Pyrrolo[1,2-a]-azocine analogues as IAP antagonists

Abstract

The present disclosure relates to compounds that inhibit IAP (preferably XIAP, cIAP1, or cIAP2) protein, pharmaceutical compositions comprising the same and methods of using the IAP protein inhibitors in the treatment of diseases and conditions wherein inhibition of IAP protein provides a benefit.

Description

[0001] PYRROLO [1,2-A]-AZOCINE ANALOGUES AS IAP ANTAGONISTS Technical Field The present disclosure relates to new inhibitors / antagonists of IAP and to therapeutic methods of treating conditions and diseases wherein inhibition / antagonism of IAP proteins provides a benefit. The present inhibitors effectively bind to IAP proteins, including XIAP, cIAPl, and cIAP2. Background of the Invention Apoptosis, or programmed cell death, is a cell process critical for homeostasis, normal development, host defense, and suppression of oncogenesis. Faulty regulation of apoptosis has been implicated in many human diseases, including cancer, and it is now recognized that resistance to apoptosis is a hallmark of cancer. As a consequence, targeting of key apoptosis regulators has emerged as an attractive strategy for the development of new approaches to human cancer treatment. Most current cancer therapies, including chemotherapeutic agents, radiation, and immunotherapy, indirectly induce apoptosis in cancer cells. The inability of cancer cells to execute an apoptotic program due to defects in the normal apoptotic machinery is thus often associated with an increase in resistance to chemotherapy, radiation, or immunotherapy-induced apoptosis. Such primary or acquired resistance of human cancers to current therapies due to apoptosis defects is a major problem in current cancer therapy. In order to improve survival and quality of life of cancer patients, current and future efforts in the design and development of new molecular target- specific anticancer therapies includes strategies that specifically target cancer cell resistance to apoptosis. In this regard, targeting negative regulators that play a central role in directly inhibiting apoptosis in cancer cells represents a highly promising therapeutic strategy for new anticancer drug design. One class of central negative regulators of apoptosis is the Inhibitors of Apoptosis Proteins (IAPs). The family of IAP proteins comprises 8 members, XIAP, cIAP1, cIAP2, NAIP, ILP2, ML-IAP, survivin and BRUCE (also known as apollon). Members of the IAP family have been shown to inhibit programmed cell death through their ability to directly inhibit members of the caspase family of apoptotic enzymes, although the precise role of all 8 members is yet to be fully defined. The common structural feature of all IAP family members is a -70 amino acid zinc-binding fold termed the baculovirus IAP repeat (BIR) domain, which is present in one to three copies. Many interactions between IAPs and other proteins are mediated via a surface groove on the BIR domain. BIR domains may be classified by their peptide-binding specificity. There are three types of BIR domains; type III domains (capable of binding caspase (and caspase-like) peptides with a specificity for proline in the third (P3) position (e.g. XIAP BIR3), type II domains (like type III domains but lacking the proline requirement e.g. XIAP BIR2) and type I domains (which do not bind caspases or similar peptides, e.g. XIAP BIR1) (Eckelman et al. Cell Death and Differentiation 2008; 15: 920-928). BIRs are small (-70 amino acids) Zn- coordinated domains and a variety of proteins use their N-terminal to interact with the BIR domains grooves. BIR antagonists prevent caspases binding to BIRs and hence result in increased caspase activity thereby inducing auto-ubiquitination and proteasomal degradation of IAPs. IAPs are overexpressed in many cancers including renal, melanoma, colon, lung, breast, ovarian and prostate cancers (Tamm et al., Clin. Cancer Research 2000; 6(5): 1796-803), and have been implicated in tumour growth, pathogenesis and resistance to chemo- and radio-therapy (Tamm 2000). Small molecule inhibitors of IAP proteins are known. For example, U.S. Patent Publication Application No. 2005 / 0197403 and U.S. Patent No. 7,960,372 disclose dimeric Smac mimetic compounds, each incorporated herein by reference in its entirety. Despite the discovery of small molecule inhibitors of IAP proteins, the design of potent inhibitors of IAP proteins remains a significant challenge in modern drug discovery. Accordingly, a need still exists in the art for IAP inhibitors having physical and pharmacological properties that permit use of the inhibitors in therapeutic applications. The present invention provides compounds designed to bind to IAP proteins and inhibit IAP protein activity. Summary of the Invention In one aspect, the present disclosure provides compounds represented by Formula I, I-1, II, III, IV, V, VI, VII or VIII below, and the pharmaceutically acceptable salts and solvates, e.g., hydrates, thereof, collectively referred to as "compounds of the disclosure." Compounds of the disclosure are IAP (especially XIAP, cIAPl, or cIAP2) inhibitors and are thus useful in treating or preventing diseases or conditions such as IAP -associated cancer wherein the inhibition of IAP provides a benefit. In another aspect, the present disclosure provides pharmaceutical compositions comprising the compound of the disclosure, and a pharmaceutically acceptable carrier. In another aspect, the present disclosure provides methods for inhibiting IAP protein activity in a cell, comprising contacting the cell in which inhibition of IAP protein activity is desired with an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition of the disclosure. In another aspect, the present disclosure provides methods of treating a disease or condition wherein inhibition of an IAP protein provides a benefit comprising administering a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition of the disclosure. In one embodiment, the disease or condition is a cancer. In another embodiment, the disease or condition is selected from the group consisting of T and B cell mediated autoimmune diseases; inflammatory diseases; infections; hyperproliferative diseases; AIDS; degenerative conditions; vascular diseases; and the like. In another embodiment, the disease or condition is selected from the group consisting of HBV, autoimmune hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac sprue, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft versus host disease, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatic arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, and the like. In another aspect, the present disclosure provides compounds or pharmaceutical compositions of the disclosure for use in inhibiting IAP protein activity in a cell. In another aspect, the present disclosure provides compounds or pharmaceutical compositions of the disclosure for use in treating a disease or condition wherein inhibition of an IAP protein provides a benefit. In another aspect, the present disclosure provides the use of compounds or pharmaceutical compositions of the disclosure in the manufacture of a medicament for inhibiting IAP protein activity in a cell. In another aspect, the present disclosure provides the use of compounds or pharmaceutical compositions of the disclosure in the manufacture of a medicament for treating a disease or condition wherein inhibition of an IAP protein provides a benefit. In another aspect, the present disclosure provides kits comprising compounds of the disclosure, and instructions for administering the compounds of the disclosure to a subject (e.g., a patient) for which the inhibition of an IAP protein provides a benefit. Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed. Description of the Drawings Figure 1 indicates the immunoblots of cIAP1 and cIAP2 treated with SM-406, SM-3001 and SM-3002. Figure 2 indicates the immunoblots of cIAP1 treated with SM-406, SM-3003, SM-3020 and SM-3022. Detailed Description of the Invention The present disclosure relates to compounds that inhibit IAP. In particular, the present disclosure relates to compounds that inhibit the activity of XIAP, cIAPl, or cIAP2, pharmaceutical compositions comprising the same and methods of use therefor. Unless otherwise defined below, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques that are generally understood in the art, including those obvious changes or equivalent replacements of the techniques for those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the disclosure. I. Definitions As used herein, the terms "including", "comprising", "having", "containing" or "comprising", and other variants thereof, are inclusive or open, and do not exclude other unlisted elements or method steps. The use of the terms "a", "an", "the", and similar referents in the context of describing the disclsoure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein merely are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure. The term "IAP proteins," as used herein, refers to any known member of the Inhibitors of Apoptosis Protein family, including, but not limited to, XIAP, cIAP-1, cIAP-2, ML-IAP, HIAP, TSIAP, KIAP, NAIP, survivin, livin, ILP-2, apollon, and BRUCE. The term "overexpression of IAP" as used herein, refers to an elevated level (e.g., aberrant level) of mRNAs encoding for an IAP protein(s), and / or to elevated levels of IAP protein(s) in cells as compared to similar corresponding non-pathological cells expressing basal levels of mRNAs encoding IAP proteins or having basal levels of IAP proteins. The term "a disease or condition wherein inhibition of an IAP protein provides a benefit" pertains to a condition in which an IAP protein, and / or an action of an IAP protein, is important or necessary, e.g., for the onset, progress, expression of that disease or condition, or a disease or a condition which is known to be treated by an IAP protein inhibitor. An example of such a condition includes, but is not limited to, a cancer. One of ordinary skill in the art is readily able to determine whether a compound treats a disease or condition mediated by an IAP protein for any particular cell type, for example, by assays which conveniently can be used to assess the activity of particular compounds. The term "disease" or "condition" denotes disturbances and / or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and / or malfunctions. As demonstrated below, a compound of structural formula (I) is a potent inhibitor of IAP proteins and can be used in treating diseases and conditions wherein inhibition an IAP protein provides a benefit. As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms "treat," "treating," "treatment," and the like may include "prophylactic treatment," which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound of the invention to an individual in need of such treatment. Within the meaning of the invention, "treatment" also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and / or malfunctions. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy. As used herein, the terms "prevent," "preventing," and "prevention" refer to a method of preventing the onset of a disease or condition and / or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent," "preventing," and "prevention" also include delaying the onset of a disease and / or its attendant symptoms and reducing a subject's risk of acquiring a disease. The terms "prevent," "preventing" and "prevention" may include "prophylactic treatment," which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition. The term “inhibitor(s)” and “antagonist(s)” are used interchangeably herein, and refer to any agent that has inhibitory or antagonistic activity on IAP protein, including but not limited to small molecule compounds, biological macromolecules, and the like. For the same reason, the term “inhibition” and “antagonism” are also used interchangeably herein. As used herein, the term “subject,” "individual," or "patient," used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. The term "therapeutically effective amount" or "effective dose" as used herein refers to an amount of the active ingredient(s) that is (are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to a subject in need thereof. In the case of a cancer or other proliferation disorder, the therapeutically effective amount of the agent may reduce (i.e., retard to some extent or stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent or stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent or stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve, to some extent, one or more of the symptoms associated with the cancer. To the extent the administered compound or composition prevents growth and / or kills existing cancer cells, it may be cytostatic and / or cytotoxic. The term "halo" or “halogen”as used herein by itself or as part of another group refers to -Cl, -F, -Br, or -I. The term "cyano" as used herein by itself or as part of another group refers to -CN. The term "hydroxy" as herein used by itself or as part of another group refers to -OH. The term "alkyl" as used herein by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms, i.e., a C1-C12 alkyl, or the number of carbon atoms designated, e.g., a C1 alkyl such as methyl, a C2alkyl such as ethyl, etc. In one embodiment, the alkyl is a C1-C10 alkyl. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4alkyl. In another embodiment, the alkyl is a C1-C3 alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C1-C12 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. In another embodiment, one or more of the hydrogen atoms of the alkyl group are replaced by deuterium atoms, i.e., the alkyl group is isotopically-labeled with deuterium. A non-limiting exemplarly deteuterated alkyl group is -CD3. In another embodiment, none of the hydrogen atoms of the alkyl group are replaced by deuterium atoms, i.e., the alkyl group is isotopically-labeled with deuterium. The term "haloalkyl" as used herein by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl is substituted by one, two, or three fluorine and / or chlorine atoms. In another embodiment, the alkyl is substituted by one, two, or three fluorine atoms. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4alkyl. In another embodiment, the alkyl group is a C1 or C2 alkyl. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups. The terms "hydroxyalkyl" or "(hydroxy)alkyl" as used herein by themselves or as part of another group refer to an alkyl group substituted with one, two, or three hydroxy groups. In one embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4alkyl. In another embodiment, the alkyl is a C1or C2 alkyl. In another embodiment, the hydroxyalkyl is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. Non-limiting exemplary (hydroxy)alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl. The term "alkoxy" as used herein by itself or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl is a C1-C6alkyl and resulting alkoxy is thus referred to as a "C1-C6alkoxy." In another embodiment, the alkyl is a C1-C4 alkyl group and resulting alkoxy is thus referred to as a C1-C4alkoxy. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy. The term "carbocyclic" or “carbocycle” as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., a C3-12carbocyclic (e.g., a 5-10 membered carbocyclic). For example, a C5 carbocyclic or a C6 carbocyclic. When the aliphatic hydrocarbons are saturated, carbocyclic may also be called as cycloalkyl, e.g., a C3cycloalkyl such a cyclopropyl, a C4cycloalkyl such as cyclobutyl, etc. In one embodiment, the carbocyclic is cycloalkyl. In one embodiment, the cycloalkyl is bicyclic, i.e., it has two rings. In another embodiment, the cycloalkyl is monocyclic, i.e., it has one ring. In another embodiment, the cycloalkyl is a C3-8 cycloalkyl. In another embodiment, the cycloalkyl is a C3-6 cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, the cycloalkyl is a C5 cycloalkyl, i.e., cyclopentyl. In another embodiment, the cycloalkyl is a C6cycloalkyl, i.e., cyclohexyl. Non-limiting exemplary C3-12 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane. The term "heterocyclyl" as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic groups containing three to fourteen ring members, i.e., a 4- to 14-membered heterocyclyl (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14-membered heterocyclyl), comprising one, two, three, or four heteroatoms，for example 4- membered , 5- membered, 6- membered, 7- membered, 8- membered, 9- membered, 10-membered heterocyclo. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom is independently oxidized to give a sulfoxide, i.e., S(=O), or sulfone, i.e., S(=O)2. The term heterocyclyl includes groups wherein one or more -CH2- groups is replaced with one or more -C(=O)- groups, including cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as pyrrolidin-2-one or piperidin-2-one, and cyclic carbamate groups such as oxazolidinyl-2-one. The term heterocyclyl also includes groups having fused optionally substituted aryl or optionally substituted heteroaryl groups such as indoline, indolin-2-one, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine,2,3,4,5-tetrahydro-1H-benzo[d]azepine, or 1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one. In one embodiment, the heterocyclyl group is a 4- to 8-membered or 5- to 10-membered cyclic group containing one ring and one or two oxygen atoms, e.g., tetrahydrofuran or tetrahydropyran, or one or two nitrogen atoms, e.g., pyrrolidine, piperidine, or piperazine, or one oxygen and one nitrogen atom, e.g., morpholine, and, optionally, one -CH2- group is replaced with one -C(=O)- group, e.g., pyrrolidin-2-one or piperazin-2-one. In another embodiment, the heterocyclo group is a 5- to 8-membered cyclic group containing one ring and one or two nitrogen atoms and, optionally, one -CH2- group is replaced with one -C(=O)- group. In another embodiment, the heterocyclo group is a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms and, optionally, one -CH2- group is replaced with one -C(=O)- group. In another embodiment, the heterocyclyl group is a 8- to 12-membered cyclic group containing two rings and one or two oxygen atoms. In another embodiment, the heterocyclo group is a 8- to 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be linked to the rest of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclyl groups include: The term "aryl" as used herein by itself or as part of another group refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C6-C14 aryl ((e.g., 6-10 membered aryl), C9-C10aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl. The term "heteroaryl" as used herein by itself or as part of another group refers to monocyclic and bicyclic aromatic ring systems having five to fourteen ring members, i.e., a 5- to 14-membered heteroaryl, a 5- to 10-membered-heteroaryl, a 5- to 7-membered (preferably 5-membered or 6-membered) comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In another embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide. The term "(cycloalkyl)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, the cycloalkyl group(s) is an optionally substituted C3-C6cycloalkyl. In another embodiment, the alkyl is a C1-C6alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. In another embodiment, the alkyl is substituted with one optionally substituted cycloalkyl group. In another embodiment, the alkyl is substituted with two optionally substituted cycloalkyl groups. Non-limiting exemplary (cycloalkyl)alkyl groups include: , . The term "carboxy" as used by itself or as part of another group refers to a radical of the formula -C(=O)OH. The term "(heterocyclo)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted heterocyclo groups. In one embodiment, the alkyl is substituted with one optionally substituted 5- to 8-membered heterocyclo group. In another embodiment, alkyl is a C1-C6 alkyl. In another embodiment, alkyl is a C1-C4 alkyl. The heterocyclo group can be linked to the alkyl group through a carbon or nitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include:

[0002] . The term "(heteroaryl)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one or two optionally substituted heteroaryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted 5- to 14-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- to 14-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- to 9-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5- or 6-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- or 6-membered heteroaryl groups. In one embodiment, the alkyl group is a C1-C6alkyl. In another embodiment, the alkyl group is a C1-C4 alkyl. In another embodiment, the alkyl group is a C1 or C2 alkyl. Non-limiting exemplary (heteroaryl)alkyl groups include: . The terms "aralkyl" or "(aryl)alkyl" as used herein by themselves or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the alkyl is substituted with one optionally substituted aryl group. In another embodiment, the alkyl is substituted with two optionally substituted aryl groups. In one embodiment, the aryl is an optionally substituted phenyl or optionally substituted naphthyl. In another embodiment, the aryl is an optionally substituted phenyl. In one embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1or C2alkyl. Non-limiting exemplary (aryl)alkyl groups include benzyl, phenethyl, -CHPh2, and -CH(4-F-Ph)2. The term "amino" as used by itself or as part of another group refers to a radical of the formula -NR55aR55b, wherein R55aand R55bare independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. In one embodiment, the amino is -NH2. The present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H (or deuterium (D)),3H,11C,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively, e.g.,3H,11C, and14C. In one embodiment, provided is a compound wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. In another embodiment, provided is a compound wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by deuterium atoms, e.g., all of the hydrogen atoms of a -CH3 group are replaced by deuterium atoms to give a -CD3 group. In another embodiment, provided is a compound wherein a portion of the atoms at a position within the Compound of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a position with an atom having a different atomic mass or mass number. In another embodiment, provided is a compound wherein none of the atoms of the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art. Compounds of the Disclosure contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure. As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers). The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached. The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction. The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive. In one embodiment, Compounds of the Disclosure are racemic. The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S. The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated. The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as │R - S│*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([α]obs / [α]max)*100, where [α]obsis the optical rotation of the mixture of enantiomers and [α]max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry. The term "about," as used herein, includes the recited number ± 10%. Thus, "about 10" means 9 to 11. The phrase “optionally substituted with one or more groups” as used herein refers to optionally substituted with 1-10 groups, preferably optionally substituted with 1-5 groups, and more preferably optionally substituted with 1,2, or 3 groups. II. Compounds In one aspect, the present disclosure provides a compound of Formula I: or a pharmaceutically acceptable salt or solvate thereof， wherein: R1and R2are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, halogen, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, and 3-10 membered carbocyclyl; wherein the above groups are optionally substituted with one or more R8, each R8 can be the same or different; or R1and R2together with the carbon to which they are attached, form a 4-10 membered heterocyclyl or 3-10 membered carbocyclyl optionally substituted with one or more R8, each R8can be the same or different; R3 and R4 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl; wherein the C1-C6 alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl is optionally substituted with one or more R8, each R8 can be the same or different; or R3 and R4 together with the nitrogen to which they are attached, form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with one or more R8, each R8 can be the same or different; R5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, amino, and halogen; R6 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, and halogen; R7 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6haloalkyl, wherein the above groups are optionally substituted with one or more R8, each R8 can be the same or different; R8 is selected from the group consisting of halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered and carbocyclyl, wherein the above groups are optionally substituted with one or more of hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -(C=O)-C1-C6 alkyl and halogen; Zis selected from the group consisting of X Y, C(R9)2, NR9, O, S, SO, SO2,and S(=O)(=N-R9), represents a single or double bond; and when represents a double bond, X and Y are each independently selected from CR9 and N, provided that X and Y cannot both be N; when represents a single bond, X and Y are each independently selected from the group consisting of C(R9)2, NR9, O, S, SO, SO2,and S(=O)(=N-R9), provided that at least one of X and Y is C(R9)2; each R9 can be the same or different, and on each occurrence, is independently selected from the group consisting of hydrogen, (SO2)-C1-C6 alkyl, -(SO2)-3-10 membered carbocyclyl, -(SO2)-4-10 membered heterocyclyl, -(SO2)-6-12 membered aryl, -(SO2)-5-12 membered heteroaryl, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6 cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered carbocyclyl, -(C=O)-C1-C6alkyl, -(C=O)-3-10 membered carbocyclyl, -(C=O)-4-10 membered heterocyclyl, -(C=O)-6-12 membered aryl, -(C=O)-5-12 membered heteroaryl, -(C=O)-O-C1-C6alkyl, -(C=O)-O-3-10 membered carbocyclyl, -(C=O)-O-4-10 membered heterocyclyl, -(C=O)-O-6-12 membered aryl, -(C=O)-O-5-12 membered heteroaryl, -(C=O)-NH-C1-C6alkyl, -(C=O)-NH-3-10 membered carbocyclyl, -(C=O)-NH-4-10 membered heterocyclyl, -(C=O)-NH-6-12 membered aryl, -(C=O)-NH-5-12 membered heteroaryl, -(C=O)-N(R8)2, and halogen, wherein the above alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl in the definition of R9 is optionally substituted with one or more of C1-C6 alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, hydroxyl, amino, cyano and halogen. In one aspect, the present disclosure provides a compound of Formula I-1: (I-1) or a pharmaceutically acceptable salt or solvate thereof， wherein: R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, cyano, halogen, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, and 3-10 membered carbocyclyl; wherein the above groups are optionally substituted with one or more R8, each R8 can be the same or different; or R1 and R2 together with the carbon to which they are attached, form a 4-10 membered heterocyclyl or 3-10 membered carbocyclyl optionally substituted with one or more R8, each R8 can be the same or different; R3and R4are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl; wherein the C1-C6alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl is optionally substituted with one or more R8,each R8can be the same or different; or R3 and R4 together with the nitrogen to which they are attached, form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with one or more R8, each R8can be the same or different; R5 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, hydroxyl, amino, and halogen; R6 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and halogen; R7is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl and C1-C6 haloalkyl, wherein the above groups are optionally substituted with one or more R8, each R8can be the same or different; R8 is selected from the group consisting of halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered and carbocyclyl, wherein the above groups are optionally substituted with one or more of hydroxyl, amino, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, -(C=O)-C1-C6 alkyl and halogen; represents a single or double bond; and when represents a double bond, X and Y are each independently selected from CR9and N, provided that X and Y cannot both be N; when represents a single bond, X and Y are each independently selected from the group consisting of C(R9)2, NR9, O, S, SO, SO2,and S(=O)(=N-R9), provided that at least one of X and Y is C(R9)2; each R9 can be the same or different, and on each occurrence, is independently selected from the group consisting of hydrogen, (SO2)-C1-C6alkyl, -(SO2)-3-10 membered carbocyclyl, -(SO2)-4-10 membered heterocyclyl, -(SO2)-6-12 membered aryl, -(SO2)-5-12 membered heteroaryl, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered carbocyclyl, -(C=O)-C1-C6 alkyl, -(C=O)-3-10 membered carbocyclyl, -(C=O)-4-10 membered heterocyclyl, -(C=O)-6-12 membered aryl, -(C=O)-5-12 membered heteroaryl, -(C=O)-O-C1-C6 alkyl, -(C=O)-O-3-10 membered carbocyclyl, -(C=O)-O-4-10 membered heterocyclyl, -(C=O)-O-6-12 membered aryl, -(C=O)-O-5-12 membered heteroaryl, -(C=O)-NH-C1-C6 alkyl, -(C=O)-NH-3-10 membered carbocyclyl, -(C=O)-NH-4-10 membered heterocyclyl, -(C=O)-NH-6-12 membered aryl, -(C=O)-NH-5-12 membered heteroaryl, -(C=O)-N(R8)2, and halogen, wherein the above alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl in the definition of R9is optionally substituted with one or more of C1-C6alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, amino, cyano and halogen. In one aspect, the present disclosure provides a compound of Formula II: (II) or a pharmaceutically acceptable salt or solvate thereof， wherein: R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, halogen, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, and 3-10 membered carbocyclyl; wherein the above groups are optionally substituted with one or more R8, each R8can be the same or different; or R1 and R2 together with the carbon to which they are attached, form a 4-10 membered heterocyclyl or 3-10 membered carbocyclyl optionally substituted with one or more R8, each R8can be the same or different; R3 and R4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl; wherein the C1-C6 alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl is optionally substituted with one or more R8, each R8 can be the same or different; or R3and R4together with the nitrogen to which they are attached, form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with one or more R8, each R8 can be the same or different; R5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, amino, and halogen; R6is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and halogen; R7 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6haloalkyl, wherein the above groups are optionally substituted with one or more R8, each R8 can be the same or different; R8is selected from the group consisting of halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered and carbocyclyl, wherein the above groups are optionally substituted with one or more of hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -(C=O)-C1-C6alkyl and halogen; represents a single or double bond; and when represents a double bond, X and Y are each independently selected from CR9 and N, provided that X and Y cannot both be N; when represents a single bond, X and Y are each independently selected from the group consisting of C(R9)2, NR9, O, S, SO, SO2, and S(=O)(=N-R9), provided that at least one of X and Y is C(R9)2; each R9can be the same or different, and on each occurrence, is independently selected from the group consisting of hydrogen, (SO2)-C1-C6 alkyl, -(SO2)-3-10 membered carbocyclyl, -(SO2)-4-10 membered heterocyclyl, -(SO2)-6-12 membered aryl, -(SO2)-5-12 membered heteroaryl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered carbocyclyl, -(C=O)-C1-C6 alkyl, -(C=O)-3-10 membered carbocyclyl, -(C=O)-4-10 membered heterocyclyl, -(C=O)-6-12 membered aryl, -(C=O)-5-12 membered heteroaryl, -(C=O)-O-C1-C6alkyl, -(C=O)-O-3-10 membered carbocyclyl, -(C=O)-O-4-10 membered heterocyclyl, -(C=O)-O-6-12 membered aryl, -(C=O)-O-5-12 membered heteroaryl, -(C=O)-NH-C1-C6alkyl, -(C=O)-NH-3-10 membered carbocyclyl, -(C=O)-NH-4-10 membered heterocyclyl, -(C=O)-NH-6-12 membered aryl, -(C=O)-NH-5-12 membered heteroaryl, -(C=O)-N(R8)2, and halogen, wherein the above alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl in the definition of R9 is optionally substituted with one or more of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, hydroxyl, amino, cyano and halogen. In some embodiments, Z is selected from the group consisting of C(R9)2, NR9, O, S, SO, SO2, and S(=O)(=N-R9), In some embodiments, represents a single bond, X is C(R9)2and Y is NR9. In some embodiments, represents a single bond, X is NR9 and Y is C(R9)2. In some embodiments, represents a single bond, X is C(R9)2and Y is O. In some embodiments, represents a single bond, X is C(R9)2 and Y is C(R9)2. In some embodiments, represents a single bond, X is C(R9)2and Y is S, SO, SO2, or S(=O)(=N-R9). In some embodiments, represents a double bond, X is C(R9) and Y is C(R9). In some embodiments, R1and R2are each independently selected from hydrogen and C1-C6 alkyl. In some embodiments, both R1 and R2 are hydrogen; or both R1 and R2 are C1-C6 alkyl, preferably methyl. In some embodiments, R1 and R2 cannot both be hydrogen. In some embodiments, R3 is hydrogen, and R4 is selected from the group consisting of C1-C6alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl optionally substituted with one or more R8. In some embodiments, R4 is selected from optionally substituted with one or more R8. In some embodiments, R4is selected from: In some embodiments, R3 and R4 together with the nitrogen to which they are attached, form 5 membered heterocyclyl optionally substituted with one or more R8. In some embodiments, the 5 membered heterocyclyl is pyrrolidinyl. In some embodiments, R5 is hydrogen. In some embodiments, R6 is C1-C6 alkyl, preferably methyl. In some embodiments, R7is C1-C6alkyl, preferably methyl. In some embodiments, R9is -(C=O)-C1-C6alkyl, preferably -(C=O)-C4alkyl, more preferably -(C=O)-isobutyl. In some embodiments, R9 is -(C=O)-O-C1-C6 alkyl, preferably -(C=O)-O-methyl. In some embodiments, R9is -(C=O)-phenyl, -(C=O)-imidazole, or -(C=O)-pyranyl optionally substituted with C1-C6 alkyl. In one aspect, the present disclosure provides a compound of Formula III:

[0003] or a pharmaceutically acceptable salt or solvate thereof， wherein: R1 and R2 are each independently selected from the group consisting of C1-C6 alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, cyano, halogen, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, and 3-10 membered carbocyclyl, wherein the above groups are optionally substituted with one or more R8; and the remaining groups and / or chirality are as defined above. In some embodiments, R1 and R2 are both methyl. In one aspect, the present disclosure provides a compound of Formula IV: or a pharmaceutically acceptable salt or solvate thereof， wherein each group and / or chirality is as defined above. In some embodiments, R1 and R2 are both hydrogen. In one aspect, the present disclosure provides a compound of Formula V:

[0004] or a pharmaceutically acceptable salt or solvate thereof， wherein each group and / or chirality is as defined above. In some embodiments, each R9 is hydrogen, and / or R1 and R2 are both methyl. In one aspect, the present disclosure provides a compound of Formula VI: or a pharmaceutically acceptable salt or solvate thereof， wherein each group and / or chirality is as defined above. In one aspect, the present disclosure provides a compound of Formula VII: or a pharmaceutically acceptable salt or solvate thereof， wherein each group and / or chirality is as defined above. In one aspect, the present disclosure provides a compound of Formula VIII: or a pharmaceutically acceptable salt or solvate thereof， wherein each group and / or chirality is as defined above. In some embodiments, for the above aspects of the disclosure, the compound is selected from the group consisting of:

[0005] or a pharmaceutically acceptable salt or solvate thereof. The present disclosure encompasses the preparation and use of salts of Compounds of the Disclosure. As used herein, the term "pharmaceutically acceptable salt" refers to salts or zwitterionic forms of Compounds of the Disclosure that are suitable for administration to a subject, e.g., a human. Salts of Compounds of the Disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with a suitable acid. The pharmaceutically acceptable salts of Compounds of the Disclosure can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Non-limiting examples of salts of Compounds of the Disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulfonate, and p-toluenesulfonate salts. In addition, available amino groups present in the compounds of the disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In light of the foregoing, any reference Compounds of the Disclosure appearing herein is intended to include compounds of Compounds of the Disclosure as well as pharmaceutically acceptable salts, hydrates, or solvates thereof. The present disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical association and / or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E.C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1): Article 12 (2004), and A.L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in a crystal of the solvate. III. Compositions In one aspect, the present disclosure provides compositions comprising the compound of the disclsoure, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of Compound of the Disclosure. These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of the Compound of the Disclosure is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a Compound of the Disclosure. When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols. When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a Compound of the Disclosure. When a therapeutically effective amount of a Compound of the Disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle. Compounds of the Disclosure can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained by adding the Compound of the Disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, disintegrating agents can be added. Compound of the Disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a Compound of the Disclosure can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Compounds of the Disclosure also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, the Compound of the Disclosure also can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the Compound of the Disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins. In particular, the Compounds of the Disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. Compound of the Disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the Compound of the Disclosure are typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood. IV. Methods and uses In one aspect, the present disclosure provides a method for inhibiting IAP protein activity in a cell, comprising contacting the cell in which inhibition of IAP protein activity is desired with an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition of the disclosure. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a IAP protein with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the IAP protein. In another aspect, the present disclosure provides a method for treating a disease or condition wherein inhibition of an IAP protein provides a benefit comprising administering a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition of the disclosure, to an individual in need thereof. In some embodiments, the diseases and conditions that can be treated in accordance to the disclosure include, for example, cancers. A variety of cancers can be treated including, but not limited to: carcinomas, including bladder (including accelerated and metastic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small and non- small cell lung cancer and lung adenocarcinoma), ovary, prostate, testes, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine pancreatic carcinoma), esophagus, stomach, gall bladder, cervix, thyroid, renal, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burketts lymphoma, hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplasia syndrome, myeloid leukemia, and promyelocytic leukemia; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas; tumors of mesenchymal origin, including fibrosarcoma, rhabdomyoscarcoma, and osteosarcoma; and other tumors, including melanoma, xenoderma pigmentosum, keratoactanthoma, seminoma, thyroid follicular cancer, teratocarcinoma, renal cell carcinoma (RCC), pancreatic cancer, myeloma, myeloid and lymphoblastic leukemia, neuroblastoma, and glioblastoma. Additional forms of cancer treatable by the IAP protein inhibitors of the present disclosure include, for example, adult and pediatric oncology, growth of solidtumors / malignancies, myxoid and round cell carcinoma, locally advanced tumors, metastatic cancer, human soft tissue sarcomas, including Ewing's sarcoma, cancer metastases, including lymphatic metastases, squamous cell carcinoma, particularly of the head and neck, esophageal squamous cell carcinoma, oral carcinoma, blood cell malignancies, including multiple myeloma, leukemias, including acute lymphocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, and hairy cell leukemia, effusion lymphomas (body cavity based lymphomas), thymic lymphoma lung cancer (including small cell carcinoma, cutaneous T cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cancer of the adrenal cortex, ACTH-producing tumors, nonsmall cell cancers, breast cancer, including small cell carcinoma and ductal carcinoma), gastrointestinal cancers (including stomach cancer, colon cancer, colorectal cancer, and polyps associated with colorectal neoplasia), pancreatic cancer, liver cancer, urological cancers (including bladder cancer, such as primary superficial bladder tumors, invasive transitional cell carcinoma of the bladder, and muscle-invasive bladder cancer), prostate cancer, malignancies of the female genital tract (including ovarian carcinoma, primary peritoneal epithelial neoplasms, cervical carcinoma, uterine endometrial cancers, vaginal cancer, cancer of the vulva, uterine cancer and solid tumors in the ovarian follicle), malignancies of the male genital tract (including testicular cancer and penile cancer), kidney cancer (including renal cell carcinoma, brain cancer (including intrinsic brain tumors, neuroblastoma, astrocytic brain tumors, gliomas, and metastatic tumor cell invasion in the central nervous system), bone cancers (including osteomas and osteosarcomas), skin cancers (including malignant melanoma, tumor progression of human skin keratinocytes, and squamous cell cancer), thyroid cancer, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms's tumors, gall bladder cancer, trophoblastic neoplasms, hemangiopericytoma, and Kaposi's sarcoma. Another embodiment of the present disclosure is to induce apoptosis and potentiate the induction of apoptosis in response to apoptosis induction signals by use of an IAP protein inhibition of the present disclosure. The present IAP protein inhibitors also sensitize cells to inducers of apoptosis, including cells that are resistant to such inducers. The IAP protein inhibitors of the present disclosure can be used to induce apoptosis in any disorder that can be treated, ameliorated, or prevented by the induction of apoptosis. Thus, the present disclosure provides compositions and methods for targeting animals characterized as overexpressing an IAP protein. In some of the embodiments, the cells (e.g., cancer cells) show elevated expression levels of IAP proteins as compared to non-pathological samples (e.g., non-cancerous cells). In other embodiments, the cells operationally manifest elevated expression levels of IAP proteins by virtue of executing the apoptosis program and dying in response to a therapeutically effective amount of a compound of the present disclosure, said response occurring, at least in part, due to the dependence in such cells on IAP protein function for their survival. In another embodiment, the present disclosure pertains to modulating an apoptosis-associated state which is associated with one or more apoptosis-modulating agents. Examples of apoptosis-modulating agents include, but are not limited to, Fas / CD95, TRAMP, TNF RI, DR1, DR2, DR3, DR4, DR5, DR6, FADD, RIP, TNFa, Fas ligand, TRAIL, antibodies to TRAIL-R1 or TRAIL-R2, Bcl-2, p53, BAX, BAD, Akt, CAD, PI3 kinase, PP1, and caspase proteins. Other agents involved in the initiation, decision, and degradation phase of apoptosis are also included. Examples of apoptosis-modulating agents include agents, the activity, presence, or change in concentration of which, can modulate apoptosis in a subject. Preferred apoptosis-modulating agents are inducers of apoptosis, such as TNF or a TNF-related ligand, particularly a TRAMP ligand, a Fas / CD95 ligand, a TNFR-1 ligand, or TRAIL. These therapies can be used in a variety of settings for the treatment of various cancers. In a specific embodiment, the individual in need of treatment has previously undergone treatment for cancer. Such previous treatments include, but are not limited to, prior chemotherapy, radiotherapy, surgery, or immunotherapy, such as cancer vaccines. In another embodiment, the present IAP protein inhibitors are used in methods of treating T and B cell mediated autoimmune diseases; inflammatory diseases; infections; hyperproliferative diseases; AIDS; degenerative conditions; vascular diseases; and the like. In some embodiments, infections suitable for treatment with the compositions and methods of the present invention include, but are not limited to, infections caused by viruses, bacteria, fungi, mycoplasma, prions, and the like. The present compounds and methods also are useful in the treatment of autoimmune disorder or a chronic inflammatory condition. As used herein, the term "autoimmune disorder" refers to any condition in which an organism produces antibodies or immune cells which recognize the organism's own molecules, cells or tissues. Non-limiting examples of autoimmune disorders include autoimmune hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac sprue, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft versus host disease, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatic arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, and the like. Additional diseases and conditions, including cancers, that can be treated by administration of a present IAP protein inhibitor are disclosed in U.S. Patent No. 7,960,372; incorporated herein by reference in its entirety. A therapeutically effective amount of a Compound of the Disclosure required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the subject, and ultimately is determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the Compound of the Disclosure that are sufficient to maintain the desired therapeutic effects. The desired dose can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses often are desired, or required. For example, a Compound of the Disclosure can be administered at a frequency of: four doses delivered as one dose per day at four-day intervals (q4d x 4); four doses delivered as one dose per day at three-day intervals (q3d x 4); one dose delivered per day at five-day intervals (qd x 5); one dose per week for three weeks (qwk3); five daily doses, with two days rest, and another five daily doses (5 / 2 / 5); or, any dose regimen determined to be appropriate for the circumstance. A Compound of the Disclosure used in a method of the present disclosure can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose. For example, a Compound of the Disclosure can be administered, per dose, in an amount of about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 milligrams, including all doses between 0.005 and 500 milligrams. The dosage of a composition containing a Compound of the Disclosure, or a composition containing the same, can be from about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg. The dosage of a composition can be at any dosage including, but not limited to, about 1 μg / kg. The dosage of a composition may be at any dosage including, but not limited to, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, or more. The above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure. In practice, the physician determines the actual dosing regimen that is most suitable for an individual subject, which can vary with the age, weight, and response of the particular subject. In certain embodiments, the therapeutically effective amount of the compound is between about 0.01 to 100 mg / kg per day. In another aspect, the present disclosure provides compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting IAP protein activity in a cell. In another aspect, the present disclosure provides compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, for use in treating a disease or condition wherein inhibition of an IAP protein provides a benefit. In another aspect, the present disclosure provides the use of the compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of the disclosure, in the manufacture of a medicament for inhibiting IAP protein activity in a cell. In another aspect, the present disclosure provides the use of the compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of the disclosure, in the manufacture of a medicament for treating a disease or condition wherein inhibition of an IAP protein provides a benefit. V. Kits In another embodiment, the present disclosure provides kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure. In one embodiment, the kit comprises Compound of the Disclosure (or a composition comprising a Compound of the Disclosure), and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject for which the inhibition of an IAP protein provides a benefit, e.g., a subject having cancer. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration. In some embodiments of the above various aspects, the IAP is preferably selected from XIAP, cIAP1, and cIAP2. Examples In order to make the objects and technical solutions of the present disclosure clearer, the present disclosure will be further described below in conjunction with specific example. It should be understood that the examples are not intended to limit the scope of the invention. Further, specific experimental methods not mentioned in the following examples were carried out in accordance with a conventional experimental method. EXAMPLE 1. Intermediate Synthesis Example Scheme 1. Synthesis of I-10, I-15 and I-16. I-1. It was prepared according to the published reference (https: / / doi.org / 10.1021 / acs.joc.2c01173, J. Org. Chem.2022, 87, 13315−13321). I-2. To a solution of I-1 (1.9 g, 7.5 mmol, 1.0 eq) in 20 mL of dry THF was added 22 mL of a 9-BBN solution (0.5 M in THF, 1.5 eq) at 0 °C. The solution was stirred at room temperature for 24 hours. To the above solution were added subsequently 3.75 mL of a 3 N NaOH solution and 6.2 mL of a 30% H2O2 solution at 0 °C. The resulting mixture was stirred at room temperature for 2 h, and then diluted with ethyl acetate and saturated brine. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate another time. The combined organic layers were dried over Na2SO4and concentrated. The residue was purified by silica gel flash column chromatography (Hexane: EtOAc=100:0 to 20:80) to give I-2 (1.8 g) as colorless oil.1H-NMR (400 MHz, CDCl3, ppm): 4.26 – 4.23 (m, 2H), 3.72 – 3.67 (m, 5H), 2.31- 2.28 (m, 1H), 2.03- 1.94 (m, 2H), 1.70 – 1.65 (m, 2H), 1.59- 1.51 (m, 1H), 1.41 (s, 9H). LC–MS: calcd for C13H24NO5 [M + H]+, 274.16; found, 274.09. I-3. I-2 (300 mg, 1.1 mmol, 1.0 eq) was added to a solution of HCl in MeOH (3.0 M, 11 mL, 30.0 eq), that was stirred for 24 hours. After removing solvent under reduced pressure, the residue was lyophilized to get I-3 as a salt with HCl that was used directly without further purification in the next step.1H-NMR (400 MHz, d4-MeOH, ppm): 4.47 (t, J = 6.72 Hz, 1H), 3.86 (s, 3H), 3.82 – 3.79 (m, 2H), 3.75 – 3.67 (m, 1H), 2.45 – 2.38 (m, 1H), 2.36 – 2.20 (m, 2H), 2.09 – 1.92 (m, 2H), 1.85 – 1.76 (m, 1H). LC–MS: calcd for C8H16NO3 [M + H]+, 174.11; found, 174.10. I-4. It is commercially available. (CAS: 1093192-07-4, Ambeed, A461085). I-5. To a solution of I-4 (2 mmol, 1.0 eq, 500 mg) in DCM (20 mL) was added Et3N ( 3.0 eq, 830 µL) and Cbz-Cl (1.2 eq, 400 mg). After stirring at room temperature overnight, the mixture was diluted with DCM (100 mL) and washed with saturated NH4Cl aqueous solution. The organic layer was dried over Na2SO4 and concentrated to get a residue that was purified by silica gel flash column chromatography (Hexane: EtOAc=100:0 to 50:50) to give I-5 (500 mg) as colorless oil.1H-NMR (400 MHz, CDCl3, ppm): 7.31 – 7.20 (m.5H), 5.05 (m, 2H), 4.64 (d, J = 5.60 Hz, 1H), 4.58 (s, 1H), 4.47 (d, J = 5.60 Hz, 1H), 3.67 (s, 3H), 1.40 – 1.28 (m, 15H). LC–MS: calcd for C19H29N2O6 [M + H]+, 381.19; found, 381.18. I-6. To a solution of 1-5 (1.3 mmol, 1.0 eq, 500 mg) in THF (20 mL) was added LiOH (4.0 eq, 125 mg) and H2O (2 mL). After stirring at room temperature overnight, dilute with saturated brine and adjust the pH to 3 with 4 N HCl aqueous solution. The mixture was then extracted with EtAOAc (50 mL) 3 times. The combined organic layers were dried over Na2SO4 and concentrated that was used directly without further purification in the next step. LC–MS: calcd for C18H27N2O6 [M + H]+, 367.18; found, 367.10. I-7. To a solution of 1-3 (1.0 mmol, 1.0 eq, 200 mg) in DCM (10 mL) was added I-6 (1.0 eq, 366 mg), DIPEA (3.0 eq, 700 µL) and HATU (1.3 eq, 500 mg) sequentially. After stirring at room temperature for 4 hours, remove the solvent under reduced pressure to get a residue that was purified by pre-HPLC [MeCN (+0.1% TFA): H2O (+0.1% TFA) = 35 : 65 to 100 : 0] to give I-7 (190 mg) as white solid.1H-NMR (400 MHz, CDCl3, ppm): 7.41 – 7.27 (m. 5H), 5.50 (d, J = 9.52 Hz, 1H), 5.22 – 4.93 (m, 3H), 4.86 – 4.38 (m, 1H), 4.55 – 4.40 (m, 1H), 4.08 (m, 3H), 3.73 – 3.60 (m, 4H), 2.50 – 1.60 (m, 6H), 1.55 – 1.25 (m, 15H). LC–MS: calcd for C26H40N3O8 [M + H]+, 521.27; found, 521.19. I-8. To a solution of I-7 (120 mg, 0.22 mmol, 1.0 eq) in DCM (5 mL) was added Dess-Martin periodinane (104 mg, 1,1 eq). After stirring at room temperature for 3 hours, the mixture was diluted with EtOAc (50 mL) and washed with saturated Na2CO3 aqueous solution (50 mL). The organic layer was dried over Na2SO4, concentrated and purified by silica gel chromatography (Hexane: EtOAc=100:0 to 30:70) to give compound I-8 (110 mg) as colorless oil.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 9.69 (s, 1H), 7.36 (m, 6H), 6.27 (d, J = 9.52 Hz, 1H), 5.10 – 4.80 (m, 3H), 4.78 (d, J = 9.48 Hz, 1H), 4.36 (m, 1H), 3.67 (m, 3H), 3.14 – 2.79 (m, 2H), 2.27 – 1.60 (m, 4H), 1.39 (s, 9H), 1.28 (s, 3H), 1.23 (s, 3H). LC–MS: calcd for C26H37N3O8 [M + H]+, 520.26; found, 519.85. I-9. To a solution of I-8 (0.12 mmol, 1.0 eq, 60 mg) in DCM (3 mL) was added TFA (0.4 mL). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure and diluted with H2O (10 mL). The mixture was then lyophilized to get a residue that was used directly in the next step without further purification. LC–MS: calcd for C21H30N3O6 [M + H]+, 420.21; found, 420.34. I-10. To the above obtained compound I-9 was added DCM (5 mL), AcOH (5.0 eq, 36 µL), DIPEA (3.0 eq, 65 µL) and NaBH(OAc)3 (2.0 eq, 50 mg) sequentially. After stirring at room temperature for 4 hours, remove solvent, and purify the residue with pre-HPLC [(H2O + 0.1% TFA): (MeCN + 0.1% TFA) = 85:15 to 0:100] to give I-10 (35 mg) as a white salt of TFA.1H-NMR (400 MHz, d4-MeOH, ppm): 7.36 (m, 5H), 5.13 (s, 2H), 5.05 (m, 1H), 4.75 (m, 1H), 4.54 (m, 1H), 3.83 (s, 3H), 3.53 (m, 1H), 3.51 (m, 1H), 2.50 (m, 1H), 2.24 (m, 1H), 2.10 – 1.88 (m, 4H), 1.47 (s, 3H), 1.32 (s, 3H). LC–MS: calcd for C21H30N3O5[M + H]+, 404.21; found, 403.99. I-11. To a 100 mL round-bottom flask was added DCM (30 mL) and oxalyl chloride (2 M in DCM, 7.3 mL, 2.0 eq), then DMSO (2 mL, 3.0 eq) was added under nitrogen at -78oC. After stirring for 20 minutes at -78oC, a solution of I-2 (2.0 g, 7.3 mmol, 1.0 eq) in DCM (10 mL) was added slowly to the above mixture that was stirred for another 1 hour at -78oC in which period the generated HCl gas was removed by reduced pressure to avoid deprotection of Boc, then Et3N (8.0 mL, 8.0 eq) was added and warmed up to room temperature. After 45 minutes, the mixture was diluted with DCM (40 mL) and washed with brine. The organic layer was dried over Na2SO4, concentrated and purified by silica gel chromatography (Hexane: EtOAc=100:0 to 40:60) to give I-11 (1.46 g) as colorless oil.1H-NMR (400 MHz, CDCl3, ppm): 9.80 (s, 1H), 4.37 – 4.23 (m, 2H), 3.75 (s, 3H), 3.19 – 3.00 (m, 1H), 2.62 (m, 1H), 2.21 (m, 1H), 1.95 (m, 1H), 1.39 (m, 9H). LC–MS: calcd for C13H22NO5[M + H]+, 272.14; found, 272.13. I-12. To a solution of methyltriphenylphosphonium bromide (2.7 g, 1.5 eq) in dry THF (30 mL) was added n-BuLi (2.5 M in hexane, 2.85 mL, 1.4 eq) at 0oC. After stirring for 30 minutes, the mixture was cooled to -78oC, and a solution of I-11 (1.4 g, 5.1 mmol, 1.0 eq) in dry THF (10 mL) was added to it. The mixture was warmed up to room temperature and stirred for 2 hours. Then add saturated NH4Cl aqueous solution (5 mL) to quench the reaction. Remove THF under reduced pressure, dilute with 60 mL of EtOAc, and wash with saturated brine. The organic layer was dried over Na2SO4, concentrated and purified by silica gel chromatography (Hexane: EtOAc=100:0 to 70:30) to give I-12 (920 mg) as colorless oil.1H-NMR (400 MHz, CDCl3, ppm): 5.79 (m, 1H), 5.10 – 5.04 (m, 2H), 4.32 – 4.18 (m, 1H), 4.00 – 3.80 (m, 1H), 3.72 (s, 3H), 2.73 – 2.52 (m, 1H), 2.19 (m, 2H), 1.95 (m, 2H), 1.77 (m, 1H), 1.46 – 1.40 (m, 9H). LC–MS: calcd for C14H24NO4[M + H]+, 270.16; found, 270.11. I-13. To a round-bottom flask (25 mL) was added compound I-12 ( 920 mg, 3.4 mmol, 1.0 eq), DCM (4 mL) and TFA(2 mL). The mixture was stirred at room temperature for 4 hours. Then remove DCM and TFA under reduced pressure. The residue was lyophilized and used directly as a salt of TFA in the next step without further purification.1H-NMR (400 MHz, d4-MeOH, ppm): 5.82 (m, 1H), 5.29 – 5.20 (m, 2H), 4.47 (m, 1H), 3.70 (m, 1H), 3.85 (s, 3H), 2.58 – 2.37 (m, 3H), 2.25 (m, 2H), 1.76 (m, 1H). LC–MS: calcd for C9H16NO2 [M + H]+, 170.11; found, 170.12. I-14. To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylpent-4-enoic acid (CAS: 676629-90-6, 534 mg, 2.2 mmol, 1.0 eq) in DCM (3 mL) was added a solution of I-13 (1.0 eq, 2.2 mmol) in DCM (3 mL). Then HATU (836 mg, 1.0 eq) and DIPEA (1.2 mL, 3.0 eq) were added subsequently. After stirring at room temperature for 4 hours, the mixture was diluted with DCM (50 mL) and washed with brine. The organic layer was dried over Na2SO4, concentrated and purified by silica gel chromatography (Hexane: EtOAc=100:0 to 70:30) to give I-14 (850 mg) as colorless oil.1H-NMR (400 MHz, CDCl3, ppm): 6.17 – 5.70 (m, 2H), 5.24 – 4.98 (m, 5H), 4.55 – 4.13 (m, 3H), 3.73 (m, 3H), 2.89 – 1.90 (m, 6H), 1.41 (m, 9H), 1.17 – 1.06 (m, 6H). LC–MS: calcd for C21H35N2O5 [M + H]+, 395.25; found, 395.38. I-15. To a sealed tube (10 mL) was added compound I-14 (200 mg, 0.5 mmol, 1.0 eq), DCM ( 5 mL) and Grubbs II catalyst (CAS: 246047-72-3, 21 mg, 0.05 eq). The mixture was degassed and filled with N2, that was stirred at 70 °C for 8 hours. Then dilute with DCM (30 mL), wash with brine, dry with Na2SO4, and purify by silica gel chromatography (Hexane: EtOAc=100:0 to 50:50) to give compound I-15 (130 mg) as a brown oil.1H-NMR (400 MHz, CDCl3, ppm): 5.60 (d, J = 11.48 Hz, 1H), 5.53 – 5.40 (m, 2H), 5.03 (d, J = 9.24 Hz, 1H), 4.52 (d, J = 9.00 Hz, 1H), 4.10 (m, 1H), 3.67 (s, 3H), 3.06 (m, 1H), 2.78 (dd, J = 14.88 Hz, J = 8.44 Hz, 1H), 2.00 – 1.95 (m, 4H), 1.43 (m, 9H), 1.15 (s, 3H), 1.03 (s, 3H). LC–MS: calcd for C19H31N2O5 [M + H]+, 367.22; found, 367.35. I-16. To a solution of compound I-15 (190 mg, 0.5 mmol, 1.0 eq) in MeOH (20 mL) was added Pd / C (10 wt%, 50 mg). The mixture was degassed and filled with H2, that was stirred at room temperature for 3 hours under a H2 balloon. After filtration with celite pad, the filtrate was purified by silica gel chromatography (Hexane: EtOAc=100:0 to 60:40) to give I-16 (160 mg) as white solid.1H-NMR (400 MHz, CDCl3, ppm): 5.38 (d, J = 9.60 Hz, 1H), 4.53 (d, J = 9.48 Hz, 1H), 4.46 (t, J = 7.80 Hz, 1H), 4.16 (t, J = 8.72 Hz, 1H), 3.74 (s, 3H), 3.26 – 1.55 (m, 10H), 1.42 (s, 9H), 0.98 (s, 3H), 0.83 (s, 3H). LC–MS: calcd for C19H33N2O5 [M + H]+, 369.23; found, 368.72. EXAMPLE 2. Synthesis of SM-3001, SM-3002 and SM-3003. Scheme 2. Synthesis of SM-3001. I-17. To a solution of I-10 (0.87 mmol, 1.0 eq, 450 mg) in DCM (10 mL) was added Et3N (10.0 eq, 1.2 mL) and isovaleric chloride (CAS: 108-12-3, 5.0 eq, 500 µL). Monitor the reaction with UPLC until most of I-10 convert to I-17, then add MeOH (2 mL) to quench the reaction and stir the mixture for another 2 hours. Dilute the mixture with DCM (100 mL) and wash with 2N HCl aqueous solution (100 mL). The organic layer was dried over Na2SO4and removed under reduced pressure to get a residue that was used directly in the next step without further purification. LC–MS: calcd for C26H38N3O6 [M + H]+, 488.27; found, 488.23. I-18. To a solution of above obtained I-17 in MeOH (20 mL) was added TFA (100 µL) and Pd / C (10%wt, 150 mg). The mixture was degassed and filled with H2, that was stirred at room temperature for 3 hours under a H2 balloon. After filtration with celite pad, remove the solvent under reduced pressure and purify with pre-HPLC [MeCN (+0.1% TFA): H2O (+0.1% TFA) = 15 : 85 to 100 : 0] to give I-18 (280 mg) as white salt of TFA.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 8.05 (b, 3H), 4.74 (s, 1H), 4.50 (t, J = 8.96 Hz, 1H), 3.93 (m, 1H), 3.70 (s, 3H), 3.64 (m, 2H), 2.39 (m, 2H), 2.22 – 1.85 (m, 5H), 1.78 (m, 2H), 1.60 (s, 3H), 1.35 (s, 3H), 0.97 (d, J = 6.60 Hz, 3H), 0.93 (d, J = 6.56 Hz, 3H). LC–MS: calcd for C18H32N3O4[M + H]+, 354.23; found, 354.00. I-19. To a solution of I-18 (0.6 mmol, 1.0 eq, 280 mg) in DCM (10 mL) was added N-(tert-butoxycarbonyl)-N-methyl-L-alanine (CAS: 16948-16-6, 1.5 eq, 180 mg), DIPEA (3.0 eq, 313 µL) and HATU (1.1 eq, 250 mg). After stirring at room temperature overnight, the mixture was diluted with DCM (100 mL) and washed with saturated NH4Cl aqueous solution (100 mL). The organic layer was dried over Na2SO4 and removed under reduced pressure to get I-19 that was used directly in the next step without further purification. LC–MS: calcd for C27H47N4O7 [M + H]+, 539.34; found, 538.99. I-20. To a solution of above obtained I-19 in THF (20 mL) was added LiOH (3.0 eq, 44 mg) and H2O (2 mL). After stirring at room temperature for 4 hours, add TFA (3.0 eq, 140 µL) to the mixture and remove the solvent under reduced pressure to get a residue that was purified with pre-HPLC [MeCN (+0.1% TFA) : H2O (+0.1% TFA) = 30 : 70 to 100 : 0] to give I-20 (260 mg) as white solid.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 7.16 (d, J = 8.72 Hz, 1H), 5.27 (d, J = 8.76 Hz, 1H), 4.57 (q, J = 7.08 Hz, 1H), 4.37 (t, J = 8.40 Hz, 1H), 4.06 (t, J = 9.92 Hz, 1H), 3.63 (m, 1H), 3.54 (m, 1H), 2.76 (s, 3H), 2.23 (m, 3H), 2.09 (m, 2H), 1.89 (m, 3H), 1.73 (m, 1H), 1.43 (s, 9H), 1.35 (s, 3H), 1.30 (s, 3H), 1.26 (d, J = 7.16 Hz, 3H), 0.93 (d, J = 6.68 Hz, 3H), 0.90 (d, J = 6.68 Hz, 3H). LC–MS: calcd for C26H45N4O7[M + H]+, 525.32; found, 524.97. I-21. To a solution of I-20 (0.34 mmol, 1.0 eq, 180 mg) in DCM (10 mL) was added diphenylmethanamine (1.1 eq, 69 mg), DIPEA (3.0 eq, 178 µL) and HTAU (1.1 eq, 142 mg). After stirring at room temperature for 2 hours, the mixture was diluted with DCM (80 mL) and washed with saturated NH4Cl aqueous solution (100 mL) twice. The organic layer was dried over Na2SO4and removed under reduced pressure to get I-21 that was used directly in the next step without further purification. LC–MS: calcd for C39H56N5O6 [M + H]+, 690.42; found, 690.13. SM-3001. To a solution of above obtained I-21 in DCM (5 mL) was added TFA (0.6 mL). After stirring at room temperature for 2 hours, remove the solvent under reduced pressure and purify with pre-HPLC [MeCN (+0.1% TFA) : H2O (+0.1% TFA) = 30 : 70 to 100 : 0] to give SM-3001 (190 mg) as white salt of TFA. LC–MS: calcd for C34H48N5O4[M + H]+, 590.36; found, 590.38. I-22. It was synthesized by following the procedure for I-21 with I-20 and (R)-1,2,3,4-tetrahydronaphthalen-1-amine as the substrates. LC–MS: calcd for C36H56N5O6 [M + H]+, 654.42; found, 654.04. SM-3002. It was synthesized by following the procedure for SM-3001 with I-22 as the substrate. LC–MS: calcd for C31H48N5O4 [M + H]+, 554.36; found, 554.35. I-23. It was synthesized by following the procedure for I-21 with I-20 and (R)-chroman-4-amine hydrochloride (CAS: 730980-59-3) as the substrates. LC–MS: calcd for C35H54N5O7 [M + H]+, 656.39; found, 656.10. SM-3003. It was synthesized by following the procedure for SM-3001 with I-23 as the substrate. LC–MS: calcd for C30H46N5O5 [M + H]+, 556.34; found, 556.34. EXAMPLE 3. Synthesis of SM-3007 to SM-3017. Scheme 3. Synthesis of SM-3007. I-24. To a sealed tube (15 mL) was added (3S,4R)-1-(tert-butoxycarbonyl)-4-phenylpyrrolidine-3-carboxylic acid (CAS: 884048-45-7, 1 mmol, 1.0 eq, 291 mg), NH4Cl (2.0 eq, 106 mg), HATU (1.1 eq, 410 mg), MeCN (10 mL) and Et3N (4.0 eq, 560 µL) sequentially. After stirring at room temperature overnight, remove the solvent under reduced pressure and purify with pre-HPLC [MeCN (+0.1% TFA): H2O (+0.1% TFA) = 20 : 80 to 100 : 0] to give I-24 (250 mg) as white salt.1H-NMR (400 MHz, CDCl3, ppm): 7.35 – 7.26 (m, 5H), 5.62 (m, 1H), 5.33 – 5.18 (m, 1H), 3.89 (m, 2H), 3.69 – 3.43 (m, 3H), 3.01 (m, 2H), 1.47 (s, 9H). LC–MS: calcd for C16H23N2O3[M + H]+, 291.16; found, 291.13. I-25. To a solution of I-24 (1 mmol, 1.0 eq, 290 mg) in dry THF (10 mL) was added Et3N (2.2 eq, 300 µL) and TFAA (1.1 eq, 153 µL) at ice bath. The warmup the mixture to room temperature and stir for 2 hours. After removing solvent under reduced pressure, add DCM (100 mL) and wash with saturated NH4Cl aqueous solution (80 mL). The organic layer was dried over Na2SO4 and removed under reduced pressure to get I-25 (250 mg) that was used directly in the next step without further purification.1H-NMR (400 MHz, CDCl3, ppm): 7.39 – 7.26 (m, 5H), 3.96 (m, 2H), 3.67 – 3.46 (m, 3H), 3.12 (q, J = 8.84 Hz, 1H), 1.48 (s, 9H). LC–MS: calcd for C16H21N2O2 [M + H]+, 273.15; found, 273.12. I-26. To a solution of I-25 (0.9 mmol, 250 mg) in DCM (4 mL) was added TFA (0.8 mL). After stirring at room temperature for 2 hours, remove the solvent under reduced pressure and lyophilize the residue to get I-26 (240 mg) as a white salt of TFA.1H-NMR (400 MHz, d4-MeOH, ppm): 7.43 (m, 5H), 3.95 (m, 1H), 3.82 (m, 2H), 3.66 (m, 2H), 3.42 (m, 1H). LC–MS: calcd for C11H13N2[M + H]+, 173.10; found, 173.12. I-27. To a solution of I-15 (0.5 mmol, 1.0 eq, 200 mg) in THF (5 mL) was added LiOH (3.0 eq, 36 mg) and H2O (1 mL). After stirring at room temperature for 3 hours, remove the solvent under reduced pressure, add HCl aqueous solution (2N, 50 ml) and extract with DCM (50 mL) for 3 times. The organic layer was dried over Na2SO4 and removed under reduced pressure to get I-27 (180 mg) that was used directly in the next step without further purification. LC–MS: calcd for C18H29N2O5 [M + H]+, 353.20; found, 353.26. I-28. To a solution of I-27 (0.17 mmol, 1.0 eq, 60 mg) in DCM (3 mL) was added I-26 (1.0 eq, 49 mg), DIPEA (5.0 eq, 150 µL) and HATU (1.0 eq, 65 mg). After stirring at room temperature overnight, the mixture was diluted with DCM (80 mL) and washed with saturated NH4Cl aqueous solution (100 mL). The organic layer was dried over Na2SO4and removed under reduced pressure to give I-28 that was used directly in the next step without further purification. LC–MS: calcd for C29H39N4O4 [M + H]+, 507.29; found, 507.00. I-29. To a solution of above obtained I-28 in DCM (3 mL) was added TFA (0.3 mL). After stirring at room temperature for 3 hours, remove the solvent under reduced pressure and purify with pre-HPLC [MeCN (+0.1% TFA) : H2O (+0.1% TFA) = 20 : 80 to 100 : 0] to give I-29 (51 mg) as a white salt of TFA.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 7.95 (b, 3H), 7.42 – 7.34 (m, 5H), 5.49 – 5.38 (m, 2H), 4.62 – 3.40 (m, 9H), 2.81 (m, 1H), 2.38 (m, 1H), 2.04 (m, 3H), 1.86 (m, 1H), 1.25 (s, 3H), 1.05 (s, 3H). LC–MS: calcd for C24H31N4O2 [M + H]+, 407.24; found, 406.95. I-30. To a solution of I-29 (0.035 mmol, 1.0 eq, 18 mg) in DCM (3 mL) was added N-(tert-butoxycarbonyl)-N-methyl-L-alanine (CAS: 16948-16-6, 1.0 eq, 7 mg), DIPEA (3.0 eq, 19 µL) and HATU (1.1 eq, 15 mg). After stirring at room temperature overnight, the mixture was diluted with DCM (50 mL) and washed with saturated NH4Cl aqueous solution (50 mL). The organic layer was dried over Na2SO4and removed under reduced pressure to get I-30 that was used directly in the next step without further purification. LC–MS: calcd for C33H46N5O5 [M + H]+, 592.34; found, 592.00. SM-3007. To a solution of above obtained I-30 in DCM (2 mL) was added TFA (0.4 mL). After stirring at room temperature for 3 hours, remove the solvent under reduced pressure and purify with pre-HPLC [MeCN (+0.1% TFA): H2O (+0.1% TFA) = 25 : 75 to 100 : 0] to give SM-3007 (14 mg) as a white salt of TFA. LC–MS: calcd 492.29; found, 492.01. I-31. It was synthesized by following the procedure for I-28 with I-27 and diphenylmethanamine as the substrates. LC–MS: calcd for C31H40N3O4 [M + H]+, 518.29; found, 518.12. I-32. It was synthesized by following the procedure for I-29 with I-31 as the substrate.1H-NMR (400 MHz, d4-MeOH, ppm): 7.57 (d, J = 7.28 Hz, 1H), 7.35 – 7.20 (m, 10H), 6.07 (d, J = 7.32 Hz, 1H), 5.35 (m, 1H), 5.02 (dd, J = 11.20 Hz, J = 1.16 Hz, 1H), 4.68 (s, 1H), 4.61 (dd, J = 7.00 Hz, J = 2.44 Hz, 1H), 4.13 (m, 1H), 2.88 (m, 1H), 2.38 (dd, J = 14.96 Hz, J = 8.76 Hz, 1H), 2.09 (m, 3H), 1.89 (m, 1H), 1.23 (s, 3H), 0.98 (s, 3H). LC–MS: calcd for C31H40N3O4[M + H]+, 418.24; found, 417.88. I-33. It was synthesized by following the procedure for I-30 with I-32 as the substrate. LC–MS: calcd for C35H47N4O5[M + H]+, 603.35; found, 602.88. SM-3008. It was synthesized by following the procedure for SM-3007 with I-33 as the substrate. LC–MS: calcd for C30H39N4O3[M + H]+, 503.29; found, 502.96. hesized by following the procedure for I-28 with I-27 and aphthalen-1-amine as the substrates. LC–MS: calcd for 482.29; found, 482.14. I-35. It was synthesized by following the procedure for I-29 with I-34 as the substrate.1H-NMR (400 MHz, d4-MeOH, ppm): 7.22 – 7.15 (m, 5H), 5.11 (m, 1H), 4.97 (m, 2H), 4.65 (s, 1H), 4.53 (d, J = 8.28 Hz, 1H), 4.11 (m, 1H), 2.78 (m, 3H), 2.31 (dd, J = 14.88 Hz, J = 8.68 Hz, 1H), 2.16 – 1.80 (m, 8H), 1.23 (s, 3H), 1.07 (s, 3H). LC–MS: calcd for C23H32N3O2[M + H]+, 382.24; found, 382.16. I-36. It was synthesized by following the procedure for I-30 with I-35 as the substrate. LC–MS: calcd for C32H47N4O5 [M + H]+, 567.35; found, 567.03. SM-3009. It was synthesized by following the procedure for SM-3007 with I-36 as the substrate. LC–MS: calcd for C27H39N4O3 [M + H]+, 467.29; found, 467.10. I-37. It was synthesized by following the procedure for I-27 with I-16 as the substrate. LC–MS: calcd for C18H31N2O5[M + H]+, 355.22; found, 355.22. I-38. It was synthesized by following the procedure for I-28 with I-26 and I-37 as the substrates. LC–MS: calcd for C29H41N4O5[M + H]+, 509.30; found, 509.26. I-39. It was synthesized by following the procedure for I-29 with I-38 as the substrate.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 7.84 (b, 3H), 7.43 – 7.34 (m, 5H), 4.59 (t, J = 8.08 Hz, 1H), 4.31 – 3.12 (m, 8H), 2.29 (m, 1H), 2.06 – 1.22 (m, 10H), 1.10 (s, 3H), 0.86 (s, 3H). LC–MS: calcd for C24H33N4O2[M + H]+, 409.25; found, 408.90. I-40. It was synthesized by following the procedure for I-30 with I-39 as the substrate. LC–MS: calcd for C33H48N5O5 [M + H]+, 594.36; found, 593.71. SM-3010. It was synthesized by following the procedure for SM-3007 with I-40 as the substrate. LC–MS: calcd for C28H40N5O3 [M + H]+, 494.31; found, 494.00. I-41. It was synthesized by following the procedure for I-28 with I-37 and diphenylmethanamine as the substrates. LC–MS: calcd for C31H42N3O4 [M + H]+, 520.31; found, 520.09. I-42. It was synthesized by following the procedure for I-29 with I-41 as the substrate. NMR (400 MHz, d4-MeOH, ppm): 8.55 (d, J = 8.00 Hz, 1H), 7.32 – 7.27 (m, 10H), 6.13 (d, J = 8.04 Hz, 1H), 4.59 (m, 1H), 4.23 (s, 1H), 4.16 (dd, J = 11.20 Hz, J = 6.60 Hz, 1H), 2.26 (m, 1H), 2.05 (m, 3H), 1.85 (m, 3H), 1.62 – 1.47 (m, 3H), 1.14 (s, 3H), 0.92 (s, 3H). LC–MS: calcd for C26H34N3O2 [M + H]+, 420.26; found, 419.79. I-43. It was synthesized by following the procedure for I-30 with I-42 as the substrate. LC–MS: calcd for C35H49N4O5[M + H]+, 605.36; found, 605.08. SM-3011. It was synthesized by following the procedure for SM-3007 with I-43 as the substrate. LC–MS: calcd for C30H41N4O3[M + H]+, 505.31; found, 504.99. I-44. It was synthesized by following the procedure for I-28 with I-37 and (R)-1,2,3,4-tetrahydronaphthalen-1-amine as the substrates. LC–MS: calcd for C28H42N3O4[M + H]+, 484.31; found, 484.04. I-45. It was synthesized by following the procedure for I-29 with I-44 as the substrate.1H-NMR (400 MHz, d4-MeOH, ppm): 8.39 (d, J = 8.60 Hz, 1H), 7.44 (d, J = 7.04 Hz, 1H), 7.13 – 7.08 (m, 3H), 5.06 (m, 1H), 4.43 (t, J = 9.36 Hz, 1H), 4.25 (s, 1H), 4.18 (dd, J = 11.24 Hz, J = 6.32 Hz, 1H), 2.80 (m, 2H), 2.24 – 1.56 (m, 14H), 1.17 (s, 3H), 1.00 (s, 3H). LC–MS: calcd for C23H34N3O2 [M + H]+, 384.26; found, 383.89. I-46. It was synthesized by following the procedure for I-30 with I-45 as the substrate. LC–MS: calcd for C32H49N4O5[M + H]+, 569.32; found, 569.05. SM-3012. It was synthesized by following the procedure for SM-3007 with I-46 as the substrate. LC–MS: calcd for C27H41N4O3 [M + H]+, 469.31; found, 469.10. I-47. It was synthesized by following the procedure for I-21 with I-20 and (R)-6-fluorochroman-4-amine hydrochloride (CAS: 911826-09-0) as the substrates. LC–MS: calcd for C36H56N5O6 [M + H]+, 674.39; found, 674.41. SM-3014. It was synthesized by following the procedure for SM-3001 with I-47 as the substrate. LC–MS: calcd for C30H45N5O5[M + H]+, 574.33; found, 574.07. I-48. It was synthesized by following the procedure for I-21 with I-20 and (R)-7-fluorochroman-4-amine hydrochloride (CAS: 1266230-22-1) as the substrates. LC–MS: calcd for C36H56N5O6 [M + H]+, 674.39; found, 674.44. SM-3015. It was synthesized by following the procedure for SM-3001 with I-48 as the substrate. LC–MS: calcd for C30H45N5O5 [M + H]+, 574.33; found, 574.08. I-49. It was synthesized by following the procedure for I-21 with I-20 and (R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-amine (CAS: 1057246-78-2) as the substrates. LC–MS: calcd for C36H54N5O6[M + H]+, 672.41; found, 672.15. SM-3016. It was synthesized by following the procedure for SM-3001 with I-49 as the substrate. LC–MS: calcd for C30H45N5O5 [M + H]+, 572.35; found, 572.10. I-50. It was synthesized by following the procedure for I-21 with I-20 and (R)-7-fluoro-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride (CAS: 1055949-62-6) as the substrates. LC–MS: calcd for C36H54N5O6[M + H]+, 672.41; found, 672.16. SM-3017. It was synthesized by following the procedure for SM-3001 with I-50 as the substrate. LC–MS: calcd for C30H45N5O5 [M + H]+, 572.35; found, 572.10. EXAMPLE 4. Synthesis of SM-3018 to SM-3020. Scheme 4. Synthesis of SM-3018. I-51. To a solution of I-10 (0.15 mmol, 1.0 eq, 60 mg) in DCM (3 mL) was added Et3N (10.0 eq, 200 µL) and tetrahydro-2H-pyran-4-carbonyl chloride (CAS: 40191-32-0, 6.0 eq, 140 µL). After stirring at room temperature for 4 hours, solvent was removed under reduced pressure to get a residue that was used directly for next step without further purification. LC–MS: calcd for C27H38N3O7[M + H]+, 516.27; found, 515.97. I-52. To a solution of above obtained I-51 in THF (3 mL) was added LiOH (60 mg) and H2O (1 mL). After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure to get a residue that was purified with pre-HPLC [MeCN (+0.1% TFA): H2O (+0.1% TFA) = 20 : 80 to 100 : 0] to give I-52 (66 mg) as white solid.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 7.37 – 7.28 (m, 5H), 6.77 (d, J = 8.20 Hz, 1H), 5.11 – 5.00 (m, 3H), 4.38 (t, J = 8.44 Hz, 1H), 4.03 (m, 1H), 3.85 (m, 2H), 3.70 – 3.51 (m, 2H), 3.38 (td, J = 11.64 Hz, J = 1.68 Hz, 2H), 2.82 (m, 1H), 2.22 (m, 1H), 2.06 (m, 1H), 1.82 – 1.53 (m, 6H), 1.52 (m, 2H), 1.35 (s, 3H), 1.20 (s, 3H). LC–MS: calcd for C26H36N3O7[M + H]+, 502.25; found, 501.96. I-53. To a solution of I-52 (0.12 mmol, 1.0 eq, 66 mg) in DCM (3 mL) was added diphenylmethanamine (1.1 eq, 25 mg), DIPEA (3.0 eq, 105 µL) and HTAU (1.1 eq, 51 mg). After stirring at room temperature for 3 hours, the solvent was removed under reduced pressure and purified with pre-HPLC [MeCN (+0.1% TFA): H2O (+0.1% TFA) = 30: 70 to 100: 0] to give I-53 (65 mg) as white solid.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 8.57 (d, J = 8.20 Hz, 1H), 7.37 – 7.20 (m, 15H), 6.77 (d, J = 9.00 Hz, 1H), 6.08 (d, J = 8.28 Hz, 1H), 5.11 – 5.00 (m, 3H), 4.64 (t, J = 8.32 Hz, 1H), 3.96 (m, 1H), 3.90 – 3.76 (m, 2H), 3.70 (m, 1H), 3.54 (dt, J = 16.16 Hz, 1H, J = 4.36 Hz, 1H), 3.38 (m, 2H), 2.84 (m, 1H), 2.19 (m, 1H), 2.00 (m, 1H), 1.88 – 1.63 (m, 6H), 1.47 (m, 2H), 1.37 (s, 3H), 1.22 (s, 3H). LC–MS: calcd for C39H47N4O6[M + H]+, 667.34; found, 667.34. I-54. To a solution of I-53 (0.09 mmol, 62 mg) in MeOH (20 mL) was added Pd / C (10%wt, 25 mg). The mixture was degassed and filled with H2, that was stirred at room temperature for 1 hour under a H2balloon. After filtration with celite pad, the solvent of filtrate was removed under reduced pressure to give I-54 that was used directly for next step without further purification. LC–MS: calcd for C31H41N4O4 [M + H]+, 533.30; found, 533.29. I-55. To a solution of I-54 (0.09 mmol, 1.0 eq, 47 mg) in DCM (3 mL) was added N-(tert-butoxycarbonyl)-N-methyl-L-alanine (CAS: 16948-16-6, 1.1 eq, 21 mg), DIPEA (3.0 eq, 47 µL) and HATU (1.1 eq, 38 mg). After stirring at room temperature overnight, the mixture was diluted with DCM (50 mL) and washed with saturated NH4Cl aqueous solution (50 mL). The organic layer was dried over Na2SO4 and removed under reduced pressure to get I-55 that was used directly in the next step without further purification. LC–MS: calcd for C40H56N5O7[M + H]+, 718.41; found, 718.43. SM-3018. To a solution of above obtained I-55 in DCM (3 mL) was added TFA (0.4 mL). After stirring at room temperature for 2 hours, remove the solvent under reduced pressure and purify with pre-HPLC [MeCN (+0.1% TFA) : H2O (+0.1% TFA) = 25 : 75 to 100 : 0] to give SM-3018 (29 mg) as a white salt of TFA. LC–MS: calcd for C35H48N5O5[M + H]+, 618.36; found, 618.32. I-56. It was synthesized by following the procedure for I-51 with I-10 and acetyl chloride as the substrates. LC–MS: calcd for C23H32N3O6[M + H]+, 446.22; found, 445.83. I-57. It was synthesized by following the procedure for I-52 with I-56 as the substrate.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 7.35 – 7.26 (m, 5H), 6.76 (d, J = 8.48 Hz, 1H), 5.08 – 4.97 (m, 3H), 4.38 (t, J = 8.44 Hz, 1H), 4.05 (t, J = 9.32 Hz, 1H), 3.66 (m, 1H), 3.52 (m, 1H), 2.22 (m, 1H), 2.07 (m, 4H), 1.92 (m, 2H), 1.81 – 1.68 (m, 2H), 1.36 (s, 6H). LC–MS: calcd for C22H30N3O6 [M + H]+, 432.21; found, 431.89. I-58. It was synthesized by following the procedure for I-53 with I-57 and diphenylmethanamine as the substrates.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 8.45 (d, J = 7.88 Hz, 1H), 7.37 – 7.20 (m, 15H), 6.78 (d, J = 8.28 Hz, 1H), 6.09 (d, J = 8.24 Hz, 1H), 5.10 – 4.99 (m, 3H), 4.63 (t, , J = 8.08 Hz, 1H), 4.00 (m, 1H), 3.70 (m, 1H), 3.47 (dt, J = 16.36 Hz, 1H, J = 4.36 Hz, 1H), 2.15 (m, 1H), 2.03 (m, 4H), 1.90 – 1.69 (m, 4H), 1.38 (s, 3H), 1.28 (s, 3H). LC–MS: calcd for C35H41N4O5[M + H]+, 597.30; found, 597.28. I-59. It was synthesized by following the procedure for I-54 with I-58 as the substrate. LC–MS: calcd for C27H35N4O3 [M + H]+, 463.26; found, 463.35. I-60. It was synthesized by following the procedure for I-55 with I-59 as the substrate. LC–MS: calcd for C36H50N5O6 [M + H]+, 648.37; found, 648.39. SM-3019. It was synthesized by following the procedure for SM-3018 with I-60 as the substrate. LC–MS: calcd for C31H42N5O4 [M + H]+, 548.32; found, 548.37. I-61. It was synthesized by following the procedure for I-51 with I-10 and methyl chloroformate as the substrates. LC–MS: calcd for C23H32N3O7 [M + H]+, 462.22; found, 462.08. I-62. It was synthesized by following the procedure for I-52 with I-61 as the substrate.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 7.37 – 7.29 (m, 5H), 6.76 (d, J = 8.20 Hz, 1H), 5.10 – 5.02 (m, 2H), 4.90 (d, J = 9.00 Hz, 1H), 4.36 (t, J = 8.44 Hz, 1H), 4.01 (t, J = 9.40 Hz, 1H), 3.59 (m, 4H), 3.42 (m, 1H), 2.20 (m, 1H), 2.05 (m, 1H), 1.89 (m, 2H), 1.69 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H). LC–MS: calcd for C22H30N3O7 [M + H]+, 448.20; found, 448.30. I-63. It was synthesized by following the procedure for I-53 with I-62 and (R)-chroman-4-amine hydrochloride (CAS: 730980-59-3) as the substrates.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 7.93 (d, J = 6.16 Hz, 1H), 7.37 – 7.30 (m, 5H), 7.23 (d, J = 7.52 Hz, 1H), 7.12 (t, J = 8.56 Hz, 1H), 6.87 – 6.83 (m, 2H), 6.74 (dd, J = 8.16 Hz, J = 1.04 Hz, 1H), 5.10 – 5.02 (m, 3H), 4.92 (d, J = 8.96 Hz, 1H), 4.46 (t, J = 7.92 Hz, 1H), 4.20 (t, J = 5.08 Hz, 2H), 3.99 (m, 1H), 3.66 (m, 1H), 3.54 (s, 3H), 3.40 (dt, J = 15.28 Hz, 1H, J = 4.72 Hz, 1H), 2.11 – 1.75 (m, 7H), 1.71 (m, 1H), 1.39 (s, 3H), 1.37 (s, 3H). LC–MS: calcd for C31H39N4O7 [M + H]+, 579.27; found, 579.29. I-64. It was synthesized by following the procedure for I-54 with I-63 as the substrate. LC–MS: calcd for C23H33N4O5[M + H]+, 445.24; found, 445.29. I-65. It was synthesized by following the procedure for I-55 with I-64 as the substrate. LC–MS: calcd for C32H48N5O8[M + H]+, 630.34; found, 630.40. SM-3020. It was synthesized by following the procedure for SM-3018 with I-65 as the substrate. LC–MS: calcd for C27H40N5O6 [M + H]+, 530.29; found, 530.09. EXAMPLE 5. Synthesis of SM-3021 to SM-3026. Scheme 5. Synthesis of I-77. I-66. A solution of I-1 (5.5 g, 22 mmol) in DCM (100 mL) was purged with O3 at -78 °C. The resulting mixture was allowed to stir at the same temperature for another 1 h. The reaction was monitored with TLC (H: EtOAc= 2: 1). After the completion of the reaction, the mixture was purged under Argon for 10 min followed by the addition of Et3N (3 mL). The resulting mixture was stirred to room temperature and diluted with DCM and water. The organic layer was separated, dried over Na2SO4and filtered. The solvent was removed under reduced pressure to give I-66 (5 g) without further purification. LC–MS: calcd for C12H19NO5Na [M + Na]+, 280.13; found, 280.29. I-67. To a solution of I-66 (4.3 g, 16.7 mmol, 1.0 eq) in DCM (30 mL) and EtOH (30 mL) was added NaBH(OAc)3 (1.78 g, 0.5 eq) and NaBH4 (0.95 g, 1.5 eq) at ice bath, and then stirred at ice bath for 2 hours. After diluted with DCM and water, the organic layer was separated, and the aqueous layer was extracted with DCM another time. The combined organic layers were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give I-67 (3.1 g) as colorless oil.1H NMR (400 MHz, CDCl3, ppm): 4.47 – 4.24 (m, 1H), 4.15 – 3.85 (m, 2H), 3.76 (m, 3H), 3.74 – 3.42 (m, 1H), 2.28 – 1.75 (m, 4H), 1.44 (m, 9H). LC–MS: calcd for C12H21NO5Na [M + Na]+, 282.14; found, 282.39. I-68. To a solution of I-67 (3.1 g, 12.0 mmol, 1.0 eq) in DCM (40 mL) was added DIPEA (3.1 g, 2.0 eq) and then EsCl (2.0 g, 1.3 eq) at ice bath. The resulting mixture was stirred at ice bath for 2 hours. After diluted with DCM and water, the organic layer was separated, and the aqueous layer was extracted with DCM another time. The combined organic layers were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give I-68 (4.0 g) as colorless oil.1H NMR (600 MHz, d6-DMSO, 363K, ppm): 4.39 – 4.33 (m, 1H), 4.27 (t, J = 7.6 Hz, 1H), 4.12 – 4.08 (m, 2H), 3.68 (s, 3H), 3.31 (q, J = 7.4 Hz, 2H), 2.28 – 2.22 (m, 1H), 2.11 – 2.03 (m, 1H), 1.97 – 1.86 (m, 2H), 1.41 (s, 9H), 1.31 (t, J = 7.4 Hz, 3H). LC–MS: calcd for C14H25O7SNa [M + Na]+, 374.14; found, 374.4. I-69. To a solution of I-68 (4.0 g, 11.4 mmol, 1.0 eq) in DMSO (40 mL) was added NaN3(1.1 g, 1.5 eq), and stirred at 100 °C for 12 hours. After diluted with ethyl acetate and water, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate another time. The combined organic layers were washed with brine and dried over Na2SO4.The organic layer was concentrated under reduced pressure, and purified by silica gel chromatography to give I-69 (1.9 g) as colorless oil.1H NMR (600 MHz, d6-DMSO, 360K, ppm): 4.26 (t, J = 7.7 Hz, 1H), 3.96 (m, 1H), 3.68 (s, 3H), 3.56 (dd, J = 12.3 Hz, J = 4.5 Hz, 1H), 3.37 (dd, J = 12.3 Hz, J = 7.4 Hz, 1H), 2.26 – 2.16 (m, 1H), 2.10 – 1.90 (m, 2H), 1.80 (m, 1H), 1.41 (s, 9H). LC–MS: calcd for C12H21N4O4 [M + H]+, 285.15; found, 285.30. I-70. To a solution of I-69 (1.9 g, 6.7 mmol, 1.0 eq) in DCM (10 mL) was added HCl in Dioxane (4.0 M, 20 mL, 12.0 eq), and stirred for 2 hours. After the reaction completed, the solvent was removed under reduced pressure to give I-70 as a salt of HCl without further purification. LC–MS: calcd for C7H13N4O2 [M + H]+, 185.10; found, 185.20. I-71. It was synthesized according to a reference (WO2015005901A1, page 125). I-72. To a solution of I-71 (2.5 g, 9.3 mmol, 1.0 eq) in DMF (40 mL) was added imidazole (1.9 g, 3.0 eq) and then TBSCl (2.1 g, 1.5 eq) at 0 °C. The resulting mixture was stirred at room temperature for 12 hours. After diluted with water, and adjusted pH value to 2.0 with 1 N HCl aqueous solution, the mixture was extracted with ethyl acetate for 3 times. The combined organic layers were washed with brine for 3 times and dried over Na2SO4. The solvent was removed under reduced pressure to give I-72 (3.2 g) without further purification. LC–MS: calcd for C17H36NO5SiNa [M + Na]+, 384.23; found, 384.30. I-73. To a mixture of I-70 (1.5 g, 6.7 mmol, 1.0 eq), I-72 (3.2 g, 8.8 mmol, 1.3 eq), DIPEA (3.5 g, 4.0 eq) and DCM (40 mL) was added HATU (3.3 g, 1.3 eq) at ice bath. The resulting solution was stirred at room temperature for 2 hours. After diluted with DCM and water, the organic layer was separated, and the aqueous layer was extracted with DCM another two times. The combined organic layers were washed with brine and dried over Na2SO4, the organic layer was concentrated under reduced pressure, and purified by silica gel chromatography to give I-73 (2.6 g). LC–MS: calcd for C24H46N5O6Si [M + H]+, 528.31; found, 528.32. I-74. To a solution of I-73 (2.6 g, 4.9 mmol, 1.0 eq) in THF (30 mL) was added TBAF (1.0M, 5.9 mL, 1.2 eq) at 0 °C, and stirred at 0 °C for 1 hours. After diluted with ethyl acetate and water, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate another time. The combined organic layers were washed with brine and dried over Na2SO4, the organic layer was concentrated under reduced pressure, and purified by silica gel chromatography to give I-74 (1.0 g). LC– MS: calcd for C18H31N5O6Na [M + Na]+, 436.23; found, 436.40. I-75. To a solution of I-74 (1.0 g, 2.4 mmol, 1.0 eq) in DCM (20 mL) was added Dess-Martin (1.3 g, 1.3 eq) at ice bath. The resulting mixture was allowed to stir at room temperature for 2 hours. After diluted with DCM and water, the organic layer was separated, and the aqueous layer was extracted with DCM another time. The combined organic layers were washed with brine and dried over Na2SO4, the organic layer was concentrated under reduced pressure, and purified by silica gel chromatography to give I-75 (0.6 g).1H NMR (600 MHz, d6-DMSO, 360K, ppm): 9.70 (s, 1H), 7.11 – 6.63 (m, 1H), 4.75 – 4.14 (m, 3H), 3.65 – 3.34 (m, 5H), 2.29 – 1.70 (m, 4H), 1.43 (s, 9H), 1.07 (s, 3H), 1.02 (s, 3H). LC–MS: calcd for C18H29N5O6Na [M + Na]+, 434.21; found, 434.31. I-76. To a 50 ml round bottom flask was added I-75 (160 mg, 0.4 mmol, 1.0 eq), MeOH (30 mL) and Pd / C (10 % wt, 50 mg). The mixture was then degassed and filled with H2 under a balloon. After stirring at room temperature for 3 hours, the mixture was filtered through celite pad, and add TFA (1.1 eq) into the filtrate to form salt with the amine product and avoid its polymerization. After removing solvent under reduced pressure, the residue was used directly in the next step. LC–MS: calcd for C18H32N3O6[M + H]+, 386.22; found, 385.96. I-77. To the above obtained residue was added DCM (25 mL), AcOH (3.0 eq, 85 µL), DIPEA (2.0 eq, 180 µL) and NaBH(OAc)3 (2.0 eq, 220 mg) in sequence. After stirring at room temperature for 2 days, remove the solvent under reduced pressure and purify with Pre-HPLC [(H2O + 0.1% TFA): (MeCN + 0.1% TFA) = 90:10 to 50:50] to give I-77 (40 mg) as a salt of TFA.1H-NMR (400 MHz, d4-MeOH, ppm): 4.49 (dd, J = 9.36 Hz, J = 6.80 Hz, 1H), 4.21 (s, 1H), 3.95 – 3.80 (m, 5H), 3.51 (dd, J = 14.32 Hz, J = 3.44 Hz, 1H), 3.37 (d, J = 9.64 Hz, 1H), 3.13 (d, J = 9.64 Hz, 1H), 2.41 (m, 1H), 2.25 (m, 2H), 1.82 (m, 1H), 1.47 (s, 9H), 1.19 (s, 3H), 0.98 (s, 3H). LC– MS: calcd for C18H32N3O5 [M + H]+, 370.23; found, 369.98. I-78. It was synthesized by following the procedure for I-17 with I-77 as the substrate. LC–MS: calcd for C23H40N3O6 [M + H]+, 454.28; found, 454.31. I-79. It was synthesized by following the procedure for I-52 with I-78 as the substrate.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 6.53 (b, 1H), 4.44 – 3.97 (m, 3H), 3.47 – 3.13 (m, 4H), 2.22 – 1.87 (m, 7H), 1.42 (s, 9H), 1.11 (s, 3H), 0.92 – 0.88 (m, 9H). LC–MS: calcd for C22H38N3O6[M + H]+, 440.27; found, 440.38. I-80. It was synthesized by following the procedure for I-53 with I-79 and (R)-chroman-4-amine hydrochloride (CAS: 730980-59-3) as the substrates.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 7.13 (m, 2H), 6.85 (t, J = 7.48 Hz, 1H), 6.76 (d, J = 8.16 Hz, 1H), 6.46 (b, 1H), 5.09 (s, 1H), 4.38 – 4.10 (m, 4H), 3.96 (d, J = 9.08 Hz, 1H), 3.37 – 3.29 (m, 3H), 3.09 (m, 1H), 2.30 – 1.90 (m, 7H), 1.83 (m, 2H), 1.42 (s, 9H), 1.12 (s, 3H), 0.91 – 0.88 (m, 9H). LC–MS: calcd for C31H47N4O6[M + H]+, 571.34; found, 571.10. I-81. It was synthesized by following the procedure for I-29 with I-80 as the substrate. After completion of the reaction monitored by UPLC, remove the solvent under reduced pressure to get a residue that was lyophilized to get I-81 without further purification. LC–MS: calcd for C26H39N4O4[M + H]+, 471.29; found, 471.34. I-82. It was synthesized by following the procedure for I-30 with I-81 as the substrate. LC–MS: calcd for C35H54N5O7 [M + H]+, 656.39; found, 656.43. SM-3021. It was synthesized by following the procedure for SM-3018 with I-82 as the substrate. LC–MS: calcd for C30H46N5O5 [M + H]+, 556.34; found, 556.60. I-83. It was synthesized by following the procedure for I-28 with I-37 and (R)-chroman-4-amine hydrochloride (CAS: 730980-59-3) as the substrates. LC–MS: calcd for C27H40N3O5[M + H]+, 486.29; found, 486.24. I-84. It was synthesized by following the procedure for I-29 with I-83 as the substrate.1H-NMR (400 MHz, d4-MeOH, ppm): 7.37 (d, J = 7.40 Hz, 1H), 7.13 (t, J = 8.44 Hz, 1H), 6.85 (td, J = 7.52 Hz, J = 1.12 Hz, 1H), 6.76 (dd, J = 8.24 Hz, J = 1.04 Hz, 1H), 5.09 (t, J = 6.52 Hz, 1H), 4.43 (t, J = 7.68 Hz, 1H), 4.24 – 4.15 (m, 4H), 2.26 (m, 1H), 2.19 – 1.80 (m, 8H), 1.71 – 1.52 (m, 3H), 1.18 (s, 3H), 1.00 (s, 3H). LC–MS: calcd for C22H32N3O3[M + H]+, 386.24; found, 386.36. I-85. It was synthesized by following the procedure for I-30 with I-84 as the substrate. LC–MS: calcd for C31H47N4O6 [M + H]+, 571.34; found, 571.41. SM-3022. It was synthesized by following the procedure for SM-3007 with I-85 as the substrate. LC–MS: calcd for C26H39N4O4 [M + H]+, 471.29; found, 471.34. I-86. It was synthesized by following the procedure for I-53 with (R)-chroman-4-amine hydrochloride (CAS: 730980-59-3) as the substrate. LC–MS: calcd for C35H45N4O7[M + H]+, 633.32; found, 633.40. I-87. It was synthesized by following the procedure for I-54 with I-86 as the substrate. LC–MS: calcd for C27H39N4O5 [M + H]+, 499.28; found, 499.43. I-88. It was synthesized by following the procedure for I-55 with I-87 as the substrate. LC–MS: calcd for C36H54N5O8 [M + H]+, 684.39; found, 684.43. SM-3023. It was synthesized by following the procedure for SM-3018 with I-88 as the substrate. LC–MS: calcd for C31H46N5O6 [M + H]+, 584.34; found, 584.08. I-89. It was synthesized by following the procedure for I-55 with I-64 and N-(((9H-fluoren-9-yl)methoxy)carbonyl)-N-cyclopropyl-L-alanine as the substrates. MeCN was used as the solvent instead of DCM. When LC-MS showed that the reaction completed, the mixture was used directly in the next step. LC–MS: calcd for C44H52N5O8[M + H]+, 778.37; found, 778.39. SM-3024. To the above reaction mixture of I-89 was added a solution of dimethylamine in THF (2.0 M, 2 mL) that was stirred overnight at room temperature. After removing solvent under reduced pressure, the residue was purified with Pre-HPLC [(H2O + 0.1% TFA): (MeCN + 0.1% TFA) = 80:20 to 0:100] to give SM-3024 as a salt of TFA. LC–MS: calcd for C29H42N5O6[M + H]+, 556.31; found, 556.05. I-90. It was synthesized by following the procedure for I-55 with I-64 and (S)-2-((tert-butoxycarbonyl)(methyl)amino)butanoic acid as the substrates. LC–MS: calcd for C33H50N5O8 [M + H]+, 644.36; found, 644.35. SM-3025. It was synthesized by following the procedure for SM-3018 with I-90 as the substrate. LC–MS: calcd for C28H42N5O6 [M + H]+, 544.31; found, 544.29. I-91. It was synthesized by following the procedure for I-55 with I-64 and N-(tert-butoxycarbonyl)-N-ethyl-L-alanine as the substrates. LC–MS: calcd for C33H50N5O8 [M + H]+, 644.36; found, 644.46. SM-3026. It was synthesized by following the procedure for SM-3018 with I-91 as the substrate. LC–MS: calcd for C28H42N5O6 [M + H]+, 544.31; found, 544.03. EXAMPLE 6. Synthesis of SM-3027. Scheme 6. Synthesis of I-101.

[0006] I-92. To a solution of tert-butyl 3-(2-ethoxy-2-oxoethylidene)azetidine-1-carboxylate (20 mmol, 1.0 eq, 4.8 g) in dry THF (70 mL) was added DIBAL (25% wt in toluene, 2.1 eq, 28 ml) at -78 °C, and the mixture was stirred for 1 hour at -78 °C. Move the reaction to ice bath, then add H2O (1.6 ml), 15% NaOH in H2O (1.6 ml) and H2O (4 mL) in sequence. The mixture was warmed up to room temperature and stirred for about 20 minutes until much heat was released. Add Na2SO4(30 g) to the mixture and stir for another 15 minutes. After filtration, collect the filtrate and remove the solvent under reduced pressure. The residue was purified by silica gel chromatography (hexane : EtOAc = 100 : 0 to 30 : 70) to give I-92 (4.0 g) as colorless oil.1H NMR (400 MHz, CDCl3, ppm): 5.48 (s, 1H), 4.53 (m, 2H), 4.44 (m, 2H), 4.05 (m, 2H), 2.27 (b, 1H), 1.42 (s, 9H). I-93. To a solution of I-92 (17.5 mmol, 1.0 eq, 3.5 g) in triethyl orthoformate (4.0 eq, 13 mL) and DMF (9 mL) was added propionic acid (0.1 eq, 130 µL). The mixture was attired at 180 °C for 1 hour in microwave reactor. The mixture was then diluted with brine (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with saturated NaHCO3 aqueous solution (60 mL) and brine (80 mL) twice. Separate the organic layer and remove the solvent under reduced pressure. The residue was purified by silica gel chromatography (hexane : EtOAc = 100 : 0 to 40 : 60) to give I-93 (3.7 g) as colorless oil.1H NMR (400 MHz, CDCl3, ppm): 6.02 (dd, J = 17.40 Hz, J = 10.76 Hz, 1H), 5.16 – 5.09 (m, 2H), 4.09 (q, J = 7.16 Hz, 2H), 3.88 (m, 4H), 2.71 (s, 2H), 1.42 (s, 9H), 1.21 (t, J = 7.16 Hz, 3H). I-94. To a solution of I-93 (13.8 mmol, 1.0 eq, 3.7 g) in THF (40 mL) was added LiOH (3.0 eq, 1.0 g) and H2O (5 mL). After stirring at room temperature overnight, remove the THF under reduced pressure and adjust pH to 3 with 2N HCl aqueous solution. The mixture was extracted with DCM (60 mL) for 3 times, and collect the organic layer. After removing DCM under reduced pressure, the residue was purified by silica gel chromatography (hexane : EtOAc = 100 : 0 to 0 : 100) to give I-94 (3.2 g) as colorless oil.1H NMR (400 MHz, CDCl3, ppm): 6.05 (dd, J = 17.40 Hz, J = 10.76 Hz, 1H), 5.17 (m, 2H), 3.90 (m, 4H), 2.78 (s, 2H), 1.43 (s, 9H). I-95. To a solution of I-94 (14 mmol, 1.0 eq, 3.5 g) in dry THF (20 mL) was added 4-methylmorpholine (1.1 eq, 1.7 mL) and pivaloyl chloride (1.1 eq, 1.9 mL) at ice bath. After stirring for 1 hour and a subsequent filtration, the filtrate was collected as solution A. On the other hand, to a solution of (S)-4-phenyloxazolidin-2-one (14 mmol, 1.0 eq, 2.4 g) in dry THF (40 mL) was added n-BuLi (2.5 M in hexane, 1.0 eq, 5.6 mL) at -78 °C. After stirring for 1 hour, the mixture was used as solution B. Add above obtained solution A to solution B dropwise at -78 °C. The mixture was warmed up to room temperature and stirred for 2 hours. After removing solvent under reduced pressure, dilute with EtOAc (100 mL) and wash with brine (100 mL). Remove solvent under reduced pressure and purify by silica gel chromatography (hexane : EtOAc = 100 : 0 to 50 : 50) to give I-95 (3.8 g) as white solid.1H NMR (400 MHz, CDCl3, ppm): 7.38 -7.25 (m, 5H), 6.02 (dd, J = 17.48 Hz, J = 10.76 Hz, 1H), 5.40 (dd, J = 8.72 Hz, J = 3.68 Hz, 1H), 5.09 – 4.99 (m, 2H), 4.69 (t, J = 8.84 Hz, 1H), 4.28 (dd, J = 8.96 Hz, J = 3.72 Hz, 1H), 3.91 – 3.84 (m, 3H), 3.46 (d, J = 8.84 Hz, 1H), 3.45 (m, 2H), 1.41 (s, 9H). LC–MS: calcd for C21H27N2O5[M + H]+, 387.18; found, 386.92. I-96. To a solution of I-95 (7.3 mmol, 1.0 eq, 2.8 g) in dry THF (40 mL) was added NaHMDS (1.0 M in THF, 1.3 eq, 9.5 mL) at -78 °C. After stirring for 1 hour at -78 °C, (2,4,6-triisopropylbenzenesulfonyl azide (1.4 eq, 3.2 g) was added into the mixture that was stirred for another 1 hour. Then add AcOH (6.0 eq, 2.5 mL) and tetramethylammonium acetate (4.0 eq, 3.9 g). The mixture was warmed up to room temperature and stirred for another 3 hours. After removing the solvent under reduced pressure, dilute with EtOAc (100 mL) and wash with brine (100 mL). Collect the organic layer and remove the solvent under reduced pressure to give a residue that was purified by silica gel chromatography (hexane : EtOAc = 100 : 0 to 50 : 50) to give I-96 (2.3 g) as colorless oil.1H NMR (400 MHz, CDCl3, ppm): 7.42 – 7.26 (m, 5H), 5.99 (dd, J = 17.48 Hz, J = 10.76 Hz, 1H), 5.49 (s, 1H), 5.41 (dd, J = 8.84 Hz, J = 4.44 Hz, 1H), 5.32 – 5.22 (m, 2H), 4.74 (t, J = 8.92 Hz, 1H), 4.31 (dd, J = 9.04 Hz, J = 4.48 Hz, 1H), 4.06 (m, 2H), 3.87 (d, J = 9.36 Hz, 1H), 3.82 (d, J = 8.72 Hz, 1H), 1.42 (s, 9H). LC–MS: calcd for C21H26N5O5[M + H]+, 428.19; found, 428.05. I-97. To a solution of I-96 (2 mmol, 1.0 eq, 854 mg) in THF (9 mL) and H2O (2 mL) was added H2O2 (30% in H2O, 6.6 eq, 1.4 mL) at ice bath. After stirring for 10 minutes, LiOH (2.2 eq, 106 mg in 3 mL of H2O) was added to the mixture that was stirred for another 1 hour at ice bath. Then add saturated Na2SO3 aqueous solution (30 mL) to quench the reaction and adjust pH to 3 with HCl aqueous solution. Extract with EtOAc (80 mL) for twice and collect the organic layer. After removing solvent under reduced pressure, the residue was used directly for the next step. LC–MS: calcd for C12H19N4O4 [M + H]+, 283.13; found, 282.63. I-98. To a solution of above obtained I-97 in DCM (20 mL) and MeOH (2.5 mL) was added TMSCHN2(2.0 M in Et2O, 2.0 eq, 2 mL). After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure to give the residue that was purified by silica gel chromatography (hexane : EtOAc = 100 : 0 to 50 : 50) to give I-98 (450 mg) as colorless oil.1H NMR (400 MHz, CDCl3, ppm): 5.91 (dd, J = 17.36 Hz, J = 10.80 Hz, 1H), 5.34 – 5.25 (m, 2H), 4.31 (s, 1H), 4.08 (d, J = 9.08 Hz, 1H), 4.00 (d, J = 9.00 Hz, 1H), 3.91 – 3.85 (m, 2H), 3.78 (s, 3H), 1.44 (s, 9H). LC–MS: calcd for C13H21N4O4[M + H]+, 297.15; found, 296.97. I-99. To a solution of I-98 (2 mmol, 1.0 eq, 580 mg) in MeOH (1 mL) and THF (15 mL) was added AcOH (5.0 eq, 600 µL) and Zn dust (5.0 eq, 650 mg). After stirring at room temperature for 2 hours and a filtration, the filtrate was collected and purified by Pre-HPLC [(H2O + 0.1% TFA): (MeCN + 0.1% TFA) = 90:10 to 0:100] to give I-99 (700 mg) as a salt of TFA.1H-NMR (400 MHz, d4-MeOH, ppm): 5.92 (dd, J = 17.24 Hz, J = 10.76 Hz, 1H), 5.55 – 5.45 (m, 2H), 4.63 (s, 1H), 4.24 (d, J = 9.24 Hz, 1H), 4.09 (d, J = 8.72 Hz, 1H), 3.97 – 3.93 (m, 2H), 3.85 (s, 3H), 1.45(s, 9H). LC–MS: calcd for C13H23N2O4 [M + H]+, 271.16; found, 271.06. I-100. To a solution of I-99 (0.75 mmol, 1.0 eq, 290 mg) in DCM (5 mL) was added Et3N (5.0 eq, 500 µL) and CbzCl (2.0 eq, 260 mg). After diluted with DCM (50 mL) and washed with saturated NH4Cl aqueous solution (50 mL), the organic layer was separated and purified by silica gel chromatography (hexane : EtOAc = 100 : 0 to 50 : 50) to give I-100 (300 mg) as colorless oil.1H NMR (400 MHz, CDCl3, ppm): 7.36 (m, 5H), 5.79 (dd, J = 17.28 Hz, J = 10.80 Hz, 1H), 5.35 – 5.22 (m, 3H), 5.12 (s, 2H), 4.79 – 4.70 (m, 1H), 4.18 (d, J = 8.84 Hz, 1H), 3.95 – 3.78 (m, 3H), 3.72 (s, 3H), 1.44 (s, 9H). LC–MS: calcd for C21H29N2O6 [M + H]+, 405.19; found, 404.87. I-101. To a solution of I-100 (0.5 mmol, 1.0 eq, 200 mg) in THF (3 mL) was added LiOH (3.0 eq, 36 mg) and H2O (0.5 mL). After stirring at room temperature for 2 hours, the mixture was purified by Pre-HPLC [(H2O + 0.1% TFA): (MeCN + 0.1% TFA) = 90:10 to 0:100] to give I-101 (140 mg) as colorless oil.1H NMR (400 MHz, CDCl3, ppm): 9.04 (b, 1H), 7.34 (m, 5H), 5.85 (dd, J = 17.28 Hz, J = 10.80 Hz, 1H), 5.38 – 5.25 (m, 3H), 5.12 (s, 2H), 4.81 (d, J = 9.28 Hz, 1H), 4.27 (d, J = 9.04 Hz, 1H), 4.01 (d, J = 8.76 Hz, 1H), 3.89 (d, J = 8.72 Hz, 1H), 3.85 (d, J = 8.72 Hz, 1H), 3.85 (d, J = 9.24 Hz, 1H), 1.44 (s, 9H). LC–MS: calcd for C20H27N2O6[M + H]+, 391.18; found, 390.49. I-102. It was synthesized by following the procedure for I-14 with I-101 as the substrate.1H-NMR (400 MHz, d6-DMSO, 360K, ppm): 7.78 (b, 1H), 7.35 (m, 5H), 6.08 (dd, J = 17.28 Hz, J = 10.88 Hz, 1H), 5.75 (m, 1H), 5.25 (m, 2H), 5.08 (m, 4H), 4.53 (m, 2H), 4.56 – 3.81 (m, 4H), 3.64 (m, 5H), 2.46 – 1.71 (m, 6H), 1.38 (s, 9H). LC–MS: calcd for C29H40N3O7 [M + H]+, 542.28; found, 541.79. I-103. It was synthesized by following the procedure for I-15 with I-102 as the substrate.1H NMR (400 MHz, CDCl3, ppm): 7.35 (m, 5H), 6.08 (d, J = 11.56 Hz, 1H), 5.98 (d, J = 8.04 Hz, 1H), 5.67 (m, 1H), 5.27 (m, 1H), 5.11 (m, 2H), 4.49 (d, J = 7.72 Hz, 1H), 4.22 (d, J = 9.52 Hz, 1H), 4.14 (d, J = 8.72 Hz, 1H), 4.10 (m, 1H), 3.73 (d, J = 8.68 Hz, 1H), 3.67 (s, 3H), 3.60 (d, J = 9.52 Hz, 1H), 2.93 (m, 1H), 2.37 (m, 1H), 2.04 (m, 2H), 1.94 (m, 2H), 1.41 (s, 9H). LC–MS: calcd for C27H36N3O7[M + H]+, 514.25; found, 514.79. I-104. It was synthesized by following the procedure for I-27 with I-103 as the substrate. LC–MS: calcd for C26H34N3O7[M + H]+, 500.23; found, 500.30. I-105. It was synthesized by following the procedure for I-28 with I-104 and (R)-chroman-4-amine hydrochloride (CAS: 730980-59-3) as the substrates. LC–MS: calcd for C35H43N4O7 [M + H]+, 631.31; found, 631.31. I-106. It was synthesized by following the procedure for I-29 with I-105 as the substrate. After completion of the reaction monitored by UPLC, remove the solvent under reduced pressure to get a residue that was lyophilized to get I-106 without further purification. LC–MS: calcd for C30H35N4O5[M + H]+, 531.25; found, 531.30. I-107. It was synthesized by following the procedure for I-17 with I-106 and acetyl chloride as the substrates. After completion of the reaction monitored by UPLC, purify by Pre-HPLC [(H2O + 0.1% TFA): (MeCN + 0.1% TFA) = 90:10 to 0:100] to give I-107 as white solid.1H-NMR (400 MHz, d6-DMSO : D2O = 4 : 1, 360K, ppm): 7.33 (m, 5H), 7.15 (m, 2H), 6.88 (t, J = 7.68 Hz, 1H), 6.77 (d, J = 7.92 Hz, 1H), 5.45 – 5.34 (m, 2H), 5.15 – 5.02 (m, 3H), 4.84 (t, J = 5.08 Hz, 1H), 4.53 – 3.78 (m, 7H), 3.42 (m, 1H), 2.67 (m, 1H), 2.33 (m, 1H), 2.10 – 1.86 (m, 5H), 1.78 – 1.56 (m, 4H). LC–MS: calcd for C32H37N4O6 [M + H]+, 573.26; found, 573.28. I-108. It was synthesized by following the procedure for I-18 with I-107 as the substrate. LC–MS: calcd for C24H33N4O4[M + H]+, 441.24; found, 441.27. I-109. It was synthesized by following the procedure for I-19 with I-108 as the substrate. LC–MS: calcd for C33H48N5O7 [M + H]+, 626.35; found, 626.29. SM-3027. It was synthesized by following the procedure for SM-3001 with I-109 as the substrate. LC–MS: calcd for C28H40N5O5 [M + H]+, 526.30; found, 526.14. EXAMPLE 7. Synthesis of SM-Tracer-YQY. Scheme 7. Synthesis of SM-Tracer-YQY. I-110. It was synthesized by following the procedure for I-52 with I-10 as the substrate. LC–MS: calcd for C20H28N3O5[M + H]+, 390.20; found, 390.39. I-111. It was synthesized by following the procedure for I-53 with I-110 (R)-chroman-4-amine hydrochloride (CAS: 730980-59-3) as the substrates. LC–MS: calcd for C29H37N4O5[M + H]+, 521.27; found, 521.34. I-112. It was synthesized by following the procedure for I-107 with I-111 and methyl 6-chloro-6-oxohexanoate as the substrates. LC–MS: calcd for C36H47N4O8[M + H]+, 663.33; found, 663.01. I-113. It was synthesized by following the procedure for I-54 with I-112 as the substrate. LC–MS: calcd for C28H41N4O6[M + H]+, 529.29; found, 529.06. I-114. It was synthesized by following the procedure for I-55 with I-113 as the substrate. LC–MS: calcd for C37H56N5O9 [M + H]+, 714.40; found, 714.50. I-115. It was synthesized by following the procedure for I-52 with I-114 as the substrate. LC–MS: calcd for C36H54N5O9 [M + H]+, 700.38; found, 700.33. I-116. It was synthesized by following the procedure for I-53 with I-115 2,2'-oxybis(ethan-1-amine) as the substrates. LC–MS: calcd for C40H64N7O9[M + H]+, 786.47; found, 786.36. I-117. To a solution of I-116 (23 mg, 0.03 mmol, 1.0 eq) in DMF (2 mL) was added 5-isothiocyanatofluorescein (CAS: 3326-32-7, 1.0 eq, 10 mg) and DIPEA (10.0 eq, 60 µL). After stirring at room temperature for 3 hours, the mixture was purified by Pre-HPLC [(H2O + 0.1% TFA): (MeCN + 0.1% TFA) = 80:20 to 0:100] to give I-117 as yellow solid (15 mg). LC–MS: calcd for C61H75N8O14S [M + H]+, 1175.50; found, 1175.56. SM-Tracer-YQY. It was synthesized by following the procedure for SM-3001 with I-117 as the substrate. LC–MS: calcd for C56H67N8O12S [M + H]+, 1075.45; found, 1075.51. EXAMPLE 8. Synthesis of SM-3028 to SM-3035. I-118. It was synthesized by following the procedure for I-54 with I-111 as the substrate. LC–MS: calcd for C21H31N4O3 [M + H]+, 387.23; found, 387.04. I-119. It was synthesized by following the procedure for I-55 with I-118 as the substrate. LC–MS: calcd for C30H46N5O6[M + H]+, 572.34; found, 572.00. s synthesized by following the procedure for SM-3001 with I-119 MS: calcd for C25H38N5O4 [M + H]+, 472.28; found, 472.14. SM-3029. It was synthesized by following the synthetic route for SM-3019 with (R)-chroman-4-amine hydrochloride (CAS: 730980-59-3) as the substrate instead of diphenylmethanamine. LC–MS: calcd for C27H40N5O5 [M + H]+, 514.30; found, 514.35. SM-3030. It was synthesized by following the synthetic route for SM-3029 with dimethylcarbamic chloride as the substrate instead of acetyl chloride. LC–MS: calcd for C28H43N6O5[M + H]+, 543.32; found, 543.37. I-120. It was synthesized by following the procedure for I-13 with I-1 as the substrate. LC–MS: calcd for C8H14NO2[M + H]+, 156.09; found, 155.94. I-121. It was synthesized by following the synthetic route for I-16 with I-120 as the substrate. LC–MS: calcd for C18H31N2O5 [M + H]+, 355.22; found, 354.94. SM-3031. It was synthesized by following the synthetic route for SM-3022 with I-121 as the substrate instead of I-16. LC–MS: calcd for C25H37N4O4[M + H]+, 457.27; found, 457.42. SM-3032. It was synthesized by following the synthetic route for SM-3029 with 1-methyl-1H-pyrazole-4-carbonyl chloride as the substrate instead of acetyl chloride. LC–MS: calcd for C30H42N7O5 [M + H]+, 580.32; found, 580.42. SM-3033. It was synthesized by following the synthetic route for SM-3029 with benzoyl chloride as the substrate instead of acetyl chloride. LC–MS: calcd for C32H42N5O5 [M + H]+, 576.31; found, 576.44. SM-3034. It was synthesized by following the synthetic route for SM-3029 with methylcarbamic chloride as the substrate instead of acetyl chloride. LC–MS: calcd for C27H41N6O5[M + H]+, 529.31; found, 529.41. I-122. It was synthesized by following the synthetic route for I-108 with I-120 as the substrate instead of I-13. LC–MS: calcd for C23H31N4O4[M + H]+, 427.23; found, 427.37. SM-3035. It was synthesized by following the synthetic route for SM-3027 with I-122 as the substrate instead of I-108. LC–MS: calcd for C27H38N5O5[M + H]+, 512.28; found, 512.02. Biological Examples Example 9: Cell Growth Assay. MDA-MB-231 cells (ATCC) were maintained in DMEM medium with 10% FBS at 37°C and an atmosphere of 5% CO2. Cells grown in 384-well white plates (CorningCostar) were incubated with serially diluted compounds for 4 days. At the end of treatment, CellTiter-Glo (Promega) is added to the wells and luminescence is acquired on TECAN SPARK plate reader. Untreated cells are used as control. Data points are fit with an equation (e.g., a four-parameter equation) to generate a concentration-response curve. IC50 values are calculated using a nonlinear regression analysis of the mean ± SD from triplicate. Binding Affinity Assay. Sensitive and quantitative fluorescence polarization (FP) based assays were used to determine the binding affinities of compounds to cIAP1 BIR3 and XIAP BIR3 proteins with SM-Tracer-YQY as the tracer by following the procedure reported before (J. Med. Chem. 2011, 54, 2714–2726, dx.doi.org / 10.1021 / jm101505d). Immunoblotting. MDA-MB-231 cells (ATCC) were maintained in DMEM medium with 10% FBS at 37°C and an atmosphere of 5% CO2. Cells were treated as indicated, collectd, washed with PBS and lysed in 1X Cell Lysis Buffer (Cell Signaling Technology, #9803). Proteins were resolved by SDS-PAGE NuPAGE gel (Thermo Fisher Scientific) and transferred to a PVDF membrane (Millipore). Membranes were blocked using Odyssey TBS Blocker Buffer (LI-COR). IRDye 680RD and 800CW Dye-labeled secondary antibodies (LI-COR) were used. The washed membranes were scanned using Odyssey CLx imager (LI-COR). The intensity of Western blot signaling was quantitated using the Odyssey software. Primary antibodies used are: cIAP1 rabbit mAb (Cell Signaling Technology, #7065), cIAP2 rabbit mAb (Cell Signaling Technology, #3130), β-actin mouse monoclonal antibody (Cell Signaling Technology, #4967) and GAPDH mouse monoclonal antibody (Santa Cruz Biotechnology, sc-47724). The data for some exemplary compounds are shown in Table 1 and Table 2. Table 1. Cell growth inhibition data (For the IC50, A = <10 nM; B = 10 – 100 nM; and C = 100 – 1000 nM).

[0007] Table 2. Binding affinity data (For the IC50, A <10 nM; B = 10 – 30 nM; C = 30 – 100 nM; D = 100 – 300 nM and E > 300 nM).

[0008] It can be seen from the data in Table 1 and Table 2 that compounds of the present disclosure have IC50 values at the nM level. The introduction of non-hydrogen substituents at the R1 and / or R2 positions results in a further significant improvement in inhibitory activity and binding affinity in contrst to control compound SM-406. In addition, it can be seen from Figure 1 and Figure 2 that compounds with non-hydrogen substituents at the R1 and / or R2 positions result in much stronger degradations of cIAP1 and / or cIAP2 than the control compound SM-406. Having now fully described the methods, compounds, and compositions herein, it will be understood by those of skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the methods, compounds, and compositions provided herein or any embodiment thereof. All patents, patent applications, and publications cited herein are fully incorporated by reference herein in their entirety.

Claims

Claims 1. A compound of Formula I:or a pharmaceutically acceptable salt or solvate thereof， wherein: R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, cyano, halogen, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, and 3-10 membered carbocyclyl; wherein the above groups are optionally substituted with one or more R8, each R8can be the same or different; or R1 and R2 together with the carbon to which they are attached, form a 4-10 membered heterocyclyl or 3-10 membered carbocyclyl optionally substituted with one or more R8, each R8 can be the same or different; R3 and R4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl; wherein the C1-C6alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl is optionally substituted with one or more R8, each R8 can be the same or different; or R3and R4together with the nitrogen to which they are attached, form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with one or more R8, each R8can be the same or different; R5 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, amino, and halogen;R6 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, and halogen; R7 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6haloalkyl, wherein the above groups are optionally substituted with one or more R8, each R8 can be the same or different; R8 is selected from the group consisting of halogen, hydroxyl, amino, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered and carbocyclyl, wherein the above groups are optionally substituted with one or more of hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -(C=O)-C1-C6 alkyl and halogen; Zis selected from the group consisting of X Y, C(R9)2, NR9, O, S, SO, SO2,and S(=O)(=N-R9), represents a single or double bond; and when represents a double bond, X and Y are each independently selected from CR9 and N, provided that X and Y cannot both be N; when represents a single bond, X and Y are each independently selected from the group consisting of C(R9)2, NR9, O, S, SO, SO2,and S(=O)(=N-R9), provided that at least one of X and Y is C(R9)2; each R9 can be the same or different, and on each occurrence, is independently selected from the group consisting of hydrogen, (SO2)-C1-C6 alkyl, -(SO2)-3-10 membered carbocyclyl, -(SO2)-4-10 membered heterocyclyl, -(SO2)-6-12 membered aryl, -(SO2)-5-12 membered heteroaryl, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered carbocyclyl, -(C=O)-C1-C6alkyl, -(C=O)-3-10 membered carbocyclyl, -(C=O)-4-10 membered heterocyclyl, -(C=O)-6-12 membered aryl, -(C=O)-5-12 membered heteroaryl, -(C=O)-O-C1-C6 alkyl, -(C=O)-O-3-10 membered carbocyclyl, -(C=O)-O-4-10 membered heterocyclyl, -(C=O)-O-6-12 membered aryl, -(C=O)-O-5-12 membered heteroaryl, -(C=O)-NH-C1-C6 alkyl, -(C=O)-NH-3-10 membered carbocyclyl, -(C=O)-NH-4-10 membered heterocyclyl, -(C=O)-NH-6-12 membered aryl, -(C=O)-NH-5-12 membered heteroaryl, -(C=O)-N(R8)2, and halogen,wherein the above alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl in the definition of R9is optionally substituted with one or more of C1-C6alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, amino, cyano and halogen.

2. A compound of Formula I-1:(I-1) or a pharmaceutically acceptable salt or solvate thereof， wherein: R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, cyano, halogen, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, and 3-10 membered carbocyclyl; wherein the above groups are optionally substituted with one or more R8, each R8can be the same or different; or R1 and R2 together with the carbon to which they are attached, form a 4-10 membered heterocyclyl or 3-10 membered carbocyclyl optionally substituted with one or more R8, each R8 can be the same or different; R3 and R4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl; wherein the C1-C6alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl is optionally substituted with one or more R8, each R8 can be the same or different; or R3and R4together with the nitrogen to which they are attached, form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with one ormore R8, each R8 can be the same or different; R5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, amino, and halogen; R6is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and halogen; R7 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6haloalkyl, wherein the above groups are optionally substituted with one or more R8, each R8 can be the same or different; R8is selected from the group consisting of halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered and carbocyclyl, wherein the above groups are optionally substituted with one or more of hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -(C=O)-C1-C6alkyl and halogen; represents a single or double bond; and when represents a double bond, X and Y are each independently selected from CR9 and N, provided that X and Y cannot both be N; when represents a single bond, X and Y are each independently selected from the group consisting of C(R9)2, NR9, O, S, SO, SO2, and S(=O)(=N-R9), provided that at least one of X and Y is C(R9)2; each R9can be the same or different, and on each occurrence, is independently selected from the group consisting of hydrogen, (SO2)-C1-C6 alkyl, -(SO2)-3-10 membered carbocyclyl, -(SO2)-4-10 membered heterocyclyl, -(SO2)-6-12 membered aryl, -(SO2)-5-12 membered heteroaryl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered carbocyclyl, -(C=O)-C1-C6 alkyl, -(C=O)-3-10 membered carbocyclyl, -(C=O)-4-10 membered heterocyclyl, -(C=O)-6-12 membered aryl, -(C=O)-5-12 membered heteroaryl, -(C=O)-O-C1-C6alkyl, -(C=O)-O-3-10 membered carbocyclyl, -(C=O)-O-4-10 membered heterocyclyl, -(C=O)-O-6-12 membered aryl, -(C=O)-O-5-12 membered heteroaryl, -(C=O)-NH-C1-C6alkyl, -(C=O)-NH-3-10 membered carbocyclyl, -(C=O)-NH-4-10 membered heterocyclyl, -(C=O)-NH-6-12membered aryl, -(C=O)-NH-5-12 membered heteroaryl, -(C=O)-N(R8)2, and halogen, wherein the above alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl in the definition of R9 is optionally substituted with one or more of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, hydroxyl, amino, cyano and halogen.

3. A compound of Formula II:(II) or a pharmaceutically acceptable salt or solvate thereof， wherein: R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, cyano, halogen, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, and 3-10 membered carbocyclyl; wherein the above groups are optionally substituted with one or more R8, each R8can be the same or different; or R1 and R2 together with the carbon to which they are attached, form a 4-10 membered heterocyclyl or 3-10 membered carbocyclyl optionally substituted with one or more R8, each R8can be the same or different; R3 and R4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl; wherein the C1-C6 alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl is optionally substituted with one or more R8, each R8 can be the same or different; or R3and R4together with the nitrogen to which they are attached, form a 5-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with one ormore R8, each R8 can be the same or different; R5is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxyl, amino, and halogen; R6is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and halogen; R7 is selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6haloalkyl, wherein the above groups are optionally substituted with one or more R8, each R8 can be the same or different; R8is selected from the group consisting of halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered and carbocyclyl, wherein the above groups are optionally substituted with one or more of hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, -(C=O)-C1-C6alkyl and halogen; represents a single or double bond; and when represents a double bond, X and Y are each independently selected from CR9 and N, provided that X and Y cannot both be N; when represents a single bond, X and Y are each independently selected from the group consisting of C(R9)2, NR9, O, S, SO, SO2, and S(=O)(=N-R9), provided that at least one of X and Y is C(R9)2; each R9can be the same or different, and on each occurrence, is independently selected from the group consisting of hydrogen, (SO2)-C1-C6 alkyl, -(SO2)-3-10 membered carbocyclyl, -(SO2)-4-10 membered heterocyclyl, -(SO2)-6-12 membered aryl, -(SO2)-5-12 membered heteroaryl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, 3-10 membered carbocyclyl, -(C=O)-C1-C6 alkyl, -(C=O)-3-10 membered carbocyclyl, -(C=O)-4-10 membered heterocyclyl, -(C=O)-6-12 membered aryl, -(C=O)-5-12 membered heteroaryl, -(C=O)-O-C1-C6alkyl, -(C=O)-O-3-10 membered carbocyclyl, -(C=O)-O-4-10 membered heterocyclyl, -(C=O)-O-6-12 membered aryl, -(C=O)-O-5-12 membered heteroaryl, -(C=O)-NH-C1-C6alkyl, -(C=O)-NH-3-10 membered carbocyclyl, -(C=O)-NH-4-10 membered heterocyclyl, -(C=O)-NH-6-12membered aryl, -(C=O)-NH-5-12 membered heteroaryl, -(C=O)-N(R8)2, and halogen, wherein the above alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl in the definition of R9 is optionally substituted with one or more of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, hydroxyl, amino, cyano and halogen.

4. The compound of any one of claims 1-3, wherein Z is selected from the group consisting of C(R9)2, NR9, O, S, SO, SO2,and S(=O)(=N-R9).

5. The compound of any one of claims 1-3, wherein represents a single bond, X is C(R9)2 and Y is NR9.

6. The compound of any one of claims 1-3, wherein represents a single bond, X is NR9 and Y is C(R9)2.

7. The compound of any one of claims 1-3, wherein represents a single bond, X is C(R9)2 and Y is O.

8. The compound of any one of claims 1-3, wherein represents a single bond, X is C(R9)2and Y is C(R9)2.

9. The compound of any one of claims 1-3, wherein represents a single bond, X is C(R9)2and Y is S, SO, SO2,or S(=O)(=N-R9).

10. The compound of any one of claims 1-3, wherein represents a double bond, X is C(R9) and Y is C(R9).

11. The compound of any one of claims 1-10, wherein R1and R2are each independently selected from hydrogen and C1-C6 alkyl.

12. The compound of any one of claims 1-10, wherein both R1 and R2 are hydrogen;or R1 and R2 cannot both be hydrogen; or both R1 and R2 are C1-C6 alkyl, preferably methyl.

13. The compound of any one of claims 1-12, wherein R3is hydrogen, and R4is selected from the group consisting of C1-C6 alkyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-10 membered saturated or unsaturated carbocyclyl or 4-10 membered heterocyclyl optionally substituted with one or more R8.

14. The compound of claim 13, wherein R4is selected from15. The compound of claim 13, wherein R4is selected from:.

16. The compound of any one of claims 1-12, wherein R3 and R4 together with the nitrogen to which they are attached, form 5 membered heterocyclyl optionally substituted with one or more R8.

17. The compound of claim 16, wherein the 5 membered heterocyclyl is pyrrolidinyl.

18. The compound of any one of claims 1-17, wherein R5 is hydrogen.

19. The compound of any one of claims 1-18, wherein R6 is C1-C6 alkyl, preferably methyl.

20. The compound of any one of claims 1-19, wherein R7 is C1-C6 alkyl, preferably methyl.

21. The compound of any one of claims 1-20, wherein R9is -(C=O)-C1-C6alkyl, preferably -(C=O)-C4 alkyl, more preferably -(C=O)-isobutyl.

22. The compound of any one of claims 1-20, wherein R9is -(C=O)-O-C1-C6alkyl, preferably -(C=O)-O-methyl; or R9 is -(C=O)-phenyl, -(C=O)-imidazole, or -(C=O)-pyranyl optionally substituted with C1-C6alkyl.

23. The compound of any one of claims 1-20, wherein R9 is -(C=O)-NH-C1-C6 alkyl, -(C=O)-N(C1-C6alkyl)2,or -(C=O)-pyrazolyl optionally substituted with C1-C6alkyl.

24. A compound of Formula III:or a pharmaceutically acceptable salt or solvate thereof， wherein: R1 and R2 are each independently selected from the group consisting of C1-C6 alkyl, C1-C6haloalkyl, C1-C6alkoxy,C3-C6cycloalkyl, cyano, halogen, 6-12 membered aryl, 5-12 membered heteroaryl, 4-10 membered heterocyclyl, and 3-10 memberedcarbocyclyl, wherein the above groups are optionally substituted with one or more R8; and the remaining groups and / or chirality are as defined in any one of claims 1-23.

25. The compound of claim 24, wherein R1and R2are both methyl.

26. A compound of Formula IV:or a pharmaceutically acceptable salt or solvate thereof， wherein each group and / or chirality is as defined in any one of claims 1-23.

27. The compound of claim 26, wherein R1 and R2 are both hydrogen.

28. A compound of Formula V:or a pharmaceutically acceptable salt or solvate thereof， wherein each group and / or chirality is as defined in any one of claims 1-23.

29. The compound of claim 28, wherein each R9 is hydrogen, and / or R1 and R2 are both methyl.

30. A compound of Formula VI:or a pharmaceutically acceptable salt or solvate thereof， wherein each group and / or chirality is as defined in any one of claims 1-23.

31. A compound of Formula VII:or a pharmaceutically acceptable salt or solvate thereof， wherein each group and / or chirality is as defined in any one of claims 1-23.

32. A compound of Formula VIII:or a pharmaceutically acceptable salt or solvate thereof， wherein each group and / or chirality is as defined in any one of claims 1-23.

33. A compound selected from:or a pharmaceutically acceptable salt or solvate thereof.

34. A pharmaceutical composition comprising the compound of any one of claims 1-33, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

35. A method for inhibiting IAP protein activity in a cell, comprising contacting the cell in which inhibition of IAP protein activity is desired with an effective amount of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt or solvate thereof; or the pharmaceutical composition of claim 34.

36. A method of treating a disease or condition wherein inhibition of an IAP protein provides a benefit comprising administering a therapeutically effective amount of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt or solvate thereof; or the pharmaceutical composition of claim 34, to an individual in need thereof.

37. The method of claim 36, wherein the disease or condition is a cancer.

38. The method of claim 36, wherein the disease or condition is selected from the group consisting of T and B cell mediated autoimmune diseases; inflammatory diseases; infections; hyperproliferative diseases; AIDS; degenerative conditions; vascular diseases; and the like.

39. The method of claim 36, wherein the disease or condition is selected from the group consisting of HBV, autoimmune hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac sprue, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft versus host disease, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatic arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, and the like.

40. The method of claim 36, wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg / kg per day.

41. A compound of any one of claims 1-33, or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting IAP protein activity in a cell.

42. A compound of any one of claims 1-33, or a pharmaceutically acceptable salt or solvate thereof, for use in treating a disease or condition wherein inhibition of an IAP protein provides a benefit.

43. Use of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 34, in the manufacture of a medicament for inhibiting IAP protein activity in a cell.

44. Use of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of claim 34, in the manufacture of a medicament for treating a disease or condition wherein inhibition of an IAP protein provides a benefit.

45. A kit comprising a compound of any one of claims 1-33, and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject for which the inhibition of an IAP protein provides a benefit.

Images