Withania A analogs and methods of treatment using the same

Abstract

This disclosure generally relates to compounds, compositions, and methods for treating a variety of diseases and disorders using therapeutically effective amounts of a compound of formula (I), its pharmaceutically acceptable salts, or derivatives.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 587,721, filed October 3, 2023. The contents of this application are incorporated herein by reference in their entirety for all purposes. Technical Field

[0003] This disclosure generally relates to compounds, compositions, and methods for treating a variety of diseases and ailments, and more specifically for treating inflammatory-related diseases. Background Technology

[0004] Inflammation plays a crucial role in the immune response to injury and infection, but excessive or chronic inflammation can be harmful, 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 cause debilitating symptoms and complications, including severe pain, weight loss, and malnutrition. Alcoholic hepatitis, on the other hand, is a significant inflammatory disorder caused by long-term excessive alcohol consumption. Its symptoms can range from mild (including jaundice and malaise) to severe (leading to liver failure and potential death). Current treatment options for alcoholic hepatitis and other liver diseases are limited and often not entirely effective, necessitating the exploration of more targeted and effective therapeutic agents.

[0005] TNF-α, a pro-inflammatory cytokine, has been widely identified as a key player in the pathogenesis of IBD. Overproduction of TNF-α leads to enhanced inflammatory responses, tissue damage, and promotes the chronicity of intestinal inflammation observed in IBD patients. Therefore, therapies aimed at neutralizing TNF-α, such as monoclonal antibodies, have demonstrated efficacy in IBD treatment. However, despite the therapeutic benefits of anti-TNF-α therapy, it may also lead to potential adverse effects, such as infections, malignancies, and the development of anti-drug antibodies. Furthermore, important subgroups of IBD patients become unresponsive or lose their responsiveness to anti-TNF-α therapy over time. Therefore, there is an urgent need for alternative or complementary strategies targeting the TNF-α pathway.

[0006] The NLR family Pyrin domain 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 the inflammatory response, including the release of pro-inflammatory cytokines such as IL-1β and IL-18, which further exacerbate liver injury. Dysregulated NLRP3 inflammasome activation has been shown to be associated with the pathogenesis of both IBD and alcoholic hepatitis, thus presenting an attractive target for therapeutic intervention. Current IBD treatments primarily focus on reducing inflammation and maintaining remission, but do not directly target the underlying pathophysiological processes of the disease.

[0007] HSP90 is a heat shock protein, a molecular chaperone involved in the folding and function of various proteins. HSP90 functions as a homodimer, and each monomer consists of three distinct domains: the N-terminal domain (N-domain), the intermediate domain, and the C-terminal domain. Each of these domains has a specific function and characteristics. The N-domain is well-known for its ATP / ADP binding pocket and is the primary site for most known HSP90 inhibitors. Examples of HSP90 inhibitors targeting the N-domain include galdromycin and its derivative 17-AAG (tanespimycin), Ganetespib (STA-9090), and PU-H71.

[0008] Interestingly, HSP90 has been found to regulate the stability of both TNF-α and NLRP3 inflammasomes. Specifically, the C-terminal domain of HSP90 binds to TNF-α and NLRP3, contributing to their stability and proper function. However, uncontrolled activation of TNF-α or NLRP3 (often due to persistent interaction with HSP90) can lead to persistent inflammation observed in diseases such as IBD and alcoholic hepatitis.

[0009] Therefore, there is a continued need in the art for compounds, compositions, and methods for treating inflammatory-related diseases (such as IBD and alcoholic hepatitis) as well as a variety of other diseases and disorders. Summary of the Invention

[0010] The embodiments described herein relate to compounds, compositions, and methods for treating, alleviating, or improving various diseases, conditions, or disorders in subjects of need. Although inflammation is a protective response of the host to infection, it can be excessively harmful and destructive. In various contexts, inflammation is considered a disease-improving mechanism, prompting considerable effort to address the harmful inflammatory responses observed in conditions such as inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, and other diseases.

[0011] This article provides a compound of formula (I). The compound of formula (I) is as follows: (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 For hydrogen, -NR 9 R 10 -COOR 9 -CN or ; R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cyclic aliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; R 3 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, -(NR 9 R 10 R 11 ) + or -OC(=O)NH-(C2-C6 ynyl), wherein the C1-C6 alkyl, the aryl, the heteroaryl, the cycloaliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; T, U, V, W, and X are each independently CH and CR. 12 Sulfur, nitrogen, NH, NR 12 or N + -O - ; R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independently classified as deuterium, halogen, =O, -OR 9 -SR9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or -O- (heterocyclic group); The conditions are: (1) When R 1 When it is hydrogen, then R 2 It is a halogen; (2) When R 1 for And each of T, U, V, W, and X is CH or CR. 12 When , only one of T, U, V, W, and X is CR. 12 , where R 12 for Or -OCH3, and the remaining T, U, V, W and X are CH; and (3) When R 1 for If T and X are CH, one of W or U is nitrogen, and the other of W or U is CH, then V is not C(-OCH3).

[0012] These compounds and pharmaceutically acceptable compositions can be used to treat or reduce the severity of a variety of diseases, conditions, or disorders, including but not limited to inflammatory diseases such as inflammatory bowel disease (IBD), Crohn's disease (CD), and alcoholic hepatitis; and cancers 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), inflammasomes containing the NLR family Pyrin domain 3 (NLRP3), tumor necrosis factor α (TNF-α), and transforming growth factor β (TGF-β), and are therefore used to treat or reduce the severity of the various diseases, conditions, or disorders described herein.

[0013] This article also provides a method for treating, improving, or preventing lesions or diseases mediated by NLR family Pyrin domain 3 (NLRP3) inflammasomes, or comprising administering a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: R1 For hydrogen, -NR 9 R 10 -COOR 9 -CN or ; R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cyclic aliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; R 3 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, -(NR 9 R 10 R 11 ) + or -OC(=O)NH-(C2-C6 ynyl), wherein the C1-C6 alkyl, the aryl, the heteroaryl, the cycloaliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; T, U, V, W, and X are each independently CH and CR. 12 Sulfur, nitrogen, NH, NR 12 or N + -O - ; R 4 R 5 R6 R 7 R 8 R 9 R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independently classified as deuterium, halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, or -O- (heterocyclic group). In some embodiments, the compound of formula (I) is administered in a therapeutically effective amount.

[0014] On the other hand, this article provides a method for treating, improving, or preventing tumor necrosis factor α (TNF-α)-mediated disorders or diseases, said method comprising administering a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 For hydrogen, -NR 9 R 10 -COOR 9 -CN or ; R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cyclic aliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups.12 replace; R 3 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, -(NR 9 R 10 R 11 ) + or -OC(=O)NH-(C2-C6 ynyl), wherein the C1-C6 alkyl, the aryl, the heteroaryl, the cycloaliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; T, U, V, W, and X are each independently CH and CR. 12 Sulfur, nitrogen, NH, NR 12 or N + -O - ; R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independently classified as deuterium, halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, or -O- (heterocyclic group). In some embodiments, the compound of formula (I) is administered in a therapeutically effective amount. Attached Figure Description

[0015] This application can be understood with reference to the following description taken in conjunction with the accompanying drawings.

[0016] Figure 1A and Figure 1B Graphs and plots illustrating experimental results of a non-limiting embodiment of a compound of formula I that inhibits the NLRP3 pathway in primary human cells.

[0017] Figure 2A and Figure 2B Images and graphical representations illustrating the stability of NLRP3 regulated by compounds of formula I according to one or more exemplary embodiments of this disclosure.

[0018] Figure 3A and Figure 3B This indicates dose-dependent NLRP3 protein degradation by compounds of Formula I according to one or more exemplary embodiments of this disclosure. Figure 3C This indicates the proteasome rescue of the NLRP3 protein by a compound of Formula I according to one or more exemplary embodiments of this disclosure.

[0019] Figure 4 The illustration depicts dose-dependent in vitro target binding of a Formula I compound according to one or more exemplary embodiments of the present disclosure.

[0020] Figures 5A to 5D The illustration depicts a dose-dependent reduction in disease activity index and combined histopathological score in a mouse model of colitis induced by sodium dextran sulfate (DSS) of Formula I, according to one or more exemplary embodiments of the present disclosure.

[0021] Figures 6A to 6F This invention describes one or more exemplary embodiments of reducing the disease activity index in a chronic dextran sulfate sodium (DSS)-induced IBD mouse model by means of a compound of formula I.

[0022] Figure 7A and Figure 7B The dose-responsive efficacy of a compound of formula I in a mouse model of colitis induced by sodium dextran sulfate (DSS) (prevention mode) according to one or more exemplary embodiments of the present disclosure is described.

[0023] Figures 8A to 8D The illustration depicts the DAI score induced by compound of formula I on day 8 in a dextran sulfate sodium (DSS)-induced colitis mouse model, according to one or more exemplary embodiments of the present disclosure.

[0024] Figure 9A and Figure 9BThe illustration depicts the reduction of DSS-induced colonic shortening by a compound of formula I in a mouse model of colitis induced by sodium dextran sulfate (DSS) according to one or more exemplary embodiments of the present disclosure.

[0025] Figures 10A to 10D This invention demonstrates, according to one or more exemplary embodiments of the present disclosure, that a compound of formula I prevents DSS-induced intestinal permeability in a mouse model of colitis induced by sodium dextran sulfate (DSS).

[0026] Figures 11A to 11C The present disclosure describes a reduction in DSS-induced clinically relevant biomarkers in a dextran sulfate sodium (DSS)-induced mouse model by a compound of Formula I according to one or more exemplary embodiments.

[0027] Figures 12A to 12C The role of a compound of formula I in DSS-induced pro-inflammatory markers in the colon is described according to one or more exemplary embodiments of the present disclosure.

[0028] Figures 13A to 13C The effects of Formula I compounds on DSS-induced systemic inflammation are described according to one or more exemplary embodiments of the present disclosure.

[0029] Figure 14A and Figure 14B The effects of a compound of formula I on DSS-induced pro-inflammatory markers in serum are described according to one or more exemplary embodiments of the present disclosure.

[0030] Figure 15 The role of a compound of formula I in DSS-induced systemic inflammation is described according to one or more exemplary embodiments of the present disclosure.

[0031] Figure 16 The effect of a compound of formula I on inhibiting the release of IL-1β from differentiated THP1 cells is described according to one or more exemplary embodiments of the present disclosure.

[0032] Figure 17 The effects of a compound of formula I on pyroptosis in differentiated THP1 cells are described according to one or more exemplary embodiments of the present disclosure.

[0033] Figures 18A to 18D The effects of a compound of formula I in a mouse model of alcohol-induced liver injury are described according to one or more exemplary embodiments of the present disclosure. Detailed Implementation

[0034] This article provides compounds, compositions, and methods for treating, alleviating, or improving various diseases, conditions, or disorders in subjects of need. Although inflammation is a protective response of the host to infection, it can be excessively harmful and destructive. In various cases, inflammation is considered a disease-improving mechanism, prompting considerable efforts to address harmful inflammatory responses observed in conditions such as inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, and other diseases.

[0035] As used herein, the term "subject" refers to primates (e.g., human males or females), dogs, rabbits, guinea pigs, pigs, rats, and mice. In some embodiments, the subject is a primate. In another embodiment, the subject is a human.

[0036] As used herein, a subject "needs" or "has a need for" the treatment if the subject will benefit biologically, medically, or in terms of quality of life as a result of the treatment.

[0037] As a fundamental part of the innate immune system, NLRP3 (protein 3 containing the NACHT, LRR, and PYD domains) acts as a pattern recognition receptor (PRR) in cells such as macrophages. The NLRP3 protein is a multimolecular complex that plays a crucial role in the pathogenesis of various diseases characterized by harmful inflammatory responses. The NLRP3 protein detects cellular stress induced by pathogens or injury and forms a complex with a connective protein called ASC (an apoptosis-associated speckle-like protein containing CARD). This complex, known as the inflammasome, is responsible for activating the protease apoptosis protease-1. Apoptosis protease-1 then cleaves the precursor forms of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18, converting them into their active forms, which are subsequently released. Apoptosis protease-1 is responsible for the proteolytic cleavage of apoptosis D, leading to the formation of pores in the cell membrane and subsequent pyroptosis. This process allows the inflammasome complex to be released into the extracellular space, thereby amplifying the inflammatory response. In the context of Alzheimer's disease models, inoculation of extracellular ASC spots to induce amyloid deposition and aggregation has been observed.

[0038] As used herein, the term "NLRP3" is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and their active fragments.

[0039] Therefore, there is significant interest in developing inhibitors targeting the NLRP3 inflammasome. Heat shock protein 90 (HSP90) is a highly abundant protein that plays a crucial role in many cellular signaling pathways, including inflammation. This is achieved through its ability to interact with and regulate the activity of various client proteins within the cellular environment. HSP90 has been proposed to interact with NLRP3, thereby exerting control over the activation of the inflammasome and the secretion of IL-1β. Therefore, the compounds and compositions considered in this paper are HSP90 inhibitors that inhibit NLRP3-dependent inflammation.

[0040] In some embodiments, this disclosure relates to compounds and compositions that modulate NLRP3 stability by inhibiting the interaction between NLRP3 and the C-terminal domain of HSP90 to regulate the activity of the NLRP3 inflammasome. By blocking the stabilizing effect of HSP90, the compounds and compositions described herein reduce the overactivation of the inflammasome, thereby alleviating the inflammatory response.

[0041] TNF-α, or tumor necrosis factor-α, 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 crucial role in the body's immune response by promoting inflammation, mediating apoptosis (cell death), regulating cell proliferation, and coordinating a variety of cellular activities essential for the host's defense against pathogens. However, excessive production or prolonged presence of TNF-α can lead to pathological inflammation and is associated with various diseases, including alcoholic liver disease, inflammatory bowel disease, and psoriasis.

[0042] As used herein, the term “TNF-α” is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous TNF-α, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and their active fragments.

[0043] Therefore, there is significant interest in developing inhibitors targeting TNF-α. HSP90 has been shown to interact with TNF-α. Therefore, the compounds and compositions considered in this paper are HSP90 inhibitors that inhibit TNF-α-dependent inflammation.

[0044] In some embodiments, this disclosure relates to compounds and compositions that modulate TNF-α stability by inhibiting the interaction between TNF-α and the C-terminal domain of HSP90 to regulate TNF-α activity. By blocking the stabilizing effect of HSP90, the compounds and compositions described herein can reduce the overactivation of TNF-α, thereby alleviating the inflammatory response.

[0045] In other embodiments, HSP90 plays an important role as a molecular chaperone protein in stabilizing and assisting the conformational maturation of various proteins involved in signaling pathways that can directly or indirectly affect the production, stability, or activity of cytokines. Non-limiting examples of cytokines or cytokine pathways affected by proteins regulated by HSP90 include: (1) NF-κB pathway: HSP90 regulates the stability of IκB kinase (IKK). IKK plays a role in the degradation of IκB, leading to the activation of NF-κB. Activated NF-κB then translocates to the cell nucleus and can induce the expression of various cytokines, including TNF-α, IL-1β, IL-6, and IL-8.

[0046] (2) STAT proteins, among which HSP90 is involved in stabilizing signal transducers and transcription activator (STAT) proteins. Once activated, STAT can induce the expression of various cytokines and growth factors.

[0047] (3) HIF-1α: Under hypoxic conditions, the stabilizing effect of HSP90 on hypoxia-inducible factor 1-α (HIF-1α) can lead to the expression of VEGF and other cytokines.

[0048] (4) Toll-like receptors (TLRs): HSP90 is involved in the maturation and stability of some TLRs. TLRs play an important role in innate immunity and can induce the production of various cytokines when activated.

[0049] (5) Receptor tyrosine kinases: HSP90 stabilizes various receptor tyrosine kinases. These receptors, once activated, can activate downstream pathways, leading to the production of various growth factors and cytokines.

[0050] (6) IL-1 receptor-associated kinase (IRAK): HSP90 stabilizes IRAK, which is involved in IL-1 signaling and can affect the production of downstream cytokines.

[0051] It should be noted that HSP90 may not directly regulate cytokines, but rather stabilize and assist the function of many client proteins, which in turn affect cytokine production, stability, or activity.

[0052] The compounds and compositions described herein are intended for the treatment, prevention, or improvement (reducing the severity) of one or more symptoms associated with diseases and disorders characterized by aberrant NLRP3 inflammasome activity, aberrant TNF-α activity, or both. Such diseases and disorders include inflammatory bowel disease, systemic inflammatory diseases, inflammatory skin diseases, gastrointestinal diseases, kidney diseases, cardiovascular diseases, liver diseases, autoimmune diseases, and respiratory diseases. Pharmaceutical compositions comprise the compounds described herein and pharmaceutically acceptable carriers. This disclosure also includes a cassette containing the pharmaceutical composition. This disclosure also includes methods for treating pathological conditions in mammals by administering any of the compounds or compositions described herein.

[0053] compound This article provides a compound of formula (I). The compound of formula (I) is as follows: (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 For hydrogen, -NR 9 R 10 -COOR 9 -CN or ; R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cyclic aliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; R 3 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11-CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, -(NR 9 R 10 R 11 ) + or -OC(=O)NH-(C2-C6 ynyl), wherein the C1-C6 alkyl, the aryl, the heteroaryl, the cycloaliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; T, U, V, W, and X are each independently CH and CR. 12 Sulfur, nitrogen, NH, NR 12 or N + -O - ; R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independently classified as deuterium, halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or -O- (heterocyclic group); The conditions are: (1) When R 1 When it is hydrogen, then R 2 It is a halogen; (2) When R 1 for And each of T, U, V, W, and X is CH or CR. 12 When , only one of T, U, V, W, and X is CR. 12 , where R 12 for Or -OCH3, and the remaining T, U, V, W and X are CH; and (3) When R 1 for If T and X are CH, one of W or U is nitrogen, and the other of W or U is CH, then V is not C(-OCH3).

[0054] Among some variations of the aforementioned content, R 1 For hydrogen, -NR 9 R 10 -COOR 9 -CN or ; R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkylcyclo, heterocycloalkyl or Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cycloalkyl ring, or the heterocycloalkyl group is not substituted or is replaced by one or more R groups. 12 replace; R 3 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkyl ring, heterocycloalkyl, -(NR 9 R 10 R 11 ) +or -OC(=O)NH-(C2-C6 ynyl), wherein the C1-C6 alkyl, the aryl, the heteroaryl, the cycloalkyl ring, or the heterocycloalkyl is not substituted or is replaced by one or more R 12 replace; T, U, V, W, and X are each independently CH and CR. 12 Sulfur, nitrogen, NH, NR 12 or N + -O - ; R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independently classified as deuterium, halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkyl ring, heterocyclic alkyl or -O- (heterocyclic alkyl).

[0055] For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. Additionally, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th edition, Smith, MB, and March, J., John (eds.), Wiley & Sons, New York: 2001.

[0056] As described herein, the compounds of this disclosure may optionally be substituted with one or more substituents, such as those generally illustrated herein or exemplified by specific classes, subclasses, and species of this disclosure. As will be appreciated by those skilled in the art, the combinations of substituents contemplated in this disclosure are those combinations that result in the formation of stable or chemically viable compounds.

[0057] The phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” Generally, the term “substituted,” whether preceded by the term “optionally” or not, refers to the replacement of a hydrogen group in a given structure by a group of the specified substituent. Specific substituents are described in the definitions above and in the description of the compounds and their examples below. Unless otherwise indicated, the optionally substituted group may have a substituent at each substituted position of the group, and the substituent at each position may be the same or different when more than one position in any given structure may be substituted by more than one substituent selected from the specified group. Cyclic substituents (e.g., heterocyclic groups) may combine with another ring (e.g., a cycloaliphatic ring) to form a spirobicyclic system, such as two rings sharing a common atom. As those skilled in the art will recognize, the substituent combinations contemplated in this disclosure are those combinations that result in the formation of stable or chemically viable compounds.

[0058] As used herein, the term "alkyl" or "alkyl group" means a fully saturated straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain. Unless otherwise specified, an alkyl group contains 1 to 20 carbon atoms. In some embodiments, the alkyl group contains 1 to 10 carbon atoms. In other embodiments, the group contains 1 to 8 carbon atoms. In other embodiments, the group contains 1 to 6 carbon atoms, and in other embodiments, the group contains 1 to 4 carbon atoms. Suitable alkyl groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl groups.

[0059] As used herein, the term "alkenyl" or "alkenyl group" means an unsaturated linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain containing at least one moiety of the formula (C=C). Unless otherwise specified, an alkenyl group contains 2-20 carbon atoms. In some embodiments, the alkenyl group contains 2-10 carbon atoms. In other embodiments, the alkenyl group contains 2-8 carbon atoms. In other embodiments, the alkenyl group contains 2-6 carbon atoms, and in other embodiments, the alkenyl group contains 2-4 carbon atoms. Suitable alkenyl groups include, but are not limited to, linear or branched, substituted or unsubstituted alkenyl groups.

[0060] As used herein, the term "alkynyl" or "alkynyl group" means an unsaturated linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain containing at least a carbon-carbon triple bond. Unless otherwise specified, an alkynyl group contains 2-20 carbon atoms. In some embodiments, the alkynyl group contains 2-10 carbon atoms. In other embodiments, the alkynyl group contains 2-8 carbon atoms. In other embodiments, the alkynyl group contains 2-6 carbon atoms, and in other embodiments, the alkynyl group contains 2-4 carbon atoms. Suitable alkynyl groups include, but are not limited to, linear or branched, substituted or unsubstituted alkynyl groups.

[0061] The term "cycloaliphatic ring" refers to a monocyclic hydrocarbon ring or a polycyclic hydrocarbon ring system without heteroatoms, which is fully saturated or contains one or more unsaturated units, but is not aromatic and has a single connection point to the rest of the molecule. As used herein, the term "polycyclic system" includes bicyclic and tricyclic 4- to 12-membered structures forming at least two rings, wherein the two rings have at least one common atom (e.g., two common atoms), including fused, bridged, or spirocyclic ring systems. Specific cycloaliphatic ring groups include those having 3 to 12 carbon atoms (C3-C4). 12 Cycloaliphatic rings include those with 3 to 6 carbon atoms (C3-C6 cycloaliphatic rings) and those with 5 to 6 carbon atoms (C5-C6 cycloaliphatic rings). Other exemplary cycloaliphatic ring groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

[0062] As used in this article, the terms "halogen" or "halogen group" refer to F, Cl, Br, or I.

[0063] Unless otherwise specified, the term "heterocyclic group" as used herein means a non-aromatic monocyclic, bicyclic, or tricyclic ring system in which one or more ring atoms in one or more ring members are independently selected heteroatoms. The heterocycle may be saturated or may contain one or more unsaturated bonds. In some embodiments, the "heterocyclic group" has three to fourteen ring members, wherein one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the ring system contains three to seven ring members. Specific heterocyclic groups include 3- to 12-membered heterocyclic groups; 4- to 6-membered heterocyclic groups; 5- to 6-membered heterocyclic groups; 5- to 6-membered heterocyclic groups containing one or more heteroatoms selected from N, O, or S; and 5- to 6-membered heterocyclic groups containing one to two heteroatoms selected from N or O.

[0064] The term "heteroatom" means oxygen, sulfur, nitrogen, phosphorus, or silicon (including: any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of basic nitrogen; or substituted nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or NR). +(e.g., in N-substituted pyrroleyl groups). In some embodiments, the heteroatom may be oxygen, sulfur, or nitrogen.

[0065] As used in this article, the term "unsaturated" means that a part has one or more unsaturated units, but is not an aromatic group.

[0066] As used herein, the terms “alkoxy” or “thioalkyl” refer to an alkyl group as previously defined, which is attached to the main carbon chain by an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

[0067] The term "aryl" used alone or as part of a larger portion (such as "aranyl," "aranalkoxy," or "aranoxyalkyl") refers to a monocyclic, bicyclic, or tricyclic cyclic system having a total of five to fourteen ring carbon atoms, 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" is used interchangeably with the term "aromatic ring." Specific aryl groups include those having 6 to 12 carbon atoms (C6-C12). 12 Aryl groups or those having 6 to 10 carbon atoms (C6-C) 10 Aryl groups). Additional exemplary aryl groups include phenyl and naphthyl groups.

[0068] The term "heteroaryl," used alone or as part of a larger portion of terms such as "heteroarylalkyl" or "heteroarylalkoxy," refers to a monocyclic, bicyclic, or tricyclic cyclic system 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 terms "heteroaryl ring" or "heteroaryl family." Specific heteroaryls include 5- to 12-membered heteroaryls, 5- to 10-membered heteroaryls, and 5- to 6-membered heteroaryls.

[0069] Both “D” and “d” refer to deuterium.

[0070] Unless otherwise stated, the structures described herein are intended to include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)); for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformational isomers), are within the scope of this disclosure. Unless otherwise stated, all tautomers of the compounds of formula (I) of this disclosure are within the scope of this disclosure. Therefore, tautomers of compounds of formula (I) are included within the scope of this disclosure. Where appropriate, the structures also include zwitterionic forms of compounds or salts of formula (I).

[0071] Furthermore, unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched or isotopically labeled atoms. One or more atoms in an isotopically labeled compound may be replaced by atoms having atomic masses or mass numbers commonly 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, isotopes of these elements. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 35 S and 18 F. In addition to their use as therapeutic agents, certain isotopically labeled compounds of formula (I) can also be used for drug and / or substrate tissue distribution assays, as analytical tools, or as probes in other bioassays. In one aspect of this disclosure, tritium (e.g. 3 H) and carbon-14 (e.g. H) and carbon-14 14 C) Isotopes are suitable due to their ease of detection. In another aspect of this disclosure, heavier isotopes such as deuterium (e.g., 2 Replacing one or more hydrogen atoms with H can provide certain therapeutic benefits.

[0072] In some embodiments, the compound of formula (I) is of formula (Ia): (Ia), or a pharmaceutically acceptable salt thereof, wherein: R 1 For hydrogen, -NR 9 R 10 -COOR 9 -CN or ; R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cyclic aliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; R 3 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, -(NR 9 R 10 R 11 ) + or -OC(=O)NH-(C2-C6 ynyl), wherein the C1-C6 alkyl, the aryl, the heteroaryl, the cycloaliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; T, U, V, W, and X are each independently CH and CR. 12 Sulfur, nitrogen, NH, NR 12 or N + -O - ; R 4 R 5 R 6 R 7 R 8 R 9 R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independently classified as deuterium, halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11-CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or -O- (heterocyclic group); The conditions are: (1) When R 1 When it is hydrogen, then R 2 It is a halogen; (2) When R 1 for And each of T, U, V, W, and X is CH or CR. 12 When , only one of T, U, V, W, and X is CR. 12 , where R 12 for Or -OCH3, and the remaining T, U, V, W and X are CH; and (3) When R 1 for If T and X are CH, one of W or U is nitrogen, and the other of W or U is CH, then V is not C(-OCH3).

[0073] In some embodiments, the compound of formula (Ia) is a compound of formula (Ia-1): (Ia-1), or a pharmaceutically acceptable salt thereof.

[0074] In some implementations, R of formula (I) or (Ia) 1 for In these and other embodiments, the compound of formula (Ia) may be of formula (Iaa): (Iaa), or a pharmaceutically acceptable salt thereof, wherein: R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cyclic aliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups.12 replace; R 3 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, -(NR 9 R 10 R 11 ) + or -OC(=O)NH-(C2-C6 ynyl), wherein the C1-C6 alkyl, the aryl, the heteroaryl, the cycloaliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; T, U, V, W, and X are each independently CH and CR. 12 Sulfur, nitrogen, NH, NR 12 or N + -O - ; R 9 R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independently classified as deuterium, halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or -O- (heterocyclic group); The conditions are: (1) When R 1 When it is hydrogen, then R 2 It is a halogen; (2) When R 1 for And each of T, U, V, W, and X is CH or CR. 12 When , only one of T, U, V, W, and X is CR. 12 , where R 12 for Or -OCH3, and the remaining T, U, V, W and X are CH; and (3) When R 1 for If T and X are CH, one of W or U is nitrogen, and the other of W or U is CH, then V is not C(-OCH3).

[0075] In some implementation schemes, R 1 for And each of T, U, V, W, and X is CH or CR. 12 In these and other embodiments, the compound of formula (Iaa) is selected from the group consisting of: , , , Or its pharmaceutically acceptable salts or stereoisomers.

[0076] In some implementation schemes, R 1 for Among T, U, V, W, and X, only one is sulfur, nitrogen, NH, or NR. 12 or N + -O - And the rest of T, U, V, W, and X are CH or CR. 12 In these and other embodiments, the compound of formula (Iaa) is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Or its pharmaceutically acceptable salts or stereoisomers.

[0077] In some implementation schemes, R 1 for At least two of T, U, V, W and X are sulfur, nitrogen, NH, and NR. 12 or N + -O - And the rest of T, U, V, W, and X are CH or CR. 12 In these and other embodiments, the compound of formula (Iaa) is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Or its pharmaceutically acceptable salts or stereoisomers.

[0078] In some implementations, R of formula (I) or (Ia) 1 for In these and other embodiments, the compound of formula (Ia) may be of formula (Iab): (Iab), or a pharmaceutically acceptable salt thereof, wherein: R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cyclic aliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; R 3 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, -(NR 9 R 10 R 11 ) + or -OC(=O)NH-(C2-C6 ynyl), wherein the C1-C6 alkyl, the aryl, the heteroaryl, the cycloaliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; T, U, V, and W are each independently CH and CR. 12 Sulfur, nitrogen, NH, NR 12 or N + -O - ; R 9 R 10 and R 11Each is independently hydrogen, deuterium, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independently classified as deuterium, halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or -O- (heterocyclic group).

[0079] In an exemplary embodiment, the compound of formula (Iab) is selected from the group consisting of: , or its pharmaceutically acceptable salt or stereoisomer.

[0080] In some implementations, R of formula (I) or (Ia) 1 For hydrogen. In these embodiments, when R 1 When the hydrogen is present, the compound of formula (Ia) can be of formula (Iac): (Iac), or a pharmaceutically acceptable salt thereof, wherein: R 2 It is a halogen; R 3 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, -(NR 9 R 10 R 11 ) +or -OC(=O)NH-(C2-C6 ynyl), wherein the C1-C6 alkyl, the aryl, the heteroaryl, the cycloaliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; R 9 R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independently classified as deuterium, halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or -O- (heterocyclic group).

[0081] In an exemplary embodiment, the compound of formula (Iac) is: Or its pharmaceutically acceptable salts or stereoisomers.

[0082] In some implementation schemes, R 1 for , where m is 0, 1, 2, 3, 4, 5 or 6.

[0083] In some implementation schemes, R 1 for , , or , where n is 0, 1, 2, 3 or 4.

[0084] In some implementation schemes, R 1 for , , , , , or , where n is 0, 1, 2 or 3.

[0085] In some implementation schemes, R 1 for , where q is 0, 1, or 2. In some implementations, R1 for Where p is 0, 1, 2, or 3. In some implementations, R 1 for , where q is 0, 1 or 2.

[0086] In some implementation schemes, R 2 For halogen, -OR 9 -NR 9 R 10 5-membered heterocyclic group or , where R 9 and R 10 Each is independently hydrogen or C1-C6 alkyl. In some embodiments, R 2 -OH, -F, -N(CH3)2, or .

[0087] In some implementation schemes, R 3 For hydrogen, halogen, -OR 9 -NR 9 R 10 C1-C6 alkoxy, 5- to 6-membered heterocyclic groups optionally substituted with one or more C1-C6 alkyl groups, -(NR 9 R 10 R 11 ) + -OC(=O)NH-(C2-C6 ynyl group) or , where R 9 R 10 and R 11 Each is independently hydrogen or C1-C6 alkyl. In some embodiments, R 3 For hydrogen, -OH, -OCH3, -N(CH3)2, -F , , , , , , or .

[0088] In some implementation schemes, R 12 For deuterium, halogens, =O, -NR 9 R 10 -CN, C1-C6 alkyl, C1-C6 alkoxy, 4-membered heterocyclic group or -O- (heterocyclic group), wherein R 9 and R 10 Each is independently hydrogen or C1-C6 alkyl. In some embodiments, R 12For deuterium, -F, -CN, =O, -CH3, -CH(CH3) 2、 -OCH3, -OCD3, -OCH(CH3)2, -NH2, -N(CH3)2, or .

[0089] Non-limiting examples of suitable compounds include any of the following compounds or their pharmaceutically acceptable salts.

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114] Pharmaceutically acceptable salts, prodrugs, and combinations As described herein, compounds of formula (I) are provided as inhibitors or modulators of one or more of the following therapeutic targets: HSP90, NLRP3 inflammasome, and TGF-β. In association with or independent of such inhibitory or modulatory activity, the compounds of the present invention can be used to treat diseases, conditions, and disorders, including but not limited to inflammatory bowel disease, systemic inflammatory diseases, inflammatory skin diseases, gastrointestinal diseases, kidney diseases, cardiovascular diseases, liver diseases, autoimmune diseases, and respiratory diseases. Therefore, in another aspect of this disclosure, pharmaceutically acceptable compositions are provided, wherein such compositions comprise any of the compounds of formula (I) described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant, or mediator. In some embodiments, such compositions optionally further comprise one or more additional therapeutic agents.

[0115] It should also be understood that certain compounds of this disclosure may be present in a free form for therapeutic purposes, or, where appropriate, in the form of their pharmaceutically acceptable derivatives. According to this disclosure, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adducts or derivatives that, upon administration to a subject in need, can directly or indirectly provide the compounds otherwise described herein or their metabolites or residues. Furthermore, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs that, upon administration to a subject in need, can directly or indirectly provide the compounds otherwise described herein or their metabolites or residues.

[0116] As used herein, the term "pharmaceutically acceptable salt" means those salts that, to a reasonable medical judgment, are suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" means any non-toxic salt or ester salt of the compounds disclosed herein that, upon administration to a recipient, can directly or indirectly provide the compound disclosed herein or its inhibitory metabolites or residues. As used herein, the term "inhibitory metabolites or residues" means metabolites or residues of inhibitors or modulators of one or more of the therapeutic targets.

[0117] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference in its entirety. Pharmaceutically acceptable salts of the compounds of formula (I) disclosed herein include those derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, disglucuronate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucohepanoate, glyceryl phosphate, glucuronate, hemisulfate, heptasulfate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, p-valerate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N salts. + (C 1-4 Alkyl)4 salts. This disclosure also contemplates the quaternization of any basic nitrogen-containing group in compounds of formula (I) disclosed herein. Such quaternization can yield water- or oil-soluble or dispersible products. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions.

[0118] As used herein, the term "pharmaceuticalally acceptable prodrug" refers to those prodrugs of the disclosed compounds that are suitable for use in human and lower animal tissues, within the limits of reasonable medical judgment, without undue toxicity, irritation, allergic reactions, etc., in proportion to a reasonable benefit / risk ratio, and effective for their intended use; and the zwitterionic form of the disclosed compounds (where possible). The term "prodrug" refers, for example, a compound that is rapidly converted in vivo by hydrolysis in the blood to produce the parent compound of the above formula, such as an ester. Full discussion is provided in Higuchi, T. and V. Stella, "Pro-drugs as Novel Delivery Systems", ACS Symposium Series 14 and "Bioreversible Carriers in Drug Design", Edward B. Roche (ed.), American Pharmaceutical Association, Pergamon Press, 1987, both of which are incorporated herein by reference.

[0119] As described herein, pharmaceutically acceptable compositions of this disclosure may further comprise pharmaceutically acceptable carriers, adjuvants, or mediators, as used herein, including any and all solvents, diluents or other liquid mediators, dispersants or suspending agents, surfactants, isotonants, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., as suitable for the desired particular dosage form. Remington's Pharmaceutical Sciences, 16th edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutically acceptable compositions and their known preparation techniques. The use of any conventional carrier medium within the scope of this disclosure is contemplated unless it is incompatible with the compounds of formula (I) of this disclosure, for example, producing any undesirable biological effects or otherwise interacting in a harmful manner with any other one or more components of the pharmaceutically acceptable composition. Examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., phosphates, glycine, sorbic acid, or potassium sorbate), mixtures of metaglycerides of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars (e.g., lactose, ... Glucose and sucrose; starch, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered astragalus; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotropic brine; Ringer's solution; ethanol and phosphate buffer solutions and other non-toxic and compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), and colorants, release agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition at the formulator's discretion.

[0120] In another aspect, this disclosure provides a pharmaceutical composition comprising a compound of formula (I) of this disclosure and a pharmaceutically acceptable carrier.

[0121] In another aspect, this disclosure is characterized by a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or mediators.

[0122] The compound of formula (I) or a pharmaceutically acceptable salt thereof used in the applied composition may be obtained from any commercially available source or by any method or technique 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 method known in the art.

[0123] Compositions intended for enteral or parenteral administration are, for example, those in unit dosage forms such as sugar-coated tablets, tablets, capsules, suppositories, or ampoules. Unless otherwise specified, these are prepared in a manner known in the art, such as by conventional mixing, granulation, sugar coating, dissolving, or lyophilizing methods. It should be understood that the unit amount of the compound of formula (I) contained in a single dose of each dosage form need not itself constitute a therapeutically effective amount, as the necessary effective amount can be achieved by administering multiple dose units.

[0124] In various embodiments, the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally consists substantially of a compound of formula (I) or a pharmaceutically acceptable salt thereof. As used herein, the phrase “consistently composed of” generally covers the element / component specifically described for a particular embodiment. Furthermore, the phrase “consistently composed of” generally covers and allows for the presence of additional or optional elements / components that do not substantially affect the basis and / or novel features of a particular embodiment. In some embodiments, “consistently composed of” allows for the presence of ≤10, ≤5, or ≤1% by weight (wt.%) of additional or optional components based on the total weight of the composition.

[0125] In various embodiments, the composition includes one or more pharmaceutically acceptable additives as inactive ingredients. Examples of inactive ingredients include, but are not limited to, excipients (e.g., diluents and binders), granulating agents, slip agents (or flow aids), fillers, lubricants, preservatives, stabilizers, coatings, disintegrants, fragrances, pigments, solvents (e.g., alcohols), and combinations thereof. If used to form a composition, the inactive ingredient may be used in various amounts and combined with a compound of formula (I) or a pharmaceutically acceptable salt thereof to form a composition suitable for oral administration to humans or animals. It should be further understood that the amount of active ingredient described herein may be normalized relative to 100 parts by weight of the composition to account for the presence of inactive ingredients (if used).

[0126] Optionally, the composition may include one or more other components, such as additives. Suitable additives include those understood in the art, including but not limited to: moisturizers, emollients, emulsifiers, surfactants, oils, extracts, skin care agents, disinfectants, preservatives, pharmaceuticals and pharmaceutical substances, analgesic compounds, antineuralgia compounds, antioxidants, blood circulation promoters, antidepressant compounds, anti-anxiety compounds, anti-stress compounds, sunscreens, insect repellents, preservatives, exfoliants, fragrances, pigments, fillers, solvents, mediators, carriers, other types of additives known to those skilled in the art, and combinations thereof. Such additives may be used alone or in combination. Generally, optional additives may be of any type used in pharmaceuticals, nutritional preparations, personal care products, and cosmetic products.

[0127] Examples of such carrier components include oils, fats, waxes, surfactants, humectants, thickeners, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, fragrances, dyes, and lower alkanols. Other components may be incorporated into the composition as needed, such as anti-inflammatory agents, antibacterial agents, antifungal agents, disinfectants, vitamins, sunscreens, antibiotics, skin bleaching agents, healing enhancers / fibroblast proliferation compounds, neuromuscular blocking agents, sunscreens, or other anti-acne agents.

[0128] Examples of oils that can serve as carriers include: fats and oils, such as olive oil and hydrogenated oils; waxes, such as beeswax and lanolin; hydrocarbons, such as liquid paraffin, pure ceresin, and squalene; fatty acids, such as stearic acid and oleic acid; alcohols, such as cetyl alcohol, stearyl alcohol, lanolin alcohol, and hexadecyl alcohol; and esters, such as isopropyl myristate, isopropyl palmitate, and butyl stearate. Examples of surfactants used as carriers include: anionic surfactants such as sodium stearate, sodium cetyl sulfate, polyoxyethylene lauryl ether phosphate, and sodium N-acylglutamate; cationic surfactants such as stearyl dimethylbenzyl ammonium chloride and stearyl trimethyl ammonium chloride; amphoteric surfactants such as alkylaminoethyl glycine hydrochloride solution and lecithin; and nonionic surfactants such as glyceryl monostearate, sorbitan monostearate, sucrose fatty acid esters, propylene glycol monostearate, polyoxyethylene oil-based ethers, polyethylene glycol monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene coconut fatty acid monoethanolamide, polyoxypropylene glycol (e.g., materials sold under the trademark "Pluronic"), polyoxyethylene castor oil, and polyoxyethylene lanolin. Examples of humectants used as carriers include glycerin, 1,3-butanediol, and propylene glycol; examples of lower alcohols include ethanol and isopropanol; and examples of thickeners include saffron gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and sodium carboxymethyl cellulose. Examples of antioxidants include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, citric acid, ethoxyquin, alpha-lipoic acid, vitamin C, vitamin E, coenzyme Q-10, and idebenone; plant antioxidants include carotenoids such as lycopene; flavonoids such as silymarin (milk thistle), silybin, silydianin, and silychristine; soybean (isoflavin) and grape seed extract; polyphenols such as green tea extract, rosmarinic acid (rosemary), hypericin (Saint John's wort), oleuropein (olive leaf), curcumin (turmeric root), tetrahydrocurcumin, and pycogenol (marine bark pine). Examples of anti-inflammatory agents include anti-inflammatory herbal remedies such as allantoin, aloe vera, ginkgo, and green tea (antioxidants are also considered). Examples of skin bleaching agents are hydroquinone or kojic acid. Examples of healing enhancers / fibroblast proliferation compounds include copper peptides or palmitoyl-pentapeptide (pal-KTTKS). Examples of neuromuscular blocking agents include acetyl hexapeptide-3 (argircline) or dimethylaminoethanol. Examples of chelating agents include disodium EDTA and ethanedihydroxybisphosphate.Examples of buffers used as carriers include citric acid, sodium citrate, boric acid, borax, and disodium hydrogen phosphate; and examples of preservatives include methylparaben, ethylparaben, dehydroacetic acid, salicylic acid, and benzoic acid.

[0129] It should be understood that certain components or additives may be classified under different technical terms, and only because the classification of a component or additive under such terms does not imply that it is limited to the stated function. If used, one or more additives may be present in the composition in multiple amounts. Other ingredients optionally used in the composition are described in: U.S. Patent No. 5,747,006 to Dornoff et al.; U.S. Patent 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 in their entirety by reference.

[0130] The compositions can be prepared using various methods. For example, the active ingredient and optionally one or more inactive ingredients of the composition can be mixed or blended and pressed or compounded using various techniques understood in the art. The compositions disclosed herein are not limited to a specific sequence of manufacturing steps or methods.

[0131] The composition may contain 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 a compound 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.

[0132] In certain variations, the composition comprises approximately 0.1% to approximately 20% w / w, approximately 0.1% to approximately 15% w / w, approximately 0.1% to approximately 5% w / w, approximately 0.1% to approximately 3% w / w, approximately 0.1% to approximately 1.5% w / w, approximately 0.1% to approximately 1% w / w, approximately 0.1% to approximately 0.75% w / w, approximately 0.1% to approximately 0.375% w / w, approximately 0.375% to approximately 5% w / w, approximately 0.375% to approximately 3% w / w, approximately 0.375% to approximately 1.5% w / w, approximately 0.375% to approximately 1% w / w, approximately 0.375% to approximately 0.75% w / w, approximately 0.75% to approximately 5% w / w, and approximately 0.75% to approximately 3%. Compounds of formula (I) or pharmaceutically acceptable salts thereof, between w / w and approximately 0.75% to approximately 1.5% w / w, between approximately 0.75% to approximately 1% w / w, between approximately 1% to approximately 5% w / w, between approximately 1% to approximately 3% w / w, between approximately 1% to approximately 1.5% w / w, between approximately 1.5% to approximately 5% w / w, between approximately 1.5% to approximately 3% w / w, between approximately 3% to approximately 5% w / w, between approximately 1% to approximately 15% w / w, between approximately 2% to approximately 10% w / w, between approximately 4% to approximately 8% w / w, between approximately 5% to approximately 15% w / w, or between approximately 8% to approximately 12% w / w.

[0133] In other embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is present in the composition with 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.

[0134] In other variations of the foregoing, the composition may also contain one or more other components, including, for example, fragrances, colorants and / or excipients.

[0135] Use of compounds and pharmaceutically acceptable salts and compositions In one aspect, this article provides a method for treating, improving, or preventing a symptom or disease in a subject of need, said method comprising administering a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 For hydrogen, -NR9 R 10 -COOR 9 -CN or ; R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cyclic aliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; R 3 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, -(NR 9 R 10 R 11 ) + or -OC(=O)NH-(C2-C6 ynyl), wherein the C1-C6 alkyl, the aryl, the heteroaryl, the cycloaliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; T, U, V, W, and X are each independently CH and CR. 12 Sulfur, nitrogen, NH, NR 12 or N + -O - ; R 4 R 5 R 6 R 7R 8 R 9 R 10 and R 11 Each is independently hydrogen, deuterium, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independently classified as deuterium, halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group, or -O- (heterocyclic group). In some embodiments, the compound of formula (I) is administered in a therapeutically effective amount. In some embodiments, the ailment or disease is mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3). In some embodiments, the ailment or disease is mediated by tumor necrosis factor α (TNF-α).

[0136] On the other hand, this document provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment, improvement, or prevention of a lesion or disease. In some embodiments, the lesion or disease is mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3). In some embodiments, the lesion or disease is mediated by tumor necrosis factor α (TNF-α).

[0137] On the other hand, this document provides the use of compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, for the manufacture of medicaments for the treatment, improvement, or prevention of diseases or ailments. In some embodiments, the disease or ailment is mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3). In some embodiments, the disease or ailment is mediated by tumor necrosis factor α (TNF-α).

[0138] In some embodiments, the ailment 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 diseases, cryptothermal protein-associated periodic syndrome, familial cold-cause autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous joint (CINCA) syndrome, and neonatal paroxysmal multisystem 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 nephropathy; cardiovascular diseases, such as coronary atherosclerotic heart disease, cardiomyopathy, myocardial infarction, cardiac hypertrophy, and ischemia-reperfusion injury; liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, chronic hepatitis C virus infection, acetaminophen-induced liver injury, and alcoholic liver injury; autoimmune diseases, such as gout, pseudogout, rheumatoid arthritis (RA), multiple sclerosis (MS), Addison's disease, celiac disease, systemic lupus erythematosus (SLE), and vitiligo; and respiratory diseases, such as chronic lung disease, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and asthma. In various embodiments, the compound of formula (I) and the pharmaceutically acceptable composition are inhibitors or modulators of one or more of the following therapeutic targets: HSP90, NLRP3 inflammasome and TGF-β, and are therefore suitable for treating or reducing the severity of the various diseases, conditions or disorders described herein.

[0139] In some embodiments, the disease is a tumor necrosis factor-α (TNF-α)-mediated disease. In some embodiments, the disease is a disease mediated by an NLR family Pyrin domain 3 (NLRP3) inflammasome. In some embodiments, the disease is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof. In some embodiments, the disease is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, or a combination thereof. In some embodiments, the disease is selected from the group consisting of colorectal cancer, alcoholic hepatitis, or a combination thereof.

[0140] In some embodiments, the compound of formula (I) is Or its pharmaceutically acceptable salt.

[0141] In some embodiments, this document provides a method for treating, improving, or preventing inflammatory bowel disease (IBD) in a subject of need, the method comprising administering to the subject a therapeutically effective dose of... Or its pharmaceutically acceptable salt.

[0142] In some embodiments, the compound of formula (I) is Or its pharmaceutically acceptable salt.

[0143] In some embodiments, this document provides a method for treating, improving, or preventing alcoholic hepatitis in a subject of need, the method comprising administering to the subject a therapeutically effective dose of... Or its pharmaceutically acceptable salt.

[0144] In various embodiments, the terms "inhibition" and "regulation" are used interchangeably to refer to the reduction or suppression of a given symptom or condition or disease, or a significant decrease in the baseline activity of a biological activity or process. Specifically, in some embodiments, inhibition of NLRP3 or the NLRP3 inflammasome pathway includes reducing the ability of NLRP3 or the NLRP3 inflammasome pathway to induce the production of IL-1β and / or IL-18. This can be achieved through mechanisms including, but not limited to, inactivating, destabilizing, and / or altering the distribution of NLRP3. In other embodiments, inhibition of HSP90 or the HSP90 pathway includes reducing the ability of HSP90 to stabilize NLRP3, and thus reducing the ability of NLRP3 to induce the production of IL-1β and / or IL-18. This can be achieved through mechanisms including, but not limited to, inactivating, destabilizing, and / or altering the distribution of HSP90.

[0145] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt inhibits or modulates one or more of the therapeutic targets, wherein IC 50 Less than 50 micromoles (µM), optionally less than 40 µM, optionally less than 30 µM, optionally less than 20 µM, optionally less than 10 µM, or optionally less than 1 µM. Alternatively, a compound of formula (I) or a pharmaceutically acceptable salt thereof in an IC50 concentration of about 0.01 µM to about 100 µM, optionally about 0.1 µM to about 75 µM, optionally about 1 µM to about 50 µM, optionally about 1 µM to about 25 µM, or optionally about 1 µM to about 10 µM. 50 Inhibit or modulate one or more of the therapeutic targets.

[0146] In some implementations, “treating” or “treatment” means prophylactic or preventative treatment as well as curative or disease-modifying treatment, including treatment of patients at risk of contracting or suspected of contracting the disease, and patients who have contracted or have been diagnosed with the disease or medical condition, and includes suppression of clinical relapse. In these and other implementations, “treating” or “treatment” means obtaining a beneficial or desired outcome in a subject, such as a clinical outcome, including: (1) relief of one or more symptoms caused by or associated with the disease, condition, or disorder; (2) reduction of the severity of the disease, condition, or disorder; (3) slowing or stopping the development or progression of one or more symptoms caused by or associated with the disease, condition, or disorder (e.g., stabilizing the disease, condition, or disorder); and (4) disease relief, for example, by causing the resolution of one or more clinical symptoms (e.g., improving disease status, enhancing the effect of another agent, delaying or stopping disease progression, and / or improving quality of life).

[0147] In some aspects, this disclosure provides a method for treating or reducing the severity of a variety of diseases, symptoms or disorders in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof of a compound or a pharmaceutically acceptable salt thereof.

[0148] The term "therapeuticly effective amount" of the compound of this disclosure means an amount of the compound of this disclosure that will induce a biological or medical response in a subject, such response as reducing or inhibiting enzyme or protein activity, or improving symptoms, alleviating ailments, slowing or delaying disease progression, or preventing disease, etc. In one non-limiting embodiment, the term "therapeuticly effective amount" means an amount of the compound of this disclosure that, when administered to a subject, effectively (1) at least partially alleviates, inhibits, prevents and / or improves (i) ailments or conditions or diseases mediated by NLRP3, or (ii) associated with NLRP3 activity, or (iii) characterized by (normal or abnormal) NLRP3 activity; (2) reduces or inhibits NLRP3 activity (e.g., by binding to the C-terminus of HSP90 to prevent NLRP3 stabilization by HSP90); or (3) reduces or inhibits NLRP3 expression. In another non-limiting embodiment, the term "therapeuticly effective amount" for a compound of this disclosure refers to an amount that, when administered to cells or tissues or non-cellular biological materials or culture media, effectively at least partially reduces or inhibits the activity of NLRP3; or at least partially reduces or inhibits the expression of NLRP3. Therapeuticly effective amount may be determined experimentally.

[0149] In some embodiments, the method includes administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof to form a composition in an excipient. The composition may contain 10-500 mg, or 10-800 mg, or 20-1,000 mg, or 30-1,200 mg, or 50-1,500 mg, or 100-2,000 mg, or even more of a compound of formula (I) or a pharmaceutically acceptable salt thereof in a single dose unit. From different perspectives, 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof. Therefore, the preferred single oral dose (or recommended daily intake) will be 20-200 mg, or 40-400 mg, or 60-600 mg, or 80-800 mg, or 100-1,000 mg, or 200-2,000 mg, and in some cases even higher.

[0150] As used herein, the term “administration” of a pharmaceutical composition or medicine refers to the direct and indirect administration of a pharmaceutical composition or medicine, wherein direct administration of a pharmaceutical composition or medicine is typically performed by a healthcare professional (e.g., physician, nurse, etc.), and wherein indirect administration includes the steps of providing or preparing a pharmaceutical composition or medicine available to a healthcare professional for direct administration (e.g., via injection, infusion, oral delivery, local delivery, etc.).

[0151] In some variations, the method includes administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof in a petroleum-based medium (e.g., 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.

[0152] In various implementation schemes, the amount of composition administered to the subject is based on skin area (unit: square centimeter (cm²)). 2 The amount (in milligrams (mg)) of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The composition may be administered to the subject in the following amounts: at least 0.01 mg / cm³. 2 (mg compound / cm) 2 (skin), at least 0.02 mg / cm 2 At least 0.03 mg / cm 2 At least 0.04 mg / cm 2 At least 0.05 mg / cm 2 At least 0.06 mg / cm 2 At least 0.07 mg / cm 2 At least 0.08 mg / cm 2 At least 0.09 mg / cm 2 At least 0.1 mg / cm 2 At least 0.12 mg / cm 2 At least 0.14 mg / cm 2At least 0.16 mg / cm 2 At least 0.18 mg / cm 2 At least 0.2 mg / cm 2 At least 0.22 mg / cm 2 At least 0.24 mg / cm 2 At least 0.26 mg / cm 2 At least 0.28 mg / cm 2 At least 0.3 mg / cm 2 At least 0.32 mg / cm 2 At least 0.34 mg / cm 2 At least 0.36 mg / cm 2 At least 0.38 mg / cm 2 At least 0.4 mg / cm 2 Or even more. The composition may be administered to the subject in the following amounts: approximately 0.01 mg / cm³. 2 Approximately 0.4 mg / cm 2 Approximately 0.05 mg / cm 2 Approximately 0.3 mg / cm 2 Approximately 0.1 mg / cm 2 Approximately 3 mg / cm 2 or approximately 0.15 mg / cm 2 To approximately 0.25 mg / cm 2 .

[0153] The composition may be administered once daily, several times daily, or in any suitable regimen as needed to achieve the desired result. In the methods of this disclosure, the frequency of administration (e.g., oral administration) may depend on several factors, including the severity of the disease or symptoms or the desired level of symptom relief. Typically, a regimen includes administering the composition once or twice daily to include administration in the morning and / or evening. The amount and / or frequency of administration of the composition may depend on several factors, including the level of desired result and the specific composition. In some embodiments, the composition is administered once daily. In other embodiments, the composition is administered twice daily. In still other embodiments, the composition is administered three times daily. In yet another embodiment, the composition is administered four times daily. However, it should be understood that the composition may be administered more than four times daily.

[0154] In some variations, the application of the composition lasts 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 some variations, the application of the composition lasts 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 application of the composition lasts for about 1 week to about 1 year, about 4 weeks to about 8 weeks, about 4 weeks to about 12 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 32 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 48 weeks, or about 4 weeks to about 1 year.

[0155] Compounds of formula (I) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, may be administered as described herein. In some embodiments, the composition is administered topically to a subject. In other embodiments, the composition is administered orally.

[0156] In another aspect, this disclosure provides a method for inhibiting at least one of a therapeutic target (e.g., HSP90, NLRP3 inflammasome, and TGF-β) in a subject, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0157] In some exemplary embodiments, this disclosure provides a method for treating or reducing the severity of inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease) in a subject, the method 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.

[0158] In other exemplary embodiments, this disclosure provides a method for treating or reducing the severity of a gastrointestinal disease, such as colorectal cancer, in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof.

[0159] In some variations of the foregoing, the subject is formally or clinically diagnosed with inflammatory bowel disease, such as ulcerative colitis and Crohn's disease, or gastrointestinal disease, such as colorectal cancer.

[0160] Manufacturing drugs Unless otherwise specified herein or clearly contradicted, all methods described herein may be performed in any suitable order. Otherwise, the use of any and all embodiments or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate the disclosure and does not impose a limitation on the scope of any additionally claimed disclosure.

[0161] Any asymmetric atom (e.g., carbon, etc.) in the compounds of this disclosure may be racemic or enantiomerically enriched, for example, present in (R)-configuration, (S)-configuration, or (R,S)-configuration. In some embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% in the (R)-configuration or (S)-configuration.

[0162] Therefore, as used herein, the compounds disclosed herein may be in the form of possible stereoisomers, rotational isomers, tautomers, tautomers or mixtures thereof, for example, in the form of substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0163] Any mixture of resulting stereoisomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example by chromatography and / or stepwise crystallization, based on the physicochemical differences of the components.

[0164] Any resulting racemic product of the compounds or intermediates of this disclosure can be resolved into optical enantiomers by known methods, such as by separating their diastereomeric salts obtained with optically active acids or bases and releasing optically active acidic or basic compounds. Specifically, the basic moiety can therefore be used to resolve the compounds of this disclosure into their optical enantiomers, for example by causing stepwise crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-tolyltartaric 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 chiral adsorbents).

[0165] A method for preparing a compound (e.g., a compound of formula (I)) is provided. In various embodiments, the compound is of formula (Iaa). The method includes the step of providing a pyrazine as a first intermediate. The method further includes the step of combining a 2-pyranone with the first intermediate to form a second intermediate. The method may also include purifying the second intermediate in ammonium bicarbonate to form the compound of formula (Iaa).

[0166] In some embodiments, the method may further include the step of providing a solvent, salt, ligand, catalyst, or a combination thereof. Other components may be provided, including (but not limited to) bases, acids, oxidizing agents, reducing agents, halogenating agents, coupling agents, protecting groups, etc.

[0167] In these and other embodiments, the step of providing pyrazine as a first intermediate is further defined as combining (i) a solvent, a salt, a ligand, a catalyst, or a combination thereof with (ii) pyrazine to form the first intermediate. In some aspects, the pyrazine is 2-chloro-5-isopropoxypyrazine.

[0168] In these and other embodiments, the step of combining 2-pyranone with a first intermediate to form a second intermediate is further defined as combining (i) a solvent, a salt, a ligand, a catalyst, or a combination thereof with (ii) 2-pyranone and the first intermediate to form a second intermediate. In some aspects, 2-pyranone is (4S,4aR,5aR,6aS,6bS,9R,9aS,11aS,11bR)-4-hydroxy-9-((S)-1-((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,10,11,11a,11b-dodecylhydrocyclopenta[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one.

[0169] The solvent may be selected from the group consisting of 1,4-dioxane, tetrahydrofuran, ethyl acetate, heptane, water, or combinations thereof. The salt may be selected from the group consisting of lithium chloride, sodium sulfate, ammonium bicarbonate, or combinations thereof.

[0170] The ligand may be selected from hexabutyldistannane, tributyl(5-isopropoxy-2-pyrazinyl)stannane, tricyclohexylphosphine, triphenylarsine, and combinations thereof. The catalyst may be selected from the following group: palladium-(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one (2 / 3), tris((1E,4E)-1,5-diphenylpenten-1,4-diene-3-one)dipalladium [Pd2(dba)3], copper iodide [CuI], triphenylarsine [AsPh3], tetra(triphenylphosphine)palladium(0) [Pd(PPh3)4], bis((triphenylphosphine)palladium(II) chloride [PdCl2(PPh3)2], and combinations thereof.

[0171] The base may be selected from the following group: sodium hydride, potassium carbonate, triethylamine, sodium hydroxide, lithium diisopropylamine, and combinations thereof. The acid may be selected from the following group: hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and combinations thereof.

[0172] The oxidant may be selected from the following group: hydrogen peroxide, m-chloroperoxybenzoic acid, potassium permanganate, pyridinium chlorochromate, and combinations thereof. The reducing agent may be selected from the following group: sodium borohydride, lithium aluminum hydride, hydrogen and palladium catalyst, diisobutylaluminum hydride, and combinations thereof.

[0173] The halogenating agent may be selected from the group consisting of thionyl chloride, phosphorus tribromide, iodine monochloride, and combinations thereof. The coupling agent may be selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC), benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP), and combinations thereof. The protecting group may be selected from the group consisting of tert-butyldimethylchlorosilane (TBSCl), ditert-butyl dicarbonate (Boc anhydride), benzyl bromide, and combinations thereof.

[0174] The compounds disclosed herein can be prepared according to the compounds of formula (I) or their pharmaceutically acceptable salts via the routes described in the following schemes or examples. Unless otherwise specified herein or clearly contradicted, all methods described herein may be performed in any suitable order. The use of any and all embodiments or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate the invention and does not constitute a limitation on the scope of this disclosure as otherwise claimed. In the following general methods, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 T, U, V, W, and X are as defined above in the embodiments and are limited to the names used in the embodiments. Unless otherwise stated, the starting materials are commercially available or prepared by known methods.

[0175] In some embodiments, the compounds disclosed herein, as described herein, can be prepared by the reaction sequence shown in Scheme 1 below and described below to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0176]

[0177] Step 1: Synthesis of (4S,4aR,5aR,6aS,6bS,9R,9aS,11aS,11bR)-4-hydroxy-9-((S)-1-((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,10,11,11a,11b-dodecylhydrocyclopentan[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: Under an inert atmosphere, N,N-dimethylpyridin-4-amine (1.17 g, 1.5 equivalent, 9.56 mmol) was added to a stirred solution of solanine-A (3 g, 1 equivalent; 6.37 mmol) in dichloromethane (30 mL). After 10 minutes, iodine (1.94 g, 1.2 equivalent, 7.65 mmol) was added to the reaction mixture, and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium thiosulfate (50 mL). The aqueous layer was extracted with dichloromethane (3 x 45 mL). The organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. The crude substance was purified by combi-flash chromatography (using dichloromethane containing 5% methanol) to obtain a white solid (4S,4aR,5aR,6aS,6bS,9R,9aS,11aS,11bR)-4-hydroxy-9-((S)-1-((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,10,11,11a,11b-dodecylhydrocyclopenta[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one (2.1 g, 55%).

[0178] Analyze the data: LCMS:90.55% (m / z: 595.18, [MH] + Observed value 595.18, [M+H] + , 2.29 min (4 min run).

[0179] 1 H-NMR (400 MHz, DMSO- d 6): δ 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: Method A: Add potassium carbonate (2 equivalents, 2.04 mmol) and potassium-λ to a stirred solution of (4S,4aR,5aR,6aS,6bS,9R,9aS,11aS,11bR)-4-hydroxy-9-((S)-1-((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,10,11,11a,11b-dodecylhydrocyclopenta[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one (1 equivalent; 1.02 mmol) in 1,4-dioxane and water. 6 - Borane (1.5 equivalents, 1.53 mmol). The resulting reaction mixture was degassed by purging with nitrogen for 30 min. Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.2 equivalents, 204 µmol) was added to the mixture, and the mixture was heated at 85 °C for 5 h. The reaction was monitored by TLC (dichloromethane containing 5% methanol). After the reaction was complete, the reactants were quenched with citric acid solution, followed by extraction with dichloromethane (2 x 40 mL). The organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to give the crude substance. The crude substance was purified by combi-flash chromatography (dichloromethane containing 5-10% methanol) to give the corresponding compounds.

[0180] Method B: To (1S,2R,6S,7R,9R,11S,12S,15R,16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 ,9 .0 12 , 16 Add λ to a stirred solution of octadecyl-4-en-3-one (1 equivalent; 2.35 mmol) in tetrahydrofuran (14 mL). 1 -Copper iodide (1+) (0.1 equivalent, 235 µmol), triphenylarsine (71.9 mg, 0.1 equivalent, 235 µmol), and (tributyltinyl) reagent (2 equivalent, 4.69 mmol). The reaction mixture was purged with a continuous stream of nitrogen for 30 min. Subsequently, tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (0.01 equivalent, 23.5 µmol) was added, and the resulting reaction mixture was degassed with nitrogen for 5 min. The resulting reaction mixture was stirred at 80 °C for 16 h. After the reaction was complete (monitored by TLC: dichloromethane containing 5% methanol), the reaction mixture was filtered through a diatomaceous earth bed, and the filtrate was diluted with water (30 mL) and then extracted with dichloromethane (2 x 50 mL). The organic matter was collected, dried over sodium sulfate, and then concentrated under reduced pressure to give a crude substance, which was purified by preparative HPLC to obtain the compound.

[0181] The method is scalable to prepare any of the compounds of formula (I) as described herein, any of their sub-formulas, or pharmaceutically acceptable salts thereof. Depending on the starting materials and chosen route as mentioned in Scheme 1 above, those skilled in the art will know how to prepare compounds of formula (I) or pharmaceutically acceptable salts thereof. Certain variations or alternative methods are described in the experimental section below.

[0182] This disclosure also includes any variations of the method, wherein an intermediate product available at any stage is used as a starting material and the remaining steps are performed, or wherein the starting material is formed in situ under reaction conditions, or wherein the reaction components are used in the form of their salts or optically pure materials. The compounds and intermediates of this disclosure may also be converted to each other according to methods commonly known to those skilled in the art.

[0183] In one aspect, this disclosure provides the use of compounds or pharmaceutical compositions of formula (I) described herein for manufacturing agents for inhibiting at least one of therapeutic targets, such as HSP90, NLRP3 inflammasome, and TGF-β.

[0184] Pharmaceutically acceptable application of salts and compositions The compounds and compositions of formula (I) according to the methods of this disclosure may be administered in any amount and via any route of administration that are effective in treating one or more of the pain or non-pain conditions described herein or in reducing their severity. The precise amount required will vary from subject to subject, depending on the subject's species, age and general condition, severity of infection, specific agent, mode of administration, etc. The compounds of formula (I) of this disclosure may be formulated in unit dosage form for ease of administration and uniform dosage. As used herein, the expression "unit dosage form" refers to a physically discrete unit of agent suitable for the subject to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of formula (I) of this disclosure will be determined by the attending physician within the bounds of reasonable medical judgment. The specific effective dose level for any particular subject or organism will depend on a variety of factors, including the condition to be treated and its severity; the activity of the specific compound used; the specific composition used; the subject's age, weight, general health condition, sex, and diet; the time of administration, route of administration, and rate of excretion of the specific compound used; duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field. As used herein, the terms “subject” or “patient” refer to an animal, preferably a mammal and most preferably a human.

[0185] The pharmaceutically acceptable compositions disclosed herein may be administered to humans and other animals, depending on the severity of the infection being treated, via oral, rectal, parenteral, intracisional, vaginal, intraperitoneal, topical (e.g., by powder, ointment, or drops), buccal, as an oral or nasal spray, etc. As used herein, the phrases “parenteral administration” and “via parenteral” refer to modes of administration other than enteral and topical administration, typically by injection, and include (but are not limited to) intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intracystic, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions. In some embodiments, the compound of formula (I) of this disclosure may be administered orally or parenterally at dose levels of about 0.01 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, and optionally about 1 mg / kg to about 25 mg / kg of the subject's body weight once or more daily to achieve the desired therapeutic effect.

[0186] 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 compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol; and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0187] In addition to active compounds, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragali and mixtures thereof.

[0188] It is well known that sterols (such as cholesterol) will form complexes with cyclodextrins. Therefore, in some embodiments, when the inhibitor is a steroid alkaloid, it can be formulated with cyclodextrins (such as α-, β- and γ-cyclodextrins, dimethyl-β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin).

[0189] Injectable formulations can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques, such as sterile injectable aqueous or oily suspensions. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, for example, in the form of a solution in 1,3-butanediol. Among acceptable media and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solution can be used. Additionally, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild, non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids, such as oleic acid, are used in the preparation of injectable formulations.

[0190] Injectable formulations can be sterilized, for example, by filtration via a bacterial trap, by autoclaving, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use. In various embodiments, a first portion (e.g., the compound) of the formulation may be sterilized by filtration, and a second portion (e.g., the excipient) may be sterilized by autoclaving.

[0191] To prolong the effects of the disclosed compounds, it is generally necessary to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the compound then depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of parenteral-administered compounds can be achieved by dissolving or suspending the compound in an oil medium. Injectable storage forms are manufactured by forming a microcapsule matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolic acid. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Reservoir-type injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0192] 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 (e.g., sodium citrate or dicalcium phosphate) and / or the following: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants such as glycerin; d) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution blockers such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0193] Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well-known in the pharmaceutical formulation field. They may optionally contain emulsifiers and may also have compositions that release the active ingredient only or preferentially in a portion of the intestine or optionally in a delayed manner. Examples of usable encapsulation compositions include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol.

[0194] Tablets can be manufactured by compression or molding, optionally together with one or more adjuncts. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. Molded tablets can be manufactured by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0195] The pharmaceutical compositions of this disclosure in tablet and other solid dosage forms (e.g., sugar-coated pills, capsules, pellets, and granules) may optionally be scored or prepared with a coating and shell, such as enteric coating and other coatings well known in the pharmaceutical formulation art. They may also be formulated using, for example, different proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile in order to provide a slow or controlled release of the active ingredient therein. They may be sterilized, for example, by filtration via a bacterial trap or by incorporation of a sterilizing agent, in the form of a sterile solid composition soluble in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain a light-blocking agent and may be compositions that optionally release the active ingredient only or preferentially in a delayed manner into a portion of the gastrointestinal tract. Examples of encapsulation compositions that may be used include polymeric substances and waxes. The active ingredient may also be microencapsulated with one or more of the above-described excipients, where appropriate.

[0196] Formulations of the pharmaceutical compositions of this disclosure for administration rectally, vaginally, or transurethral may be presented in suppository form, said suppository being prepared by mixing one or more compounds with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, and said suppository being solid at room temperature but liquid at body temperature, and thus melting in the rectum or vaginal cavity and releasing the active compound.

[0197] Alternatively, the composition may be formulated for delivery via catheters, stents, wires or other intraluminal devices. Delivery via such devices is particularly suitable for delivery to the bladder, urethra, urethra, rectum or intestine.

[0198] Preparations suitable for vaginal application also include pessaries, tampons, creams, gels, pastes, foams or sprays containing carriers known in the art, for example.

[0199] The active compound may also be in a microencapsulated form with one or more excipients as described above. Solid dosage forms, such as tablets, sugar-coated pills, capsules, pellets, and granules, can be prepared with coatings and shells (e.g., enteric coatings, release-controlled coatings, and other coatings well known in the pharmaceutical formulation field). In such solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). As is normal practice, such dosage forms may also contain additional substances besides inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain a buffer. It may optionally contain an emulsifier and may also have a composition that releases the active ingredient only or preferentially in a portion of the intestine or optionally in a delayed manner. Examples of encapsulation compositions that can be used include polymers and waxes.

[0200] Dosage forms for topical or transdermal application of the compounds disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

[0201] Dosage forms of compounds intended for topical or transdermal application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. Active compounds may be mixed under sterile conditions with pharmaceutically acceptable carriers and with any preservatives, buffers, or propellants that may be required.

[0202] In addition to the active compounds disclosed herein, ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragali, cellulose derivatives, polyethylene glycol, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0203] In addition to the compounds disclosed herein, powders and sprays may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof. Sprays may also contain commonly used propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0204] Transdermal patches offer the added advantage of providing controlled delivery of compounds into the body. Such dosage forms can be manufactured by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. This flux rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0205] Ophthalmic preparations, eye ointments, eye drops, and ear drops are also covered within the scope of this disclosure. Pharmaceutical compositions suitable for parenteral administration comprise one or more compounds combined with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use. The pharmaceutical compositions may contain antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0206] Examples of suitable aqueous and non-aqueous carriers that can be used in pharmaceutical compositions include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). Appropriate flowability can be maintained, for example, by using coating materials (e.g., lecithin), by maintaining the desired particle size in the case of a dispersion, and by using surfactants.

[0207] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial activity can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenolic sorbic acid. Isotonic agents, such as sugars and sodium chloride, may also be required in the composition. Furthermore, prolonged absorption of injectable drug forms can be achieved by including agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0208] In some cases, to prolong the action of a drug, it is necessary to slow the absorption of subcutaneously or intramuscularly injected drugs. This can be achieved by using liquid suspensions of crystalline or amorphous substances with poor water solubility. The absorption rate of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, parenteral administration of drugs can achieve delayed absorption by dissolving or suspending the drug in an oily medium.

[0209] When the compound of formula (I) is administered to humans and animals as a pharmaceutical agent, it may be given either on its own or in the form of a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient and a pharmaceutically acceptable carrier.

[0210] Adding an active compound to animal feed is preferably achieved by preparing a suitable feed premix containing a therapeutically effective amount of the active compound and incorporating the premix into a complete diet.

[0211] Alternatively, intermediate concentrates or feed supplements containing active ingredients can be incorporated into the feed. Methods for preparing and administering such feed premixes and complete diets are described in reference books (e.g., "Applied Animal Nutrition", WH Freedman and CO., San Francisco, USA, 1969, or "Livestock Feeds and Feeding" O and B books, Corvallis, Ore., USA, 1977).

[0212] Introduction methods can also be provided via refillable or biodegradable devices. In recent years, various sustained-release polymer devices for controlled drug delivery, including protein biopharmaceuticals, have been developed and tested in vivo. A variety of biocompatible polymers, including hydrogels, encompassing both biodegradable and non-degradable polymers, can be used to form inserts that sustainably release compounds at specific target sites.

[0213] The actual dose level of the active ingredient in a pharmaceutical composition can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and administration mode without toxicity to the patient.

[0214] The chosen dose level will depend on a number of factors, including the activity of the specific compound used or its esters, salts or amides; the route of administration; the time of administration; the excretion rate of the specific compound used; the duration of treatment; other drugs, compounds and / or materials used in combination with the specific compound used; the age, sex, weight, disease, general health and prior medical history of the patient being treated; and similar factors well known in the medical field.

[0215] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may start with a dose of the compound of formula (I) used in the pharmaceutical composition below the level required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0216] Generally, the appropriate daily dose of a compound will be the lowest amount of compound that effectively produces a therapeutic effect. This effective dose will usually depend on the factors mentioned above. Typically, the intravenous, intraventricular, and subcutaneous doses of compound of formula (I) for patients will range from about 0.0001 to about 100 mg per kilogram of body weight per day.

[0217] If necessary, the effective daily dose of the active compound may be administered in sub-dose form 2, 3, 4, 5, 6 or more times, which may optionally be administered in unit dose form at appropriate time intervals throughout the day.

[0218] Patients receiving this treatment are any animals in need, including primates, especially humans, and other mammals such as horses, cattle, pigs, and sheep, and are often poultry and pets.

[0219] The compound may be administered as is or in a form blended with a pharmaceutically acceptable and / or sterile carrier, and may also be administered in combination with other antimicrobial agents (e.g., penicillins, cephalosporins, aminoglycosides, and glycopeptides). Therefore, combination therapy includes the sequential, simultaneous, and separate administration of the active compound, such that the therapeutic effect of the first-administered therapy can still be detected when subsequent therapies are administered.

[0220] This disclosure covers formulations of the subject compound in any of the aforementioned pharmaceutical compositions and formulations. Furthermore, this disclosure contemplates administration via any of the aforementioned routes of administration. Those skilled in the art can select appropriate formulations and routes of administration based on the disease being treated and the overall health condition, age, and body type of the patient being treated.

[0221] The activity of the compounds used in this disclosure as inhibitors of therapeutic targets can be determined according to the methods generally described in the embodiments herein or according to methods available to those skilled in the art.

[0222] Combination products and combination therapies It should also be understood that the compounds of formula (I) and pharmaceutically acceptable compositions disclosed herein can be used in combination therapies, i.e., the compounds of formula (I) and pharmaceutically acceptable compositions can be administered concurrently with, before, or after one or more other desired therapeutic agents or medical procedures. The specific combination of therapies (therapeutic agents or procedures) used in a combination regimen will take into account the compatibility of the desired therapeutic agents and / or procedures and the desired therapeutic effect to be achieved. It should also be understood that the therapy employed may achieve the desired effect against the same condition (e.g., the compound of formula (I) may be administered concurrently with an additional therapeutic agent for treating the same condition), or it may achieve a different effect (e.g., controlling any adverse effects). As used herein, an additional therapeutic agent typically administered to treat or prevent a particular disease or ailment is referred to as “suitable for the disease or ailment being treated.”

[0223] "Combination" refers to a fixed combination or combination administration in a single dosage form, wherein the disclosed compound and the combination partner (e.g., another drug described below, also referred to as a "therapeutic agent" or "adjuvant") may be administered simultaneously and independently or separately at time intervals, particularly where these time intervals allow the combination partner to exhibit synergistic effects, such as a co-effect. Individual components may be packaged in a box or separately. One or both of the components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration. Terms such as "co-administration" or "combination administration" as used herein are intended to cover administration of the selected combination partner to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the agents are not necessarily administered via the same route of administration or simultaneously. The term "drug combination" as used herein means a product resulting from mixing or combining more than one therapeutic agent and includes both fixed and non-fixed combinations of therapeutic agents. As used herein, the term "drug combination" refers to a fixed combination in a single dosage form, or a non-fixed combination or a package of dispensing portions for combined administration, wherein two or more therapeutic agents may be administered simultaneously and independently or separately at time intervals, particularly where these time intervals allow the combination partners to exhibit a synergistic effect, such as a co-existing effect. The term "fixed combination" means that the therapeutic agents (e.g., the compounds and combination partners disclosed herein) are administered simultaneously to a patient in a single entity or dose. The term "non-fixed combination" means that the therapeutic agents (e.g., the compounds and combination partners disclosed herein) are administered simultaneously, in parallel, or sequentially to a patient in separate entities, without a specific time limit, wherein this administration provides a therapeutically effective level of the two compounds in the patient's body. The latter also applies to mixed-solution therapies, such as the administration of three or more therapeutic agents.

[0224] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic ailment or condition described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in the form of a single capsule containing the active ingredients in a fixed ratio. Alternatively, such administration encompasses the co-administration of each active ingredient in multiple or separate containers (e.g., tablets, capsules, powders, and liquids). Powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration also encompasses the sequential use of each type of therapeutic agent at substantially the same time or at different times. In either case, the treatment regimen will provide the beneficial effect of the combination of drugs in treating the ailment or condition described herein.

[0225] The compounds disclosed herein may be administered simultaneously, before, or after one or more additional therapeutic agents. The compounds disclosed herein may be administered alone via the same or different routes of administration, or together with other agents in the same pharmaceutical composition. The therapeutic agents are, for example, compounds, peptides, antibodies, antibody fragments, or nucleic acids that have therapeutic activity or enhance therapeutic activity when administered to a patient in combination with the compounds disclosed herein.

[0226] In one embodiment, this document provides a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent, as a combination formulation for simultaneous, separate, or sequential use in a therapy. In one embodiment, the therapy is for treating a disease or ailment mediated by NLRP3. Products provided as combination formulations include compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutic agent together in the same pharmaceutical composition, or compounds of formula (I) or a pharmaceutically acceptable salt thereof and an additional therapeutic agent in a separate form, for example, in the form of a cassette.

[0227] In one embodiment, this disclosure provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an additional therapeutic agent. Optionally, the pharmaceutical combination may comprise a pharmaceutically acceptable carrier, as described above.

[0228] In one embodiment, this document provides a pillbox 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 pillbox is configured to individually hold the compositions, such as in a container, a separator bottle, or a separator foil seal. An example of such a pillbox is a blister pack, as commonly used for packaging tablets, capsules, etc.

[0229] The compounds disclosed herein may be administered simultaneously, before, or after one or more additional therapeutic agents. The compounds disclosed herein may be administered alone via the same or different routes of administration, or together with other therapeutic agents in the same pharmaceutical composition. The therapeutic agents are, for example, compounds, peptides, antibodies, antibody fragments, or nucleic acids that have therapeutic activity or enhance therapeutic activity when administered to a patient in combination with the compounds disclosed herein.

[0230] In one embodiment, this disclosure provides a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one additional therapeutic agent, as a combination formulation for simultaneous, separate, or sequential use in a therapy. In one embodiment, the therapy is for treating a disease or ailment mediated by NLRP3. Products provided as combination formulations include compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutic agent together in the same pharmaceutical composition, or in a separate form, such as in a kit.

[0231] In some embodiments, this disclosure provides a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an additional therapeutic agent. Optionally, the pharmaceutical combination may comprise a pharmaceutically acceptable carrier, as described above.

[0232] In various embodiments, this disclosure provides a pillbox 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 pillbox is configured to separately hold the compositions, such as in a container, a separator bottle, or a separator foil seal. An example of such a pillbox is blister packaging, commonly used for packaging tablets, capsules, etc.

[0233] The kits disclosed herein can be used to administer different dosage forms (e.g., oral and parenteral), to administer individual compositions at different dosing intervals, or to titrate individual compositions relative to each other. To aid compliance, the kits of this disclosure typically include instructions for use.

[0234] In some embodiments, this disclosure relates to a medicine box comprising a pharmaceutical composition and specific instructions explaining how to use the pharmaceutical composition to treat, improve, or prevent one or more diseases and conditions (e.g., diseases or conditions mediated by NLRP3) in a subject of need.

[0235] In the combination therapies disclosed herein, the compound of formula (I) and the additional therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of formula (I) and the additional therapeutic agent may be used together as a combination therapy in the following situations: (i) before the combination product is given to a physician (e.g., in cases where the kit contains the compound of formula (I) and the additional therapeutic agent); (ii) shortly before administration by the physician (or under the physician's guidance); and (iii) by the patient, for example, during the sequential administration of the compound of formula (I) and the additional therapeutic agent.

[0236] Therefore, this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a disease or ailment mediated by NLRP3, wherein said agent is prepared for administration in conjunction with an additional therapeutic agent. This disclosure also provides the use of an additional therapeutic agent for treating a disease or ailment mediated by NLRP3, wherein the agent is administered in conjunction with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0237] This disclosure also provides a method for treating a disease or ailment mediated by NLRP3 using a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared for administration with an additional therapeutic agent. This disclosure also provides an additional therapeutic agent in a method for treating a disease or ailment mediated by NLRP3, wherein the additional therapeutic agent is prepared for administration with a compound of formula (I) or a pharmaceutically acceptable salt thereof. This disclosure also provides an additional therapeutic agent in a method for treating a disease or ailment mediated by NLRP3 using a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered with an additional therapeutic agent. This disclosure also provides an additional therapeutic agent in a method for treating a disease or ailment mediated by NLRP3, wherein the additional therapeutic agent is administered with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0238] This disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder mediated by NLRP3, wherein the patient has previously (e.g., within 24 hours) been treated with an additional therapeutic agent. This disclosure also provides the use of an additional therapeutic agent for the treatment of a disease or disorder mediated by the 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.

[0239] In some implementations, the additional therapeutic agent is a therapeutic agent suitable for treating inflammasome-related diseases / conditions, immune diseases, inflammatory diseases, autoimmune diseases, autoinflammatory diseases, or cancer, as disclosed herein.

[0240] In various implementation schemes, additional therapeutic agents that can be used in combination therapy are selected from farnesoid X receptor (FXR) agonists; anti-fatty degeneration agents; anti-fibrotic agents; JAK inhibitors; checkpoint inhibitors; chemotherapy, radiation therapy, and surgery; urate-lowering therapy; anabolic and cartilage regeneration therapy; IL-17 blocking; complement inhibitors; Bruton's tyrosine kinase inhibitors (BTK inhibitors); Toll-like receptor inhibitors (TLR7 / 8 inhibitors); CAR-T therapy; antihypertensive agents; cholesterol-lowering agents; leukotriene A4 hydrolase (LTAH4) inhibitors; SGLT2 inhibitors; β2-agonists; anti-inflammatory agents; nonsteroidal anti-inflammatory drugs (“NSAIDs”); acetylsalicylic acid drugs (ASA), including aspirin; acetaminophen; regenerative therapy; cystic fibrosis treatment; and atherosclerosis treatment.

[0241] The amount of other therapeutic agents present in the compositions disclosed herein will not exceed the amount typically applied in a composition comprising the therapeutic agent as the sole active agent. The amount of other therapeutic agents in the compositions disclosed herein is in the range of about 10% to 100% of the amount typically present in a composition comprising the pharmaceutical agent as the sole active agent.

[0242] The compounds of formula (I) of this disclosure, or pharmaceutically acceptable compositions thereof, may also be incorporated into compositions for coating implantable medical devices (e.g., prostheses, artificial valves, vascular grafts, endovascular stents, and catheters). Thus, in another aspect, this disclosure includes a composition for coating an implantable device comprising compounds of this disclosure as generally described above and described herein by class and subclass, and a carrier suitable for coating said implantable device. In yet another aspect, this disclosure includes an implantable device coated with a composition comprising compounds of this disclosure as generally described above and described herein by class and subclass, and a carrier suitable for coating said implantable device. General preparation of suitable coatings and coated implantable devices is described in U.S. Patent Nos. 6,099,562, 5,886,026, and 5,304,121. Coatings are typically biocompatible polymeric materials, such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further covered by a top coating of a suitable fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or combination thereof to impart controlled release characteristics to the composition.

[0243] Another aspect of this disclosure relates to inhibiting the activity of a therapeutic target in a biological sample or a subject, the method comprising administering a compound of formula (I) or a composition comprising said compound to said subject, or contacting said biological sample with a compound of formula (I) or a composition comprising said compound. As used herein, the term “biological sample” includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

[0244] Inhibiting the activity of therapeutic targets in biological samples can be used for a variety of purposes known to those skilled 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 novel inhibitors of therapeutic targets.

[0245] References to “about” a value or parameter in this document include (and describe) embodiments relating to said value or parameter. For example, a description of “about X” includes a description of “X”. In some embodiments, when the term “about” is used in conjunction with a measurement or to modify a value, unit, constant, or range of values, it refers to a change of + / - 10%, 5%, 2%, or 1%.

[0246] In this document, references to "between" two values ​​or parameters include (and describe) implementations that include those two values ​​or parameters themselves. For example, a reference to "between x and y" includes a description of "x" and "y" themselves.

[0247] The listed implementation schemes The embodiments listed below represent some aspects of the present invention.

[0248] Implementation Scheme 1. A compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 For hydrogen, -NR 9 R 10 -COOR 9 -CN or ; R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11-CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: and Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cycloalkane, or the heterocycloalkane is not substituted or is modified by one or more R groups. 12 replace; R 3 Independent of halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: , , , , , and Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cycloalkane, or the heterocycloalkane is not substituted or is modified by one or more R groups. 12 replace; T, U, V, W, and X are each independently CH and CR. 12 Sulfur, nitrogen, NR 12 or N + R 12 ; R 4 To R 11 Each is independently hydrogen, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independent of halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11-CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, isopropyl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: and ; The conditions are: When R 1 When it is hydrogen, R 2 It is a halogen; When R 1 for Furthermore, none of T, U, V, W, and X are sulfur, nitrogen, or NR. 12 or N + R 12 When, only one of T, U, V, W, and X has CR 12 R 12 for Or -OCH2; and When W is nitrogen The V is not -OCH2.

[0249] Implementation Scheme 2. The compound as described in Implementation Scheme 1, wherein the compound of formula (I) is of formula (Ia): (Ia), or a pharmaceutically acceptable salt thereof, wherein: R 1 For hydrogen, -NR 9 R 10 -COOR 9 -CN or ; R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: and Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cycloalkane, or the heterocycloalkane is not substituted or is modified by one or more R groups. 12 replace; R 3 Independent of halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: , , , , , and Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cycloalkane, or the heterocycloalkane is not substituted or is modified by one or more R groups. 12 replace; T, U, V, W, and X are each independently CH and CR. 12 Sulfur, nitrogen, NR 12 or N + R 12 ; R 9 To R 11 Each is independently hydrogen, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independent of halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, isopropyl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: and ; The conditions are: When R 1 for Furthermore, none of T, U, V, W, and X are sulfur, nitrogen, or NR. 12 or N + R 12 When, only one of T, U, V, W, and X has CR 12 R 12 for Or -OCH2; and When W is nitrogen The V is not -OCH2.

[0250] Implementation Scheme 3. The compound as described in Implementation Scheme 2, wherein R 1 for: .

[0251] Implementation Scheme 4. The compound as described in Implementation Scheme 3, wherein the compound of formula (Ia) is of formula (Iaa): (Iaa), or a pharmaceutically acceptable salt thereof, wherein: R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: and Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cycloalkane, or the heterocycloalkane is not substituted or is modified by one or more R groups. 12 replace; R 3 Independent of halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11-CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: , , , , , and Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cycloalkane, or the heterocycloalkane is not substituted or is modified by one or more R groups. 12 replace; T, U, V, W, and X are each independently CH and CR. 12 Sulfur, nitrogen, NR 12 or N + R 12 ; R 9 To R 11 Each is independently hydrogen, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independent of halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, isopropyl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: and ; The conditions are: When R 1 for Furthermore, none of T, U, V, W, and X are sulfur, nitrogen, or NR. 12 or N + R 12 When, only one of T, U, V, W, and X has CR 12 R 12 for Or -OCH2; and When W is nitrogen The V is not -OCH2.

[0252] Implementation Scheme 5. The compound as described in Implementation Scheme 4, wherein T, U, V, W and X are CR 12 .

[0253] Implementation Scheme 6. The compound as described in Implementation Scheme 5, wherein the compound of formula (Iaa) is selected from the group consisting of: , , , or its pharmaceutically acceptable salt or stereoisomer.

[0254] Implementation Scheme 7. The compound as described in Implementation Scheme 4, wherein one of T or X is sulfur, nitrogen, or NR. 12 or N + R 12 The other of T or X is CR 12 And U, V, W and X are CR 12 .

[0255] Implementation Scheme 8. The compound as described in Implementation Scheme 7, wherein the compound of formula (Iaa) is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or its pharmaceutically acceptable salt or stereoisomer.

[0256] Implementation Scheme 9. The compound as described in Implementation Scheme 4, wherein at least two of T, U, V, W and X are sulfur, nitrogen, and NR. 12 or N + R 12 The remaining ones among T, U, V, W, and X are CR 12 .

[0257] Implementation Scheme 10. The compound of embodiment 9, wherein the compound of formula (Iaa) is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or its pharmaceutically acceptable salt or stereoisomer.

[0258] Implementation Scheme 11. The compound as described in Implementation Scheme 2, wherein R 1 for: .

[0259] Implementation Scheme 12. The compound as described in Implementation Scheme 11, wherein the compound of formula (Ia) is of formula (Iab): (Iab), or a pharmaceutically acceptable salt thereof, wherein: R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: and Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cycloalkane, or the heterocycloalkane is not substituted or is modified by one or more R groups. 12 replace; R 3 Independent of halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: , , , , , and Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cycloalkane, or the heterocycloalkane is not substituted or is modified by one or more R groups. 12 replace; T, U, V, and W are each independently CH and CR. 12 Sulfur, nitrogen, NR 12 or N + R 12 ; R 9 To R 11 Each is independently hydrogen, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independent of halogen, =O, -OR 9 -SR 9 -NR 9 R10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, isopropyl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: and .

[0260] Implementation Scheme 13. The compound as described in Implementation Scheme 11, wherein the compound of formula (Iab) is selected from the group consisting of: , or its pharmaceutically acceptable salt or stereoisomer.

[0261] Implementation Scheme 14. The compound as described in Implementation Scheme 2, wherein R 1 It is hydrogen.

[0262] Implementation Scheme 15. The compound as described in Implementation Scheme 14, wherein the compound of formula (Ia) is of formula (Iac): (Iac), or a pharmaceutically acceptable salt thereof, wherein: R 2 It is a halogen; R 3 Independent of halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: , , , , , and Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cycloalkane, or the heterocycloalkane is not substituted or is modified by one or more R groups.12 replace; R 9 To R 11 Each is independently hydrogen, halogen, or a C1-C6 unsubstituted or substituted alkyl group; and Each R 12 Independent of halogen, =O, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, isopropyl, cycloalkanes, heterocycloalkanes, or hetero(aryl)alkyl selected from the group consisting of: and .

[0263] Implementation Scheme 16. The compound as described in Implementation Scheme 15, wherein the compound of formula (Iac) is: Or its pharmaceutically acceptable salts or stereoisomers.

[0264] Implementation Scheme 17. A pharmaceutical composition comprising a compound as described in any one of Implementation Schemes 1 to 16, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable carrier.

[0265] Implementation Scheme 18. A method for treating, improving, or preventing a disease or ailment mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3), the method comprising administering a therapeutically effective amount of any one of Implementation Schemes 1 to 16.

[0266] Implementation Scheme 19. The method of Implementation Scheme 18, wherein the disease or ailment is selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

[0267] Implementation Scheme 20. A method for treating, improving, or preventing tumor necrosis factor α (TNF-α)-mediated disorders or diseases, said method comprising administering a therapeutically effective amount of a compound according to any one of Implementation Schemes 1 to 16.

[0268] Implementation Scheme 21. The method of Implementation Scheme 20, wherein the disease or ailment is selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

[0269] Implementation Scheme 22. A method for treating, improving, or preventing a disease or ailment mediated by an NLR family Pyrin domain 3 (NLRP3) inflammasome, said method comprising administering a therapeutically effective amount of a pharmaceutical composition according to any one of Implementation Schemes 17.

[0270] Implementation Scheme 23. The method of Implementation Scheme 22, wherein the disease or ailment is selected from the group consisting of: cardiovascular disease or ailment, endocrine disease or ailment, neurological disease or ailment, gastrointestinal disease or ailment, or a combination thereof.

[0271] Implementation Scheme 24. A method for treating, improving, or preventing tumor necrosis factor α (TNF-α)-mediated disorders or diseases, said method comprising administering a therapeutically effective amount of a pharmaceutical composition according to any one of Implementation Schemes 17.

[0272] Implementation Scheme 25. The method of Implementation Scheme 24, wherein the disease or ailment is selected from the group consisting of: cardiovascular disease or ailment, endocrine disease or ailment, neurological disease or ailment, gastrointestinal disease or ailment, or a combination thereof.

[0273] Implementation Scheme 26. A pharmaceutical composition comprising any one of the compounds of embodiments 1 to 16 or a pharmaceutically acceptable salt or stereoisomer thereof, for use in methods of treating, improving or preventing diseases or ailments mediated by NLR family Pyrin domain 3 (NLRP3) inflammasomes.

[0274] Implementation Scheme 27. The pharmaceutical composition of Implementation Scheme 26, wherein the disease or ailment is selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

[0275] Implementation Scheme 28. A pharmaceutical composition comprising any one of the compounds of embodiments 1 to 16 or a pharmaceutically acceptable salt or stereoisomer thereof, in a method of treating, improving or preventing tumor necrosis factor α (TNF-α) mediated diseases or ailments.

[0276] Implementation Scheme 29. The pharmaceutical composition of Implementation Scheme 28, wherein the disease or ailment is selected from the group consisting of inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

[0277] Implementation Scheme 30. Use of the compound of any one of Schemes 1 to 16 or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of an agent for the treatment, improvement or prevention of diseases or ailments mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3).

[0278] Implementation Scheme 31. The use as described in Implementation Scheme 30, wherein the disease or ailment is selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

[0279] Implementation Scheme 32. Use of the compound of any one of Schemes 1 to 16 or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of an agent for the treatment, improvement or prevention of tumor necrosis factor α (TNF-α) mediated diseases or ailments.

[0280] Implementation Scheme 33. The use as described in Implementation Scheme 32, wherein the disease or ailment is selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

[0281] Implementation Scheme 34. A method for treating, improving, or preventing a disease or ailment mediated by an NLR family Pyrin domain 3 (NLRP3) inflammasome, said method comprising administering an inhibitor of the C-terminal domain of heat shock protein 90 (hsp90).

[0282] Implementation Scheme 35. The method as described in Implementation Scheme 34, wherein the disease or ailment is selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

[0283] Implementation Scheme 36. A method for treating, improving, or preventing tumor necrosis factor α (TNF-α)-mediated disorders or diseases, said method comprising administering an inhibitor of the C-terminal domain of heat shock protein 90 (hsp90).

[0284] Implementation Scheme 37. The method of Implementation Scheme 36, wherein the disease or ailment is selected from the group consisting of: inflammatory bowel disease (IBD), Crohn's disease, colorectal cancer, alcoholic hepatitis, or a combination thereof.

[0285] Example The subject matter disclosed herein will be better understood by referring to the following embodiments, which are provided as exemplary implementations of this disclosure and not as limitations.

[0286] The compounds disclosed herein can be prepared by organic synthetic methods known in the art. In all methods, it should be understood that protecting groups for sensitive or reactive groups may be used, when necessary, according to general chemical principles. Protecting groups are operated according to standard organic synthetic methods (TW Green and PGM Wuts (2014) Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons). These groups are removed at an appropriate stage of compound synthesis using methods readily apparent to those skilled in the art.

[0287] Unless otherwise specified, reagents and solvents should be used as is from the commercial supplier.

[0288] Use ChemBioDraw Ultra v14 from CambridgeSoft to generate chemical names.

[0289] Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporation is carried out under reduced pressure, typically between approximately 15 mm Hg and 100 mm Hg (=20–133 mbar). The structures of the end products, intermediates, and starting materials are determined by standard analytical methods (e.g., microanalysis) and spectroscopic characteristics (e.g., MS, IR, NMR). The abbreviations used are those conventional in the art.

[0290] LC-MS: System: Waters Acquity UPLC with Waters SQ detector. Column: Acquity HSS T3 1.8 μm 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 rate: 1.0 mL / min. Mass spectrometry results are reported as mass-to-charge ratios.

[0291] HPLC: System: Shimadzu LH-40 autosampler with PDA detector column; X-Bridge PREP C18 (19*250) mm, 10 μm; Mobile phase: Acetonitrile; H2O containing 5 mM ammonium bicarbonate. NMR: Measurements were performed on a Bruker Ultrashield™ 400 (400 MHz) or Bruker Ascend™ (400 MHz) or Bruker Cryogenic System (600 MHz) spectrometer with or without tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are reported in TMS low-field ppm, and spectral splitting modes are specified as singlets (s), doublets (d), triplets (t), quartets (q), quintets, septets, multiplets, unresolved or overlapping signals (m), and broad signals (bf). Deuterated solvents are given in parentheses and chemical shifts are given for dimethyl sulfoxide (δ 2.50 ppm), methanol (δ 3.31 ppm), chloroform (δ 7.26 ppm), or other solvents as indicated in the NMR spectral data.

[0292] Synthesis of an exemplary embodiment of the compound of formula (I) Synthetic compound 1

[0293] Step 1: Synthesis of (4S,4aR,5aR,6aS,6bS,9R,9aS,11aS,11bR)-4-hydroxy-9-((S)-1-((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,10,11,11a,11b-dodecylhydrocyclopentan[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: Add to a stirred solution of solanine-A (3 g, 1 equivalent; 6.37 mmol) in dichloromethane (30 mL) under an inert atmosphere. N,N -Dimethylpyridin-4-amine (1.17 g, 1.5 equivalents, 9.56 mmol). After 10 minutes, iodine (1.94 g, 1.2 equivalents, 7.65 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with a saturated aqueous sodium thiosulfate solution (50 mL). The aqueous layer was extracted with dichloromethane (3 x 45 mL). The organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to give crude material. The crude material was purified by combi-flash chromatography (using dichloromethane containing 5% methanol) to give a white solid (4... S , 4a R , 5a R , 6a S , 6b S , 9 R , 9aS ,11a S , 11b R )-4-hydroxy-9-(( S )-1-(( 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, 11a, 11b-dodecylhydrocyclopenta[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (2.1 g, 55%).

[0294] Analyze the data: LCMS:90.55% (m / z: 595.18, [MH] + Observed value 595.18, [M+H] + , 2.29 min (4 min run).

[0295] 1 H-NMR (400 MHz, DMSO- d 6): δ 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: Synthesis (4) S ,4a R ,5a R ,6a S ,6b S ,9a S ,11a S ,11bR )-4-hydroxy-9-(( S )-1-(( R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-phenyl-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentan[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: Potassium carbonate (282 mg, 2 equivalents, 2.04 mmol) and potassium trifluoro(phenyl)-λ were added to a stirred solution of (4S,4aR,5aR,6aS,6bS,9R,9aS,11aS,11bR)-4-hydroxy-9-((S)-1-((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,10,11,11a,11b-dodecylhydrocyclopenta[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one (609 mg, 1 equivalent; 1.02 mmol) in 1,4-dioxane (9.74 mL) and water (2.44 mL). 6 1,1'-borane (282 mg, 1.5 equivalents, 1.53 mmol). The resulting reaction mixture was degassed by purging with nitrogen for 30 min. Then, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (149 mg, 0.2 equivalents, 204 µmol) was added to the mixture, and the mixture was heated at 85 °C for 5 h. The reaction was monitored by TLC (dichloromethane containing 5% methanol). After the reaction was complete, the reactants were quenched with citric acid solution, followed by extraction with dichloromethane (2 x 40 mL). The organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude substance was purified by combi-flash chromatography (dichloromethane containing 5-10% methanol) to obtain a white solid (4S,4aR, 5aR, 6aS, 6bS, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-phenyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopenta[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one (20 mg, 6%).

[0296] Analyze the data: LCMS:99.10% (m / z: 547.45, [M+1] + , 569.45 [M+23] + , 6.12 min (10 min run).

[0297] 1 H-NMR (400 MHz, DMSO- d 6): δ 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 0.72 (s, 3H).

[0298] Synthetic compound 2

[0299] Step 1: Synthesis ((4) S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-2-(4-fluorophenyl)-4-hydroxy-9-( S )-1-(( 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,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: Add 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane (335 μmol) to a stirred solution of (4S,4aR,5aR,6aS,6bS,9R,9aS,11aS,11bR)-4-hydroxy-9-((S)-1-((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,10,11,11a,11b-dodecylhydrocyclopenta[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one (450 mg, 1 equivalent; 754 µmol) in a stirred solution of (4S,4aR,5aR,6aS,6bS,9R,9aS,11aS,11bR) in DME / water (1 / 1) (90 mL) to a stirred solution. The mixture was degassed with nitrogen for 15 minutes. Then, 10% palladium / carbon (0.1 g, 0.12 equivalents, 94 µmol) was added to the mixture and stirred continuously at room temperature for 16 hours. After the reaction was complete (monitored by TLC: dichloromethane containing 5% methanol), the reaction mixture was passed through superfluid diatomaceous earth and the filtrate was extracted with dichloromethane (3 x 25 mL). The organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude substance was further purified by preparative HPLC (using the AA method) to obtain a white solid ((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS,11bR)-2-(4-fluorophenyl)-4-hydroxy-9-((S)-1-((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, 11a,11b-dodecylhydrocyclopenta[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (239 mg, 56%).

[0300] Analyze the data: LCMS:99.44% (m / z: 565.40, [M+1] + , 587.40 [M+23] + , 6.16 min (10 min run).

[0301] 1 H-NMR (400 MHz, DMSO- d 6): δ 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, J = 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).

[0302] Synthetic compound 3

[0303] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-(4-methoxyphenyl)-9a,11b-dimethyl-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To (1) S , 2 R , 6 S , 7 R , 9 R , 11 S , 12 S , 15 R , 16 S )-6-hydroxy-15-[(1 S )-1-[(2 R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iod-2,16-dimethyl-8-oxapentane [9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (250 mg, 1 equivalent; 419 µmol) was added to a stirred solution of dimethoxyethane and water (1:1 ratio; 5 mL) with (4-methoxyphenyl)boronic acid (127 mg, 2 equivalent; 838 µmol) and disodium carbonate (88.8 mg, 2 equivalent; 838 µmol), and the reaction mixture was then purged with N2 gas for 15 min. Subsequently, 10% palladium / carbon (70 mg) was added to the mixture and the reactants were again purged with N2 gas for 5 min. The reaction mixture was stirred further overnight at room temperature. The reaction mixture was then passed through a diatomaceous earth bed and the filtrate was washed with dichloromethane (30 mL). The collected organic matter was dried over sodium sulfate and concentrated under reduced pressure to give a crude substance. The crude substance was purified by preparative HPLC (AA method) to give a white solid (1... S , 2 R , 6 S , 7 R , 9 R , 11 S , 12 S , 15 R ,16 S )-6-hydroxy-15-[(1 S )-1-[(2 R [9.7.0.0]-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-(4-methoxyphenyl)-2,16-dimethyl-8-oxapentane [9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadec-4-en-3-one (62 mg, 26%).

[0304] Analysis details: LCMS: 99.55% (m / z: 577.40, [M+1]+, 6.07 min (10 min run).

[0305] 1 H-NMR (400 MHz, DMSO- d6): δ 7.25 (d, J = 8.80 Hz, 2H), 7.16 (d, J = 6.80Hz, 1H), 6.96 (d, J = 8.80 Hz, 2H), 5.62 (d, J = 3.60 Hz, 1H), 4.57 (t, J = 5.20Hz, 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).

[0306] Synthetic compound 4

[0307] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(2-(trifluoromethyl)phenyl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: Add [2-(trifluoromethyl)phenyl]boronic acid (287 mg, 2 equivalents, 1.51 mmol) and disodium carbonate (160 mg, 2 equivalents, 1.51 mmol) to a stirred solution of 2-iodosuccinate-A (450 mg, 754 µmol) in DME-water (7.89 mL). Degas the resulting reaction mixture for 15 min. Then, heat with 10% palladium / carbon (0.1 g, 940 μmol) at 50 °C for 16 h. The reaction progress was monitored by TLC (dichloromethane containing 5% methanol), which showed the formation of new spots. After the reaction was complete, the reaction mixture was passed through diatomaceous earth and the filtrate was extracted with dichloromethane (3 x 25 mL). The collected organic matter was dried over sodium sulfate and then concentrated under reduced pressure to give the crude product. The crude substance was purified by preparative HPLC (AA method) to obtain a white solid (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-(( S )-1-(( R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(2-(trifluoromethyl)phenyl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one (15 mg, 3%).

[0308] Analyze the data: LCMS:98.45% (m / z: 615.45, [M+1] + , 637.40 [M+23] + , 6.37 min (10 min run).

[0309] 1 H-NMR (400 MHz, DMSO- d 6): δ 7.76 (d, J = 7.60 Hz, 1H), 7.70 (t, J = 7.60Hz, 1H), 7.59 (t, J = 7.60 Hz, 1H), 7.28 (d, J = 7.20 Hz, 1H), 7.00 (d, J = 6.40Hz, 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).

[0310] Synthetic compound 5

[0311] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(pyridin-3-yl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Add λ to a stirred solution of 1.4 g (1 equivalent; 2.35 mmol) in tetrahydrofuran (14 mL). 1-(1+)copper iodide (44.7 mg, 0.1 equivalent, 235 µmol), triphenylarsine (71.9 mg, 0.1 equivalent, 235 µmol), and 3-(tributyltinyl)pyridine (1.73 g, 2 equivalent, 4.69 mmol). The reaction mixture was purged with a continuous stream of nitrogen for 30 min. Subsequently, tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (21.5 mg, 0.01 equivalent, 23.5 µmol) was added, and the resulting reaction mixture was degassed with nitrogen for 5 min. The resulting reaction mixture was stirred at 80 °C for 16 h. After the reaction was complete (monitored by TLC: dichloromethane containing 5% methanol), the reaction mixture was filtered through a diatomaceous earth bed, and the filtrate was diluted with water (30 mL) and then extracted with dichloromethane (2 x 50 mL). The organic matter was collected, dried with sodium sulfate, and then concentrated under reduced pressure to obtain the crude substance.

[0312] Note: Crude materials from different batches were mixed together and enriched by combi-flash chromatography (dichloromethane containing 4-10% methanol) to obtain 47 g of crude material, which was 93% according to LCMS. This was further purified by SFC (0.1% NH4OH) to obtain 20.7 g of 99% pure (4%) white solid. S , 4a R , 5a R , 6a S , 6b S , 9 R ,9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(pyridin-3-yl) 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10,11, 11a, 11b-dodecylhydrocyclopentane[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (20.7 g).

[0313] Analyze the data: LCMS:99.47% (m / z: 548.45, [M+1] + , 5.14 min (10 min run).

[0314] 1 H-NMR (400 MHz, DMSO- d6): δ 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, 6.40Hz, 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).

[0315] 13 C-NMR (400 MHz, DMSO- d 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.

[0316] Synthetic compound 6

[0317] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S, 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-((R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.4 g, 1 equivalent; 671 µmol) was added to a stirred solution of DME / water (1 / 1, 10 mL) with (1-methyl-1H-pyrazol-4-yl)boronic acid (169 mg, 2 equivalent, 1.34 mmol) and disodium carbonate (142 mg, 2 equivalent, 1.34 mmol). The reaction mixture was degassed with nitrogen for 15 min, and then 10% palladium / carbon (101 mg) was added. The resulting reaction mixture was stirred at 50 °C for 16 h. After the reaction was complete (in dichloromethane containing 5% methanol), the reaction mixture was passed through superfluid diatomaceous earth and the filtrate was quenched with saturated NaHCO3 (40 mL), followed by extraction from dichloromethane (3 x 50 mL). The collected organic matter was dried over sodium sulfate and then concentrated under reduced pressure to give crude material. The crude substance was purified by preparative HPLC (using the AA method) to obtain (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(1-methyl-1H-pyrazol-4-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (106 mg, 29%).

[0318] Analyze the data: LCMS:98.31% (m / z: 551.45, [M+1] + , 573.40 [M+23] + , 5.42 min (10 min run).

[0319] 1 H-NMR (400 MHz, DMSO- d 6): δ 7.88 (s, 1H), 7.69 (s, 1H), 7.11 (d, J = 6.80Hz, 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, J = 3.60, 6.80 Hz, 1H), 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).

[0320] Synthetic compound 7

[0321] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(pyrimidin-5-yl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentan[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To (1) S , 2 R , 6 S , 7 R , 9 R , 11 S , 12 S , 16 S )-6-hydroxy-15-[(1 S )-1-[(2 R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iod-2,16-dimethyl-8-oxapentane [9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (1 g, 1 equivalent; 1.68 mmol) was added to a stirred solution of 1,4-dioxane:water (12 mL, 5:1) with (pyrimidin-5-yl)boronic acid (312 mg, 1.5 equivalent, 2.51 mmol) and cesium carbonate (1.64 g, 3 equivalent, 5.03 mmol). The reaction mixture was degassed with N2 for 30 min and then palladium(2+)bis(triphenylphosphine) dichloride (118 mg, 0.1 equivalent, 168 µmol) was added. The reaction mixture was stirred at 90 °C for 16 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and then extracted with dichloromethane (3 x 50 mL). The organic matter was collected, dried over Na2SO4, and concentrated under reduced pressure to give crude product. The crude residue was purified by combi-flash chromatography (using dichloromethane containing 10% methanol) to obtain the crude substance. The crude substance was then purified by preparative HPLC (method: AA) to obtain a white solid (4... S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(pyrimidin-5-yl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one (119 mg; 13%).

[0322] Analyze the data: LCMS:95.51% (m / z: 549.40, [M+1] + , 5.61 min (10 min run).

[0323] 1 H-NMR (400 MHz, DMSO- d 6): δ 9.18 (s, 1H), 8.77 (s, 2H), 7.61 (d, J = 6.80Hz, 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).

[0324] 13 C-NMR (400 MHz, DMSO- d 6): δ 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.

[0325] Synthetic compound 8

[0326] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(pyridin-4-yl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Add λ to a stirred solution of 1.2 g (1 equivalent; 2.01 mmol) of octadecyl-4-en-3-one in tetrahydrofuran (24 mL). 1-Copper iodide (1+) (38.3 mg, 0.1 equivalent, 201 µmol), triphenylarsine (61.6 mg, 0.1 equivalent, 201 µmol), and 4-(tributyltinyl)pyridine (1.48 g, 2 equivalent, 4.02 mmol). The resulting reaction mixture was degassed under nitrogen for 30 min. Subsequently, tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (92.1 mg, 0.05 equivalent, 101 µmol) was added to the above reaction mixture, and the mixture was stirred at 80 °C for 16 h. After the reaction was complete (monitored by TLC), the mixture was filtered through a diatomaceous earth bed, and the filtrate was extracted with dichloromethane (3 x 30 mL). The organic matter was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude substance was purified by preparative HPLC (ABC method) to obtain (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS,11bR)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(pyridin-4-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (112 mg, 10%) as a white solid.

[0327] Analyze the data: LCMS:93.94% (m / z: 548.35, [M+1] + , 5.10 min (10 min run).

[0328] 1 H-NMR (400 MHz, DMSO- d 6): δ 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, J= 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).

[0329] 13 C-NMR (400 MHz, DMSO- d 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 Synthetic compound 9

[0330] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-2-(3-Fluoropyridin-4-yl)-4-hydroxy-9-( S )-1-(( 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,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: At room temperature, the molecule is converted to (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iod-2,16-dimethyl-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.5 g, 1 equivalent; 838 µmol) was added to a stirred solution of water (0.5 mL) and 1,4-dioxane (5 mL) with stirring. (3-fluoropyridin-4-yl)boronic acid (177 mg, 1.5 equivalent, 1.26 mmol) and dicesium carbonate (1+) (819 mg, 3 equivalent, 2.51 mmol) were then added to the reaction mixture. The reaction mixture was purged with nitrogen for 35 min, and then bis(triphenylphosphine)palladium dichloride (2+) (58.8 mg, 0.1 equivalent, 83.8 μmol) was added to the reaction mixture. The reaction mixture was again purged with nitrogen for 5 min. The reaction vessel was sealed and stirred at 85 °C for 16 h. After the reaction was complete (monitored by TLC: dichloromethane solution containing 5% methanol), the reaction mixture was quenched with water (10 mL) and then extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried with anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the crude substance. The crude residue was purified by combi-flash chromatography (using dichloromethane containing 5% methanol) and then by preparative HPLC (TFA method) as a white solid (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-2-(3-fluoropyridin-4-yl)-4-hydroxy-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopentane[1, 2]phenanthro[8a, 9-b]Epoxy-1(4H)-one (16 mg, 3%).

[0331] Analyze the data: LCMS:98.88% (m / z: 566.35, [M+1] + , 5.78 min (10 min run).

[0332] 1H-NMR (400 MHz, DMSO- d 6): δ 8.59 (d, J = 2.00 Hz, 1H), 8.49 (d, J = 4.80Hz, 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).

[0333] Synthetic compound 10

[0334] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(thiazolyl-5-yl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentan[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: At room temperature, the molecule is converted to (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iod-2,16-dimethyl-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.5 g, 1 equivalent; 838 µmol) was added to a stirred solution of 1,4-dioxane (5 mL) and water (1 mL) along with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3-thiazole (265 mg, 1.5 equivalent, 1.26 mmol) and potassium carbonate (348 mg, 3 equivalent, 2.51 mmol). The reaction mixture was purged with nitrogen for 35 min, and then [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (68.6 mg, 0.1 equivalent, 83.8 μmol) was added. The reaction mixture was purged with nitrogen again for 5 min. The reaction vessel was sealed, and the reaction mixture was stirred at 100 °C for 16 h. After the reaction was complete (monitored by LCMS), the reaction mixture was passed through diatomaceous earth, and the filtrate was concentrated to give the crude product. The crude substance was enriched by combi-flash chromatography (dichloromethane containing 5% methanol) and then purified by preparative HPLC (ABC method) as a white solid: 4S,4aR,5aR,6aS,6bS,9R,9aS,11aS,11bR)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(thiazolyl-5-yl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentan[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one (18 mg, 4%).

[0335] Analyze the data: LCMS:95.19% (m / z: 554.30, [M+1] + , 5.82 min (10 min run).

[0336] 1 H-NMR (400 MHz, DMSO- d 6): δ9.08 (s, 1H), 8.20 (s, 1H), 7.48 (d, J = 6.40Hz, 1H), 5.80 (s, 1H), 4.29-4.25 (m, 1H), 4.17-4.08 (m, 2H), 3.72 (d, J = 6.8Hz, 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).

[0337] Synthetic compound 11

[0338] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( 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,10,11,11a,11b-dodecylhydrocyclopentan[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16[Octadecyl-4-en-3-one (0.4 g, 1 equivalent; 671 µmol)] was added to a stirred solution of N,N-dimethylformamide (4 mL) along with copper diiodide (31.9 mg, 0.15 equivalent, 101 µmol) and 2-(tributyltinyl)pyrazine (248 mg, 671 µmol). The reaction mixture was degassed with N2 for 30 min, and then 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane (27.4 mg, 0.05 equivalent, 33.5 µmol) was added. The reaction mixture was stirred at 60 °C for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with ice-cold water (15 mL) and then extracted with dichloromethane (3 x 55 mL). The organic matter was collected, dried over Na2SO4, and concentrated under reduced pressure to give crude material. The crude residue was purified by combi-flash chromatography (eluting with dichloromethane containing 10% methanol) to obtain the crude substance. The crude substance was further purified by preparative HPLC (method: AA) to obtain a white solid 4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (111 mg; 30%).

[0339] Analyze the data: LCMS:99.41% (m / z: 549.40, [M+1] + , 5.80 min (10 min run).

[0340] 1 H-NMR (400 MHz, DMSO- d 6): δ 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, 18.20Hz, 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).

[0341] Synthetic compound 12

[0342] Step 1: Synthesize 3-((4) S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( 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,10,11,11a,11b-tetradecylhydrocyclopenta[1,2]phenanthro[8a,9-b]epoxyethylene-2-yl)benzonitrile To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16A stirred solution of octadecyl-4-en-3-one (0.5 g, 1 equivalent; 838 µmol) in 1,4-dioxane (1 mL, 11.7 mmol) was supplemented with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzonitrile (192 mg, 838 µmol) and sodium bicarbonate (42.2 mg, 3 equivalent, 503 µmol). The resulting solution was purged with nitrogen for 40 min. Subsequently, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane (27.4 mg, 0.2 equivalent, 33.5 µmol) was added and the solution was again purged with nitrogen for 5 min. The reaction mixture was heated to 60 °C and stirred for 16 h. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth and the filtrate was extracted with dichloromethane (3 x 40 mL). Organic matter was collected, dried over sodium sulfate, and then concentrated under reduced pressure to obtain crude material. The crude residue was enriched by Combi-flash (eluting with n-heptane containing 60% ethyl acetate) and then purified by preparative HPLC (ABC method) to obtain 3-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((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,10,11,11a, 11b-Tetradecylhydrocyclopenta[1,2]phenanthrene[8a,9-b]epoxyethylene-2-yl)benzonitrile (18 mg, 4%).

[0343] Analyze the data: LCMS:95.30% (m / z: 572.45, [M+1] + , 594.35, [M+23], 6.33 min (10 min run).

[0344] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0345] Synthetic compound 13

[0346] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( 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, 11a, 11b-dodecylhydrocyclopentane[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one: At room temperature under an inert atmosphere, the (1S, 2R, 6S, 7R, 9R, 11S, 12S, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16A solution of octadecyl-4-en-3-one (5 g, 8.38 mmol) in dimethylformamide (50 mL, 646 mmol) was supplemented with copper diiodide (399 mg, 0.15 equivalents, 1.26 mmol) and 2-(tributyltinyl)pyridine (6.17 g, 2 equivalents, 16.8 mmol). The reaction mixture was purged with nitrogen for 40 min, and then 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (342 mg, 0.05 equivalents, 419 µmol) was added. The reaction mixture was then purged with nitrogen for another 5 min. The reaction mixture was heated at 65 °C for 4 h. After the reaction was complete (as monitored by TLC: dichloromethane containing 5% methanol), the reaction mixture was quenched with ice-cold (60 mL) water and extracted with dichloromethane (3 x 15 mL). The combined organic matter was dried with sodium sulfate and evaporated under reduced pressure to obtain the crude substance. The crude substance was enriched by combi-flash chromatography (eluting with dichloromethane containing 4-10% methanol), followed by preparative HPLC purification to obtain a white solid 4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS,11bR)-4-hydroxy-9-((S)-1-((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, 11a,11b-dodecylhydrocyclopentane[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (1.1 g, 24%).

[0347] Analyze the data: LCMS:96.60% (m / z: 548.60, [M+1] + 546.7 [M-1] + , 5.36 min (10 min run).

[0348] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.60 (d, J = 4.00 Hz, 1H), 7.83 (t, J = 7.60Hz, 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,1H), 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).

[0349] 13 C-NMR (400 MHz, DMSO- d 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.

[0350] Synthetic compound 14

[0351] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(pyridazin-4-yl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 1 g of octadecyl-4-en-3-one (1 g, 1 equivalent; 1.68 mmol) was added to a stirred solution of N,N'-dimethylformamide (10 mL, 129 mmol) with 4-(tributyltinyl)pyridazine (743 mg, 1.2 equivalent, 2.01 mmol) and copper diiodide (79.8 mg, 0.15 equivalent, 251 µmol). The reaction mixture was purged with nitrogen for 35 min, and then 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (68.4 mg, 0.05 equivalent, 83.8 µmol) was added. The reaction mixture was again purged with nitrogen for 5 min. The reaction vessel was sealed and stirred at 60 °C for 16 h. After the reaction was complete (monitored by LCMS), it was quenched by adding sodium chloride solution (30 mL) followed by extraction with ethyl acetate (3 x 20 mL). Organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude material. The crude material was purified by preparative HPLC (ABC method) to obtain a white solid, (1S, 2R, 6S, 7R, 9R, 11S, 12S, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-4-(pyridazin-4-yl)-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Octadec-4-en-3-one (75 mg, 2%).

[0352] Analyze the data: LCMS:95.11% (m / z: 549.40, [M+1] + , 571.40, [M+23] + , 5.45 min (10 min run).

[0353] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0354] Synthetic compound 15

[0355] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( 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, 11a, 11b-dodecylhydrocyclopentan[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.5 g, 1 equivalent; 838 µmol) was added to a stirred solution of N,N'-dimethylformamide (2.62 mL) with 2-methyl-6-(tributyltinyl)pyridine (961 mg, 3 equivalent, 2.51 mmol) and copper diiodide (39.9 mg, 0.15 equivalent, 126 µmol). The reaction mixture was purged with nitrogen for 35 min, and then 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (34.2 mg, 0.05 equivalent, 41.9 µmol) was added. The reaction mixture was again purged with nitrogen for 5 min. The reaction vessel was sealed and stirred at 60 °C for 16 h. After the reaction was complete (monitored by LCMS), it was quenched with sodium chloride solution (30 mL). It was further extracted with ethyl acetate (2 x 40 mL). The organic matter was collected, dried with sodium sulfate, and then concentrated under reduced pressure to obtain the crude substance. The crude substance was purified by preparative HPLC (ABC method) to obtain (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (89 mg, 19%).

[0356] Analyze the data: LCMS: 98.56% (m / z: 562.6, [M+1] + , 560.6, [M-1] + , 5.21 min (10 min run).

[0357] 1 H-NMR (400 MHz, DMSO- d 6): δ 7.71 (t, J J = 8.00 Hz, 1H), 7.64 (d, J J = 6.80Hz, 1H), 7.21 (t, J J = 8.40 Hz, 2H), 5.71 (d, J J = 3.60 Hz, 1H), 4.59 (t, J J = 5.20Hz, 1H), 4.31 - 4.26 (m, 1H), 3.75 (dd, J 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).

[0358] 13 C-NMR (400 MHz, DMSO- d 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.

[0359] Synthetic compound 16

[0360] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-2-(5-Fluoropyridin-2-yl)-4-hydroxy-9-( S )-1-(( 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,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To acetic acid (1S, 2R, 6S, 7S, 9R, 11S, 12S, 16S)-15-[(1S)-1-[(2R)-5-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iod-2,16-dimethyl-3-oxo-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16Octadecto-4-en-6-yl ester (0.5 g, 1 equivalent; 664 µmol) was added to a stirred solution of tetrahydrofuran (6 mL, 73.7 mmol) along with 5-fluoro-2-(tributyltinyl)pyridine (282 mg, 1.1 equivalent, 731 µmol), triphenylarsine (20.3 mg, 0.1 equivalent, 66.4 µmol), and copper diiodide (21.1 mg, 0.1 equivalent, 66.4 µmol). The reaction mixture was purged with nitrogen for 35 min, and then tris(1,5-diphenylpentan-1,4-dien-3-one)palladium (30.4 mg, 0.05 equivalent, 33.2 µmol) was added. The reaction mixture was again purged with nitrogen for 10 min. The reaction vessel was sealed and stirred at 85 °C for 3 h. After the reaction was complete (monitored by LCMS), the reaction mixture was quenched with 10% citric acid solution (20 mL). The reaction mixture was extracted with ethyl acetate (3 x 45 mL). The collected organic matter was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude substance. The crude substance was purified by preparative HPLC (ABC method) to obtain (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-2-(5-fluoropyridin-2-yl)-4-hydroxy-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopenta[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (100 mg, 27%).

[0361] Analyze the data: LCMS:99.20% (m / z: 566.6, [M+1] + , 5.63 min (10 min run).

[0362] 1 H-NMR (400 MHz, DMSO- d 6): δ 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, J = 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).

[0363] 13 C-NMR (400 MHz, DMSO- d 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.

[0364] Synthetic compound 17

[0365] Step 1: (R)-6-[(S)-1-{(1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-4-(5-fluoro-3-pyridyl)-6-hydroxy-2,16-dimethyl-3-oxo-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 [Octadeca-4-en-15-yl]-3-(hydroxymethyl)-4-methyl-5,6-dihydro-2H-pyran-2-one At room temperature, (R)-6-[(S)-1-{(1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-4-iodo-2,16-dimethyl-3-oxo-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 [Octadeca-4-en-15-yl]ethyl-3-(hydroxymethyl)-4-methyl-5,6-dihydro-2H-pyran-2-one (4 g, 6.71 mmol) was added to a stirred solution of 1,4-dioxane (40 mL) in which 2-(5-fluoro-3-pyridyl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronylcyclopentane (2.24 g, 1.5 equivalents, 10.1 mmol) and dicesium carbonate (1+) (6.55 g, 3 equivalents, 20.1 mmol) dissolved in water (8 mL) were added. The reaction mixture was purged with N2 for 30 min, followed by the addition of bis(triphenylphosphine)palladium dichloride (2+) (471 mg, 0.1 equivalents, 671 μmol), and then further purged with N2 for 5 min. The reaction vessel was sealed and stirred at 90 °C for 4 h. After the reaction was complete (monitored by LCMS), the mixture was filtered through a diatomaceous earth bed and washed with DCM (50 mL). The filtrate was diluted with water (50 mL) and extracted with DCM (2 x 70 mL). The organic matter was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude substance. The crude substance was purified by preparative HPLC (ABC method) as a white solid (R)-6-[(S)-1-{(1S,2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-4-(5-fluoro-3-pyridyl)-6-hydroxy-2,16-dimethyl-3-oxo-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 [Octadecyl-4-en-15-yl]-3-(hydroxymethyl)-4-methyl-5,6-dihydro-2H-pyran-2-one (1 g, 25.8%).

[0366] Analyze the data: LCMS:98.01% (m / z: 566.4, [M+1] + , 5.44 min (10 min run).

[0367] 1H-NMR (400 MHz, DMSO- d 6): δ 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).

[0368] 19 F-NMR (400 MHz, DMSO- d 6): δ -127.08 13C-NMR (400 MHz, DMSO-d6): δ 200.47, 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.

[0369] Synthetic compound 18

[0370] Step 1: Synthesis of prop-2-yn-1-ylcarbamic acid (( R )-6-(( S )-1-((4 S , 4a R , 5a R , 6a S, 6b S 9 R , 9a S , 11a S , 11b R 4-Hydroxy-9a,11b-dimethyl-1-oxo-2-(pyridin-4-yl)-1,4,5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-tetradecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-9-yl)ethyl)-4-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl)methyl ester: At 0°C, the molecule is converted to (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-4-(pyridin-4-yl)-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.2 g, 1 equivalent; 365 µmol) was added dropwise to a stirred solution of dichloromethane (2 mL) with 3-isocyanatoprop-1-yne (35 mg, 1.2 equivalent, 438 µmol) and triethylamine (102 µL, 2 equivalent, 730 µmol). The resulting reaction mixture was stirred at room temperature for 45 minutes. After the reaction was complete (monitored by TLC: dichloromethane containing 5% methanol), the reactants were diluted with water (30 mL) and then extracted with dichloromethane (2 x 40 mL). The organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude substance was purified by preparative HPLC (ABC method) to obtain propionic acid ((R)-6-((S)-1-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9a, 11b-dimethyl-1-oxo-2-(pyridin-4-yl)-1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-tetradecylhydrocyclopenta[1,2]phenanthrene[8a, 9-b]epoxyethylene-9-yl)ethyl)-4-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl)methyl ester (3 mg, 1.3%), which was a white solid.

[0371] Analyze the data: LCMS:97.07% (m / z: 629.15, [M+1] + , 2.35 min (6 min run).

[0372] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0373] Synthetic compound 19

[0374] Step 1: Synthesis of prop-2-yn-1-ylcarbamic acid (( R )-6-(( S )-1-((4 S , 4a R , 5a R , 6a S , 6b S 9 R , 9a S , 11a S , 11b R 4-Hydroxy-9a,11b-dimethyl-1-oxo-2-(pyridin-3-yl)-1,4,5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-tetradecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-9-yl)ethyl)-4-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl)methyl ester: At 0°C under a nitrogen atmosphere, the molecule was synthesized into (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-4-(pyridin-3-yl)-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 A stirred solution of octadecyl-4-en-3-one (56.6 mg, 1 equivalent; 103 µmol) in dichloromethane (10 mL) was supplemented with triethylamine (41.8 mg, 4 equivalent, 413 µmol) and 4-nitrophenyl N-(prop-2-yn-1-yl)carbamate (45.5 mg, 2 equivalent, 207 µmol). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC: n-hexane containing 60% ethyl acetate), the reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (2 x 30 mL). The organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude substance was purified by preparative HPLC (ABC method) to obtain propionic acid ((R)-6-((S)-1-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS,11bR)-4-hydroxy-9a,11b-dimethyl-1-oxo-2-(pyridin-3-yl)-1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-tetradecylhydrocyclopenta[1, 2]phenanthrene[8a, 9-b]epoxyethylene-9-yl)ethyl)-4-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl)methyl ester (21 mg, 32%), which was a white solid.

[0375] Analyze the data: LCMS:99.44% (m / z: 629.30, [M+1] + , 2.35 min (6 min run).

[0376] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0377] Synthetic compound 20

[0378] Step 1: Synthesize 4-((4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( 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,10,11,11a,11b-tetradecylhydrocyclopentane[1,2]phenanthrene[8a,9-b]epoxyethylene-2-yl)benzonitrile: Add 4-(4,4,5,5-tetramethyl-1,2-dimethyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-iodo-9a,11b-dimethyl-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylcyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one (0.6 g, 1 equivalent; 1.01 mmol) to a stirred solution of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((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,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one (0.6 g, 1 equivalent; 1.01 mmol) in 1,4-dioxane (10 mL) to a stirred solution. 3,2-Dioxaborhexacyclopentan-2-yl)benzonitrile (346 mg, 1.5 equivalents, 1.51 mmol) and dicesium carbonate (1+) (983 mg, 3 equivalents, 3.02 mmol). The reaction mixture was purged with N2 for 35 min, and then bis(triphenylphosphine)palladium(II) dichloride (70.6 mg, 0.1 equivalents, 101 μmol) was added. The reaction mixture was purged with N2 again for 5 min. The reaction vessel was sealed and stirred at 80 °C for 16 h. After the reaction was complete (monitored by LCMS), the reaction mixture was passed through diatomaceous earth. The filtrate was collected, diluted with water (30 mL), and extracted with ethyl acetate (3 x 55 mL). The organic matter was collected, dried over sodium sulfate, and then concentrated under reduced pressure to give the crude product. The crude residue was purified by preparative HPLC (method: ammonium acetate) to obtain 4-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((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, 11a, 11b-tetradecylhydrocyclopenta[1, 2]phenanthrene[8a, 9-b]epoxyethylene-2-yl)benzonitrile (29 mg, 5%) as a white solid.

[0379] Analyze the data: LCMS:99.58% (m / z: 572.50, [M+1] + , 5.63 min (10 min run).

[0380] 1 H-NMR (400 MHz, DMSO- d 6- D2O): δ 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).

[0381] Synthetic compound 21

[0382] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(pyrimidin-4-yl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentan[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 ,7 .0 7 , 9 .0 12 , 16 A stirred solution of octadecyl-4-en-3-one (0.5 g, 1 equivalent; 838 µmol) in tetrahydrofuran (5 mL, 61.4 mmol) was supplemented with 4-(tributyltinalkyl)pyrimidine (340 mg, 1.1 equivalent, 922 µmol) and λ. 1 - Copper iodide (1+) (47.9 mg, 0.3 equivalents, 251 µmol). The reaction mixture was degassed under nitrogen for 30 min. Then, tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (38.4 mg, 0.05 equivalents, 41.9 µmol) was added. The reaction mixture was degassed under nitrogen for 5 min, and the reactants were refluxed at 90 °C for 16 h. After the reaction was complete (monitored by TLC and LCMS), the reaction mixture was filtered through a diatomaceous earth bed, and the filtrate was evaporated under vacuum to give the crude product. The crude substance was purified by preparative HPLC (ABC method) to obtain a white solid (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-4-(pyrimidin-4-yl)-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadec-4-en-3-one (68 mg, 26%).

[0383] Analyze the data: LCMS:89.13% (m / z: 549.60, [M+1] + , 4.98 min (10 min run).

[0384] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0385] Synthetic compound 22

[0386] Step 1: Synthesis (4 S , 4a S , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-2-iodo-4-methoxy-9-(( S )-1-(( R )-5-(methoxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: Under an inert atmosphere, the derivatives of (1S, 2R, 6S, 7R, 9R, 11S, 12S, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] were synthesized. 2 , 7 .0 7 , 9 .0 12 , 162 g of octadecyl-4-en-3-one (4.25 mmol) was added to a stirred solution of dichloromethane (20 mL, 312 mmol) with silver oxide (3.97 g, 4 equivalents, 17 mmol). Iodomethane (9.05 g, 15 equivalents, 63.7 mmol) was then added, and the reaction mixture was stirred continuously at room temperature for 4 days. After the reaction was complete (monitored by LCMS), the reaction mixture was filtered through a diatomaceous earth bed, and the filtrate was extracted with dichloromethane (3 x 30 mL). The organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude substance was purified by combi-flash chromatography using hexane (containing 70% ethyl acetate) to obtain a white solid (1S, 2R, 6S, 7S, 9R, 11S, 12S, 16S)-6-methoxy-15-[(1S)-1-[(2R)-5-(methoxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane [9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (1.2 g, 57%).

[0387] Analyze the data: LCMS:95.60% (m / z: 499.19, [M+1] + , 2.55 min (4 min run).

[0388] Step 2: Synthesis (4) S , 4a S , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-methoxy-9-(( S )-1-(( R )-5-(methoxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(pyridin-4-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopentan[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7S, 9R, 11S, 12S, 16S)-6-methoxy-15-[(1S)-1-[(2R)-5-(methoxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.4 g, 802 µmol) was added to a stirred solution of dichloromethane (5 mL) along with N,N-dimethylpyridin-4-amine (294 mg, 3 equivalents, 2.41 mmol) and iodine (285 mg, 2.8 equivalents, 2.25 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC and LCMS), it was quenched by adding sodium thiosulfate solution (20 mL) and then extracted with dichloromethane (2 x 35 mL). The organic matter was collected, dried over sodium sulfate, and then concentrated under reduced pressure to give the crude product. The crude substance was purified by combi-flash chromatography (5% methanol and dichloromethane) to obtain a white solid (1S, 2R, 6S, 7S, 9R, 11S, 12S, 16S)-4-iodo-6-methoxy-15-[(1S)-1-[(2R)-5-(methoxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadec-4-en-3-one (340 mg, 68%).

[0389] Analyze the data: LCMS:72.21% (m / z: 625.09, [M+1] + , 2.71 min (4 min run).

[0390] Step 3: Synthesis (4) S , 4a S , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11bR )-2-iodo-4-methoxy-9-(( S )-1-(( R )-5-(methoxymethyl)-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, 11a, 11b-dodecylhydrocyclopentan[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7S, 9R, 11S, 12S, 16S)-4-iodo-6-methoxy-15-[(1S)-1-[(2R)-5-(methoxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecyl-4-en-3-one (337 mg, 1 equivalent; 540 µmol) was added to a stirred solution of N,N-dimethylformamide (3.37 mL) with 4-(tributyltinyl)pyridine (397 mg, 2 equivalent, 1.08 mmol) and copper diiodide (25.7 mg, 0.15 equivalent, 80.9 µmol). The resulting reaction mixture was purged with nitrogen for 35 min, and then 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (22 mg, 0.05 equivalent, 27 µmol) was added. The reaction mixture was again purged with nitrogen for 5 min. The reaction vessel was sealed and stirred at 60 °C for 16 h. After the reaction was complete (monitored by TLC and LCMS), it was quenched by adding ice-cold water (30 mL) and a brine solution (30 mL). It was then extracted with ethyl acetate (3 x 35 mL). Organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude material. The crude product was purified by preparative HPLC (ABC method) to obtain a white solid, (1S, 2R, 6S, 7S, 9R, 11S, 12S, 16S)-6-methoxy-15-[(1S)-1-[(2R)-5-(methoxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-4-(pyridin-4-yl)-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12, 16 Octadec-4-en-3-one (22 mg, 7%).

[0391] Analyze the data: LCMS:95.01% (m / z: 576.60, [M+1] + , 6.28 min (10 min run).

[0392] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.62 (d, J = 4.00 Hz, 2H), 7.62 (d, J = 6.40Hz, 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).

[0393] Synthetic compound 23

[0394] Step 1: Synthesize 3-((4) S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S)-1-(( 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,10,11,11a,11b-tetradecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-2-yl)pyridine 1-oxide: At -20°C, the molecule is converted to (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-4-(pyridin-3-yl)-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.5 g, 1 equivalent; 913 µmol) was added to a stirred solution of dichloromethane (10 mL) along with 3-chlorobenzyl-1-peroxyformic acid (236 mg, 1.5 equivalent, 1.37 mmol), and the resulting reaction mixture was stirred at -20 °C for 16 hours. After the reaction was complete (monitored by TLC), excess solvent was evaporated under reduced pressure to give the crude product. The crude substance obtained was purified by preparative HPLC (AA method) to obtain 3-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((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,10,11,11a,11b-tetradecylhydrocyclopenta[1,2]phenanthrene[8a,9-b]epoxyethylene-2-yl)pyridine 1-oxide (82 mg, 16%), which was a grayish-white solid.

[0395] Analyze the data: LCMS:99.02% (m / z: 564.50, [M+1] + , 4.42 min (10 min run).

[0396] 1 H-NMR (400 MHz, DMSO- d6): δ 8.22 (d, J J = 6.40 Hz, 1H), 8.16 (d, J J = 1.20Hz, 1H), 7.54 (d, J J = 6.40 Hz, 1H), 7.46 (t, J J = 6.80 Hz, 1H), 7.30 (d, J J = 8.00Hz, 1H), 5.83 (d, J J = 3.60 Hz, 1H), 4.59 (t, J J = 5.20 Hz, 1H), 4.31 - 4.26 (m, 1H), 4.18 - 4.08 (m, 2H), 3.71 (dd, J 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).

[0397] 13 C - NMR (400 MHz, DMSO - d 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.

[0398] Synthetic compound 24

[0399] Step 1: Synthesis of (4 S , 4a R , 5a R , 6a S , 6bS , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( 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,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To (2R, 6S, 7R, 9R, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16Octadecto-4-en-3-one (0.8 g, 1 equivalent; 1.34 mmol) was added to a stirred solution of tetrahydrofuran (15 mL, 184 mmol) with 5-methoxy-2-(tributyltinyl)pyridine (534 mg, 1.34 mmol), triphenylarsine (41.1 mg, 0.1 equivalent, 134 µmol), and copper diiodide (42.6 mg, 0.1 equivalent, 134 µmol). The resulting reaction mixture was purged with nitrogen for 35 min, and then tris(1,5-diphenylpentan-1,4-dien-3-one)dipalladium (12.3 mg, 0.01 equivalent, 13.4 µmol) was added. The reaction mixture was again purged with nitrogen for 10 min. The reaction vessel was sealed and stirred at 85 °C for 16 h. After the reaction was complete (monitored by LCMS), it was diluted with water (90 mL) and then extracted with dichloromethane (3 x 45 mL). The organic matter was collected, dried with sodium sulfate, and concentrated under reduced pressure to obtain crude material. The crude substance was purified by preparative HPLC (ABC method) to obtain a white solid (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS,11bR)-4-hydroxy-9-((S)-1-((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, 11,11a,11b-dodecylhydrocyclopenta[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (113 mg, 15%).

[0400] Analyze the data: LCMS:97.28% (m / z: 578.60, [M+1] + , 5.32 min (10 min run).

[0401] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.32 (d, J = 2.80 Hz, 1H), 7.55 (d, J = 6.80Hz, 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).

[0402] 13 C-NMR (400 MHz, DMSO- d 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.

[0403] Synthetic compound 25

[0404] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(5-methylpyridin-2-yl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentan[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Add λ to a stirred solution of 0.2 g (1 equivalent; 335 µmol) of octadecyl-4-en-3-one in tetrahydrofuran (2 mL). 1- Copper iodide (1+) (6.39 mg, 0.1 equivalent, 33.5 µmol), triphenylarsine (10.3 mg, 0.1 equivalent, 33.5 µmol), and 5-methyl-2-(tributyltinyl)pyridine (256 mg, 2 equivalent, 671 µmol). The reaction mixture was then degassed with nitrogen for 30 minutes. Tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (3.07 mg, 0.01 equivalent, 3.35 µmol) was added to this stirred solution, followed by further degassed with nitrogen for 5 minutes. Finally, the reaction mixture was heated at 80 °C for 16 hours. After the reaction was complete (monitored by TLC: dichloromethane containing 5% methanol), the mixture was filtered through a diatomaceous earth bed, and the filtrate was diluted with water (20 mL) and then extracted with dichloromethane (3 x 45 mL). Organic matter was collected, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude material. The crude substance was purified by preparative HPLC (ABC method) as a white solid (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a, 11b-dimethyl-2-(5-methylpyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (160 mg, 85%).

[0405] Analyze the data: LCMS:98.96% (m / z: 562.60, [M+1] + , 5.44 min (10 min run).

[0406] 1 H-NMR (400 MHz, DMSO- d 6): δ 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, J= 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).

[0407] Synthetic compound 26

[0408] Step 1: Synthesis (4 S , 4a R , 5a R , 6a S , 6b S , 9 R , 9a S , 11a S , 11b R )-4-hydroxy-9-(( S )-1-(( R )-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(4-methylpyridin-2-yl)-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecylhydrocyclopentane[1,2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Add λ to a stirred solution of 0.2 g (1 equivalent, 335 µmol) of octadecyl-4-en-3-one in tetrahydrofuran (2 mL). 1- Copper iodide (1+) (6.39 mg, 0.1 equivalent, 33.5 µmol), 4-methyl-2-(tributyltinyl)pyridine (247 mg, 2 equivalent; 671 µmol), and then the reactants were degassed with nitrogen for 30 min. Subsequently, tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (3.07 mg, 0.01 equivalent, 3.35 µmol) was added, and the mixture was again degassed with nitrogen for 5 min. Finally, the reaction mixture was heated at 80 °C for 16 h. After the reaction was complete (monitored by TLC: dichloromethane containing 5% methanol), the reaction mixture was filtered through a diatomaceous earth bed, and the filtrate was diluted with water (20 mL) and then extracted with dichloromethane (3 x 45 mL). The organic matter was collected, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give the crude product. The crude substance was purified by preparative HPLC (ABC method) to obtain (4S,4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-2-(4-methylpyridin-2-yl)-5a,6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopenta[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (115 mg, 61%) as a white solid.

[0409] Analyze the data: LCMS:97.47% (m / z: 562.60, [M+1] + , 5.40 min (10 min run).

[0410] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.45 (d, J = 5.20 Hz, 1H), 7.63 (d , J = 6.40Hz, 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).

[0411] Synthetic compound 27

[0412] Step 1: Synthesis of 6-(tributyltinyl)pyridinecarboxynitrile: Bis(tributyltinane) (4.77 g, 1.5 equivalents, 8.2 mmol) was added to a stirred solution of 6-bromopyridine-2-carboxynitrile (1 g, 5.46 mmol) in N,N-dimethylformamide (1 mL) and 1,2-dimethoxyethane (8 mL). The mixture was purged with nitrogen for 30 min. Tetra(triphenylphosphine)palladium(0) (0.505 g, 0.08 equivalents, 0.436 mmol) was added and the mixture was purged with nitrogen for 5 min. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was quenched with chilled water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by combi flash using hexane containing 25-30% ethyl acetate to obtain the desired product, 6-(tributyltinyl)pyridinecarboxynitrile (0.26 g, 12.1%), as a colorless liquid.

[0413] Analyze the data: 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0414] Step 2: Synthesis of 6-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((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,10,11,11a,11b-tetradecylhydrocyclopenta[1,2]phenanthrene[8a,9-b]epoxyethylene-2-yl)pyridinecarboxynitrile: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 [0.2 g, 335 µmol] of octadecyl-4-en-3-one was added to a stirred solution of N,N-dimethylformamide (2.6 mL) with copper diiodophosphate (16 mg, 0.15 equivalent, 50.3 µmol) and 6-(tributyltinyl)pyridin-2-carboxylonitrile (132 mg, 335 µmol). The reaction mixture was purged with nitrogen for 35 min. 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (13.7 mg, 0.05 equivalent, 16.8 µmol) was added and the mixture was purged with nitrogen for 5 min. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude substance was purified by preparative HPLC (ABC method) to obtain 6-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((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, 11a, 11b-tetradecylhydrocyclopenta[1, 2]phenanthrene[8a,9-b]epoxyethylene-2-yl)pyridinecarboxynitrile (42 mg, 21.8%) as a white solid.

[0415] Analyze the data: LCMS:99.92% (m / z: 573.35, [M+1] + , 6.24 min (10 min run).

[0416] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.12 (t, J = 7.60 Hz, 1H), 8.02 (d , J = 7.60Hz, 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).

[0417] 13 C-NMR (400 MHz, DMSO- d 6): δ200.09, 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.

[0418] Synthetic compound 28

[0419] Step 1: Propyl-2-ynyl-1-carbamate ((R)-6-((S)-1-((4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9a,11b-dimethyl-1-oxo-2-(pyridin-2-yl)-1, 4, 5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-tetradecylhydrocyclopentane[1, 2]phenanthro[8a, 9-b]epoxyethylene-9-yl)ethyl)-4-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl)methyl ester: At -78°C, the molecule is converted to (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-4-(pyridin-2-yl)-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16Octadecto-4-en-3-one (0.5 g, 913 µmol) was added to a stirred solution of bis(trimethylsilyl)aminolithium (1+) (7.33 mg, 1.2 equivalents, 43.8 µmol) and N-(prop-2-yn-1-yl)carbamate 4-nitrophenyl ester (9.65 mg, 1.2 equivalents, 43.8 µmol) in tetrahydrofuran (5 mL, 12.3 mmol). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete (as monitored by TLC: heptane containing 70% ethyl acetate), the reaction mixture was quenched with saturated NH4Cl (30 mL) and extracted with DCM (2 x 30 mL). The organic matter was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude material. The crude residue was purified by combi flash (12 g Welch column) to give 93% of the desired compound. The compound was further purified by preparative HPLC (ABC method) to give (3S, 4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-3-(3,3-difluoropiperidin-1-yl)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyltetradecylcyclopenta[1,2]phenanthro[8a, 9-b]epoxyethylene-1(2H)-one (72 mg, 12%) as a white solid.

[0420] Analyze the data: LCMS: 99.10% (m / z: 629.6, [M+1]+, 5.97 min (10 min run).

[0421] 1H-NMR (400 MHz, DMSO-d6- D2O): δ 1H-NMR (400 MHz, DMSO-d6): δ 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)。

[0422] 13 C-NMR (400 MHz, DMSO- d 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。

[0423] Synthetic compound 29

[0424] Step 1: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a, 11b-dimethyl-2-(pyrimidin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopentan[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16A stirred solution of octadecyl-4-en-3-one (0.5 g, 838 µmol), 2-(tributyltinyl)pyrimidine (340 mg, 1.1 equivalent, 922 µmol), copper diiodophosphate (39.9 mg, 0.15 equivalent, 126 µmol), and triphenylarsine (25.7 mg, 0.1 equivalent, 83.8 µmol) in tetrahydrofuran (7 mL, 86 mmol) was purged with nitrogen for 30 min, and tris(1,5-diphenylpentan-1,4-dien-3-one)palladium (38.4 mg, 0.05 equivalent, 41.9 µmol) was added. The reaction mixture was purged with nitrogen again for 5 min. The reaction mixture was stirred at 80 °C for 5 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 300 mg of crude substance. The compound was purified by preparative HPLC using the ABC method to obtain the desired product (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a, 11b-dimethyl-2-(pyrimidin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopentane[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (43 mg, 9.35%).

[0425] Data analysis: 97.96% (m / z: 549.5, [M+1]) + , 5.03 min (10 min run).

[0426] 1 H-NMR (400 MHz, DMSO- d 6): δ8.83 (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, 1H), 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).

[0427] 13 C-NMR (400 MHz, DMSO- d 6): δ 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.

[0428] Synthetic compound 30

[0429] Step 1: Synthesis of 5-fluoro-2-(tributyltinyl)pyrimidine: Hexabutyltin (650 mg, 1.68 mmol) was added to a solution of 2-chloro-5-fluoropyrimidine (2 g, 15.1 mmol) in 1,4-dioxane (20 mL, 234 mmol) and purged with nitrogen for 30 min. Tetra(triphenylphosphine)palladium(0) (1.74 g, 0.1 equivalent, 1.51 mmol) was added and purged with nitrogen again for 5 min. The reaction mixture was stirred at 90 °C for 16 h. The reaction was monitored by TLC. After the reaction was complete, it was filtered through a diatomaceous earth bed and washed with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude material. The crude material was purified by Combi Flash using hexane containing 25-30% ethyl acetate to give 5-fluoro-2-(tributyltinalkyl)pyrimidine (650 mg, 11.13%).

[0430] Analyze the data: LCMS:82.76% 3.68 min (m / z: 389.10, [M+1] + (4 min run).

[0431] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0432] Step 2: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-2-(5-fluoropyrimidin-2-yl)-4-hydroxy-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopenta[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0]2 , 7 .0 7 , 9 .0 12 , 16 A stirred solution of octadecyl-4-en-3-one (0.3 g, 503 µmol) in tetrahydrofuran (6 mL, 73.7 mmol) was supplemented with diiodocopper (23.9 mg, 0.15 equivalents, 75.4 µmol), triphenylarsine (15.4 mg, 0.1 equivalents, 50.3 µmol), and 5-fluoro-2-(tributyltinyl)pyrimidine (292 mg, 1.5 equivalents, 754 µmol). The reaction mixture was purged with nitrogen for 35 min. Tris(1,5-diphenylpentan-1,4-dien-3-one)dipalladium (23 mg, 0.05 equivalents, 25.1 µmol) was added, and the mixture was purged with nitrogen again for 5 min. The reaction mixture was stirred at 85 °C for 16 h. After the reaction was complete, the mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The organic layer was washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude substance was purified by preparative HPLC (ABC method) to obtain (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-2-(5-fluoropyrimidin-2-yl)-4-hydroxy-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (28 mg, 9.82%) as a white solid.

[0433] Analyze the data: LCMS:97.71% (m / z: 567.50, [M+1] + , 6.56 min (15 min run).

[0434] 1 H-NMR (400 MHz, DMSO- d 6): δ 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)。

[0435] 13 C-NMR (400 MHz, DMSO- d 6): δ 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。

[0436] 19 F-NMR (400 MHz, DMSO- d 6): δ 138.25。

[0437] Synthetic compound 31

[0438] Step 1: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-9-((S)-1-((R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-4-hydroxy-2-iodo-9a, 11b-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a,11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one: (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopenta[1,2]phenanthrene[8a, 9-b]epoxyethylene-1(4H)-one (5 g, 8.38 mmol) was reacted with dimethylformamide (0.1 L, 1.29 mmol). 4-(pyrrolidone-1-yl)pyridin-1-onium (6.25 g, 5 equivalents, 41.9 mmol) was added to a stirred solution. After 10 minutes, tert-butyl(chloro)dimethylsilane (12.6 g, 10 equivalents, 83.8 mmol) was added and the reaction mixture was heated to 85 °C and maintained for 3 hours. After the reaction was complete (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 layers were washed with saturated salt solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude substance. This crude substance was purified by column chromatography in heptane containing 0-100% ethyl acetate to obtain a grayish-white solid compound (4S,4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-9-((S)-1-((R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-4-hydroxy-2-iodo-9a,11b-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11,11a,11b-dodecylhydrocyclopentane[1, 2]phenanthrene[8a, [9-b]Epoxy-1(4H)-one (1.8 g, 2.41 mmol, 29%).

[0439] Analyze the data: LCMS:95.79% (m / z: 711.10, [M+H] + , 4.10 min (6 min run).

[0440] 1 H-NMR (400 MHz, DMSO- d 6): δ 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 = 2.80Hz, 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).

[0441] Step 2: Synthesis of (1S, 2R, 6S, 7R, 9R, 11S, 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-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 ] Octadec-4-en-3-one To (1S, 2R, 6S, 7R, 9R, 11S, 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-iodine-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16Octadecto-4-en-3-one (450 mg, 0.633 mmol) and 5-methoxy-2-(tributyltinyl)pyridine (378 mg, 1.5 equivalents, 0.950 mmol) were added to a stirred solution of THF (8 mL) with triphenylarsine (19.4 mg, 0.1 equivalents, 0.063 mmol) and cuprous iodide (18.1 mg, 0.15 equivalents, 0.095 mmol). The resulting mixture was purged with argon for 30 min. Tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (58 mg, 0.1 equivalents, 0.063 µmol) was added to the reaction mixture and stirred at 85 °C for 3 h. The reaction was monitored by TLC, quenched by the addition of water (50 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic compounds were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Combi flash column chromatography using heptane containing (70-90%) ethyl acetate as the eluent to obtain a grayish-white solid: (1S, 2R, 6S, 7R, 9R, 11S, 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-oxapentane [9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (180 mg, 0.26 mmol, 41%).

[0442] Analyze the data: LCMS:91.13% (m / z: 692.28, [M+1] + ), 3.08 min (4 min run).

[0443] Step 3: Synthesis of (1S, 2R, 6R, 7S, 9R, 11S, 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-oxapentane[9.7.0.0] 2 , 7 .0 7 ,9 .0 12 , 16 ] Octadec-4-en-3-one At -78°C under an inert atmosphere, the reaction proceeds to the formation of (1S, 2R, 6S, 7R, 9R, 11S, 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-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 [A solution of 180 mg, 0.26 mmol, of octadecyl-4-en-3-one in dichloromethane (6 mL) was added dropwise to a stirred solution.] 4 (-Thio)amine (0.041 mL, 1.2 equivalents, 0.312 mmol) (dissolved in DCM (1 mL)) and stirred for 15 min. The reaction was monitored by TLC, quenched with saturated sodium bicarbonate solution (20 mL), and extracted with dichloromethane (2 x 35 mL). The combined organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product. The crude substance was purified by combi-flash chromatography (hexane containing 10-20% ethyl acetate) on a silica column to obtain a pale yellow solid, (1S, 2R, 6R, 7S, 9R, 11S, 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-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.1 g, 0.144 mmol, 55%).

[0444] Analyze the data: LCMS:97.14 % (m / z: 694.28, [M+1] + ), 3.37 min (4 min run).

[0445] Step 4: Synthesis of (1S, 2R, 6R, 7S, 9R, 11S, 12S, 15R, 16S)-6-fluoro-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-(5-methoxypyridin-2-yl)-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 ] Octadec-4-en-3-one At 0°C, the molecule is converted to (1S, 2R, 6R, 7S, 9R, 11S, 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-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.1 g, 0.144 mmol) was added dropwise to a solution of THF (1 mL) and methanol (1 mL) with 2N hydrogen chloride solution (1 mL, 14 eq, 2 mmol) and stirred for 30 min. The reaction was monitored by TLC, quenched with saturated sodium bicarbonate solution (20 mL), and extracted with dichloromethane (2 x 30 mL). The combined organic compounds were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude substance. This crude substance was purified by silica column combi-flash chromatography (using dichloromethane containing 0-5% methanol) to obtain a grayish-white solid, (1S, 2R, 6R, 7S, 9R, 11S, 12S, 15R, 16S)-6-fluoro-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-(5-methoxypyridin-2-yl)-2,16-dimethyl-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (45 mg, 0.077 mmol, 53%).

[0446] Analyze the data: LCMS:93.34% (m / z: 580.5, [M+1] + , 6.22 min (10 min run).

[0447] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0448] 13 C-NMR (400 MHz, DMSO- d 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.

[0449] Synthetic compound 32

[0450] Step 1: Synthesis of 5-(trimethyltinyl)pyrazine-2-amine: Hexamethyldistinane (941 mg, 2.87 mmol) was added to a stirred solution of 5-bromopyrazin-2-amine (0.5 g, 2.87 mmol) in toluene (10 mL). The mixture was purged with nitrogen for 30 min, followed by the addition of tetra(triphenylphosphine)palladium (99.6 mg, 0.03 equivalent, 86.2 µmol), and then further purged with nitrogen for 5 min. The reaction mixture was stirred at 130 °C for 3 h. After the reaction was complete, it was filtered through a diatomaceous earth bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel combi flash using hexane containing 0–30% ethyl acetate to give 5-(trimethylstanyl)pyrazin-2-amine (710 mg, 95.2%) as a white solid.

[0451] Analyze the data: LCMS:99.82% (m / z: 259.93, [M+1] + , 1.82min (4 min run).

[0452] 1 H-NMR (400 MHz, DMSO- d 6): δ 8.05 (s, 1H), 7.84 (s, 1H), 6.24 (br s,2H), 0.23 (s, 9H).

[0453] Step 2: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-2-(5-aminopyrazin-2-yl)-4-hydroxy-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopentan[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one: To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 A stirred solution of octadecyl-4-en-3-one (0.9 g, 1.51 mmol) in tetrahydrofuran (9 mL, 111 mmol) was supplemented with diiodocopper (71.8 mg, 0.15 equivalents, 226 µmol), triphenylarsine (46.2 mg, 0.1 equivalents, 151 µmol), and 5-(trimethyltinyl)pyrazine-2-amine (584 mg, 1.5 equivalents, 2.26 mmol). The reaction mixture was purged with nitrogen for 35 min, and then tris(1,5-diphenylpentan-1,4-dien-3-one)dipalladium (69.1 mg, 0.05 equivalents, 75.4 µmol) was added. The reaction mixture was again purged with nitrogen for 5 min. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was enriched using hexane containing 40-50% ethyl acetate via Combi Flash. The compound was further purified by preparative HPLC (ABC method) to give (4S, 4aR,5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-2-(5-aminopyrazin-2-yl)-4-hydroxy-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopenta[1,2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (20 mg) as a white solid.

[0454] Analyze the data: LCMS:96.59% (m / z: 564.40, [M+1] + , 5.34 min (10 min run).

[0455] 1 H-NMR (400 MHz, DMSO-d 6): δ 7.93–7.89 (m, 2H), 7.42 (d, J = 6.80 Hz, 1H), 6.72 (s , 2H), 5.63 (d, J = 3.20 Hz, 1H), 4.59 (t, J = 5.20 Hz, 1H), 4.29-4.25 (m,1H), 4.17-4.07 (m, 2H), 3.71 (dd, J = 3.20, 6.80 Hz, 1H), 3.13 (s, 1H), 2.41-2.33 (m, 1H), 2.10-2.05 (m, 2H), 1.98 (s, 3H), 1.92-1.89 (m, 1H), 1.82-1.77(m, 1H), 1.73-1.70 (m, 1H), 1.60-1.54 (s, 1H), 1.36- 1.20 (m, 8H), 1.14-1.02(m, 3H), 0.97-0.86 (m, 4H), 0.84-0.79 (m, 1H), 0.65 (s, 3H), 13 C-NMR (400 MHz, DMSO- d 6): δ 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.

[0456] Synthetic compound 33

[0457] Step 1: N -[6-(tributyltinyl)pyridin-3-yl]tert-butyl carbamate: At -78℃ Ntert-butyl 6-bromopyridin-3-yl)carbamate (2 g, 1.0 eq, 7.32 mmol) was added to a stirred solution of tetrahydrofuran (20 mL) with butyl-1-lithium (1+) (797 mg, 1.7 equivalence, 12.4 mmol). The reaction mixture was stirred at the same temperature for 1 h. Then, tributyltin chloride (3.71 mL, 1.7 equivalence, 12.4 mmol) was added dropwise to the resulting reaction mixture, and the reaction mixture was further stirred at room temperature for 3 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with a saturated ammonium chloride solution (30 mL) and then extracted with DCM (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude residue was purified by combi-flash column chromatography (eluting with heptane containing 20% ​​ethyl acetate) to give a yellow gel. N -[6-(tributyltinyl)pyridin-3-yl]tert-butyl carbamate (1.3 g, 2.69 mmol).

[0458] Analyze the data: LCMS:95.10% (m / z: 485.22, [M+H] + Observed value 485.25, [M+H] + , 3.37 min (4 min run).

[0459] Step 2: (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadec-4-en-3-one: At 0°C, the molecule is converted to (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16Add 20 g (1.0 eq, 42.5 mmol) of octadecyl-4-en-3-one (42.5 mmol) to a stirred solution in dichloromethane (0.2 L). N , N -Dimethylpyridin-4-amine (7.79 g, 1.5 equivalents, 63.7 mmol) was added, followed by diiodine (12.9 g, 1.2 equivalents, 51 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with 20% sodium thiosulfate solution (300 mL) and extracted with dichloromethane (3 x 300 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude material was purified by combi-flash column chromatography (eluting with DCM containing 5% methanol) to obtain a white solid (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadec-4-en-3-one (14 g, 23.5 mmol).

[0460] Analyze the data: LCMS:90.55% (m / z: 595.16, [M+H] + Observed value 595.18, [M+H] + , 2.29 min (4 min run).

[0461] Step 3: N -{6-[(1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-3-oxo-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 [Octadecyl-4-en-4-yl]pyridin-3-yl]tert-butyl carbamate To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Add λ to a stirred solution of 0.8 g (1.34 mmol) of octadecyl-4-en-3-one in tetrahydrofuran (10 mL, 123 mmol). 1 - Copper iodide (1+) (25.5 mg, 0.1 equivalent, 134 µmol), triphenylarsine (41.1 mg, 0.1 equivalent, 134 µmol), and N-[6-(tributyltinyl)pyridin-3-yl]tert-butyl carbamate (778 mg, 1.2 equivalent, 1.61 mmol). The reaction mixture was purged with argon for 30 min. Tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (12.3 mg, 0.01 equivalent, 13.4 µmol) was added to the reaction mixture, and the mixture was purged with argon again for 5 min. The reaction mixture was stirred at 80 °C for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed and concentrated under reduced pressure to give a crude product. The crude residue was purified by combi-flash column elution (eluting with DCM containing 3% methanol) to obtain N -{6-[(1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-3-oxo-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 [Octadecyl-4-en-4-yl]pyridin-3-yl}tert-butyl carbamate (0.6 g, 905 µmol).

[0462] Analyze the data: LCMS:93.68% (m / z: 663.3, [M+1] + , 2.07 min (4 min run).

[0463] 1 H-NMR (400 MHz, DMSO- d 6): δ 9.68 (s, 1H), 8.63 (s, 1H), 7.88 (dd, J = 8.4Hz, 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).

[0464] Step 4: (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-4-(5-aminopyridin-2-yl)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 ] Octadec-4-en-3-one At 0℃ N -{6-[(1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-3-oxo-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16[Octadecyl-4-en-4-yl]pyridin-3-yl]tert-butyl carbamate (0.6 g, 905 µmol) was added dropwise to a stirred solution in dichloromethane (6 mL, 93.7 mmol) with 1.5 mL of trifluoroacetic acid added. The reaction mixture was stirred at 0 °C for 3 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude residue was purified by preparative HPLC (ABC method) to obtain a yellow solid (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-4-(5-aminopyridin-2-yl)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (61 mg, 19.6%, 0.177 µmol).

[0465] Analyze the data: LCMS:93.72% (m / z: 563.5, [M+H] + Observed value 563.50, [M+H] + 6.11 min (15 min run).

[0466] 1 H-NMR (400 MHz, DMSO- d 6) δ 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 (b s , 3H), 4.59 (b s , 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).

[0467] 13 C-NMR (400 MHz, DMSO- d 6) δ 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.

[0468] Synthetic compound 34

[0469] Step 1: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-9-((S)-1-((R)-5-((dimethylamino)methyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-4-hydroxy-9a, 11b-dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopentan[1, 2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one: At 0°C, the molecule is converted to (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-4-(pyridin-2-yl)-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 ,9 .0 12 , 16 Ethylbis(propyl-2-yl)amine (147 mg, 2.5 equivalents, 1.14 mmol) was added to a stirred solution of octadecyl-4-en-3-one (250 mg, 456 µmol) in dichloromethane (2.5 mL, 39 mmol), followed by the addition of methanesulfonyl chloride (52.3 mg, 456 µmol). The reaction mixture was stirred at 0 °C for 30 min. After the reaction was complete (monitored by TLC), it was quenched with water (40 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic layers were washed with a saturated brine solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give methanesulfonic acid [(6R)-6-[(1S)-1-[(1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-2,16-dimethyl-3-oxo-4-(pyridin-2-yl)-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 [Octadecyl-4-en-15-yl]ethyl]-4-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl]methyl ester. Transfer it as is to the next reaction.

[0470] Dimethylamine (27 mg, 1.5 equivalents, 599 µmol) was added to a stirred solution of potassium carbonate (110 mg, 2 equivalents, 799 µmol) in acetonitrile (3 mL, 57.4 mmol) at 0 °C, followed by the addition of methanesulfonic acid [(6R)-6-[(1S)-1-[(1S,2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-2,16-dimethyl-3-oxo-4-(pyridin-2-yl)-8-oxapentane[9.7.0.0]]. 2 , 7 .0 7 , 9 .0 12 , 16[Octadecyl-4-en-15-yl]ethyl]-4-methyl-2-oxo-5,6-dihydro-2H-pyran-3-yl]methyl ester (250 mg, 0.4 mmol). The resulting reaction mixture was stirred at 60 °C for 30 min. After the reaction was complete (monitored by TLC), it was quenched with water (40 ml) and extracted with ethyl acetate (2 x 40 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude substance was purified by preparative HPLC using the ammonium acetate method to obtain a white solid (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-9-((S)-1-((R)-5-((dimethylamino)methyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-4-hydroxy-9a, 11b-dimethyl-2-(pyridin-2-yl)-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (15 mg, 6.53%).

[0471] Analyze the data: LCMS:88.53% (m / z: 575.50, [M+1] + , 4.81 min (10 min run).

[0472] 1 H-NMR (400 MHz, DMSO- d 6): δ 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, J = 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).

[0473] Synthetic compound 35

[0474] Step 1: Synthesis of (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-fluoro-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopentan[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one At -78°C under an inert atmosphere, 0.5 g of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopentane[1, 2]phenanthrene[8a, 9-b]epoxyethylene-1(4H)-one (0.913 g) was prepared (0.5 g, 0.913 g) of phenanthrene[8a, 9-b]epoxyethylene-1(4H)-one (0.5 g, 0.913 g) Diethyl(trifluoro-λ) was added dropwise to a stirred solution of dichloromethane (10 mL) at a concentration of mmol. 4(-Thio)amine (0.241 mL, 2 equivalents, 1.83 mmol) (dissolved in DCM (1 mL)) and stirred for 15 min. After the reaction was complete (monitored by TLC and LCMS), it was quenched with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (3 x 30 mL). The organic matter was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude material. The crude substance was purified by silica column combi-flash chromatography (hexane containing 10-20% ethyl acetate), followed by preparative HPLC purification using the ammonium acetate method to obtain a white solid (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-fluoro-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopentane[1, 2]phenanthrene[8a, 9-b]Epoxy-1(4H)-one (7 mg, 0.0127 mmol, 2%).

[0475] Analyze the data: LCMS:97.63% (m / z: 552.50, [M+1] + , 6.87 min (10 min run).

[0476] 1 H-NMR (400 MHz, DMSO- d 6): δ 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, J0.93 (d, J = 6.4 Hz, 3H), 0.68 (s, 3H).

[0477] 19 F-NMR (400 MHz, DMSO- d 6): δ 201.92, 206.73.

[0478] Synthetic compound 36

[0479] Step 1: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-(5-methoxypyrazin-2-yl)-9a, 11b-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16A stirred solution of octadecyl-4-en-3-one (0.2 g, 335 µmol), 2-methoxy-5-(tributyltinyl)pyrazine (161 mg, 1.2 equivalents, 402 µmol), triphenylarsine (10.3 mg, 0.1 equivalents, 33.5 µmol), and copper diiodophosphate (16 mg, 0.15 equivalents, 50.3 µmol) in tetrahydrofuran (5 mL, 61.4 mmol) was purged with nitrogen for 35 min. Palladium-(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one (2 / 3) (15.4 mg, 0.05 equivalents, 16.8 µmol) was added and purged again with nitrogen for 5 min. The reaction mixture was stirred at 80 °C for 8 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled and quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude substance. This crude substance was purified by the ABC method in preparative HPLC to obtain a white solid (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-(5-methoxypyrazin-2-yl)-9a,11b-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopentane[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (39 mg, 20.1%).

[0480] Data analysis: 98.57% (m / z: 579.5, [M+1]) + , 5.62 min (10 min run).

[0481] 1 H-NMR (400 MHz, DMSO- d 6): δ1H-NMR (400 MHz, DMSO-d6): δ 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).

[0482] Synthetic compound 37

[0483] Step 1: Synthesis of (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-(5-methoxypyrimidin-2-yl)-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 ] Octadec-4-en-3-one To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16Octadecto-4-en-3-one (0.2 g, 0.335 mmol) and 5-methoxy-2-(tributyltinyl)pyrimidine (0.2 g, 1.5 equivalents, 0.503 mmol) were added to a stirred solution of N,N-dimethylformamide (4 mL), followed by triphenylarsine (0.010 g, 0.1 equivalents, 0.033 mmol) and copper iodide (1+) (0.009 g, 0.15 equivalents, 0.05 mmol). The resulting reaction mixture was purged with argon for 30 min. Tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (0.03 g, 0.1 equivalents, 0.033 mmol) was added and purged with argon for 5 min. The mixture was stirred at 60 °C for 3 h. It was cooled to room temperature. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). Organic matter was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude material. The crude product was purified by Combi flash column chromatography using hexane containing (70-90%) ethyl acetate as eluent, followed by preparative HPLC purification using the ammonium acetate method to obtain a white solid (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-(5-methoxypyrimidin-2-yl)-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.027 g, 0.046 mmol, 14%).

[0484] Data analysis: 99.25% (m / z: 579.5, [M+1]) + , 5.24 min (10 min run).

[0485] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0486] 13 C-NMR (400 MHz, DMSO- d 6): δ 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.

[0487] Synthetic compound 38

[0488] Step 1: Synthesis of 5-methoxy-2-(tributyltinyl)pyrimidine Hexabutyltinane (5.62 g, 1.4 equivalents, 9.68 mmol) was added to a stirred solution of 2-chloro-5-methoxypyrimidine (1 g, 6.92 mmol) in toluene (10 mL). The reaction mixture was purged with argon for 30 min, and then tetrakis(triphenylphosphine)palladium(0) (0.399 g, 0.05 equivalents, 0.346 mmol) was added. The reaction mixture was purged with argon again for 5 min. The reaction mixture was stirred at 110 °C for 16 h. After the reaction was complete, the mixture was filtered through a diatomaceous earth bed and washed with ethyl acetate. The filtrate was concentrated to give a crude substance, which was then purified by column chromatography using heptane containing 0-10% ethyl acetate as the eluent to give 5-methoxy-2-(tributyltinyl)pyrimidine (1 g, 2.51 mmol, 36%) as a colorless liquid.

[0489] Analyze the data: LCMS:99.0% (m / z: 401.15, [M+1] + , 3.48 min (4 min run).

[0490] Step 2: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-9-((S)-1-((R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-4-hydroxy-2-iodo-9a, 11b-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a,11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one: (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-hydroxy-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (5 g, 8.38 mmol) was reacted with dimethylformamide (0.1 L, 1.29 mmol). 4-(pyrrolidone-1-yl)pyridin-1-onium (6.25 g, 5 equivalents, 41.9 mmol) was added to a stirred solution. After 10 minutes, tert-butyl(chloro)dimethylsilane (12.6 g, 10 equivalents, 83.8 mmol) was added and the reaction mixture was heated to 85 °C and maintained for 3 hours. After the reaction was complete (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 layers were washed with saturated salt solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude substance. This crude substance was purified by column chromatography in heptane containing 0-100% ethyl acetate to obtain a grayish-white solid compound (4S,4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-9-((S)-1-((R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-4-hydroxy-2-iodo-9a,11b-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopentane[1, 2]Phenanthene[8a, 9-b]epoxyethylene-1(4H)-one (1.8 g, 2.41 mmol, 29%).

[0491] Analyze the data: LCMS:95.79% (m / z: 711.10, [M+H] + , 4.10 min (6 min run).

[0492] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0493] Step 3: Synthesis of (1S, 2R, 6S, 7R, 9R, 11S, 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-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 ] Octadec-4-en-3-one At room temperature, the methyl group (1S, 2R, 6S, 7R, 9R, 11S, 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-iodide-2,16-dimethyl-8-oxapentane[9.7.0.0] is oxidized to methyl ethyl ... 2 , 7 .0 7 , 9 .0 12 , 16 Octadecyl-4-en-3-one (0.8 g, 1.13 mmol) and 5-methoxy-2-(tributyltinyl)pyrimidine (0.674 g, 1.5 equivalents, 1.69 mmol) were added to a stirred solution of THF (10 mL) with triphenylarsine (0.035 g, 0.1 equivalents, 0.113 mmol) and λ. 1-Copper iodide (1+) (0.032 g, 0.15 equivalents, 0.169 mmol). The resulting mixture was purged with argon for 30 min. Subsequently, tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (0.103 g, 0.1 equivalents, 0.113 mmol) was added to the mixture and stirred at 85 °C for 3 h. After the reaction was complete (monitored by TLC and LCMS), it was quenched by adding water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic compounds were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude substance. This crude substance was purified by combi flash column chromatography on a silica gel column using heptane containing (70-90%) ethyl acetate as the eluent, yielding a grayish-white solid: (1S, 2R, 6S, 7R, 9R, 11S, 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-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.15 g, 19%).

[0494] Data analysis: LCMS: 98.06% (m / z: 693.26, [M+1]) + , 3.03 min (4 min run).

[0495] Step 4: Synthesis of (1S, 2R, 6R, 7S, 9R, 11S, 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-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadec-4-en-3-one: At -78°C under an inert atmosphere, the molecule is synthesized into (1S, 2R, 6S, 7R, 9R, 11S, 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-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Diethyl(trifluoro-λ) was added dropwise to a stirred solution of 0.15 g (0.216 mmol) of octadecyl-4-en-3-one in dichloromethane (5 mL). 4 (-Thio)amine solution (0.034 mL, 1.2 equivalents, 0.26 mmol) (dissolved in DCM (1 mL)) was stirred for 15 minutes. After the reaction was complete (monitored by TLC and LCMS), it was quenched by adding saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (2 x 30 mL). Organic matter was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude material. This crude material was purified by combi-flash chromatography on a silica gel column (using heptane containing 10-20% ethyl acetate) to obtain a grayish-white solid: (1S, 2R, 6R, 7S, 9R, 11S, 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-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.055 mg, 0.079 mmol, 36%).

[0496] Analysis data: LCMS: 78.08% (m / z: 695.30, [M+1]) + , 4.52 min (6 min run).

[0497] Step 5: Synthesis of (1S, 2R, 6R, 7S, 9R, 11S, 12S, 15R, 16S)-6-fluoro-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-(5-methoxypyrimidin-2-yl)-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadec-4-en-3-one: At 0°C, the molecule is converted to (1S, 2R, 6R, 7S, 9R, 11S, 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-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (50 mg, 0.309 mmol) was added dropwise to a solution of THF (0.5 mL) and methanol (0.5 mL) with 0.5 mL of 2N HCl solution and stirred for 30 minutes. After the reaction was complete (monitored by TLC and LCMS), it was quenched by adding sodium bicarbonate solution (20 mL). It was then extracted with dichloromethane (2 x 20 mL). Organic matter was collected, dried over sodium sulfate, and concentrated under reduced pressure to obtain a crude substance, which was then purified by combi-flash chromatography (5% methanol and dichloromethane), followed by preparative HPLC purification using the ammonium acetate method to obtain a white solid (1S, 2R, 6R, 7S, 9R, 11S, 12S, 15R, 16S)-6-fluoro-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-(5-methoxypyrimidin-2-yl)-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (10.8 mg, 60%).

[0498] Data analysis: 92.82% (m / z: 581.5, [M+1]) + , 7.65 min (14 min run).

[0499] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0500] 19 F-NMR (400 MHz, DMSO- d 6): δ 202.31 Synthetic compound 39

[0501] Step 1: Synthesis of 5-fluoro-4-(trimethyltinyl)pyrimidine: Hexamethyldistinane (1.85 g, 1.5 equivalent, 5.66 mmol) was added to a stirred solution of 4-chloro-5-fluoropyrimidine (0.5 g, 3.77 mmol) in anhydrous toluene (8 mL, 75.3 mmol). The reaction mixture was purged with argon for 30 min. Then tetra(triphenylphosphine)palladium (218 mg, 0.05 equivalent, 189 µmol) was added. The reaction mixture was again purged with argon for 5 min. The reaction mixture was heated at 110 °C for 3 h. The reaction was monitored by TLC. The reactants were cooled to room temperature. The crude residue was poured into KF solution (100 mL) and extracted with EtOAc (3 x 50 mL), dried over Na2SO4, filtered, and evaporated under vacuum to obtain the crude residue. The crude residue was used directly in the next step without further purification. LCMS quality was not supported. TLC showed obvious nonpolar spots.

[0502] Step 2: Synthesis of (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-4-(5-fluoropyrimidin-4-yl)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadec-4-en-3-one: (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.5 g, 838 µmol), 5-fluoro-4-(trimethyltinyl)pyrimidine (437 mg, 2 equivalents, 1.68 mmol) and λ 1A stirred solution of copper iodide (1+) (23.9 mg, 0.15 equivalents, 126 µmol) in dimethylformamide (5 mL, 64.6 mmol) was purged with N2 for 35 min, followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (34.2 mg, 0.05 equivalents, 41.9 µmol). The reaction mixture was again purged with N2 for 5 min. The reaction vessel was sealed and stirred at 60 °C for 16 h. The reaction was monitored by TLC (SM was exhausted) and quenched by the addition of 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 sulfate and filtered. The filtrate was evaporated under high vacuum to obtain a crude residue, which was purified by preparative HPLC (ABC method) to obtain the desired compound (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-4-(5-fluoropyrimidin-4-yl)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadec-4-en-3-one (62 mg, 13.05%).

[0503] Analyze the data: LCMS:98.77% (m / z: 567.70, [M+1] + , 5.33 min (10 min run).

[0504] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0505] 13 C-NMR (400 MHz, DMSO- d 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.

[0506] Synthetic compound 40

[0507] Step 1: Synthesis of (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-9-((S)-1-((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, 11b-dimethyl-5a, 6, 6a, 6b, 7, 8, 9,9a, 10, 11, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one To (1S, 2R, 6S, 7R, 9R, 11S, 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-iodine-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (1 g, 1.41 mmol), 2-methoxy-5-(tributyltinyl)pyrazine (618 mg, 1.1 equivalent, 1.55 mmol), triphenylarsine (43.1 mg, 0.1 equivalent, 141 µmol), and copper diiodide (67 mg, 0.15 equivalent, 211 µmol) were added to a stirred solution of tetrahydrofuran (12 mL). The reaction mixture was purged with nitrogen for 35 min and palladium-(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one (2 / 3) (64.4 mg, 0.05 equivalent, 70.3 µmol) was added. The reaction mixture was purged with nitrogen again for 5 min. The reaction mixture was stirred at 60 °C for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was cooled and quenched with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to obtain the crude substance. The crude residue was purified by a Combi-Flash purifier (12 g silica gel Welch column) and eluted with heptane containing 40-50% EtOAc. The pure eluent was collected and evaporated under reduced pressure to obtain the desired product (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-9-((S)-1-((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, 11b-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one (350 mg, 35%), which was a pale yellow solid.

[0508] Data analysis: 66.8% (m / z: 693.20, [M+1]) + , 2.67 min (4 min run).

[0509] Step 2: Synthesis of (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one At -78°C under an inert atmosphere, (4S, 4aR, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-9-((S)-1-((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, 11b-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthrene[8a, 9-b]epoxyethylene-1(4H)-one (230 mg, 332 µmol) was reacted with dichloromethane (3 Add dropwise diethyl(trifluoro-λ) dissolved in DCM (1 mL) to the stirred solution in mL. 4(-Thio)amine (52.6 µL, 1.2 equivalents, 398 µmol) was added and stirred for 15 min. After the reaction was complete (monitored by TLC and LCMS), it was quenched by adding saturated sodium bicarbonate solution (30 mL) and extracted with dichloromethane (2 x 30 mL). The organic matter was collected, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude material. The obtained crude residue was purified by a Combi-Flash purifier (4 g gel Welch column) and eluted with heptane containing 10-15% ethyl acetate. The pure eluent was collected and evaporated under reduced pressure to obtain the desired product (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-9-((S)-1-((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, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthrene[8a, 9-b]epoxyethylene-1(4H)-one (0.1 g, 43%), which was a pale yellow solid.

[0510] Data analysis: 49.91% (m / z: 695.35, [M+1]) + , 4.39 min (6 min run).

[0511] Step 3: Synthesis of (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-fluoro-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-(5-methoxypyrazin-2-yl)-9a, 11b-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a, 9-b]epoxyethylene-1(4H)-one At 0°C, (R)-6-[(S)-1-{(1S, 2R, 6R, 7S, 9R, 11S, 12S, 15R, 16S)-6-fluoro-2,16-dimethyl-3-oxo-4-(2-pyrimidinyl)-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16[[octadecyl-4-en-15-yl]ethyl]-3-{[(tert-butyl)bis(methyl)siloxane]methyl}-4-methyl-5,6-dihydro-2H-pyran-2-one (450 mg, 677 µmol) was added to a stirred solution of tetrahydrofuran (4 mL) and methanol (4 mL) with 2N HCl (4 mL). The reaction mixture was stirred at 0 °C for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with a saturated solution of NaHCO3 (40 mL) and extracted with ethyl acetate (2 x 40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude substance. The compound was purified by preparative HPLC using the ABC method to obtain the desired product (4R, 4aS, 5aR, 6aS, 6bS, 9R, 9aS, 11aS, 11bR)-4-fluoro-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-(5-methoxypyrazin-2-yl)-9a, 11b-dimethyl-5a, 6, 6a, 6b, 7, 8, 9, 9a, 10, 11, 11a, 11b-dodecylhydrocyclopenta[1, 2]phenanthro[8a,9-b]epoxyethylene-1(4H)-one (12 mg, 14%) as a white solid.

[0512] Data analysis: 97.79% (m / z: 581.5, [M+1]) + , 6.49 min (10 min run).

[0513] 1 H-NMR (400 MHz, DMSO- d 6): δ8.38 (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).

[0514] 19 F-NMR (400 MHz, DMSO- d 6): δ -201.82 Synthetic compound 41

[0515] Step 1: Synthesis of 6-(trimethyltinyl)pyridine-2-amine (0.4 g, 1.48 mmol) Hexamethyldistinane (1.89 g, 5.78 mmol) was added to a stirred solution of 6-bromopyridin-2-amine (1 g, 5.78 mmol) in toluene (8 mL, 75.3 mmol). The reaction mixture was purged with nitrogen for 10 min. Tetra(triphenylphosphine)palladium (0.2 g, 0.03 equivalent, 173 µmol) was added to the resulting reaction mixture. The reaction mixture was stirred at 130 °C for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude compound was purified by combi flash column chromatography on a silica column (containing 0–20% ethyl acetate in heptane) to give the desired product, 6-(trimethylstinyl)pyridin-2-amine (0.4 g, 25.5%), as a brown gel.

[0516] Analyze the data: LCMS: 91% (m / z: 259.02, [M+1]) +, 1.49 min (4 min run).

[0517] Step 2: Synthesis of (1S, 2R, 6S, 7R, 9R, 11S, 12S, 16S)-4-(6-aminopyridin-2-yl)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.1 g, 172 µmol) To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 161.5 g (2.51 mmol) of octadecyl-4-en-3-one was added to a stirred solution of tetrahydrofuran (10 mL) with 6-(trimethyltinyl)pyridin-2-amine (775 mg, 1.2 equivalents, 3.02 mmol). The reaction mixture was purged with nitrogen for 10 min. Copper iodide (1+) (47.9 mg, 0.1 equivalents, 251 µmol) and triphenylarsine (77 mg, 0.1 equivalents, 251 µmol) were added to the resulting mixture, followed by tris((1E,4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (115 mg, 0.05 equivalents, 126 µmol). The reaction mixture was stirred at 80 °C for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through a diatomaceous earth bed. The filtrate was diluted with water (70 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by preparative HPLC in ABC buffer to obtain the desired compound (1S, 2R, 6S, 7R, 9R, 11S, 12S, 16S)-4-(6-aminopyridin-2-yl)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.1 g, 6.86%).

[0518] Analyze the data: LCMS:97.76% (m / z: 563.5), [M+1] + , 5.16 min (10 min run).

[0519] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0520] 13 C-NMR (400 MHz, DMSO- d 6): δ 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.

[0521] Synthetic compound 42

[0522] Step 1: Synthesis of 5-(tributyltinyl)pyrimidine-2-amine Hexabutyltinane (3.15 g, 1.2 equivalents, 5.43 mmol) was added to a stirred solution of 5-iodopyrimidine-2-amine (1 g, 4.52 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was purged with argon for 30 min, and then tris(diphenylmethyleneacetone)dipalladium (0.41 g, 0.1 equivalents, 0.45 mmol) was added. The reaction mixture was purged with argon again for 5 min. The reaction mixture was stirred at 65 °C for 3 h. The reaction mixture was cooled to room temperature, quenched with chilled water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The organic matter was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi flash column chromatography using hexane containing (20-30%) ethyl acetate as the eluent to obtain 5-(tributyltinyl)pyrimidine-2-amine (1.4 g, 3.64 mmol, 80%) as a grayish-white solid.

[0523] Analyze the data: LCMS:99.89% (m / z: 386.21, [M+1] + , 3.12 min (4 min run).

[0524] Step 2: Synthesis of (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-4-(2-aminopyrimidin-5-yl)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 ] Octadec-4-en-3-one To (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iodo-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16A solution of octadecyl-4-en-3-one (0.25 g, 0.41 mmol) and 5-(tributyltinyl)pyrimidin-2-amine (0.24 g, 1.5 equivalents, 0.63 mmol) in N,N-dimethylformamide (3 mL) was stirred, and then triphenylarsine (0.013 g, 0.1 equivalents, 0.042 mmol) and λ were added. 1 -Copper iodide (1+) (0.012 g, 0.15 equivalents, 0.063 mmol). The resulting mixture was purged with argon for 30 min. Subsequently, tris((1E, 4E)-1,5-diphenylpentan-1,4-dien-3-one)dipalladium (0.038 g, 0.1 equivalents, 0.042 mmol) was added and the mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the mixture was quenched by adding water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic matter was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude substance. The crude product was purified by Combi flash column chromatography using DCM containing (5-10%) methanol as eluent, followed by preparative HPLC purification via the ammonium acetate method to obtain a white solid (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-4-(2-aminopyrimidin-5-yl)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 Octadecto-4-en-3-one (0.022 g, 0.039 mmol, 9%).

[0525] Data analysis: 98.14% (m / z: 564.5, [M+1]) + , 4.80 min (10 min run).

[0526] 1 H-NMR (400 MHz, DMSO- d 6): δ 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).

[0527] Synthetic compound 43

[0528] Step 1: Synthesis of 2-(tributyltinyl)pyrimidine-5-amine Hexabutyltin-5-amine (21.5 g, 1.2 equivalents, 37.1 mmol) was added to a stirred solution of 2-chloropyrimidin-5-amine (4 g, 30.9 mmol) in toluene (40 mL) at room temperature. The reaction mixture was purged with N2 for 30 min. After purging, tetra(triphenylphosphine)palladium (3.57 g, 0.1 equivalents, 3.09 mmol) was added and the mixture was purged with N2 again for 5 min. The reaction mixture was heated at 130 °C for 16 h. The reaction mixture was filtered through an ultrafluid diatomaceous earth bed and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by Combi flash column chromatography using heptane containing 40-50% ethyl acetate as eluent to give 2-(tributyltinyl)pyrimidin-5-amine (362 mg) as a grayish-white solid.

[0529] Analyze the data: LCMS:90.82% (m / z: 385.21, [M+1] + , 2.59 min (4 min run).

[0530] Step 2: Synthesis of (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-4-(5-aminopyrimidin-2-yl)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-2,16-dimethyl-8-oxapentane[9.7.0.0] 2 , 7 .07 , 9 .0 12 , 16 ] Octadec-4-en-3-one At room temperature, the molecule is converted to (1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-15-[(1S)-1-[(2R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl]-4-iod-2,16-dimethyl-8-oxapentane[9.7.0.0]. 2 , 7 .0 7 , 9 .0 12 , 16 Add 2-(tributyltinyl)pyrimidin-5-amine (155 mg, 1.2 equivalents, 402 µmol) to a stirred soluti...

Claims

1. A compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 For hydrogen, -NR 9 R 10 -COOR 9 -CN or ; R 2 For hydrogen, halogen, -OR 9 -SR 9 -NR 9 R 10 -COOR 9 -COHR 9 R 10 -CR 9 R 10 R 11 -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cyclic aliphatic ring, heterocyclic group or Wherein the C1-C6 alkyl group, the aryl group, the heteroaryl group, the cyclic aliphatic ring, or the heterocyclic group is not substituted or is replaced by one or more R groups. 12 replace; R 3 is hydrogen, halogen, -OR 9 , -SR 9 , -NR 9 R 10 , -COOR 9 , -COHR 9 R 10 , -CR 9 R 10 R 11 , -CN, -N3, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, -(NR 9 R 10 R 11 ) + or -OC(=O)NH-(C2-C6alkynyl), wherein said C1-C6alkyl, said aryl, said heteroaryl, said cycloaliphatic ring, or said heterocyclyl is unsubstituted or substituted with one or more R 12 ; T, U, V, W and X are each independently CH, CR 12 sulfur, nitrogen, NH, NR 12 or N + -O - ; R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, deuterium, halogen or Ci-C6unsubstituted or substituted alkyl; and each R is independently hydrogen, deuterium, halogen, =0, -OR 12 is independently hydrogen, deuterium, halogen, =0, -OR 9 , -SR 9 , -NR 9 R 10 , -COOR 9 , -COHR 9 R 10 , -CR 9 R 10 R 11 , -CN, -N3, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, aryl, aralkyl, heteroaryl, cycloaliphatic ring, heterocyclyl, or -O-(heterocyclyl); The conditions are: (1) When R 1 When it is hydrogen, then R 2 It is a halogen; (2) When R 1 for And each of T, U, V, W, and X is CH or CR. 12 When , only one of T, U, V, W, and X is CR. 12 , where R 12 for Or -OCH3, and the rest of T, U, V, W and X are CH; as well as (3) When R 1 for If T and X are CH, one of W or U is nitrogen, and the other of W or U is CH, then V is not C(-OCH3).

2. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (Ia): (Ia) or its pharmaceutically acceptable salt.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 For halogen, -OR 9 -NR 9 R 10 5-membered heterocyclic group or , where R 9 and R 10 Each is independently hydrogen or C1-C6 alkyl.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 -OH, -F, -N(CH3)2, or .

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 For hydrogen, halogen, -OR 9 -NR 9 R 10 C1-C6 alkoxy, 5- to 6-membered heterocyclic groups optionally substituted with one or more C1-C6 alkyl groups, -(NR 9 R 10 R 11 ) + -OC(=O)NH-(C2-C6 ynyl group) or , where R 9 R 10 and R 11 Each is independently hydrogen or C1-C6 alkyl.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3 For hydrogen, -OH, -OCH3, -N(CH3)2, -F , , , , , , or .

7. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 for: 。 8. The compound of claim 7, wherein the compound of formula (Ia) is a compound of formula (Iaa): (Iaa) or its pharmaceutically acceptable salt.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein T, U, V, W and X are each CH or CR. 12 .

10. The compound of claim 9, wherein the compound of formula (Iaa) is selected from the group consisting of: , , , or its pharmaceutically acceptable salt or stereoisomer.

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, or NR. 12 or N + -O - And the remaining ones among T, U, V, W, and X are each CH or CR. 12 .

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R 1 for , , or , where n is 0, 1, 2, 3 or 4.

13. The compound of claim 11, wherein the compound of formula (Iaa) is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or its pharmaceutically acceptable salt or stereoisomer.

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, and NR. 12 or N + R 12 And the rest of T, U, V, W, and X are CH or CR. 12 .

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 1 for , , , , , , , where p is 0, 1, 2 or 3.

16. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 1 for , where q is 0, 1 or 2.

17. The compound of claim 14, wherein the compound of formula (Iaa) is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or its pharmaceutically acceptable salt or stereoisomer.

18. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 for: .

19. The compound of claim 18, wherein R 1 for , where p is 0, 1, 2 or 3.

20. The compound of claim 18, wherein R 1 for , where q is 0, 1 or 2.

21. The compound of claim 18, wherein the compound of formula (Ia) is a compound of formula (Iab): (Iab) or a pharmaceutically acceptable salt thereof.

22. The compound of claim 18, wherein the compound of formula (Iab) is selected from the group consisting of: , or its pharmaceutically acceptable salt or stereoisomer.

23. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydrogen.

24. The compound of claim 23, wherein the compound of formula (Ia) is a compound of formula (Iac): (Iac) or a pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen.

25. The compound of claim 24, wherein the compound of formula (Iac) is: Or its pharmaceutically acceptable salts or stereoisomers.

26. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

27. The compound of claim 1, wherein the compound is Or its pharmaceutically acceptable salt.

28. A pharmaceutical composition comprising the compound of any one of claims 1 to 27 or a pharmaceutically acceptable salt or stereoisomer thereof and at least one pharmaceutically acceptable carrier.

29. A method for treating, improving, or preventing a disease or ailment of a subject in need, wherein the disease is mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3) or by tumor necrosis factor α (TNF-α), and wherein the method comprises administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 27.

30. The method of claim 29, wherein the ailment or disease is mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3).

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

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

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

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

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

36. The method of claim 29, wherein the disease or ailment is inflammatory bowel disease (IBD), and wherein the compound is... Or its pharmaceutically acceptable salt.

37. The method of claim 29, wherein the disease or ailment is alcoholic hepatitis, and wherein the compound is... Or its pharmaceutically acceptable salt.

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

39. A method for treating, improving, or preventing a disease or ailment of a subject in need, wherein the disease is mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3) or by tumor necrosis factor α (TNF-α), and wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 28.

40. The method of claim 39, wherein the ailment or disease is mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3).

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

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

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

44. A pharmaceutical composition comprising any one of claims 1 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment, improvement, or prevention of a disease or ailment mediated by an NLR family Pyrin domain 3 (NLRP3) inflammasome or by tumor necrosis factor α (TNF-α).

45. The pharmaceutical composition for use as claimed in claim 44, wherein the ailment or disease is mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3).

46. ​​The pharmaceutical composition for use as claimed in claim 44, wherein the disease or ailment is mediated by tumor necrosis factor α (TNF-α).

47. The pharmaceutical composition for use as claimed in claim 44, wherein the disease or ailment is a cardiovascular disease or ailment, an endocrine disease or ailment, a neurological disease or ailment, a gastrointestinal disease or ailment, or a combination thereof.

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

49. The pharmaceutical composition for use as claimed in claim 44, wherein the disease or ailment is inflammatory bowel disease (IBD), Crohn's disease, or a combination thereof.

50. The pharmaceutical composition for use as claimed in claim 44, wherein the disease or ailment is colorectal cancer, alcoholic hepatitis, or a combination thereof.

51. The use of any compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof, for the preparation of an agent for the treatment, improvement or prevention of a disease or ailment mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3) or by tumor necrosis factor α (TNF-α).

52. The use as claimed in claim 51, wherein the ailment or disease is mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3).

53. The use as claimed in claim 51, wherein the disease or ailment is mediated by tumor necrosis factor α (TNF-α).

54. The use as claimed in claim 51, wherein the disease or ailment is a cardiovascular disease or ailment, an endocrine disease or ailment, a neurological disease or ailment, a gastrointestinal disease or ailment, or a combination thereof.

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

56. The use as claimed in claim 51, wherein the disease or ailment is inflammatory bowel disease (IBD), Crohn's disease, or a combination thereof.

57. The use as claimed in claim 51, wherein the disease or ailment is colorectal cancer, alcoholic hepatitis, or a combination thereof.

58. A method for treating, improving, or preventing a disease or ailment of a subject in need, wherein the disease is mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3) or by tumor necrosis factor α (TNF-α), 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 ailment or disease is mediated by an inflammasome containing the NLR family Pyrin domain 3 (NLRP3).

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

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

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

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

64. A method for preparing the compound of claim 17, wherein the compound has the formula (Iaa), the method comprising: Pyrazine is provided as the first intermediate; as well as The 2-pyranone and the first intermediate are combined to form the second intermediate.

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

66. The method of claim 65, wherein: The step of providing pyrazine as the first intermediate is further defined as a combination: (i) the solvent, the salt, the ligand, the catalyst, or a combination thereof, and (ii) the pyrazine to form the first intermediate; and The step of combining 2-pyranone with the first intermediate to form the second intermediate is further defined as combination: (i) the solvent, the salt, the ligand, the catalyst, or a combination thereof, and (ii) The 2-pyranone and the first intermediate are used 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)-1-{(1S, 2R, 6S, 7R, 9R, 11S, 12S, 15R, 16S)-6-hydroxy-4-iodo-2,16-dimethyl-3-oxo-8-oxapentane[9.7.0.0] 2 , 7 .0 7 , 9 .0 12 , 16 [Octadecyl-4-en-15-yl]-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 consisting of 1,4-dioxane, tetrahydrofuran, ethyl acetate, heptane, water, and combinations thereof.

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

71. The method of claim 65, wherein the ligand is selected from the group consisting of hexabutyldistannane, tributyl(5-isopropoxy-2-pyrazinyl)stannane, tricyclohexylphosphine, triphenylarsine, and combinations thereof.

72. The method of claim 65, wherein the catalyst is selected from the group consisting of palladium-(1E,4E)-1,5-diphenyl-1,4-pentadien-3-one (2 / 3), tris((1E,4E)-1,5-diphenylpenten-1,4-diene-3-one)dipalladium [Pd2(dba)3], copper iodide [CuI], triphenylarsine [AsPh3], tetra(triphenylphosphine)palladium(O) [Pd(PPh3)4], bis((triphenylphosphine)palladium(II) dichloride [PdCl2(PPh3)2], and combinations thereof.

Images