Inhibitor of apoptosis (IAP) protein antagonists

Abstract

To provide compounds that modulate the activity of inhibitor of apoptosis (IAPs) proteins, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.SOLUTION: A compound having the following structure, or a pharmaceutically acceptable salt thereof, is provided.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 933,190, filed November 8, 2019, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under Contract Nos. R01CA195227 and R01AI124843 awarded by the National Institutes of Health (NIH). The government has certain rights in this invention. Summary of the Invention

[0003] Described herein are compounds that modulate the activity of specific proteins involved in apoptosis pathways or signal transduction pathways associated with inflammation and / or autoimmune diseases and / or cell division and / or angiogenesis. In some embodiments, the compounds described herein are inhibitor of apoptosis (IAP) protein antagonists. In some embodiments, the compounds disclosed herein are pan-IAP antagonists. In some embodiments, the compounds described herein are useful for treating cancer, inflammatory diseases, and / or autoimmune diseases described herein.

[0004] In one aspect, provided herein is a compound having the structure of Formula I, a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof,

[0005] [ka] During the ceremony, X 1 are each independently O, S, S(=O), or S(=O)2; R 1 , R 3 , and R 4are each independently H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, and heteroaryl are each independently selected from one, two, or three R a is optionally replaced by R 2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(C3-C6 cycloalkyl), or -NR 5 R 6 wherein alkyl and cycloalkyl are each independently one, two, or three R b is optionally replaced by R 5 and R 6 are each independently H, C1-C6 alkyl, or —C1-C6 alkyl-(C3-C6 cycloalkyl); R 7 are each independently H, halogen, C1-C6 alkyl, or OH; n is independently 1 or 2; X 3 are each independently -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, -NHS(=O)2NH-, -NHC(R 1a )(R 1b )-, or -C(R 1a )(R 1b )NH-, A 1 and A 2 are independently C1-C6 alkylene, C3-C 10 Cycloalkylene, C5-C 10 Arylene, C2-C 10 heterocycloalkylene, or 4- to 10-membered heteroarylene, wherein alkyl, cycloalkylene, arylene, heterocycloalkylene, and heteroarylene each independently have one, two, or three R cis optionally replaced by L is -X 5 -(CH2) n1 -Q 1 -(CH2) n2 -X 5 - and X 5 are each independently O, S, or absent; n 1 and n 2 are each independently 0-5, Q 1 is -C1-C6 alkylene-, -C2-C6 alkenylene-, -C2-C6 alkynylene-, -C(O)NH-C1-C6 alkylene-NHC(O)-, -SO2-, -C2-C6 alkynylene-C6-C 10 Arylene, -C2-C6 alkynylene, -C6-C 10 Arylene-C2-C6 alkynylene-, or -C6-C 10 Arylene-C6-C 10 Arylene- is alkylene, alkenylene, C2-C6 alkynylene, and C6-C 10 Each arylene independently has one, two, or three R d is optionally replaced by R 1a and R 1b are each independently H, OH, NH, CN, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; R 2a and R 2b are each independently H, OH, NH, CN, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; or R 2a and R 2btogether form a C3-C6 cycloalkyl or a C2-C5 heterocycloalkyl, and R a , R b , R c , and R d are each independently halogen, OH, NH, CN, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkene, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; However, the compound is

[0006] [ka]

[0007] [ka]

[0008] [ka]

[0009] [ka] isn't it.

[0010] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, N-oxide, racemate, stereoisomer thereof, and a pharmaceutically acceptable carrier.

[0011] Further disclosed herein are methods for treating a hyperproliferative disorder in an individual, the methods comprising administering to the individual a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof. In some embodiments of the methods for treating a hyperproliferative disorder, the hyperproliferative disorder is cancer or an autoimmune disease. In some embodiments of the methods for treating a hyperproliferative disorder, the autoimmune disease is hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac disease, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibrositis, graft-versus-host disease, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, or vitiligo.

[0012] Further disclosed herein are methods of treating cancer in an individual, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof. In some embodiments of the methods of treating cancer, the cancer is sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or a combination thereof. In some embodiments of the methods of treating cancer, the cancer is skin cancer, lung cancer, breast cancer, prostate cancer, colon cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combination thereof. In some embodiments of the methods of treating cancer, the cancer is acute myeloid leukemia (AML). In some embodiments of the methods of treating cancer, the cancer is renal cell carcinoma. In some embodiments of the methods of treating cancer, the cancer is ovarian cancer. In some embodiments of the methods of treating cancer, the cancer is prostate cancer. In some embodiments of the methods of treating cancer, the cancer is renal cell carcinoma. In some embodiments of the methods of treating cancer, the cancer is glioblastoma. In some embodiments of the methods of treating cancer, the cancer is gastric cancer. In some embodiments of the methods of treating cancer, the cancer is esophageal squamous cell carcinoma. In some embodiments of the methods of treating cancer, the cancer is lung cancer. In some embodiments of the methods of treating cancer, the cancer is non-small cell lung cancer or small cell lung cancer. In some embodiments of the methods of treating cancer, the cancer is multiple myeloma. In some embodiments of the methods of treating cancer, the cancer is pancreatic cancer. In some embodiments of the methods of treating cancer, the cancer is breast cancer.

[0013] Further disclosed herein are methods for treating diseases associated with undesired angiogenesis in an individual, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof. In some embodiments of the methods for treating diseases associated with undesired angiogenesis, the disease associated with undesired angiogenesis is macular degeneration, rheumatoid arthritis, psoriasis, diabetic retinopathy, retinopathy of prematurity, corneal transplant rejection, neovascular glaucoma, retrolental fibroplasia, skin flushing, Osler-Webber syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophilic joints, angiofibroma, wound granulation, intestinal adhesions, atherosclerosis, scleroderma, or hypertrophic scars. In some embodiments of the methods for treating diseases associated with undesired angiogenesis, the disease associated with undesired angiogenesis is cancer. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or a combination thereof. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, or other leukemia. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is skin cancer, lung cancer, breast cancer, prostate cancer, colon cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combination thereof. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is acute myeloid leukemia (AML). In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is renal cell carcinoma. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is ovarian cancer. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is prostate cancer. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is renal cell carcinoma. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is glioblastoma.In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is gastric cancer. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is esophageal squamous cell carcinoma. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is lung cancer. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the lung cancer is non-small cell lung cancer or small cell lung cancer. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is multiple myeloma. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is pancreatic cancer. In some embodiments of the method for treating a disease associated with undesired angiogenesis, the cancer is breast cancer.

[0014] Further disclosed herein is a method of treating human immunodeficiency virus (HIV) in a mammal, said method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

[0015] Further disclosed herein are methods for reversing human immunodeficiency virus (HIV) latency in a mammal, the methods comprising administering to the individual a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof. In some embodiments of the methods for reactivating human immunodeficiency virus (HIV) latency, the HIV latency is reactivated without T cell activation. In some embodiments of the methods for reactivating human immunodeficiency virus (HIV) latency, the methods further comprise administering an additional latency reversal agent, killer agent, CarT, immunotherapeutic agent, neutralizing antibody agent, or other agent.

[0016] In some embodiments of the method for reactivating human immunodeficiency virus (HIV) latency, the additional latency-reactivating agent is a histone deacetylase inhibitor (HDACi), a bromodomain and extraterminal domain inhibitor (BETi), or a protein kinase C (PKC) agonist. [Brief explanation of the drawings]

[0017] [Figure 1] 1 illustrates comparative data between compound 18a and various known compounds in potency and efficacy in HIV latency reactivation in the latently infected cell line 2D10. [Figure 2] FIG. 1 shows the effect of compound 18a and various control conditions on the activation of resting CD4+ T cells isolated from healthy donors, as assessed by measuring CD69 expression. [Figure 3] 1 shows the effect of compound 18a and various control conditions on cytokine release in peripheral blood mononuclear cells and resting CD4+ T cells isolated from healthy donors. [Figure 4] Figure 1 shows the induction of cIAP1 degradation, p100 cleavage, and GPF expression in a latently infected Jurkat 2D10 cell line upon treatment with compound 18a. [Figure 5] Figure 1 shows the effect of compound 18a in combination with other latency reactivators on the activation of HIV transcription in latently infected Jurkat 2D10 cells. The heatmap shows the excess over Bliss (EOB) score, where a score greater than zero indicates synergy between the compounds. [Figure 6] 1 shows the effect of compound 18m compared to other IAP antagonists in potency and efficacy in patient-derived AML samples. DETAILED DESCRIPTION OF THE INVENTION

[0018] This paper provides a potent ML-IAP inhibitor that can be used as a tool or potential drug for treating cancer and other medical conditions. Genetic silencing of ML-IAP has shown efficacy in various tumors as well as in xenograft studies. The development of IAP antagonists will improve the survival of cancer patients, including AML patients, and provide new hope for severely ill patients. This will be a major advance in the treatment of cancer, especially AML cancer.

[0019] AML is a diverse group of blood cancers characterized by the bone marrow's overproduction of immature myeloid blood cells. This rapid proliferation of abnormal progenitor cells leads to the disruption of normal blood and bone marrow function. The American Cancer Society estimates that AML will cause approximately 11,000 deaths and 21,500 new cases in the United States in 2019. While leukemia is the fourth most common cancer in the 17-34 age group, AML is more deadly in older patients. AML is considered a "late-effect" disease, and exposure to ionizing radiation and / or chemicals has been implicated in the development of leukemia and other blood cancers. Leukemia is curable in approximately 30% of patients under 60 years of age, but the cure rate is only approximately 10% in older patients. In fact, elderly patients who cannot tolerate invasive chemotherapy have an average survival time of only seven months. Although prognosis varies somewhat among various AML subtypes, more than 30% of all AML patients do not achieve complete remission with standard chemotherapy regimens. Without bone marrow transplantation (BMT), most patients who initially respond will relapse within 5 years. Therefore, the need for novel targets and agents to treat acute myeloid leukemia represents a significant unmet medical need. This is particularly true in patient populations who cannot tolerate invasive chemotherapy or for whom BMT is not possible or advisable. The current standard of care (SOC) for AML has remained the same for decades: the nucleoside analog cytarabine ("ara-C") in combination with an anthracycline, usually daunorubicin, remains the leading-edge agent. While many patients achieve remission, nearly all will relapse, and new therapies are desperately needed.

[0020] Apoptosis, a type of programmed cell death, is often uncontrolled in malignant cells, and evasion of apoptosis is a hallmark of cancer. As cancer cells divide and proliferate, the normal control of cell death is lost, leading to tumor formation. The IAP protein family is involved in blocking or attenuating programmed cell death pathways, primarily through regulation of the caspase cascade (Figure 1). IAP proteins are often upregulated in cancer and are thought to underlie the resistance of many malignant cells to chemotherapy. Therefore, ablation or antagonism of IAP proteins is an attractive therapeutic strategy for the treatment of cancer.

[0021] Proteins and genes are assigned to the IAP family if they contain a baculovirus IAP protein repeat (BIR) domain. Of the eight IAP proteins, five also contain a RING E3 ligase domain, and cIAP1 and cIAP2 also contain a caspase recruitment domain (CARD). The representative member of the IAP family is XIAP, a potent binder and inhibitor of caspase-3, a protease that influences apoptosis. Another highly related member of the IAP protein family is ML-IAP, also known as Livin or KIAP, which was first identified as a member of the IAP protein family due to its single BIR domain (49,50). The ML-IAP BIR domain is also involved in apoptosis inhibition, and small molecule antagonists have great potential for development as therapeutic agents. The RING domain of ML-IAP has been shown to function as an E3 ligase, promoting its own ubiquitination and subsequent degradation, and more importantly, the degradation of second mitochondrial-derived activator of caspases (SMAC), a natural caspase antagonist that regulates apoptotic signaling. Thus, inhibiting ML-IAP directly increases SMAC and resensitizes cells to apoptotic stimuli. Importantly, both protein and mRNA levels of ML-IAP are low or undetectable in most adult tissues, but are highly expressed in many cancers, including hematological malignancies.

[0022] AML cells have been shown to overexpress multiple anti-apoptotic proteins, including Bcl2 and IAP protein family members, which is thought to potentially underlie treatment resistance and eventual relapse. IAP protein family members may be potential therapeutic targets for AML, and IAP protein expression levels have been shown to determine prognosis. Provided herein is a new series of highly potent bivalent IAP antagonists with single-agent malignant cell-killing activity in culture. IAP antagonists may also be effective against AML.

[0023] Abnormal and uncontrollable cell proliferation due to the inhibition of apoptosis is a hallmark of cancer cells. Cancer cells often exhibit aberrant upregulation of pathways that inhibit apoptosis, allowing cancer cells to proliferate. One such pathway that is upregulated in cancer cells is the inhibitor of apoptosis (IAP) pathway. Members of the IAP family are functionally and structurally related proteins that inhibit apoptosis. IAPs share the baculovirus IAP (BIR) repeat domain, each of which has one to three copies. Eight members of the IAP protein family have been identified to date in both baculovirus and humans. Five human members of the IAP protein family include XIAP, c-IAPl (also BIRC2), cIAP2 (also BIRC3), NAIP, and survivin. In particular, XIAP inhibits apoptosis by binding to and inhibiting the activity of caspase-9, caspase-3, and caspase-7.

[0024] Alterations in IAP proteins are found in many types of human cancer and are associated with chemoresistance, disease progression, and poor prognosis. When the IAP pathway is upregulated, IAP proteins bind to initiator and effector caspases, preventing them from cleaving downstream cellular proteins.

[0025] The proteolytic activity of caspases is required for the normal progression of the cell death cascade.Therefore, compounds that bind to upregulated IAP proteins are provided herein.In some embodiments, the compounds provided herein bind to IAP proteins and prevent IAP proteins from suppressing caspase activity, thereby allowing the cell death cascade to proceed normally.In other words, compounds that inhibit the action of IAP proteins and thereby cause cell apoptosis are provided herein.

[0026] One protein involved in binding with IAPs is SMAC, a mitochondrial protein that negatively regulates apoptosis, also known as programmed cell death. When cells are stimulated for apoptosis through the final execution step of caspase activation, SMAC binds to IAPs and prevents them from binding to and deactivating caspases. Thus, SMAC promotes apoptosis through caspase activation.

[0027] In some embodiments, the compounds described herein are non-peptide second mitochondrial-derived activators of caspases (SMAC) mimetics and induce apoptosis (e.g., in cancer cells). In some embodiments, the compounds described herein are IAP antagonists.

[0028] In certain instances, IAP proteins not only coordinate caspases and apoptosis, but also regulate inflammatory signaling and immunity, mitogenic kinase signaling, proliferation, and mitosis, as well as cell invasion and metastasis. Inhibitor of apoptosis (IAP) proteins have emerged as regulators of innate immune signaling downstream of pattern recognition receptors (PRRs), such as Toll-like receptor 4 (TLR4), nucleotide-binding oligomerization domain 1 (NOD1) and NOD2 receptors, and retinoic acid-inducible gene (RIG)-I receptor. In particular examples, cellular inhibitor of apoptosis protein-1 (cIAP1; also known as Baculoviral IAP Repeat Containing 2, or BIRC2), cellular inhibitor of apoptosis protein-2 (cIAP2; also known as Baculoviral IAP Repeat Containing 3, or BIRC3), and X-linked Inhibitor of Apoptosis (XIAP) promote ubiquitin-dependent signaling activated by these PRRs, mediating activation of the nuclear factor kappa B (NF-κB) transcription factor, as well as MAP kinases p38 and JNK. Accordingly, the compounds described herein are also useful for treating non-neoplastic, and / or inflammatory, and / or autoimmune diseases.

[0029] Recent advances in combination antiretroviral therapy (ART) have enabled individuals infected with human immunodeficiency virus (HIV) to live longer and otherwise more normal lives. However, antiretroviral therapy only targets actively replicating HIV, not dormant, replication-competent HIV present in certain cell types. These latent HIV viruses reactivate and trigger new viral replication upon discontinuation of antiretroviral therapy. In addition to targeting actively replicating HIV, a strategy for improving HIV treatment is to also target dormant, replication-competent HIV viruses present in latently infected cells, which are cells that are infected with HIV but do not actively produce HIV. These latently infected cells do not undergo active viral replication, and the viral genome is integrated into the host DNA, making the viral DNA indistinguishable from the host's DNA. Latently infected cells are not recognized by the immune system and are resistant to antiretroviral therapy (ART). Therefore, the dormant virus and latently infected cells can remain hidden and persist indefinitely. One approach to targeting latently infected cells is to develop new therapeutic agents or drugs that can reactivate latency in infected cells by inducing active HIV replication. Once the dormant HIV virus "awakens," the infected cells become susceptible to immune system clearance or additional treatments, such as killer drugs, to eliminate the infected cells. Combination therapy with antiretroviral drugs prevents the spread of reactivated virus and suppresses new HIV infections. The combination of therapeutic agents that can reactivate latency in HIV-infected cells and drugs to eradicate the awakened HIV virus is called the "shock and kill" or "kick and kill" approach. IAP inhibition has been implicated in the reactivation of HIV latency. IAP antagonists may be used alone or in combination with other therapeutic agents, such as those used to treat HIV.In some embodiments, other therapeutic agents that can be used in combination with the IAP antagonist include a therapeutic agent that activates HIV transcription in latently infected cells, a therapeutic agent that inhibits active HIV replication, or any combination thereof. In some embodiments, the additional therapeutic agent that inhibits active HIV replication comprises an antiretroviral therapy. In some embodiments, pharmaceutical compositions are described that include an IAP antagonist alone or in combination with one or more additional therapeutic agents useful in treating HIV in a mammal. In some embodiments, the mammal is a human.

[0030] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to an "agent" includes a plurality of such agents, a reference to a "cell" includes a reference to one or more cells (or cells), and equivalents known to those of skill in the art, and so forth. When ranges for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, are used herein, all combinations and subcombinations of ranges and specific embodiments within the ranges are intended to be encompassed. The term "about," when referring to a number or range of numbers, means that the referenced number or range of numbers is approximate within experimental variation (or within statistical experimental error), and thus the number or range of numbers may, in some cases, vary by 1%-15% of the stated number or range of numbers. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other embodiments, such as, for example, any composition of matter, composition, method, or process described herein, "consist of" or "consist essentially of" the described features.

[0031] As used in this specification and the appended claims, unless specified to the contrary, the following terms have the meanings specified below.

[0032] "Oxo" refers to =O.

[0033] "Alkyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, or 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Wherever a numerical range appears herein, such as "C1-C6 alkyl," it means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is any of C1-C6 alkyl groups. 10The alkyl group may be alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, or C1 alkyl. Unless otherwise specified herein, an alkyl group is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, —OMe, —NH2, or —NO2. In some embodiments, an alkyl is optionally substituted with oxo, halogen, —CN, —CF3, —OH, or —OMe. In some embodiments, an alkyl is optionally substituted with halogen.

[0034] "Alkenyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans configuration about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH)=CH], butenyl, 1,3-butadienyl, and the like. Wherever appearing herein, a numerical range such as "C2-C6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" when no numerical range is explicitly stated. In some embodiments, alkenyl refers to any C2-C6 alkenyl. 10Alkenyl is C2-C9 alkenyl, C2-C8 alkenyl, C2-C7 alkenyl, C2-C6 alkenyl, C2-C5 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl, or C2 alkenyl. Unless otherwise specified in the specification, alkenyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkenyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0035] "Alkynyl" refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever appearing herein, a numerical range such as "C2-C6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" when no numerical range is explicitly stated. In some embodiments, alkynyl refers to any of C2-C6 alkynyl groups. 10alkynyl, C2-C9 alkynyl, C2-C8 alkynyl, C2-C7 alkynyl, C2-C6 alkynyl, C2-C5 alkynyl, C2-C4 alkynyl, C2-C3 alkynyl, or C2 alkynyl. Unless otherwise specified in the specification, alkynyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0036] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specified in the specification, an alkylene group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0037] "Alkoxy" is a group of formulas -OR a refers to the radical of R ais an alkyl radical as defined. Unless otherwise specified in the specification, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, -CN, -CF3, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0038] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines, as defined above. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Hydroxyalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the hydroxyalkyl is aminomethyl.

[0039] "Aryl" refers to a radical derived from a hydrocarbon ring system containing hydrogen, 6 to 30 carbon atoms, and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. In some embodiments, the aryl is phenyl. Unless otherwise specified herein, an aryl can be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0040] "Cycloalkyl" refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), bridged, and spirocyclic ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls containing 3 to 15 carbon atoms (C3-C4). 15 cycloalkyl), 3 to 10 carbon atoms (C3-C 10Examples of cycloalkyl include cycloalkyls having 3 to 8 carbon atoms (C3-C8 cycloalkyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl), 3 to 5 carbon atoms (C3-C5 cycloalkyl), or 3 to 4 carbon atoms (C3-C4 cycloalkyl). In some embodiments, cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified herein, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0041] "Deuteroalkyl" refers to an alkyl radical, as defined above, substituted with one or more deuterium atoms. In some embodiments, the alkyl is substituted with one deuterium atom. In some embodiments, the alkyl is substituted with one, two, or three deuterium atoms. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuterium atoms. Deuterated alkyls include, for example, CD3, CHD, CHD, CHCD, CDCD, CHDCD, CHCHD, or CHCHD. In some embodiments, the deuterated alkyl is CD3.

[0042] "Haloalkyl" refers to an alkyl radical, as defined above, substituted with one or more halogens. In some embodiments, the alkyl is substituted with 1, 2, or 3 halogen atoms. In some embodiments, the alkyl is substituted with 1, 2, 3, 4, 5, or 6 halogens. Haloalkyl includes, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl is trifluoromethyl.

[0043] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0044] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof, where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH3, -CHCHOCH3, -CHCHOCH2CH2OCH3, or -CH(CH3)OCH3. Unless otherwise specified in the specification, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0045] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0046] "Heterocycloalkyl" refers to a stable 3- to 24-membered, partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a heterocycloalkyl contains 1 to 2 heteroatoms selected from nitrogen and oxygen. Unless otherwise specified herein, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is joined by a non-aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls containing 2 to 15 carbon atoms (C2-C3). 15 heterocycloalkyl), 2 to 10 carbon atoms (C2-C 10Heterocycloalkyls include heterocycloalkyls having 2 to 8 carbon atoms (C2-C8 heterocycloalkyl), 2 to 6 carbon atoms (C2-C6 heterocycloalkyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl). In some embodiments, heterocycloalkyls are 3- to 6-membered heterocycloalkyls. In some embodiments, cycloalkyls are 5- to 6-membered heterocycloalkyls. Examples of such heterocyclylalkyls include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, Examples of heterocycloalkyls include pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term "heterocycloalkyl" also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. When referring to the number of carbon atoms in a heterocycloalkyl, it is noted that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise in the specification, heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0047] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl. Unless otherwise specified herein, a heteroalkyl is optionally substituted with, e.g., oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0048] "Heteroaryl" refers to a radical of a 5- to 14-membered ring system containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is joined by an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, Includes isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryl is optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0049] An "effective amount" or "therapeutically effective amount" refers to an amount of a compound administered to a subject (e.g., a mammal such as a human) in a single dose or as part of a series, effective to produce the desired therapeutic effect.

[0050] "Treatment" of a subject (e.g., a mammal such as a human) includes any type of intervention used to attempt to alter the natural course of the subject's disease. In some embodiments, treatment includes administration of a pharmaceutical composition after the initiation of a pathological event or after contact with a pathogen, and includes stabilization of the disease (e.g., the condition does not worsen, e.g., cancer does not metastasize, etc.) or amelioration of the disease (e.g., reduction in tumor size, remission of cancer, absence of symptoms of an autoimmune disease, etc.). In other embodiments, treatment further includes prophylactic therapy (e.g., administration of a composition described herein when an individual is suspected of being afflicted with a disease described herein).

[0051] As used herein, "subject," "individual," and "patient" are used interchangeably. None of these terms suggest that a medical professional is required to administer the compounds disclosed herein.

[0052] compound Some embodiments relate to compounds having the structure of Formula (I), a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof:

[0053] [ka] During the ceremony, X 1 are each independently O, S, S(=O), or S(=O)2; R 1 , R 3 , and R 4 are each independently H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10aryl, or 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, and heteroaryl are each independently selected from one, two, or three R a is optionally replaced by R 2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(C3-C6 cycloalkyl), or -NR 5 R 6 wherein alkyl and cycloalkyl are each independently one, two, or three R b is optionally replaced by R 5 and R 6 are each independently H, C1-C6 alkyl, or —C1-C6 alkyl-(C3-C6 cycloalkyl); R 7 are each independently H, halogen, C1-C6 alkyl, or OH; n is independently 1 or 2; X 3 are each independently -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, -NHS(=O)2NH-, -NHC(R 1a )(R 1b )-, or -C(R 1a )(R 1b )NH-, A 1 and A 2 are independently C1-C6 alkylene, C3-C 10 Cycloalkylene, C5-C 10 Arylene, C2-C 10 heterocycloalkylene, or 4- to 10-membered heteroarylene, wherein alkyl, cycloalkylene, arylene, heterocycloalkylene, and heteroarylene each independently have one, two, or three R c is optionally replaced by L is -X 5 -(CH2) n1 -Q1 -(CH2) n2 -X 5 - and X 5 are each independently O, S, or absent; n 1 and n 2 are each independently 0-5, Q 1 is -C1-C6 alkylene-, -C2-C6 alkenylene-, -C2-C6 alkynylene-, -C(O)NH-C1-C6 alkylene-NHC(O)-, -SO2-, -C2-C6 alkynylene-C6-C 10 Arylene, -C2-C6 alkynylene, -C6-C 10 Arylene-C2-C6 alkynylene-, or -C6-C 10 Arylene-C6-C 10 Arylene- is alkylene, alkenylene, C2-C6 alkynylene, and C6-C 10 Each arylene independently has one, two, or three R d is optionally replaced by R 1a and R 1b are each independently H, OH, NH, CN, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; R 2a and R 2b are each independently H, OH, NH, CN, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; or R 2a and R 2b together form a C3-C6 cycloalkyl or a C2-C5 heterocycloalkyl, and Ra , R b , R c , and R d are each independently halogen, OH, NH, CN, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkene, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C 10 It is aryl, or 5- to 10-membered heteroaryl.

[0054] Some embodiments relate to compounds having the structure of Formula (I) below, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof:

[0055] [ka] During the ceremony, X 1 are each independently O, S, S(=O), or S(=O)2; R 1 , R 3 , and R 4 are each independently H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, and heteroaryl are each independently selected from one, two, or three R a is optionally replaced by R 2 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-(C3-C6 cycloalkyl), or -NR 5 R 6 wherein alkyl and cycloalkyl are each independently one, two, or three R b is optionally replaced by R 5 and R 6 are each independently H, C1-C6 alkyl, or —C1-C6 alkyl-(C3-C6 cycloalkyl); R 7 are each independently H, halogen, C1-C6 alkyl, or OH; n is independently 1 or 2; X 3 are each independently -NHC(=O)-, -C(=O)NH-, -NHS(=O)2-, -S(=O)2NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, -NHS(=O)2NH-, -NHC(R 1a )(R 1b )-, or -C(R 1a )(R 1b )NH-, A 1 and A 2 are independently C1-C6 alkylene, C3-C 10 Cycloalkylene, C5-C 10 Arylene, C2-C 10 heterocycloalkylene, or 4- to 10-membered heteroarylene, wherein alkyl, cycloalkylene, arylene, heterocycloalkylene, and heteroarylene each independently have one, two, or three R c is optionally replaced by L is -X 5 -(CH2) n1 -Q 1 -(CH2) n2 -X 5 - and X 5 are each independently O, S, or absent; n 1 and n 2 are each independently 0-5, Q 1 is -C1-C6 alkylene-, -C2-C6 alkenylene-, -C2-C6 alkynylene-, -C(O)NH-C1-C6 alkylene-NHC(O)-, -SO2-, -C2-C6 alkynylene-C6-C 10 Arylene, -C2-C6 alkynylene, -C6-C 10 Arylene-C2-C6 alkynylene-, or -C6-C 10 Arylene-C6-C 10Arylene- is alkylene, alkenylene, C2-C6 alkynylene, and C6-C 10 Each arylene independently has one, two, or three R d is optionally replaced by R 1a and R 1b are each independently H, OH, NH, CN, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; R 2a and R 2b are each independently H, OH, NH, CN, C1-C6 alkoxy, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; or R 2a and R 2b together form a C3-C6 cycloalkyl or a C2-C5 heterocycloalkyl, and R a , R b , R c , and R d are each independently halogen, OH, NH, CN, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkene, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6-C 10 aryl, or 5- to 10-membered heteroaryl; However, the compound

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka] isn't it.

[0060] In some embodiments of the compound of Formula (I), each n is 1. In some embodiments of the compound of Formula (I), each n is 2.

[0061] In some embodiments of the compounds of Formula (I), R 7 are each independently H or OH. In some embodiments of the compound of Formula (I), R 7 are H respectively.

[0062] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, have the structure of Formula II:

[0063] [ka]

[0064] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, have the structure of Formula III.

[0065] [ka]

[0066] In some embodiments of compounds of Formula (I), (II), or (III), X 1is S, S(=O), or S(=O)2. In some embodiments of compounds of Formula (I), (II), or (III), X 1 and each is S. In some embodiments of compounds of Formula (I), (II), or (III), X 1 are each O. In some embodiments of compounds of Formula (I), (II), or (III), X 1 are S(=O)2, respectively.

[0067] In some embodiments of compounds of Formula (I), (II), or (III), R 2a and R 2b are each independently H, OH, C1-C6 alkyl, or C2-C6 alkene; or R 2a and R 2b together form a C3-C6 cycloalkyl.

[0068] In some embodiments of compounds of Formula (I), (II), or (III), R 2a and R 2b are each independently OH or a C2-C6 alkene; or R 2a and R 2b together form a C-C cycloalkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 2a or R 2b are each independently H or OH. In some embodiments of compounds of Formula (I), (II), or (III), R 2a is OH. In some embodiments of compounds of Formula (I), (II), or (III), R 2b is H. In some embodiments of compounds of Formula (I), (II), or (III), R 2a is H, and R 2b is OH. In some embodiments of compounds of Formula (I), (II), or (III), R 2a is OH, and R 2b is H. In some embodiments of compounds of Formula (I), (II), or (III), R2a and R 2b are each independently a C1-C6 alkyl or a C2-C6 alkene. In some embodiments of compounds of Formula (I), (II), or (III), R 2a and R 2b are each independently C1-C6 alkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 2a and R 2b are each independently C-C alkenyl. In some embodiments of compounds of Formula (I), (II), or (III), R 2a and R 2b are each independently C-C alkenyl. In some embodiments of compounds of Formula (I), (II), or (III), R 2a and R 2b together form a C-C cycloalkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 2a and R 2b together form a C3-C5 cycloalkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 2a and R 2b together form a C5 cycloalkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 2a and R 2b together form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl. In some embodiments of compounds of Formula (I), (II), or (III), R 2a and R 2b together form cyclopentyl or cyclopentenyl.

[0069] In some embodiments of compounds of Formula (I), (II), or (III), X 3 are each independently -NHC(=O)- or -C(=O)NH-. In some embodiments of compounds of Formula (I), (II), or (III), X 3and X are each -NHC(=O)-. In some embodiments of compounds of Formula (I), (II), or (III), X 3 and X are each -C(=O)NH-. In some embodiments of compounds of Formula (I), (II), or (III), X 3 and X are each -NHS(=O)2-. In some embodiments of compounds of Formula (I), (II), or (III), X 3 are each -S(=O)2NH-. In some embodiments of compounds of Formula (I), (II), or (III), X 3 are each -NHC(=O)NH-. In some embodiments of compounds of Formula (I), (II), or (III), X 3 and X are each -NH(C=O)O-. In some embodiments of compounds of Formula (I), (II), or (III), X 3 and X are each —O(C═O)NH—. In some embodiments of compounds of Formula (I), (II), or (III), X 3 are each -NHS(=O)2NH-. In some embodiments of compounds of Formula (I), (II), or (III), X 3 are -NHC(R 1a )(R 1b )- or -C(R 1a )(R 1b )NH-.

[0070] In some embodiments of compounds of Formula (I), (II), or (III), R 1a and R 1b are each independently H, OH, or C1-C6 alkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 1a and R 1b are each independently H.

[0071] In some embodiments of compounds of Formula (I), (II), or (III), R 1 are each independently H or C1-C3 alkyl. In some embodiments of compounds of Formula (I), (II), or (III), R1 are each H. In some embodiments of compounds of Formula (I), (II), or (III), R 1 are each independently 1, 2, or 3 R a is C1-C6 alkyl independently optionally substituted with

[0072] In some embodiments of compounds of Formula (I), (II), or (III), R 2 are each independently -NR 5 R 6 In some embodiments of compounds of Formula (I), (II), or (III), R 5 and R 6 are each independently H or C1-C6 alkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 2 are each independently -NH2 or -NHCH3.

[0073] In some embodiments of compounds of Formula (I), (II), or (III), R 3 are each independently H or C1-C3 alkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 3 are each independently H or CH. In some embodiments of compounds of Formula (I), (II), or (III), R 3 are each independently H or C2-C3 alkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 3 is CH2CH3. In some embodiments of compounds of Formula (I), (II), or (III), R 3 are each H. In some embodiments of compounds of Formula (I), (II), or (III), R 3 are each independently C1-C6 alkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 3 are each independently C3-C6 cycloalkyl.

[0074] In some embodiments of compounds of Formula (I), (II), or (III), R 4 are each independently H or C1-C3 alkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 4 are each independently H or CH. In some embodiments of compounds of Formula (I), (II), or (III), R 4 are each independently H or C2-C3 alkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 4 is CH2CH3. In some embodiments of compounds of Formula (I), (II), or (III), R 4 are each CH3. In some embodiments of compounds of Formula (I), (II), or (III), R 4 are each H. In some embodiments of compounds of Formula (I), (II), or (III), R 4 are each independently 1, 2, or 3 R a In some embodiments of compounds of Formula (I), (II), or (III), R 4 are each independently 1, 2, or 3 R a In some embodiments of compounds of Formula (I), (II), or (III), R 3 are each independently C1-C3 alkyl, and R 4 are each independently C1-C3 alkyl. In some embodiments of compounds of Formula (I), (II), or (III), R 3 are CH3 and R 4 are CH3 respectively.

[0075] In some embodiments of compounds of Formula (I), (II), or (III),

[0076] [ka] are each independently

[0077] [ka] In some embodiments of the compound of Formula (I), (II), or (III),

[0078] [ka] are each independently

[0079] [ka] In some embodiments of the compound of Formula (I), (II), or (III),

[0080] [ka] are each independently

[0081] [ka] In some embodiments of the compound of Formula (I), (II), or (III),

[0082] [ka] are each independently

[0083] [ka] In some embodiments of the compound of Formula (I), (II), or (III),

[0084] [ka] are each independently

[0085] [ka] is.

[0086] In some embodiments of compounds of Formula (I), (II), or (III), A 1 and A 2 are independently 1, 2, or 3 R c In some embodiments of compounds of Formula (I), (II), or (III), A is C1-C6 alkylene optionally substituted independently with 1 and A 2 are independently 1, 2, or 3 R c C3-C optionally substituted independently with 10 In some embodiments of compounds of Formula (I), (II), or (III), A is cycloalkylene. 1 and A 2 are independently 1, 2, or 3 R c C5-C optionally substituted independently with 10 In some embodiments of compounds of Formula (I), (II), or (III), A is arylene. 1 and A 2 are independently 1, 2, or 3 R c In some embodiments of compounds of Formula (I), (II), or (III), A is a 4-10 membered heterocycloalkylene optionally substituted independently with 1 and A 2 are independently 1, 2, or 3 R c In some embodiments of compounds of Formula (I), (II), or (III), A is a 4-10 membered heteroarylene optionally substituted independently with 1 and A 2 are independently C1-C6 alkylene or C3-C 10 cycloalkylene, where alkylene and cycloalkylene each independently have one, two, or three R c is optionally replaced by

[0087] In some embodiments of compounds of Formula (I), (II), or (III), A 1 and A2 teeth

[0088] [ka] In some embodiments of compounds of Formula (I), (II), or (III), A 1 and A 2 teeth,

[0089] [ka] is.

[0090] In some embodiments of compounds of Formula (I), (II), or (III),

[0091] [ka] teeth,

[0092] [ka] is.

[0093] In some embodiments of compounds of Formula (I), (II), or (III), X 5 are each independently O. In some embodiments of compounds of Formula (I), (II), or (III), X 5 and each is S. In some embodiments of compounds of Formula (I), (II), or (III), each X 5 does not exist.

[0094] In some embodiments of compounds of Formula (I), (II), or (III), n 1 and n 2 are each independently 1 to 3. In some embodiments of compounds of Formula (I), (II), or (III), n 1 and n 2 are each independently 0 to 3. In some embodiments of compounds of Formula (I), (II), or (III), n1 and n 2 are each independently 0 to 2. In some embodiments of compounds of Formula (I), (II), or (III), n 1 and n 2 are each independently 1 to 2. In some embodiments of compounds of Formula (I), (II), or (III), n 1 and n 2 are each independently 1. In some embodiments of compounds of Formula (I), (II), or (III), n 1 and n 2 are each independently 2. In some embodiments of compounds of Formula (I), (II), or (III), n 1 and n 2 are each independently 0.

[0095] In some embodiments of compounds of Formula (I), (II), or (III), Q 1 -C1-C6 alkylene-, -C2-C6 alkynylene-, -C2-C6 alkynylene-C6-C 10 Arylene, -C2-C6 alkynylene, -C6-C 10 Arylene-C2-C6 alkynylene-, or -C6-C 10 Arylene-C6-C 10 arylene-, where alkylene, C-C alkynylene, and C-C 10 Each arylene independently contains one, two, or three R d In some embodiments of compounds of Formula (I), (II), or (III), Q 1 can contain one, two, or three R d is -C2-C6 alkynylene- optionally substituted with

[0096] In some embodiments of compounds of Formula (I), (II), or (III), Q 1 is -C1-C6 alkylene. In some embodiments, Q 1 is -C2-C6 alkenylene. In some embodiments of compounds of Formula (I), (II), or (III), Q1 is -C2-C6 alkynylene. In some embodiments, Q 1 is —C(O)NH—C1-C6 alkylene-NHC(O)—. In some embodiments of compounds of Formula (I), (II), or (III), Q 1 In some embodiments of compounds of Formula (I), (II), or (III), Q 1 -C2-C6 alkynyl-C6-C 10 In some embodiments of compounds of Formula (I), (II), or (III), Q is arylene-. 1 -C2-C6 alkynylene-C6-C 10 In some embodiments of compounds of Formula (I), (II), or (III), Q is arylene-C-C alkynylene. 1 Ha-C6-C 10 Arylene-C6-C 10 In some embodiments of compounds of Formula (I), (II), or (III), Q is arylene. 1 is -C4 alkylene-,

[0097] [ka] , -C(O)NH-(CH2) 1-3 In some embodiments of compounds of Formula (I), (II), or (III), Q is —NHC(O)—, or —SO. 1 teeth,

[0098] [ka] , -C(O)NH-(CH2) 1-3 In some embodiments of compounds of Formula (I), (II), or (III), Q is —NHC(O)—, or —SO. 1 teeth,

[0099] [ka] , -C(O)NH-(CH2) 1-3In some embodiments of compounds of Formula (I), (II), or (III), Q is —NHC(O)—, or —SO. 1 is -C4 alkylene-. In some embodiments of compounds of Formula (I), (II), or (III), Q 1 teeth,

[0100] [ka] In some embodiments of compounds of Formula (I), (II), or (III), Q 1 teeth,

[0101] [ka] In some embodiments of compounds of Formula (I), (II), or (III), Q 1 teeth,

[0102] [ka] In some embodiments of compounds of Formula (I), (II), or (III), Q 1 teeth,

[0103] [ka] In some embodiments of compounds of Formula (I), (II), or (III), Q 1 teeth,

[0104] [ka] In some embodiments of compounds of Formula (I), (II), or (III), Q 1 teeth,

[0105] [ka] In some embodiments of compounds of Formula (I), (II), or (III), Q 1 teeth,

[0106] [ka] In some embodiments of compounds of Formula (I), (II), or (III), Q 1 is -C(O)NH-(CH2) 1-3 In some embodiments of compounds of Formula (I), (II), or (III), Q is —NHC(O)—. 1 is —C(O)NH—(CH 2 ) 2 —NHC(O)—. In some embodiments of compounds of Formula (I), (II), or (III), Q 1 is -SO2-.

[0107] In some embodiments of compounds of Formula (I), (II), or (III), Q 1 teeth,

[0108] [ka] and X 1 is —O—. In some embodiments of compounds of Formula (I), (II), or (III),

[0109] [ka] teeth,

[0110] [ka] In some embodiments of compounds of Formula (I), (II), or (III), R c are each independently C aryl. In some embodiments of compounds of Formula (I), (II), or (III),

[0111] [ka] teeth,

[0112] [ka] is.

[0113] In some embodiments of compounds of Formula (I), (II), or (III), R a , R b , R c , and R d are each independently halogen, OH, NH, CN, C-C alkoxy, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C cycloalkyl, or C-C heterocycloalkyl. In some embodiments of compounds of Formula (I), (II), or (III), R a , R b , R c , and R d are each independently halogen, OH, NH, CN, C-C alkyl, or C-C haloalkyl. In some embodiments of compounds of Formula (I), (II), or (III), R a , R b , R c , and R d are each independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0114] In some embodiments of the compound of Formula (I), (II), or (III), the compound is

[0115] [ka]

[0116] [ka]

[0117] [ka]

[0118] [ka] isn't it.

[0119] In some embodiments of the compound of Formula (I), (II), or (III), the compound is selected from Table A.

[0120] [Table 1-1]

[0121] [Table 1-2]

[0122] [Table 1-3]

[0123] Any combination of the above or below groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0124] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some circumstances, the compounds described herein contain one or more chiral centers, with each center existing in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparation step, combination, or interconversion, are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomer. In some embodiments, separable complexes are preferred. In some embodiments, diastereomers have distinctive physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are recovered with the resolving agent.

[0125] labeled compound In some embodiments, the compounds described herein exist in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering isotopically labeled compounds, such as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein except for the fact that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein, or their solvates or stereoisomers, respectively, include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as Cl. Compounds described herein, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of this disclosure. Certain isotopically labeled compounds, e.g., 3 H and 14 Isotopically labeled compounds, into which radioactive isotopes such as C are incorporated, are useful in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e., 14 The C isotope is particularly preferred because it is easy to prepare and detect. 2Substitution with heavy isotopes such as H may confer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically labeled compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are prepared by any suitable method.

[0126] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0127] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0128] In some embodiments, the compounds described herein possess acidic or basic groups and thus form pharmaceutically acceptable salts by reaction with any of a number of inorganic or organic bases and inorganic and organic acids. In some embodiments, these salts are prepared during the final isolation and purification of the compounds disclosed herein, or in situ by separately reacting the purified compound in free form with a suitable acid or base and isolating the salt thus formed.

[0129] Examples of pharmaceutically acceptable salts include salts prepared by reaction of a mineral, organic acid, or inorganic base with the compounds described herein, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, etc. Salt, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate Included are metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

[0130] Additionally, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like, and organic acids including, but not limited to, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)-2-methyl-2-propanol, ... ) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0131] In some embodiments, these compounds described herein containing free acid groups are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate salt of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Illustrative examples of bases are sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4, etc.

[0132] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is noted that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or dispersible products are obtained by such quaternization.

[0133] solvate In some embodiments, the compounds described herein exist as solvates. The present disclosure provides a method for treating a disease by administering such a solvate. The present disclosure further provides a method for treating a disease by administering such a solvate as a pharmaceutical composition.

[0134] Solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in both solvated and unsolvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0135] tautomers In some circumstances, compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, accompanied by the switching of a single bond and an adjacent double bond. In bond structures that allow tautomerization, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0136] Compound synthesis In some embodiments, synthesis of the compounds described herein is achieved using means described in the chemical literature, using methods described herein, or by a combination thereof. In addition, solvents, temperatures, and other reaction conditions given herein may be varied.

[0137] In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and AcrosOrganics.

[0138] In further embodiments, the compounds described herein, and other related compounds with various substituents, are synthesized using techniques and materials described herein and art-recognized methods, such as those described in the following references: Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989); March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001); and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compounds as disclosed herein may be derived from reactions, which may be modified using appropriate reagents and conditions to introduce the various moieties found in the formulas as provided herein. The following synthetic methods may be used as a guide.

[0139] Synthesis of Compounds of Formula I The synthetic route to the divalent compounds of formula (I) provides access to analogs in a highly stereospecific approach. As shown in Scheme 1, intermediate VII can be prepared and then converted to intermediate X in three steps (Scheme 2). Finally, the preparation of exemplary compounds of formula (I) is completed using the chemistry shown in Scheme 3.

[0140] [ka] (a) LDA, MeI, THF (90%); (b) 2,2-diphenylpropane-1,3-diol, CH2Cl2 (76%); (c) DIBAL-H (60%); (d) CH3NO2, NEt3 (95%); (e) MsCl, NEt3, CH2Cl2 (75%); (f) oxazolidin-2-one 24, tBuOK, 18-crown-6 (70%).

[0141] [ka] (g) 1. NaNO2, CH3COOH, DMSO 2. K2CO3, CH3I, DMF (89% over two steps). (h) Pd / C, MeOH. (i) HOBt, NMM, EDC·HCl, THF (71% over two steps).

[0142] [ka] (j) 1. HCl in dioxane. 2. N-Boc-N-methyl-L-alanine, HOBt, NMM, EDC·HCl, DMF (77%). (k) LiOH, HO, THF (69%). (l) COMU®, DIPEA, THF (69%). (m) HCl in dioxane (88%).

[0143] It is understood that the reactions shown in Schemes 1-3 above are illustrative and further applicable to the synthesis of compounds of Formulas II and III, and such disclosure is contemplated within the scope of the embodiments described herein. The synthesis of compounds of Formulas I, II, and III is also shown in more detail in the Chemical Examples section.

[0144] Administration and Pharmaceutical Compositions In general, the compounds of the present invention are administered in therapeutically effective amounts by any of the approved modes of administration for drugs that serve similar utilities. Therapeutically effective amounts of compounds of Formula I, II, or III may range from about 0.01 to about 500 mg / kg of patient body weight per day, which may be administered in single or multiple doses. Preferably, dosage levels are from about 0.1 to about 250 mg / kg per day, more preferably from about 0.5 to about 100 mg / kg per day. Suitable dosage levels may be from about 0.01 to about 250 mg / kg per day, from about 0.05 to about 100 mg / kg per day, or from about 0.1 to about 50 mg / kg per day. Within this range, dosages may be from about 0.05 to about 0.5 mg / kg per day, from about 0.5 to about 5 mg / kg, or from about 5 to about 50 mg / kg per day. For oral administration, the composition is preferably provided in the form of a tablet containing about 1.0 to about 1000 milligrams of active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient. The actual amount of a compound of the invention, i.e., active ingredient, will depend on many factors, such as the severity of the disease being treated, the age and relative health of the subject, the potency of the compound utilized, the route and form of administration, and other factors.

[0145] Generally, the compounds of the present invention are administered as pharmaceutical compositions by one of the following routes: oral, systemic (e.g., intranasal, suppository, intrapulmonary), or parenteral (e.g., intramuscular, intravenous, intrathecal, or intraperitoneal) administration.The preferred method of administration is oral administration, using a convenient daily dosage regimen that can be adjusted according to the severity of the affliction.The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, liposome, exosome, nanoparticle, or any other suitable composition.

[0146] The choice of formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills, or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed, particularly for drugs exhibiting low bioavailability, based on the principle that increasing the surface area, i.e., decreasing particle size, can enhance bioavailability. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles ranging in size from 10 to 1,000 nm in which the active material is supported in a crosslinked polymer matrix. U.S. Patent No. 5,145,684 describes the production of a pharmaceutical formulation exhibiting significantly higher bioavailability by milling a drug substance into nanoparticles (average particle size 400 nm) in the presence of a surface modifier and then dispersing the nanoparticles in a liquid medium.

[0147] The compositions generally comprise a compound of Formula I, II, or III in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid in administration, and do not adversely affect the therapeutic effect of the compound of Formula I, II, or III. Such excipients may be any solid, liquid, semi-solid, or, in the case of aerosol compositions, gaseous excipients commonly available to those skilled in the art.

[0148] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, nonfat dry milk, etc. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0149] Compressed gases may be used to disperse the compounds of the invention in aerosol form. Suitable inert gases for this purpose include nitrogen, carbon dioxide, and the like.

[0150] Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000).

[0151] The level of the compound in the formulation can vary within a range acceptable to those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, about 0.01 to 99.99 wt% of the compound of Formula I, II, or III, based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1 to 80 wt%.

[0152] The compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention or other drugs may be useful, where the combination of drugs is safer or more effective than either drug alone. Such other drugs may be administered simultaneously or sequentially with the compounds of the present invention by commonly used routes and amounts. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compounds of the present invention is preferred. However, combination therapy may also include treatment in which the compounds of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used alone.

[0153] Accordingly, the pharmaceutical compositions of the present invention further include those that contain one or more other active ingredients, in addition to a compound of the present invention.

[0154] The above combinations include combinations of compounds of the present invention with not only one other active compound but also two or more other active compounds. Similarly, compounds of the present invention may be used in combination with other drugs used in the prevention, treatment, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered simultaneously or sequentially with the compounds of the present invention by a route and in an amount commonly used therefor. When a compound of the present invention is used concurrently with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Thus, pharmaceutical compositions of the present invention also include those containing one or more other active ingredients in addition to the compound of the present invention. The weight ratio of the compound of the present invention to the second active ingredient may vary and depends on the effective amount of each ingredient. Generally, an effective amount of each is used.

[0155] If the patient's condition improves, at the discretion of the physician, administration of the compounds described herein can optionally be continued, or the administered drug dose can be temporarily reduced or temporarily discontinued for a specified period of time (i.e., a drug holiday). The length of the drug holiday is optional and can vary from 2 days to 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during drug holidays include, by way of example only, 10% to 100%, including 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0156] Once improvement of the patient's condition occurs, a maintenance dose is administered as needed. Thereafter, the dosage or frequency of administration, or both, may be reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. In some embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0157] Combination therapy In some cases, the compound described herein is administered in combination with another anticancer agent.The example of the anticancer agent that can be used in combination with the compound of Formulas I, II or III includes mitogen-activated protein kinase signaling inhibitor, for example, U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY43-9006, wortmannin or LY294002; Syk inhibitor; mTOR inhibitor; and antibody (for example, Rituxan).

[0158] Other anticancer agents that may be employed in combination with the compounds of Formula I, II, or III include adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacytidine; azetepa; aztomycin; batimastat; benzodepa; bicalutamide; hydrochloride Bisantrene; Bisnafide dimesylate; Biceresin; Bleomycin sulfate; Brequinar sodium; Bropirimine; Busulfan; Cactinomycin; Calsterone; Caracemide; Carvetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carzelesin; Cedefingal; Chlorambucil; Ciloremycin; Cladribine; Crisnatol mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin hydrochloride; Decitabine; Dextromaplatin; Dezaguamine; Dezaguamine Diaziconazole mesylate; Diazicon; Doxorubicin; Doxorubicin hydrochloride; Droloxifene; Droloxifene citrate; Dromostanolone propionate; Duazomycin; Edatrexate; Eflornithine hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropizine; Epirubicin hydrochloride; Elbrozole; Esorubicin hydrochloride; Estramustine; Estramustine phosphate sodium; Etanidazole; Etoposide; Etoposide phosphate; Etoprine; Fadrozole hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fluda phosphate Rabin; fluorouracil; fluroocitabine; foskidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; irmofosine; interleukin II (including recombinant interleukin II, i.e., rIL2); interferon alpha-2a; interferon alpha-2b; interferon alpha-n1; interferon alpha-n3; interferon beta-1a; interferon gamma-1b; iproplatin; irinotecan hydrochloride; lanreotide acetate;Letrozole; Leuprolide acetate; Liarozole hydrochloride; Lometrexol sodium; Lomustine; Losoxantrone hydrochloride; Masoprocol; Maytansine; Mechlorethamine hydrochloride; Megestrol acetate; Melenguesrol acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocalcin; Mitochromin; Mitoziline; Mitomarcin; Mitomycin; Mitospel; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogalamycin; Ormaplatin; Oxislan; Pegaspargase; Periomycin; Pentamustine; Peplomycin sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone hydrochloride; Plicamycin; Promestane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pirazofurin; Ribopurin; Rogreti Mido; Safingol; Safingol hydrochloride; Semustine; Simtrazene; Sparfosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Surofenal; Tallysomycin; Tecogalan sodium; Tegafur; Teroxantrone hydrochloride; Temoporfin; Teniposide; Teloxylon; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Tolemipirimidazole citrate Contains phen; trestron acetate; tricibirine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tuburozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglisinate sulfate; vinleurodine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzoquidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride;

[0159] Other anticancer agents that may be employed in combination with the compounds of Formula I, II, or III include 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adzelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1 (anti-dorsalizing morphogenetic protein-1). protein-1); antiandrogens, prostate cancer; antiestrogens; antineoplastons; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulaculin; atamestane; atlimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxins; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists Antiagonists; Benzochlorins; Benzoylstaurosporines; Beta-lactam derivatives; Beta-arretin; Betaclamycin B; Betulinic acid; bFGF inhibitors; Bicalutamide; Bisantrene; Bisaziridinylspermine; Biansafide; Bistraten A; Biceresin; Breflate; Bropirimine; Budotitane; Buthionine sulfoximine; Calcipotriol; Calphostin C; Camptothecin derivatives; Canaripox IL-2; Capecitabine; Carboxamido-amino-triazoles; Carboxamidotriazoles; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorin; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomiphene analogs; clotrimazole; colismycin A; colismycin B; combretastatin A4; combretastatin analogs; conagenin; crambescidin 816;Crisnatol; Cryptophycin 8; Cryptophycin A derivatives; Curacin A; Cyclopentylchinoside; Cycloplatin; Sipemycin; Cytarabine ocfosfate; Cytotoxic factors; Cytostatin; Daclizumab; Decitabine; Dehydrodidemin B; Deslorelin; Dexamethasone; Dexphosphamide; Dexrazoxane; Dexverapamil; Diazicon; Dididemin B; Didox; Diethylnorspermine; Dihydro-5-azacytidine; 9-dioxamycin; Diphenylspiromustine; Docosanol; Dolasetron; Doxifluri Gin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogs; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride (fmasteride); flavopiridol; frezelastine; fluasterone; fludarabine; fluorouracil hydrochloride Daunorhynchus; Forfenimex; Formestane; Fostriecin; Fotemustine; Gadolinium texapyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitors; Gemcitabine; Glutathione inhibitors; Hepsulfam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifene; Idramantone; Ilmofosine; Ilmostat; Imidazoacridone; Imiquimod; Immunostimulant peptides; Insulin-like growth factor-1 receptor inhibitors; Interleukin-1 -Interferon agonists; Interferons; Interleukins; Iobenguane; Iododoxorubicin; Ipomeanol, 4-; Ilopract; Irsogladine; Isobengazole; Isohomohalichondrin B; Itasetron; Jasplakinolide; Kahalalide F; Lamellarin-N triacetate; Lanreotide; Leinamycin; Lenograstim; Lentinan sulfate; Leptolstatin; Letrozole; Leukemia inhibitory factor; Leukocyte alpha interferon; Leuprolide + estrogen + progesterone; Leuprorelin; Levamisole; Liarozole;Linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; liclinamide (lissoclinamide); lobaplatin; lombricin; lometerexol; lonidamine; losoxantrone; lovastatin; loxolibine; lurtotecan; lutetium texaphyrin; lisofylline; cytolytic peptides; maytansine; mannostatin A; marimastat; massoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; mervalone; metalarelin; methioninase; metoclopramide; MI F inhibitors; mifepristone; miltefosine; millimostim; incompatible double-stranded RNA; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofalotene; molgramostim; monoclonal antibodies (human placental gonadotropin); monophosphoryl lipid A + myobacterial cell wall sk; mopidamol; multidrug resistance gene inhibitors; multiple tumor suppressor gene 1-based therapy; mustard anticancer drugs; mycaloxide B; mycobacterial cell wall extract; miriaporone; n- Acetyldinaline; N-substituted benzamides; Nafarelin; Nagressip; Naloxone + pentazocine; Napavine; Nafterpine; Nartograstim; Nedaplatin; Nemorubicin; Neridronic acid; Neutral endopeptidases; Nilutamide; Nisamycin; Nitric oxide modulators; Nitroxide antioxidants; Nitrulline; O6-benzylguanine; Octreotide; Oxenone; Oligonucleotides; Onapristone; Ondansetron; Ondansetron; Oracin; Oral cytokinin inducers; Ormaplatin; Osateron; Oxaliplatin rhizoxin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomyphen; parabactin; pazelliptin; pegaspargase; perdecin; pentosan polysulfate sodium; pentostatin; pentrolozole; perflubron; perfosfamide; peryl alcohol; phenazinomycin; phenyl acetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; prasetin A; prasetin B; plasminogen activator inhibitors; platinum complexes; platinum compounds;Platinum-triamine complexes; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; protein kinase C inhibitors, microalgae; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridines; pyridoxylated hemoglobin polyoxyethylene conjugates; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; demethylated reterliptin; rhenium Re 186 Etidronate; Rhizoxin; Ribozyme; R11 retinamide; Rogletimide; Rohitucin; Romurtide; Roquinimex; Rubiginone B1; Ruboxil; Safingol; Saintopin; SarCNU; Sarcophytol A; Sargramostim; Sdi1 mimetic; Semustine; Senescence derived 1; Sense oligonucleotide; Signal transduction inhibitor; Signal transduction modulator; Single-chain antigen binding protein; Sizofiran; Sobuzoxane; Borocaptate sodium; Sodium phenylacetate; Soberol; Somatomedin binding protein; Sonermin; Sparfosic acid; Spicamycin D; Spiromustine; Splenopentin; Spongestatin 1; Squalamine; Stem cell inhibitor; Stem cell division inhibitor; Stipiamide; Stromelysin inhibitor; Sulfinodine; Superactive vasoactive intestinal peptide antagonist; Sladista; Suramin; Swainsonine; Synthetic Glycosaminoglycans; Talimustine; Tamoxifen methiodide; Tauromustine; Tazarotene; Tecogalan sodium; Tegafur; Telluropyrylium; Telomerase inhibitors; Temoporfin; Temozolomide; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Talicarpine; Thiocoraline; Thrombopoietin; Thrombopoietin mimetics; Thymalfasin; Thymopoietin receptor agonists; Thymotrin; Thyroid-stimulating hormone; Tin ethyl etioproprine; Tirapazamine; Titanocene dichloride; Topsentin; Toremifene; Totipotent stem cell factor; Translation inhibitors; Tretinoin;Triacetyluridine; tricibirine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitors; urokinase receptor antagonists; vapreotide; variolin B; vector-based, erythrocyte gene therapy; veraresol; veramine; verdins; verteporfin; vinorelbine; vinxartin; vitaxin; vorozole; zanoteron; zeniplatin; zilascorub; and zinostatin stimalamer.

[0160] Still other anticancer agents that can be employed in combination with the compounds of Formula I, II, or III include alkylating agents, antimetabolites, natural products, or hormones, such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., bursufane), nitrosoureas (e.g., carmustine, lomustine, etc.), or triazenes (e.g., dacarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0161] Examples of natural products useful in combination with compounds of Formula I, II, or III include, but are not limited to, vinca alkaloids (e.g., vinblastine, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).

[0162] Examples of alkylating agents that can be employed in combination with the compounds of Formula I, II, or III include nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethylenimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., bursufane), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (e.g., decarbazine, etc.). Examples of antimetabolites include, but are not limited to, folic acid analogs (e.g., methotrexate) or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[0163] Examples of hormones and antagonists useful in combination with the compounds of Formula I, II, or III include, but are not limited to, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), gonadotropin-releasing hormone analogs (e.g., leuprolide). Other agents that can be used in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthracenediones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical suppressants (e.g., mitotane, aminoglutethimide).

[0164] Examples of anti-cancer agents that act by arresting cells in the G2M phase by stabilizing microtubules and that can be used in combination with irreversible EGFR tyrosine kinase inhibitor compounds include, but are not limited to, the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mibobulin Isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296), ABT-751. (Abbott, also known as E-7010), Altorhyrtins (also known as Altrilutin A and Altrilutin C), Spongistatins (also known as Spongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (Epothilone A, Epothilone B, Epothilone C (also known as Desoxyepothilone A or dEpoA), Epothilone D (KOS-862, also known as Desoxyepothilone B), Epothilone E, Epothilone F, Epothilone B N-oxide, epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as desoxyepothilone F and dEpoF), 26-fluoroepothilone), auristatin PE (also known as NSC-654663), sobridotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF ILX-651 and LU-223651), SAH-49960 (Lilly / Novartis), SDZ-268970 (Lilly / Novartis), AM-97 (Armad / Kyowa Hakko), AM-132 (Armad), AM-138 (Armad / Kyowa Hakko), IDN-5005 (Indena), cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A), vitilevuamide, tubulysin A, canadensol, centaureydin (also known as NSC-106969), T-138067 (Tularik; also known as T-67, TL-138067, and TI-138067), COBRA-1 (Parker Hughes Institute; also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B. laurimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute)Institute; also known as SPIKET-P), 3-IAABU (Cytoskeleton / Mt. Sinai School of Medicine; also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterin, 3-BAABU (Cytoskeleton / Mt. Sinai School of Medicine; also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (also known as NSC-698666), 3-1AABE (Cytoskeleton / Mt. Sinai School of Medicine, A-204197 (Abbott), T-607 (Tuiarik; also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as desmethyleleutherobin, desaetyleleutherobin, isoeleutherobin A and Z-eleutherobin), caribaeolin, halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-),-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (AstaMedica), myoseverin B, D-43411 (Zentaris; also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (SPA-110, also known as trifluoroacetate) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), resverastatin sodium phosphate, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

[0165] In some cases, the compounds described herein (e.g., compounds of Formula I, II, or III) are administered in combination with TNF-alpha and / or TNF-related apoptosis-inducing ligand (TRAIL). TRAIL is homologous to other members of the TNF-alpha family of proteins. In some cases, the compounds described herein (e.g., compounds of Formula I, II, or III) are administered in combination with TNF-alpha modulators and / or TNF-alpha analogs (e.g., lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID), thalidomide, etc.). In some cases, the compounds described herein (e.g., compounds of Formula I, II, or III) are administered in combination with adjuvants, hormonal therapy agents, immunotherapy agents, or any combination thereof.

[0166] In some cases, the compounds described herein are administered in combination with antiretroviral therapy (ART). Examples of antiretroviral therapy (ART) for use in combination with the compounds of Formula I, II, or III include Combivir, Kaletra, Aluvia, Trizivir, Epzicom, Kybexa, Triomune, Duovir-N, Truvada, Atripla, Complela, Eviplera, Stribild, Triumeq, Evotaz, Prezicovix, Rezolsta, Dutrebis, Genvoya, Odefci, Descovy, Jarka, Symfi, Symfi Lo, Biktarvy, Cimduo, Simtuza, Delstrigo, and Dovate.

[0167] In some cases, the compounds described herein are administered in combination with a latency reactivator (LRA), with or without antiretroviral therapy (ART). Examples of latency reactivators (LRAs) for use in combination with the compounds of Formula I, II, or III include histone deacetylase inhibitors (HDACi), bromodomain and extraterminal domain inhibitors (BETi), protein kinase C (PKC) agonists, activators of transcription elongation factor b (P-TEFb), Toll-like receptor (TLR) agonists, immune checkpoint inhibitors, tetraethylthiuram disulfide (disulfiram), benzotriazole derivatives, quinolines, cytokines, methyltransferase inhibitors, and methylation inhibitors.

[0168] In some cases, the compounds described herein are administered in combination with killer agents, CarT, immunotherapeutic agents, neutralizing antibodies, or other agents. Additional latency reactivation agents are described in Stoszko et al., Curr Opin Virol. 2019 Jul 16; 38:37-53, which is incorporated herein by reference for disclosure purposes.

[0169] How to use In certain embodiments, disclosed herein are methods of inhibiting the activity of an inhibitor of apoptosis (IAP) protein in an individual, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein. In some embodiments, the IAP protein is XIAP, cIAP-1, cIAP-2, ML-IAP, survivin, NAIP, apollon, ILP2, or any combination thereof.

[0170] Provided herein are methods of treating a hyperproliferative disorder in an individual, the methods comprising administering to an individual in need thereof a therapeutically effective amount of any one of the compounds described herein.

[0171] In some such embodiments, the hyperproliferative disorder is cancer or an autoimmune disease.

[0172] In some such embodiments, the autoimmune disease is hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac disease, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft-versus-host disease, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, or vitiligo.

[0173] Provided herein are methods of treating cancer in an individual, the methods comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of Formulas I, II, or III.

[0174] In some embodiments, the cancer is an epithelial cancer, carcinoma, neoplasm, sarcoma, chondrosarcoma, blastoma, cancer of the central nervous system, or cancer of the blood. In some embodiments, the cancer is an epithelial cancer or carcinoma. In some embodiments, the cancer is a neoplasm or sarcoma or chondrosarcoma or blastoma or cancer of the central nervous system. In some embodiments, the cancer is a cancer of the blood.

[0175] Also provided herein is a method of treating an angiogenesis-related disease in an individual, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of the formulae described herein.

[0176] In some embodiments, the disease associated with angiogenesis is macular degeneration, rheumatoid arthritis, psoriasis, diabetic retinopathy, retinopathy of prematurity, corneal transplant rejection, neovascular glaucoma, retrolental fibroplasia, skin flushing, Osler-Webber syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophilic joints, angiofibroma, wound granulation, intestinal adhesions, atherosclerosis, scleroderma, or hypertrophic scarring.

[0177] Also provided herein is a method of inhibiting the activity of an inhibitor of apoptosis (IAP) protein in an individual, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of any one of the formulas described herein.

[0178] In some embodiments, the IAP protein is XIAP, cIAP-1, cIAP-2, ML-IAP, survivin, NAIP, apollon, or ILP2.

[0179] Also provided herein are methods for inducing apoptosis in cells, comprising contacting a cell with a therapeutically effective amount of a compound of any one of the formulas described herein. In some such embodiments, the compound of any one of the formulas described herein binds to the XIAP BIR3 domain and thus antagonizes the action of IAP.

[0180] In some embodiments, inhibition of IAP protein activity causes apoptosis of multiple cells. In some embodiments, the cells are cancer cells. In some embodiments, the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or a combination thereof. In some embodiments, the cancer is skin cancer, lung cancer, breast cancer, prostate cancer, colon cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combination thereof. In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is esophageal squamous cell carcinoma. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer or small cell lung cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer.

[0181] In some embodiments, the cancer is a cancer of the oral cavity and pharynx. In some embodiments, the cancer is a cancer of the tongue, mouth, pharynx, or other oral cavity cancer. In some embodiments, the cancer is a cancer of the digestive system. In some embodiments, the cancer is esophageal cancer, stomach cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, anal canal cancer, anorectal cancer, liver cancer, intrahepatic bile duct cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, or other digestive tract cancer. In some embodiments, the cancer is a cancer of the respiratory system. In some embodiments, the cancer is laryngeal cancer, lung cancer, bronchial cancer, or other respiratory tract cancer. In some embodiments, the cancer is skin cancer. In some embodiments, the cancer is cutaneous melanoma or other non-epithelial skin cancer.

[0182] In some embodiments, the cancer is a cancer of the reproductive system selected from the uterine corpus, cervix, uterine corpus, ovary, vulva, vagina, other female genitalia, prostate, testicles, penis, and other male genitalia. In some embodiments, the cancer is a cancer of the urinary system selected from the bladder, kidney, renal pelvis, ureter, and other urinary organs. In some embodiments, the cancer is a cancer of the endocrine system selected from the thyroid and other endocrine glands. In some embodiments, the cancer is a cancer of the blood. In some embodiments, the cancer is Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, or other leukemia.

[0183] In some embodiments, inhibiting the activity of an IAP protein treats a hyperproliferative disorder. In some embodiments, the hyperproliferative disorder is cancer or an autoimmune disease. In some embodiments, the autoimmune disease is hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac disease, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibrositis, graft-versus-host disease, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, or vitiligo. In some embodiments, the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or a combination thereof. In some embodiments, the cancer is skin cancer, lung cancer, breast cancer, prostate cancer, colon cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combination thereof. In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is esophageal squamous cell carcinoma. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer or small cell lung cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer.

[0184] In some embodiments, disclosed herein are methods of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein. In some embodiments, the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or a combination thereof. In some embodiments, the cancer is skin cancer, lung cancer, breast cancer, prostate cancer, colorectal cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combination thereof. In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is esophageal squamous cell carcinoma. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer or small cell lung cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer.

[0185] In certain embodiments, disclosed herein are methods for treating a disease associated with unwanted angiogenesis in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a compound disclosed herein. In some embodiments, the disease associated with unwanted angiogenesis is macular degeneration, rheumatoid arthritis, psoriasis, diabetic retinopathy, retinopathy of prematurity, corneal transplant rejection, neovascular glaucoma, retrolental fibroplasia, skin flushing, Osler-Webber syndrome, myocardial angiogenesis, plaque angiogenesis, telangiectasia, hemophilic joints, angiofibroma, scar granulation, intestinal adhesions, atherosclerosis, scleroderma, or hypertrophic scarring. In some embodiments, the disease associated with unwanted angiogenesis is cancer. In some embodiments, the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or a combination thereof. In some embodiments, the cancer is skin cancer, lung cancer, breast cancer, prostate cancer, colorectal cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combination thereof. In some embodiments, the cancer is acute myeloid leukemia (AML). In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is renal cell carcinoma. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is esophageal squamous cell carcinoma. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer or small cell lung cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is breast cancer.

[0186] Some embodiments relate to methods of reactivating human immunodeficiency virus (HIV) latency in a mammal, comprising administering to an individual a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer. In some embodiments, HIV latency is reactivated without T cell activation.

[0187] Chemical Examples The following examples are intended to illustrate, but not limit, the disclosed embodiments. All solvents were used as purchased from commercial sources or, in the case of moisture-sensitive reactions, dried over 4 Å molecular sieves prior to use. Reactions performed under microwave irradiation were carried out in a CEM Discover microwave reactor using either a CEM 10 mL reaction vessel or a ChemGlass thick-walled pressure vessel (100 mL, 38 mm x 190 mm). Reaction progress was monitored by reverse-phase HPLC and / or thin-layer chromatography (TLC). High-resolution mass spectrometry was performed using ESI-TOFMS, EI-MS (reference: perfluorokerosene), and APCI-MS. TLC was performed using silica gel 60 F254 pre-coated plates (0.25 mm). Flash chromatography was carried out using silica gel (32-63 μm particle size) or aluminum oxide (activated, basic, ~150 mesh size). All products were purified to homogeneity by TLC analysis (single spot unless otherwise stated) using a UV lamp, and / or iodine, and / or CAM or basic KMnO4 for detection purposes. NMR spectra were recorded on 400 MHz and 500 MHz spectrometers at ambient temperature. 1 H and 13C NMR chemical shifts are reported as δ using residual solvent as internal standard; CDCl: 7.26, 77.16 ppm; CDOD: 3.31, 49.00 ppm; DMSO-D: 2.50, 39.52 ppm, CDCN: 1.94 (H), 1.32 (C) ppm. The following abbreviations were used: alanine (Ala), 1-hydroxybenzotriazole (HOBT), N-methylmorpholine (NMM), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), palladium on carbon (Pd-C), dichloromethane (DCM), diethyl ether (EtO), ethyl acetate (EtOAc), 2,2,2-trifluoroethanol (TFE), methanol (MeOH), homoserine (HSer), tetrahydrofuran (THF), trifluoroacetic acid (TFA), and diisobutylaluminum hydride (DIBAL).

[0188] [ka]

[0189] The boc-protected compound was treated with HCl (4 M, 40.0 equiv.) in dioxane and stirred at room temperature for 2 h. After completion, all volatiles were removed under reduced pressure. The residue was washed with diethyl ether on a fritted funnel and dried under reduced pressure.

[0190] [ka]

[0191] Under a N atmosphere, N-ethyl-N-(propan-2-yl)propan-2-amine (5.00 equiv.) and COMU® (2.50 equiv.) were added to a solution of carboxylic acid (2.10 equiv.) dissolved in dry THF (287 equiv.) and stirred at room temperature. After 45 min, diamine dihydrochloride (1.00 equiv.) was added and stirring was continued for 20–23 h. Upon completion, ethyl acetate (30 mL) was added and washed with NaOH solution (1 M, 2 × 10 mL), HCl solution (1 M, 2 × 10 mL), water (10 mL), and brine (10 mL), dried (NaSO), and concentrated in vacuo. The resulting residue was purified by fc (hexanes / ethyl acetate) to give 17a-m.

[0192] Synthetic scheme for the preparation of (di)amine 6a described below

[0193] [ka]

[0194] Example 1. Preparation of tert-butyl (1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-ylcarbamate (2)

[0195] [ka]

[0196] Compound 2 was prepared according to established literature procedures; Abdur-Rashid, K.; Guo, R.; Chen, X.; Jia, W. Application: see WO 2008148202 A1.

[0197] Example 2. Preparation of tert-butyl [(1S,2R)-2-(prop-2-yn-1-yloxy)-2,3-dihydro-1H-inden-1-yl]carbamate (3)

[0198] [ka]

[0199] Under a N2 atmosphere, alcohol 2 (2.50 g, 10.0 mmol, 1.00 equiv) was dissolved in dry DMF (20.0 mL) and the solution was cooled to 0 °C. Propargyl bromide in toluene (80%, 1.34 mL, 12.0 mmol, 1.20 equiv) was added. The resulting solution was treated portionwise with powdered KOH (1.15 g, 420.6 mmol, 2.05 equiv), and stirring was continued at 0 °C. After 1.5 h, water (40 mL) was added, and the resulting mixture was extracted with ethyl acetate (4 × 40 mL). The combined organic layers were washed with water (2 × 40 mL) and brine (20 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by FC (hexane / ethyl acetate). Colorless solid, yield 2.29 g (79%). 1 H NMR(400MHz,CDCl3):δ(ppm)=1.51(s,9H,C(CH3)3),2.43(t,1H),3.02(dd,1H),3.09(dd,1H),4.22( dd,2H),4.48(dq,1H),5.03-5.27(m,2H),7.19-7.25(m,3H),7.30-7.35(m,1H).LC-MS:m / z=287.90.

[0200] Example 3. Preparation of (1S,2R)-2-(prop-2-yn-1-yloxy)-2,3-dihydro-1H-indene-1-ammonium chloride (4)

[0201] [ka]

[0202] Carbamate 3 (100 mg, 0.348 mmol, 1.00 equiv) was treated with HCl in dioxane (4 M, 2.61 mL, 10.4 mmol, 30.0 equiv) at room temperature. After 2 h, all volatiles were removed under reduced pressure, and the residue was transferred onto a fritted funnel and washed with EtO. The remaining product was dried under reduced pressure. Colorless solid, yield 71 mg (91%). 1H NMR(400MHz,DMSO-D6):δ(ppm)=3.07-3.20(m,2H),3.55(t,1H),4.29-4.39(m,2H),4.51(q,1H ),4.71(s,1H),7.25-7.36(m,3H),7.60(d,1H),8.61(s,3H).LC-MS:m / z=188.05(calcd.188.11 for C 12 H 14 NO + [M+H + ]).

[0203] Example 4. Preparation of tert-butyl N-[(1S,2R)-2-[(6-{[(1S,2R)-1-{[(tert-butoxy)carbonyl]amino}-2,3-dihydro-1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamate (5a)

[0204] [ka]

[0205] Copper(II) acetate hydrate (216 mg, 1.08 mmol, 1.15 equiv) was added to a solution of alkyne 4 (270 mg, 0.940 mmol, 1.00 equiv) and pyridine (450 μL, 5.58 mmol, 5.94 equiv) in acetonitrile (8.5 mL). The resulting mixture was placed in a preheated oil bath at 80 °C. After 1 h, the reaction mixture was cooled to room temperature and concentrated in vacuo. Aqueous NH OH (3%, 10 mL) was added to the residue and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL). The brine layer was extracted with ethyl acetate (2 × 10 mL), and the combined organic layers were dried (Na SO ) and concentrated in vacuo. The residue was purified by fc(cyclohexane / ethyl acetate). Colorless solid, yield 166 mg (62%). R f =0.55 (hexane / ethyl acetate 8:2). 1H NMR (400MHz, CDCl3): δ(ppm)=1.51(s,18H),2.98-3.11(m,4H),4.30(s,4H),4.45(q,2H) ,4.99-5.25(m,4H),7.22(dd,6H),7.30-7.34(m,2H).LC-MS:m / z=573.25(calcd.573.30 for C 34 H 41 N2O6 + [M+H + ]), 595.25(calcd.595.28 for C 34 H 40 N2NaO6 + [M+Na + ]).

[0206] Example 5. Preparation of (1S,2R)-2-[(6-{[(1S,2R)-1-ammonio-2,3-dihydro-1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-indene-1-ammonium dichloride (6a)

[0207] [ka]

[0208] Compound 6a was prepared according to the general procedure. Colorless compound, yield 99 mg (95%). 1 H NMR(400MHz,DMSO-D6):δ(ppm)=3.08-3.19(m,4H),4.47-4.58(m,6H),4.72(t,2H) ),7.23-7.39(m,6H),7.60(d,2H),8.66(s,6H).LC-MS:m / z=373.00(calcd.373.19 for C 24 H 25 N2O2 + [M+H + ]), 187.05(calcd.187.10 for C 24 H 26 N2O2 2+ [M+2H + ]).

[0209] Synthetic scheme for the preparation of dimer 18a and monomer 16

[0210] [ka]

[0211] Example 6. Preparation of 4,4-dimethoxy-2,2-dimethylbutanal (8)

[0212] [ka]

[0213] Compound 8 was prepared according to established literature procedures; Vamos, M.; Welsh, K.; Finlay, D.; Lee, PS; Mace, PD; Snipas, SJ; Gonzalez, ML; Ganji, SR; Ardecky, RJ; Riedl, Stefan J.; Salvesen, GS; Vuori, K.; Reed, JC; Cosford, ND, see ACS Chem. Biol. 2013, 8, 725-732.

[0214] Example 7. Preparation of 1-(2,2-dimethoxyethyl)-2-isocyanobenzene (9)

[0215] [ka]

[0216] Isocyanide 9 was prepared according to established literature procedures; see Gilley, Cynthia B.; Buller, MJ; Kobayashi, Y. Org. Lett. 2007, 9(18), 3631-3634.

[0217] Example 8. Preparation of tert-butyl [(2S)-1-{[(4S,7S,9aS)-7-(1H-indole-1-carbonyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (13)

[0218] [ka]

[0219] A mixture of N-(tert-butoxycarbonyl)-S-trityl-L-homocysteine (1.34 g, 2.80 mmol, 1.00 equiv.), 4,4-dimethoxy-2,2-dimethylbutanal 8 (471 mg, 2.94 mmol, 1.05 equiv.), 1-(2,2-dimethoxyethyl)-2-isocyanobenzene 9 (616 mg, 3.22 mmol, 1.15 equiv.), and NH in MeOH (7 M, 800 μL, 5.60 mmol, 2.00 equiv.) in 2,2,2-trifluoroethanol (2.1 mL) was stirred under microwave irradiation at 80° C. After 20 min, all volatiles were removed under reduced pressure.

[0220] The residue was treated with HCl (4 M, 7.00 mL, 28.0 mmol, 10.0 equiv) in dioxane at 40° C. for 2.5 h. After removing all volatiles, the residue was dissolved in ethyl acetate (150 mL) and washed with NaOH (1 M, 30 mL), water (30 mL), and brine (30 mL). The organic solvent was dried (NaSO) and removed under reduced pressure.

[0221] The amine, N-(tert-butoxycarbonyl)-N-methyl-L-alanine (683 mg, 3.36 mmol, 1.20 equiv.), 1-hydroxybenzotriazole hydrate (623 mg, 3.64 mmol, 1.30 equiv.), and N-methylmorpholine (926 μL, 8.40 mmol, 3.00 equiv.) were dissolved in dry THF (10 mL) and cooled to 0 °C. EDC·HCl (698 mg, 3.64 mmol, 1.30 equiv.) was added. After stirring at 0 °C for 30 min, stirring was continued at room temperature for 16 h. All volatiles were removed in vacuo, and the residue was dissolved in ethyl acetate (100 mL). The organic layer was washed with NaOH solution (1 M, 50 mL), HCl solution (1 M, 50 mL), water (50 mL), and brine (20 mL), dried (NaSO), and concentrated in vacuo. The residue was purified by fc(cyclohexane / ethyl acetate).

[0222] Isomer 1: Yellow solid, yield 214 mg (14%). f =0.47 (hexane / ethyl acetate 5:5).

[0223] Isomer 2: Yellow solid, yield 254 mg (17%). f =0.20 (hexane / ethyl acetate 5:5). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.02(s,3H),1.24-1.26(m,3H),1.33(d,3H),1.43( s,9H),1.96(q,1H),2.25-2.33(m,3H),2.75(s,3H),2.90(ddd,1H),3.30(ddd,1H ),4.61(dd,1H),4.71(s,broad,1H),5.09(s,1H),5.26(t,1H),6.70(d,1H),7.27 -7.37(m,3H),7.55-7.59(m,2H),8.57(d,1H).LC-MS:m / z=565.26(calcd.565.25 for C 28 H 38 N4NaO5S + [M+Na + ]).

[0224] Example 9. Preparation of (4S,7S,9aS)-4-({(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoyl}amino)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (14a)

[0225] [ka]

[0226] Indole amide 13 (130 mg, 0.240 mmol, 1.00 equiv) was dissolved in methanol (3.0 mL) and aqueous NaOH (1 M, 1.20 mL, 1.20 mmol, 5.00 equiv) was added. The resulting mixture was stirred at 32 °C for 5 h, after which the methanol was removed in vacuo. NaOH solution (1 M, 30 mL) and brine (10 mL) were added and washed with ethyl acetate (3 × 10 mL). The aqueous layer was acidified to pH ≤ 2 with HCl solution (3 M) and extracted with CHCl (2 × 20 mL, 1 × 10 mL). The combined CHCl layers were dried (NaSO) and concentrated in vacuo. The residue was purified by fc (cyclohexane / ethyl acetate with 1% HCOOH). Colorless solid, yield 56 mg (53%). R f = 0.52 (hexane / ethyl acetate / formic acid 3:7:0.2, ammonium cerium molybdate stain). 1 H NMR (400 MHz, CDCl3): δ (ppm) = 1.17 (d, 3H), 1.21 (d, 3H), 1.35 (d, 3H), 1.46 (d, 9H), 1.93 (q, 1H), 2.02 (dd, 1H), 2.21-2.35 (m, 2H), 2.77-2.91 (m, 4H), 3.25 (ddd, 1H), 4.23 (d, 1H), 4.60 (q, 1H), 5.19 (t, 1H), 7.38 (s, 1H). CHCH3 and COOH are not present in the spectrum. LC-MS: m / z = 444.10 (calcd. 444.22 for C 20 H 34 N3O6S + [M+H + ]).

[0227] Example 10 Preparation of tert-butyl [(2S)-1-{[(4S,7S,9aS)-8,8-dimethyl-5-oxo-7-{[(1S,2R)-2-(prop-2-yn-1-yloxy)-2,3-dihydro-1H-inden-1-yl]carbamoyl}octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (15)

[0228] [ka]

[0229] Under a N atmosphere, N-ethyl-N-(propan-2-yl)propan-2-amine (80 μL, 0.460 mmol, 3.00 equiv.) and COMU® (85 mg, 0.199 mmol, 1.30 equiv.) were added to a solution of carboxylic acid 14 (68 mg, 0.153 mmol, 1.00 equiv.) in dry THF (1.5 mL) at 0° C. After stirring the reaction mixture at 0° C. for 30 min, amine hydrochloride 4 (41 mg, 0.184 mmol, 1.20 equiv.) was added and stirring was continued at room temperature for 16 h. All volatiles were then removed under reduced pressure, and the residue was dissolved in ethyl acetate (30 mL) and washed with NaOH solution (1 M, 2 × 10 mL), HCl solution (1 M, 2 × 10 mL), water (2 × 10 mL), and brine (10 mL), dried (NaSO), and concentrated in vacuo. The residue was purified by fc (hexane / ethyl acetate). Colorless solid, yield 67 mg (71%). f = 0.41 (hexane / ethyl acetate 7:3, cerium(IV) sulfate staining). 1H NMR(400MHz,CDCl3):δ(ppm)=1.13(s,3H),1.20(s,3H),1.34(d,3H),1.48(s,9H),1.83(dd,1 H),1.98-2.10(m,1H),2.24-2.32(m,2H),2.49(s,1H),2.79(s,4H),3.09(dd,2H),3.30(ddd, 1H), 4.07-4.13 (m, 1H), 4.14-4.19 (m, 1H), 4.31 (s, 1H), 4.48 (q, 1H), 4.54 (dd, 1H), 5.16 (dd, 1H), 5.54 (dd, 1H), 7.19-7.23 (m, 3H), 7.31 (d, 1H), 7.35-7.43 (m, 2H). CHCH3 is not present in the spectrum. LC-MS: m / z = 613.40 (calcd. 613.79 for C 32 H 45 N4O6S + [M+H + ]).

[0230] Example 11. Preparation of (2S)-1-{[(4S,7S,9aS)-8,8-dimethyl-5-oxo-7-{[(1S,2R)-2-(prop-2-yn-1-yloxy)-2,3-dihydro-1H-inden-1-yl]carbamoyl}octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-N-methyl-1-oxopropane-2-ammonium chloride (16)

[0231] [ka]

[0232] Carbamate 15 (67 mg, 0.109 mmol, 1.00 equiv) was treated with HCl in dioxane (4 M, 820 μL, 3.28 mmol, 30.0 equiv) at room temperature. After 2 h, all volatiles were removed under reduced pressure, and the residue was transferred onto a fritted funnel and washed with EtO (3 × 1.5 mL). The remaining product was dried under reduced pressure. Colorless solid, yield 51 mg (85%). 1H NMR(400MHz,CD3OD):δ(ppm)=1.12-1.19(m,6H),1.55(d,3H),1.81(dd,1H),2.07-2.20 (m,1H),2.21-2.30(m,1H),2.34(dd,1H),2.68(s,3H),2.87-2.96(m,2H),3.09(dd,1H), 3.16(dd,1H),3.28-3.37(m,1H),3.94(q,1H),4.16(dd,1H),4.21-4.28(m,2H),4.52(td ,1H),4.75(dd,1H),5.40-5.52(m,2H),7.17-7.26(m,3H),7.32(d,1H),8.00(d,1H).NH2 + and H3CNCHC(O)NH are not seen in the spectrum. LC-MS: m / z = 513.65 (calculated 513.25 for C 27 H 37 N4O4S + [M+H + ]).

[0233] Example 12. tert-Butyl [(2S)-1-{[(4S,7S,9aS)-7-({(1S,2R)-2-[(6-{[(1S,2R)-1-({[(4S,7S,9aS)4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-dihydro- Preparation of 1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl]oxo]-2,3-dihydro-1H-inden-1-yl}carbamoyl-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (17a)

[0234] [ka]

[0235] The compound was prepared according to general procedure B. Colorless solid, yield 68 mg (69%). f= 0.59 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.15(m,12H),1.36(d,6H),1.46(s,18H),1.81(dd,2H),1.9 7(q,2H),2.20-2.28(m,2H),2.31(dd,2H),2.76-2.91(m,8H),3.03-3.16(m,4H),3.22-3. 34(m,2H),4.21-4.35(m,6H),4.43(q,2H),4.53(s,broad,2H),4.63(d,2H),5.45(dt,4H) ,7.15-7.25(m,6H),7.31(d,2H),7.85-8.02(m,2H).LC-MS:m / z=1223.70(calcd.1223.59 for C 64 H 87 N8O 12 S2 + [M+H + ]).

[0236] Example 13. (2S)-1-{[(4S,7S,9aS)-7-({(1S,2R)-2-[(6-{[(1S,2R)-1-({[(4S,7S,9aS)-8,8-dimethyl-4-{[(2S)-2-(methylammonio)propanoyl]amino}-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2, Preparation of 3-dihydro-1H-inden-2-yl]oxo}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl}carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-N-methyl-1-oxopropane-2-ammonium dichloride (18a)

[0237] [ka]

[0238] The compound was prepared according to general procedure A. Colorless solid, yield 53 mg (88%). f= 0.53 (ethyl acetate / methanol / NEt38:2:0.2, ammonium cerium molybdate stain). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.15(s,12H),1.55(d,6H),1.81(dd,2H),2. 04(q,2H),2.21-2.38(m,4H),2.68(s,6H),2.91(d,2H),3.05-3.17(m,4H) ,3.30(dt,2H),3.95(q,2H),4.22-4.39(m,6H),4.46(q,2H),4.75(d,2H), 5.46(t,4H),7.16-7.26(m,6H),7.32(d,2H),8.02(d,2H),8.73(d,2H).NH2 + is not seen in the spectrum. 13 C NMR(101 MHz,CD3OD):δ(ppm)=16.4,24.2,28.9,31.9,32.4,33.5,37.2,40.8,47.3,54.4,56.8,58.0,58.3,61.8,71.1,73. 6,76.9,81.0,125.5,126.2,128.1,129.4,141.0,142.2,169.3,172.2,172.5.LC-MS:m / z=1223.70(calcd.1223.59 for C 64 H 87 N8O 12 S2 + [M+H + ]).

[0239] Synthetic scheme for the preparation of diamines 6b-h

[0240] [ka]

[0241] Example 14. Preparation of tert-butyl N-[(1S,2R)-2-[(6-{[(1S,2R)-1-{[(tert-butoxy)carbonyl]amino}-2,3-dihydro-1H-inden-2-yl]oxy}hexyl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamate (5b)

[0242] [ka]

[0243] Pd / C (10%, 18 mg, 0.05 equiv.) was added to a solution of alkyne 5a (200 mg, 0.349 mmol, 1.00 equiv.) in methanol (3 mL) and THF (1 mL). The resulting mixture was stirred under a H atmosphere (balloon) for 16 h. After Celite® filtration with CHCl, the solvent was removed in vacuo and the resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid, yield 182 mg (90%). R f =0.38 (hexane / ethyl acetate 8.5:1.5). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.31(q,4H),1.46-1.55(m,22H),2.91-3.04(m,4H),3.37-3.45(m,2H),3.46-3.56(m,2H),4 .15-4.24(m,2H),5.10-5.19(m,2H),5.22-5.32(m,2H),7.16-7.24(m,6H),7.33(q,2H).LC-MS:m / z=581.25(calcd.581.36 for C 34 H 49 N2O6 + [M+H + ]).

[0244] Example 15. Preparation of tert-butyl N-[(1S,2R)-2-({3-[4-(3-{[(1S,2R)-1-{[(tert-butoxy)carbonyl]amino}-2,3-dihydro-1H-inden-2-yl]oxy}prop-1-yn-1-yl)phenyl]prop-2-yn-1-yl}oxy)-2,3-dihydro-1H-inden-1-yl]carbamate (5c)

[0245] [ka]

[0246] Under a N2 atmosphere, 1,4-diiodobenzene (120 mg, 0.364 mmol, 1.00 equiv.) was added to a solution of alkyne 3 (418 mg, 1.45 mmol, 4.00 equiv.) dissolved in NEt3 (3.0 mL, 21.8 mmol, 60.0 equiv.). Pd(PPh3)4 (21 mg, 0.05 equiv.) and CuI (3 mg, 0.05 equiv.) were added, and the resulting mixture was stirred at 80 °C for 4 h. After completion, water (10 mL) was added to the mixture, which was then extracted with CHCl2 (3 x 10 mL). The combined organic layers were washed with water (10 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid, yield 188 mg (80%). R f =0.37 (hexane / ethyl acetate 8:2). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.50(s,18H),3.05(dd,2H),3.14(dd,2H),4.45(s,4H),4.54(td,2H),5. 18-5.32(m,4H),7.21-7.25(m,6H),7.32-7.37(m,2H),7.39(s,4H).LC-MS:m / z=671.30(calcd.671.31 for C 40 H 44 N2NaO6 + [M+Na + ]).

[0247] Example 16. Preparation of tert-butyl N-[(1S,2R)-2-({3-[3-(3-{[(1S,2R)-1-{[(tert-butoxy)carbonyl]amino}-2,3-dihydro-1H-inden-2-yl]oxy}prop-1-yn-1-yl)phenyl]prop-2-yn-1-yl}oxy)-2,3-dihydro-1H-inden-1-yl]carbamate (5d)

[0248] [ka]

[0249] Under a N2 atmosphere, 1,3-diiodobenzene (110 mg, 0.333 mmol, 1.00 equiv.) was added to a solution of alkyne 3 (383 mg, 1.33 mmol, 4.00 equiv.) dissolved in NEt3 (1.9 mL, 13.3 mmol, 40.0 equiv.). Pd(PPh3)4 (19 mg, 0.05 equiv.) and CuI (3 mg, 0.05 equiv.) were added, and the resulting mixture was stirred at 80 °C for 4 h. After completion, water (15 mL) was added to the mixture, which was then extracted with CHCl2 (3 x 15 mL). The combined organic layers were washed with water (15 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid, yield 178 mg (82%). R f =0.40 (hexane / ethyl acetate 8:2). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.49(s,18H),3.05(dd,2H),3.13(dd,2H),4.44(s,4H),4.54(td,2H),5.18-5.34 (m,4H),7.23(d,6H),7.28(d,1H),7.34(dt,2H),7.40(dd,2H),7.52(t,1H).LC-MS:m / z=671.20(calcd.671.31 for C 40 H 44 N2NaO6+[M+Na + ]).

[0250] Example 17. Preparation of tert-butyl {(1S,2R)-2-[(4-iodobenzyl)oxy]-2,3-dihydro-1H-inden-1-yl}carbamate (19)

[0251] [ka]

[0252] Under a N2 atmosphere, 1-(bromomethyl)-4-iodobenzene (357 mg, 1.20 mmol, 1.20 equiv) was added to a solution of alcohol 2 (250 mg, 1.00 mmol, 1.00 equiv) dissolved in dry DMF (2.0 mL). The resulting mixture was treated with powdered KOH (115 mg, 2.06 mmol, 2.05 equiv) and stirred at room temperature for 1.5 h. After completion, water (15 mL) was added to the mixture and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexanes / ethyl acetate). Colorless solid, yield 148 mg (32%). R f = 0.66 (hexane / ethyl acetate 8.5:1.5). 1 H NMR(400MHz,CDCl3):δ(ppm)=1.50(s,9H),3.00(dd,1H),3.06(dd,1H),4.34(dp,1H),4.51(d,1H),4.56(d,1H) ),5.21(s,2H),7.05(d,2H),7.21(p,3H),7.34(q,1H),7.62-7.67(m,2H,).LC-MS:m / z=487.90(calcd.488.07 for C 21 H 24 INNaO3 + [M+Na + ]).

[0253] Example 18. Preparation of tert-butyl N-[(1S,2R)-2-({3-[4-({[(1S,2R)-1-{[(tert-butoxy)carbonyl]amino}-2,3-dihydro-1H-inden-2-yl]oxy}methyl)phenyl]prop-2-yn-1-yl}oxy)-2,3-dihydro-1H-inden-1-yl]carbamate (5e)

[0254] [ka]

[0255] Under a N2 atmosphere, alkyne 3 (158 mg, 0.550 mmol, 2.00 equiv.) was added to a solution of iodobenzene 19 (128 mg, 0.275 mmol, 1.00 equiv.) dissolved in NEt3 (1.5 mL, 11.0 mmol, 40.0 equiv.). Pd(PPh3)4 (9 mg, 0.03 equiv.) and CuI (1 mg, 0.03 equiv.) were added, and the resulting mixture was stirred at 70 °C for 4 h. After completion, water (10 mL) was added to the mixture, which was then extracted with CHCl2 (3 x 10 mL). The combined organic layers were washed with water (10 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexanes / ethyl acetate). Colorless solid, yield 130 mg (76%). R f =0.51 (hexane / ethyl acetate 8:2). 1 H NMR(400MHz,CDCl3):δ(ppm)=1.48-1.51(m,18H),2.95-3.10(m,3H),3.14(dd,1H),4.32-4.37(m,1H),4.44(s,2H),4.53(dt,1H),4 .57(d,1H),4.61(d,1H),5.22(tt,4H),7.19-7.26(m,8H),7.31-7.37(m,2H),7.38-7.43(m,2H).LC-MS:m / z=647.25(calcd.647.31 for C 38 H 44 N2NaO6 + [M+Na + ]).

[0256] Example 19. Preparation of tert-butyl N-[(1S,2R)-2-{[4'-({[(1S,2R)-1-{[(tert-butoxy)carbonyl]amino}-2,3-dihydro-1H-inden-2-yl]oxy}methyl)-[1,1'-biphenyl]-4-yl]methoxy}-2,3-dihydro-1H-inden-1-yl]carbamate)

[0257] [ka]

[0258] Under a N2 atmosphere, 1-(bromomethyl)-4-(4-(bromomethyl)phenyl)benzene (93 mg, 0.273 mmol, 1.00 equiv) was added to a solution of alcohol 2 (150 mg, 0.602 mmol, 2.20 equiv) dissolved in dry DMF (1.0 mL) at 0 °C. The resulting mixture was treated with powdered KOH (49 mg, 0.875 mmol, 3.20 equiv) and stirred at 0 °C for 1 h, then at room temperature for 3 h. After completion, water (30 mL) was added to the mixture and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water (2 × 10 mL), brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexanes / CHCl2, CHCl2 / MeOH). Colorless solid, crude yield 131 mg (71%). R f =0.43 (hexane / ethyl acetate 8:2).

[0259] Example 20. Preparation of tert-butyl N-[(1S,2R)-2-{[4-({[(1S,2R)-1-{[(tert-butoxy)carbonyl]amino}-2,3-dihydro-1H-inden-2-yl]oxy}methyl)phenyl]methoxy}-2,3-dihydro-1H-inden-1-yl]carbamate (5 g)

[0260] [ka]

[0261] Under a N2 atmosphere, 1,4-bis(bromomethyl)benzene (81 mg, 0.310 mmol, 1.00 equiv) was added to a solution of alcohol 2 (170 mg, 0.682 mmol, 2.20 equiv) dissolved in dry DMF (1.1 mL) at 0 °C. The resulting mixture was treated with powdered KOH (55 mg, 0.992 mmol, 3.20 equiv) and stirred at 0 °C for 2 h. After completion, water (10 mL) was added to the mixture and extracted with ethyl acetate (4 × 10 mL). The combined organic layers were washed with water (2 × 10 mL), brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid, yield 84 mg (45%). 1 H NMR (400 MHz, CDCl3): δ (ppm) = 1.50 (s, 18H), 2.99 (dd, 2H), 3.07 (dd, 2H), 4.34 (q, 2H), 4.55 (d, 2H), 4.60 (d, 2H), 5.16-5.23 (m, 2H), 7.17-7.23 (m, 6H), 7.27 (s, 4H), 7.32-7.36 (m, 2H). CHNH is not present in the spectrum. LC-MS: m / z = 623.20 (calculated 623.31 for C). 36 H 44 N2NaO6 + [M+Na + ]).

[0262] Example 21. Preparation of tert-butyl N-[(1S,2R)-2-[2-(2-{[(1S,2R)-1-{[(tert-butoxy)carbonyl]amino}-2,3-dihydro-1H-inden-2-yl]oxy}ethanesulfonyl)ethoxy]-2,3-dihydro-1H-inden-1-yl]carbamate (5h)

[0263] [ka]

[0264] Under a N2 atmosphere, triphenylphosphine (9 mg, 0.10 equiv.) was added to a solution of alcohol 2 (250 mg, 1.00 mmol, 3.00 equiv.) dissolved in dry CHCl (0.70 mL). Divinyl sulfone (33 μL, 0.334 mmol, 1.00 equiv.) was added, and the resulting mixture was stirred at room temperature for 24 h. After completion, the volatiles were removed in vacuo, and the resulting residue was purified by FC (hexane / ethyl acetate). Colorless solid, yield 150 mg (73%). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.46(s,18H,C(CH3)3),2.90(dd,2H),2.95-3.21(m,6H),3.72-3.81(m,2H),3.90-3.98 (m,2H),4.18-4.24(m,2H),5.17(dd,2H),5.40(d,2H),7.01(d,2H),7.17(dt,6H).LC-MS:m / z=617.20(calcd.617.29 for C 32 H 45 N2O8S + [M+H + ]).

[0265] Example 22. Preparation of (1S,2R)-2-[(6-{[(1S,2R)-1-ammonio-2,3-dihydro-1H-inden-2-yl]oxy}hexyl)oxy]-2,3-dihydro-1H-indene-1-ammonium dichloride (6b)

[0266] [ka]

[0267] The compound was prepared according to general procedure A. Colorless solid, yield 107 mg (91%). LC-MS: m / z = 381.00 (calculated 381.25 for C). 24 H 33 N2O2 + [M+H + ]).

[0268] Example 23 Preparation of (1S,2R)-2-({3-[4-(3-{[(1S,2R)-1-ammonio-2,3-dihydro-1H-inden-2-yl]oxy}prop-1-yn-1-yl)phenyl]prop-2-yn-1-yl}oxy)-2,3-dihydro-1H-indene-1-ammonium dichloride (6c)

[0269] [ka]

[0270] The compound was prepared according to general procedure A. Colorless solid, yield 122 mg (91%). LC-MS: m / z = 449.10 (calculated 449.22 for C). 30 H 29 N2O2 + [M+H + ]).

[0271] Example 24. Preparation of (1S,2R)-2-({3-[3-(3-{[(1S,2R)-1-ammonio-2,3-dihydro-1H-inden-2-yl]oxy}prop-1-yn-1-yl)phenyl]prop-2-yn-1-yl}oxy)-2,3-dihydro-1H-indene-1-ammonium dichloride (6d)

[0272] [ka]

[0273] The compound was prepared according to general procedure A. Colorless solid, yield 104 mg (81%). LC-MS: m / z = 449.00 (calculated 449.22 for C 30 H 29 N2O2 + [M+H + ]).

[0274] Example 25. Preparation of (1S,2R)-2-({3-[4-({[(1S,2R)-1-ammonio-2,3-dihydro-1H-inden-2-yl]oxy}methyl)phenyl]prop-2-yn-1-yl}oxy)-2,3-dihydro-1H-indene-1-ammonium dichloride (6e)

[0275] [ka]

[0276] The compound was prepared according to general procedure A. Colorless solid, yield 136 mg (93%). LC-MS: m / z = 425.05 (calculated 425.22 for C). 28 H 29 N2O2 + [M+H + ]).

[0277] Example 26. Preparation of (1S,2R)-2-({4-[4-({[(1S,2R)-1-ammonio-2,3-dihydro-1H-inden-2-yl]oxy}methyl)phenyl]benzyl}oxy)-2,3-dihydro-1H-indene-1-ammonium dichloride (6f)

[0278] [ka]

[0279] The compound was prepared according to general procedure A. Colorless solid, yield 93 mg (87%). LC-MS: m / z = 477.20 (calculated for C). 32 H 33 N2O2 + [M+H + ]).

[0280] Example 27. Preparation of (1S,2R)-2-{[4-({[(1S,2R)-1-ammonio-2,3-dihydro-1H-inden-2-yl]oxy}methyl)benzyl]oxy}-2,3-dihydro-1H-indene-1-ammonium dichloride (6 g)

[0281] [ka]

[0282] The compound was prepared according to general procedure A. Colorless solid, yield 51 mg (81%). LC-MS: m / z = 401.00 (calculated 401.22 for C). 26 H 29 N2O2 + [M+H + ]).

[0283] Example 28 Preparation of (1S,2R)-2-{2-[(2-{[(1S,2R)-1-ammonio-2,3-dihydro-1H-inden-2-yl]oxy}ethyl)sulfonyl]ethoxy}-2,3-dihydro-1H-indene-1-ammonium dichloride (6h)

[0284] [ka]

[0285] The compound was prepared according to general procedure A. Colorless solid, yield 104 mg (87%). LC-MS: m / z = 417.35 (calculated 417.18 for C). 22 H 29 N2O4S + [M+H + ]).

[0286] Synthetic scheme for the preparation of diamine 6i

[0287] [ka]

[0288] Example 29. Preparation of tert-butyl [(1R)-3-hydroxy-1-phenylpropyl]carbamate (21)

[0289] [ka]

[0290] Compound 21 was prepared according to established literature procedures; Barnes, D.; Bebernitz, GR; Cohen, SL; Damon, RE; Day, RF; Jain, M.; Karki, RG; Kirman, LC; Patel, TJ; Raymer, BK; Schuster, HF; Zhang, W. Application: see WO 2011067306 A1.

[0291] Example 30. Preparation of tert-butyl [(1R)-1-phenyl-3-(prop-2-yn-1-yloxy)propyl]carbamate (22)

[0292] [ka]

[0293] Under a N2 atmosphere, propargyl bromide (80%, 106 μL, 0.955 mmol, 1.20 equiv) in toluene was added to a solution of alcohol 21 (200 mg, 0.796 mmol, 1.00 equiv) dissolved in dry DMF (1.6 mL) at 0 °C. The solution was treated with powdered KOH (92 mg, 1.63 mmol, 2.05 equiv) and stirred at 0 °C for 1.5 h. After completion, water (10 mL) was added to the mixture and extracted with ethyl acetate (4 × 10 mL). The combined organic layers were washed with water (2 × 10 mL), brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by FC (hexanes / ethyl acetate). Colorless solid, yield 147 mg (64%). Rf = 0.56 (hexanes / ethyl acetate 8:2). 1H NMR (400MHz, CDCl3): δ(ppm)=1.41(s,9H),2.04(dq,2H),2.38-2.41(m,1H),3.49(q,2H),4.11(s,1H) ,4.11-4.16(m,1H),4.84(s,1H,),5.30(s,1H),7.19-7.37(m,5H).LC-MS:m / z=289.90(calcd.290.18 for C 17 H 24 No. 3 + [M+H + ]).

[0294] Example 31. Preparation of tert-butyl N-[(1R)-3-({6-[(3R)-3-{[(tert-butoxy)carbonyl]amino}-3-phenylpropoxy]hexa-2,4-diyn-1-yl}oxy)-1-phenylpropyl]carbamate (5i)

[0295] [ka]

[0296] Copper(II) acetate (96 mg, 0.530 mmol, 1.15 equiv) was added to a solution of alkyne 22 (133 mg, 0.461 mmol, 1.00 equiv) and pyridine (220 μL, 2.74 mmol, 5.94 equiv) in acetonitrile (4.1 mL). The resulting solution was placed in a preheated oil bath at 80 °C and stirred for 1 h. After completion, all volatiles were removed under reduced pressure, and aqueous NH OH (3%, 10 mL) was added to the residue and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried (Na SO ), and concentrated in vacuo. The resulting residue was purified by fc (hexanes / ethyl acetate). Colorless solid, yield 112 mg (42%). R f =0.33 (hexane / ethyl acetate 8:2). 1H NMR (400MHz, CDCl3): δ(ppm)=1.40(s,18H),1.91-2.13(m,4H),3.38-3.56(m,4H),4.09- 4.26(m,4H),4.83(s,2H),5.27(s,2H),7.31(td,10H).LC-MS:m / z=577.20(calcd.577.33 for C 34 H 45 N2O6 + [M+H + ]).

[0297] Example 32. Preparation of (1R)-3-[(6-{[(3R)-3-ammonio-3-phenylpropyl]oxy}hexa-2,4-diyn-1-yl)oxy]-1-phenylpropane-1-ammonium dichloride (6i)

[0298] [ka]

[0299] The compound was prepared according to general procedure A. Colorless solid, yield 68 mg (90%). LC-MS: m / z = 377.35 (calculated 377.22 for C). 24 H 29 N2O2 + [M+H + ]).

[0300] Synthetic scheme for the preparation of diamine 6j

[0301] [ka]

[0302] Example 33: Preparation of 4-[(tert-butyldimethylsilyl)oxy]but-2-yn-1-ol (41)

[0303] [ka]

[0304] Compound 41 was prepared according to established literature procedures; see Zbieg, JR; McInturff, EL; Leung, JC; Krische, MJJ Am. Chem. Soc. 2011, 133(4), 1141-1144.

[0305] Example 34: Preparation of 4-[(tert-butyldimethylsilyl)oxy]but-2-yn-1-yl 4-methylbenzene-1-sulfonate (42)

[0306] [ka]

[0307] Compound 42 was prepared according to established literature procedures; see Kopfer, A.; Breit, B. Angew. Chem. 2015, 54(23), 6913-6917.

[0308] Example 35: Preparation of tert-butyl [(1S,2R)-2-({4-[(tert-butyldimethylsilyl)oxy]but-2-yn-1-yl}oxy)-2,3-dihydro-1H-inden-1-yl]carbamate (43)

[0309] [ka]

[0310] Alcohol 2 (70 mg, 0.281 mmol, 1.00 equiv) was dissolved in dry DMF (567 μL) under a N atmosphere, and the solution was cooled to 0 °C. Tosylate 42 (110 mg, 0.309 mmol, 1.10 equiv) was added. The resulting solution was treated with powdered KOH (32 mg, 0.576 mmol, 2.05 equiv), and stirring was continued at 0 °C. After 2 h, water (10 mL) was added, and the resulting mixture was extracted with ethyl acetate (4 × 10 mL). The combined organic layers were washed with water (2 × 10 mL) and brine (10 mL), dried (NaSO), and concentrated in vacuo. The residue was purified by FC (hexane / ethyl acetate). A yellow resin, yield 61 mg (50%). 1 H NMR (400MHz, CDCl3): δ(ppm)=0.11(s,6H),0.90(s,9H),1.50(s,9H),2.99(d,1H),3.07(d,1H),4.22-4.26(m,2H),4. 35(dd,2H),4.42-4.48(m,1H),5.15-5.30(m,2H),7.20(s,3H),7.29-7.36(m,1H).LC-MS:m / z=454.20(calcd.454.24 for C 24 H 37 NNaO4Si + [M+Na + ]).

[0311] Example 36: Preparation of tert-butyl [(1S,2R)-2-[(4-hydroxybut-2-yn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamate (44)

[0312] [ka]

[0313] Compound 43 (60 mg, 0.139 mmol, 1.00 equiv.) was dissolved in THF (153 μL) and TBAF in THF (1.00 M, 153 μL, 0.153 mmol, 1.10 equiv.) was added. After stirring the mixture at room temperature for 16 hours, saturated NH4Cl solution (10 mL) was added and the resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by FC (hexane / ethyl acetate, ammonium cerium molybdate staining). A yellow resin, 32 mg (73%) yield. R f =0.36 (hexane / ethyl acetate 7:3). 1 H NMR (400 MHz, CDCl): δ (ppm) = 1.50 (s, 9H), 3.02 (d, 2H), 4.18-4.30 (m, 4H), 4.45 (q, 1H), 5.16-5.23 (m, 1H), 5.28 (d, 1H), 7.17-7.25 (m, 3H), 7.28-7.36 (m, 1H). OH is not present in the spectrum. LC-MS: m / z = 339.95 (calculated 340.15 for C). 18 H 23 NNaO4 + [M+Na + ]).

[0314] Example 37: Preparation of tert-butyl [(1S,2R)-2-({4-[(4-methylbenzenesulfonyl)oxy]but-2-yn-1-yl}oxy)-2,3-dihydro-1H-inden-1-yl]carbamate (45)

[0315] [ka]

[0316] Alcohol 44 (85 mg, 0.267 mmol, 1.00 equiv) was dissolved in diethyl ether (415 μL) and the mixture was cooled to 0 °C. Tosyl chloride (71 mg, 0.373 mmol, 1.40 equiv) and powdered KOH (80 mg, 1.43 mmol, 5.35 equiv) were added. After stirring at room temperature for 1 h, water (10 mL) was added and the resulting mixture was extracted with CHCl (3 × 10 mL). The combined organic layers were dried (NaSO) and concentrated in vacuo. The residue was purified by FC (hexane / ethyl acetate, cerium ammonium molybdate staining). Red resin, yield 84 mg (67%). R f =0.33 (hexane / ethyl acetate 8:2). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.50(s,9H),2.43(s,3H),2.91-3.04(m,2H),4.12(s,2H),4.30(t,1H),4.73(s, 2H),5.15(s,2H),7.16-7.24(m,3H),7.28-7.36(m,3H),7.74-7.85(m,2H).LC-MS:m / z=494.05(calcd.494.16 for C 25 H 29 NNaO6S + [M+Na + ]).

[0317] Example 38 Preparation of tert-butyl [(1S,2R)-2-[(4-{[(1S,2R)-1-{[(tert-butoxy)carbonyl]amino}-2,3-dihydro-1H-inden-2-yl]oxy}but-2-yn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamate (5j)

[0318] [ka]

[0319] Under a N2 atmosphere, alcohol 2 (42 mg, 0.170 mmol, 1.20 equiv) was dissolved in dry DMF (560 μL) and the solution was cooled to 0 °C. Tosylate 45 (67 mg, 0.142 mmol, 1.00 equiv) was added. The resulting solution was treated with powdered KOH (16 mg, 0.291 mmol, 2.05 equiv) and stirring was continued at 0 °C. After 2 h, water (10 mL) was added and the resulting mixture was extracted with ethyl acetate (4 × 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by fc (hexane / ethyl acetate). White solid, yield 41 mg (53%). R f = 0.42 (hexane / ethyl acetate 9:1, cerium ammonium molybdate stain). 1 H NMR(400MHz,CDCl3):δ(ppm)=1.50(s,18H),3.01(dd,2H),3.08(dd,2H),4.27(s,4H),4.44(q,2 H),5.04-5.28(m,4H),7.18-7.24(m,6H),7.30-7.35(m,2H).LC-MS:m / z=549.25(calcd.549.30 for C 32 H 41 N2O6 + [M+H + ]).

[0320] Example 39 Preparation of 1S,2R)-2-[(4-{[(1S,2R)-1-(chloroamino)-2,3-dihydro-1H-inden-2-yl]oxy}but-2-yn-1-yl)oxy]-2,3-dihydro-1H-indene-1-ammonium dichloride (6j)

[0321] [ka]

[0322] The compound was prepared according to general procedure A. White solid, yield 27 mg (86%). LC-MS: m / z = 349.25 (calculated 349.19 for C). 22 H 25 N2O2+ [M+H + ]).

[0323] Synthetic scheme for the highly stereoselective preparation of carboxylic acid 14

[0324] [ka]

[0325] Example 40: Preparation of (4S,5R)-4,5-diphenyl-1,3-oxazolidin-2-one (24)

[0326] [ka]

[0327] Compound 24 was prepared according to established literature procedures; see Akiba T.; Tamura O.; Terashima S. (4R,5S)-4,5-Diphenyl-3-vinyl-2-oxazolidinone, Org. Synth. 1998, 75, 45.

[0328] Example 41: Preparation of 2,2-diphenylpropane-1,3-diol (26)

[0329] [ka]

[0330] Compound 26 was prepared according to established literature procedures; see Sato T.; Onuma T.; Nakamura I.; Terada M. Platinum-Catalyzed Cycloisomerization of 1,4-Enynes via 1,2-Alkenyl Rearrangement, Org. Lett. 2011, 13, 4992-4995.

[0331] Example 42: Preparation of 3-(5,5-diphenyl-1,3-dioxan-2-yl)-2,2-dimethylpropanenitrile (27)

[0332] [ka]

[0333] To a mixture of dimethyl acetal 8 (9.08 g, 57.8 mmol, 1.05 equiv.) and diol 26 (12.5 g, 55.0 mmol, 1.00 equiv.) in CHCl (80 mL) was added camphor-10-sulfonic acid (1.28 g, 5.50 mmol, 0.10 equiv.) in portions at 0 °C. The resulting mixture was stirred at 60 °C for 18 h. Saturated NaHCO solution was then added (20 mL) and extracted with CHCl (3 × 50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried (NaSO), and concentrated in vacuo. The resulting residue was purified by FC (petroleum ether / ethyl acetate). A colorless oil, yield 13.3 g (76%). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.37(s,6H),1.87(d,2H),4.17-4.27(m,2H),4.68-4.79(m,2H),4.93 (t,1H),7.00-7.08(m,2H),7.18-7.35(m,6H),7.41-7.48(m,2H).LC-MS:m / z=322.20(calcd.322.18 for C 21 H 24 NO2 + [M+H + ]).

[0334] Example 43: Preparation of 3-(5,5-diphenyl-1,3-dioxan-2-yl)-2,2-dimethylpropanal (28)

[0335] [ka]

[0336] Under a N2 atmosphere, DIBAL-H in hexane (1 M, 123 mL, 124 mmol, 3.00 equiv.) was added dropwise to a solution of nitrile 27 (13.2 g, 41.2 mmol, 1.00 equiv.) in dry CHCl (200 mL) at −78 °C. The mixture was stirred at 0 °C for 2 h. Saturated potassium sodium tartrate solution (20 mL) was then added, and the mixture was stirred at room temperature for 1 h. After filtration through a Celite® pad, the filtrate was concentrated in vacuo. The resulting residue was purified by fc (petroleum ether / ethyl acetate). White solid, yield 8.01 g (60%). 1 H NMR(400MHz,DMSO-D6):δ(ppm)=0.86-1.03(m,6H),1.75(d,2H),4.10(d,2H),4.69-4.82(m,3H),7.08-7.13(m ,2H),7.14-7.22(m,2H),7.24-7.33(m,4H),7.38-7.45(m,2H),9.31(s,1H).LC-MS:m / z=325.20(calcd.325.18 for C 21 H 25 O3 + [M+H + ]).

[0337] Example 44: Preparation of 4-(5,5-diphenyl-1,3-dioxan-2-yl)-3,3-dimethyl-1-nitrobutan-2-ol (29)

[0338] [ka]

[0339] To a solution of aldehyde 28 (8.01 g, 24.7 mmol, 1.00 equiv.) in nitromethane (30 mL, 560 mmol, 22.7 equiv.) was added NEt3 (10 mL, 71.7 mmol, 2.90 equiv.) slowly at 0 °C. The mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by fc (petroleum ether / ethyl acetate). White solid, yield 9.04 g (95%). 1H NMR(400MHz,CDCl3):δ(ppm)=0.93(s,3H),1.03(s,3H),1.54(dd,1H),1.86(dd,1H),3.41(d,1H),4.14-4.28(m,3H),4.32-4.47( m,2H),4.75(ddd,2H),4.86(dd,1H),6.99-7.06(m,2H),7.19-7.35(m,6H),7.38-7.44(m,2H).LC-MS:m / z=386.20(calcd.386.20 for C 22 H 28 No. 5 + [M+H + ]).

[0340] Example 45: Preparation of 2-[(3E)-2,2-dimethyl-4-nitrobut-3-en-1-yl]-5,5-diphenyl-1,3-dioxane (30)

[0341] [ka]

[0342] To a solution of nitroaldol 29 (9.02 g, 23.4 mmol, 1.00 equiv.) in CHCl (100 mL) was added methanesulfonyl chloride (4.5 mL, 58.4 mmol, 2.50 equiv.). The mixture was cooled to 0 °C, and NEt (14.2 mL, 105 mmol, 4.50 equiv.) was added dropwise. The resulting mixture was stirred at room temperature for 2 h. Water (40 mL) was then added and extracted with CHCl (3 × 50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried (NaSO), and concentrated in vacuo. The resulting residue was purified by fc (petroleum ether / ethyl acetate). White solid, yield 6.75 g (75%). 1H NMR(400MHz,CDCl3):δ(ppm)=1.16(s,6H),1.81(d,2H),4.10-4.16(m,3H),4.60-4.73(m,3H),6.84(d,1H),6 .97-7.05(m,2H),7.20-7.23(m,1H),7.27-7.36(m,4H),7.38-7.45(m,2H).LC-MS:m / z=368.20(calcd.368.19 for C 22 H 26 No. 4 + [M+H + ]).

[0343] Example 46. Preparation of (4S,5R)-3-[(2S)-4-(5,5-diphenyl-1,3-dioxan-2-yl)-3,3-dimethyl-1-nitrobutan-2-yl]-4,5-diphenyl-1,3-oxazolidin-2-one (31)

[0344] [ka]

[0345] Under a N2 atmosphere, KOtBu (3.05 g, 27.2 mmol, 1.60 equiv) was added portionwise to a suspension of oxazolidone 24 (6.51 g, 27.2 mmol, 1.60 equiv) and 18-crown-6 (7.18 g, 27.2 mmol, 1.60 equiv) in THF (240 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was then cooled to -78 °C, and nitroalkene 30 (6.24 g, 17.0 mmol, 1.00 equiv) in THF (50 mL) was added dropwise. The resulting mixture was stirred at -78 °C for 30 min, after which saturated NH4Cl solution (50 mL) was added. After the reaction mixture was warmed to room temperature, the aqueous layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc(CH2Cl2 / ethyl acetate). White solid, yield 7.22 g (70%). 1H NMR(400MHz,CDCl3):δ(ppm)=1.00(s,3H,),1.14(s,3H),1.64(dd,1H),2.08(dd,1H),3.97(d, 1H),4.23(t,1H),4.41(d,1H),4.63(dd,1H),4.73(dd,1H),4.76-4.85(m,2H,),4.92(d,1H),5 .23(dd,1H),5.81(d,1H),6.39(d,2H),6.86-6.92(m,2H),6.94-7.00(m,2H),7.01-7.11(m,6H ),7.21-7.33(m,4H),7.37-7.43(m,2H),7.54-7.59(m,2H).LC-MS:m / z=607.25(calcd.607.28 for C 37 H 39 N2O6 + [M+H + ]).

[0346] Example 47. Preparation of (2S)-4-(5,5-diphenyl-1,3-dioxan-2-yl)-3,3-dimethyl-2-((4S,5R)-2-oxo-4,5-diphenyl-1,3-oxazolidin-3-yl)butanoate (33)

[0347] [ka]

[0348] Under a N2 atmosphere, sodium nitrite (5.00 g, 72.5 mmol, 3.00 equiv.) and dry acetic acid (13.8 mL, 242 mmol, 10.0 equiv.) were added to a solution of nitro derivative 31 (14.6 g, 24.2 mmol, 1.00 equiv.) suspended in dry DMSO (60 mL). The resulting mixture was stirred at 35 °C for 7 h. After completion, citric acid solution (5%, 200 mL) was added and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with water (200 mL) and brine (150 mL), dried (Na2SO4), and concentrated in vacuo.

[0349] The crude carboxylic acid 32 was dissolved in dry DMF (28 mL) and cooled to 0 °C. K2CO3 (3.68 g, 26.6 mmol, 1.10 equiv) was added and stirred for 10 min. CH3I (3.02 mL, 48.3 mmol, 2.00 equiv) was added, and stirring was continued at 0 °C for 30 min. The solution was then stirred at room temperature for 12 h, at which point additional K2CO3 (3.68 g, 26.6 mmol, 1.10 equiv) and CH3I (3.02 mL, 48.3 mmol, 2.00 equiv) were added. After stirring for an additional 7 h, water (200 mL) was added and extracted with CHCl2 (3 × 200 mL). The combined organic layers were washed with water (200 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexanes / ethyl acetate). Colorless solid, yield 13.3 g (89%). f = 0.38 (hexane / ethyl acetate 8:2). 1 H NMR(400MHz,CDCl3):δ(ppm)=1.21(s,3H),1.22(s,3H),1.72(dd,1H),1.94( dd,1H),3.63(s,3H),3.96(d,1H),4.00(s,1H),4.30(d,1H),4.57(dd,1H),4. 72(dd,1H),4.78(dd,1H),5.08(d,1H),5.83(d,1H),6.91-7.09(m,11H),7.2 0-7.31(m,5H),7.37(t,2H),7.52(dt,2H).LC-MS:m / z=606.15(calcd.606.29 for C 38 H 40 No. 6 + [M+H + ]).

[0350] Example 48. Preparation of methyl (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-4-(tritylsulfanyl)butanoyl}amino)-4-(5,5-diphenyl-1,3-dioxan-2-yl)-3,3-dimethylbutanoate (35)

[0351] [ka]

[0352] Pd / C (10%, matrix activated carbon support, Sigma Aldrich, 439 mg, 0.25 equiv.) was added to a solution of carbamate 33 (1.00 g, 1.65 mmol, 1.00 equiv.) in methanol (20 mL). The resulting mixture was stirred at 45° C. for 4 h under an H atmosphere. After filtration through Celite® with methanol, all volatiles were removed in vacuo.

[0353] Under a N atmosphere, amine 34, carboxylic acid 7 (788 mg, 1.65 mmol, 1.00 equiv.), 1-hydroxybenzotriazole hydrate (303 mg, 1.98 mmol, 1.20 equiv.), and N-methylmorpholine (546 μL, 4.95 mmol, 3.00 equiv.) were dissolved in dry THF (5.9 mL) and cooled to 0 °C. EDC·HCl (380 mg, 1.98 mmol, 1.20 equiv.) was added, and the resulting mixture was stirred at 0 °C for 30 min and then at room temperature for 14 h. After completion, water (30 mL) was added and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with saturated NaHCO solution (30 mL), citric acid solution (5%, 30 mL), water (30 mL), and brine (30 mL), dried (NaSO), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid, yield 994 mg (71%). f =0.36 (hexane / ethyl acetate 8:2). 1H NMR(400MHz,CDCl3):δ(ppm)=0.97(s,3H),1.00(s,3H),1.40(s,10H),1.59(dd,1H),1.69( dd,1H),1.72-1.83(m,1H),2.16-2.32(m,2H),3.64(s,3H),3.89-3.99(m,1H),4.18(d,1H), 4.22(d,1H),4.46(d,1H),4.57(d,1H),4.69(d,2H),4.78(t,1H),6.88(d,1H,),7.02(d,2H) ),7.19(dd,5H),7.27(q,10H),7.39(d,6H),7.43(d,2H).LC-MS:m / z=865.40(calcd.865.39 for C 51 H 58 N2NaO7S + [M+Na + ]).

[0354] Example 49. Preparation of methyl (4S,7S,9aS)-4-({(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoyl}amino)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylate (37a)

[0355] [ka]

[0356] Compound 35 (1.21 g, 1.43 mmol, 1.00 equiv) was treated with HCl in dioxane (4 M, 7.2 mL, 28.7 mmol, 20.0 equiv) and stirred for 2 h at 40° C. After completion, all volatiles were removed under reduced pressure.

[0357] The resulting amine 36, N-(tert-butoxycarbonyl)-N-methyl-L-alanine (349 mg, 1.72 mmol, 1.20 equiv.), 1-hydroxybenzotriazole hydrate (263 mg, 1.72 mmol, 1.20 equiv.), and 4-methylmorpholine (473 μL, 3.00 equiv.) were dissolved in dry DMF (6.7 mL) under a N atmosphere and cooled to 0 °C. EDC·HCl (329 mg, 1.72 mmol, 1.20 equiv.) was added, and the resulting mixture was stirred at 0 °C for 30 min and then at room temperature for 17 h. After completion, water (30 mL) was added and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with NaOH solution (1M, 30 mL), citric acid solution (5%, 30 mL), water (30 mL), and brine (30 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid, yield 506 mg (77%). R f = 0.22 (hexane / ethyl acetate 6:4, ammonium cerium molybdate stain). 1 H NMR(400MHz,CDCl3):δ(ppm)=1.09(s,3H),1.13(s,3H),1.33(d,3H),1.45( s,9H),1.84-1.95(m,1H),2.00(dd,1H,),2.22-2.31(m,2H),2.77(s,3H),2 .84(ddd,1H),3.24(ddd,1H),3.75(s,3H),4.24(s,1H),4.53(dd,1H),4.70 (s,1H,broad),5.15(t,1H),7.30(s,1H).LC-MS:m / z=458.10(calcd.458.23 for C 21 H 36 N3O6S + [M+H + ]).

[0358] Example 50: Preparation of (4S,7S,9aS)-4-({(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoyl}amino)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (14a)

[0359] [ka]

[0360] Lithium hydroxide solution (1 M, 2.21 mL, 2.21 mmol, 2.00 equiv) was added to a solution of methyl ester 37a (506 mg, 1.11 mmol, 1.00 equiv) dissolved in THF (2.2 mL) at room temperature. The resulting emulsion was stirred at 40 °C for 15 h. After completion, EtO (10 mL) was added and washed with a mixture of 1 M NaOH solution and brine (7:1, 3 × 8 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL), and the ethyl acetate layer was washed with a mixture of 1 M NaOH solution and brine (7:1, 2 × 8 mL). The combined aqueous layers were acidified to pH 1 with concentrated hydrochloric acid, and then the aqueous layer was extracted with CHCl (3 × 10 mL) and ethyl acetate (2 × 10 mL). The combined organic layers were dried (NaSO) and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate / formic acid 0.2%). Colorless solid, yield 337 mg (69%). f = 0.60 (hexane / ethyl acetate / formic acid 3:7:0.1, ammonium cerium molybdate stain).

[0361] Example 51: Preparation of methyl (4S,7S,9aS)-4-({2-[(tert-butoxycarbonyl)(methyl)amino]-2-methylpropanoyl}amino)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylate (37b)

[0362] [ka]

[0363] Compound 35 (250 mg, 0.297 mmol, 1.00 equiv) was treated with HCl in dioxane (4 M, 1.5 mL, 5.93 mmol, 20.0 equiv) and stirred for 2 h at 40° C. After completion, all volatiles were removed under reduced pressure.

[0364] The resulting amine 36, N-(tert-butoxycarbonyl)-N,2-dimethylalanine (77 mg, 0.356 mmol, 1.20 equiv.), 1-hydroxybenzotriazole hydrate (54 mg, 0.356 mmol, 1.20 equiv.), and 4-methylmorpholine (98 μL, 0.890 mmol, 3.00 equiv.) were dissolved in dry DMF (1.4 mL) under a N atmosphere and cooled to 0 °C. EDC·HCl (68 mg, 0.356 mmol, 1.20 equiv.) was added, and the resulting mixture was stirred at 0 °C for 30 min and at room temperature for 16 h. After completion, water (10 mL) was added and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated NaHCO3 solution (10 mL), citric acid solution (5%, 10 mL), water (10 mL), and brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid, yield 57 mg (41%). R f = 0.42 (hexane / ethyl acetate 6:4, ammonium cerium molybdate staining). 1 H NMR(400MHz,CDCl3):δ(ppm)=1.09-1.13(m,6H,CHC(CH3)2),1.36-1.42(m,15H),1.79-1.91(m,1H),2.03(dd,1H),2.27(dd,1H),2.34-2.42(m,1H) ,2.83(ddd,1H),2.89(s,3H),3.28(ddd,1H),3.76(s,3H),4.23(s,1H),4. 52(ddd,1H),5.18(t,1H),7.13(d,1H).LC-MS:m / z=472.05(calcd.472.25 for C 22 H 38 N3O6S + [M+H + ]).

[0365] Example 52: Preparation of (4S,7S,9aS)-4-({2-[(tert-butoxycarbonyl)(methyl)amino]-2-methylpropanoyl}amino)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (14b)

[0366] [ka]

[0367] Lithium hydroxide solution (1 M, 375 μL, 0.375 mmol, 2.00 equiv) was added to a solution of methyl ester 37b (88 mg, 0.187 mmol, 1.00 equiv) dissolved in THF (375 μL) at room temperature. The resulting emulsion was stirred at 40 °C for 17 h. After completion, EtO (10 mL) was added and washed with a mixture of 1 M NaOH solution and brine (7:1, 3 × 8 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL), and the ethyl acetate layer was washed with a mixture of 1 M NaOH solution and brine (7:1, 2 × 8 mL). The combined aqueous layers were acidified to pH 1 with concentrated hydrochloric acid, and then extracted with CHCl (3 × 10 mL) and ethyl acetate (2 × 10 mL). The combined organic layers were dried (NaSO) and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate / formic acid 0.2%). Colorless solid, yield 41 mg (48%). f = 0.42 (hexane / ethyl acetate / formic acid 6:4:0.1, ammonium cerium molybdate stain). 1 H NMR (400 MHz, CDCl3): δ (ppm) = 1.14 (s, 3H), 1.19 (s, 3H), 1.35-1.41 (m, 15H), 1.84 (q, 1H), 2.00 (dd, 1H), 2.27 (dd, 1H), 2.32-2.40 (m, 1H), 2.77-2.84 (m, 1H), 2.89 (s, 3H), 3.27 (t, 1H), 4.20 (s, 1H), 4.59 (dd, 1H), 5.22 (t, 1H), 7.18 (d, 1H). No COOH is present in the spectrum. LC-MS: m / z = 458.10 (calcd. 458.23 for C21 H 36 N3O6S + [M+H + ]).

[0368] Example 53: Methyl (4S,7S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}butanamido]-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylate (37c)

[0369] [ka]

[0370] Compound 35 (406 mg, 0.481 mmol, 1.10 equiv) was treated with HCl in dioxane (4 M, 2.4 mL, 9.62 mmol, 20.0 equiv) and stirred for 2 h at 40° C. After completion, all volatiles were removed under reduced pressure.

[0371] The resulting amine 36, (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}butanoic acid (95 mg, 0.437 mmol, 1.00 equiv.), 1-hydroxybenzotriazole hydrate (80 mg, 0.524 mmol, 1.20 equiv.), and 4-methylmorpholine (144 μL, 3.00 equiv.) were dissolved in dry DMF (2.0 mL) under a N atmosphere and cooled to 0 °C. EDC·HCl (101 mg, 0.524 mmol, 1.20 equiv.) was added, and the resulting mixture was stirred at 0 °C for 30 min and then at room temperature for 20 h. After completion, water (10 mL) was added and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated NaHCO3 solution (2 x 10 mL), citric acid solution (5%, 2 x 10 mL), water (10 mL), and brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless resin, quantitative yield. 1H NMR (400 MHz, CDCl3): δ (ppm) = 0.89 (t, 3H), 1.09-1.16 (m, 6H), 1.47 (s, 9H), 1.66 (s, 1H), 1.86-2.04 (m, 3H), 2.27 (dd, 2H), 2.76 (s, 3H), 2.84 (d, 1H), 3.21-3.30 (m, 1H), 3.77 (s, 3H), 4.26 (s, 1H), 4.55 (dd, 1H), 5.16 (d, 1H), 7.34 (d, 1H). CHCH3 is not present in the spectrum. LC-MS: m / z = 472.15 (calcd. 472.25 for C 22 H 38 N3O6S + [M+H + ]).

[0372] Example 54: (4S,7S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}butanamido]-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (14c)

[0373] [ka]

[0374] Lithium hydroxide solution (1 M, 848 μL, 0.848 mmol, 2.00 equiv.) was added to a solution of methyl ester 37c (200 mg, 0.424 mmol, 1.00 equiv.) dissolved in THF (848 μL) at room temperature. The resulting emulsion was stirred at 40 °C for 39 h. After 16 and 22 h, lithium hydroxide monohydrate (18 mg, 0.424 mmol, 1.00 equiv.) was added, respectively. After completion, EtO (12 mL) was added and the mixture was washed with a mixture of 1 M NaOH solution and brine (10:2, 3 × 12 mL). The combined aqueous layers were extracted with EtO (12 mL), and the EtO layer was washed with a mixture of 1 M NaOH solution and brine (10:2, 2 × 12 mL). The combined aqueous layers were acidified to pH 1 with concentrated hydrochloric acid, and then extracted with CHCl (3×10 mL) and ethyl acetate (2×10 mL). The combined organic layers were dried (NaSO) and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate / formic acid 0.2%). Colorless resin, yield 134 mg (69%). 1 H NMR (400 MHz, CDCl3): δ (ppm) = 0.88 (t, 3H), 1.17 (s, 3H), 1.20 (s, 3H), 1.47 (s, 9H), 1.66 (s, 1H), 1.87-2.03 (m, 3H), 2.21-2.32 (m, 2H), 2.77 (s, 3H), 2.79-2.87 (m, 1H), 3.24 (t, 1H), 4.25 (s, 1H), 4.49-4.67 (m, 2H), 5.21 (t, 1H), 7.38 (d, 1H). No COOH was observed in the spectrum. LC-MS: m / z = 458.20 (calculated 458.23 for C). 21 H 36 N3O6S + [M+H + ]).

[0375] Synthetic scheme for the preparation of aldehyde 47

[0376] [ka]

[0377] Example 55: 2-(2,2-dimethoxyethyl)-2-(prop-2-en-1-yl)pent-4-enenitrile (46)

[0378] [ka]

[0379] Under a N2 atmosphere, LDA (2 M, 34.1 mL, 68.1 mmol, 2.20 equiv.) in THF / heptane / ethylbenzene was added dropwise to a solution of 4,4-dimethoxybutanenitrile at -78 °C. After 30 min, allyl bromide (6.70 mL, 77.4 mmol, 2.50 equiv.) was added slowly at -78 °C. After stirring at -78 °C for 1 h, stirring was continued at room temperature for 16 h. The mixture was carefully poured into a saturated solution of NH4Cl (300 mL) and extracted with CHCl (3 x 200 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by fc (hexane / ethyl acetate). Colorless liquid, yield 3.41 mg (53%). R f = 0.65 (hexane / ethyl acetate 8:2, KMnO4 staining). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.85(d,2H),2.36-2.42(m,4H),3.37(s,6H),4.63(t,1H),5. 20(dq,2H),5.25(ddt,2H),5.78-5.90(m,2H,-CH=CH2).LC-MS:m / z=210.10(calcd.210.15 for C 12 H 20 NO2 + [M+H + ]).

[0380] Example 56: 2-(2,2-dimethoxyethyl)-2-(prop-2-en-1-yl)pent-4-enal (47)

[0381] [ka]

[0382] Under a N2 atmosphere, DIBAL-H (1 M, 6.21 mL, 6.21 mmol, 1.30 equiv.) in hexane was added dropwise over 45 min to a solution of nitrile 46 (1.00 g, 4.78 mmol, 1.00 equiv.) in dry CHCl (1.00 mL) at −78 °C. After stirring at −78 °C for 2 h, stirring was continued at 0 °C for 2 h. Saturated NH4Cl solution (7.5 mL), saturated sodium potassium tartrate solution (11 mL), and Et2O (35 mL) were then added, and the mixture was stirred at room temperature for 1 h. After filtration through a Celite® pad, the organic solvent was removed in vacuo. The aqueous phase was extracted with CHCl (3 × 30 mL). The combined organic layers were washed with brine (30 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (cyclohexane / ethyl acetate). Colorless liquid, yield 0.766g (76%). f = 0.65 (hexane / ethyl acetate 8.5:1.5, KMnO4 staining). 1 H NMR(400MHz,CDCl3):δ(ppm)=1.87(d,2H),2.20(ddt,2H),2.35(ddt,2H),3.30(s,6H),4.39(t,1H), 5.07-5.12(m,2H),5.13(tq,2H),5.70(dddd,2H),9.42(s,1H).LC-MS:m / z=181.00(calcd.181.12for C 11 H 17 O2 + [M-H3C-O - ]).

[0383] Synthetic scheme for the preparation of carboxylic acid 14d

[0384] [ka]

[0385] Example 57: tert-butyl N-[(1S)-1-{[(4S,7S,9aS)-7-(1H-indole-1-carbonyl)-5-oxo-8,8-bis(prop-2-en-1-yl)-octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]carbamoyl}ethyl]-N-methylcarbamate (51)

[0386] [ka]

[0387] A mixture of N-(tert-butoxycarbonyl)-S-trityl-L-homocysteine (2.00 g, 4.19 mmol, 1.00 equiv.), aldehyde 47 (888 mg, 4.19 mmol, 1.00 equiv.), 1-(2,2-dimethoxyethyl)-2-isocyanobenzene 9 (800 mg, 4.19 mmol, 1.00 equiv.), and NH in MeOH (7 M, 1.20 mL, 8.37 mmol, 2.00 equiv.) in 2,2,2-trifluoroethanol (3.4 mL) was stirred under microwave irradiation at 80° C. After 30 min, all volatiles were removed under reduced pressure.

[0388] The residue was treated with HCl in dioxane (4 M, 10.5 mL, 41.8 mmol, 10.0 equiv) for 2 h at 40° C. Afterwards, all volatiles were removed under reduced pressure.

[0389] Amine 49, N-(tert-butoxycarbonyl)-N-methyl-L-alanine (1.02 g, 5.02 mmol, 1.20 equiv.), 1-hydroxybenzotriazole hydrate (931 mg, 5.44 mmol, 1.30 equiv.), and N-methylmorpholine (1.38 mL, 12.6 mmol, 3.00 equiv.) were dissolved in dry THF (20 mL) and cooled to 0 °C. EDC·HCl (1.04 g, 5.44 mmol, 1.30 equiv.) was added. After stirring at 0 °C for 30 min, stirring was continued at room temperature for 16 h. All volatiles were removed in vacuo, and the residue was dissolved in ethyl acetate (150 mL). The organic layer was washed with NaOH solution (1M, 50 mL), HCl solution (1M, 50 mL), water (50 mL), and brine (25 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by fc (hexane / ethyl acetate).

[0390] Isomer 1: Yellowish solid, yield 617 mg (25%). f =0.63 (hexane / ethyl acetate 6:4).

[0391] Isomer 2: Brown solid, yield 868 mg (35%). f =0.49 (hexane / ethyl acetate 6:4). 1 H NMR(400MHz,CDCl3):δ(ppm)=1.33(d,3H),1.42(s,9H),1.91-2.01(m,2H),2.08-2.21(m,2H), 2.24-2.36(m,3H),2.43(dd,1H),2.70-2.92(m,4H),3.29(ddd,1H),4.61(ddd,1H),4.92(dd,1 3H), 4.98 (dd, 1H), 5.18-5.25 (m, 2H), 5.31-5.36 (m, 2H), 5.53-5.65 (m, 1H), 5.82-5.95 (m, 1H), 6.68 (d, 1H), 7.27-7.36 (m, 3H), 7.56 (d, 1H), 7.62 (d, 1H), 8.57 (d, 1H). CHCH3 is not present in the spectrum. LC-MS: m / z = 595.20 (calcd. 595.25 for C) 32 H 43 N4O5S + [M+H+ ]).

[0392] Example 58: (4S,7S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-5-oxo-8,8-bis(prop-2-en-1-yl)-octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (14d)

[0393] [ka]

[0394] Indole amide 51 (250 mg, 0.420 mmol, 1.00 equiv) was dissolved in methanol (5.0 mL) and aqueous NaOH (1 M, 1.26 mL, 1.26 mmol, 3.00 equiv) was added. The resulting mixture was stirred at 30 °C for 3 h, after which the methanol was removed in vacuo. EtO (10 mL) was added and washed with NaOH solution (1 M, 3 × 15 mL). The combined NaOH layers were extracted with EtO (2 × 10 mL), and the aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and extracted with CHCl (2 × 10 mL, 1 × 20 mL) and EtOAc (1 × 20 mL). The combined organic layers were dried (NaSO) and concentrated in vacuo. The residue was purified by FC (hexane / ethyl acetate with 0.2% HCOOH). Colorless solid, yield 81 mg (39%). 1 H NMR(400MHz,CDCl3):δ(ppm)=1.35(d,3H),1.46(s,9H),1.92(q,1H),2.01(dd,1H),2.15(dd,3H),2.23-2.31(m,1H),2.37(dd,2H),2.75-2.87(m,4H) ),3.18-3.31(m,1H),3.71(s,1H),4.49(s,1H),4.58(dd,1H),5.05-5.22( m,5H),5.67-5.86(m,2H),7.37(s,1H).LC-MS:m / z=496.20(calcd.496.25 for C 24 H 38 N3O6S + [M+H +]).

[0395] Synthetic scheme for the preparation of carboxylic acid 14e

[0396] [ka]

[0397] Example 59: tert-Butyl N-[(1S)-1-{[(4'S,7'S,9'aS)-7'-(1H-indole-1-carbonyl)-5'-oxo-3',4',5',7',9',9'a-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepine]-3-en-4'-yl]carbamoyl}ethyl]-N-methylcarbamate (52)

[0398] [ka]

[0399] Under N2 atmosphere, Grubbs Catalyst (登録商標) The first generation (71 mg, 0.086 mmol, 0.125 equiv) was added to a solution of indole 51 (5.78 mL) in dry 1,2-dichloroethane, and the resulting mixture was stirred at reflux for 4 days. After 4, 8, 23, 27, 39, 51, 63, 75, and 87 hours, the Grubbs Catalyst (登録商標) 1st Generation (71 mg, 0.086 mmol, 0.125 equiv.) was added respectively. All volatiles were removed in vacuo and the resulting residue was purified by fc (hexane / ethyl acetate).

[0400] Isomer 1: Brown solid, yield 37 mg (10%). f =0.33 (hexane / ethyl acetate 6:4).

[0401] Isomer 2: Brown solid, yield 86 mg (22%). f=0.21 (hexane / ethyl acetate 6:4). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.34(d,3H),1.44(s,9H),1.68(s,2H),1.95(q,1H),2.18- 2.29(m,2H),2.42(s,2H),2.50-2.63(m,2H),2.76(s,3H),2.85-2.93(m,1H),3.30(dd,1 H),4.61(d,1H),5.20-5.26(m,2H),5.60-5.65(m,1H),5.69-5.75(m,1H),6.66(t,1H),7 .32(ddtd,3H),7.57(d,1H),7.61(d,1H),8.56(d,1H).LC-MS:m / z=567.25(calcd.567.26 for C 30 H 39 N4O5S + [M+H + ]).

[0402] Example 60: (4'S,7'S,9'aS)-4'-(2-{[(tert-butoxy)carbonyl](methyl)amino}acetamido)-5'-oxo-3',4',5',7',9',9'a-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepine]-3-ene-7'-carboxylic acid (14e)

[0403] [ka]

[0404] Indole amide 52 (86 mg, 0.152 mmol, 1.00 equiv) was dissolved in methanol (1.84 mL) and aqueous NaOH (1 M, 456 μL, 0.456 mmol, 3.00 equiv) was added. The resulting mixture was stirred at 40 °C for 2 days, after which the methanol was removed in vacuo. EtO (10 mL) was added and washed with NaOH solution (1 M, 3 × 10 mL). The combined NaOH layers were extracted with EtO (2 × 10 mL), after which the aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and extracted with CHCl (3 × 10 mL) and EtOAc (2 × 10 mL). The combined organic layers were dried (NaSO) and concentrated in vacuo. The residue was purified by FC (hexane / ethyl acetate with 0.2% HCOOH). Colorless solid, yield 48 mg (68%). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.34(d,3H),1.45(s,9H),1.93(t,1H),2.15(ddd,1H),2.22-2.36(m,4H),2.46(ddd,1H),2.73( d,1H),2.79(s,3H),3.25(t,1H),4.46(s,1H),4.63(t,1H),5.18(td,1H),5.60-5.66(m,1H),5.68-5.74(m,1H),7.40(s,1H).

[0405] Synthetic scheme for the preparation of carboxylic acid 14f

[0406] [ka]

[0407] Example 61: Methyl 2-(1,3-dioxan-2-yl)acetate (55)

[0408] [ka]

[0409] Compound 55 was prepared according to established literature procedures; Gobbi, L.; Jaeschke, G.; Rodriguez S., Rosa M.; Steward, L. Application: see WO 2010031735 A1.

[0410] Example 61: 2-(1,3-dioxan-2-yl)acetaldehyde (56)

[0411] [ka]

[0412] Under a N2 atmosphere, DIBAL-H in hexane (1 M, 5.91 mL, 5.91 mmol, 1.10 equiv.) was added dropwise over 30 min to a solution of ester 55 (860 mg, 4.78 mmol, 5.37 equiv.) in dry CHCl (11.2 mL) at −78 °C. After stirring at −78 °C for 1.5 h, saturated sodium potassium tartrate solution (12.5 mL) was added, and the mixture was stirred at room temperature for 2 h. The two layers were separated, and the aqueous phase was extracted with CHCl (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (NaSO), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). A colorless liquid, 356 mg yield (50%). Analytical data correspond to literature.

[0413] Example 62: Benzyl (2S,3S)-2-amino-4-(1,3-dioxan-2-yl)-3-hydroxybutanoate (62)

[0414] [ka]

[0415] Compound 62 was prepared according to established literature procedures; see Boger, DL; Schule GJ Org. Chem. 1998, 63, 6421-6424.

[0416] Example 63: Benzyl (2S,3S)-2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(triphenylmethyl)sulfanyl]butanamido]-4-(1,3-dioxan-2-yl)-3-hydroxybutanoate (63)

[0417] [ka]

[0418] PPh3 (270 mg, 1.03 mmol, 2.00 equiv) was added to azide 61 (166 mg, 0.515 mmol, 1.00 equiv) dissolved in THF (1.80 mL) and water (93 μL). The resulting mixture was stirred at 50 °C for 16 h, after which all volatiles were removed in vacuo.

[0419] Under a N atmosphere, amine 62, carboxylic acid 7 (246 mg, 0.515 mmol, 1.00 equiv.), 1-hydroxybenzotriazole hydrate (95 mg, 0.618 mmol, 1.20 equiv.), and N-methylmorpholine (170 μL, 1.55 mmol, 3.00 equiv.) were dissolved in dry THF (1.84 mL) and cooled to 0 °C. EDC·HCl (119 mg, 0.618 mmol, 1.20 equiv.) was added, and the resulting mixture was stirred at 0 °C for 30 min and then at room temperature for 16 h. After completion, ethyl acetate (30 mL) was added and washed with saturated NaHCO solution (2 × 10 mL), citric acid solution (5%, 2 × 10 mL), water (10 mL), and brine (10 mL), dried (NaSO), and concentrated in vacuo. The resulting residue was purified by FC (hexane / ethyl acetate). Colorless solid, yield 235 mg (60%). 1H NMR (400MHz, CDCl3): δ(ppm)=1.40(s,9H),1.69-1.88(m,4H),1.98-2.11(m,2H),2.16-2. 32(m,2H),3.67-3.78(m,2H),3.98(s,1H),4.03-4.10(m,2H),4.18-4.24(m,1H),4.51-4. 58(m,1H),4.66-4.75(m,2H),5.14(d,1H),5.19(d,1H),6.86(d,1H),7.16-7.22(m,3H),7 .23-7.30(m,7H),7.31-7.35(m,4H),7.37-7.41(m,6H).LC-MS:m / z=777.30(calcd.777.32 for C 43 H 50 N2NaO8S + [M+Na + ]).

[0420] Example 64: Benzyl (4S,7S,8S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-8-hydroxy-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylate (65)

[0421] [ka]

[0422] Compound 63 (222 mg, 0.294 mmol, 1.00 equiv) dissolved in 1,4-dioxane (1.47 mL) was treated with HCl in dioxane (4 M, 1.47 mL, 5.88 mmol, 20.0 equiv) and stirred for 2 h at 40° C. After completion, all volatiles were removed under reduced pressure.

[0423] The resulting amine 64, N-(tert-butoxycarbonyl)-N-methyl-L-alanine (60 mg, 0.294 mmol, 1.00 equiv.), 1-hydroxybenzotriazole hydrate (54 mg, 0.353 mmol, 1.20 equiv.), and 4-methylmorpholine (97 μL, 0.882 mmol, 3.00 equiv.) was dissolved in dry DMF (1.37 mL) under a N atmosphere and cooled to 0 °C. EDC·HCl (68 mg, 0.353 mmol, 1.20 equiv.) was added, and the resulting mixture was stirred at 0 °C for 30 min and then at room temperature for 15 h. After completion, water (30 mL) was added and the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with saturated NaHCO3 solution (2 x 10 mL), citric acid solution (5%, 2 x 10 mL), water (10 mL), and brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). A yellow resin, yield 67 mg (43%). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.32(d,3H),1.46(s,9H),1.84-1.91(m,1H),2 .05-2.14(m,1H),2.19-2.28(m,1H),2.48-2.57(m,1H),2.77(s,3H),2.79-2. 85(m,1H),3.21-3.39(m,2H),4.51-4.59(m,2H),4.68(s,1H),5.14-5.23(m, 2H),5.30-5.35(m,1H),7.29-7.38(m,6H).LC-MS:m / z=522.25(calcd.522.23 for C 25 H 36 N3O7S + [M+H + ]).

[0424] Example 65: (4S,7S,8S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-8-hydroxy-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (14f)

[0425] [ka]

[0426] Lithium hydroxide solution (1 M, 255 μL, 0.255 mmol, 2.00 equiv.) was added to a solution of ester 65 (67 mg, 0.127 mmol, 1.00 equiv.) dissolved in THF (255 μL) at room temperature. The resulting emulsion was stirred at 40 °C for 15 h. After completion, EtO (10 mL) was added and washed with a mixture of 1 M NaOH solution and brine (8:2, 3 × 10 mL). The combined aqueous layers were extracted with EtO (10 mL), and the EtO layer was washed with a mixture of 1 M NaOH solution and brine (8:2, 2 × 10 mL). The combined aqueous layers were acidified to pH 1 with concentrated hydrochloric acid, and then extracted with CHCl (3 × 10 mL) and ethyl acetate (2 × 10 mL). The combined organic layers were dried (NaSO) and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate / formic acid 0.2%): yellow resin, yield 32 mg (59%).

[0427] Synthetic scheme for the preparation of dimers 18b-k

[0428] [ka]

[0429] Example 66: Preparation of tert-butyl [(2S)-1-{[(4S,7S,9aS)-7-({(1S,2R)-2-[(6-{[(1S,2R)-1-({[(4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-dihydro-1H-inden-2-yl]oxy}hexyl)oxy]-2,3-dihydro-1H-inden-1-yl}carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (17b)

[0430] [ka]

[0431] The compound was prepared according to general procedure B. White solid, yield 49 mg (62%). f = 0.64 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.14(s,12H),1.31(d,4H),1.36(d,6H),1.47(s,18H),1.49-1 .56(m,4H),1.80(dd,2H),1.89-2.00(m,2H),2.19-2.27(m,2H),2.30(dd,2H),2.81-2.86(m , 8H), 3.05 (d, 4H), 3.27 (d, 2H), 3.40-3.52 (m, 4H), 4.22 (q, 2H), 4.27 (s, 2H), 4.64 (d, 4H), 5.38-5.48 (m, 4H), 7.15-7.25 (m, 6H), 7.30-7.35 (m, 2H), 7.92 (d, 2H). C(O)NH is not observed in the spectrum. LC-MS: m / z = 1231.65 (calcd. 1231.65 for C 64 H 95 N8O 12 S2 + [M+H + ]).

[0432] Example 67: tert-Butyl [(2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-({3-[4-(3-{[(1S,2R)-1-({[(4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-dihydro-1H-yne Preparation of)-2,3-dihydro-1H-inden-1-yl]oxy}prop-1-yn-1-yl)phenyl]prop-2-yn-1-yl}oxy)-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (17c)

[0433] [ka]

[0434] The compound was prepared according to general procedure B. White solid, yield 57 mg (66%). f = 0.56 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.16(d,12H),1.33(d,6H),1.46(s,18H),1.81(dd,2H),1.98-2. 10(m,2H),2.23(dd,2H),2.32(dd,2H),2.78-2.89(m,8H),3.11(dd,2H),3.20(dd,2H),3.26-3 .31 (m, 2H), 4.29 (s, 2H), 4.40 (d, 2H), 4.47 (d, 2H), 4.56 (q, 2H), 4.65 (dd, 2H), 5.42-5.52 (m, 4H), 7.22 (ddt, 6H), 7.33 (d, 2H), 7.43 (s, 4H), 7.86 (d, 2H), 8.07 (d, 2H). CHCH3 is not observed in the spectrum. LC-MS: m / z = 1299.45 (calcd. 1299.62 for C 70 H 91 N8O 12 S2 + [M+H +]).

[0435] Example 68: tert-Butyl [(2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-({3-[3-(3-{[(1S,2R)-1-({[(4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-dihydro-1H-yne Preparation of]inden-2-yl]oxy}prop-1-yn-1-yl)phenyl]prop-2-yn-1-yl}oxy-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (17d)

[0436] [ka]

[0437] The compound was prepared according to general procedure B. White solid, yield 57 mg (68%). f = 0.54 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.14(s,6H),1.16(s,6H),1.33(d,6H),1.45(s,18H),1.81(dd,2H),1.98- 2.10(m,2H),2.19-2.26(m,2H),2.31(dd,2H),2.77-2.88(m,8H),3.12(dd,2H,),3.19(dd,2H),3.26-3.3 0 (m, 2H), 4.29 (s, 2H), 4.39 (d, 2H), 4.46 (d, 2H), 4.53-4.58 (m, 2H), 4.64 (dd, 2H), 5.41-5.52 (m, 4H), 7.22 (dt, 6H), 7.31-7.37 (m, 3H), 7.44 (d, 2H), 7.51 (s, 1H), 7.86 (d, 2H), 8.07 (d, 2H). CHCH3 is not present in the spectrum. LC-MS: m / z = 1299.60 (calcd. 1299.62 for C70 H 91 N8O 12 S2 + [M+H + ]).

[0438] Example 69: tert-Butyl [(2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-{[4-(3-{[(1S,2R)-1-({[(4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-dihydro- Preparation of 1H-inden-2-yl]oxy}prop-1-yn-1-yl)benzyl]oxy}-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (17e)

[0439] [ka]

[0440] The compound was prepared according to general procedure B. White solid, yield 53 mg (65%). f = 0.43 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1H NMR(400MHz,CD3OD):δ(ppm)=1.09-1.17(m,12H,C(CH3)2),1.28-1.35(m,6H),1.42-1.48(m,18H),1.58-1. 68(m,1H),1.72-1.85(m,2H),1.94-2.11(m,2H),2.18-2.26(m,1H),2.31(dt,2H),2.48-2.57(m,1H),2.76-2 0.86 (m, 8H), 3.04-3.23 (m, 5H), 4.24-4.30 (m, 2H), 4.34-4.47 (m, 3H), 4.52-4.67 (m, 5H), 5.38-5.51 (m, 4H), 7.19-7.34 (m, 10H), 7.39 (d, 2H), 7.73 (d, 1H), 7.87 (d, 1H), 8.01 (d, 1H), 8.06 (d, 1H). CHCH3 is not present in the spectrum. LC-MS: m / z = 1275.55 (calculated 1275.62 for C 68 H 91 N8O 12 S2 + [M+H + ]).

[0441] Example 70: Preparation of tert-butyl [(2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-({4-[4-({[(1S,2R)-1-({[(4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-dihydro-1H-inden-2-yl]oxy}methyl)phenyl]benzyl}oxy)-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (17f)

[0442] [ka]

[0443] The compound was prepared according to general procedure B. White solid, yield 42 mg (49%).f = 0.63 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.13(s,12H),1.30(d,6H),1.43(s,18H),1.58-1.70(m,2H),1.76(dd, 2H),1.93-2.00(m,2H),2.30(dd,2H),2.46-2.54(m,2H),2.77(s,6H),3.07(dd,2H),3.14-3.23(m,4H ),4.28(s,2H),4.36-4.41(m,2H),4.46-4.67(m,8H),5.41(t,2H),5.48(dd,2H),7.18-7.27(m,6H),7 .33(d,2H),7.37(d,4H),7.56(d,4H),7.74(d,2H),8.03(d,2H).LC-MS:m / z=1327.85(calcd.1327.65 for C 72 H 95 N8O 12 S2 + [M+H + ]).

[0444] Example 71: Preparation of tert-butyl [(2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-{[4-({[(1S,2R)-1-({[(4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-dihydro-1H-inden-2-yl]oxy}methyl)benzyl]oxy}-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (17 g)

[0445] [ka]

[0446] The compound was prepared according to general procedure B. White solid, yield 39 mg (49%). f = 0.63 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.13(s,12H),1.35(d,6H),1.45(s,18H),1.61-1.8 4(m,4H),1.98-2.04(m,2H),2.26-2.34(m,2H),2.45-2.56(m,2H),2.82(s,6H),3 .04(dd,2H),3.15(dd,4H),4.27(s,2H),4.31-4.37(m,2H),4.58(s,6H),5.37-5. 50(m,4H),7.17-7.35(m,12H),7.81(d,2H),8.01(d,2H,).CHCH3 is not seen in the spectrum. LC-MS:m / z=1251.65(calcd.1251.62 for C 66 H 91 N8O 12 S2 + [M+H + ]).

[0447] Example 72. Preparation of tert-butyl [(2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-{2-[(2-{[(1S,2R)-1-({[(4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-dihydro-1H-inden-2-yl]oxy}ethyl)sulfonyl]ethoxy}-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (17h)

[0448] [ka]

[0449] The compound was prepared according to general procedure B. White solid, yield 41 mg (50%). f = 0.72 (ethyl acetate / methanol 10:1, ammonium cerium molybdate staining). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.16(d,12H),1.37(d,6H),1.46(s,18H),1.87(dd,2H),1.98(dd, 2H),2.19-2.26(m,2H),2.30(dd,2H),2.81-2.92(m,8H),3.03(d,4H),3.14(dt,2H),3.24-3.30 (m,4H),3.76-3.90(m,4H),4.05(q,2H),4.41(s,2H),4.67(dd,4H),5.31(dd,2H),5.45(t,2H), 7.04-7.22(m,6H),7.36(d,2H),7.90(d,1H),7.96(d,2H).LC-MS:m / z=1267.60(calcd.1267.58 for C 62 H 91 N8O 14 S3 + [M+H + ]).

[0450] Example 73. Preparation of tert-butyl [(2S)-1-{[(4S,7S,9aS)-7-({(1R)-3-[(6-{[(3R)-3-({[(4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-3-phenylpropyl]oxy}hexa-2,4-diyn-1-yl)oxy]-1-phenylpropyl}carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (17i)

[0451] [ka]

[0452] The compound was prepared according to general procedure B. White solid, yield 48 mg (61%).f = 0.58 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.02(s,6H),1.14(s,6H),1.37(d,6H),1.47(s,18H),1.85-1.96(m ,4H),2.02-2.08(m,4H),2.21-2.34(m,4H),2.86(s,6H),2.88-2.95(m,2H),3.32-3.36(m,2H),3. 46-3.56(m,4H),4.17-4.23(m,4H),4.26(d,2H),4.47-4.71(m,4H),5.07(q,2H),5.46(t,2H),7.2 1-7.27(m,2H),7.31-7.40(m,8H),7.94(d,2H),8.18(d,2H).LC-MS:m / z=1227.65(calcd.1227.62 for C 64 H 91 N8O 12 S2 + [M+H + ]).

[0453] Example 74. tert-Butyl [(1S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-[(4-{[(1S,2R)-1-[(4S,7S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine Preparation of -7-amido]-2,3-dihydro-1H-inden-2-yl]oxy}but-2-yn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (17j)

[0454] [ka]

[0455] The compound was prepared according to general procedure B. White solid, yield 51 mg (66%). f = 0.80 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.15(s,6H),1.18(s,6H),1.39(d,6H),1.48(s,18H),1.81(d d,2H),1.93-2.05(m,2H),2.07-2.18(m,2H),2.35(dd,2H),2.66(d,2H),2.86(s,6H),3.11 (d,6H),4.15-4.32(m,6H),4.43(d,2H),4.55-4.70(m,4H),5.38-5.47(m,2H),5.55(dd,2H) ),7.18-7.30(m,8H),7.81-7.88(m,2H),7.95(d,2H).LC-MS:m / z=1199.60(calcd.1199.59 for C 62 H 87 N8O 12 S2 + [M+H + ]).

[0456] Example 75. Preparation of tert-butyl (1-{[(4S,7S,9aS)-7-({(1S,2R)-2-[(6-{[(1S,2R)-1-({[(4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-dihydro-1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl}carbamoyl-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-2-methyl-1-oxopropan-2-yl)(methyl)carbamate (17k)

[0457] [ka]

[0458] The compound was prepared according to general procedure B. White solid, yield 34 mg (65%). f = 0.58 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.09-1.19(m,12H),1.40(d,30H),1.80(dd,2H),1.89-2.0 0(m,2H),2.22-2.29(m,2H),2.33(dd,2H),2.81-2.89(m,2H),2.94(s,6H),3.06-3.17(m, 4H),3.35(s,2H),4.21-4.28(m,4H),4.33(d,2H),4.43(q,2H),4.59(dd,2H),5.42-5.50( m,4H),7.18-7.34(m,8H),7.56(d,2H),7.99(d,2H).LC-MS:m / z=1251.70(calcd.1251.62 for C 66 H 91 N8O 12 S2 + [M+H + ]).

[0459] Example 76: tert-Butyl N-[(1S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-[(6-{[(1S,2R)-1-[(4S,7S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}butanamido]-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiaze Preparation of]-2,3-dihydro-1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]carbamoyl}propyl]-N-methylcarbamate (17m)

[0460] [ka]

[0461] The compound was prepared according to general procedure B. Modifications: Ethyl acetate (30 mL) was added to the reaction mixture, which was washed with saturated NaHCO solution (3 × 10 mL), citric acid solution (5%, 2 × 10 mL), water (10 mL), and brine (10 mL), dried (NaSO), and concentrated in vacuo. White solid, yield 117 mg (75%). 1 H NMR (400 MHz, CDCl): δ (ppm) = 0.89 (t, 6H), 1.12 (s, 6H), 1.19 (s, 6H), 1.48 (s, 18H), 1.67 (s, 2H), 1.79-1.93 (m, 6H), 2.23-2.34 (m, 4H), 2.75-2.83 (m, 8H), 3.10 (d, 4H), 3.21-3.32 (m, 2H), 4.14-4.28 (m, 6H), 4.47 (q, 2H), 4.53 (s, 2H), 5.16 (t, 2H), 5.52 (dd, 2H), 7.18-7.34 (m, 8H), 7.42 (s, 2H). BocNCH and C(=O)NH are not seen in the spectrum. LC-MS:m / z=1251.65(calcd.1251.62 for C 66 H 91 N8O 12 S2 + [M+H + ]).

[0462] Example 78: tert-Butyl N-[(1S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-[(6-{[(1S,2R)-1-[(4S,7S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-5-oxo-8,8-bis(prop-2-en-1-yl)-octahydropyrrolo[2,1-b][1,3]thiazolinone] Preparation of]-2,3-dihydro-1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl}-5-oxo-8,8-bis(prop-2-en-1-yl)-octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]carbamoyl}ethyl]-N-methylcarbamate (17n)

[0463] [ka]

[0464] The compound was prepared according to general procedure B. Colorless solid, yield 60 mg (63%). 1 H NMR (400MHz, CDCl3): δ(ppm)=1.35(d,6H),1.48(s,18H),1.79-1.94(m,6H),2.00-2.10(m ,6H),2.31(d,2H),2.39(dd,2H),2.43-2.50(m,2H),2.76-2.83(m,8H),3.10(d,4H),3.21- 3.31(m,2H),4.16(d,2H),4.25(d,2H),4.48(d,6H),5.02-5.19(m,11H),5.47-5.54(m,2H) ),5.68-5.88(m,4H),7.17-7.25(m,6H),7.34(t,6H).LC-MS:m / z=1327.60(calcd.1327.65 for C 72 H 95 N8O 12 S2 + [M+H + ]).

[0465] Example 79: tert-Butyl N-[(1S)-1-{[(4'S,7'S,9'aS)-7'-{[(1S,2R)-2-[(6-{[(1S,2R)-1-{[(4'S,7'S,9'aS)-4'-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-5'-oxo-3',4',5',7',9',9'a-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepine] Preparation of {(2,3-dihydro-1H-inden-2-yl)oxy}hexa-2,4-diyn-1-yl)oxy}-2,3-dihydro-1H-inden-1-yl)carbamoyl}-5'-oxo-3',4',5',7',9',9'a-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepine]-3-en-4'-yl]carbamoyl}ethyl]-N-methylcarbamate (17o)

[0466] [ka]

[0467] The compound was prepared according to general procedure B. Modifications: Ethyl acetate (30 mL) was added to the reaction mixture, which was washed with saturated NaHCO solution (2 × 10 mL), citric acid solution (5%, 2 × 10 mL), water (10 mL), and brine (10 mL), dried (NaSO), and concentrated in vacuo. Colorless solid, yield 37 mg (60%). 1 H NMR(400MHz,CDCl3):δ(ppm)=1.35(d,6H),1.47(s,18H),1.85(t,4H),2.09(d,2H),2.23( d,8H),2.51(dd,2H),2.77-2.85(m,8H),2.95(d,2H),3.10(d,4H),3.31(dd,2H),4.21(d, 2H),4.28(d,2H),4.45-4.50(m,4H),4.54(t,2H),5.14(d,2H),5.53(dd,2H),5.59-5.64( m,2H),5.76(d,2H),7.17-7.25(m,6H),7.30(t,6H).LC-MS:m / z=1271.70(calcd.1271.59 for C 68 H 87 N8O 12 S2 + [M+H + ]).

[0468] Example 80: tert-Butyl N-[(1S)-1-{[(4S,7S,8S,9aS)-7-{[(1S,2R)-2-[(6-{[(1S,2R)-1-[(4S,7S,8S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-8-hydroxy-5-oxo-octahydropyrrolo[2,1-b][1,3 Preparation of]thiazepine-7-amido]-2,3-dihydro-1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8-hydroxy-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]carbamoyl}ethyl]-N-methylcarbamate (17p)

[0469] [ka]

[0470] The compound was prepared according to general procedure B. Modification: The reaction was carried out in a 4:1 mixture of THF and DMF. Additionally, water (10 mL) was added to the reaction mixture and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated NaHCO3 solution (2 × 10 mL), citric acid solution (5%, 2 × 10 mL), water (10 mL), and brine (10 mL), dried (Na2SO4), and concentrated in vacuo. Colorless solid, yield 31 mg (69%). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.36(d,6H),1.45(s,18H),1.93(q,2H),2.11(ddd, 2H),2.26(dd,2H),2.55(dd,2H),2.84(s,6H),3.05-3.16(m,4H),3.21-3.31(m,2 H),4.27-4.36(m,4H),4.39-4.46(m,2H),4.56(d,2H),4.64-4.71(m,4H),5.40-5 .52(m,4H),7.17-7.29(m,9H),7.88(d,2H).LC-MS:m / z=1199.60(calcd.1199.52 for C 60 H 79 N8O14 S2 + [M+H + ]).

[0471] Example 81 (2S)-1-{[(4S,7S,9aS)-7-({(1S,2R)-2-[(6-{[(1S,2R)-1-({[(4S,7S,9aS)-8,8-dimethyl-4-{[(2S)-2-(methylammonio)propanoyl]amino}-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}a Preparation of)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-N-methyl-1-oxopropane-2-ammonium dichloride (18b)

[0472] [ka]

[0473] Compound 18b was prepared according to general procedure A. White solid, yield 34 mg (82%). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.14(s,12H),1.31(d,4H),1.36(d,6H),1.47(s,18H),1.49-1 .56(m,4H),1.80(dd,2H),1.89-2.00(m,2H),2.19-2.27(m,2H),2.30(dd,2H),2.81-2.86(m , 8H), 3.05 (d, 4H), 3.27 (d, 2H), 3.40-3.52 (m, 4H), 4.22 (q, 2H), 4.27 (s, 2H), 4.64 (d, 4H), 5.38-5.48 (m, 4H), 7.15-7.25 (m, 6H), 7.30-7.35 (m, 2H), 7.92 (d, 2H). C(O)NH is not seen in the spectrum. 13C NMR(101 MHz,CD3OD):δ(ppm)=14.5,24.1,27.0,28.7,28.8,30.9,31.2,32.4,33.9,37.5,40.9,47.1,54.2,56.9,6 1.9,70.7,73.4,81.6-81.7,125.5,126.1,127.9,129.2,141.3,142.7,172.0,172.8,173.2.CHCH3 and C=O カルバメート is not seen in the spectrum. LC-MS: m / z = 1231.65 (calculated for C 64 H 95 N8O 12 S2 + [M+H + ]).

[0474] Example 82 (2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-({3-[4-(3-{[(1S,2R)-1-({[(4S,7S,9aS)-8,8-dimethyl-4-{[(2S)-2-(methylammonio)propanoyl]amino}-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-dihydr Preparation of (2,3-dihydro-1H-inden-1-yl)oxy}prop-1-yn-1-yl)phenyl]prop-2-yn-1-yl}oxy)-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-N-methyl-1-oxopropane-2-ammonium dichloride (18c)

[0475] [ka]

[0476] Compound 18c was prepared according to general procedure A. White solid, yield 40 mg (81%). 11H NMR (400 MHz, CD3OD): δ (ppm) = 1.16 (s, 12H), 1.53 (d, 6H), 1.82 (dd, 2H), 2.11 (q, 2H), 2.25 (d, 2H), 2.33 (dd, 2H), 2.65 (s, 6H), 2.90 (q, 2H), 3.12 (dd, 2H), 3.16 - 3.23 (m, 2H), 3.25 - 3.30 (m, 2H), 3.89 (q, 2H), 4.26 (s, 2H), 4.40 (d, 2H), 4.49 (d, 2H), 4.54 - 4.60 (m, 2H), 4.75 (d, 2H), 5.48 (q, 4H), 7.17 - 7.36 (m, 8H), 7.43 (s, 4H), 8.07 (d, 2H), 8.71 (d, 2H). NH2 + is not seen in the spectrum. 13 13C NMR (101 MHz, CD3OD): δ (ppm) = 16.4, 24.2, 28.9, 31.8, 32.4, 33.5, 37.3, 40.8, 47.3, 54.4, 56.9, 58.2, 58.3, 61.7, 73.6, 80.7, 86.6, 88.4, 124.1, 125.5, 126.1, 128.0, 129.4, 132.8, 141.1, 142.3, 169.3, 172.2, 172.4. LC-MS: m / z = 1099.50 (calcd. 1099.51 for C 60 18 75 N8O8S2 + [M + H + .

[0477] Example 83 (2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-({3-[3-(3-{[(1S,2R)-1-({[(4S,7S,9aS)-8,8-dimethyl-4-{[(2S)-2-(methylammonio)propanoyl]amino}-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-dihydr Preparation of (2,3-dihydro-1H-inden-1-yl)oxy}prop-1-yn-1-yl)phenyl]prop-2-yn-1-yl}oxy)-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-N-methyl-1-oxopropane-2-ammonium dichloride (18d)

[0478] [ka]

[0479] Compound 18d was prepared according to general procedure A. White solid, yield 41 mg (86%). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.12-1.18(m,12H),1.53(d,6H),1.82(dd,2H),2.10(q,2H),2 .21-2.36(m,4H),2.65(s,6H),2.90(d,2H),3.13(dd,2H),3.20(dd,2H),3.26(s,2H),3.88(q ,2H),4.26(s,2H),4.40(d,2H),4.49(d,2H),4.58(q,2H),4.74(dt,2H),5.42-5.52(m,4H),7 .17-7.27(m,6H),7.31-7.38(m,3H),7.44(d,2H),7.51(s,1H),8.07(d,2H),8.70(d,2H).NH2 + is not seen in the spectrum. 13C NMR(101 MHz,CD3OD):δ(ppm)=16.4,24.2,28.9,31.9,32.4,33.5,37.3,40.8,47.3,54.4,56.8,58.2,58.3,61.8,73.5,80.7,86.2,87.3, 124.4,125.5,126.2,128.0,129.4,130.0,132.8,135.5,141.1,142.3,169.2,172.2,172.4.LC-MS:m / z=1099.50(calcd.1099.51 for C 60 H 75 N8O8S2 + [M+H + ]).

[0480] Example 84 (2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-({3-[4-({[(1S,2R)-1-({[(4S,7S,9aS)-8,8-dimethyl-4-{[(2S)-2-(methylammonio)propanoyl]amino}-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3 Preparation of (dihydro-1H-inden-2-yl)oxy}methyl)phenyl]prop-2-yn-1-yl}oxy)-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-N-methyl-1-oxopropane-2-ammonium dichloride (18e)

[0481] [ka]

[0482] Compound 18e was prepared according to general procedure A. White solid, yield 36 mg (89%). 1H NMR(400MHz,CD3OD):δ(ppm)=1.09-1.17(m,12H),1.49-1.57(m,6H),1.72-1.87(m,3H),2.00-2.08(m,1H),2.08- 2.17(m,1H),2.20-2.38(m,3H),2.56(dd,1H),2.60-2.67(m,6H),2.83-2.94(m,1H),3.02-3.29(m,6H),3.86-3.96 (m,2H),4.22-4.29(m,2H),4.30-4.41(m,2H),4.47(d,1H),4.53-4.59(m,1H),4.61(s,2H),4.68(d,1H),4.75(d,1 C(O)NH and NH2 + is not seen in the spectrum. 13 C NMR(101 MHz,CD3OD):δ(ppm)=15.1-15.2,22.7-22.9,27.6,30.5-30.7,31.0-31.1,32.0-32.2,35.9-36.0 ,39.5-39.6,45.8-46.0,53.0-53.2,55.4-55.6,56.9,57.0-57.1,60.4-60.5,70.3,72.2,79.2,7 9.9,85.1,85.8,121.7,124.1-124.2,124.8,126.7-126.8,127.5,128.0-128.1,131.4,139.2,13 9.8-139.8,141.0,141.2,167.9,168.0,170.7,170.8,171.1.LC-MS:m / z=1075.60(calcd.1075.51 for C 58 H 75 N8O8S2 + [M+H + ]).

[0483] Example 85 (2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-({4-[4-({[(1S,2R)-1-({[(4S,7S,9aS)-8,8-dimethyl-4-{[(2S)-2-(methylammonio)propanoyl]amino}-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino Preparation of )-2,3-dihydro-1H-inden-2-yl]oxy}methyl)phenyl]benzyl}oxy)-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-N-methyl-1-oxopropane-2-ammonium dichloride (18f)

[0484] [ka]

[0485] Compound 18f was prepared according to general procedure A. White solid, yield 34 mg (89%). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.05-1.16(m,12H),1.53(d,6H),1.74-1.88(m,4H), 2.05(d,2H),2.27-2.37(m,2H),2.62(d,8H),3.08(dd,2H),3.14-3.24(m,4H),3.88 (q,2H),4.26(s,2H),4.35-4.42(m,2H),4.60-4.73(m,6H),5.39-5.51(m,4H),7.18 -7.28(m,6H),7.34(d,2H),7.40(d,4H),7.59(d,4H),8.05(d,2H),8.63(d,2H).NH2 + is not seen in the spectrum. 13C NMR(101 MHz, CD3OD): δ(ppm)=16.4,24.1,28.9,31.8,32.3,33.3,37.3,40.9,47.2,54.4,56.8,58.3,61.7,71.8,73.5,80.9,125.5 ,126.2,127.8,128.0,129.4,129.5,138.9,141.2-141.3,142.6,169.2,172.1,172.5.LC-MS:m / z=1127.60(calcd.1127.55 for C 62 H 79 N8O8S2 + [M+H + ]).

[0486] Example 86 (2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-{[4-({[(1S,2R)-1-({[(4S,7S,9aS)-8,8-dimethyl-4-{[(2S)-2-(methylammonio)propanoyl]amino}-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino Preparation of N-methyl-1-oxopropane-2-ammonium dichloride (18 g)

[0487] [ka]

[0488] Compound 18g was prepared according to general procedure A. White solid, yield 25 mg (71%). 1H NMR(400MHz,CD3OD):δ(ppm)=1.10(d,12H),1.55(d,6H),1.62-1.83(m,4H ),2.00(d,2H),2.29(dd,2H),2.56(d,2H),2.62-2.73(m,6H),3.00-3.25( m,6H),4.02(q,1H),4.20(s,2H),4.29-4.41(m,2H),4.53(s,4H),4.74(d, 2H),5.33-5.52(m,4H),7.14-7.37(m,12H),7.96(d,2H),8.65(d,2H).NH2 + is not seen in the spectrum. 13 C NMR(101 MHz,CD3OD):δ(ppm)=16.9,24.0,28.9,32.0,32.4,33.6,37.3,41.0,47.0,54.5,56.6,58.3,61.8,72.1,73.8,80.8 ,125.7,126.2,128.1,129.3,129.6,139.1,141.1,142.5,169.3,172.0,172.9.LC-MS:m / z=1051.60(calcd.1051.51 for C 56 H 75 N8O8S2 + [M+H + ]).

[0489] Example 87 (2S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-{2-[(2-{[(1S,2R)-1-({[(4S,7S,9aS)-8,8-dimethyl-4-{[(2S)-2-(methylammonio)propanoyl]amino}-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino Preparation of N-(2,3-dihydro-1H-inden-2-yl)oxy}ethyl)sulfonyl]ethoxy}-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-N-methyl-1-oxopropane-2-ammonium dichloride (18h)

[0490] [ka]

[0491] Compound 18h was prepared according to general procedure A. White solid, yield 28 mg (76%). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.10-1.23(m,12H),1.55(d,6H),1.83-1.94(m,2H),2.0 3(q,2H),2.23-2.37(m,4H),2.68(s,6H),2.92(d,2H),2.97-3.07(m,4H),3.14-3.30( m,6H),3.84(s,4H),3.95(q,2H),4.02-4.09(m,2H),4.38(s,2H),4.75(d,2H),5.28-5 .38(m,2H),5.46(t,2H),7.02-7.23(m,6H),7.35(d,2H),7.95(d,2H),8.68(d,2H).NH2 + is not seen in the spectrum. 13 C NMR(101 MHz,CD3OD):δ(ppm)=16.4,24.0,28.8,31.9,32.2,33.6,37.3,40.9,47.4,54.5,55.7,57.2,58.4,61.8,64.0,7 3.5,82.3,125.7,126.2,128.1,129.3,141.1,142.4,169.2,172.3,172.4.LC-MS:m / z=1067.55(calcd.1067.48 for C 52 H 75 N8O 10 S3 + [M+H + ]).

[0492] Example 88. Preparation of (2S)-1-{[(4S,7S,9aS)-7-({(1R)-3-[(6-{[(3R)-3-({[(4S,7S,9aS)-8,8-dimethyl-4-{[(2S)-2-(methylammonio)propanoyl]amino}-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-3-phenylpropyl]oxy}hexa-2,4-diyn-1-yl)oxy]-1-phenylpropyl}carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-N-methyl-1-oxopropane-2-ammonium dichloride (18i)

[0493] [ka]

[0494] Compound 18i was prepared according to general procedure A. White solid, yield 27 mg (61%). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.03(s,6H),1.15(s,6H),1.55(d,6H),1.87-1.95(m ,2H),1.99(d,2H),2.03-2.09(m,4H),2.23-2.37(m,4H),2.67(s,6H),2.95(d,2H), 3.32-3.36(m,2H),3.44-3.54(m,4H),3.92(q,2H),4.17-4.29(m,6H),4.72-4.79( m,2H),5.07(q,2H),5.47(t,2H),7.18-7.47(m,10H),8.20(d,2H),8.73(d,2H).NH2 + is not seen in the spectrum. 13C NMR(101 MHz,CD3OD):δ(ppm)=16.3,23.9,28.8,31.8,32.3,33.6,37.6,40.9,47.2,52.2,54.4,58.3,59.4,61.8,68 .0,70.9,73.5,76.8,127.7,128.3,129.6,143.4,169.3,171.6,172.3.LC-MS:m / z=1027.55(calcd.1027.51 for C 54 H 75 N8O8S2 + [M+H + ]).

[0495] Example 89: (1R)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-[(6-{[(1S,2R)-1-[(4S,7S,9aS)-4-[(1R)-1-formamido-1-methylpropan-2-ylium]-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine-7-amide]-2,3- Preparation of {dihydro-1H-inden-2-yl)oxy}hexa-2,4-diyn-1-yl)oxy}-2,3-dihydro-1H-inden-1-yl)carbamoyl}-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]carbamoyl}-1-methylpropan-2-ylium dichloride (18j)

[0496] [ka]

[0497] Compound 18j was prepared according to general procedure A. White solid, yield 33 mg (72%). 1H NMR(400MHz,CD3OD):δ(ppm)=1.08-1.19(m,12H),1.45-1.60(m,6H),1.77(t,2H),2.15(d,4H),2.38(dd,2H),2.65-2.87(m,8H),3.02-3.15(m,4H) ,3.17-3.27(m,2H),4.06(d,2H),4.19(d,6H),4.42(dd,2H),4.76-4.83(m ,2H),5.34-5.57(m,4H),7.08-7.35(m,8H),7.93(t,2H),8.66(d,2H).NH2 + is not seen in the spectrum. 13 C NMR(101 MHz,CD3OD):δ(ppm)=16.8,24.1,29.0,31.9,32.4,33.9,37.6,40.9,47.1,54.4,56.6,58.1,58.2,61.9,74.1, 80.9,83.7,125.5,126.2,128.1,129.5,141.1,142.2,169.2,172.0,173.0.LC-MS:m / z=999.50(calcd.999.48 for C 52 H 71 N8O8S2 + [M+H + ]).

[0498] Example 90. 1-{[(4S,7S,9aS)-7-({(1S,2R)-2-[(6-{[(1S,2R)-1-({[(4S,7S,9aS)-8,8-dimethyl-4-{[2-methyl-2-(methylammonio)propanoyl]amino}-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-2,3-di Preparation of]-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-N,2-dimethyl-1-oxopropane-2-ammonium dichloride (18k)

[0499] [ka]

[0500] Compound 18k was prepared according to general procedure A. White solid, yield 23 mg (75%). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.12-1.20(m,12H),1.58-1.68(m,12H),1.77-1 .86(m,2H),2.09(q,2H),2.26(d,2H),2.32(dd,2H),2.62(s,6H),2.91(d,2H), 3.06-3.17(m,4H),3.25(d,2H),4.20-4.32(m,4H),4.37(d,2H),4.42-4.50(m, 2H),4.73(d,2H),5.47(dd,4H),7.16-7.38(m,8H),8.02(d,2H).C(O)NH and NH2 + is not seen in the spectrum. 13 C NMR(101 MHz,CD3OD):δ(ppm)=20.4,20.9,22.9,27.1,27.5,31.1,31.6,35.8,39.5,45.9,53.5,55.5,56.7,60.5,61.8,69.7,7 2.2,75.6,79.7,124.2,124.8,126.8,128.1,139.7,140.85,170.3,170.8,171.4.LC-MS:m / z=1051.60(calcd.1051.51 for C 56 H 75 N8O8S2 + [M+H + ]).

[0501] Example 91: [(1S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-[(6-{[(1S,2R)-1-[(4S,7S,9aS)-8,8-dimethyl-4-[(2S)-2-(methylazaniniumyl)butanamide]-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine-7-amide]-2,3 -dihydro-1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]carbamoyl}propyl](methyl)azanium dichloride (18m)

[0502] [ka]

[0503] Compound 18m was prepared according to general procedure A. White solid, yield 83 mg (92%). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.07(t,6H),1.17(s,12H),1.82(dd,2H),1.96(tt ,4H),2.09(q,2H),2.26-2.39(m,4H),2.68(s,6H),2.92(d,2H),3.06-3.17(m,4H ),3.25-3.31(m,2H),3.87(t,2H),4.22-4.31(m,4H),4.38(d,2H),4.47(d,2H), 4.79(d,2H),5.43-5.51(m,4H),7.18-7.27(m,6H),7.33(d,2H),8.01(d,2H).NH2 + and C(O)NH are not seen in the spectrum. 13C NMR(101 MHz,CD3OD):δ(ppm)=9.2,24.2,24.9,28.9,32.3-32.5,33.5,37.2,40.8,47.4,54.5,56.7,58.1,61.7,63.7,71.1,7 3.5,76.9,81.0,125.5,126.1,128.1,129.4,141.0,142.2,168.0,172.1,172.3.LC-MS:m / z=1051.50(calcd.1051.51 for C 56 H 75 N8O8S2 + [M+H + ]).

[0504] Example 92: (2S)-2-{[(4S,7S,9aS)-7-{[(1S,2R)-2-[(6-{[(1S,2R)-1-[(4S,7S,9aS)-4-[(2S)-2-(methylamino)propanamido]-5-oxo-8,8-bis(prop-2-en-1-yl)-octahydropyrrolo[2,1-b][1,3]thiazepine-7-amide]-2,3-dihydr 1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl}-5-oxo-8,8-bis(prop-2-en-1-yl)-octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]carbamoyl}-2-(methylazaniumyl)ethanide dichloride (18n)

[0505] [ka]

[0506] Compound 18n was prepared according to general procedure A. Colorless solid, yield 45 mg (83%). 1H NMR(400MHz,CD3OD):δ(ppm)=1.59(d,6H),1.83(dd,2H),2.00-2.14(m,4H),2.19(d,4H) ),2.31(d,2H),2.45(dd,4H),2.70(s,6H),2.93(d,2H),3.16(d,4H),3.98(q,2H),4.28( d,2H),4.39(d,2H),4.50(s,4H),4.75(d,2H),5.13(dt,8H),5.47(d,4H),5.81-5.96(m ,4H),7.19-7.31(m,6H),7.35(d,2H),8.05(d,2H).LC-MS:m / z=1127.55(calcd.1127.55 for C 62 H 79 N8O8S2 + [M+H + ]).

[0507] Example 93: [(1S)-1-{[(4'S,7'S,9'aS)-7'-{[(1S,2R)-2-[(6-{[(1S,2R)-1-{[(4'S,7'S,9'aS)-4'-[(2S)-2-(methylazaniumyl)propanamido]-5'-oxo-3',4',5',7',9',9'a-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepine]-3-en-7'-yl]a [Imidobioxido(2,3-dihydro-1H-inden-2-yl)oxy]hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl}-5'-oxo-3',4',5',7',9',9'a-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepine]-3-en-4'-yl]carbamoyl}ethyl](methyl)azanium dichloride (18o)

[0508] [ka]

[0509] Compound 18o was prepared according to general procedure A. Colorless solid, yield 26 mg (78%). 1H NMR(400MHz,CD3OD):δ(ppm)=1.54(d,6H),2.02(t,4H),2.24(dd,6H),2.42(d,2H) ,2.52(dd,2H),2.68(s,6H),2.82-2.94(m,4H),3.09(q,4H),3.95(q,2H),4.29(d, 2H),4.36(d,2H),4.46(d,4H),4.74(d,2H),5.45(t,4H),5.65(s,2H),5.76(s,2H) ,7.16-7.27(m,6H),7.30(d,2H),8.07(d,1H).LC-MS:m / z=1071.50(calcd.1071.48 for C 58 H 71 N8O8S2 + [M+H + ]).

[0510] Example 94: [(1S)-1-{[(4S,7S,8S,9aS)-7-{[(1S,2R)-2-[(6-{[(1S,2R)-1-[(4S,7S,8S,9aS)-8-hydroxy-4-[(2S)-2-(methylazaniumyl)propanamide]-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine-7-amide] -2,3-dihydro-1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8-hydroxy-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]carbamoyl}ethyl](methyl)azanium dichloride (18p)

[0511] [ka]

[0512] Compound 18p was prepared according to general procedure A. Colorless solid, yield 24 mg (87%). 1H NMR(400MHz,CD3OD):δ(ppm)=1.54(d,6H),1.96-2.06(m,2H),2.13(ddd,2H),2. 29(d,2H),2.56(dd,2H),2.67(d,6H),2.93(d,2H),3.06-3.13(m,4H),3.32-3.35 (m,2H),3.90-4.00(m,2H),4.35(d,4H),4.42-4.48(m,2H),4.56(d,2H),4.65(s, 2H),4.79(d,2H),5.44(d,2H),5.50(t,2H),7.16-7.27(m,8H),7.30(d,2H).-NH2 + , C(O)NH, and OH are not seen in the spectrum. 13 C NMR(101 MHz,CD3OD):δ(ppm)=15.1,30.7,31.2,32.6,36.0,40.9,53.0,55.7,57.0,60.6,69.6,70.6,71.3,75.7, 80.1,124.1,124.8,126.7,128.0,139.7,140.7,168.0,169.8,171.6.LC-MS:m / z=999.45(calcd.999.41 for C 50 H 63 N8O 10 S2 + [M+H + ]).

[0513] Synthetic scheme for the preparation of dimer 18l

[0514] [ka]

[0515] Example 95: Preparation of methyl (4R)-4-{[(4S,7S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]formamido}-4-phenylbutanoate (38)

[0516] [ka]

[0517] Under a N atmosphere, N-ethyl-N-(propan-2-yl)propan-2-amine (153 μL, 0.879 mmol, 3.00 equiv.) and COMU® (157 mg, 0.366 mmol, 1.25 equiv.) were added to a solution of carboxylic acid 14 (130 mg, 0.293 mmol, 1.00 equiv.) in dry THF (2.4 mL) and stirred at room temperature. After 45 min, (1R)-4-methoxy-4-oxo-1-phenylbutane-1-ammonium chloride (80 mg, 0.352 mmol, 1.20 equiv.) was added, and stirring was continued for 22 h. After completion, ethyl acetate (30 mL) was added and washed with NaOH solution (1 M, 2 × 10 mL), HCl solution (1 M, 2 × 10 mL), water (10 mL), and brine (10 mL), dried (NaSO), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid, yield 123 mg (68%). R f = 0.30 (hexane / ethyl acetate 3:7, ammonium cerium molybdate stain). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.00(s,3H,C(CH3)2),1.13(s,3H),1.37(d,3H),1.47(s,9H),1 .82-1.98(m,2H),2.02-2.15(m,2H),2.20-2.33(m,2H),2.37(td,2H),2.85(s,3H),2.91(ddd, 1H), 3.31-3.35 (m, 1H), 3.65 (s, 3H), 4.20 (s, 1H), 4.61-4.67 (m, 1H), 4.89-4.95 (m, 1H), 5.46 (d, 1H), 7.22-7.28 (m, 1H), 7.31-7.39 (m, 4H), 8.15 (d, 1H). CHCH3 and C(O)NH are not observed in the spectrum. LC-MS: m / z = 619.30 (calculated 619.32 for C 31 H 47 N4O7S + [M+H + ]).

[0518] Example 96. Preparation of (4R)-4-{[(4S,7S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]formamido}-4-phenylbutanoic acid (39)

[0519] [ka]

[0520] Lithium hydroxide solution (1M, 250 μL, 0.250 mmol, 2.00 equiv.) was added to a solution of methyl ester 38 (77 mg, 0.125 mmol, 1.00 equiv.) dissolved in THF (250 μL) at room temperature. The resulting emulsion was stirred at 40° C. for 16 h. After completion, ethyl acetate (30 mL) was added and washed with HCl solution (1M, 10 mL), water (10 mL), and brine (10 mL), dried (NaSO), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate / formic acid 0.2%). Colorless oil, yield 53 mg (70%). R f = 0.56 (hexane / ethyl acetate / formic acid 1:9:0.1, ammonium cerium molybdate stain). 1 H NMR(400MHz,CD3OD):δ(ppm)=0.99(s,3H),1.11(s,3H),1.35(d,3H),1.45(s,9H),1.81-1.94 (m,2H),2.00-2.12(m,2H),2.19-2.25(m,1H),2.25-2.29(m,1H),2.32(td,2H),2.83(s,3H),2 0.85-2.92 (m, 1H), 3.29-3.34 (m, 1H), 4.18 (s, 1H), 4.63 (d, 1H), 4.89-4.93 (m, 1H), 5.44 (t, 1H), 7.20-7.26 (m, 1H), 7.28-7.38 (m, 4H), 8.14 (d, 1H). CHCH3, C(O)NH, and COOH are not observed in the spectrum. LC-MS: m / z = 605.25 (calculated 605.30 for C 30 H45 N4O7S + [M+H + ]).

[0521] Example 97. Preparation of tert-butyl [(2S)-1-{[(4S,7S,9aS)-7-({(1R)-4-[(2-{[(4R)-4-({[(4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-4-phenylbutanoyl]amino}ethyl)amino]-4-oxo-1-phenylbutyl}carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-1-oxopropan-2-yl](methyl)carbamate (171)

[0522] [ka]

[0523] Under a N atmosphere, ethane-1,2-diamine (3 μL, 0.0495 mmol, 1.00 equiv.), carboxylic acid 39 (63 mg, 0.104 mmol, 2.10 equiv.), 1-hydroxybenzotriazole hydrate (21 mg, 0.139 mmol, 2.80 equiv.), and NEt (21 μL, 0.149 mmol, 3.00 equiv.) were dissolved in dry THF (0.8 mL). * HCl (24 mg, 0.124 mmol, 2.50 equiv) was added and stirred for 23 h. After completion, ethyl acetate (30 mL) was added to the residue and washed with NaOH solution (1 M, 2 × 10 mL), HCl solution (1 M, 2 × 10 mL), water (10 mL), and brine (10 mL), dried (NaSO), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid, yield 35 mg (57%). R f =0.35 (ethyl acetate / methanol 9:1, cerium ammonium molybdate stain). 1H NMR(400MHz,CD3OD):δ(ppm)=0.97(s,6H),1.13(s,6H),1.35(d,6H),1.46(s,18H),1.83(dd,2H) ,1.88-1.98(m,2H),2.01-2.28(m,10H),2.33(dd,2H),2.85(s,6H),2.90-2.97(m,2H),3.20-3.3 1 (m, 4H), 3.34-3.39 (m, 2H), 4.18 (s, 2H), 4.44-4.73 (m, 4H), 4.82-4.86 (m, 2H), 5.51 (t, 2H), 7.22-7.28 (m, 2H), 7.30-7.37 (m, 8H), 8.05 (d, 2H). C(O)NHCHCHHN(O)C and C(O)NH are not observed in the spectrum. LC-MS: m / z = 1233.70 (calcd. 1233.64 for C 62 H 93 N 10 O 12 S2 + [M+H + ]).

[0524] Example 98. Preparation of (2S)-1-{[(4S,7S,9aS)-7-({(1R)-4-[(2-{[(4R)-4-({[(4S,7S,9aS)-8,8-dimethyl-4-{[(2S)-2-(methylammonio)propanoyl]amino}-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-7-yl]carbonyl}amino)-4-phenylbutanoyl]amino}ethyl)amino]-4-oxo-1-phenylbutyl}carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepin-4-yl]amino}-N-methyl-1-oxopropane-2-ammonium dichloride (181)

[0525] [ka]

[0526] Compound 18l was prepared according to general procedure A. White solid, yield 29 mg (92%). 1H NMR(400MHz,CD3OD):δ(ppm)=0.95(s,6H),1.12(s,6H),1.52(s,6H),1.77-1.87(m,2H),1.96-2.37(m,14H),2.65( s,6H),2.96(d,2H),3.28-3.37(m,6H),3.95(s,2H),4.15(s,2H),4.78(d,4H),5.50(s,2H),7.21-7.36(m,10H).NH2 + is not seen in the spectrum. 13 C NMR(101 MHz,CD3OD):δ(ppm)=16.5,23.9,28.9,32.2,32.4,33.4,33.7,34.0,40.1,40.8,47.2,54.3,54.4,58 .3,61.8,73.7,127.6,128.5,129.7,143.3,169.3,171.6,172.7.LC-MS:m / z=1033.55(calcd.1033.54 for C 52 H 77 N 10 O8S2 + [M+H + ]).

[0527] Synthetic scheme for the preparation of dimeric 18q

[0528] [ka]

[0529] Example 99: Preparation of (2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(tert-butyldimethylsilyl)oxy]butanoic acid (67)

[0530] [ka]

[0531] N-(tert-butoxycarbonyl)-L-homoserine 66 (1.00 g, 4.56 mmol, 1.00 equiv.) was dissolved in dry CHCl (10 mL) and tert-butyl(chloro)dimethylsilane (1.72 g, 11.4 mmol, 2.50 equiv.) was added. The solution was cooled to 0 °C, and N-ethyl-N-(propan-2-yl)propan-2-amine (1.99 mL, 11.4 mmol, 2.50 equiv.) was added. Stirring was continued at room temperature for 17 h. After completion, all volatiles were removed in vacuo. Citric acid solution (5%, 20 mL) was added to the residue and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (NaSO), and concentrated in vacuo. The crude material 67 (2.02 g) was used without further purification. LC-MS:m / z=334.55(calcd.334.51 for C 15 H 32 NO5Si + [M+H + ]).

[0532] Example 100: Preparation of methyl (2S)-2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(tert-butyldimethylsilyl)oxy]butanamido]-4-(5,5-diphenyl-1,3-dioxan-2-yl)-3,3-dimethylbutanoate (68)

[0533] [ka]

[0534] Under a N atmosphere, amine 34, crude carboxylic acid 67 (1.10 g, 3.30 mmol, 2.00 equiv.), 1-hydroxybenzotriazole hydrate (506 mg, 3.30 mmol, 2.00 equiv.), and N-methylmorpholine (1.09 mL, 9.91 mmol, 6.00 equiv.) were dissolved in dry THF (5.89 mL) and cooled to 0 °C. EDC·HCl (633 mg, 3.30 mmol, 2.00 equiv.) was added, and the resulting mixture was stirred at 0 °C for 30 min and then at room temperature for 18 h. After completion, ethyl acetate (30 mL) was added and washed with saturated NaHCO solution (2 × 10 mL), citric acid solution (5%, 2 × 10 mL), water (10 mL), and brine (10 mL), dried (NaSO), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless oil, yield 727 mg (63%). f =0.25 (hexane / ethyl acetate 2:8, ammonium cerium molybdate stain). 1 H NMR(400MHz,CDCl3):δ(ppm)=0.05(d,6H,),0.90(s,9H),1.01(s,3H),1.03(s,3H),1.43(s, 9H),1.63(dd,1H),1.70(dd,1H),1.95(q,2H),3.67(s,3H),3.72(t,1H),3.76-3.83(m,1H), 4.16-4.27(m,3H),4.56(d,1H),4.68(d,2H),4.81(t,1H),5.95(dd,1H),7.02-7.06(m,2H), 7.17-7.23(m,3H),7.24-7.32(m,4H),7.42-7.47(m,2H).LC-MS:m / z=699.40(calcd.699.40 for C 38 H 59 N2O8Si + [M+H + ]).

[0535] Example 101: Preparation of methyl (4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxylate (69)

[0536] [ka]

[0537] Compound 68 (590 mg, 0.844 mmol, 1.00 equiv) was treated with HCl in dioxane (4 M, 4.22 mL, 16.8 mmol, 20.0 equiv) and stirred for 2 h at 40° C. After completion, all volatiles were removed under reduced pressure.

[0538] Example 102: Preparation of methyl (4S,7S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxylate (70)

[0539] [ka]

[0540] Under a N atmosphere, amine 69, N-(tert-butoxycarbonyl)-N-methyl-L-alanine (349 mg, 1.72 mmol, 1.20 equiv.), 1-hydroxybenzotriazole hydrate (206 mg, 1.01 mmol, 1.20 equiv.), and 4-methylmorpholine (279 μL, 2.53 mmol, 3.00 equiv.) were dissolved in dry DMF (3.9 mL) and cooled to 0 °C. EDC·HCl (194 mg, 1.01 mmol, 1.20 equiv.) was added, and the resulting mixture was stirred at 0 °C for 30 min and then at room temperature for 18 h. After completion, water (30 mL) was added and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with NaOH solution (1M, 30 mL), citric acid solution (5%, 30 mL), water (30 mL), and brine (30 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid 70, yield 254 mg (68%). R f = 0.36 (hexane / ethyl acetate 4:6, ammonium cerium molybdate staining). 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.05 (s, 3H), 1.11 (s, 3H), 1.31 (d, 3H), 1.44 (s, 9H), 1.81-1.99 (m, 3H), 2.12 (dd, 1H), 2.75 (s, 3H), 3.73 (s, 3H), 3.92 (t, 1H), 4.12-4.20 (m, 2H), 4.63-4.70 (m, 1H), 5.18-5.22 (m, 1H), 7.15 (s, 1H). CHCH3 is not present in the spectrum. LC-MS: m / z = 442.40 (calcd. 442.53 for C 21 H 36 N3O7 + [M+H + ]).

[0541] Example 103: Preparation of (4S,7S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]oxazepine-7-carboxylic acid (71)

[0542] [ka]

[0543] Lithium hydroxide solution (1 M, 1.15 mL, 1.15 mmol, 2.00 equiv.) was added to a solution of methyl ester 70 (254 mg, 0.574 mmol, 1.00 equiv.) dissolved in THF (1.15 mL) at room temperature. The resulting emulsion was stirred at 40 °C for 17 h. After completion, EtO (10 mL) was added and washed with a mixture of 1 M NaOH solution and brine (8:1, 3 × 9 mL). The combined aqueous layers were extracted with ethyl acetate (10 mL), and the ethyl acetate layer was washed with a mixture of 1 M NaOH solution and brine (8:1, 2 × 9 mL). The combined aqueous layers were acidified to pH 1 with concentrated hydrochloric acid, and then the aqueous layer was extracted with CHCl (3 × 15 mL) and ethyl acetate (2 × 15 mL). The combined organic layers were dried (NaSO) and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate / formic acid 0.2%): colorless solid, yield 186 mg (76%). 1 H NMR (400 MHz, CDCl3): δ (ppm) = 1.09-1.19 (m, 6H), 1.35 (d, 3H), 1.46 (s, 9H), 1.83-2.03 (m, 3H), 2.15 (dd, 1H), 2.79 (s, 3H), 3.88-3.98 (m, 1H), 4.17 (d, 2H), 4.69-4.76 (m, 1H), 5.21-5.25 (m, 1H), 7.29 (s, 1H). CHCH3 and COOH are not present in the spectrum. LC-MS: m / z = 442.50 (calculated 442.53 for C 21 H 36 N3O7 + [M+H + ]).

[0544] Example 104: tert-Butyl N-[(1S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-[(6-{[(1S,2R)-1-[(4S,7S,9aS)-4-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]oxa Preparation of]-2,3-dihydro-1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]oxazepin-4-yl]carbamoyl}ethyl]-N-methylcarbamate (17q)

[0545] [ka]

[0546] Compound 17q was prepared according to general procedure B. Colorless solid, yield 51 mg (59%). f = 0.48 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.12(s,12H),1.38(d,6H),1.44-1.50(m,18H),1.83-1.93(m,4H),1. 98-2.08(m,2H),2.18-2.28(m,2H),2.85(s,6H),3.04-3.13(m,4H),3.97(t,2H),4.10-4.16(m,2H) ,4.19(s,2H),4.27(d,2H),4.35(d,2H),4.41-4.48(m,2H),4.64(s,2H),4.82(d,2H),5.42-5.52(m ,4H),7.17-7.26(m,6H),7.29-7.35(m,2H),7.80-7.91(m,4H).LC-MS:m / z=1192.65(calcd.1192.44 for C 64 H 87 N8O 14 + [M+H + ]).

[0547] Example 105: [(1S)-1-{[(4S,7S,9aS)-7-{[(1S,2R)-2-[(6-{[(1S,2R)-1-[(4S,7S,9aS)-8,8-dimethyl-4-[(2S)-2-(methylazaniumyl)propanamide]-5-oxo-octahydropyrrolo[2,1-b][1,3]oxazepine-7-amide]-2,3 Preparation of]-dihydro-1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl}-8,8-dimethyl-5-oxo-octahydropyrrolo[2,1-b][1,3]oxazepin-4-yl]carbamoyl}ethyl](methyl)azanium dichloride (18q)

[0548] [ka]

[0549] Compound 18q was prepared according to general procedure A. Colorless solid, yield 35 mg (78%). 1 H NMR(400MHz,CD3OD):δ(ppm)=1.05-1.16(m,12H),1.59(d,6H),1.80-1.94(m,4H ),2.06-2.18(m,2H),2.24(dd,2H),2.69(s,6H),3.10(d,4H),3.93-4.03(m,4H) ,4.13-4.22(m,4H),4.29(d,2H),4.40(d,2H),4.48(q,2H),4.91-4.97(m,2H),5 .41-5.55(m,4H),7.17-7.27(m,6H),7.33(d,2H),7.91(d,2H),8.70(d,2H).-NH2 + is not seen in the spectrum. 13C NMR(101 MHz,CD3OD):δ(ppm)=16.5,24.3,29.4,31.9,33.0,37.0,40.3,47.0,54.0,56.7,58.0,58.4,71.1,71.4,71.9,76 .9,80.9,90.4,125.5,126.1,128.1,129.4,140.9,142.2,169.6,172.2,172.4.LC-MS:m / z=992.50(calcd.992.21 for C 54 H 71 N8O 10 + [M+H + ]).

[0550] Synthetic scheme for the preparation of dimer 18r

[0551] [ka]

[0552] Example 107: Preparation of 2-[(5,5-dimethyl-1,3-dioxan-2-yl)methyl]-2-(prop-2-en-1-yl)pent-4-enenitrile (73)

[0553] [ka]

[0554] Compound 73 was prepared from dimethyl acetal 55 and the appropriate 2,2-dimethylpropane-1,3-diol according to Example 42. Yield (76%).

[0555] Example 108: Preparation of 1-[(5,5-dimethyl-1,3-dioxan-2-yl)methyl]cyclopent-3-ene-1-carbonitrile (74)

[0556] [ka]

[0557] Compound 74 was prepared from intermediate 73 according to example 59. Yield (100%).

[0558] Example 109: Preparation of 1-[(5,5-dimethyl-1,3-dioxan-2-yl)methyl]cyclopent-3-ene-1-carbaldehyde (75)

[0559] [ka]

[0560] Compound 75 was prepared from nitrile 74 and DIBAL-H in hexane according to Example 43. Yield (70%).

[0561] Example 110: Preparation of 1-{1-[(5,5-dimethyl-1,3-dioxan-2-yl)methyl]cyclopent-3-en-1-yl}-2-nitroethan-1-ol (76)

[0562] [ka]

[0563] Compound 76 was prepared from aldehyde 75, nitromethane, and NEt according to Example 44. Yield (82%).

[0564] Example 111: Preparation of 5,5-dimethyl-2-({1-[(E)-2-nitroethenyl]cyclopent-3-en-1-yl}methyl)-1,3-dioxane (77)

[0565] [ka]

[0566] Compound 77 was prepared from nitroaldol 76, nitromethane, and NEt according to Example 45. Yield (94%).

[0567] Example 112: Preparation of (4S,5R)-3-[(1S)-1-{1-[(5,5-dimethyl-1,3-dioxan-2-yl)methyl]cyclopent-3-en-1-yl}-2-nitroethyl]-4,5-diphenyl-1,3-oxazolidin-2-one (78)

[0568] [ka]

[0569] Compound 78 was prepared from nitroalkene 77 according to Example 46. Yield (64%). 1 H NMR(400MHz,CDCl3):δ(ppm)=0.74(s,3H),1.24(s,3H),1.91(dd,1H),2.03(dd,1H),2 .22-2.33(m,2H),2.49(d,1H),2.86(d,1H),3.42(d,2H),3.57-3.66(m,2H),4.14(dd,1 H),4.45-4.54(m,2H),5.16(d,1H),5.54(dd,2H),5.59-5.65(m,1H),5.93(d,1H),6.83 -6.89(m,2H),6.99-7.03(m,2H),7.05-7.13(m,6H).LC-MS:m / z=507.15(calcd.507.25 for C 29 H 35 N2O6 + [M+H + ]).

[0570] Example 113: Preparation of (S)-2-(1-((5,5-dimethyl-1,3-dioxan-2-yl)methyl)cyclopent-3-en-1-yl)-2-((4S,5R)-2-oxo-4,5-diphenyloxazolidin-3-yl)acetic acid (79)

[0571] [ka]

[0572] Under a N2 atmosphere, sodium nitrite (2.08 g, 30.2 mmol, 3.00 equiv.) and dry acetic acid (5.76 mL, 101 mmol, 10.0 equiv.) were added to a solution of nitro derivative 78 (5.10 g, 10.1 mmol, 1.00 equiv.) suspended in dry DMSO (25 mL). The resulting mixture was stirred at 35 °C for 6 h. After completion, citric acid solution (5%, 80 mL) was added and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water (2 × 50 mL) and brine (50 mL), dried (Na2SO4), and concentrated in vacuo.

[0573] Example 114: Preparation of methyl (2S)-2-{1-[(5,5-dimethyl-1,3-dioxan-2-yl)methyl]cyclopent-3-en-1-yl}-2-[(4S,5R)-2-oxo-4,5-diphenyl-1,3-oxazolidin-3-yl]acetate (80)

[0574] [ka]

[0575] The crude carboxylic acid 79 was dissolved in dry DMF (20 mL) and cooled to 0 °C. K2CO3 (1.53 g, 11.1 mmol, 1.10 equiv) was added and stirred for 10 min. After adding CH3I (1.26 mL, 20.1 mmol, 2.00 equiv), stirring was continued at 0 °C for 30 min. The solution was then stirred at room temperature for 12 h. Water (50 mL) was added and extracted with CHCl2 (3 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexane / CHCl2). Beige solid 80, yield 2.18 g (43%). R f = 0.72 (hexane / ethyl acetate 7:3). 1H NMR(400MHz,CDCl3):δ(ppm)=0.68(s,3H),1.13(s,3H),1.61-1.68(m,1H),1.81(dd,1 H),2.15(d,1H),2.31(d,1H),2.60(dp,1H),2.71(dp,1H),3.29(dd,2H),3.48(ddd,2H) ,3.76(s,3H),4.39(dd,1H),4.41(s,1H),5.31(d,1H),5.47-5.51(m,1H),5.52-5.56( m,1H),5.94(d,1H),6.98-7.03(m,3H),7.07(m,7H).LC-MS:m / z=506.15(calcd.506.25 for C 30 H 36 No. 6 + [M+H + ]).

[0576] Example 115: Preparation of methyl (S)-2-amino-2-(1-((5,5-dimethyl-1,3-dioxan-2-yl)methyl)cyclopentyl)acetate (81)

[0577] [ka]

[0578] Pd / C (10%, matrix activated carbon support, Sigma Aldrich, 526 mg, 0.25 equiv.) was added to a solution of carbamate 80 (1.00 g, 1.97 mmol, 1.00 equiv.) in methanol (24 mL). The resulting mixture was stirred at 45° C. for 5 h under an H atmosphere. After filtration through Celite® with methanol, all volatiles were removed in vacuo.

[0579] Example 116: Preparation of methyl (2S)-2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-[(triphenylmethyl)sulfanyl]butanamido]-2-{1-[(5,5-dimethyl-1,3-dioxan-2-yl)methyl]cyclopentyl}acetate (82)

[0580] [ka]

[0581] Under a N atmosphere, amine 81, carboxylic acid 7 (945 mg, 1.98 mmol, 1.00 equiv.), 1-hydroxybenzotriazole hydrate (363 mg, 2.37 mmol, 1.20 equiv.), and N-methylmorpholine (654 μL, 5.93 mmol, 3.00 equiv.) were dissolved in a mixture of dry THF (7.1 mL) and DMF (1.0 mL) and cooled to 0 °C. EDC·HCl (455 mg, 2.37 mmol, 1.20 equiv.) was added, and the resulting mixture was stirred at 0 °C for 30 min and then at room temperature for 14 h. After completion, NaOH solution (1 M, 30 mL) was added to the residue and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with NaOH solution (1M, 30 mL), citric acid solution (5%, 30 mL), HCl solution (1M, 30 mL), water (30 mL), and brine (30 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid, yield 1.07 g (73%). R f = 0.66 (hexane / ethyl acetate 8:2). 1 H NMR (400MHz, CDCl3): δ(ppm)=0.68(s,3H),1.16(s,3H),1.41(s,9H),1.46-1.88 (m,12H),2.17-2.37(m,2H),3.40(d,1H),3.50(d,1H),3.56(dd,1H),3.62-3.67 (m,4H),3.95-4.04(m,1H),4.43(d,1H),4.52(dd,1H),4.73(d,1H),7.18-7.23( m,3H),7.25-7.30(m,6H),7.37-7.42(m,7H).LC-MS:m / z=767.35(calcd.767.37 for C 43 H 56 N2NaO7S + [M+H + ]).

[0582] Example 117: Preparation of methyl (4'S,7'S,9a'S)-4'-amino-5'-oxohexahydro-7'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepine]-7'-carboxylate (83)

[0583] [ka]

[0584] Compound 82 (1.00 g, 1.34 mmol, 1.00 equiv) was treated with HCl in dioxane (4 M, 6.7 mL, 26.9 mmol, 20.0 equiv) and stirred for 2 h at 40° C. After completion, all volatiles were removed under reduced pressure.

[0585] Example 118: Preparation of methyl (4'S,7'S,9'aS)-4'-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-5'-oxo-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepine]-7'-carboxylate (84)

[0586] [ka]

[0587] Under a N atmosphere, amine 83, N-(tert-butoxycarbonyl)-N-methyl-L-alanine (327 mg, 1.61 mmol, 1.20 equiv.), 1-hydroxybenzotriazole hydrate (247 mg, 1.61 mmol, 1.20 equiv.), and 4-methylmorpholine (444 μL, 4.00 mmol, 3.00 equiv.) were dissolved in dry DMF (6.2 mL) and cooled to 0 °C. EDC·HCl (308 mg, 1.61 mmol, 1.20 equiv.) was added, and the resulting mixture was stirred at 0 °C for 30 min and then at room temperature for 14 h. After completion, water (20 mL) was added and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic layers were washed with NaOH solution (1 M, 20 mL), HCl solution (1 M, 2 × 20 mL), water (20 mL), and brine (10 mL), dried (NaSO), and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate). Colorless solid 84, quantitative yield. R f =0.51 (hexane / ethyl acetate 5:5, ammonium cerium molybdate stain). 1 H NMR (400 MHz, CDCl3): δ (ppm) = 1.33 (d, 3H), 1.46 (s, 9H), 1.52-1.77 (m, 8H), 1.83-1.95 (m, 1H), 2.09-2.17 (m, 1H), 2.23-2.34 (m, 2H), 2.77 (s, 3H), 2.83 (ddd, 1H), 3.19-3.29 (m, 1H), 3.75 (s, 3H), 4.34 (s, 1H), 4.53 (dd, 1H), 5.10 (t, 1H), 7.30 (s, 1H). CHCH3 is not present in the spectrum. LC-MS: m / z = 484.20 (calculated for C 23 H 38 N3O6S + [M+H + ]).

[0588] Example 119: Preparation of (4'S,7'S,9'aS)-4'-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamide]-5'-oxo-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepine]-7'-carboxylic acid (85)

[0589] [ka]

[0590] Lithium hydroxide solution (1 M, 2.68 mL, 2.68 mmol, 2.00 equiv) was added to a solution of methyl ester 84 (649 mg, 1.34 mmol, 1.00 equiv) dissolved in THF (2.7 mL) at room temperature. The resulting emulsion was stirred at 40 °C for 19 h. After completion, EtO (15 mL) was added and washed with a mixture of 1 M NaOH solution and brine (8:1, 3 × 9 mL). The combined aqueous layers were extracted with EtO (15 mL), and the EtO layer was washed with a mixture of 1 M NaOH solution and brine (8:1, 2 × 8 mL). The combined aqueous layers were acidified to pH 1 with concentrated hydrochloric acid, and then extracted with CHCl (2 × 10 mL) and ethyl acetate (3 × 10 mL). The combined organic layers were dried (NaSO) and concentrated in vacuo. The resulting residue was purified by fc (hexane / ethyl acetate / formic acid 0.2%). Colorless solid 85, yield 428 mg (68%). f = 0.45 (hexane / ethyl acetate / formic acid 4:6:0.1, ammonium cerium molybdate stain). 1 H NMR (400 MHz, CDCl3): δ (ppm) = 1.34 (d, 3H), 1.46 (s, 9H), 1.53-1.84 (m, 8H), 1.91 (q, 1H), 2.12 (dd, 1H), 2.22-2.34 (m, 2H), 2.77-2.84 (m, 4H), 3.24 (ddd, 1H), 4.34 (s, 1H), 4.62 (dd, 1H), 5.15 (dd, 1H), 7.41 (s, 1H). COOH and CHCH3 are not present in the spectrum. LC-MS: m / z = 470.15 (calcd. 470.23 for C22 H 36 N3O6S + [M+H + ]).

[0591] Example 120: tert-Butyl N-[(1S)-1-{[(4'S,7'S,9'aS)-7'-{[(1S,2R)-2-[(6-{[(1S,2R)-1-{[(4'S,7'S,9'aS)-4'-[(2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanamido]-5'-oxo-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3] Preparation of {(2,3-dihydro-1H-inden-2-yl)oxy}hexa-2,4-diyn-1-yl)oxy}-2,3-dihydro-1H-inden-1-yl)carbamoyl}-5'-oxo-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepin]-4'-yl]carbamoyl}ethyl}N-methylcarbamate (17r)

[0592] [ka]

[0593] Compound 17r was prepared according to general procedure B. Modifications: Ethyl acetate (30 mL) was added to the reaction mixture, which was washed with saturated NaHCO3 solution (2 x 10 mL), citric acid solution (5%, 2 x 10 mL), water (10 mL), and brine (10 mL), dried (Na2SO4), and concentrated in vacuo. White solid, yield 23 mg (22%). R f = 0.82 (ethyl acetate / methanol 10:0.5, ammonium cerium molybdate staining). 1H NMR (400MHz, CDCl3): δ(ppm)=1.34(d,6H),1.45-1.49(m,18H),1.49-1.92( m,18H),1.98-2.02(m,2H),2.24-2.39(m,4H),2.74-2.83(m,8H),3.03-3.14 (m,4H),3.29(d,2H),4.18(d,2H),4.26(d,2H),4.35(s,2H),4.49(dt,4H), 5.06-5.15(m,2H),5.52(dd,2H),7.18-7.42(m,12H).CHCH3 is not seen in the spectrum. LC-MS:m / z=1275.65(calcd.1275.62 for C 68 H 91 N8O 12 S2 + [M+H + ]).

[0594] Example 121: [(1S)-1-{[(4'S,7'S,9'aS)-7'-{[(1S,2R)-2-[(6-{[(1S,2R)-1-{[(4'S,7'S,9'aS)-4'-[(2S)-2-(methylazaniumyl)propanamido]-5'-oxo-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepine]-7'-yl]amido Preparation of {do}-2,3-dihydro-1H-inden-2-yl]oxy}hexa-2,4-diyn-1-yl)oxy]-2,3-dihydro-1H-inden-1-yl]carbamoyl}-5'-oxo-hexahydro-2'H-spiro[cyclopentane-1,8'-pyrrolo[2,1-b][1,3]thiazepine]-4'-yl]carbamoyl}ethyl](methyl)azanium dichloride (18r)

[0595] [ka]

[0596] Compound 18r was prepared according to general procedure A. Colorless solid, yield 13 mg (61%). 1H NMR(400MHz,CD3OD):δ(ppm)=1.45-2.08(m,26H),2.27(d,2H),2.34-2.46(m,2H),2.68(s,6H),2.91(d,2H),3.03-3.17(m,4H),3.18-3.27( m,2H),3.94(d,2H),4.22-4.40(m,6H),4.46(s,2H),4.73(d,2H),5.35 -5.52(m,4H),7.15-7.35(m,8H),8.02-8.09(m,2H),8.73(s,2H).-NH2 + is not seen in the spectrum. 13 C NMR(101 MHz,CD3OD):δ(ppm)=16.4,24.6,25.0,31.8,32.3,33.9,37.1,40.3,45.2,52.3,54.5,56.8,57.9,58.3,61.8,71. 0,72.0,76.9,81.0,125.4,126.1,128.1,129.4,141.0,142.2,169.3,172.3.LC-MS:m / z=1075.55(calcd.1075.51 for C 58 H 75 N8O8S2 + [M+H + ]).

[0597] Example A. Compound 18a was tested in 16 different cell lines. For 6-day compound treatment, 1700 cells per well were plated in a 384-well plate (Corning #781098) and incubated overnight at 37°C / 5% CO2. The following day, compounds in 10-fold dilutions were added to the plates, and the plates were incubated for 6 days. 20 μL of Cell Titer-Glo reagent (Promega, #G7570) was then added to each well outside the incubator, and the plates were read for luminescence on a Spark® multimode microplate reader (Tecan). Data were fitted to a nonlinear regression curve in GraphPad Prism 8 to determine the IC of compounds. 50 It was decided that:

[0598] [Table 2]

[0599] Example B. 1700 cells per well were plated in a 384-well plate and incubated at 37°C / 5% CO2. The next day, 10-fold dilutions of compounds were added to the plate and the plate was returned to the incubator for 48 hours. After 48 hours, the plate was removed to the bench, 20 μL of Cell Titer-Glo reagent was added to each well, and the plate was read for luminescence on a Spark® Multimode Microplate Reader (Tecan). Data were fitted to a nonlinear regression curve using PRISM to determine the IC of compounds. 50 It was decided that:

[0600] [Table 3]

[0601] Example C. Binding of compounds to the ML-IAP and BIR3 domains of cIAP1, cIAP2, and XIAP was determined by fluorescence polarization. Assay buffer was prepared as described by Z. Nikolovska-Coleska et al. 9 The buffer was 100 mM KH2PO4, 50 μM ZnSO4, 1 mM TCEP (Tris(2-carboxyethyl)phosphine hydrochloride), and 50 nM SMAC-FITC probe (AbuRPF-K(5-Fam)-NH2) at pH 7.5 as described by

[14] . cIAP1 and XIAP were present at 800 nM, while cIAP2 and MLIAP were present at 1.5 μM. Compounds in 3-fold dilutions were added to the plate over the range of 30 μM to 1.5 nM. Assays were performed in a 384-well black plate reader (Greiner Bio-One #784076) in Analyst in fluorescence polarization mode with excitation at 485 nm and emission at 535 nm. Data were fitted to a nonlinear regression curve in GraphPad Prism 8 to determine the IC values of compounds. 50The value was then determined. Then, Z. Nikolovska-Coleska et al. formulated the formula: K i =[I] 50 / ([L] 50 / K d +[P]0 / K d +1) to IC 50 Ki was calculated from the values.

[0602] [Table 4]

[0603] Example D. Patient AML samples were collected from Scripps MD Anderson, La Jolla, CA (IRB 13-6180). Fresh blood samples were subjected to gradient density centrifugation using Ficoll-Paque™ PLUS (17-1440-02, GE Healthcare) to purify peripheral blood mononuclear cells according to the manufacturer's protocol.

[0604] Using a Labcyte Echo acoustic dispenser, 75 nL of 1000-fold serially diluted IAP inhibitors were spotted in triplicate onto 384-well tissue culture-treated plates (Greiner). Patient-derived AML cells were maintained in mTeSR1 + 1x supplement (Stemcell Technologies) and penicillin / streptomycin / L-glutamine (Omega Scientific Inc.) and fungizone (HyClone). 25 μL of cell dilutions were plated into the drug-containing 384-well plates and incubated for 72 hours. Cell viability was assessed by adding 25 μL of CellTiterGlo (Promega Corp.) to a Synergy2 plate reader equipped with Gen5 software (Biotek). % viability was calculated by normalizing luminescence to the vehicle-only control (DMSO) in Microsoft Excel and plotted using GraphPad Prism 8. IC 50Values were calculated using the log(inhibitor) vs. response-variable slope (four parameter) formula (Figure 6).

[0605] [Table 5]

[0606] Example E. Several compounds (Table 5) were tested for their efficacy in reactivating HIV latency in the latently infected cell line Jurkat 2D10. Jurkat 2D10 cells were treated for 48 hours with various doses of compound or one of the following compounds: BV-6, SM-164, Birinapant, LCL-161, GDC-0152, or AT-406. HIV latency reactivation was assessed by analyzing GFP expression using flow cytometry. Induction of GFP expression was compared to baseline GFP levels detected in the absence of treatment. The results are shown in Table 5 and Figure 1. Compound 18a has high potency in activating latently infected cell lines compared to many known compounds (Figure 1).

[0607] [Table 6]

[0608] Compound 18a was also tested for its effects on T cell activation and cytokine release. Peripheral blood mononuclear cells (PBMCs) were isolated from buffy coats (San Diego Blood Bank) of three healthy human donors by Ficoll density gradient centrifugation (Histopaque, Sigma-Aldrich). Resting CD4+ T cells were then isolated by negative selection using magnetic beads (Miltenyi Biotec). Cells were treated with compound 18a, 50 ng / ml phorbol myristate acetate (PMA) and 1 μM ionomycin, or Dynabeads Human T-Activator CD3 / CD28 (ThermoFisher Scientific) at a 1:1 bead-to-cell ratio, or left untreated. Expression of the early and late activation markers CD69 and CD25 on CD4+ T cells was assessed by flow cytometry using a phycoerythrin-labeled anti-CD69 antibody (BioLegend; Cat# 310906) and an allophycocyanin-labeled anti-CD25 antibody (BioLegend; Cat# 302610). Cytokine expression levels in cultures of PBMCs or resting CD4+ T cells were analyzed using the LEGENDplex Human Inflammation Panel 13-plex (BioLegend). As shown in Figures 2 and 3, treatment with compound 18a did not result in activation of resting CD4+ T cells or cytokine release in PBMCs or resting CD4+ T cells.

[0609] Figure 4 shows compound-induced cIAP1 degradation and NFκB pathway activation. JLat 10.6 cells were treated with various concentrations of compound 18a for 24 hours. GFP expression, indicating reactivation of latency, was measured by flow cytometry. cIAP1 degradation and p100 cleavage were assessed by Western blot using antibodies AF8181 (R&D Systems) and #4882 (Cell Signaling Technology), respectively. As shown, cIAP1 degradation and p100 cleavage upon treatment of JLat 10.6 cells with compound 18a correlated with HIV reactivation of latency.

[0610] Compound 18 was also tested in combination with other LRA reagents for synergistic activation of the latently infected cell line Jurkat 2D10. Jurkat 2D10 cells were treated for 48 hours with a combination of compound 18a and a BET inhibitor (JQ1, I-BET 151) or a PKC agonist (bryostatin, ingenol-3-angelate). HIV latency reactivation was assessed by analyzing GFP expression using flow cytometry. Synergy was assessed using the Bliss Independence model, in which the observed effect of the combination of compound f12 was calculated using the equation E(f12) = f1 + f2 - (f1 * The observed effect of the combined compound (f12) is compared to the expected effect E(f12), which is calculated based on the observed effects of individual compounds f1 and f2. The difference between the observed effect of the combined compound (f12) and the expected combined effect E(f12) of the two compounds is expressed as an excess on Bliss score (EOB). An EOB value greater than 0 indicates synergy between the compounds. As shown in Table 6 and Figure 5, compound 18a synergizes with the tested LRA compounds to reactivate HIV latency.

[0611] [Table 7]

[0612] Example F. Pharmacokinetic studies of compounds in mice All animal procedures were approved by the Sanford Burnham Prebys Medical Discovery Institute Institutional Animal Care and Use Committee and conducted in accordance with the NIH Guidelines for the Care and Use of Laboratory Animals. Adult female C57BL / 6J mice were purchased from JAX Laboratories and housed with a 12-hour light / dark cycle and free access to food and water. Compounds were formulated in 5% DMSO, 10% Tween-80, and 85% dH2O and injected intraperitoneally (i.p.) into mice at a dose of 10 mg / kg. For snapshot PK analysis, blood samples were collected retroorbitally 1 hour after injection. For time-course PK studies, blood samples were collected at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours. For blood samples, plasma was separated by centrifugation. Plasma samples were extracted with 4:1 acetonitrile:water containing 0.1% formic acid, containing indomethacin as an internal standard. Samples were centrifuged and the supernatants diluted with acetonitrile:water and analyzed by LC-MS / MS on a Shimadzu Nexera X2 HPLC connected to an AB Sciex 6500 QTRAP.

[0613] [Table 8]

[0614] [Table 9]

[0615] Plasma levels of the parent compound were determined 1 hour after ip injection of 10 mg / kg.

[0616] While preferred embodiments of the present technology have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be utilized in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

1. A compound having the structure of Formula I, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein: 【Chemical 1】 During the ceremony, X １ are each independently O, S, S(=O), or S(=O) ２ and R １ , R ３ , and R ４ are each independently H, halogen, or C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, wherein alkyl, cycloalkyl, aryl, and heteroaryl are each independently selected from one, two, or three R ａ is optionally replaced by R ２ are each independently H, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, —C １ -C ６ Alkyl-(C ３ -C ６ cycloalkyl), or —NR ５ R ６ wherein alkyl and cycloalkyl are each independently one, two, or three R ｂ is optionally replaced by R ５ and R ６ are each independently H, C １ -C ６ Alkyl, or -C １ -C ６ Alkyl-(C ３ -C ６ cycloalkyl), R ７ are each independently H, halogen, or C １ -C ６ alkyl, or OH; n is independently 1 or 2; X ３ are each independently -NHC(=O)-, -C(=O)NH-, or -NHS(=O) ２ -, -S(=O) ２ NH-, -NHC(=O)NH-, -NH(C=O)O-, -O(C=O)NH-, -NHS(=O) ２ NH-, -NHC(R １ａ ) (R １ｂ ) - or -C(R １ａ ) (R １ｂ ) NH—, A １ and A ２ is independent, C １ -C ６ Alkylene, C ３ -C １０ Cycloalkylene, C ５ -C １０ Arylene, C ２ -C １０ heterocycloalkylene, or 4- to 10-membered heteroarylene, wherein alkyl, cycloalkylene, arylene, heterocycloalkylene, and heteroarylene are each independently selected from one, two, or three R ｃ is optionally replaced by L is -X ５ - (CH ２ ) ｎ１ -Q １ - (CH ２ ) ｎ２ -X ５ - and X ５ are each independently O, S, or absent; n １ and ２ are each independently 0 to 5, Q １ is -C １ -C ６ Alkylene-, -C ２ -C ６ Alkenylene-, -C ２ -C ６ Alkynylene-, —C(O)NH—C １ -C ６ Alkylene -NHC(O)-, -SO ２ -, -C ２ -C ６ Alkynylene-C ６ -C １０ Arylene-, -C ２ -C ６ Alkynylene-C ６ -C １０ Arylene-C ２ -C ６ Alkynylene-, or -C ６ -C １０ Arylene-C ６ -C １０ arylene-, alkylene, alkenylene, C ２ -C ６ Alkynylene, and C ６ -C １０ Each arylene independently has one, two, or three R ｄ is optionally replaced by R １ａ and R １ｂ are each independently H, OH, or NH ２ , C.N., C. １ -C ６ Alkoxy, C １ -C ６ Alkyl, C ２ -C ６ Alkene, C ２ -C ６ Alkynyl, C １ -C ６ Heteroalkyl, C ３ -C ６ Cycloalkyl, C ２ -C ５ Heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl; R ２ａ and R ２ｂ are each independently H, OH, or NH ２ , C.N., C. １ -C ６ Alkoxy, C １ -C ６ Alkyl, C ２ -C ６ Alkene, C ２ -C ６ Alkynyl, C １ -C ６ Heteroalkyl, C ３ -C ６ Cycloalkyl, C ２ -C ５ Heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl; or R ２ａ and R ２ｂ are united, C ３ -C ６ Cycloalkyl or C ２ -C ５ forming a heterocycloalkyl, and R ａ , R ｂ , R ｃ , and R ｄ are each independently a halogen, OH, or NH ２ , C.N., C. １ -C ６ Alkoxy, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ２ -C ６ Alkene, C ２ -C ６ Alkynyl, C １ -C ６ Heteroalkyl, C ３ -C ６ Cycloalkyl, C ２ -C ５ Heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl; However, the compound 【Chemistry 2-1】 【Chemistry 2-2】 【Chemistry 2-3】 【Chemistry 2-4】 or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, which is not

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein each n is 1.

3. 2. The compound of claim 1, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein each n is 2.

4. R ７ are each independently H or OH, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

5. R ７ 5. The compound of any one of claims 1-4, wherein each is H, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

6. 10. The compound of claim 1, having the structure of Formula II, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof. 【Chemistry 3】

7. 10. The compound of claim 1, having the structure of Formula III: or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof. 【Chemistry 4】

8. X １ is S, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

9. X １ is O, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

10. R ２ａ and R ２ｂ are each independently H, OH, or C １ -C ６ Alkyl, or C ２ -C ６ an alkene, or R ２ａ and R ２ｂ are united, C ３ -C ６ 10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, which forms a cycloalkyl.

11. R ２ａ and R ２ｂ are each independently OH or C ２ -C ６ an alkene, or R ２ａ and R ２ｂ are united, C ３ -C ６ 9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, which forms a cycloalkyl.

12. R ２ａ and R ２ｂ are each independently ２ -C ６ 12. The compound of claim 11, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, which is an alkene.

13. R ２ｂ is H, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

14. R ２ａ 12. The compound of claim 11, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein:

15. R ２ａ and R ２ｂ are united, C ３ -C ６ 12. The compound of claim 11, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, which forms a cycloalkyl.

16. R ２ａ and R ２ｂ 16. The compound of claim 15, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein:

17. R ２ａ and R ２ｂ are each independently １ -C ６ Alkyl or C ２ -C ６ alkenyl, or R ２ａ and R ２ｂ are united, C ５ 10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, which forms a cycloalkyl.

18. R ２ａ and R ２ｂ are each independently １ -C ６ 10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein R is alkyl.

19. X ３ 19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein: is -NHC(=O)- or -C(=O)NH-.

20. R １ are each independently H or C １ -C ３ 20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein R is alkyl.

21. R ２ are each independently -NR ５ R ６ 21. The compound of any one of claims 1-20, wherein:

22. R ２ are each independently —NH ２ or NHCH ３ 22. The compound of any one of claims 1-21, wherein:

23. R ３ are each independently H or C １ -C ３ 23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein R is alkyl.

24. R ３ are each independently H or CH ３ 24. The compound of any one of claims 1-23, wherein:

25. R ３ are C ２ -C ３ 25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein R is alkyl.

26. R ３ 26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein is ethyl.

27. R ４ are each independently H or C １ -C ３ 23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein R is alkyl.

28. R ４ are each independently H or CH ３ 23. The compound of any one of claims 1-22, wherein:

29. R ４ 23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein each is H.

30. R ４ are CH ３ 23. The compound of any one of claims 1-22, wherein:

31. R ３ are each independently １ -C ３ alkyl, and R ４ are each independently １ -C ３ 23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein R is alkyl.

32. R ３ are CH ３ and R ４ are CH ３ 23. The compound of any one of claims 1-22, wherein:

33. 【Chemical 5】 teeth, 【Chemistry 6】 20. The compound of any one of claims 1-19, wherein:

34. 【Chemical 7】 teeth, 【Chemistry 8】 20. The compound of any one of claims 1-19, wherein:

35. 【Chemical 9】 teeth, 【Chemistry 10】 20. The compound of any one of claims 1-19, wherein:

36. [Catalog 11] teeth 【Chemistry 12】 20. The compound of any one of claims 1-19, wherein:

37. 【Catalog 13】 teeth 【Chemistry 14】 20. The compound of any one of claims 1-19, wherein:

38. A １ and A ２ is independent, C １ -C ６ Alkylene or C ３ -C １０ and cycloalkylene, each of the alkylene and cycloalkylene independently having one, two, or three R ｃ 38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, optionally substituted with:

39. A １ and A ２ teeth 【Chemistry 15】 39. The compound of any one of claims 1-38, wherein:

40. A １ and A ２ teeth 【Chemistry 16】 39. The compound of any one of claims 1-38, wherein:

41. 【Catalog 17】 teeth, 【Chemistry 18】 40. The compound of any one of claims 1-39, wherein:

42. X ５ 42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein each is O.

43. n １ and ２ 43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein each independently is 1-3.

44. n １ and ２ 44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein each is 1.

45. n １ and ２ 44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein each is 2.

46. n １ and ２ 43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein each is 0.

47. Q １ Ha-C ４ alkylene-, 【Chemistry 19】 , -C(O)NH-(CH ２ ) １－３ -NHC(O)- or -SO ２ 47. The compound of any one of claims 1-46, wherein:

48. Q １ teeth, 【Chemistry 20】 , -C(O)NH-(CH ２ ) １－３ -NHC(O)- or -SO ２ 48. The compound of any one of claims 1-47, wherein: - or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

49. Q １ Ha-C ４ 48. The compound of any one of claims 1-47, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, which is alkylene-.

50. Q １ teeth 【Chemical 21】 48. The compound of any one of claims 1-47, wherein:

51. Q １ teeth 【Chemical 22】 48. The compound of any one of claims 1-47, wherein:

52. Q １ teeth 【Chemical 23】 48. The compound of any one of claims 1-47, wherein:

53. Q １ teeth 【Chemistry 24】 48. The compound of any one of claims 1-47, wherein:

54. Q １ teeth 【Chemistry 25】 48. The compound of any one of claims 1-47, wherein:

55. Q １ teeth 【Chemical 26】 48. The compound of any one of claims 1-47, wherein:

56. Q １ teeth 【Chemical 27】 48. The compound of any one of claims 1-47, wherein:

57. Q １ is -C(O)NH-(CH ２ ) １－３ 48. The compound of any one of claims 1-47, which is -NHC(O)-, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

58. Q １ Ha-SO ２ 48. The compound of any one of claims 1-47, wherein: - or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

59.

28. teeth, 【Chemical 29】 48. The compound of any one of claims 1-47, wherein:

60. R ｃ are each independently C ６ 60. The compound of claim 59, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, which is aryl.

61. The compound has one of the structures shown in Table A: However, the compound 【Chemistry 30】 2. The compound of claim 1, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, wherein:

62. 62. A pharmaceutical composition comprising a compound of any one of claims 1-61, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.

63. 62. A method of treating a hyperproliferative disorder in an individual, said method comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1-61, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

64. 64. The method of claim 63, wherein the hyperproliferative disorder is cancer or an autoimmune disease.

65. 65. The method of claim 64, wherein the autoimmune disease is hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac disease, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft-versus-host disease, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, or vitiligo.

66. 62. A method of treating cancer in an individual, said method comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1-61, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

67. 67. The method of claim 66, wherein the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or a combination thereof.

68. 67. The method of claim 66, wherein the cancer is skin cancer, lung cancer, breast cancer, prostate cancer, colon cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combination thereof.

69. 67. The method of claim 66, wherein the cancer is acute myeloid leukemia (AML).

70. 67. The method of claim 66, wherein the cancer is renal cell carcinoma.

71. 67. The method of claim 66, wherein the cancer is ovarian cancer.

72. 67. The method of claim 66, wherein the cancer is prostate cancer.

73. 67. The method of claim 66, wherein the cancer is renal cell carcinoma.

74. 67. The method of claim 66, wherein the cancer is glioblastoma.

75. 67. The method of claim 66, wherein the cancer is gastric cancer.

76. 67. The method of claim 66, wherein the cancer is esophageal squamous cell carcinoma.

77. 67. The method of claim 66, wherein the cancer is lung cancer.

78. 78. The method of claim 77, wherein the lung cancer is non-small cell lung cancer or small cell lung cancer.

79. 67. The method of claim 66, wherein the cancer is multiple myeloma.

80. 67. The method of claim 66, wherein the cancer is pancreatic cancer.

81. 67. The method of claim 66, wherein the cancer is breast cancer.

82. 62. A method of treating a disease associated with undesired angiogenesis in an individual, said method comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1-61, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

83. 83. The method of claim 82, wherein the disease associated with unwanted angiogenesis is macular degeneration, rheumatoid arthritis, psoriasis, diabetic retinopathy, retinopathy of prematurity, corneal transplant rejection, neovascular glaucoma, retrolental fibroplasia, skin flushing, Osler-Webber syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophilic joints, angiofibroma, wound granulation, intestinal adhesions, atherosclerosis, scleroderma, or hypertrophic scar.

84. 83. The method of claim 82, wherein the disease associated with unwanted angiogenesis is cancer.

85. 85. The method of claim 84, wherein the cancer is a sarcoma, carcinoma, blastoma, myeloma, leukemia, lymphoma, or a combination thereof.

86. 85. The method of claim 84, wherein the cancer is Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, or other leukemia.

87. 85. The method of claim 84, wherein the cancer is skin cancer, lung cancer, breast cancer, prostate cancer, colon cancer, cervical cancer, uterine cancer, pancreatic cancer, liver cancer, or any combination thereof.

88. 85. The method of claim 84, wherein the cancer is acute myeloid leukemia (AML).

89. 85. The method of claim 84, wherein the cancer is renal cell carcinoma.

90. 85. The method of claim 84, wherein the cancer is ovarian cancer.

91. 85. The method of claim 84, wherein the cancer is prostate cancer.

92. 85. The method of claim 84, wherein the cancer is renal cell carcinoma.

93. 85. The method of claim 84, wherein the cancer is glioblastoma.

94. 85. The method of claim 84, wherein the cancer is gastric cancer.

95. 85. The method of claim 84, wherein the cancer is esophageal squamous cell carcinoma.

96. 85. The method of claim 84, wherein the cancer is lung cancer.

97. 97. The method of claim 96, wherein the lung cancer is non-small cell lung cancer or small cell lung cancer.

98. 85. The method of claim 84, wherein the cancer is multiple myeloma.

99. 85. The method of claim 84, wherein the cancer is pancreatic cancer.

100. 85. The method of claim 84, wherein the cancer is breast cancer.

101. 62. A method of treating human immunodeficiency virus (HIV) in a mammal, said method comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1-61, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

102. 62. A method for reactivating latent human immunodeficiency virus (HIV) in a mammal, said method comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1-61, or a pharmaceutically acceptable salt, N-oxide, racemate, or stereoisomer thereof.

103. 103. The method of claim 102, wherein the latent state of HIV is reactivated without T cell activation.

104. 104. The method of claim 102 or 103, further comprising administering an additional latency reactivating agent, killer agent, CarT, immunotherapeutic agent, neutralizing antibody agent, or other agent.

105. 105. The method of claim 104, wherein the additional latency reactivator is a bromodomain and extraterminal domain inhibitor (BETi) or a protein kinase C (PKC) agonist.

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