-2: Synthesis of 6-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, llaS, llbR)-4- hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-9a, llb-dimethyl-l-oxo-1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-2-yl) picolinonitrile:To a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.2 g, 335 pmol) in N,N- dimethylformamide (2.6 mL) added diiodocopper (16 mg, 0.15 eq., 50.3 pmol) and 6- (tributylstannyl) pyridine-2-carbonitrile (132 mg, 335 pmol). The reaction mixture was purged with nitrogen gas for 35 min. Added l,l'-Bis (diphenylphosphino) ferrocene] palladium(II) dichloride di chloromethane adduct (13.7 mg, 0.05 eq., 16.8 pmol) and purged with nitrogen gas for 5 min. Stirred the reaction mixture at 60 °C for 2h. Quenched the reaction mass with water (50 ml) and extracted with ethyl acetate (2 X 50 ml). The combined organic layer was washed with saturated brine solution, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified through preparative-HPLC (ABC method) to obtain 6-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l-((R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-1- oxo-1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-tetradecahydrocyclopenta [1, 2] phenanthro [8a ,9-b] oxiren-2-yl) picolinonitrile (42 mg, 21.8%) as a white solid.

[0311] Analytical data:LCMS: 99.92% (m / z: 573.35, [M+l]+, 6.24 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.12 (t, J= 7.60 Hz, 1H), 8.02 (d, J = 7.60 Hz, 1H), 7.76 - 7.71 (m, 2H), 5.85 (d, J= 3.60 Hz, 1H), 4.58 (t, J= 5.60 Hz, 1H), 4.30-4.25 (m, 1H), 4.17- 4.07 (m, 2H), 3.79 (dd, J= 3.20, 6.40 Hz, 1H), 3.17 (s, 1H), 2.42-2.33 (m, 1H), 2.11-2.03 (m, 2H), 1.99 (s, 3H), 1.92 (d, J = 12.4 Hz, 1H), 1.83-1.76 (m, 1H), 1.76-1.68 (m, 1H), 1.60-1.52 (m, 1H), 1.46-1.34 (m, 3H), 1.32 (s, 3H), 1.29-1.23 (m, 2H), 1.14-1.01 (m, 3H), 0.92 (m, 5H), 0.66 (s, 3H).13C-NMR (400 MHz, DMSO-6): 8200.09, 165.29, 154.65, 154.23, 142.35, 139.47, 139.03, 132.60, 128.29, 126.18, 125.43, 117.29, 77.50, 68.33, 63.03, 57.56, 55.25, 54.51, 51.06, 47.92, 42.05, 41.98, 30.68, 29.23, 29.01, 26.49, 23.96, 20.44, 19.86, 15.09, 13.04, 11.24.

[0312] Synthesis of Compound 28

[0313] Step-1: ((R)-6-((S)-l-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, HaS, HbR)-4- hydroxy-9a,llb-dimethyl-l-oxo-2-(pyridin-2-yl)-l, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, llb-tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-9-yl)ethyl)-4-methyl-2- oxo-5, 6-dihydro-2H-pyran-3-yl) methyl prop-2-yn-l-ylcarbamate :To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-4- (pyridin-2-yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.5 g, 913 pmol) in tetrahydrofuran (5 mL, 12.3 mmol) added lithium(l+) bis(trimethylsilyl)azanide (7.33 mg, 1.2 eq., 43.8 pmol) and 4-nitrophenyl N-(prop-2-yn-l-yl)carbamate (9.65 mg, 1.2 eq., 43.8 pmol) at -78 °C. Reaction was stirred for 4h at room temperature. After completion of the reaction (monitored by TLC: 70 % ethyl acetate in heptane), the reaction mixture was quenched with saturated NH4C1 (30 ml) and extracted with DCM (2 X 30 ml). Collected organics, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The crude residue was purified by combi flash (12g welch column) to afford 93% of desiredcompound. The compound was further purified by preparative HPLC (ABC method) to get (3S, 4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-3-(3,3-difhioropiperidin-l-yl)-4-hydroxy- 9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 11b- dimethyltetradecahydrocyclopenta [1,2] phenanthro [8a, 9-b] oxiren-l(2H)-one (72 mg, 12%) as a white solid.

[0314] Analytical data:LCMS: 99.10% (m / z: 629.6, [M+l]+, 5.97 min (10 min run).’H-NMR (400 MHz, DMSO-d6- D2O): 5 1H-NMR (400 MHz, DMSO-d6): 5 8.60 (d, J = 4.40 Hz, 1H), 7.83 (t, J = 7.60 Hz, 1H), 7.68 (d, J = 6.80 Hz, 1H), 7.58 (t, J = 5.60 Hz, 1H), 7.34-7.37 (m, 2H), 5.75 (s, 1H), 4.71 (t, J = 13.60 Hz, 2H), 4.29-4.32 (m, 1H), 3.75-3.76 (m, 3H), 3.16 (s, 1H), 3.09 (t, J = 2.40 Hz, 1H), 2.02-2.45 (m, 6H), 1.22-1.93 (m, 12H), 0.86-1.16 (m, 8H), 0.66 (s, 3H).13C-NMR (400 MHz, DMSO-6): 200.57, 164.65, 158.45, 155.84, 152.48, 149.58, 141.12, 139.80, 136.92, 123.39, 122.16, 120.79, 81.36, 77.60, 72.99, 68.50, 63.52, 57.82, 57.55, 55.32, 50.96, 47.89, 42.08, 42.01, 30.75, 29.77, 29.23, 29.16, 26.44, 23.96, 20.48, 20.11, 15.12, 12.96, 11.23.

[0315] Synthesis of Compound 29

[0316] Step-1: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, llaS, HbR)-4-hydroxy- 9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(pyrimidin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-oneA stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.5 g, 838 pmol), 2- (tributylstannyl) pyrimidine (340 mg, 1.1 eq., 922 pmol), diiodocopper (39.9 mg, 0.15 eq., 126 pmol) and triphenylarsane (25.7 mg, 0.1 eq., 83.8 pmol) in tetrahydrofuran (7 mL, 86 mmol) was purged with nitrogen for 30 min and tris (l,5-diphenylpenta-l,4-dien-3-one) dipalladium (38.4 mg, 0.05 eq., 41.9 pmol) was added to it . The reaction mixture was again purged with nitrogen for 5 min. Stirred the reaction mass at 80 °C for 5h. After the completion of reaction (monitoring by tic), the reaction mixture was quenched with water (30 mL) and extracted with (2 x 30 mL) ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 300 mg of crude. The compound was purified by Prep- HPLC purification in ABC method, to afford desired product (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS,l laS,l lbR)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo- 3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-2-(pyrimidin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro[8a, 9-b]oxiren-l(4H)-one (43 mg, 9.35%) as off white solid .

[0317] Analytical data: 97.96% (m / z: 549.5, [M+l]+, 5.03 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.83 (d, J = 5.20 Hz, 2H), 7.66 (d, J = 6.40 Hz, 1H), 7.44 (t, J = 4.80 Hz, 1H), 5.80 (d, J = 3.20 Hz, 1H), 4.59 (t, J = 5.20 Hz, 1H), 4.26-4.30 (m, 1H), 4.08-4.18 (m, 2H), 3.74-3.76 (m, lH), 3.15 (s, 1H), 2.33-2.43 (m, 1H), 1.93-2.13 (m, 6H), 1.49- 1.90 (m, 5H), 1.24-1.36 (m, 7H), 0.92-1.15 (m, 9H), 0.66 (s, 3H).13C-NMR (400 MHz, DMSO-6): d 198.91, 165.31, 162.62, 157.53, 154.67, 141.93, 141.82, 125.43, 120.26, 77.53, 68.53, 63.76, 57.45, 55.44, 54.51, 51.01, 47.84, 42.02, 41.75, 30.85, 29.04, 26.52, 23.97, 20.18, 19.88, 14.83, 13.03, 11.22.

[0318] Synthesis of Compound 30

[0319] Step-1: Synthesis of 5-fluoro-2-(tributylstannyl)pyrimidine:To a solution of 2-chloro-5-fluoropyrimidine (2 g, 15.1 mmol) in 1,4-dioxane (20 mL, 234 mmol) was added hexabutylditin (650 mg, 1.68 mmol) and purged nitrogen for 30 minutes. Add tetrakis (triphenylphosphine) palladium(O) (1.74 g, 0.1 eq., 1.51 mmol) and again purged with nitrogen gas for 5 minutes. The reaction mixture was stirred at 90°C for 16h. Reaction was monitored by TLC. After completion of reaction, it was filtered through celite bed and washed with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude material. The crude material was purified by Combi Flash by using 25-30% ethyl acetate in hexane to get 5-fhioro-2-(tributylstannyl) pyrimidine (650 mg, 11.13%).

[0320] Analytical data:LCMS: 82.76% 3.68 min (m / z: 389.10, [M+l]+, (4 min run).’H-NMR (400 MHz, DMSO-6): d 8.86 (d, J = 1.60 Hz, 2H), 1.61-1.47 (m, 6H), 1.33-1.23 (m, 6H), 1.19-1.02 (m, 6H), 0.95-0.75 (m, 9H).

[0321] Step-2: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, HaS, HbR)-2-(5- fluoropyrimidin-2-yl)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.3 g, 503 pmol) in tetrahydrofuran (6 mL, 73.7 mmol) were added diiodocopper (23.9 mg, 0.15 eq., 75.4 pmol), triphenylarsane (15.4 mg, 0.1 eq., 50.3 pmol) and 5-fluoro-2-(tributylstannyl) pyrimidine (292 mg, 1.5 eq., 754 pmol). Purged the reaction mixture with nitrogen gas for 35 min. Added tris(l,5-diphenylpenta-l,4-dien-3-one) dipalladium (23 mg, 0.05 eq., 25.1 pmol) and again purged with nitrogen gas for 5 min. Stirred the reaction mass at 85 °C for 16h. After completion of reaction, it was filtered through celite bed and washed with ethyl acetate. The organic layer was washed with saturated brine solution, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get the crude. The crude was purified through preparative HPLC (ABC method) to afford (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-2- (5-fluoropyrimidin-2-yl)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (28 mg, 9.82%) as a white solid.

[0322] Analytical data:LCMS: 97.71% (m / z: 567.50, [M+l]+, 6.56 min (15 min run).’H-NMR (400 MHz, DMSO-6): 8 8.93 (s, 2H), 7.65 (d, J = 6.80 Hz, 1H), 5.83 (d, J = 3.20 Hz, 1H), 4.59 (t, J= 5.20 Hz, 1H), 4.31-4.26 (m, 1H), 4.18-4.07 (m, 2H), 3.76 - 3.74 (m, 1H), 3.14 (s, 1H), 2.41 0-2.31 (m, 1H), 2.12-2.07 (m, 2H), 1.99 (s, 3H), 1.93-1.89 (m, 1H), 1.81- 1.78 (m, 1H), 1.77-1.72 (m, 1H), 1.57-1.47 (m, 2H), 1.36-1.23 (m, 7H), 1.21-1.11 (m, 3H), 1.08-0.91 (m, 5H), 0.65 (s, 3H).13C-NMR (400 MHz, DMSO-6): d 198.75, 165.33, 158.94, 158.88, 157.85, 155.23, 154.71, 145.68, 145.47, 142.22, 140.73, 125.44, 77.54, 68.47, 63.69, 57.47, 55.44, 54.52, 51.03, 47.86, 42.03, 41.81, 30.84, 29.06, 26.52, 23.98, 20.19, 19.90, 14.87, 13.05, 11.24.19F-NMR (400 MHz, DMSO-6): d 138 25

[0323] Synthesis of Compound 31

[0324] Step-1: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, llaS, HbR)-9-((S)-l- ((R)-5-(((tert-butyldimethylsilyl) oxy) methyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-4-hydroxy-2-iodo-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b]oxiren-l(4H)-one:To a stirred solution of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l- ((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-2-iodo-9a, 11b- dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 lb-dodecahydrocyclopenta[l,2] phenanthro [8a, 9-b]oxiren-l(4H)-one (5 g, 8.38 mmol) in dimethylformamide (0.1 L, 1.29 mol) was added 4-(pyrrolidin-l-yl) pyridin-l-ium (6.25 g, 5 eq., 41.9 mmol). After 10 minutes tert- butyl(chloro)dimethylsilane (12.6 g, 10 eq., 83.8 mmol) was added and heated the reaction up to 85°C for 3hrs. After completion of reaction (monitored by TLC) the mixture was diluted with ice cold water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with saturated brine solution (50 mL), dried the organic layer over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain the crude material, which was purified by column chromatography in 0 - 100% ethyl acetate in Heptane to obtain the compound (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-9-((S)-l-((R)-5-(((tert- butyldimethylsilyl)oxy)methyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-4- hydroxy-2-iodo-9a, 1 lb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11,11a, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b]oxiren-l(4H)-one (1.8 g, 2.41 mmol, 29%) as off white solid.

[0325] Analytical data:LCMS: 95.79% (m / z: 711.10, [M+H]+, 4.10 min (6 min run).’H-NMR (400 MHz, DMSO-6): d 5.89 (d, J = 4.00 Hz, 1H), 4.27-4.35 (m, 3H), 3.48-3.51 (m, 1H), 3.19 (s, 1H), 2.31-2.51 (m, 1H), 2.16 (d, J = 2.80 Hz, 1H), 2.02 (m, 4H), 1.51-1.90 (m, 4H), 1.21-1.38 (m, 8H), 0.91-1.20 (m, 8H), 0.85 (s, 9H), 0.64 (s, 3H).

[0326] Step-2: Synthesis of (IS, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-15-[(1S)-1-[(2R)- 5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl]ethyl]-6-hydroxy-4-(5-methoxypyridin-2-yl)-2, 16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16] octadec-4-en-3-oneTo a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-15-[(lS)-l-[(2R)-5-{[(tert- butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-6- hydroxy-4-iodo-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (450 mg, 0.633 mmol) and 5-methoxy-2-(tributylstannyl) pyridine (378 mg, 1.5 eq., 0.950 mmol) in THF (8 mL) were added triphenylarsane (19.4 mg, 0.1 eq., 0.063 mmol) and iodocopper (18.1 mg, 0.15 eq., 0.095 mmol). The resulting mixture was purged with argon for 30 min. Tris ((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (58 mg, 0.1 eq., 0.063 pmol) was added to the reaction mixture and stirred for 3h at 85 °C. The reaction was monitored by TLC, quenched by adding water (50 mL) and extracted with ethyl acetate (3 x 50 mL). Combined organics were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The crude product was purified by combi flash column chromatography using (70-90%) ethyl acetate in heptane as an eluent to afford (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S) -15-[(lS)-l-[(2R)-5-{[(tert-butyldimethylsilyl)oxy]methyl}-4- methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-6-hydroxy-4-(5-methoxypyridin-2-yl)-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (180 mg, 0.26 mmol, 41%) as an off white solid.

[0327] Analytical data:LCMS: 91.13% (m / z: 692.28, [M+l]+), 3.08 min (4 min run).

[0328] Step-3: Synthesis of (IS, 2R, 6R, 7S, 9R, IIS, 12S, 15R, 16S)-15-[(1S)-1-[(2R)- 5-{[(tert-butyldimethylsilyl) oxy] methyl} -4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl]ethyl]-6-fluoro-4- (5-methoxypyridin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-oneTo a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-15-[(l S)-l-[(2R)-5-{ [(tert- butyldimethylsilyl) oxy] methyl }-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-6-hydroxy -4-(5-methoxypyridin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (180 mg, 0.26 mmol) in dichloromethane (6 mL) was added diethyl(trifluoro-X4-sulfanyl) amine (0.041 mL, 1.2 eq., 0.312 mmol) (dissolved in DCM (1 mL)) drop wise at -78°C under inert atmosphere and stirred for 15 min. Monitored the reaction by TLC, quenched it by saturated sodium bicarbonate solution (20 mL) and extracted using di chloromethane (2 x 35 mL). Combined organics were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The crude was purified by over combi-flash chromatography in silica column (10-20% ethyl acetate in hexane) to yield (IS, 2R, 6R, 7S, 9R, 11 S, 12S, 15R, 16S)-15-[(lS)-l-[(2R)-5- {[(tert-butyldimethylsilyl) oxy] methyl }-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl] ethyl] -6-fluoro-4- (5-methoxypyridin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.1 g, 0.144 mmol, 55%) as light yellow solid.

[0329] Analytical data:LCMS: 97.14 % (m / z: 694.28, [M+l]+), 3.37 min (4 min run).

[0330] Step-4: Synthesis of (IS, 2R, 6R, 7S, 9R, IIS, 12S, 15R, 16S)-6-fluoro-15-[(lS)- l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl] ethyl] -4-(5- methoxypyridin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-oneTo a solution of (IS, 2R, 6R, 7S, 9R, 11 S, 12S, 15R, 16S)-15-[(lS)-l-[(2R)-5-{[(tert- butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-6-fluoro-4-(5-methoxypyridin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4- en-3-one (0.1 g, 0.144 mmol) in THF (1 mL) and methanol (1 mL) was added 2N hydrogen chloride solution (1 mL, 14 eq, 2 mmol) drop wise at 0 °C and stirred for 30 min. Monitored the reaction by TLC, quenched it by adding saturated sodium bicarbonate solution (20 mL) and extracted using dichloromethane (2 x 30 mL). Combined organics were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude which was purified by combi-flash chromatography over silica column (0 - 5% methanol in dichloromethane) to afford (IS, 2R, 6R, 7S, 9R, 11 S, 12S, 15R, 16S)-6-fluoro-15-[(lS)-l- [(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-(5-methoxypyridin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3- one (45 mg, 0.077 mmol, 53%) as off white solid.

[0331] Analytical data:LCMS: 93.34% (m / z: 580.5, [M+l]+, 6.22 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.33 (d, J= 1.6 Hz, 1H), 7.46-7.41 (m, 3H), 5.83 (d, J = 50.4 Hz, 1H), 4.59 (t, J= 5.2 Hz, 1H), 4.28 (d, J = 13.2 Hz, 1H), 4.18-4.07 (m, 2H), 3.85 (s, 3H), 3.51 (s, 1H), 3.40-3.35 (m, 1H), 2.42-2.32 (m, 1H), 2.12-2.02 (m, 2H), 1.99 (s, 3H), 1.90- 1.93 (m, 1H), 1.89-1.58 (m, 2H), 1.58 - 1.50 (m, 2H), 1.44-1.28 (m, 4H), 1.21 (s, 3H), 1.16- 0.95 (m, 5H), 0.92 (d, J= 6.40 Hz, 3H), 0.67 (s, 3H).13C-NMR (400 MHz, DMSO-6): 197.91, 165.34, 155.34, 154.7, 143.3, 137.88, 137.75, 137.71, 137.62, 125.44, 123.22, 120.56, 85.20, 83.44, 77.52, 64.94, 63.03, 62.88, 55.73, 55.04, 54,51, 54.07, 53.95, 51.12, 47.32, 47.27, 43.16, 41.97, 40.14, 30.07, 29.07, 29.01, 26.49, 23.96, 20.98, 19.91, 15.19, 13.06, 12.81, 11.32.

[0332] Synthesis of Compound 32

[0333] Step-1: Synthesis of 5-(trimethylstannyl) pyrazin-2-amine:To a stirred solution of 5-bromopyrazin-2-amine (0.5 g, 2.87 mmol) in toluene (10 mL) was added hexamethyldistannane (941 mg, 2.87 mmol). Purged with nitrogen for 30 min then added tetrakis(triphenylphosphine)palladium (99.6 mg, 0.03 eq., 86.2 pmol) followed by furtherpurging with nitrogen for 5 min. The reaction mixture was stirred at 130°C for 3h. After completion of reaction, it was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to get crude. The crude material was purified by combi flash over silica gel using 0-30% ethyl acetate in hexane, to get 5 -(trimethyl stannyl) pyrazin-2-amine (710 mg, 95.2%) as white solid.

[0334] Analytical data:LCMS: 99.82% (m / z: 259.93, [M+l]+, 1.82min (4 min run).’H-NMR (400 MHz, DMSO-< / 6): 8 8.05 (s, 1H), 7.84 (s, 1H), 6.24 (br s, 2H), 0.23 (s, 9H).

[0335] Step-2: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, llaS, llbR)-2-(5- aminopyrazin-2-yl)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.9 g, 1.51 mmol) in tetrahydrofuran (9 mL, 111 mmol) were added diiodocopper (71.8 mg, 0.15 eq., 226 pmol), triphenylarsane (46.2 mg, 0.1 eq., 151 pmol) and 5 -(trimethyl stannyl)pyrazin-2-amine (584 mg, 1.5 eq., 2.26 mmol). The reaction mixture was purged with nitrogen for 35 min and then tris(l,5-diphenylpenta-l,4-dien-3-one)dipalladium (69.1 mg, 0.05 eq., 75.4 pmol) was added to it .The reaction mixture was again purged with nitrogen for 5 min. The reaction was stirred at 80°C for 16h. The reaction mixture was quenched with cool water (50 mL) and was extracted with Ethyl acetate (2 x 50mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was enriched by Combi Flash by using 40-50% ethyl acetate in hexane. Compound was further purified by preparative- HPLC (ABC method) to afford (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-2-(5- aminopyrazin-2-yl)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 11b- dodecahydrocyclopenta [1,2] phenanthro [8a, 9-b] oxiren-l(4H)-one (20 mg) as a white solid.

[0336] Analytical data:LCMS: 96.59% (m / z: 564.40, [M+l]+, 5.34 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 7.93-7.89 (m, 2H), 7.42 (d, J= 6.80 Hz, IH), 6.72 (s, 2H), 5.63 (d, = 3.20 Hz, IH), 4.59 (t, J= 5.20 Hz, IH), 4.29-4.25 (m, IH), 4.17-4.07 (m, 2H), 3.71 (dd, J = 3.20, 6.80 Hz, IH), 3.13 (s, IH), 2.41-2.33 (m, IH), 2.10-2.05 (m, 2H), 1.98 (s, 3H), 1.92-1.89 (m, IH), 1.82-1.77 (m, IH), 1.73-1.70 (m, IH), 1.60-1.54 (s, IH), 1.36- 1.20 (m, 8H), 1.14-1.02 (m, 3H), 0.97-0.86 (m, 4H), 0.84-0.79 (m, IH), 0.65 (s, 3H),13C-NMR (400 MHz, DMSO-6): d 200.69, 165.31, 155.19, 154.65, 140.42, 139.08, 135.28, 135.17, 132.11, 125.43, 77.52, 68.56, 63.57, 57.59, 55.25, 54.51, 51.03, 47.90, 42.16, 41.98, 30.79, 29.27, 29.02, 26.48, 23.96, 20.57, 19.87, 15.14, 13.02, 11.23.

[0337] Synthesis of Compound 33

[0338] Step-1: tert-butyl-7V-[6-(tributylstannyl)pyridin-3-yl]carbamate:To a stirred solution of tert-butyl-7V-(6-bromopyridin-3-yl)carbamate (2 g, 1.0 eq, 7.32 mmol) in tetrahydrofuran (20 mL) was added lithium(l+) butan-l-ide (797 mg, 1.7 eq., 12.4 mmol) at -78 °C. The reaction mixture was allowed to stir for Ih at same temperature. Then, tributyltin chloride (3.71 mL, 1.7 eq., 12.4 mmol) was added dropwise to the resultant reaction mixtureand further the reaction was stirred for 3 hours at room temperature. After the completion of reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and then extracted by DCM (30 mL X 3). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude product. The crude residue was purified by combi-flash column (eluted at 20% ethyl acetate in heptane) to afford / c / 7-butyl-A-[6-(tributylstannyl)pyridin-3- yl]carbamate (1.3 g, 2.69 mmol) as yellow gum.

[0339] Analytical data:LCMS: 95.10% (m / z: 485.22, [M+H]+, observed 485.25, [M+H]+, 3.37 min (4 min run).

[0340] Step-2: (IS, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl] ethyl] -4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8- oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (20 g, 1.0 eq, 42.5 mmol) in dichloromethane (0.2 L) was added? / , A-dimethylpyridin-4-amine (7.79 g, 1.5 eq., 63.7 mmol) followed by diiodine (12.9 g, 1.2 eq., 51 mmol) at 0 °C. The resultant reaction mixture was stirred for 2 h at room temperature. After the completion of reaction (monitored by TLC), the reaction mixture was quenched with 20% sodium thiosulfate solution (300 mL) and was extracted by dichloromethane (3 X 300 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude product. The crude was purified by combi-flash column (eluted at 5% methanol in DCM) to afford (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6- oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (14 g, 23.5 mmol) as a white solid.

[0341] Analytical data:LCMS: 90.55% (m / z: 595.16, [M+H]+, observed 595.18, [M+H]+, 2.29 min (4 min run).

[0342] Step-3: tert-butyl-A-{6-[(l S, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-6-hydroxy-15- [(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-3-oxo-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-4-yl]pyridin-3-yl} carbamateTo a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.8 g, 1.34 mmol) in tetrahydrofuran (10 mL, 123 mmol) was added X1-copper(l+) iodide (25.5 mg, 0.1 eq., 134 pmol), triphenylarsane (41.1 mg, 0.1 eq., 134 pmol), and tert-butyl N-[6-(tributylstannyl) pyridin-3-yl]carbamate (778 mg, 1.2 eq., 1.61 mmol). The reaction mixture was purged with argon for 30 min. Tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (12.3 mg, 0.01 eq., 13.4 pmol) was added to the reaction mixture and again purged with argon for 5 min. The resultant reaction mixture was stirred for 2 hours at 80°C. After the completion of reaction (monitored by TLC), the reaction mixture was filtered through celite bed and was concentrated under reduced pressure to get crude product. The crude residue was purified by combi-flash column (eluted at 3% methanol in DCM) to afford tert-butyl-7V-{6-[(lS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-3-oxo-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-4-yl] pyridin-3-yl} carbamate (0.6 g, 905 pmol).

[0343] Analytical data:LCMS: 93.68% (m / z: 663.3, [M+l]+, 2.07 min (4 min run).’H-NMR (400 MHz, DMSO-6): d 9.68 (s, 1H), 8.63 (s, 1H), 7.88 (dd, J= 8.4 Hz, 6.0 Hz, 1H), 7.55 (d, J= 6.4 Hz, 1H), 7.33 (d, J= 8.8 Hz, 1H), 5.66 (d, J= 1.6 Hz, 1H), 4.57 (t, J= 0.8 Hz, 1H), 4.11-4.30 (m, 3H), 3.72-3.74 (m, 1H), 3.14 (s, 1H), 2.49-2.50 (m, 1H), 2.10-2.10 (m, 3H), 1.99 (s, 5H), 1.40-1.49 (m, 4H), 1.40 (s, 9H), 1.07-1.33 (m, 22H), 0.66 (s, 3H).

[0344] Step-4: (IS, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-4-(5-aminopyridin-2-yl)-6- hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl]ethyl]-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-oneTo a stirred solution of tert-butyl-A-{6-[(lS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-3-oxo-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-4-yl]pyri din-3 - yljcarbamate (0.6 g, 905 pmol) in dichloromethane (6 mL, 93.7 mmol) was added trifluoroacetic acid (1.5 mL) dropwise at 0°C. The reaction mass was stirred for 3 hours at 0 °C. After the completion of reaction (monitored by TLC), the reaction mixture was quenched by saturated sodium bicarbonate solution (30 mL) and extracted with di chloromethane (3 x 30mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude product. The crude residue was purified by preparative HPLC (ABC method) to afford (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-4-(5- aminopyridin-2-yl)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec- 4-en-3-one (61 mg, 19.6%, 0.177 pmol) as yellow solid.

[0345] Analytical data:LCMS: 93.72% (m / z: 563.5, [M+H]+, observed 563.50, [M+H]+,6.11 min (15 min run).’H-NMR (400 MHz, DMSO-6) d 7.94 (d, J= 2.8 Hz, 1H), 7.40 (d, J= 6.8 Hz, 1H), 7.07 (d, J= 8.8 Hz, 1H), 6.88-6.90 (m, 1H), 5.57 (bs, 3H), 4.59 (bs, 1H), 4.26-4.30 (m, 1H), 4.08-4.17 (q, J = 19.6 Hz, 2H), 3.68 (d, J = 6.4 Hz, 1H), 3.13 (s, 1H), 2.41-2.50 (m, 1H), 2.01-2.11 (m, 5H), 1.92-1.99 (m, 1H), 1.54-1.89 (m, 3H), 1.22-1.37 (m, 8H), 1.00-1.20 (m, 3H), 0.91-0.95 (m, 5H), 0.65 (s, 3H).13C-NMR (400 MHz, DMSO-6) d 201.02, 165.31, 154.66, 144.77, 141.07, 139.49, 136.04, 134.62, 125.43, 122.48, 119.40, 77.52, 68.67, 63.70, 57.56, 55.33, 54.51, 51.02, 47.88, 42.14, 42.0, 30.84, 29.26, 29.01, 26.49, 23.97, 20.55, 19.88, 15.13, 13.02, 11.24.

[0346] Synthesis of Compound 34Compound 34

[0347] Step-1: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, HaS, HbR)-9-((S)-l- ((R)-5-((dimethylamino)methyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-4- hydroxy-9a, llb-dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a,9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-4- (pyridin-2-yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (250 mg, 456 pmol)in dichloromethane (2.5 mL, 39 mmol) was added ethylbis (propan-2-yl)amine (147 mg, 2.5 eq., 1.14 mmol) then methanesulfonyl chloride (52.3 mg, 456 pmol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. After the completion of reaction, (monitored by TLC) quenched it with water (40 ml) and extracted with ethyl acetate (2 X 40 ml). The combined organic layer was washed with saturated brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to get [(6R)-6-[(lS)-l-[(lS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-2,16-dimethyl-3-oxo-4-(pyridin-2-yl)-8-oxapentacyclo[9.7.0.02,7.07,9.012,16] octadec-4-en-15-yl]ethyl]-4-methyl-2-oxo-5, 6-dihydro-2H-pyran-3- yl]methyl methanesulfonate. It was forwarded as such to next reaction.To a stirred solution of dipotassium carbonate (110 mg, 2 eq., 799 pmol) in acetonitrile (3 mL, 57.4 mmol) was added dimethylamine (27 mg, 1.5 eq., 599 pmol) followed by addition of [(6R)-6-[(lS)-l-[(lS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-2, 16-dimethyl-3-oxo- 4-(pyri din-2 -yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-15-yl]ethyl]-4-methyl-2- oxo-5, 6-dihydro-2H-pyran-3-yl] methyl methanesulfonate (250 mg, 0.4 mmol) at 0°C. The resultant reaction mixture was stirred at 60°C for 30 min. After the completion of reaction (monitored by TLC), quenched it with water (40 ml) and extracted with ethyl acetate (2 X 40 ml). The organic layer was washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude. The crude was purified by using preparative-HPLC using ammonium acetate method to afford (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-9-((S)-l-((R)-5-((dimethylamino)methyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-4-hydroxy-9a, 1 lb-dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (15 mg, 6.53%) as a white solid.

[0348] Analytical data:LCMS: 88.53% (m / z: 575.50, [M+l]+, 4.81 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.60 (d, J= 4.40 Hz, 1H), 7.85-7.80 (m, 1H), 7.68 (d, J= 6.80 Hz, 1H), 7.39 (d, = 8.40 Hz, 1H), 7.35-7.34 (m, 1H), 5.74 (d, J= 3.60 Hz, 1H), 4.29-4.26 (m, 1H), 3.76 (dd, J= 3.20, 6.80 Hz, 1H), 3.18 (d, J= 10.8 Hz, 2H), 2.98 (d, J= 12.4 Hz, 1H), 2.39 (d, J= 4.40 Hz, 1H), 2.12 (d, J= 2.80 Hz, 1H), 2.07 (s, 6H), 2.02-1.98 (m, 4H), 1.93-1.90 (m, 1H), 1.79-1.75 (m, 3H), 1.60-1.19 (m, 8H), 1.14-1.04 (m, 4H), 0.97-0.87 (m, 4H), 0.66 (s, 3H).

[0349] Synthesis of Compound 35

[0350] Step-1: Synthesis of (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, llaS, llbR)-4-fluoro-9- ((S)-l-((R)-5-(fluoromethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 11b- dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, llb-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-oneTo a stirred solution of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l- ((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 11b- dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, l lb-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (0.5 g, 0.913 mmol) in dichloromethane (10 mL) was added diethyl(trifluoro-X4-sulfanyl)amine (0.241 mL, 2 eq., 1.83 mmol) (dissolved in DCM (1 mL)) dropwise at -78 °C under inert atmosphere and stirred for 15 min. After completion of reaction (monitored by TLC and by LCMS), quenched it by saturated Sodium bicarbonate solution (20 mL) and extracted using dichloromethane (3 x 30 mL). Collected organics, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The crude was purified by combi-flash chromatography over silica column (10-20% ethyl acetate in hexane) followed by prep HPLC purification in ammonium acetate method to yield (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-fhioro-9-((S)-l-((R)-5-(fhioromethyl)- 4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, l lb-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren- l(4H)-one (7 mg, 0.0127 mmol, 2%) as white solid.

[0351] Analytical data:LCMS: 97.63% (m / z: 552.50, [M+l]+, 6.87 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.62 (d, J= 4.4 Hz, 1H), 7.85 (t, J= 7.6 Hz, 1H), 7.56 (d, J= 16.8 Hz, 1H), 7.47 (d, J= 7.6 Hz, 1H), 7.40-7.37 (m, 1H), 5.87 (d, J= 50.1 Hz, 1H), 5.19 - 5.14 (m, 1H), 5.07 - 5.02 (m, 1H), 4.36 (d, J= 12.8 Hz, 1H), 3.52 (s, 1H), 2.32-2.21 (m, 1H), 2.08-2.05 (m, 4H), 1.93-1.29 (m, 9H), 1.23 (s, 3H), 1.16-0.97 (m, 5H), 0.93 (d, J = 6.4 Hz, 3H), 0.68 (s, 3H).19F-NMR (400 MHz, DMSO-6): d 201.92, 206.73.

[0352] Synthesis of Compound 36

[0353] Step-1: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, HaS, HbR)-4-hydroxy- 9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-2-(5- methoxypyrazin-2-yl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-oneA stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.2 g, 335 pmol), 2-methoxy-5- (tributylstannyl) pyrazine (161 mg, 1.2 eq., 402 pmol), triphenylarsine (10.3 mg, 0.1 eq., 33.5 pmol) and diiodocopper (16 mg, 0.15 eq., 50.3 pmol) in tetrahydrofuran (5 mL, 61.4 mmol) were purged with nitrogen for 35 min. Added palladium — (lE,4E)-l,5-diphenyl-l,4- pentadien-3-one (2 / 3) (15.4 mg, 0.05 eq., 16.8 pmol) and again purged with nitrogen for 5 min. The reaction was stirred at 80°C for 8h. After completion of reaction (monitoring by TLC). The reaction mixture was cooled & quenched with water (50 mL) and was extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afforded the crude, which was purified in prep-HPLC by ABC method to get (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 1 laS, 1 lbR)-4-hydroxy-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-(5-methoxypyrazin-2-yl)-9a, 1 lb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (39 mg, 20.1%) as white solid.

[0354] Analytical data: 98.57 % (m / z: 579.5, [M+l]+, 5.62 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 1H-NMR (400 MHz, DMSO-d6): 5 8.36 (d, J = 1.60 Hz, 1H), 8.22 (d, J = 1.20 Hz, 1H), 7.60 (d, J = 6.80 Hz, 1H), 5.78 (d, J = 3.20 Hz, 1H), 4.60 (t, J = 5.60 Hz, 1H), 4.26-4.30 (m, 1H), 4.07-4.18 (m, 2H), 3.93 (s, 3H), 3.74-3.77 (m, 1H), 3.17 (s, 1H), 2.33-2.50 (m, 1H), 2.07-2.11 (m, 1H), 2.06 (s, 3H), 1.55-2.02 (m, 4H), 1.22-1.40 (m, 8H), 0.86-1.14 (m, 8H), 0.66 (s, 3H).

[0355] Synthesis of Compound 37

[0356] Step-1: Synthesis of (IS, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-6-hydroxy-15- [(1 S)-l- [(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl] ethyl]-4-(5- methoxypyrimidin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4- en-3-oneTo a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.2 g, 0.335 mmol) and 5- methoxy-2-(tributylstannyl) pyrimidine (0.2g, 1.5 eq., 0.503 mmol) in N,N- dimethylformamide (4 mL) were added triphenylarsane (0.010 g, 0.1 eq., 0.033 mmol) andcopper(l+) iodide (0.009 g, 0.15 eq., 0.05 mmol). The resulting reaction mixture was purged with argon for 30 min. Added tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (0.03 g, 0.1 eq., 0.033 mmol) and purged with argon for 5min. Stirred at 60°C for 3h. Cooled to room temperature. Quenched with water (50 mL) and extracted using ethyl acetate (3 x 50 mL). Collected organics, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The crude product was purified by combi flash column chromatography using (70-90% ) ethyl acetate in hexane as an eluent followed by Prep HPLC purification in ammonium acetate method to afford (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)- 6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl]ethyl]-4-(5-methoxypyrimidin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.027 g, 0.046 mmol, 14% ) as white solid.

[0357] Analytical data: 99.25% (m / z: 579.5, [M+l]+, 5.24 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.57 (s, 2H), 7.53 (d, J =6.8, 1H), 5.76 (d, J= 3.6 Hz, 1H), 4.60 (t, J= 5.6 Hz, 1H), 4.30-4.26 (m, 1H), 4.18-4.07 (m, 2H), 3.92 (s, 3H), 3.74-3.71 (m, 1H), 3.13 (s, 1H), 2.40-2.32 (m, 1H), 2.13-2.07 (m, 2H), 1.99 (s,3H), 1.92-1.90 (m, 2H), 1.80-1.71 (m, 2H), 1.57-1.48 (m, 2H), 1.39-1.23 (m, 7H), 1.16-1.04 (m, 3H), 0.93 (m, 5H), 0.65 (s, 3H).13C-NMR (400 MHz, DMSO-6): 3 199.02, 165.33, 155.23, 154.70, 152.06, 143.61, 141.42, 139.96, 125.44, 77.54, 68.57, 63.83, 57.45, 56.19, 55.47, 54.51, 51.04, 42.03, 41.80, 30.89, 29.06, 29.02, 26.52, 23.98, 22.51, 21.21, 20.19, 19.90, 14.82, 13.05, 11.24.

[0358] Synthesis of Compound 38

[0359] Step-1: Synthesis of 5-methoxy-2-(tributylstannyl)pyrimidineTo a stirred solution of 2-chloro-5-methoxypyrimidine (1 g, 6.92 mmol) in toluene (10 mL) was added hexabutyldi stannane (5.62 g, 1.4 eq., 9.68 mmol). The reaction mixture was purged with argon gas for 30 min then Tetrakis (triphenylphosphine) palladium(O) (0.399 g, 0.05 eq., 0.346 mmol) was added to it. The reaction mixture was again purged with argon gas for 5 min. The reaction was stirred at 110°C for 16h. After completion of the reaction, the mixture was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated to get the crude which was then purified by column chromatography using 0-10% ethyl acetate in heptane as an eluent to afford 5 -methoxy -2-(tributylstannyl) pyrimidine (1 g, 2.51 mmol, 36%) as colourless liquid.

[0360] Analytical data:LCMS: 99.0% (m / z: 401.15, [M+l]+, 3.48 min (4 min run).

[0361] Step-2: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, llaS, llbR)-9-((S)-l- ((R)-5-(((tert-butyldimethylsilyl) oxy) methyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-4-hydroxy-2-iodo-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-hydroxy-9-((S)-l- ((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-2-iodo-9a, 11b- dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (5 g, 8.38 mmol) in dimethylformamide (0.1 L, 1.29 mol) was added 4-(pyrrolidin-l-yl)pyridin-l-ium (6.25 g, 5 eq., 41.9 mmol). After 10 minutes tert-butyl (chloro) dimethylsilane (12.6 g, 10 eq., 83.8 mmol) was added and heated the reaction up to 85 °C for 3hrs. After completion of reaction (monitored by TLC) the mixture was diluted with ice cold water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with saturated brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain the crude material, which was purified by column chromatography in 0 - 100% ethyl acetate in Heptane to obtain the compound (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-9-((S)-l-((R)-5-(((tert- butyldimethylsilyl)oxy)methyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-4- hydroxy-2-iodo-9a, 1 lb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 11b-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (1.8 g, 2.41 mmol, 29%) as off white solid.

[0362] Analytical data:LCMS: 95.79% (m / z: 711.10, [M+H]+, 4.10 min (6 min run).’H-NMR (400 MHz, DMSO-6): d 5.89 (d, J = 4.00 Hz, 1H), 4.27-4.35 (m, 3H), 3.48-3.51 (m, 1H), 3.19 (s, 1H), 2.31-2.51 (m, 1H), 2.16 (d, J = 2.80 Hz, 1H), 2.02 (m, 4H), 1.51-1.90 (m, 4H), 1.21-1.38 (m, 8H), 0.91-1.20 (m, 8H), 0.85 (s, 9H), 0.64 (s, 3H), 0.41 (s, 6H).

[0363] Step-3: Synthesis of (IS, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-15-[(1S)-1-[(2R)- 5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl]ethyl]-6-hydroxy-4-(5-methoxypyrimidin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-oneTo a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-15-[(lS)-l-[(2R)-5-{[(tert- butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-6- hydroxy-4-iodo-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.8 g, 1.13 mmol) and 5 -methoxy -2-(tributylstannyl) pyrimidine (0.674 g, 1.5 eq., 1.69 mmol) in THF (10 mL) were added triphenylarsane (0.035 g, 0.1 eq., 0.113 mmol) and X1-copper(l+) iodide (0.032 g, 0.15 eq., 0.169 mmol) at room temperature. The resulting mixture was purged with argon for 30 min. After that tris ((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (0.103 g, 0.1 eq., 0.113 mmol) was added to the mixture and stirred for 3h at 85°C. After completion of the reaction (monitored by TLC and LCMS), it was quenched by adding water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organics were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude, which was purified by combi flash column chromatography on silica column using (70-90%) ethyl acetate in heptane as an eluent to afford (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-15- [(lS)-l-[(2R)-5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H- pyran-2-yl]ethyl]-6-hydroxy-4-(5-methoxypyrimidin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.15 g, 19%) as an off white solid.

[0364] Analytical data: LCMS: 98.06% (m / z: 693.26, [M+l]+, 3.03 min (4 min run).

[0365] Step-4: Synthesis of (IS, 2R, 6R, 7S, 9R, IIS, 12S, 15R, 16S)-15-[(1S)-1-[(2R)- 5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-6-fluoro-4-(5-methoxypyrimidin-2-yl)-2, 16-dimethyl-8-oxapentacyclo[9.7.0.02,7.07,9.012,16] octadec-4-en-3-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-15-[(lS)-l-[(2R)-5-{[(tert- butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-6- hydroxy-4-(5-methoxypyrimidin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.15 g, 0.216 mmol) in dichloromethane (5 mL) was added diethyl(trifluoro-X4-sulfanyl) amine solution (0.034 mL, 1.2 eq., 0.26 mmol) (dissolved in DCM (1 mL)) drop wise at -78°C under inert atmosphere and stirred for 15 min. After completion of reaction (monitored by TLC and by LCMS), quenched by adding saturated Sodium bicarbonate solution (30 mL) and extracted using dichloromethane (2 x 30 mL). Collected organics, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude, which was purified by combi-flash chromatography on silica column (10-20% ethyl acetate in heptane) to yield (IS, 2R, 6R, 7S, 9R, 11 S, 12S, 15R, 16S)- 15-[(lS)-l-[(2R)-5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H- pyran-2-yl]ethyl]-6-fluoro-4-(5-methoxypyrimidin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.055 mg, 0.079 mmol, 36%) as off white solid.

[0366] Analytical data: LCMS: 78.08% (m / z: 695.30, [M+l]+, 4.52 min (6 min run).

[0367] Step-5: Synthesis of (IS, 2R, 6R, 7S, 9R, IIS, 12S, 15R, 16S)-6-fluoro-15-[(lS)- l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl] ethyl] -4-(5- methoxypyrimidin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4- en-3-one:To a solution of (IS, 2R, 6R, 7S, 9R, 11 S, 12S, 15R, 16S)-15-[(lS)-l-[(2R)-5-{[(tert- butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-6-fluoro- 4-(5-methoxypyrimidin-2-yl)-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4- en-3-one (50 mg, 0.309 mmol) in THF (0.5 mL) and methanol (0.5 mL) was added 2N HC1 solution (0.5 mL) drop wise at 0°C and stirred for 30 min. After completion of the reaction (monitored by TLC and LCMS), it was quenched by adding sodium bicarbonate solution (20 mL). It was then extracted using dichloromethane (2 x 20 mL). Collected organics, dried over sodium sulphate and concentrated under reduced pressure to obtain crude which was then purified by combi-flash chromatography (5% methanol and di chloromethane) followed by prep HPLC purification in ammonium acetate method to afford (IS, 2R, 6R, 7S, 9R, 1 IS, 12S, 15R,16S)-6-fluoro-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran- 2-yl]ethyl]-4-(5-methoxypyrimidin-2-yl)-2, 16-dimethyl-8 oxapentacyclo[9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (10.8 mg, 60%) as white solid.

[0368] Analytical data: 92.82% (m / z: 581.5, [M+l]+, 7.65 min (14 min run).’H-NMR (400 MHz, DMSO-6): d 8.60 (s, 2H), 7.41 (dd, J= 1.6 Hz, 16.8 Hz, 1H), 5.85 (d, J = 50.0 Hz, 1H), 4.60 (t, J= 5.6 Hz, 1H), 4.30-4.27 (m, 1H), 4.18-4.07 (m, 2H), 3.93 (s, 3H), 3.50 (s, 1H), 2.43-2.32 (m, 1H), 2.13-2.06 (m, 2H), 2.00 (s, 3H), 1.93-1.89 (m, 2H), 1.81-1.71 (m, 2H), 1.58 (br, 2H), 1.40-1.27 (m, 4H), 1.20 (s, 3H), 1.18-0.98 (m, 4H), 0.93 (d, J= 6.4 Hz, 3H), 0.67 (s, 3H).19F-NMR (400 MHz, DMSO-6): d 202 31

[0369] Synthesis of Compound 39

[0370] Step-1: Synthesis of 5-fluoro-4-(trimethylstannyl)pyrimidine:To a stirred solution of 4-chloro-5-fluoropyrimidine (0.5 g, 3.77 mmol) in dry toluene (8 mL, 75.3 mmol) added hexamethyldistannane (1.85 g, 1.5 eq., 5.66 mmol). The reaction mixture was purged with argon gas for 30 min. Then tetrakis(triphenylphosphane) palladium (218 mg, 0.05 eq., 189 pmol) was added. Again, the reaction mixture was purged with argon gas for 5 min. The reaction mixture was heated at 110 °C for 3h. Monitored the reaction by TLC. Cooled the reaction mass to room temperature. The crude residue was poured into a KF solution (100mL) and extracted with EtOAc (3 X 50 mL), dried over Na2SO4, filtered and evaporated under vacuum to get crude residue. The crude was directly forwarded to the next step without further purification. LCMS mass not supported. TLC showed prominent non-polar spot.

[0371] Step-2: Synthesis of (IS, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-4-(5- fluoropyrimidin-4-yl)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one:A stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.5 g, 838 pmol), 5-fluoro-4- (trimethylstannyl) pyrimidine (437 mg, 2 eq., 1.68 mmol) and X1-copper(l+) iodide (23.9 mg, 0.15 eq., 126 pmol) in dimethylformamide (5 mL, 64.6 mmol) were purged with N2 gas for 35 min, followed by addition of [1, 1 '-Bis (diphenylphosphino) ferrocene] dichloropalladium(II) (34.2 mg, 0.05 eq., 41.9 pmol). The reaction mixture was again purged with N2 gas for 5 min. The reaction vessel was sealed and stirred at 60°C for 16h.The reaction was monitored by TLC (SM was consumed) and was quenched by adding ice-cold water (30 mL). The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated by high vacuum to get the crude residue, which was purified by prep. HPLC (ABC method) to afforded (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-4-(5-fhioropyrimidin-4-yl)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8- oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (62 mg, 13.05%) desired compound.

[0372] Analytical data:LCMS: 98.77% (m / z: 567.70, [M+l]+, 5.33 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.93 (s, 2H), 7.64 (d, J= 6.8 Hz, 1H), 5.83 (d, J= 4.0 Hz, 1H), 4.60 (t, J= 5.2 Hz, 1H), 4.28 (m, 1H), 4.18 - 4.07 (m, 2H), 3.67 - 3.74 (m, 1H), 3.15 (s, 1H), 2.49-2.39 (m, 1H), 2.18 - 2.07 (m, 5H), 1.93-1.63 (m, 3H), 1.61 - 1.44 (m, 2H), 1.39-1.23 (m, 7H), 1.18-1.04 (m, 3H), 0.98 - 0.05 (m, 5H), 0.66 (s, 3H).13C-NMR (400 MHz, DMSO-6): 198.75, 165.33, 158.94, 158.89, 157.85, 155.23, 154.70, 145.67, 145.47, 142.22, 140.73, 125.44, 77.54, 68.47, 63.69, 57.47, 55.44, 54.52, 51.03, 47.86, 30.84, 29.06, 26.53, 23.98, 21.29, 20.19, 19.9, 14.86, 13.05, 11.24.

[0373] Synthesis of Compound 40

[0374] Step-1: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, llaS, llbR)-9-((S)-l- ((R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-4-hydroxy-2-(5-methoxypyrazin-2-yl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, llb-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-oneTo a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-15-[(lS)-l-[(2R)-5-{[(tert- butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-6- hydroxy-4-iodo-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (1 g, 1.41 mmol), 2-methoxy-5-(tributylstannyl)pyrazine (618 mg, 1.1 eq., 1.55 mmol), triphenylarsine (43.1 mg, 0.1 eq., 141 pmol) and diiodocopper (67 mg, 0.15 eq., 211 pmol) in tetrahydrofuran (12 mL). The reaction mixture was purged with nitrogen for 35 min and palladium — (lE,4E)-l,5-diphenyl-l,4-pentadien-3-one (2 / 3) (64.4 mg, 0.05 eq., 70.3 pmol) was added to it . The reaction mixture was again purged with nitrogen for 5 min. The reaction was stirred at 60°C for 2h. After completion of reaction (monitoring by TLC), the reaction mixture was cooled & quenched water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under vacuum to afford the crude. The crude residue was purified through combi-flash purifier (12 g silica gelwelch column) and eluted with 40-50% EtOAc in heptane. The pure fractions were collected and evaporated under reduced pressure to get desired product (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-9-((S)-l-((R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-4-hydroxy-2-(5-methoxypyrazin-2-yl)-9a, 1 lb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren- l(4H)-one (350 mg, 35%) as yellowish solid.

[0375] Analytical data: 66.8 % (m / z: 693.20, [M+l]+, 2.67 min (4 min run).

[0376] Step-2: Synthesis of (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, llaS, llbR)-9-((S)-l- ((R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-4-fluoro-2-(5-methoxypyrazin-2-yl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, llb-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-oneTo a stirred solution of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-9-((S)-l-((R)-5-(((tert- butyldimethylsilyl) oxy) methyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-4- hydroxy-2-(5-methoxypyrazin-2-yl)-9a, 1 lb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, l lb-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (230 mg, 332 pmol) in dichloromethane (3 mL) at -78°C, was added diethyl(trifluoro-X4-sulfanyl) amine (52.6 pL, 1.2 eq., 398 pmol) dissolved in DCM (1 mL) drop wise under inert atmosphere and stirred for 15 min. After completion of reaction (monitored by TLC and by LCMS), quenched by adding saturated sodium bicarbonate solution (30 mL) and extracted using di chloromethane (2 x 30 mL). Collected organics, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The crude residue obtained was purified by combi-flash purifier (4g gel welch column) and eluted with 10-15% ethyl acetate in heptane. The pure fractions were collected and evaporated under reduced pressure to get desired product (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-9-((S)-l-((R)-5-(((tert-butyldimethylsilyl) oxy) methyl)-4-methyl- 6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-4-fluoro-2-(5-methoxypyrazin-2-yl)-9a, 11b- dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, l lb-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (0.1 g, 43%) as yellowish solid.

[0377] Analytical data: 49.91 % (m / z: 695.35, [M+l]+, 4.39 min (6 min run).

[0378] Step-3: Synthesis of (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, llaS, llbR)-4-fluoro-9- ((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-2-(5-methoxypyrazin-2-yl)-9a, llb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, 11b- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-oneTo a stirred solution of (R)-6-[(S)-l-{(lS, 2R, 6R, 7S, 9R, I IS, 12S, 15R, 16S)-6-fluoro-2, 16- dimethyl-3-oxo-4-(2-pyrimidinyl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-15- yl}ethyl]-3-{[(tert-butyl)bis(methyl)siloxy]methyl}-4-methyl-5, 6-dihydro-2H-pyran-2-one (450 mg, 677 pmol) in tetrahydrofuran (4 mL), and methanol (4 mL), 2N HC1 (4 mL) was added at 0°C. Stirred the reaction mixture for 30 min at 0°C. After the completion of reaction (monitoring by TLC), the reaction mixture was quenched with saturated NaHCO3 solution (40 mL) and extracted with ethyl acetate (2 x 40 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to afford the crude. The compound was purified by prep-HPLC using ABC method to obtain desired product (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-fhioro-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl) ethyl)-2-(5-methoxypyrazin-2-yl)-9a, 1 lb-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (12 mg, 14%) as white solid.

[0379] Analytical data: 97.79 % (m / z: 581.5, [M+l]+, 6.49 min (10 min run).’H-NMR (400 MHz, DMSO-< / 6): 8 8.38 (d, J = 1.20 Hz, 1H), 8.33 (d, J = 0.80 Hz, 1H), 7.50 (dd, J = 1.60, 16.80 Hz, 1H), 5.88 (d, J = 49.60 Hz, 1H), 4.60 (t, J = 5.20 Hz, 1H), 4.27-4.30 (m, 1H), 4.08-4.18 (m, 2H), 3.94 (s, 3H), 3.53 (s, 1H), 2.33-2.43 (m, 1H), 2.08-2.13 (m, 2H), 2.00 (s, 3H), 1.28-1.93 (m, 9H), 1.23 (s, 3H), 0.97-1.16 (m, 4H), 0.92 (d, J = 6.80 Hz, 3H), 0.68 (s, 3H).19F-NMR (400 MHz, DMSO-6): d -201 82

[0380] Synthesis of Compound 41

[0381] Step-1: Synthesis of 6-(trimethylstannyl)pyridin-2-amine (0.4 g, 1.48 mmol)To a stirred solution of 6-bromopyridin-2-amine (1 g, 5.78 mmol) in toluene (8 mL, 75.3 mmol) was added hexamethyldistannane (1.89 g, 5.78 mmol). The reaction mixture was purged by using nitrogen gas for 10 min. To the resulting reaction mixture, was added tetrakis (triphenylphosphane) palladium (0.2 g, 0.03 eq., 173 pmol). The reaction mixture was stirred at 130 °C for 4h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by combi flash over silica column (0 - 20% ethyl acetate in heptane) to obtain desired product 6-(trimethylstannyl)pyridin-2- amine (0.4 g, 25.5%) as brown gum.

[0382] Analytical data:LCMS: 91% (m / z: 259.02, [M+l]+, 1.49 min (4 min run).

[0383] Step-2: Synthesis of (IS, 2R, 6S, 7R, 9R, IIS, 12S, 16S)-4-(6-aminopyridin-2- yl)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H- pyran-2-yl]ethyl]-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.1 g, 172 pmol)To a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 16S)-6-hydroxy-15-[(lS)-l-[(2R)-5- (hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16-dimethyl- 8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (1.5 g, 2.51 mmol) in tetrahydrofuran (10 mL) was added 6-(trimethylstannyl) pyridin-2-amine (775 mg, 1.2 eq., 3.02 mmol). The reaction mixture was purged with nitrogen gas for 10 min. To the resulting mixture, were added copper(l+) iodide (47.9 mg, 0.1 eq., 251 pmol) and triphenylarsane (77 mg, 0.1 eq., 251 pmol) followed by tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (115 mg, 0.05 eq., 126 pmol). The reaction was stirred at 80°C for 2 hours. After the completion of the reaction (monitoring by TLC), reaction mixture was filtered through celite bed. The filtrate was diluted with water (70 mL) and extracted with ethyl acetate (2 x 50 ml). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to get crude compound. The crude compound was purified by prep HPLC in ABC buffer to obtain the desired compound (IS, 2R, 6S, 7R, 9R, 1 IS, 12S, 16S)-4- (6-aminopyri din-2 -yl)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec- 4-en-3-one (0.1 g, 6.86%) as yellow solid.

[0384] Analytical data:LCMS: 97.76% (m / z: 563.5), [M+l]+, 5.16 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 7.53 (d, J= 6.8 Hz, 1H), 7.37 (t, J= 7.6 Hz, 1H) ,6.53 (d, J= 7.6 Hz, 1H), 6.41 (d, J= 8.4 Hz, 1H), 5.95 (bs, 2H), 5.63 (d, J = 3.2 Hz, 1H), 4.59 (t, J = 5.2 Hz, 1H), 4.30 - 4.25 (m, 1H), 4.17 - 4.07 (m, 2H), 3.72 - 3.70 (m, 1H), 3.13 (s, 1H), 2.41 - 2.33 (m, 1H), 2.11 -2.01 (m, 1H), 1.98 (s, 3H), 1.91 - 1.51 (m, 4H), 1.37 - 1.19 (m, 8H), 1.14 - 0.77 (m, 8H), 0.65 (s, 3H).13C-NMR (400 MHz, DMSO-6): d 200.75, 165.29, 159.22, 154.66, 149.88, 141.39, 137.85, 137.52, 125.40, 110.34, 108.40, 77.49, 68.52, 63.65, 57.40, 55.32, 54.49, 50.97, 47.91, 42.08, 41.98, 40.12, 30.79, 29.20, 28.98, 26.48, 23.94, 20.54, 19.86, 15.02, 12.99, 11.22.

[0385] Synthesis of Compound 42

[0386] Step-1: Synthesis of 5-(tributylstannyl) pyrimidin-2-amineTo a stirred solution of 5-iodopyrimidin-2-amine (1 g, 4.52 mmol) in N, N-dimethylformamide (10 mL) was added hexabutyl di stannane (3.15 g, 1.2 eq., 5.43 mmol). The reaction mixture was purged with argon gas for 30 min then tris(dibenzylideneacetone)dipalladium (0.41 g, 0.1 eq., 0.45 mmol) was added to it . The reaction mixture was again purged with argon gas for 5min. The reaction mixture was stirred at 65°C for 3h. Cooled the reaction mass to room temperature, quenched with chilled water (50 mL) and extracted using ethyl acetate (2 x 50 mL). Collected organics, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The crude product was purified by combi flash column chromatography using (20-30% ) ethyl acetate in hexane as an eluent to afford 5- (tributylstannyl) pyrimidin-2-amine (1.4 g, 3.64 mmol, 80%) as an off white solid.

[0387] Analytical data:LCMS: 99.89% (m / z: 386.21, [M+l]+, 3.12 min (4 min run).

[0388] Step-2: Synthesis of (IS, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-4-(2- aminopyrimidin-5-yl)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-oneTo a stirred solution of (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.25 g, 0.41 mmol) and 5- (tributylstannyl) pyrimidin-2-amine (0.24 g, 1.5 eq., 0.63 mmol) in N, N-dimethylformamide (3 mL) were added triphenylarsane (0.013 g, 0.1 eq., 0.042 mmol) and X’-coppe^H-) iodide (0.012 g, 0.15 eq., 0.063 mmol). The resulting mixture was purged with argon for 30 min. After that tris((lE, 4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (0.038 g, 0.1 eq., 0.042 mmol) was added and stirred for 3h at 60°C. Cooled to room temperature, quenched by adding water (50 mL) and extracted using ethyl acetate (2 x 50 mL). Collected organics, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The crude product was purified by combi flash column chromatography using (5-10%) methanol in DCM as an eluent followed by Prep HPLC purification in ammonium acetate method to afford (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-4-(2-aminopyrimidin-5-yl)-6- hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl]ethyl]-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.022 g, 0.039 mmol, 9% ) as white solid.

[0389] Analytical data: 98.14% (m / z: 564.5, [M+l]+, 4.80 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.20 (s, 2H), 7.26 (d, J =6.8, 1H), 6.90 (s, 2H), 5.66 (d, J = 3.2 Hz, 1H), 4.59 (t, J= 5.2 Hz, 1H), 4.29-4.26 (m, 1H), 4.17-4.07 (m, 2H), 3.67-3.64 (m,1H), 3.16 (s, 1H), 2.41-2.33 (m, 1H), 2.10-2.01 (m, 2H), 1.99 (s,3H), 1.90-1.70 (m, 3H), 1.59- 1.55 (m, 1H), 1.35-1.23 (m, 8H), 1.14-0.95 (m, 4H), 0.92 (d, J = 6.8 Hz, 3H), 0.86-0.80 (m, 1H), 0.65 (s, 3H).

[0390] Synthesis of Compound 43

[0391] Step-1: Synthesis of 2-(tributylstannyl) pyrimidin-5-amineTo a stirred solution of 2-chloropyrimidin-5-amine (4 g, 30.9 mmol) in toluene (40 mL) was added hexabutyl di stannane (21.5 g, 1.2 eq., 37.1 mmol) at room temperature. The reaction mixture was purged with N2 for 30 minutes. After purging tetrakis (triphenylphosphane) palladium (3.57 g, 0.1 eq., 3.09 mmol) was added and again purged with N2 for 5 minutes. Reaction mixture was heated at 130 °C for 16h. Filtered the reaction mixture through hyper flow celite bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain crude. Crude product was purified by combi flash column chromatography using 40-50% ethyl acetate in heptane as an eluent to afford 2-(tributylstannyl) pyrimidin-5- amine (362 mg) as an off white solid.

[0392] Analytical data:LCMS: 90.82% (m / z: 385.21, [M+l]+, 2.59 min (4 min run).

[0393] Step-2: Synthesis of (IS, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-4-(5- aminopyrimidin-2-yl)-6-hydroxy-15-[(lS)-l-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-oneTo a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2, 16- dimethyl-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.2 g, 335 pmol) in dimethylformamide (3 mL), added 2-(tributylstannyl) pyrimidin-5-amine (155 mg, 1.2 eq., 402 pmol), X1-copper(l+) diiodide (16 mg, 0.15 eq., 50.3 pmol) and triphenylarsane (10.3 mg, 0.1 eq., 33.5 pmol) at room temperature. The reaction mixture was purged with N2 gas for 30 min and tris((lE,4E)-l,5-diphenylpenta-l,4-dien-3-one) dipalladium (3.07 mg, 0.01 eq., 3.35 pmol) was added to it . The reaction mixture was again purged with N2 gas for 5 min. The reaction was stirred at 60 °C for 4h. Subsequently, the reaction mass was quenched by adding water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The collected organics, dried over sodium sulphate and concentrated under reduced pressure to obtain crude. The crude product was purified by combi flash column chromatography using (5-10%) methanol in DCM as an eluent followed by Prep HPLC purification in ammonium bicarbonate method to afford (IS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-4-(5-aminopyrimidin-2-yl)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-8- oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (9 mg, 4.3%) as white solid.

[0394] Analytical data: 92.29% (m / z: 564.5, [M+l]+, 4.72 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.08 (s, 2H), 7.35 (d, J= 6.8 Hz, 1H), 5.73 (s, 2H), 5.62 (d, .7=3.2 Hz, 1H), 4.60 (t, J= 5.2 Hz, 1H), 4.30-4.07 (m, 3H), 3.68-3.66 (m, 1H), 3.10 (s, 1H), 2.42-2.35 (m, 2H), 2.12-1.99 (m, 6H), 1.91-1.71 (m, 3H), 1.61-1.43 (m, 2H), 1.38-1.00 (m, 11H), 0.65 (s, 3H).

[0395] Synthesis of Compound 44

[0396] Step-l:Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, llaS, llbR)-9-((S)-l- ((R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-4-hydroxy-9a, llb-dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, llb-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-4- (pyridin-2-yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (1 g, 1.83 mmol) in N, N-dimethylformamide (20 mL) were added 4-(l-pyrrolidinyl)pyridine (1.35 g, 5 eq., 9.13 mmol) and tert-butyl(chloro)dimethylsilane (2.75 g, 10 eq., 18.3 mmol) at room temperature. The resulting mixture was stirred at 85°C for Ih. Reaction was monitored by TLC. Quenched the reaction with water (40 mL) and extracted with ethyl acetate (2 X 50 mL). The organic layer was washed with chilled water followed by brine solution (50 mL). Dried the organics over sodium sulphate, filtered and concentrated under reduced pressure to get crude. The crude material was purified by Combi Flash by using 40-50% ethyl acetate in heptane as eluent, concentrated the desired fraction under reduced pressure to get (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-9-((S)-l-((R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-4-hydroxy-9a, 1 lb-dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1,2] phenanthro [8a, 9-b] oxiren-l(4H)-one (310 mg, 16.93%).

[0397] Analytical data:LCMS: 66.10% 2.57 min (m / z: 662.30, [M+l]+, (4 min run).

[0398] Step-2: Synthesis of (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, llaS, HbR)-9-((S)-l- ((R)-5-(((tert-butyldimethylsilyl) oxy) methyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl)ethyl)-4-fluoro-9a, llb-dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, llb-dodecahydrocyclopenta [1 ,2] phenanthro [8a, 9-b] oxiren-l(4H)-one:A mixture of (R)-6-[(S)-l-{(lS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-2, 16- dimethyl-3-oxo-4-(2-pyridyl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-15- yl}ethyl]-3-{[(tert-butyl) bis(methyl) siloxy] methyl}-4-methyl-5, 6-dihydro-2H-pyran-2-one (0.3 g, 453 pmol) in dichloromethane (3 mL) was added diethyl(trifluoro-X4-sulfanyl)amine (71.9 pL, 1.2 eq., 544 pmol) at -78°C. The reaction mixture was stirred at the same temperature for 5 minutes. After the completion of reaction (as monitored by TLC), was quenched with sodium bicarbonate solution (20 mL) and extracted with DCM (2 X 20 mL). The organic layer was washed with brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to get crude. The crude material was purified by Combi Flash using 25-30% ethyl acetate in heptane as a eluent, concentrated the desired fraction under reduced pressure to get (R)-6-[(S)-l-{(lS, 2R, 6R, 7S, 9R, 1 IS, 12S, 15R, 16S)-6-fluoro-2, 16-dimethyl-3-oxo- 4-(2-pyridyl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-15-yl} ethyl] -3- {[(tertbutyl) bis (methyl) siloxy] methyl}-4-methyl-5, 6-dihydro-2H-pyran-2-one (90 mg, 26.41%) as yellow solid.

[0399] Analytical data:LCMS: 88.29% (m / z: 664.30, [M+l]+, 2.83 min (4 min run).’H-NMR (400 MHz, DMSO-6): d 8.63 (d, J= 5.20 Hz, 1H), 7.95-7.84 (m, 1H), 7.59 (t, J= 16.50 Hz, 1H), 7.49 (d, J= 7.30 Hz, 1H), 7.40 (t, J = 6.20 Hz, 1H), 5.93-5.70 (m, 1H), 4.38- 4.27 (m, 3H), 3.54 (s, 1H), 2.43 (t, J = 15.7 Hz, 1H), 2.17 (s, 1H), 2.11 (d, J= 12.6 Hz, 3H), 1.93 (d, J= 12.5 Hz, 1H), 1.83 (d, = 6.9 Hz, 1H), 1.73 (s, 1H), 1.61 (t, J= 15.1 Hz, 2H), 1.43 (t, J = 10.9 Hz, 2H), 1.34 (d, J = 13.4 Hz, 2H), 1.24 (s, 4H), 1.14 (d, J= 9.8 Hz, 4H), 1.15- 1.03 (m, 2H), 1.01 (t, J= 8.90 Hz, 3H), 0.94 (d, J = 6.30 Hz, 8H), 0.73 (s, 3H), 0.05 (d, J = 3.10 Hz, 6H).

[0400] Step-3: Synthesis of (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, llaS, HbR)-4-fluoro-9- ((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, llb- dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:To a stirred solution of (R)-6-[(S)-l-{(lS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-2, 16-dimethyl-3-oxo-4-(2-pyridyl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-15- yl}ethyl]-3-{[(tert-butyl)bis(methyl)siloxy]methyl}-4-methyl-5, 6-dihydro-2H-pyran-2-one (90 mg, 136 pmol) in tetrahydrofuran (0.9 mL) was added methanol (0.9 mL) and 2N HC1 (0.9 mL) at 0°C. The resultant reaction mixture was stirred for 1 hour at 0°C. After completion of reaction (as monitored by TLC), it was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with DCM (2 x 30 mL). The combined organics were dried over sodium sulphate, filtered and concentrated under reduced pressure to get crude. The crude was purified by using preparative-HPLC (ABC method) to afford desired product (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-fluoro-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (12 mg, 15.58%) as a white solid.

[0401] Analytical data:LCMS: 97.03% (m / z: 550.50, [M+l]+, 6.40 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 8.62 (d, J = 4.40 Hz, 1H), 7.87-7.83 (m, 1H), 7.58-7.54 (m, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.40-7.37 (m, 1H), 5.88 (d, =50.4 Hz, 1H), 4.60 (t, J= 5.60 Hz, 1H), 4.30-4.27 (m, 1H), 4.17-4.07 (m, 2H), 3.52 (s, 1H), 2.42-2.34 (m, 1H), 2.12-2.08 (m, 2H), 2.04 (s, 3H), 1.99-1.81 (m, 1H), 1.80-1.73 (m, 1H), 1.73-1.71 (m, 1H), 1.63-1.55 (m, 2H), 1.53-1.44 (m, 2H), 1.42-1.31 (m, 2H), 1.22 (s, 3H), 1.65-1.08 (m, 3H), 1.07-0.97 (m, 2H), 0.92 (d, J= 6.80 Hz, 3H), 0.68 (s, 3H).19F-NMR (400 MHz, DMSO-6): d -202.099.

[0402] Synthesis of Compound 45

[0403] Step-1: Synthesis of (R)-6-[(S)-l-{(lS, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-6- hydroxy-2, 16-dimethyl-4-(6-methyl-2-pyridyl)-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16] octadec-4-en- 15-yl} ethyl] -3-(hydroxymethyl)-4-methyl-5, 6-dihydro- 2H-pyran-2-one:To a stirred solution of (R)-6-[(S)-l-{(lS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-4- iodo-2, 16-dimethyl-3-oxo-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-15-yl}ethyl]-3- (hydroxymethyl)-4-methyl-5, 6-dihydro-2H-pyran-2-one (1 g, 1.68 mmol), in tetrahydrofuran (12 mL) added tributyl(6-methyl-2-pyridyl)stannane (769 mg, 1.2 eq., 2.01 mmol), triphenylarsine (51.3 mg, 0.1 eq., 168 pmol) and diiodocopper (79.8 mg, 0.15 eq., 251 pmol). The reaction mixture was purged with nitrogen gas for 30 min and palladium — (IE, 4E)-1,5- diphenyl-l,4-pentadien-3-one (2 / 3) (76.8 mg, 0.05 eq., 83.8 pmol) was added to it . The reaction mixture was again purged with nitrogen gas for 5 min. The reaction was stirred at 80 °C for 2h. After the completion of reaction (as monitored by TLC 100% Ethyl acetate in hexane), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with saturated brine solution (50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The crude was purified by combi flash column chromatography using (60-70%) in ethyl acetate in hexane as an eluent to afford (R)-6-[(S)-l-{(lS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-2, 16-dimethyl-4-(6-methyl-2-pyridyl)-3-oxo-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4- en-15-yl}ethyl]-3-(hydroxymethyl)-4-methyl-5, 6-dihydro-2H-pyran-2-one (0.8 g, 68.8%b) as yellow solid.

[0404] Analytical data:LCMS: 80.92% (m / z: 562.20, [M+l]+, 2.033 min (4 min run).

[0405] Step-2: Synthesis of (IS, 2R, 6S, 7R, 9R, IIS, 12S, 15R, 16S)-15-[(1S)-1-[(2R)- 5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2- yl] ethyl] -6-hydr oxy-2, 16-dimethyl-4-(6-methylpyridin-2-yl)-8-oxapentacyclo[9.7.0.02,7.07,9.012,16] octadec-4-en-3-one:To a stirred solution of (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-6-hydroxy-15-[(lS)-l-[(2R)- 5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-2, 16-dimethyl-4-(6- methylpyridin-2-yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.8 g, 1.42 mmol) in dimethylformamide (16 mL) was added 4-(pyrrolidin-l-yl)pyridin-l-ium (1.06 g, 5 eq., 7.12 mmol) and tert-butyl(chloro)dimethylsilane (2.15 g, 10 eq., 14.2 mmol) at room temperature. The reaction was stirred at 80°C for Ih. After the completion of reaction (as monitored by TLC 70% Ethyl acetate in hexane), the reaction mixture was diluted with ice cold water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with saturated brine solution (50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain crude. The crude was purified by combi flash column chromatography using (40-50%) ethyl acetate in hexane as an eluent to afford (IS, 2R, 6S, 7R, 9R, I IS, 12S, 15R, 16S)-15-[(lS)-l-[(2R)-5-{[(tert-butyldimethylsilyl)oxy]methyl}-4- methyl-6-oxo-3, 6-dihydro-2H-pyran-2-yl]ethyl]-6-hydroxy-2, 16-dimethyl-4-(6- methylpyridin-2-yl)-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one (0.3 g, 29%) as white solid.

[0406] Analytical data:LCMS: 94.23% (m / z: 676.65, [M+l]+, 2.66 min (4 min run).

[0407] Step-3: Synthesis of (IS, 2R, 6R, 7R, 9R, IIS, 12S, 15R,16S)-15-[(1S)-1-[(2R)- 5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2- yl] ethyl] -6-(dimethylamino)-2, 16-dimethyl-4-(6-methylpyr idin-2-yl)-8- oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-3-one:To a stirred solution of (R)-6-[(S)-l-{(lS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-2, 16-dimethyl-4-(6-methyl-2-pyridyl)-3-oxo-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4- en-15-yl}ethyl]-3-{[(tert-butyl)bis(methyl)siloxy]methyl}-4-methyl-5,6-dihydro-2H-pyran-2- one (0.4 g, 592 pmol) in di chloromethane (4 mL) was added ethylbis (propan-2-yl)amine (382 mg, 5 eq., 2.96 mmol) then methane sulfonyl chloride (136 mg, 2 eq., 1.18 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. After the completion of reaction (monitoredby TLC 50% Ethyl acetate in hexane) mixture was diluted with water (20 mL) and extracted with DCM (2 x 30 mL). The organic layer was washed with brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to get ((R)-6-((S)-l-((4R, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, 1 lbR)-4-(dimethyl amino)-9a, 1 lb-dimethyl-2-(6-methylpyridin-2- yl)-l-oxo-l, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-9-yl) ethyl)-4-methyl-2-oxo-5, 6-dihydro-2H-pyran-3-yl) methyl methanesulfonate. It was forwarded as such to the next step. To a stirred solution of triethylamine (268 mg, 5 eq., 2.65 mmol) in acetonitrile (4 mL) was added dimethylamine (38.3 mg, 1.6 eq., 849 pmol) followed by addition of ((R)-6-((S)-l-((4R, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, 1 lbR)-4-(dimethylamino)-9a, 1 lb-dimethyl-2-(6- methylpyridin-2-yl)-l -oxo-1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 11b- tetradecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-9-yl)ethyl)-4-methyl-2-oxo-5,6- dihydro-2H-pyran-3-yl)m ethyl methanesulfonate (0.4 g, 530 pmol) at 0°C. The resultant reaction mixture was stirred at 60°C for 30 min. After the completion of reaction (monitored by TLC, 70% ethyl acetate in hexane), mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was washed with saturated brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to get crude (410 mg crude). The crude material was as such used for next step without further purification.

[0408] Analytical data:LCMS: 54.46% (m / z: 703.85, [M+l]+, 4.59 min (6 min run).

[0409] Step-4: Synthesis of (4R, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, llaS, llbR)-4- (dimethylamino)-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6-dihydro-2H- pyran-2-yl)ethyl)-9a, llb-dimethyl-2-(6-methylpyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, Ila, llb-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one:

[0410] To a stirred solution of (R)-6-[(S)-l-{(lS, 2R, 6R, 7R, 9R, 11 S, 12S, 15R, 16S)-6- (dimethylamino)-2,16-dimethyl-4-(6-methyl-2-pyridyl)-3-oxo-8-oxapentacyclo[9.7.0.02,7.07,9.012,16] octadec-4-en-15-yl}ethyl]-3-{[(tert-butyl) bis (methyl) siloxy] methyl}- 4-methyl-5, 6-dihydro-2H-pyran-2-one (410 mg, 583 pmol) in tetrahydrofuran (4 mL) was added methanol (4 mL) and 2N HC1 solution (4 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 min. After completion of reaction (monitoring by TLC 100% ethyl acetate inhexane), reaction mixture was quenched with saturated NaHC03 solution (30 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude. The crude was purified by using preparative-HPLC ammonium acetate method to afford (4R, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, l laS, l lbR)-4-(dimethylamino)-9-((S)-l-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3, 6- dihydro-2H-pyran-2-yl)ethyl)-9a, 1 lb-dimethyl-2-(6-methylpyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, I la, 1 Ib-dodecahydrocyclopenta [1, 2] phenanthro [8a, 9-b] oxiren-l(4H)-one (55 mg, 15%) as off white solid.

[0411] Analytical data:LCMS: 95.56% (m / z: 589.50, [M+l]+, 6.86 min (10 min run).’H-NMR (400 MHz, DMSO-6): d 7.69 (t, J= 7.6 Hz, 1H), 7.53 (d, J= 6.80 Hz, 1H), 7.29 (d, J = 8.00 Hz, 1H), 7.20 (d, J = 7.60 Hz, 1H), 4.59 (t, J = 5.6 Hz, 1H), 4.32-4.27 (m, 1H), 4.18-4.08 (m, 2H), 3.72 (d, J= 3.6 Hz, 1H), 3.57 (d, J= 2.00 Hz, 1H), 2.47 (s, 3H), 2.41-2.35 (m, 1H), 2.23 (s, 6H), 2.18 - 2.14 (m, 1H), 2.01- 1.98 (m, 4H), 1.95-1.57 (m, 5H), 1.42 - 1.32 (m, 2H), 1.35-1.01 (m, 10H), 0.93 (d, J= 6.8 Hz, 3H), 0.67 (s, 3H).13C-NMR (400 MHz, DMSO-6): d 201.42, 165.33, 157.61, 154.75, 151.67, 140.18, 138.97, 136.80, 130.04, 125.43, 122.53, 119.77, 118.59, 77.56, 64.16, 61.61, 58.24, 55.16, 54.52, 51.29, 49.49, 42.29, 42.14, 41.97, 30.53, 29.05, 28.77, 26.45, 24.30, 23.98, 22.67, 19.89, 16.62, 13.06, 11.51.

[0412] Synthesis of Compound 46Compound 46

[0413] Step-1: Synthesis of tert-butyl N-[(tert-butoxy) carbonyl]-N-[5-(tributylstannyl) pyrimidin-2-yl] carbamate.To a stirred solution of 5-(tributylstannyl)pyrimidin-2-amine (2.3 g, 5.99 mmol) in THF (25 mL) were added N,N-dimethylpyridin-4-amine (0.073 g, 0.1 eq., 0.599 mmol) and di-tert-butyl dicarbonate (2.75 mL, 2 eq., 12.0 mmol) sequentially at 0 °C. The resulting mixture was stirred at 60 °C for 4h. After completion of the reaction (monitored by TLC), it was quenched by adding water (100 mL) and then extracted using ethyl acetate (2 x 100 mL). Combined organics were was...

Claims

CLAIMSWhat is claimed is:

1. A compound of F ormula (I) :pharmaceutically acceptable salt thereof, wherein:R1is hydrogen,R2is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, -CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl,wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;R3is hydrogen, halogen, -OR9, -SR9, -NR9R10, -COOR9, -COHR9R10, -CR9R10Rn, - CN, -N3, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, -(NR9R10Rn)+, or -0C(=0)NH-(C2-Ce alkynyl), wherein the Ci-Ce alkyl, the aryl, the heteroaryl, cycloaliphatic ring, or heterocyclyl are unsubstituted or substituted with one or more R12;T, U, V, W, and X are each, independently, CH, CR12, sulfur, nitrogen, NH, NR12, or N -O’;R4, R5, R6, R7, R8, R9, R10, and R11are each, independently, hydrogen, deuterium, halogen, or a Ci-Ce unsubstituted or substituted alkyl; and each R12is, independently, deuterium, halogen, =0, -OR9, -SR9, -NR9R10, -C00R9, - COHR9R10, -CR9R10RU, -CN, -NS, CI-C6alkyl, Ci-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Ce alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, or -O- (heterocyclyl); with the proviso:(1) when R1is hydrogen, then R2is a halogen;(2) wheneach of T, U, V, W, and X is CH or CR12, then only one of T, U, V, W, and X is CR12, whereinthe remaining T, U, V, W, and X are CH; and(3) whenare CH, one of W or U is nitrogen, and the other of W or U is CH, then V is not C(-0CH3).

2. The compound of claim 1, wherein the compound of Formula (I) is a compound ofpharmaceutically acceptable salt thereof.The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2is halogen, -OR9, -NR9R10, 5-membered heterocyclyl,whereinR9and R10are each independently hydrogen or Ci-Ce alkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R2isThe compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen, halogen, -OR9, -NR9R10, Ci-Ce alkoxy, 5- to 6-membered heterocyclyl optionally substituted by one or more Ci-Ce alkyl, -(NR9R10Rn)+, -0C(=0)NH-(C2-Ce alkynyl),wherein R9, R10, and R11are each independently hydrogen or Ci-Ce alkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R3is7. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R18. The compound of claim 7, wherein the compound of Formula (la) is a compound ofFormula (laa):pharmaceutically acceptable salt thereof.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein T, U, V, W, and X are each CH or CR12.

10. The compound of claim 9, wherein the compound of Formula (laa) is selected from the group consisting of:acceptable salt or stereoisomer thereof.

11. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein only one of T, U, V, W, and X is sulfur, nitrogen, NH, NR12, or N+-O', and the remainder of T U, V, W, and X are each CH or CR12.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R1w , , , , .

13. The compound of claim 11, wherein the compound of Formula (laa) is selected from the group consisting of:, or a pharmaceutically acceptable salt or stereoisomer thereof.

14. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein at least two of T, U, V, W, and X are sulfur, nitrogen, NR12, or N+R12, and the remaining T, U, V, W, and X are CH or CR12.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R116. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R1wherein q is 0, 1, or 2.

17. The compound of claim 14, wherein the compound of Formula (laa) is selected from the group consisting of:, or a pharmaceutically acceptable salt or stereoisomer thereof.

18. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1laim 18, wherein, wherein p is 0, 1, 2, or 3.

20. The compound of claim 18, whereinwherein q is 0, 1, or 2.

21. The compound of claim 18, wherein the compound of Formula (la) is a compound ofFormula (lab):pharmaceutically acceptable salt thereof.

22. The compound of claim 18, wherein the compound of Formula (lab) is selected from the group consisting of:or a pharmaceutically acceptable salt or stereoisomer thereof.

23. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen.

24. The compound of claim 23, wherein the compound of Formula (la) is a compound of Formula (lac):(lac), or a pharmaceutically acceptable salt thereof, and wherein R2is halogen.

25. The compound of claim 24, wherein the compound of Formula (lac) is:thereof.

26. The compound of claim 1, wherein the compound is, or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1, wherein the compound is, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising the compound of any one of claims 1 to27, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.

29. A method of treating, ameliorating, or preventing a condition or disease in a subject in need thereof, wherein the disease is mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome or by tumor necrosis factor alpha (TNF-a), and wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein the condition or disease is mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome.

31. The method of claim 29, wherein the condition or disease is mediated by tumor necrosis factor alpha (TNF-a).

32. The method of claim 29, wherein the condition or disease is a cardiovascular condition or disease, an endocrine condition or disease, a neurological condition or disease, a gastrointestinal condition or disease, or a combination thereof.

33. The method of claim 29, wherein the condition or disease is inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

34. The method of claim 32, wherein the condition or disease is inflammatory bowel disease (IBD), Crohn's disease, or a combination thereof.

35. The method of claim 32, wherein the condition or disease is colorectal cancer, alcoholic hepatitis, or a combination thereof.

36. The method of claim 29, wherein the condition or disease is inflammatory boweldisease (IBD), and wherein the compound is or a pharmaceutically acceptable salt thereof.

37. The method of claim 29, wherein the condition or disease is alcoholic hepatitis, andpharmaceutically acceptable salt thereof.

38. The method of claim 29, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered orally.

39. A method of treating, ameliorating, or preventing a condition or disease in a subject in need thereof, wherein the disease is mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome or by tumor necrosis factor alpha (TNF-a), and wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 28.

40. The method of claim 39, wherein the condition or disease is mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome.

41. The method of claim 39, wherein the condition or disease is mediated by tumor necrosis factor alpha (TNF-a).

42. The method of claim 39, wherein the condition or disease is a cardiovascular condition or disease, an endocrine condition or disease, a neurological condition or disease, a gastrointestinal condition or disease, or a combination thereof.

43. The method of claim 39, wherein the pharmaceutical composition is administered orally.

44. A pharmaceutical composition comprising a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in a method of treating, ameliorating, or preventing a condition or disease mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome or by tumor necrosis factor alpha (TNF-a).

45. The pharmaceutical composition for use of claim 44, wherein the condition or disease is mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome.

46. The pharmaceutical composition for use of claim 44, wherein the condition or disease is mediated by tumor necrosis factor alpha (TNF-a).

47. The pharmaceutical composition for use of claim 44, wherein the condition or disease is a cardiovascular condition or disease, an endocrine condition or disease, a neurological condition or disease, a gastrointestinal condition or disease, or a combination thereof.

48. The pharmaceutical composition for use of claim 44, wherein the condition or disease is inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

49. The pharmaceutical composition for use of claim 44, wherein the condition or disease is inflammatory bowel disease (IBD), Crohn’s disease, or a combination thereof.

50. The pharmaceutical composition for use of claim 44, wherein the condition or disease is colorectal cancer, alcoholic hepatitis, or a combination thereof.

51. Use of a compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a medicament for use in treating, ameliorating, or preventing a condition or disease mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome or by tumor necrosis factor alpha (TNF-a).

52. The use of claim 51, wherein the condition or disease is mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome.

53. The use of claim 51, wherein the condition or disease is mediated by tumor necrosis factor alpha (TNF-a).

54. The use of claim 51, wherein the condition or disease is a cardiovascular condition or disease, an endocrine condition or disease, a neurological condition or disease, a gastrointestinal condition or disease, or a combination thereof.

55. The use of claim 51, wherein the condition or disease is inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

56. The use of claim 51, wherein the condition or disease is inflammatory bowel disease (IBD), Crohn’s disease, or a combination thereof.

57. The use of claim 51, wherein the condition or disease is colorectal cancer, alcoholic hepatitis, or a combination thereof.

58. A method of treating, ameliorating, or preventing a condition or disease in a subject in need thereof, wherein the disease is mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome or by tumor necrosis factor alpha (TNF-a), and wherein the method comprises administering to the subject a therapeutically effective amount of an inhibitor of the C-terminal domain of heat shock protein 90 (hsp90).

59. The method of claim 58, wherein the condition or disease is mediated by the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome.

60. The use of method of claim 58, wherein the condition or disease is mediated by tumor necrosis factor alpha (TNF-a).

61. The method of claim 58, wherein the condition or disease is inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

62. The method of claim 58, wherein the condition or disease is inflammatory bowel disease (IBD), Crohn's disease, or a combination thereof.

63. The method of claim 58, wherein the condition or disease is colorectal cancer, alcoholic hepatitis, or a combination thereof.

64. A method of making a compound of claim 17, wherein the compound is of Formula (laa), the method comprising: providing a pyrazine as a first intermediate; and combining a 2-pyranone and the first intermediate to form a second intermediate.

65. The method of claim 64 further comprising providing a solvent, salt, a ligand, a catalyst, or combinations thereof.

66. The method of claim 65, wherein: the step of providing a pyrazine as a first intermediate is further defined as combining:(i) the solvent, the salt, the ligand, the catalyst, or combinations thereof, and(ii) the pyrazine to form the first intermediate; and the step of combining a 2-pyranone and the first intermediate to form a second intermediate is further defined as combining:(i) the solvent, the salt, the ligand, the catalyst, or combinations thereof, and(ii) the 2-pyranone and the first intermediate to form the second intermediate.

67. The method of claim 64, wherein the pyrazine is 2-chloro-5-isopropoxypyrazine.

68. The method of claim 64, wherein the 2-pyranone is (R)-6-[(S)-l-{(lS, 2R, 6S, 7R, 9R, 11 S, 12S, 15R, 16S)-6-hydroxy-4-iodo-2, 16-dimethyl-3-oxo-8-oxapentacyclo [9.7.0.02,7.07,9.012,16] octadec-4-en-15-yl}ethyl]-3-(hydroxymethyl)-4-methyl-5, 6-dihydro- 2H-pyran-2-one.

69. The method of claim 65, wherein the solvent is selected from the group of 1,4- dioxane, tetrahydrofuran, ethyl acetate, heptane, water, and combination thereof.

70. The method of claim 65, wherein the salt is selected from the group of lithium chloride, sodium sulphate, ammonium bicarbonate, and combinations thereof.

71. The method of claim 65, wherein the ligand is selected from the group of hexabutyl distannane, tributyl(5-isopropoxy-2-pyrazinyl) stannane, tricyclohexyl phosphine, triphenylarsane, and combinations thereof.

72. The method of claim 65, wherein the catalyst is selected from the group of palladium — ( 1 E,4E)- 1 , 5 -diphenyl- 1 ,4-pentadien-3 -one (2 / 3 ), Tri s(( 1 E,4E)- 1,5- diphenylpenta-l,4-dien-3-one) dipalladium [Pd2(dba)3], Copper Iodide [Cui], Triphenylarsane [AsPh3], Tetrakis (triphenylphosphine)palladium(O) [Pd(PPh3)4], Bis(triphenylphosphine)palladium(II) dichloride [PdC12(PPh3)2], and combinations thereof.

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