Novel compounds as IAP antagonists

Abstract

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

Description

Technical Field

[0001] The present disclosure relates to novel inhibitors / antagonists of inhibitor of apoptosis proteins (IAPs), and to therapeutic methods for treating conditions and diseases in which inhibition / antagonism of IAP proteins provides benefit. The inhibitors of the invention effectively bind to IAP proteins, including cIAP1, cIAP2, and XIAP. Background Art

[0002] Apoptosis, or programmed cell death, is a cellular process that is critical for homeostasis, normal development, host defense, and suppression of tumorigenesis. Misregulation of apoptosis has been implicated in many human diseases, including cancer, and resistance to apoptosis is now recognized as a hallmark of cancer. Therefore, targeting of key apoptosis regulators has become an attractive strategy for developing new therapeutic approaches for human cancer.

[0003] Most current cancer therapies, including chemotherapeutic agents, radiation, and immunotherapy, induce apoptosis in cancer cells indirectly. Therefore, the inability of cancer cells to execute the apoptotic program due to defects in the normal apoptotic machinery is often associated with increased resistance to chemotherapy-, radiation-, or immunotherapy-induced apoptosis. This primary or acquired resistance of human cancers to current therapies due to defects in apoptosis is a major problem in current cancer therapy.

[0004] To improve the survival rate and quality of life of cancer patients, current and future efforts in designing and developing new molecular target-specific anticancer therapies include strategies to specifically target cancer cells' resistance to apoptosis. In this regard, targeting negative regulators that play a key role in directly inhibiting apoptosis of cancer cells represents a very promising therapeutic strategy for the design of new anticancer drugs.

[0005] A class of central negative regulators of apoptosis is the inhibitor of apoptosis proteins (IAPs). The IAP protein family contains eight members, XIAP, cIAP1, cIAP2, NAIP, ILP2, ML-IAP, survivin, and BRUCE (also known as apollon). IAP family members have been shown to be able to inhibit programmed cell death by directly inhibiting members of the caspase family of apoptotic enzymes, although the exact role of all eight members has not been fully determined. The common structural feature of all IAP family members is a zinc-binding fold of ~70 amino acids, called the baculovirus IAP repeat (BIR) domain, which exists in one to three copies.

[0006] Many interactions between IAPs and other proteins are mediated by surface grooves on the BIR domains. BIR domains can be classified by their peptide binding specificity. There are three types of BIR domains; type III domains (capable of binding to caspase (and caspase-like) peptides specific for proline at the third position (P3)) (e.g., XIAP BIR3), type II domains (similar to type III domains but lacking the proline requirement, e.g., XIAP BIR2), and type I domains (not binding to caspases or similar peptides, e.g., XIAP BIR1) (Eckelman et al., Cell Death and Differentiation, 2008, Vol. 15: pp. 920-928). BIRs are small (~70 amino acids) Zn-coordinating domains, and a variety of proteins interact with the BIR domain grooves using their N-termini. BIR antagonists prevent caspases from binding to BIRs, thus resulting in increased caspase activity, thereby inducing autoubiquitination and proteasomal degradation of IAPs.

[0007] IAP is overexpressed in many cancers, including renal, melanoma, colon, lung, breast, ovarian, and prostate cancers (Tamm et al., Clin. Cancer Research, 2000, Vol. 6, No. 5: pp. 1796-1803), and has been implicated in tumor growth, pathogenesis, and resistance to chemotherapy and radiotherapy (Tamm 2000).

[0008] Small molecule inhibitors of IAP proteins are known. For example, U.S. Patent Publication No. 2005 / 0197403 and U.S. Patent No. 7,960,372, each of which is incorporated herein by reference in its entirety, disclose dimeric Smac mimetic compounds.

[0009] Despite the discovery of small molecule inhibitors of IAP proteins, the design of potent inhibitors of IAP proteins remains a major challenge in modern drug development. Therefore, there remains a need in the art for IAP inhibitors that have physical and pharmacological properties that allow the use of the inhibitors in therapeutic applications. The present invention provides compounds designed to bind to IAP proteins and inhibit the activity of IAP proteins. Summary of the invention

[0010] In one aspect, the present disclosure provides compounds represented by the following formula I, II, III and pharmaceutically acceptable salts and solvates (e.g., hydrates), which are collectively referred to as "compounds of the present disclosure". The compounds of the present disclosure are IAP (especially cIAP1, cIAP2 or XIAP) inhibitors and are therefore useful for treating or preventing diseases or conditions in which inhibition of IAP provides benefits, such as IAP-related cancers.

[0011] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0012] In another aspect, the present disclosure provides a method for inhibiting IAP protein activity in a cell, comprising contacting the cell in which IAP protein activity inhibition is required with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present disclosure.

[0013] In another aspect, the disclosure provides a method of treating a disease or condition in which inhibition of an IAP protein provides a benefit, the method 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.

[0014] In one embodiment, the disease or condition is cancer. In another embodiment, the disease or condition is selected from the group consisting of: T and B cell-mediated autoimmune diseases; inflammatory diseases; infection; hyperproliferative diseases; AIDS; degenerative diseases; vascular diseases, etc. 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 disease, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft-versus-host disease, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatic arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, etc.

[0015] In another aspect, the present disclosure provides a compound or pharmaceutical composition of the present disclosure for use in inhibiting the activity of an IAP protein in a cell.

[0016] In another aspect, the disclosure provides a compound or pharmaceutical composition of the disclosure for use in treating a disease or condition in which inhibition of an IAP protein provides a benefit.

[0017] In another aspect, the present disclosure provides use of the compound or pharmaceutical composition of the present disclosure in the preparation of a medicament for inhibiting the activity of an IAP protein in a cell.

[0018] In another aspect, the disclosure provides the use of a compound or pharmaceutical composition of the disclosure in the preparation of a medicament for treating a disease or condition in which inhibition of an IAP protein provides a benefit.

[0019] In another aspect, the disclosure provides kits comprising a compound of the disclosure and instructions for administering the compound of the disclosure to a subject (eg, a patient) in which inhibition of an IAP protein provides a benefit.

[0020] Other embodiments and advantages of the present disclosure will be set forth in part in the following description and will be derived from the description, or may be learned through the practice of the present disclosure. The embodiments and advantages of the present disclosure will be realized and obtained through the elements and combinations particularly pointed out in the appended claims.

[0021] It should be understood that the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. DETAILED DESCRIPTION

[0022] The present disclosure relates to compounds that inhibit IAPs. In particular, the present disclosure relates to compounds that inhibit the activity of cIAP1, cIAP2, or XIAP, pharmaceutical compositions comprising these compounds, and methods of use thereof.

[0023] Unless otherwise defined below, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. Reference to technology used herein is intended to refer to technology commonly understood in the art, including those obvious changes or equivalent substitutions to technology by those skilled in the art. Although it is believed that the following terms are fully understood by those skilled in the art, the following definitions are proposed to better explain the present disclosure.

[0024] I. Definitions

[0025] As used herein, the terms "comprises," "comprising," "having," "containing," or "including" and other variations thereof are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0026] In the context of describing the present disclosure (especially in the context of the claims), the use of the terms "one", "the / said" and similar references should be understood to cover the singular and the plural, unless otherwise specified. Unless otherwise specified herein, the enumeration of numerical ranges herein is intended only to be used as a shorthand method of individually referring to each individual value falling within the range, and each individual value is incorporated into the specification as if it were individually described herein. Unless otherwise required, the use of any and all examples or exemplary language (e.g., "such as") provided herein is intended to better illustrate the present disclosure without limiting the scope of the present disclosure. The language in the specification should not be understood to indicate that any unclaimed element is necessary for the practice of the present disclosure.

[0027] As used herein, the term "IAP protein" refers to any known member of the inhibitor 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.

[0028] As used herein, the term "overexpression of IAP" refers to elevated levels (e.g., abnormal levels) of mRNA encoding an IAP protein in a cell, and / or elevated levels of an IAP protein, compared to similar corresponding non-pathological cells that express basal levels of mRNA encoding the IAP protein or have basal levels of the IAP protein.

[0029] The term "disease or condition in which inhibition of an IAP protein provides a benefit" relates to a condition in which an IAP protein and / or the action of an IAP protein is important or necessary, for example, for the onset, progression, expression of the disease or condition, or a disease or condition known to be treated with an IAP protein inhibitor. Examples of such conditions include, but are not limited to, cancer. One of ordinary skill in the art can readily determine whether a compound treats a disease or condition mediated by an IAP protein of any particular cell type, for example, by assays that are readily available to assess the activity of a particular compound.

[0030] The term "disease" or "condition" refers to a disorder and / or abnormality that is generally regarded as a pathological condition or function and that may manifest itself in the form of specific signs, symptoms and / or malfunctions. As described below, the compounds of structural formula (I) are potent inhibitors of IAP proteins and are useful for treating diseases and conditions in which inhibition of IAP proteins provides a benefit.

[0031] As used herein, the term "treatment" refers to eliminating, alleviating or ameliorating a disease or condition and / or symptoms associated with the disease and / or condition. Although this is not excluded, the treatment of a disease or condition does not require the complete elimination of the disease, condition or symptoms associated with the disease or condition. As used herein, the term "treatment" may include "preventive treatment", which refers to reducing the risk of not having a disease or condition, but having a disease or condition again or the disease or condition recurring, or the possibility of a subject who is prone to having a disease or condition again or the disease or condition recurring, or the possibility of a previously controlled disease or condition recurring. The term "treatment" and synonyms encompass administering a therapeutically effective amount of a compound of the present invention to an individual in need of such treatment.

[0032] Within the meaning of the present invention, "treatment" also includes relapse prevention or stage prevention, as well as the treatment of acute or chronic signs, symptoms and / or dysfunction. Treatment can be symptomatic, for example, to suppress symptoms. Treatment can be effective in the short term, for the medium term, or can be long-term treatment, for example in the context of maintenance therapy.

[0033] As used herein, the term "prevention" refers to a method of preventing the onset of a disease or condition and / or its associated symptoms or preventing a subject from becoming ill. As used herein, "prevention" also includes delaying the onset of a disease and / or its associated symptoms and reducing the risk of a subject becoming ill. The term "prevention" may include "prophylactic treatment", which refers to reducing the likelihood of a subject who does not have a disease or condition but is at risk of having a disease or condition again or having the disease or condition relapse, or a subject who is prone to having a disease or condition again or having the disease or condition relapse, or a previously controlled disease recurring.

[0034] The terms "inhibitor" and "antagonist" are used interchangeably herein to refer to any agent having inhibitory or antagonistic activity on IAP proteins, including but not limited to small molecule compounds, biological macromolecules, etc. For the same reason, the terms "inhibit" and "antagonize" are also used interchangeably herein.

[0035] As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of the disease or condition to be treated and / or prevented.

[0036] As used herein, the term "therapeutically effective amount" or "effective dose" refers to an amount of active ingredient sufficient to effectively deliver the active ingredient for treating the target condition or disease to a subject in need thereof when administered by the methods of the present disclosure. In the case of cancer or other proliferative disorders, a therapeutically effective amount of an agent can reduce (i.e., delay or terminate to some extent) undesirable cell proliferation; reduce the number of cancer cells; reduce tumor size; inhibit (i.e., delay or terminate to some extent) cancer cell infiltration into peripheral organs; inhibit (i.e., delay or terminate to some extent) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more symptoms associated with cancer to some extent. To the extent that the compound or composition administered prevents the growth of existing cancer cells and / or kills existing cancer cells, it can be cytostatic and / or cytotoxic.

[0037]

[0046] The term "halo" or "halogen" as used herein alone or as part of another group refers to -Cl, -F, -Br or -I.

[0038]

[0046] The term "cyano" as used herein alone or as part of another group refers to -CN.

[0039]

[0046] The term "hydroxy" as used herein alone or as part of another group refers to -OH.

[0040] The term "alkyl" as used herein alone or as part of another group refers to a straight or branched chain aliphatic hydrocarbon (i.e., C1-C2) containing from one to twelve carbon atoms. 12 In one embodiment, the alkyl group is C1-C 10 In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1-C3 alkyl group, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C1-C 12 Alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl and decyl. In another embodiment, one or more of the hydrogen atoms of the alkyl are replaced by deuterium atoms, i.e., the alkyl is labeled with deuterium isotopes. Non-restrictive exemplary deuterated alkyl is -CD3. In another embodiment, none of the hydrogen atoms of the alkyl are replaced by deuterium atoms, i.e., the alkyl is labeled with deuterium isotopes.

[0041] The term "haloalkyl" as used herein alone or as part of another group refers to an alkyl group substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. In one embodiment, the alkyl group is substituted with one, two or three fluorine and / or chlorine atoms. In another embodiment, the alkyl group is substituted with one, two or three fluorine atoms. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. 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.

[0042] As used herein, the term "hydroxyalkyl" or "(hydroxy)alkyl" when used alone or as part of another group refers to an alkyl group substituted with one, two or three hydroxy groups. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. In another embodiment, the hydroxyalkyl group 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, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxypropyl-2-yl.

[0043] The term "alkoxy" as used herein alone or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl group is a C1-C6 alkyl group, and the resulting alkoxy group is referred to as a "C1-C6 alkoxy group". In another embodiment, the alkyl group is a C1-C4 alkyl group, and the resulting alkoxy group is referred to as a C1-C4 alkoxy group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0044] The term "carbocycle" as used herein alone or as part of another group refers to saturated and partially unsaturated, for example, monocyclic, bicyclic or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., C 3-12 A carbocyclic ring. For example, a C5 carbocyclic ring or a C6 carbocyclic ring. When the aliphatic hydrocarbon is saturated, the carbocyclic ring may also be referred to as a cycloalkyl, for example, a C3 cycloalkyl such as cyclopropyl, a C4 cycloalkyl such as cyclobutyl, etc. In one embodiment, the carbocyclic ring is a 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 C 3-8 In another embodiment, the cycloalkyl group is C 3-6 In another embodiment, the cycloalkyl group is a C5 cycloalkyl group, i.e., a cyclopentyl group. In another embodiment, the cycloalkyl group is a C6 cycloalkyl group, i.e., a cyclohexyl group. Non-limiting exemplary C 3-12 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl and spiro[3.3]heptane.

[0045] The term "heterocyclyl" as used herein alone or as part of another group refers to saturated and partially unsaturated, for example, monocyclic, bicyclic or tricyclic groups containing one or two double bonds, three to fourteen ring members, i.e., 4-14 membered heterocyclyls, which contain one, two, three or four heteroatoms, such as 4, 5, 6, 7, 8, 9, 10 membered heterocyclyls. Each heteroatom is independently oxygen, sulfur or nitrogen. Each sulfur atom is independently oxidized to give sulfoxide (i.e., S(=O)) or sulfone (i.e., S(=O)2).

[0046] The term heterocyclyl includes groups in which one or more -CH2- groups are replaced by one or more -C(=O)- groups, including cyclic urea groups (such as imidazolidin-2-one), cyclic amide groups (such as pyrrolidin-2-one or piperidin-2-one) and cyclic carbamate groups (such as oxazolidin-2-one).

[0047] The term heterocyclyl also includes groups with 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]azepin or 1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.

[0048] In one embodiment, heterocyclyl is a 4-8 membered cyclic group containing one ring and one or two oxygen atoms (e.g., tetrahydrofuran or tetrahydropyran), a 4-8 membered cyclic group containing one ring and one or two nitrogen atoms (e.g., pyrrolidine, piperidine or piperazine), or a 4-8 membered cyclic group containing one ring and one oxygen atom and one nitrogen atom (e.g., morpholine), and optionally, a -CH2- group is replaced by a -C(=O)- group, such as pyrrolidin-2-one or piperazin-2-one. In another embodiment, heterocyclyl is a 5-8 membered cyclic group containing one ring and one or two nitrogen atoms, and optionally, a -CH2- group is replaced by a -C(=O)- group. In another embodiment, heterocyclyl is a 5 or 6 membered cyclic group containing one ring and one or two nitrogen atoms, and optionally, a -CH2- group is replaced by a -C(=O)- group. In another embodiment, the heterocyclic group is an 8-12 membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclic ring can be connected to the rest of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclic groups include:

[0049]

[0050] The term "aryl" as used herein alone or as part of another group refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C6-C 14Aryl, C9-C 10 Aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl. In one embodiment, aryl is phenyl or naphthyl. In another embodiment, aryl is phenyl.

[0051] The term "heteroaryl" herein, when used alone or as part of another group, refers to monocyclic and bicyclic aromatic ring systems with five to fourteen ring members, i.e., 5-14 heteroaryl, 5-10 heteroaryl, 5-7 (preferably 5 or 6) heteroaryl containing one, two, three or four heteroatoms. Each heteroatom is independently oxygen, sulfur or nitrogen. In one embodiment, heteroaryl has three heteroatoms. In another embodiment, heteroaryl has two heteroatoms. In another embodiment, heteroaryl has one heteroatom. In another embodiment, heteroaryl is 5-10 heteroaryl. In another embodiment, heteroaryl has 5 ring atoms, such as thienyl, which is a 5 heteroaryl with four carbon atoms and one sulfur atom. In another embodiment, heteroaryl has 6 ring atoms, such as pyridyl, which is a 6 heteroaryl with five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furanyl, benzofuranyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, 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, heteroaryl is selected from thienyl (e.g., thien-2-yl and thien-3-yl), furanyl (e.g., 2-furanyl and 3-furanyl), 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), pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

[0052] As used herein, the term "(cycloalkyl)alkyl" when used alone or as part of another group refers to an alkyl group substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, the cycloalkyl group is an optionally substituted C3-C6 cycloalkyl group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. In another embodiment, the alkyl group is substituted with one optionally substituted cycloalkyl group. In another embodiment, the alkyl group is substituted with two optionally substituted cycloalkyl groups. Non-limiting exemplary (cycloalkyl)alkyl groups include:

[0053]

[0054] The term "carboxy" when used alone or as part of another group refers to a group of formula -C(=O)OH.

[0055] As used herein, the term "(heterocyclyl)alkyl" when used alone or as part of another group refers to an alkyl group substituted with one, two or three optionally substituted heterocyclyl groups. In one embodiment, the alkyl group is substituted with an optionally substituted 5-8 membered heterocyclyl group. In another embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. The heterocyclyl group may be attached to the alkyl group via a carbon or nitrogen atom. Non-limiting exemplary (heterocyclyl)alkyl groups include:

[0056]

[0057] The term "(heteroaryl)alkyl" herein, when used alone or as part of another group, refers to an alkyl group substituted with one or two optionally substituted heteroaryls. In one embodiment, the alkyl group is substituted with one optionally substituted 5-14 membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-14 membered heteroaryls. In another embodiment, the alkyl group is substituted with one optionally substituted 5-9 membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5-9 membered heteroaryls. 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 heteroaryls. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary (heteroaryl)alkyl groups include:

[0058]

[0059] As used herein, the term "aralkyl" or "(aryl)alkyl" when used alone or as part of another group refers to an alkyl group substituted with one, two or three optionally substituted aryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted aryl group. In another embodiment, the alkyl group is substituted with two optionally substituted aryl groups. In one embodiment, the aryl group is an optionally substituted phenyl group or an optionally substituted naphthyl group. In another embodiment, the aryl group is an optionally substituted phenyl group. In one embodiment, the alkyl group is a C1-C6 alkyl group. In another embodiment, the alkyl group is a C1-C4 alkyl group. In another embodiment, the alkyl group is a C1 or C2 alkyl group. Non-limiting exemplary (aryl)alkyl groups include benzyl, phenethyl, -CHPh2, and -CH(4-F-Ph)2.

[0060] The term "amino" when used alone or as part of another group refers to a group of the formula -NR 55a R 55b A group in which R 55a and R 55b and are independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl or (heteroaryl)alkyl.

[0061] In one embodiment, the amino group is -NH2.

[0062] The present disclosure encompasses any compound of the present disclosure that has been isotopically labeled (i.e., radiolabeled) by replacing one or more atoms with an atom having a different atomic mass or mass number. Examples of isotopes that may be incorporated into the present disclosure compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H (or deuterium (D)), 3 H. 11 C. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl, e.g. 3 H. 11 C and 14C. In one embodiment, a compound is provided, wherein substantially all atoms at a certain position in the disclosed compounds are replaced by atoms with different atomic masses or mass numbers. In another embodiment, a compound is provided, wherein substantially all atoms at a certain position in the disclosed compounds are replaced by deuterium atoms, for example, all hydrogen atoms of the -CH3 group are replaced by deuterium atoms to obtain the -CD3 group. In another embodiment, a compound is provided, wherein a portion of atoms at a certain position in the disclosed compounds are replaced, i.e., a certain position of the disclosed compounds is enriched with atoms with different atomic masses or mass numbers. In another embodiment, a compound is provided, wherein none of the atoms of the disclosed compounds are replaced by atoms with different atomic masses or mass numbers. The isotope-labeled compounds of the present disclosure can be prepared by methods known in the art.

[0063] The disclosed compounds contain one or more asymmetric centers and therefore can produce enantiomers, diastereomers and other stereoisomeric forms. The disclosure encompasses the use of all these possible forms and their racemic and resolved forms and their mixtures. In view of the disclosure, individual enantiomers can be separated according to methods known in the art. When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, unless otherwise stated, they are intended to include both E and Z geometric isomers. All tautomers are also encompassed in the disclosure.

[0064] As used herein, the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. Stereoisomers include enantiomers and isomers of compounds with more than one chiral center that are not mirror images of each other (diastereomers).

[0065] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

[0066] The terms "enantiomer" and "enantiomer" refer to optically active molecules that are non-superimposable on their mirror images wherein the enantiomer rotates the plane of polarized light in one direction while its mirror image compound rotates the plane of polarized light in the opposite direction.

[0067] The term "racemate" refers to a mixture of equal parts of enantiomers, and the mixture is optically inactive. In one embodiment, the compounds of the present disclosure are racemic.

[0068] The term "absolute configuration" refers to the spatial arrangement of atoms of a chiral molecular entity (or group) and its stereochemical description, eg, R or S.

[0069] Unless otherwise noted, stereochemical terms and conventions used in the specification are consistent with those described in Pure & Appl. Chem, Vol. 68: p. 2193 (1996).

[0070] The term "enantiomeric excess" or "ee" refers to a measure of the amount of one enantiomer present compared to the other. For a mixture of R and S enantiomers, the enantiomeric excess is defined as |RS|*100, where R and S are the respective mole fractions or weight fractions of the enantiomers in the mixture such that R+S=1. In the case of a chiral substance with known optical rotation, the enantiomeric excess is defined as ([α] obs / [α] max )*100, where [α] obs is the optical rotation of a mixture of enantiomers, and [α] max is the optical rotation of the pure enantiomer. Enantiomeric excess can be determined using a variety of analytical techniques including NMR spectroscopy, chiral column chromatography, or polarimetry.

[0071] As used herein, the term "about" includes ±10% of the cited number. Thus, "about 10" means 9 to 11.

[0072] As used herein, the phrase "optionally substituted with one or more groups" means optionally substituted with 1-10 groups, preferably optionally substituted with 1-5 groups, and more preferably optionally substituted with 1, 2 or 3 groups.

[0073] II.Compounds

[0074] In one aspect, the present disclosure provides a compound of Formula I:

[0075]

[0076] or a pharmaceutically acceptable salt or solvate thereof,

[0077] in:

[0078] R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and halogen;

[0079] R2, R3, R4 and R5 may be the same or different and are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl, C3-C6 heterocycloalkyl, OR a 、C(O)R a and NR a R b ; and Ra and R b Each is independently selected from the group consisting of H, benzylcarbonyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkenyl, C1-C6 heteroalkyl and C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2 and C1-C6 alkoxy; or

[0080] R2 and R3 or R4 and R5 together with the carbon to which they are attached form -C(=O)- or -C(=N-OH)- or C3-C6 carbocyclic ring or C3-C6 heterocarbocyclic ring;

[0081] R6 and R7 may be the same or different, each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; or R6 and R7 together with the carbon to which they are attached form -C(=O)- or C3-C6 carbocyclic ring;

[0082] R8 is –X1-X2-R 10 Module, where X1 is a bond or -C(O)NH-; X2 is a bond or CHR c , where R c is selected from hydrogen, C1-C6 alkyl or phenyl optionally substituted by one or more halogens; and R 10 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered saturated or unsaturated carbocyclic group or optionally substituted by one or more R 11 A substituted 5-10 membered heterocyclic group, wherein each R 11 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkylcarbonyl, 5-6 membered heteroaryl, phenylcarbonyl or phenyl optionally substituted with one or more halogens; and

[0083] R9 is selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl.

[0084] In some embodiments, R1 is selected from C1-C6 alkyl.

[0085] In some embodiments, R1 is selected from methyl or ethyl, preferably methyl.

[0086] In some embodiments, R2 is selected from OR a ; and R aSelected from the group consisting of H, benzylcarbonyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkenyl, C1-C6 heteroalkyl and C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2 and C1-C6 alkoxy; and R3, R4 and R5 are hydrogen.

[0087] In some embodiments, R5 is selected from OR a ; and R a Selected from the group consisting of H, benzylcarbonyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkenyl, C1-C6 heteroalkyl and C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2 and C1-C6 alkoxy; and R2, R3 and R4 are hydrogen.

[0088] In some embodiments, R a The group consisting of C1-C6 heteroalkyl and C1-C6 alkyl optionally substituted by one or more of deuterium, halogen, OH, NH2 and C1-C6 alkoxy.

[0089] Without wishing to be bound by theory, it is believed that the above OR a The introduction of groups, especially alkoxy groups, is particularly beneficial to the activity and pharmacokinetic properties of the compounds.

[0090] In some embodiments, R6 and R7 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl; or R6 and R7 together with the carbon to which they are attached form a C3-C6 carbocycle.

[0091] In some embodiments, X1 is a bond; X2 is a bond; and R 10 Selected from optionally one or more R 11 substituted 5-10 membered heteroaryl, wherein each R 11 Independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, phenylcarbonyl or phenyl optionally substituted with one or more halogens.

[0092] In some embodiments, R 10 Selected from:

[0093] It is optionally replaced by one or more R 11 Substitute, where each R 11 Independently selected from the group consisting of phenylcarbonyl or phenyl optionally substituted with one or more halogens.

[0094] In some embodiments, R 10 Selected from:

[0095]

[0096] In some embodiments, X1 is a bond; X2 is CH2; and R 10 Selected from optionally one or more R 11 substituted 5-10 membered heteroaryl, wherein each R 11 Independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkylcarbonyl.

[0097] In some embodiments, R 10 Selected from:

[0098] It is optionally replaced by one or more R 11 Substitute, where each R 11 Independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkylcarbonyl.

[0099] In some embodiments, R 10 Selected from:

[0100]

[0101] In some embodiments, the compound has Formula II:

[0102]

[0103] Where X2 is a bond or CHR c , where R c is selected from hydrogen, C1-C6 alkyl or phenyl optionally substituted by one or more halogens; and R 10 is selected from phenyl, 5-10 membered heteroaryl, 5-10 membered saturated or unsaturated carbocyclic group or optionally substituted by one or more R 11 A substituted 5-10 membered heterocyclic group, wherein each R 11 Independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 5-6 membered heteroaryl or phenyl optionally substituted with one or more halogens.

[0104] In some embodiments, -X2-R 10 Modules are selected from:

[0105] It is optionally replaced by one or more R 11 Substitute, where each R 11 Independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl.

[0106] In some embodiments, -X2-R 10 Modules are selected from:

[0107]

[0108] In some embodiments, -X2-R 10 Modules are selected from:

[0109] It is optionally replaced by one or more R 11 Substitute, where each R 11 are independently selected from the group consisting of: halogen or C1-C6 alkyl; X3 is -CH2- or -O-; and n is 0 or 1.

[0110] In some embodiments, -X2-R 10 Modules are selected from:

[0111]

[0112] In some embodiments, -X2-R 10 Modules are selected from:

[0113]

[0114] In some embodiments, R9 is selected from C1-C6 alkyl, preferably methyl.

[0115] In some embodiments, the compound has Formula III:

[0116]

[0117] In some embodiments, for the above aspects of the disclosure, the compound is selected from the group consisting of:

[0118]

[0119]

[0120]

[0121]

[0122] or a pharmaceutically acceptable salt or solvate thereof.

[0123] The present disclosure encompasses the preparation and use of salts of the disclosed compounds. As used herein, the term "pharmaceutically acceptable salt" refers to a salt or zwitterionic form of the disclosed compounds suitable for administration to a subject, such as a human. The salts of the disclosed compounds can be prepared during the final separation and purification of the compounds, or prepared separately by reacting the compounds with a suitable acid. The pharmaceutically acceptable salts of the disclosed compounds can be acid addition salts formed with a pharmaceutically acceptable acid. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Non-limiting examples of salts of compounds of the present disclosure include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogenphosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthenate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, edisylate, benzenesulfonate, and p-toluenesulfonate. In addition, available amino groups present in the compounds of the present disclosure may be quaternized with: methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl and diamyl sulfates; decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and benzyl and phenethyl bromides. In light of the foregoing, any reference to compounds of the present disclosure appearing herein is intended to include compounds of the present disclosure and pharmaceutically acceptable salts, hydrates or solvates thereof.

[0124] The present disclosure covers the preparation and use of solvates of the disclosed compounds. Solvates generally do not significantly change the physiological activity or toxicity of the compound, and therefore can function as pharmacological equivalents. As used herein, the term "solvate" is a combination, physical association and / or solvated form of the disclosed compounds and solvent molecules, such as a disolvate, a monosolvate or a hemisolvate, wherein the ratio of the solvent molecules to the disclosed compounds 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 some cases, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate can be separated. Therefore, "solvate" covers solution phase and separable solvates. The disclosed compounds may exist in solvated forms with pharmaceutically acceptable solvents such as water, methanol and ethanol, and the present disclosure is intended to include both solvated and non-solvated forms of the disclosed compounds. One type of solvate is a hydrate. "Hydrate" refers to a specific subgroup of solvates in which the solvent molecule is water. Solvates can generally function as pharmacological equivalents. The preparation of solvates is known in the art. See, for example, M. Caira et al., J. Pharmaceut. Sci., Vol. 93, No. 3: pp. 601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparations of solvates, hemisolvates, hydrates, etc. are described by EC van Tonder et al., AAPS Pharm. Sci. Tech., Vol. 5, No. 1, Article 12 (2004) and AL Bingham et al., Chem. Commun. pp. 603-604 (2001). A typical non-limiting method for preparing solvates involves dissolving a compound of the present disclosure in a desired solvent (organic solvent, water, or a mixture thereof) at a temperature of greater than 20° C. to about 25° C., then cooling the solution at a rate sufficient to form crystals, and separating 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 the solvate crystals.

[0125] III. Composition

[0126] In one aspect, the present disclosure provides compositions comprising a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0127] Pharmaceutical compositions for use in accordance with the present disclosure are formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and / or auxiliaries which facilitate processing of the compounds of the disclosure.

[0128] These pharmaceutical compositions can be prepared by, for example, conventional mixing, dissolving, granulating, lozenge making, emulsifying, encapsulating, embedding or lyophilizing methods. The appropriate formulation depends on the selected route of administration. When a therapeutically effective amount of the disclosed compound is administered orally, the composition is generally in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the composition may additionally contain a solid carrier, such as gelatin or an adjuvant. Tablets, capsules and powders contain about 0.01% to about 95%, preferably about 1% to about 50% of the disclosed compound. When administered in liquid form, a liquid carrier such as water, petroleum or oil of animal or plant origin may be added. The composition in liquid form may also contain physiological saline solution, glucose or other sugar solution or ethylene glycol. When administered in liquid form, the composition contains about 0.1% to about 90%, preferably about 1% to about 50% of the disclosed compound by weight.

[0129] When a therapeutically effective amount of the disclosed compounds is administered by intravenous, cutaneous or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. It is within the skill of the art to prepare such parenterally acceptable solutions with due consideration of factors such as pH, isotonicity, stability, etc. Preferred compositions for intravenous, cutaneous or subcutaneous injection typically contain an isotonic vehicle.

[0130] The disclosed compounds can be easily combined with pharmaceutically acceptable carriers known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th edition, 1995. Such carriers enable active agents to be formulated into tablets, pills, lozenges, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by subjects to be treated. Oral pharmaceutical preparations can be obtained by the following method: the disclosed compounds are added to solid excipients, optionally after adding suitable adjuvants (if necessary) grinding the resulting mixture and processing the particle mixture to obtain tablets or lozenge cores. Suitable excipients include, for example, fillers and cellulose preparations. If necessary, disintegrants can be added.

[0131] The disclosed compounds can be formulated for parenteral administration by injection (e.g., by push injection or continuous infusion). Injectable preparations can exist in unit dosage form, such as ampoules or multi-dose containers with added preservatives. Compositions can take the form of suspensions, solutions, or emulsions such as in oily or aqueous solvents, and can contain preparatons such as suspending agents, stabilizers, and / or dispersants.

[0132] Pharmaceutical compositions for parenteral administration include aqueous solutions of active agents in water-soluble form. In addition, suspensions of the disclosed compounds can be prepared into suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound and allow the preparation of highly concentrated solutions. Alternatively, the disclosed compositions may be in powder form so that they can be prepared with a suitable solvent such as sterile pyrogen-free water before use.

[0133] The disclosed compounds may also be formulated into rectal compositions, such as suppositories or retention enemas containing traditional suppository bases. In addition to the aforementioned preparations, the disclosed compounds may also be formulated into depot preparations. Such long-acting preparations may be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, the disclosed compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., in the form of an emulsion in an acceptable oil) or ion exchange resins.

[0134] In particular, the disclosed compounds can be administered orally, buccally or sublingually in the form of tablets containing excipients (such as starch or lactose), or capsules or ovules alone or mixed with excipients, or elixirs or suspensions containing flavoring agents or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives such as suspending agents. The disclosed compounds can also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously or intracoronary. For parenteral administration, the disclosed compounds are generally used in the form of sterile aqueous solutions, which may contain other substances, such as salts or monosaccharides (such as mannitol or glucose), to make the solution isotonic with the blood.

[0135] IV. Methods and Uses

[0136] In one aspect, the present disclosure provides a method for inhibiting IAP protein activity in a cell, comprising contacting the cell in which IAP protein activity inhibition is required with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present disclosure.

[0137] In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

[0138] As used herein, the term "contacting" refers to bringing the specified moieties together in an in vitro system or an in vivo system. For example, "contacting" an IAP protein with a compound provided herein includes administering 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 cells or purified preparations containing an IAP protein.

[0139] In another aspect, the disclosure provides a method of treating a disease or condition in which inhibition of an IAP protein provides a benefit, the method comprising administering to an individual in need thereof 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.

[0140] In some embodiments, diseases and conditions that can be treated according to the present disclosure include, for example, cancer. A variety of cancers can be treated, including, but not limited to: carcinomas, including bladder cancer (including accelerated and metastatic bladder cancer), breast cancer, colon cancer (including colorectal cancer), kidney cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer and lung adenocarcinoma), ovarian cancer, prostate cancer, testicular cancer, genitourinary tract cancer, lymphatic system cancer, rectal cancer, laryngeal cancer, pancreatic cancer (including exocrine pancreatic cancer), esophageal cancer, gastric cancer, gallbladder cancer, cervical cancer, thyroid cancer, kidney cancer, and skin cancer (including squamous cell carcinoma); hematopoietic tumors of the lymphoid lineage (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, leukemias, B-cell lymphomas, T-cell lymphomas, Hodgkin lymphomas, non-Hodgkin lymphomas, hairy cell lymphomas, histiocytic lymphomas, and Burkitt lymphomas), hematopoietic neoplasms of the myeloid lineage (including acute and chronic myeloid leukemias, myelodysplastic syndromes, myeloid leukemias, and promyelocytic leukemias); neoplasms of the central and peripheral nervous systems (including astrocytomas, neuroblastomas, gliomas, and schwannomas); neoplasms of mesenchymal origin (including fibrosarcomas, rhabdomyosarcomas, and osteosarcomas); and other neoplasms (including melanomas, xenoderma pigmentosum, keratoacanthomas, seminoma, follicular thyroid carcinoma, teratocarcinomas, renal cell carcinoma (RCC), pancreatic cancer, myeloma, myeloid and lymphoblastic leukemias, neuroblastomas, and glioblastomas).

[0141] Other forms of cancer that may be treated with the disclosed IAP protein inhibitors include, for example, adult and pediatric tumors, growths of solid tumors / malignancies, myxoid and round cell carcinomas, locally advanced tumors, metastatic cancers, human soft tissue sarcomas (including Ewing sarcoma), carcinoma metastases (including lymphatic metastases), squamous cell carcinomas (particularly head and neck squamous cell carcinomas and esophageal squamous cell carcinomas), oral cancers, blood cell malignancies (including multiple myeloma), leukemias (including acute lymphocytic leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia), effusion lymphomas (body cavity-based lymphomas), thymic lymphomas, lung cancers (including small cell carcinomas, cutaneous T-cell lymphomas, Hodgkin lymphomas, non-Hodgkin lymphomas), adrenocortical carcinomas, ACTH-producing tumors, non-small cell carcinomas, breast cancers (including small cell carcinomas and ductal carcinomas), gastrointestinal cancers (including gastric cancer, colon cancer, colorectal cancer, and colorectal cancers related to The following are some of the following: malignancies: pancreatic cancer, liver cancer, urinary tract cancer (including bladder cancer, such as primary superficial bladder tumor, invasive bladder transitional cell carcinoma and muscle invasive bladder cancer), prostate cancer, female genital tract malignancies (including ovarian cancer, primary peritoneal epithelial tumors, cervical cancer, endometrial cancer, vaginal cancer, vulvar cancer, uterine cancer and solid follicular tumors), male genital tract malignancies (including testicular cancer and penile cancer), kidney cancer (including renal cell carcinoma), brain cancer (including endogenous brain tumors, neuroblastoma, astrocytic brain tumors, gliomas and metastatic tumor cell invasion in the central nervous system), bone marrow cancer (including osteoma and osteosarcoma), skin cancer (including malignant melanoma, tumor progression of human skin keratinocytes and squamous cell carcinoma), thyroid cancer, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms' tumor, gallbladder cancer, trophoblastic tumor, hemangiopericytoma and Kaposi's sarcoma.

[0142] Another embodiment of the present disclosure is to induce apoptosis by using the IAP protein inhibition of the present disclosure, and to enhance the induction of apoptosis in response to apoptosis inducing signals. The IAP protein inhibitors of the present disclosure also sensitize cells to apoptosis inducers, including cells resistant to such inducers. The IAP protein inhibitors of the present disclosure can be used to induce apoptosis in any disease that can be treated, improved or prevented by the induction of apoptosis. Therefore, the present disclosure provides compositions and methods for targeting animals characterized by overexpression of IAP proteins. In some embodiments, cells (e.g., cancer cells) show elevated IAP protein expression levels compared to non-pathological samples (e.g., non-cancerous cells). In other embodiments, cells operatively exhibit elevated IAP protein expression levels by undergoing apoptotic programming and death in response to a therapeutically effective amount of a compound of the present disclosure, the occurrence of which is at least in part due to the fact that the survival of such cells depends on the function of IAP proteins.

[0143] In another embodiment, the disclosure relates to regulating the apoptosis-related state relevant to one or more apoptosis regulators. Examples of apoptosis regulators include, but are not limited to, antibodies, Bcl-2, p53, BAX, BAD, Akt, CAD, PI3 kinases, PP1, and caspase proteins of Fas / CD95, TRAMP, TNF RI, DR1, DR2, DR3, DR4, DR5, DR6, FADD, RIP, TNFa, Fas ligand, TRAIL, TRAIL-R1, or TRAIL-R2. Other reagents involved in the initiation, determination, and degradation stages of apoptosis are also included. Examples of apoptosis regulators include reagents that can regulate the activity, presence, or concentration changes of apoptosis in a subject. Preferred apoptosis regulators are apoptosis inducers, such as TNF or TNF related ligands, particularly TRAMP ligands, Fas / CD95 ligands, TNFR-1 ligands, or TRAIL.

[0144] These therapies can be used to treat various cancers in a variety of settings. In a specific embodiment, the individual in need of treatment has previously undergone cancer treatment. Such previous treatments include, but are not limited to, previous chemotherapy, radiotherapy, surgery, or immunotherapy (such as cancer vaccines).

[0145] In another embodiment, the IAP protein inhibitors of the present disclosure are used in methods of treating T and B cell mediated autoimmune diseases; inflammatory diseases; infections; hyperproliferative diseases; AIDS; degenerative diseases; vascular diseases, etc. In some embodiments, infections suitable for treatment with the compositions and methods of the present disclosure include, but are not limited to, infections caused by viruses, bacteria, fungi, mycoplasmas, prions, etc.

[0146] The compounds and methods disclosed herein can also be used to treat autoimmune diseases or chronic inflammation. As used herein, the term "autoimmune disease" refers to any condition in which an organism produces antibodies or immune cells that recognize its own molecules, cells or tissues. Non-limiting examples of autoimmune diseases include autoimmune hemolytic anemia, autoimmune hepatitis, Berger's disease or IgA nephropathy, celiac disease, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft-versus-host disease, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, etc.

[0147] Other diseases and conditions that may be treated by administering the disclosed IAP protein inhibitors, including cancer, are disclosed in US Pat. No. 7,960,372; herein incorporated by reference in its entirety.

[0148] The therapeutically effective amount of the disclosed compound required for use in treatment varies with the nature of the condition being treated, the length of time required for activity, and the age and condition of the subject, and is ultimately determined by the attending physician. The dosage and interval can be adjusted individually to provide a plasma level of the disclosed compound sufficient to maintain the desired therapeutic effect. The desired dose can be administered in a single dose, or in multiple doses at appropriate intervals, such as one, two, three, four or more sub-doses per day. Multiple doses are usually required or required. For example, the disclosed compound can be administered at the following frequencies: one dose per day for four days, for a total of four doses (q4d×4); one dose per day for three days, for a total of four doses (q3d×4); one dose per day for five days (qd×5); one dose per week for three weeks (qwk3); five doses per day, two days off, and five doses per day (5 / 2 / 5); or any dosage regimen determined to be suitable for the situation.

[0149] The disclosed compounds used in the disclosed methods can be administered in an amount of about 0.005 mg to about 500 mg per dose, about 0.05 mg to about 250 mg per dose, or about 0.5 mg to about 100 mg per dose. For example, the disclosed compounds can be administered in an amount of about 0.005 mg, about 0.05 mg, about 0.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg per dose (including all doses between 0.005 mg and 500 mg).

[0150] The dosage of the composition containing the compound of the present disclosure or the composition containing the compound can be 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 the composition can be any dosage, including but not limited to about 1 μg / kg. The dosage of the composition can be 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 g, 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 The dosage of the present invention is about 20mg / kg, about 25mg / kg, about 30mg / kg, about 35mg / kg, about 40mg / kg, about 45mg / kg, about 50mg / kg, about 60mg / kg, about 70mg / kg, about 80mg / kg, about 90mg / kg, about 100mg / kg, about 125mg / kg, about 150mg / kg, about 175mg / kg, about 200mg / kg or more. The above dosage is the example of the general situation, but there may be individual situations that need higher or lower dosage, and these situations are within the scope of the present disclosure. In practice, the doctor determines the actual dosage regimen that is most suitable for individual subjects, and the dosage regimen can change with the age, body weight and reaction of specific subjects.

[0151] In certain embodiments, the therapeutically effective amount of the compound is between about 0.01 mg / kg and 100 mg / kg per day.

[0152] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof for use in inhibiting IAP protein activity in a cell.

[0153] In another aspect, the disclosure provides a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, for use in treating a disease or condition in which inhibition of an IAP protein provides a benefit.

[0154] In another aspect, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the present disclosure in the preparation of a medicament for inhibiting the activity of an IAP protein in a cell.

[0155] In another aspect, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition of the disclosure, in the preparation of a medicament for treating a disease or condition in which inhibition of an IAP protein provides a benefit.

[0156] V. Kit

[0157] In another embodiment, the present disclosure provides a kit comprising a compound of the present disclosure (or a composition comprising a compound of the present disclosure), which is packaged in a manner that facilitates their use in practicing the methods of the present disclosure. In one embodiment, the kit comprises a compound of the present disclosure (or a composition comprising a compound of the present disclosure), and instructions for administering the compound or a pharmaceutically acceptable salt or solvate thereof to a subject (e.g., a subject suffering from cancer) that provides a benefit from the inhibition of an IAP protein. In one embodiment, the compound or composition is packaged in unit dosage form. The kit may also include a device suitable for administering the composition according to the intended route of administration.

[0158] In some embodiments of the above aspects, the IAP is preferably selected from the group consisting of cIAP1, cIAP2 and XIAP.

[0159] Example

[0160] In order to make the purpose and technical solution of the present disclosure clearer, the present disclosure will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are not intended to limit the scope of the present disclosure. In addition, the specific experimental methods not mentioned in the following embodiments are carried out according to conventional experimental methods.

[0161] Intermediates

[0162] The following key intermediates were synthesized as reported in the literature.

[0163]

[0164] Representative Synthesis Examples

[0165] Example 1

[0166] (3S,6S,10aR)-9-hydroxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 1)

[0167]

[0168] Step 1: (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-9-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0169]

[0170] In a flame-dried 100 mL round-bottom flask, the key intermediate I (3.5 g, 8.13 mmol, 1.0 equiv) was dissolved in MeOH (15 mL). At 0 ° C, NaBH3CN (2.55 g, 40.7 mmol, 5.0 equiv) and H2SO4 (10 drops) were added to the reaction mixture. Under N2, the reaction mixture was stirred at -15 ° C for 3 hours. Water (60 mL) was slowly added, followed by extraction with dichloromethane (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel flash column chromatography, eluted with CH3OH / DCM (1:20) to give the title compound (3.0 g, 85% yield) as an off-white solid. LC / MS (ESI) m / z 433.87 [M+H] + .

[0171] Step 2: (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-9-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0172]

[0173] The intermediate obtained above (166 mg, 0.384 mmol, 1.0 eq) was dissolved in MeOH (15 mL). 10% Pd / C (100 mg, 0.844 mmol, 2.2 eq) was added at 25°C. After stirring under H2 for 5 h, the solution was filtered and concentrated to give the title compound (131 mg, 100% yield) as a yellow solid. LC / MS (ESI) m / z 343.27 [M+H] + .

[0174] Step 3: tert-Butyl ((3S,6S,10aR)-9-hydroxy-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0175]

[0176] Under nitrogen, the intermediate obtained above (131 mg, 0.383 mmol, 1.0 equiv) and (R)-1,2,3,4-tetrahydronaphthalene-1-amine (84 mg, 0.574 mmol, 1.5 equiv) were dissolved in CH2Cl2 (15 mL). HATU (218 mg, 0.574 mmol, 1.5 equiv) and N-ethyl-N-isopropylpropane-2-amine (148 mg, 1.148 mmol, 3.0 equiv) were added to the reaction mixture at 25 °C. After stirring for 16 hours, water (60 mL) was added, followed by extraction with dichloromethane (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluted with CH3OH / DCM (1:20) to give the title compound (170 mg, 94% yield) as an off-white solid. LC / MS(ESI)m / z 472.8[M+H] + .

[0177] Step 4: (3S,6S,10aR)-6-amino-9-hydroxy-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0178]

[0179] Under nitrogen, the intermediate obtained above (170 mg, 0.360 mmol, 1.0 equiv) was dissolved in dioxane (5 mL). HCl / dioxane (5 mL) was added to the reaction mixture at 25°C. After stirring for 3 hours, the solution was concentrated to give the title compound (134 mg, 100% yield) as a white solid. LC / MS (ESI) m / z 372.37 [M+H] + .

[0180] Step 5: tert-butyl ((2S)-1-(((3S,6S,10aR)-9-hydroxy-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0181]

[0182] Under nitrogen, the intermediate obtained above (134 mg, 0.361 mmol, 1.0 equiv) and N-(tert-butoxycarbonyl)-N-methyl-L-alanine (110 mg, 0.541 mmol, 1.5 equiv) were dissolved in DCM (15 mL). HATU (206 mg, 0.541 mmol, 1.5 equiv) and N-ethyl-N-isopropylpropan-2-amine (233 mg, 1.804 mmol, 5 equiv) were added at 25 ° C. After stirring for 16 hours, water (60 mL) was added to the reaction mixture, followed by extraction with DCM (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluted with CH3OH / DCM (1:20) to give the title compound (180 mg, 90% yield) as an off-white solid. LC / MS(ESI)m / z 557.5[M+H] + .

[0183] Step 6: (3S,6S,10aR)-9-hydroxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0184]

[0185] Under nitrogen, the intermediate obtained above (30 mg, 0.054 mmol, 1.0 equiv) was dissolved in dioxane (5 mL). HCl / dioxane (5 mL) was added to the reaction mixture at 25°C. After stirring for 3 hours, the solvent was evaporated and NH3 / CH3OH was added to neutralize the crude product. After concentration, the residue was purified by preparative HPLC to give the title compound (10.1 mg, 41.0% yield) as a white solid (mixture of diastereomers). LC / MS (ESI) m / z 457.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ(ppm)8.32(d,J=8.6Hz,1H),7.92(d,J=7.8Hz,1H),7.37–7.27(m,1H),7.11(m,3H ),4.98–4.80(m,2H),4.70(d,J=3.4Hz,1H),4.43–4.25(m,2H),4.05(d,J=3.3Hz,1H ),2.92(m,1H),2.79–2.60(m,2H),2.19(s,3H),2.17–1.93(m,5H),1.84(m,3H),1.7 9–1.67(m,2H),1.67–1.58(m,2H),1.54(m,1H),1.41(m,1H),1.09(d,J=6.8Hz,3H).

[0186] Example 2

[0187] (3S,6S,10aR)-9-hydroxy-9-methyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 2)

[0188]

[0189] Step 1: (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-5,9-dioxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0190]

[0191] Key intermediate I (500 mg, 1.161 mmol, 1.0 equiv) was dissolved in MeOH (15 mL). 10% Pd / C (100 mg, 0.844 mmol, 0.727 equiv) was added. After stirring under H2 for 5 h, the solution was filtered and concentrated to give the title compound (395 mg, 100% yield) as a yellow solid. LC / MS (ESI) m / z 341.25 [M+H] + .

[0192] Step 2: tert-Butyl ((3S,6S,10aR)-5,9-dioxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0193]

[0194] Under nitrogen, the intermediate obtained above (395 mg, 1.160 mmol, 1.0 equiv) and (R)-1,2,3,4-tetrahydronaphthalene-1-amine (256 mg, 1.741 mmol, 1.5 equiv) were dissolved in DCM (15 mL). HATU (662 mg, 1.741 mmol, 1.5 equiv) and N-ethyl-N-isopropylpropane-2-amine (450 mg, 3.48 mmol, 3.0 equiv) were added to the reaction mixture at 25 °C. After stirring for 16 hours, water (60 mL) was added, followed by extraction with dichloromethane (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluted with CH3OH / DCM (1:20) to give the title compound (401 mg, 73.6% yield) as an off-white solid. LC / MS(ESI)m / z 470.55[M+H] + .

[0195] Step 3: (3S,6S,10aR)-6-amino-5,9-dioxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0196]

[0197] Under nitrogen, the intermediate obtained above (401 mg, 0.854 mmol, 1.0 equiv) was dissolved in dioxane (5 mL). HCl / dioxane (5 mL) was added to the reaction mixture at 25°C. After stirring for 3 hours, the solvent was evaporated to give the title compound (316 mg, 100%) as a white solid. LC / MS (ESI) m / z 370.74 [M+H] + .

[0198] Step 4: tert-Butyl ((S)-1-(((3S,6S,10aR)-5,9-dioxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0199]

[0200] Under nitrogen, the intermediate obtained above (316 mg, 0.855 mmol, 1.0 equiv) and N-(tert-butoxycarbonyl)-N-methyl-L-alanine (261 mg, 1.283 mmol, 1.5 equiv) were dissolved in CH2Cl2 (15 mL). HATU (488 mg, 1.283 mmol, 1.5 equiv) and N-ethyl-N-isopropylpropan-2-amine (553 mg, 4.28 mmol, 5.0 equiv) were added to the reaction mixture at 25 °C. After stirring for 16 hours, water (60 mL) was added, followed by extraction with dichloromethane (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluted with CH3OH / DCM (1:20) to give the title compound (460 mg, 97% yield) as an off-white solid. LC / MS(ESI)m / z 555.47[M+H] + .

[0201] Step 5: tert-Butyl ((2S)-1-(((3S,6S,10aR)-9-hydroxy-9-methyl-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0202]

[0203] Under nitrogen, the intermediate obtained above (90 mg, 0.162 mmol, 1.0 equiv) was dissolved in Et2O (15 mL). 3.0 N methylmagnesium bromide (0.08 mL, 0.243 mmol, 1.5 equiv) was added at 0°C. After stirring at 25°C for 16 hours, saturated NH4Cl (aqueous solution) (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluted with CH3OH / DCM (1:20) to give the title compound (90 mg, 97% yield) as an off-white solid. LC / MS (ESI) m / z 571.77 [M+H] + .

[0204] Step 6: (3S,6S,10aR)-9-hydroxy-9-methyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0205]

[0206] The intermediate obtained above (60 mg, 0.105 mmol, 1.0 equiv) was dissolved in CH2Cl2 (10 mL). 2,2,2-Trifluoroacetic acid (59.9 mg, 0.526 mmol, 5.0 equiv) was added to the reaction mixture at 25°C. After stirring for 3 hours, saturated NaHCO3 (aqueous solution) was added and the solution was filtered. After concentration, the residue was purified by preparative HPLC to give the title compound (20.9 mg, 42.2%) as a white solid (mixture of diastereomers). LC / MS (ESI) m / z 471.45 [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ(ppm)8.60(d,J=8.6Hz,1H),8.07(d,J=7.4Hz,1H),7.31(m,1H),7.22–7 .07(m,4H),4.95(s,2H),4.64(m,1H),4.31(m,2H),2.94(m,1H),2.76(m,2 H),2.23(s,4H),2.04(m,2H),1.94–1.84(m,4H),1.75(m,3H),1.66(m,2H) ,1.57(d,J=11.8Hz,1H),1.43(m,1H),1.17(s,3H),1.13(d,J=6.9Hz,3H).

[0207] Example 3

[0208] (3S,6S,9R,10aR)-9-hydroxy-9-methyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,9S,10aR)-9-hydroxy-9-methyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 2A and Compound No. 2B)

[0209]

[0210] Another batch of diastereoisomer mixtures obtained in Example 2 was further separated on CHIRALPAK ID (column size: 2 cm×25 cm, 5 μm), mobile phase A was hexane:DCM (0.5% 2 mM NH3-MeOH), mobile phase B was IPA, and a faster eluting diastereomer (peak 1, 2A, 21 mg, 99.61% de) and a slower eluting diastereomer (peak 2, 2B, 108 mg, 99.83% de) were obtained. The absolute stereochemistry of the quaternary carbon has not yet been determined.

[0211] 2A: LC / MS (ESI) m / z 471.5 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.34(d,J=8.6Hz,1H),7.82(d,J=8.2Hz,1H),7.39– 7.27(m,1H),7.17–7.07(m,3H),5.12–4.99(m,1H),4.98–4.85(m,1H),4.53(s,1H) ,4.44–4.25(m,2H),2.95–2.85(m,1H),2.78–2.67(m,2H),2.20(s,3H),2.17–1.92 (m,5H),1.90–1.58(m,6H),1.51–1.29(m,3H),1.15(s,3H),1.09(d,J=6.8Hz,3H). 2B: LC / MS(ESI)m / z 471.5[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.57(d,J=8.6Hz,1H),8.04(d,J=7.3Hz,1H),7.35–7.23(m ,1H),7.20–7.05(m,3H),5.00–4.87(m,2H),4.71–4.55(m,1H),4.36–4.17(m,2H),2.96–

[0212] 2.85(m,1H),2.82–2.66(m,2H),2.25–2.12(m,4H),2.09–1.50(m,13H),1.15(s,3H),1.11(d,J=6.9Hz,3H).

[0213] Example 4

[0214] (3S,6S,10aR)-9-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 4)

[0215]

[0216] Step 1: tert-Butyl ((2S)-1-(((3S,6S,10aR)-9-methoxy-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0217]

[0218] Under nitrogen, the intermediate shown (50 mg, 0.090 mmol, 1.0 equiv) and sodium hydride (3.23 mg, 0.135 mmol, 1.5 equiv) were dissolved in THF (15 mL). The mixture was stirred at room temperature for 30 minutes. Iodomethane (14.02 mg, 0.099 mmol, 1.1 equiv) was added to the reaction mixture at 25 ° C. After stirring for 3 hours, water (60 mL) was slowly added to the reaction mixture, followed by extraction with ethyl acetate (15 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluted with CH3OH / DCM (1:20) to give the title compound (36 mg, 70.2% yield) as an off-white solid. LC / MS (ESI) m / z 571.46 [M+H] + .

[0219] Step 2: (3S,6S,10aR)-9-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0220]

[0221] Under nitrogen, the intermediate obtained above (56 mg, 0.098 mmol, 1.0 equiv) was dissolved in dioxane (5 mL). HCl / dioxane (5 mL) was added to the reaction mixture at 25°C. After stirring at 25°C for 3 hours, the solvent was evaporated and the residue was purified by preparative HPLC to give the title compound (10.1 mg, 21.87%) as a white solid (mixture of diastereomers). LC / MS (ESI) m / z 471.45 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.36(d,J=8.7Hz,1H),7.94(d,J=7.7Hz,1H),7.37–7.25(m,1H) ,7.19–6.98(m,3H),4.92(m,1H),4.77(m,1H),4.30(m,2H),3.63(s,1H), 3.27(s,3H),2.89(m,1H),2.77–2.64(m,2H),2.18(s,3H),2.12(m,2H),2 .05–1.80(m,8H),1.72–1.57(m,4H),1.43(m,1H),1.07(d,J=6.8Hz,3H).

[0222] Example 5

[0223] (3S,6S,9S,10aR)-9-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,9R,10aR)-9-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 4A and Compound No. 4B)

[0224]

[0225] Another batch of diastereoisomer mixtures obtained in Example 4 were further separated on Lux Cellulose-2 (column size: 2 cm×25 cm, 5 μm), mobile phase A was hexane (0.5% 2 mM NH3-MeOH), mobile phase B was ethanol, and a faster eluting diastereomer (peak 1, 4A, 105 mg, 99.99% de) and a slower eluting diastereomer (peak 2, 4B, 7 mg, 98.77% de) were obtained. The stereochemistry of the quaternary carbon has not yet been determined.

[0226] 4A: LC / MS (ESI) m / z 471.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.36(d,J=8.7Hz,1H),7.96(d,J=7.6Hz,1H),7.40–7.2 8(m,1H),7.22–7.04(m,3H),5.02–4.87(m,1H),4.85–4.69(m,1H),4.39–4.25(m,2H) ,3.72–3.58(m,1H),3.29(s,3H),2.97–2.86(m,1H),2.81–2.63(m,2H),2.24–2.08(m ,5H),2.07–1.79(m,7H),1.78–1.57(m,4H),1.53–1.37(m,1H),1.10(d,J=6.9Hz,3H).

[0227] 4B: LC / MS (ESI) m / z 471.8 [M+H] + .

[0228] Example 6

[0229] (3S,6S,10aR)-9-(dimethylamino)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 5)

[0230]

[0231] Step 1: tert-Butyl ((2S)-1-(((3S,6S,10aR)-9-(dimethylamino)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0232]

[0233] Under nitrogen, the intermediate shown (100 mg, 0.180 mmol, 1.0 equiv) and dimethylamine (16.26 mg, 0.361 mmol, 2.0 equiv) were dissolved in DCE (15 mL). NaBH(OAc)3 (76 mg, 0.361 mmol, 2.0 equiv) was added, and the solution was stirred at room temperature overnight. Water (60 mL) was added to the reaction mixture, followed by extraction with DCM (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluted with CH3OH / DCM (1:20) to give the title compound (50 mg, 47.5% yield) as an off-white solid. LC / MS(ESI)m / z 584.96[M+H] + .

[0234] Step 2: (3S,6S,10aR)-9-(dimethylamino)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0235]

[0236] Under nitrogen, the intermediate obtained above (39 mg, 0.067 mmol, 1.0 equiv) was dissolved in dioxane (5 mL). HCl / dioxane (5 mL) was added to the reaction mixture at 25°C. After stirring for 3 hours, the solvent was evaporated and the residue was purified by preparative HPLC to give the title compound (20.5 mg, 63.4% yield) as a white solid (mixture of diastereomers). LC / MS (ESI) m / z 484.44 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.29(d,J=8.7Hz,1H),8.06(d,J=7.2Hz,1H),7.41–7.25(m,1H),7 .20–7.01(m,3H),5.03–4.84(m,1H),4.66–4.49(m,1H),4.34–4.17(m,2H), 2.99–2.83(m,1H),2.81–2.60(m,3H),2.19(s,3H),2.17–2.04(m,7H),2.02 –1.76(m,8H),1.74–1.47(m,5H),1.45–1.31(m,1H),1.10(d,J=6.9Hz,3H).

[0237] Example 7

[0238] (3S,6S,10aR)-8-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 20)

[0239]

[0240] Step 1: (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-5,8-dioxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0241]

[0242] In a 100 mL round bottom flask, key intermediate II (3.2 g, 7.43 mmol, 1.0 eq) and Pd / C (0.40 g, 3.72 mmol, 0.5 eq) were dissolved in MeOH (20 ml) under H2. The reaction was stirred for 12 hours. After filtration and concentration, the title compound (2.5 g, 99%) was obtained as a colorless oil, which was used without further purification. LC / MS (ESI) m / z 341.2 [M+H] + .

[0243] Step 2: tert-Butyl ((3S,6S,10aR)-5,8-dioxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0244]

[0245] The intermediate obtained above (2.5 g, 7.34 mmol, 1.0 equiv), DIPEA (1.42 g, 11.02 mmol, 1.5 equiv), (R)-1,2,3,4-tetrahydronaphthalene-1-amine (1.16 g, 7.71 mmol, 1.05 equiv) and HATU (3.07 g, 8.08 mmol, 1.1 equiv) were dissolved in DCM (20 ml). The reaction was stirred for 2 hours. Water was added to the reaction mixture followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 0%-3% MeOH / DCM to give the title compound (3.2 g, 93%) as a light yellow solid. LC / MS (ESI) m / z 470.7 [M+H] + .

[0246] Step 3: (3S,6S,10aR)-6-amino-5,8-dioxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0247]

[0248] The intermediate obtained above (3.2 g, 6.81 mmol, 1.0 equiv) was dissolved in DCM (10 ml) and 4M HCl in dioxane (4.00 ml). The resulting mixture was stirred for 2 hours and concentrated. The resulting mixture was diluted with DCM and adjusted to pH = 8 with 7M NH3 in MeOH. The reaction mixture was filtered through celite and the filter cake was rinsed with dichloromethane. The combined organic layers were concentrated to give the title compound (2.5 g, 99%) as a light yellow solid, which was used without further purification. LC / MS (ESI) m / z 370.5 [M+H] + .

[0249] Step 4: tert-Butyl ((S)-1-(((3S,6S,10aR)-5,8-dioxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0250]

[0251] The intermediate obtained above (2.5 g, 6.77 mmol, 1.0 equiv), DIPEA (1.31 g, 10.15 mmol, 1.5 equiv), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (1.44 g, 7.10 mmol, 1.05 equiv) and HATU (2.83 g, 7.44 mmol, 1.1 equiv) were dissolved in DCM (10 ml). The reaction was stirred for 2 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 0% to 5% MeOH / DCM to give the title compound (3.5 g, 93%) as a light yellow solid. LC / MS (ESI) m / z 555.7 [M+H] + .

[0252] Step 5: tert-Butyl ((2S)-1-(((3S,6S,10aR)-8-hydroxy-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0253]

[0254] The intermediate obtained above (3.5 g, 6.31 mmol, 1.0 equiv) was dissolved in MeOH (20 ml). NaBH4 (0.48 g, 12.62 mmol, 2.0 equiv) was added to the reaction mixture at 0°C. After stirring for 2 hours, saturated NH4Cl was added to the reaction mixture, followed by extraction with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 0% to 6% MeOH / DCM to give the title compound (3.4 g, 97%) as a white solid. LC / MS (ESI) m / z 557.8 [M+H] + .

[0255] Step 6: tert-butyl ((2S)-1-(((3S,6S,10aR)-8-methoxy-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0256]

[0257] The intermediate obtained above (100 mg, 0.180 mmol, 1.0 equiv) was dissolved in THF (5 ml). Sodium hydride (6.5 mg, 0.269 mmol, 1.5 equiv) was added at 0°C. The resulting mixture was stirred for 0.5 hours. Iodomethane (38.2 mg, 0.269 mmol, 1.5 equiv) was added to the reaction mixture. The mixture was stirred for 4 hours. H2O was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 0% to 5% methanol / dichloromethane to give the title compound (15 mg, 14.6%) as a white solid. LC / MS (ESI) m / z 571.7 [M+H] + .

[0258] Step 7: (3S,6S,10aR)-8-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0259]

[0260] The intermediate obtained above (15 mg, 0.026 mmol, 1.0 equiv) was dissolved in DCM (5 ml) and 4M HCl in dioxane (2 ml). The resulting mixture was stirred for 2 hours and concentrated. The resulting mixture was diluted with DCM and adjusted to pH = 8 with 7M NH3 in MeOH. The reaction mixture was filtered through celite and the filter cake was rinsed with dichloromethane. The combined organic layers were concentrated. The crude product was purified by preparative HPLC to give the title compound (6.5 mg, 52.6%) as a white solid (mixture of diastereoisomers). LC / MS (ESI) m / z 471.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.36(d,J=8.7Hz,1H),8.05(d,J=7.5Hz,1H),7.41–7.34(m,1H),7.21–7.09(m,3H ),5.01–4.92(m,1H),4.89–4.80(m,1H),4.32(t,J=8.6Hz,1H),4.22(t,J=9.3Hz,1H),3.99 –3.89(m,2H),3.23(s,3H),2.96(q,J=6.8Hz,1H),2.81–2.71(m,2H),2.52–2.50(m,2H),2. 23(s,3H),2.18–2.00(m,1H),2.18–2.00(m,9H),1.80–1.60(m,2H),1.12(d,J=6.8Hz,3H).

[0261] Example 8

[0262] (3S,6S,8R,10aR)-8-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 20A) and (3S,6S,8S,10aR)-8-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 20B)

[0263]

[0264] Another batch of diastereoisomer mixtures (196 mg) obtained in Example 7 were further separated on CHIRALPAK IH (column size: 3 cm×25 cm, 5 μm), mobile phase A was CO 2 , mobile phase B was MeOH (0.5% 2 mM NH 3 -MeOH), and a faster eluting diastereomer (peak 1, 20A, 133 mg, 100% de) and a slower eluting diastereomer (peak 2, 20B, 28 mg, 100% de) were obtained. Based on single crystal X-ray diffraction of the key intermediate, the relative stereochemistry of the methoxy-linked carbon of compound 20A was determined to be R configuration.

[0265] Example 9

[0266] (3S,6S,10aR)-8-ethyl-8-hydroxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 21)

[0267]

[0268] Step 1: tert-butyl ((2S)-1-(((3S,6S,10aR)-8-ethyl-8-hydroxy-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0269]

[0270] The intermediate shown (120 mg, 0.216 mmol, 1.0 eq) was dissolved in ether (5 ml). Ethylmagnesium bromide (115 mg, 0.865 mmol, 4 eq) was added to the reaction mixture. The reactants were stirred for 2 hours. Saturated NH4Cl was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 0% to 60% PE / EA to give the title compound (40 mg, 31.6%) as a light yellow oil. LC / MS (ESI) m / z 585.9 [M+H] +

[0271] Step 2: (3S,6S,10aR)-8-ethyl-8-hydroxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0272]

[0273] The intermediate obtained above (90 mg, 0.154 mmol, 1.0 equiv) was dissolved in DCM (5 ml) and 4M HCl in dioxane (2 ml). The resulting mixture was stirred for 2 hours and concentrated. The resulting mixture was diluted with DCM and adjusted to pH = 8 with 7M NH3 in MeOH. The reaction mixture was filtered through celite and the filter cake was rinsed with dichloromethane. The combined organic layers were concentrated. The crude product was purified by preparative HPLC to give the title compound (2.5 mg, 3.6%) as a white solid (mixture of diastereomers). LC / MS (ESI) m / z 485.9 [M+H] + .

[0274] Example 10

[0275] (3S,6S,10aR)-8-ethoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 23)

[0276]

[0277] Step 1: tert-Butyl ((2S)-1-(((3S,6S,10aR)-8-ethoxy-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0278]

[0279] The intermediate shown (100 mg, 0.180 mmol, 1.0 equiv) was dissolved in THF (5 ml). Sodium hydride (6.5 mg, 0.269 mmol, 1.5 equiv) was added to the mixture at 0°C. The resulting mixture was stirred for 0.5 hours. Ethyl bromide (29.4 mg, 0.269 mmol, 1.5 equiv) was added to the reaction mixture. The mixture was stirred for 4 hours. H2O was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 0% to 5% methanol / dichloromethane to give the title compound (10 mg, 9.52%) as a colorless oil. LC / MS (ESI) m / z 585.7 [M+H] +

[0280] Step 2: (3S,6S,10aR)-8-ethoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0281]

[0282] The intermediate obtained above (15 mg, 0.026 mmol, 1.0 equiv) was dissolved in DCM (5 ml) and 4M HCl in dioxane (2 ml). The resulting mixture was stirred for 2 hours and concentrated. The resulting mixture was diluted with DCM and adjusted to pH = 8 with 7M NH3 in MeOH. The reaction mixture was filtered through celite and the filter cake was rinsed with dichloromethane. The combined organic layers were concentrated. The residue was purified by preparative HPLC to give the title compound (0.8 mg, 6.4%) as a white solid (mixture of diastereomers). LC / MS (ESI) m / z 485.7 [M+H] + .

[0283] Embodiment 11

[0284] (3S,6S,8R,10aR)-8-ethoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 23A) and (3S,6S,8S,10aR)-8-ethoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 23B)

[0285]

[0286] Another batch of crude diastereoisomer mixture (100 mg) obtained in Example 10 was further separated by preparative HPLC under alkaline conditions to obtain a faster eluting diastereomer (peak 1, 23A, 21.7 mg, 99.78% de) and a slower eluting diastereomer (peak 2, 23B, 10.3 mg, 98.22% de). Based on single crystal X-ray diffraction of the key intermediate, the absolute stereochemistry of the ethoxy-linked carbon of compound 23A was determined to be R configuration.

[0287] Example 12

[0288] (3S,6S,8R,10aR)-8-ethoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 23A)

[0289]

[0290] Step 1: (3S,6S,8R,10aR)-6-((tert-butoxycarbonyl)amino)-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0291]

[0292] Key intermediate II (5.1 g, 11.85 mmol, 1.0 eq) was dissolved in MeOH (40 ml). NaBH4 (0.896 g, 23.69 mmol, 2.0 eq) was added to the reaction mixture at -15 °C. The reactants were stirred for 2 hours. Saturated NH4Cl was added to the reaction mixture, followed by extraction with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0% to 5% MeOH / DCM to give the title compound (5 g, 98%). LC / MS (ESI) m / z 433.7 [M+H] + .

[0293] Step 2: (3S,6S,8R,10aR)-6-((tert-butoxycarbonyl)amino)-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0294]

[0295] The intermediate obtained above (5 g, 11.56 mmol, 1.0 eq.) and Pd / C (0.492 g, 4.62 mmol, 0.4 eq.) were dissolved in MeOH (40 mL) under H2. The reaction was stirred for 12 hours. The reaction mixture was filtered through celite and the filter cake was rinsed with MeOH. The organic layer was concentrated to give the title compound (3.8 g, 96%). LC / MS (ESI) m / z 343.6 [M+H] + .

[0296] Step 3: tert-Butyl ((3S,6S,8R,10aR)-8-hydroxy-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0297]

[0298] The intermediate obtained above (3.8 g, 11.10 mmol, 1.0 equiv), DIPEA (2.152 g, 16.65 mmol, 1.5 equiv), (R)-1,2,3,4-tetrahydronaphthalene-1-amine (1.716 g, 11.65 mmol, 1.05 equiv) and HATU (4.64 g, 12.21 mmol, 1.1 equiv) were dissolved in DCM (20 mL). The reaction was stirred for 2 hours. H2O was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0% to 3% MeOH / DCM to give the title compound (5.0 g, 96%). LC / MS (ESI) m / z 472.8 [M+H] + .

[0299] Step 4: (3S,6S,8R,10aR)-6-amino-8-hydroxy-5-oxo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0300]

[0301] The intermediate obtained above (5 g, 10.60 mmol, 1.0 equiv) was dissolved in DCM (30 mL) and 4M HCl in dioxane (6 mL). The resulting mixture was stirred for 2 hours and concentrated. The reaction mixture was diluted with dichloromethane. The organic layer was adjusted to pH 8 with 7M NH3 in MeOH. The reaction mixture was filtered through celite and the filter cake was rinsed with dichloromethane. The combined organic layers were concentrated to give the title compound (3.9 g, 99%). LC / MS (ESI) m / z 372.8 [M+H] + .

[0302] Step 5: tert-Butyl ((2S)-1-(((3S,6S,8R,10aR)-8-hydroxy-5-oxo-3-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0303]

[0304] The intermediate obtained above (3.9 g, 10.50 mmol, 1.0 equivalent), DIPEA (2.035 g, 15.75 mmol, 1.5 equivalent), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (2.347 g,

[0305] 11.55mmol, 1.1 eq) and HATU (4.39g, 11.55mmol, 1.1 eq) were dissolved in DCM (30mL). The reaction was stirred for 14 hours. H2O was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0% to 5% MeOH / DCM to give the title compound (5.5g, 94%). LC / MS (ESI) m / z 557.8[M+H] + .

[0306] Step 6: tert-butyl methyl ((S)-1-oxo-1-(((3S,6S,8R,10aR)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-8-(vinyloxy)decahydropyrrolo[1,2-a]azocin-6-yl)amino)propan-2-yl)carbamate

[0307]

[0308] The intermediate obtained above (7.4 g, 13.29 mmol, 1.0 eq.), 1,10-phenanthroline (0.479 g, 2.66 mmol, 0.2 eq.), Pd(OAc)2 (0.597 g, 2.66 mmol, 0.2 eq.) and ethoxyethylene (38.3 g, 532 mmol, 40 eq.) were dissolved in DCM (70 mL). The resulting mixture was stirred at 45 °C for 14 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0% to 50% EA / PE to give the title compound (5.1 g, 65.8%). LC / MS (ESI) m / z 583.8 [M+H] + .

[0309] Step 7: tert-Butyl ((S)-1-(((3S,6S,8R,10aR)-8-ethoxy-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0310]

[0311] The intermediate obtained above (5.1 g, 8.75 mmol, 1.0 equiv) and Pd / C (0.931 g, 8.75 mmol, 1.0 equiv) were dissolved in 2-propanol (40 mL) under H2. The reactants were stirred at 50°C for 3 hours. The reaction mixture was filtered through celite and the filter cake was rinsed with MeOH. The organic layer was concentrated to give the title compound (4.9 g, 96%). LC / MS (ESI) m / z 585.9 [M+H] + .

[0312] Step 8: (3S,6S,8R,10aR)-8-ethoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0313]

[0314] The intermediate obtained above (4.9 g, 8.38 mmol, 1.0 equivalent) was dissolved in DCM (20 mL) and 4 mL of 4M HCl in dioxane. The resulting mixture was stirred for 2 hours and concentrated. The reaction mixture was diluted with DCM (20 mL). The organic layer was adjusted to pH 8 with 7M NH3 in MeOH. The reaction mixture was filtered through diatomaceous earth and the filter cake was rinsed with dichloromethane. The organic layer was concentrated. The crude product was added to a silica gel column a to give the title compound (3.0 g, 73.9%, 99% de) as a white solid. LC / MS (ESI) m / z 485.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.34(d,J=8.7Hz,1H),8.03(d,J=7.5Hz,1H),7.40–7.34(m,1H),7.23–7.08(m ,3H),5.01–4.92(m,1H),4.90–4.78(m,1H),4.32(t,J=8.6Hz,1H),4.25–4.16(m,1H), 4.08–3.98(m,1IH),3.50–3.36(m,3H),2.96(q,J=6.8Hz,1H),2.83–2.67(m,2H),2.22 (s,3H),2.17–1.98(m,2H),1.98–1.82(m,7H),1.80–1.58(m,5H),1.18–1.01(m,6H),.

[0315] Example 13

[0316] (3S,6S,8S,10aR)-8-ethoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 23B)

[0317]

[0318] According to the synthesis of Example 12, the title compound (98.0 mg, 98% de) was obtained as a white solid. LC / MS (ESI) m / z 499.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.25(d,J=8.7Hz,1H),8.15(d,J=7.1Hz,1H),7.39–7.31(m,1H),7.22–7.13(m,2H),7.16–7.0 8(m,1H),5.02–4.90(m,1H),4.68–4.56(m,1H),4.30(t,J=8.4Hz,1H),4.24–4.15(m,1H),3.54–3.46( m,1H),3.44–3.38(m,3H),2.94(q,J=6.8Hz,1H),2.84–2.70(m,2H),2.23(s,3H),2.20–2.08(m,2H),2 .08–1.96(m,2H),1.94–1.84(m,3H),1.82–1.48(m,7H),1.14(d,J=6.9Hz,3H),1.08(t,J=7.0Hz,3H).

[0319] Embodiment 14

[0320] (3S,6S,8R,10aS)-8-(dimethylamino)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,8S,10aS)-8-(dimethylamino)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 25A and Compound No. 25B)

[0321]

[0322] Step 1: Benzyl 2-acetyl-4-(4-fluorobenzyl)-8,8-dimethyl-7,8-dihydro-6H-pyrrolo[2,3-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxylate

[0323]

[0324] The intermediate shown (100 mg, 0.180 mmol, 1.0 equiv) and dimethylamine (61.0 mg, 1.352 mmol, 7.5 equiv) were dissolved in MeOH (10 ml). Pd / C (19.2 mg, 0.180 mmol, 1.0 equiv) was added to the reaction mixture. The reaction was stirred for 24 hours under H2. The mixture was filtered and concentrated to give the title compound (60 mg, 57.0%) as a light yellow oil. LC / MS (ESI) m / z 584.8 [M+H] + .

[0325] Step 2: The intermediate obtained above (60 mg, 0.103 mmol, 1.0 equiv) was dissolved in DCM (5 ml) and 4M HCl in dioxane (2 ml). The resulting mixture was stirred for 2 hours and concentrated. The resulting mixture was diluted with DCM and adjusted to pH = 8 with 7M NH3 in MeOH. The reaction mixture was filtered through diatomaceous earth and the filter cake was rinsed with dichloromethane. The combined organic layers were concentrated. The crude product was purified by preparative HPLC to give a faster eluting isomer (peak 1, 25A, 10.3 mg, 20.7% yield) and a slower eluting isomer (peak 2, 25B, 3 mg, 6.0% yield) as a white solid. The absolute stereochemistry of the tertiary carbon of each compound has not yet been determined.

[0326] Peak 1, 25A: 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.35(d,J=8.7Hz,1H),8.03(d,J=7.6Hz,1H),7.41–7.34(m,1H),7.22–7.13(m,2 H),7.16–7.08(m,1H),5.02–4.92(m,1H),4.88–4.74(m,1H),4.32(t,J=8.5Hz,1H),4.25–

[0327] 4.15(m,1H),3.34–3.19(m,2H),3.00–2.91(m,1H),2.79–2.72(m,2H),2.52–2.50(m,2H),2.22(s,3H),2.12 (s,6H),2.10–1.95(m,2H),1.94–1.78(m,5H),1.77–1.59(m,4H),1.54–1.45(m,1H),1.12(d,J=6.8Hz,3H). LC / MS(ESI)m / z 484.8[M+H] + .

[0328] Peak 2, 25B: 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.34(d,J=8.7Hz,1H),8.15(d,J=7.2Hz,1H),7.40–7.34(m,1H),7.22–7.15(m,2 H),7.15–7.08(m,1H),4.96(d,J=4.7Hz,1H),4.63–4.54(m,1H),4.35–4.19(m,2H),3.34–

[0329] 3.19(m,2H),2.93(q,J=6.8Hz,1H),2.82–2.60(m,2H),2.52–2.50(m,2H),2.23(s,3H),2. 11(s,6H),2.05–1.84(m,4H),1.80–1.56(m,6H),1.52–1.41(m,2H),1.14(d,J=6.9Hz,3H). LC / MS(ESI)m / z 484.8[M+H] + .

[0330] Embodiment 15

[0331] (3S,6S,8R,10aR)-N-((R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-8-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 31A) and (3S,6S,8S,10aR)-N-((R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-8-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 31B)

[0332]

[0333] Step 1: tert-Butyl ((3S,6S,10aR)-3-(((R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-5,8-dioxodecahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0334]

[0335] The intermediate shown (500 mg, 1.469 mmol, 1.0 equiv), DIPEA (285 mg, 2.203 mmol, 1.5 equiv), (R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-amine (255 mg, 1.542 mmol, 1.05 equiv) and HATU (614 mg, 1.616 mmol, 1.1 equiv) were dissolved in DCM (10 ml). The reaction was stirred for 2 hours. H2O was added to the reaction mixture followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 0% to 5% MeOH / DCM to give the title compound (710 mg, 99%) as a white solid. LC / MS (ESI) m / z 488.9 [M+H] + .

[0336] Step 2: tert-Butyl ((3S,6S,10aR)-3-(((R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0337]

[0338] The intermediate obtained above (710 mg, 1.456 mmol, 1.0 equiv) was dissolved in MeOH (10 ml). NaBH4 (110 mg, 2.91 mmol, 2.0 equiv) was added to the reaction mixture. The reactants were stirred for 2 hours. Saturated NH4Cl was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 0% to 10% MeOH / DCM to give the title compound (491 mg, 68.9%) as a white solid. LC / MS (ESI) m / z 490.8 [M+H] + .

[0339] Step 3: (3S,6S,10aR)-6-amino-N-((R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide

[0340]

[0341] The intermediate obtained above (490 mg, 1.001 mmol, 1.0 equiv) was dissolved in DCM (10 ml) and 4M HCl in dioxane (2 ml). The resulting mixture was stirred for 2 hours and concentrated. The resulting mixture was diluted with DCM and adjusted to pH 8 with 7M NH3 in MeOH. The reaction mixture was filtered through celite and the filter cake was rinsed with dichloromethane. The combined organic layers were concentrated to give the title compound (370 mg, 95%) as a light yellow solid. LC / MS (ESI) m / z 390.8 [M+H] +

[0342] Step 4: tert-Butyl ((2S)-1-(((3S,6S,10aR)-3-(((S)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0343]

[0344] The intermediate obtained above (390 mg, 1.001 mmol, 1.0 equivalent), DIPEA (194 mg, 1.502 mmol, 1.5 equivalent), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (214 mg,

[0345] 4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4-[4- + .

[0346] Step 5: tert-Butyl ((2S)-1-(((3S,6S,10aR)-3-(((R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-8-methoxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0347]

[0348] The intermediate obtained above (180 mg, 0.313 mmol, 1.0 equiv) was dissolved in THF (5 ml). Sodium hydride (37.6 mg, 1.57 mmol, 5.0 equiv) was added to the mixture at 0°C. The resulting mixture was stirred for 0.5 hours. Iodomethane (66.7 mg, 0.470 mmol, 1.5 equiv) was added to the reaction mixture. The mixture was stirred for 4 hours. H2O was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 0% to 5% methanol / dichloromethane to give the title compound (90 mg, 48.8%) as a white solid. LC / MS (ESI) m / z 589.8 [M+H] +

[0349] Step 6: (3S,6S,8R,10aR)-N-((R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-8-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 31A) and (3S,6S,8S,10aR)-N-((R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-8-methoxy-6-((S)-2-(methylamino)propionamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 31B)

[0350]

[0351] The intermediate obtained above (180mg, 0.306mmol, 1.0 equivalent) was dissolved in DCM (10ml) and 4M HCl in dioxane (2ml). The resulting mixture was stirred for 2 hours and concentrated. The resulting mixture was diluted with DCM and adjusted to pH=8 with 7M NH3 in MeOH. The reaction mixture was filtered through diatomaceous earth and the filter cake was rinsed with dichloromethane. The combined organic layers were concentrated. The crude product was purified by preparative HPLC under alkaline conditions to give a faster eluting isomer (peak 1, 31A, 34mg, 98%de) as a white solid and a slower eluting isomer (peak 2, 31B, 14mg, 98%de) as a white solid.

[0352] Peak 1, 31A: 1 H NMR (400 MHz, DMSO-d 6)δ(ppm)8.37(d,J=8.7Hz,1H),8.04(d,J=7.5Hz,1H),7.39(dd,J=8.6,6.0Hz,1H),7.05 –6.92(m,2H),4.99–4.90(m,1H),4.89–4.80(m,1H),4.30(t,J=8.6Hz,1H),4.22(t,J=9. 2Hz,1H),3.96–3.86(m,1H),3.23(s,3H),2.96(q,J=6.8Hz,1H),2.82–2.70(m,2H),2.23 (s,3H),2.16–2.08(m,1H),2.06–1.76(m,7H),1.76–1.59(m,4H),1.12(d,J=6.8Hz,3H). LC / MS(ESI)m / z 489.9[M+H] + .

[0353] Example 16

[0354] (S)-N-((3S,6S,9S,10aR)-9-methoxy-5-oxo-3-(7-phenyl-1H-benzo[d]imidazol-2-yl)decahydropyrrolo[1,2-a]azocine-6-yl)-2-(methylamino)propanamide (Compound No. 37)

[0355]

[0356] Step 1: tert-Butyl ((S)-1-(((3S,6S,9S,10aR)-3-((2-amino-3-bromophenyl)carbamoyl)-9-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0357]

[0358] Under argon, (3S,6S,9S,10aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-9-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid (0.4 g, 0.936 mmol, 1.0 equiv) (prepared and isolated by chiral SFC on a gram scale), 3-bromobenzene-1,2-diamine (0.210 g, 1.123 mmol, 1.2 equiv), DIEA (0.363 g, 2.81 mmol, 3.0 equiv) and HATU (0.534 g, 1.404 mmol, 1.5 equiv) were dissolved in DCM (20 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 16 h. H2O (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (0.502 g, 90%) as a white solid. LC / MS (ESI) m / z 596.7 [M+H] + .

[0359] Step 2: tert-Butyl ((S)-1-(((3S,6S,9S,10aR)-3-(7-bromo-1H-benzo[d]imidazol-2-yl)-9-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0360]

[0361] Under argon, the intermediate obtained above (0.502 g, 0.842 mmol, 1.0 equivalent) was dissolved in AcOH (5 mL) to give a colorless solution. The reaction mixture was stirred at 70 ° C for 5 hours. Saturated NaHCO3 (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-5% methanol / dichloromethane to give the title compound (0.414 g, 85%) as a white solid. LC / MS (ESI) m / z 578.6 [M+H] + .

[0362] Step 3: tert-Butyl ((S)-1-(((3S,6S,9S,10aR)-3-(7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-9-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0363]

[0364] Under argon, the intermediate obtained above (0.35 g, 0.605 mmol, 1.0 equiv), SEM-Cl (0.303 g, 1.815 mmol, 3.0 equiv) and K2CO3 (0.334 g, 2.420 mmol, 4.0 equiv) were dissolved in DMF (5 mL) to give a colored suspension. The reaction mixture was stirred at room temperature for 16 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-5% methanol / dichloromethane to give the title compound (0.338 g, 79%) as a white solid. LC / MS (ESI) m / z 708.5 [M+H] + .

[0365] Step 4: tert-Butyl ((S)-1-(((3S,6S,9S,10aR)-3-(7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-9-methoxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0366]

[0367] Under argon, the intermediate obtained above (0.338 g, 0.477 mmol, 1.0 equiv) and MeI (0.338 g, 2.384 mmol, 5.0 equiv) were dissolved in THF (15 mL) to give a colorless solution. The reaction mixture was cooled to 0°C with an ice / water bath. NaH (0.057 g, 1.431 mmol, 3.0 equiv) was added to the reaction mixture in one go. The reaction mixture was stirred at room temperature for 5 hours. Saturated NH4Cl (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-5% methanol / dichloromethane to give the title compound (0.3 g, 87%) as a white solid. LC / MS (ESI) m / z 722.3[M+H] + .

[0368] Step 5: tert-Butyl ((S)-1-(((3S,6S,9S,10aR)-9-methoxy-5-oxo-3-(7-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0369]

[0370] Under argon, the intermediate obtained above (0.15 g, 0.208 mmol, 1.0 equiv), phenylboronic acid (0.051 g, 0.415 mmol, 2.0 equiv), K2CO3 (0.086 g, 0.623 mmol, 3.0 equiv) and PdCl2(dppf)-CH2Cl2 adduct (0.034 g, 0.042 mmol, 0.2 equiv) were dissolved in 1,4-dioxane (10.00 mL) and water (1 mL) to give a brown suspension. The reaction mixture was stirred at 95 ° C for 16 hours. Saturated NaCl (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×2). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (0.15 g, 100%) as a yellow oil. LC / MS (ESI) m / z 720.7 [M+H] + .

[0371] Step 6: (S)-N-((3S,6S,9S,10aR)-9-methoxy-5-oxo-3-(7-phenyl-1H-benzo[d]imidazol-2-yl)decahydropyrrolo[1,2-a]azocin-6-yl)-2-(methylamino)propanamide

[0372]

[0373] Under argon, the intermediate obtained above (0.15 g, 0.208 mmol, 1.0 equiv) was dissolved in TFA (6.00 mL) and DCM (6 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 3 hours, the solvent was evaporated, and NH3 / CH3OH was added to neutralize the crude product. After concentration, the residue was purified by preparative HPLC to give the title compound (46.6 mg, 45.7%) as a white solid. LC / MS (ESI) m / z 490.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ(ppm)12.46(d,J=69.3Hz,1H),8.08(d,J=7.3Hz,2H),7.85(dd,J=17.1,7.6Hz,1H),7.46–

[0374] 7.30(m,5H),7.27–7.22(m,1H),5.23–5.11(m,1H),4.86–4.71(m,1H),4.49–4.39(m,1H),3.65(d,J=52.5Hz,1H),3. 16(s,3H),2.85(dt,J=6.9,5.4Hz,1H),2.46–2.28(m,3H),2.20–2.12(m,5H),2.02–1.73(m,6H),1.10–1.05(m,3H).

[0375] Embodiment 17

[0376] (3S,6S,8R,10aR)-8-(allyloxy)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 46)

[0377]

[0378] Step 1: tert-Butyl ((S)-1-(((3S,6S,8R,10aR)-8-(allyloxy)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0379]

[0380] The above scheme shows that the starting material (0.489 g, 4.04 mmol, 5.0 equiv) is dissolved in THF (15 mL) under argon to obtain a solution. The reaction mixture is cooled to 0°C with an ice / water bath. NaH (0.162 g, 4.04 mmol, 5.0 equiv) is added to the reaction mixture in one go. The reaction mixture is stirred at 0°C for 8 hours. H2O (20 mL) is added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers are dried over Na2SO4, filtered and concentrated. The crude product is added to a silica gel column and eluted with 0%-3% methanol / dichloromethane to give the title compound (0.3 g, 62.2%) as a yellow oil. LC / MS (ESI) m / z 597.7 [M+H] + .

[0381] Step 2: (3S,6S,8R,10aR)-8-(allyloxy)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0382]

[0383] Following the synthesis of Example 1, the crude residue was purified by preparative HPLC to give the title compound as a white solid (41.6 mg). LC / MS (ESI) m / z 497.7 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.32(d,J=8.7Hz,1H),8.02(d,J=7.5Hz,1H),7.38–7.28(m,1H),7.22–7.03(m,3H),5.89(ddd,J=2 2.4,10.4,5.2Hz,1H),5.23(dd,J=17.2,1.7Hz,1H),5.12–5.02(m,1H),4.94(dd,J=12.2,8.0Hz,1H),4.88–

[0384] 4.77(m,1H),4.29(t,J=8.6Hz,1H),4.19(t,J=8.3Hz,1H),4.06(dd,J=12.5,8.6Hz,1H),3.91(dd,J=3.2,1.6Hz,2H),2.93 (q,J=6.8Hz,1H),2.84–2.61(m,2H),2.19(s,3H),2.11(dt,J=11.3,7.6Hz,1H),2.05–1.55(m,14H),1.09(d,J=6.8Hz,3H).

[0385] Embodiment 18

[0386] (3S,6S,8R,10aR)-6-((S)-2-(methylamino)propionamido)-5-oxo-8-propoxy-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 45)

[0387]

[0388] Step 1: tert-butyl methyl ((S)-1-oxo-1-(((3S,6S,8R,10aR)-5-oxo-8-propoxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)propan-2-yl)carbamate

[0389]

[0390] The above scheme shows that the starting material (0.15 g, 0.251 mmol, 1.0 equiv) and rhodium (0.026 g, 0.251 mmol, 1.0 equiv) were dissolved in 2-propanol (10 mL) under H2 to give a suspension. The reaction mixture was stirred at 45 °C for 12 hours. The reaction mixture was filtered through diatomaceous earth and the filter cake was rinsed with ethyl acetate. The reaction mixture was concentrated to give the title compound (0.15 g, 100%). LC / MS (ESI) m / z 599.7 [M+H] + .

[0391] Step 2: (3S,6S,8R,10aR)-6-((S)-2-(methylamino)propionamido)-5-oxo-8-propoxy-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0392]

[0393] Following the synthesis of Example 1, the crude residue was purified by preparative HPLC to give the title compound as a white solid (35.5 mg). LC / MS (ESI) m / z 499.7 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ(ppm)8.32(d,J=8.7Hz,1H),8.01(d,J=7.5Hz,1H),7.37–7.25(m,1H),7.26–6.91(m,3H), 4.94(dd,J=12.4,8.1Hz,1H),4.87–4.72(m,1H),4.28(t,J=8.6Hz,1H),4.24–4.11(m,1H),3. 98(dd,J=13.9,8.1Hz,1H),3.31–3.22(m,2H),2.93(q,J=6.8Hz,1H),2.83–2.65(m,2H),2.19 (s,3H),2.16–1.56(m,15H),1.53–1.40(m,2H),1.09(d,J=6.8Hz,3H),0.84(t,J=7.4Hz,3H).

[0394] Embodiment 19

[0395] (3S,6S,8R,10aR)-8-isobutoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 47)

[0396]

[0397] According to the synthesis of Example 18, the title compound (148.8 mg) was obtained as a white solid. LC / MS (ESI) m / z 513.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.31(d,J=8.7Hz,1H),8.01(d,J=7.5Hz,1H),7.38–7.31(m,1H),7.12(tdd,J=15.7,8 .0,5.9Hz,3H),4.94(dd,J=12.3,8.0Hz,1H),4.88–4.70(m,1H),4.28(t,J=8.6Hz,1H),4.18( t,J=8.9Hz,1H),3.94(dd,J=13.8,8.1Hz,1H),3.18–3.04(m,2H),2.93(q,J=6.8Hz,1H),2.84 –2.63(m,2H),2.19(s,3H),2.13–1.52(m,16H),1.09(d,J=6.8Hz,3H),0.84(d,J=6.7Hz,6H).

[0398] Embodiment 20

[0399] (3S,6S,8R,10aR)-8-(2-hydroxyethoxy)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 56)

[0400]

[0401] Step 1: Ethyl 2-(((3S,6S,8R,10aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-8-yl)oxy)acetate

[0402]

[0403] The above scheme shows that the starting material (0.5 g, 0.898 mmol, 1.0 equiv) and ethyl 2-bromoacetate (0.750 g, 4.49 mmol, 5.0 equiv) were dissolved in THF (20 mL) under argon. The reaction mixture was cooled to 0 ° C with an ice / water bath. NaH (0.180 g, 4.49 mmol, 5.0 equiv) was added to the reaction mixture in one go. The reaction mixture was stirred at room temperature for 12 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-3% methanol / dichloromethane to give the title compound (0.388 g, 67.2%) as a colorless oil. LC / MS (ESI) m / z 643.4 [M+H] + .

[0404] Step 2: tert-Butyl ((S)-1-(((3S,6S,8R,10aR)-8-(2-hydroxyethoxy)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0405]

[0406] The intermediate obtained above (0.388 g, 0.604 mmol, 1.0 equiv) and LiBH4 (0.657 g, 30.2 mmol, 50 equiv) were dissolved in MeOH (10 mL) under argon. The reaction mixture was stirred at room temperature for 16 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with chloroform (20 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-5% ethyl acetate / hexane to give the title compound (0.28 g, 77%) as a yellow oil. LC / MS (ESI) m / z 601.4 [M+H] + .

[0407] Step 3: (3S,6S,8R,10aR)-8-(2-hydroxyethoxy)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0408]

[0409] According to the synthesis of Example 1, the title compound (30.5 mg) was obtained as a white solid. LC / MS (ESI) m / z 501.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.31(d,J=8.7Hz,1H),8.00(d,J=7.5Hz,1H),7.41–7.25(m,1H),7.22–6.97(m,3H),4.9 4(dd,J=12.3,7.9Hz,1H),4.87–4.77(m,1H),4.50(t,J=5.5Hz,1H),4.29(t,J=8.6Hz,1H),4.23 –4.10(m,1H),4.02(dd,J=14.0,8.0Hz,1H),3.46(dd,J=10.6,5.3Hz,2H),3.42–3.37(m,2H),2. 93(q,J=6.8Hz,1H),2.83–2.65(m,2H),2.20(s,3H),2.11–1.58(m,15H),1.09(d,J=6.8Hz,3H).

[0410] Embodiment 21

[0411] (3S,6S,8R,10aR)-8-(2-(dimethylamino)ethoxy)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 91)

[0412]

[0413] Step 1: Ethyl 2-(((3S,6S,8R,10aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-8-yl)oxy)methanesulfonate

[0414]

[0415] The above scheme shows that the starting material (0.24 g, 0.399 mmol, 1.0 equiv), Ms-Cl (0.092 g, 0.799 mmol, 2.0 equiv) and DIEA (0.155 g, 1.198 mmol, 3.0 equiv) were dissolved in DCM (15 mL) under argon. The reaction mixture was stirred at room temperature for 2 hours. Saturated brine (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (0.23 g, 85%) as a yellow oil. LC / MS (ESI) m / z 679.6 [M+H] + .

[0416] Step 2: tert-Butyl ((S)-1-(((3S,6S,8R,10aR)-8-(2-(dimethylamino)ethoxy)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0417]

[0418] The intermediate obtained above (0.23 g, 0.339 mmol, 1.0 equiv), DIEA (0.131 g, 1.016 mmol, 3.0 equiv), KI (0.056 g, 0.339 mmol, 1.0 equiv) and dimethylamine (0.076 g, 1.686 mmol, 4.98 equiv) were dissolved in acetonitrile (15 mL) under argon. The reaction mixture was stirred at 80°C for 16 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-8% methanol / dichloromethane to give the title compound (0.098 g, 46.1%) as a colored oil. LC / MS (ESI) m / z 628.4 [M+H] + .

[0419] Step 3: (3S,6S,8R,10aR)-8-(2-(dimethylamino)ethoxy)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0420]

[0421] According to the synthesis of Example 1, the title compound (26.4 mg) was obtained as a white solid. LC / MS (ESI) m / z 528.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.32(d,J=8.7Hz,1H),8.00(d,J=7.5Hz,1H),7.38–7.30(m,1H),7.20– 7.05(m,3H),4.94(dd,J=12.2,7.9Hz,1H),4.86–4.74(m,1H),4.29(t,J=8.6Hz ,1H),4.23–4.08(m,1H),4.01(dd,J=14.0,8.1Hz,1H),3.47–3.39(m,2H),2.93 (q,J=6.7Hz,1H),2.83–2.62(m,2H),2.37(t,J=6.1Hz,2H),2.19(s,3H),2.15–

[0422] 2.08(m,7H),2.06–1.81(m,9H),1.77–1.57(m,5H),1.09(d,J=6.9Hz,3H).

[0423] Embodiment 22

[0424] (3S,6S,8R,10aR)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-8-(trifluoromethoxy)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 51)

[0425]

[0426] Step 1: tert-butyl methyl ((S)-1-oxo-1-(((3S,6S,8R,10aR)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-8-(trifluoromethoxy)decahydropyrrolo[1,2-a]azocin-6-yl)amino)propan-2-yl)carbamate

[0427]

[0428] The above scheme shows that the raw material (1 g, 1.796 mmol, 1.0 equivalent), selectfluor (0.955 g, 2.69 mmol, 1.5 equivalent), 2-fluoropyridine (0.523 g, 5.39 mmol, 3.0 equivalent), potassium fluoride (0.417 g, 7.19 mmol, 4.0 equivalent), silver trifluoromethanesulfonate (1.385 g, 5.39 mmol, 3.0 equivalent) and trimethyl (trifluoromethyl) silane (0.766 g, 5.39 mmol, 3.0 equivalent) were dissolved in ethyl acetate (10 mL) under argon to obtain a suspension. The reaction mixture was stirred at room temperature for 16 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×2). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-2.5% methanol / dichloromethane to give the title compound (0.355 g, 31.6%) as a white solid. LC / MS (ESI) m / z 625.4 [M+H] + .

[0429] Step 2: (3S,6S,8R,10aR)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-8-(trifluoromethoxy)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0430]

[0431] According to the synthesis of Example 1, the title compound (104.4 mg) was obtained as a white solid. LC / MS (ESI) m / z 525.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.36(d,J=8.7Hz,1H),8.12(d,J=7.4Hz,1H),7.43–7.27(m,1H),7.12( tdd,J=13.6,7.8,6.1Hz,3H),5.27(q,J=8.3Hz,1H),4.94(dd,J=12.6,8.1Hz,1H ),4.86(dd,J=16.9,8.3Hz,1H),4.31(t,J=8.8Hz,1H),4.27–4.18(m,1H),2.95( q,J=6.8Hz,1H),2.84–2.61(m,2H),2.25–2.10(m,5H),2.09–1.78(m,9H),1.77–

[0432] 1.53(m,4H),1.09(d,J=6.8Hz,3H).

[0433] Embodiment 23

[0434] (3S,6S,8R,10aR)-8-(difluoromethoxy)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 52)

[0435]

[0436] Step 1: tert-butyl ((S)-1-(((3S,6S,8R,10aR)-8-(difluoromethoxy)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0437]

[0438] The above scheme shows that the starting material (0.4 g, 0.719 mmol, 1.0 equiv), copper (I) iodide (0.027 g, 0.144 mmol, 0.2 equiv) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.256 g, 1.437 mmol, 2.0 equiv) were dissolved in acetonitrile (5 mL) under argon to give a yellow solution. The reaction mixture was stirred at 45 ° C for 3 hours. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (0.436 g, 100%). LC / MS (ESI) m / z 607.5 [M+H] + .

[0439] Step 2: (3S,6S,8R,10aR)-8-(difluoromethoxy)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0440]

[0441] According to the synthesis of Example 1, the title compound (89.6 mg) was obtained as a white solid. LC / MS (ESI) m / z 507.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.35(d,J=8.7Hz,1H),8.08(d,J=7.4Hz,1H),7.39–7.29(m,1H),7.1 2(ddd,J=16.7,7.8,4.7Hz,3H),6.58(t,J=76.2Hz,1H),5.00–4.78(m,3H),4. 31(t,J=8.7Hz,1H),4.26–4.16(m,1H),2.96(q,J=6.8Hz,1H),2.74(dd,J=11 .8, 6.3Hz, 2H), 2.25–1.90 (m, 10H), 1.90–1.54 (m, 7H), 1.10 (d, J = 6.8Hz, 3H).

[0442] Embodiment 24

[0443] (3S,6S,10aS)-6-((S)-2-(methylamino)propionamido)-8-(4-methylpiperazin-1-yl)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 89)

[0444]

[0445] Step 1: tert-butyl methyl ((2S)-1-(((3S,6S,10aS)-8-(4-methylpiperazin-1-yl)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)carbamate

[0446]

[0447] The above scheme shows that the starting material (0.3 g, 0.541 mmol, 1.0 equiv), 1-methylpiperazine (0.542 g, 5.41 mmol, 10 equiv) and sodium cyanoborohydride (0.340 g, 5.41 mmol, 10 equiv) were dissolved in 1,2-dichloroethane (10 mL) under argon to give a suspension. The reaction mixture was stirred at room temperature for 48 hours. H2O (30 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-10% methanol / dichloromethane to give the title compound (0.166 g, 48.0%) as a yellow oil. LC / MS (ESI) m / z 639.4 [M+H] + .

[0448] Step 2: (3S,6S,10aS)-6-((S)-2-(methylamino)propionamido)-8-(4-methylpiperazin-1-yl)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0449]

[0450] According to the synthesis of Example 1, the title compound (49 mg) was obtained as a white solid (mixture of diastereomers). LC / MS (ESI) m / z 539.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ(ppm)8.30(d,J=8.7Hz,1H),7.99(d,J=7.6Hz,1H),7.38–7.30(m,1H),7.19–7.04 (m,3H),4.93(dd,J=12.3,8.0Hz,1H),4.86–4.70(m,1H),4.29(t,J=8.5Hz,1H),4.2 3–4.09(m,1H),2.93(q,J=6.8Hz,1H),2.80–2.62(m,2H),2.40(s,4H),2.22(d,J=24 .4Hz, 7H), 2.13–1.56 (m, 18H), 1.50 (dt, J=18.8, 9.5Hz, 1H), 1.09 (d, J=6.9Hz, 3H).

[0451] Embodiment 25

[0452] (3S,6S,8R,10aR)-8-ethoxy-N-((R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-6-((S)-2-(methylamino)propionamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 44)

[0453]

[0454] Step 1: (3S,6S,8R,10aR)-6-((tert-butoxycarbonyl)amino)-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0455]

[0456] Key intermediate II (15 g, 34.8 mmol, 1.0 equiv) was dissolved in MeOH (150 mL) under argon to give a colored solution. The reaction mixture was cooled to -10 °C with an ice / brine bath. NaBH4 (1.977 g, 52.3 mmol, 1.5 equiv) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. Saturated NH4Cl (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (200 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (15 g, 100%, 94% ee) as a white solid. LC / MS (ESI) m / z 433.4 [M+H] + Step 2: (3S,6S,8R,10aR)-6-amino-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0457]

[0458] Under argon, the intermediate obtained above (15 g, 34.7 mmol, 1.0 equivalent) and 4M HCl (20 mL) were dissolved in 1,4-dioxane (100 mL) to obtain a solution. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to obtain the title compound (11.53 g, 100%). LC / MS (ESI) m / z 333.4 [M+H] + .

[0459] Step 3: (3S,6S,8R,10aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0460]

[0461] Under argon, N-(tert-butoxycarbonyl)-N-methyl-L-alanine (10.57 g, 52.0 mmol, 1.5 equiv), the intermediate obtained above (11.53 g, 34.7 mmol, 1.0 equiv), HATU (19.78 g, 52.0 mmol, 1.5 equiv) and DIEA (13.45 g, 104 mmol, 3.0 equiv) were dissolved in DCM (200 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 16 hours, saturated NaCl (50 mL) was added to the reaction mixture, and then extracted with dichloromethane (150 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (17.95 g, 100%) as a colorless oil. LC / MS(ESI)m / z 518.3[M+H] + .

[0462] Step 4: (3S,6S,8R,10aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-5-oxo-8-(vinyloxy)decahydropyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0463]

[0464] Under argon, the intermediate obtained above (0.22 g, 0.425 mmol, 1.0 equiv), ethoxyethylene (0.919 g, 12.75 mmol, 30 equiv), 1,10-phenanthroline (0.015 g, 0.085 mmol, 0.2 equiv) and Pd(OAc)2 (0.019 g, 0.085 mmol, 0.2 equiv) were dissolved in DCM (5 mL) to give a brown suspension. The reaction mixture was stirred at 50 ° C for 24 hours. Saturated NaCl (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-3% methanol / dichloromethane to give the title compound (0.15 g, 64.9%) as a yellow oil. LC / MS(ESI)m / z 544.4[M+H] + .

[0465] Step 5: (3S,6S,8R,10aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-8-ethoxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0466]

[0467] Under H2, the intermediate obtained above (0.15 g, 0.276 mmol, 1.0 eq.) and Pd / C (0.107 g, 0.552 mmol, 2 eq.) were dissolved in MeOH (15 mL) to give a suspension. The reaction mixture was stirred at 35 °C for 16 hours. The reaction mixture was filtered through celite and the filter cake was rinsed with ethyl acetate. The reaction mixture was concentrated to give the title compound (0.126 g, 100%). LC / MS (ESI) m / z 456.4 [M+H] + .

[0468] Step 6: tert-Butyl ((S)-1-(((3S,6S,8R,10aR)-8-ethoxy-3-(((R)-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0469]

[0470] Under argon, the intermediate obtained above (0.126 g, 0.277 mmol, 1.0 equiv), (R)-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-amine (0.069 g, 0.415 mmol, 1.5 equiv), HATU (0.158 g, 0.415 mmol, 1.5 equiv) and DIEA (0.107 g, 0.830 mmol, 3.0 equiv) were dissolved in DCM (15 mL) to give a yellow solution. The reaction mixture was stirred at room temperature for 16 hours. Saturated NaCl (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (0.167 g, 100%, 98% de) as a yellow oil. LC / MS(ESI)m / z603.6[M+H] + .

[0471] Step 7: (3S,6S,8R,10aR)-8-ethoxy-N-((R)-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-

[0472] 6-((S)-2-(methylamino)propionamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide

[0473]

[0474] According to the synthesis of Example 1, the title compound (36.2 mg) was obtained as a white solid. LC / MS (ESI) m / z 503.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.34(d,J=8.7Hz,1H),7.99(d,J=7.5Hz,1H),7.35(dd,J=8.3,6.2Hz,1H),6. 95(ddd,J=12.0,9.0,2.5Hz,2H),4.91(d,J=4.3Hz,1H),4.87–4.76(m,1H),4.27(t,J= 8.6Hz,1H),4.23–4.11(m,1H),4.04–3.92(m,1H),3.45–3.38(m,2H),2.92(q,J=6.9H z,1H),2.74(d,J=5.5Hz,2H),2.19(s,3H),2.15–1.53(m,15H),1.07(t,J=7.5Hz,6H).

[0475] Embodiment 26

[0476] (S)-N-((3S,6S,8R,10aR)-8-ethoxy-5-oxo-3-(7-phenyl-1H-benzo[d]imidazol-2-yl)decahydropyrrolo[1,2-a]azocine-6-yl)-2-(methylamino)propanamide (Compound No. 92)

[0477]

[0478] According to the synthesis of Example 16, the title compound (76.2 mg) was obtained as a white solid. LC / MS (ESI) m / z 504.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)12.50(d,1H),8.14(d,J=7.4Hz,1H),7.97–7.03(m,8H),5.14(dd,1H),4.89–4.72(m,1H),4.41–4.24(m,1H),4.16–3.41(m ,2H),2.94–2.78(m,2H),2.70(dd,J=8.9,7.1Hz,1H),2.40–2.30(m,2H),2.21–2.10(m,4H),2.02–1.61(m,7H),1.13–0.64(m,6H).

[0479] Embodiment 27

[0480] (3'S,6'S,10a'S)-6'-((S)-2-(methylamino)propionamido)-5'-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydro-5'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]azocine]-3'-carboxamide (Compound No. 97)

[0481]

[0482] Step 1: tert-butyl ((3'S,6'S,10a'S)-2,2-dibromo-5'-oxo-3'-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)octahydro-5'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]azocine]-6'-yl)carbamate

[0483]

[0484] The above scheme shows that the starting material (0.062 g, 0.133 mmol, 1.0 equiv), bromoform (0.268 g, 1.061 mmol, 8 equiv), NaOH (0.069 g, 1.724 mmol, 13 equiv) and N-benzyl-N,N-diethylethylamine chloride (6.04 mg, 0.027 mmol, 0.2 equiv) were dissolved in DCM (3 mL) under argon to give a colored solution. The reaction mixture was stirred at 40 °C for 24 hours. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (0.06 g, 70.8%) as a yellow oil. LC / MS (ESI) m / z 638.2 [M+H] + .

[0485] Step 2: tert-Butyl ((3'S,6'S,10a'S)-5'-oxo-3'-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)octahydro-5'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]azocine]-6'-yl)carbamate

[0486]

[0487] The intermediate obtained above (0.056 g, 0.088 mmol, 1.0 equiv), potassium hydroxide (0.029 g, 0.525 mmol, 6 equiv) and Pd / C (9.32 mg, 0.088 mmol, 1.0 equiv) were dissolved in 2-propanol (15 mL) under H2 to give a colored suspension. The reaction mixture was stirred at 70°C for 16 hours. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (0.01 g, 23.71%) as a colored oil. LC-MS (ESI) m / z 482.4 [M+H] + Step 3: (3'S, 6'S, 10a'S)-6'-amino-5'-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydro-5'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]azocine]-3'-carboxamide

[0488]

[0489] Under argon, the intermediate obtained above (0.025 g, 0.052 mmol, 1.0 equivalent) and 4M HCl (5 mL) were dissolved in 1,4-dioxane (5 mL) to give a colored solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title compound (0.020 g, 100%). LC / MS (ESI) m / z 382.4 [M+H]+ .

[0490] Step 4: tert-Butyl ((S)-1-oxo-1-(((3'S,6'S,10a'S)-5'-oxo-3'-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)octahydro-5'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]azocine]-6'-yl)amino)propan-2-yl)carbamate

[0491]

[0492] Under argon, the intermediate obtained above (0.03 g, 0.079 mmol, 1.0 equiv), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (0.048 g, 0.236 mmol, 3.0 equiv), DIEA (0.051 g, 0.393 mmol, 5.0 equiv) and HATU (0.060 g, 0.157 mmol, 2.0 equiv) were dissolved in DCM (15 mL) to give a colored solution. The reaction mixture was stirred at room temperature for 16 hours. H2O (30 mL) was added to the reaction mixture, followed by extraction with dichloromethane (50 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-5% methanol / dichloromethane to give the title compound (0.045 g, 100%) as a colored oil. LC / MS(ESI)m / z 567.6[M+H] + .

[0493] Step 5: (3'S, 6'S, 10a'S)-6'-((S)-2-(methylamino)propionamido)-5'-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)octahydro-5'H-spiro[cyclopropane-1,8'-pyrrolo[1,2-a]azocine]-3'-carboxamide

[0494]

[0495] According to the synthesis of Example 1, the title compound (7.8 mg) was obtained as a white solid. LC / MS (ESI) m / z 467.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ(ppm)8.28(d,J=8.7Hz,1H),8.04(d,J=7.1Hz,1H),7.37–7.27(m,1H),7.21–7.13(m,2H) ,7.12–7.05(m,1H),4.95(d,J=3.9Hz,1H),4.71–4.54(m,1H),4.31(dt,J=14.4,7.2Hz,2H) ,2.87(q,J=6.8Hz,1H),2.82–2.66(m,2H),2.24–1.53(m,15H),1.46(dd,J=15.2,8.8Hz,1H ), 1.31 (d, J = 16.5Hz, 2H), 1.08 (t, J = 8.5Hz, 3H), 0.48 (dd, J = 18.9, 9.8Hz, 2H), 0.37 (s, 2H).

[0496] Embodiment 28

[0497] (3S,6S,8R,10aR)-8-cyclopropyloxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 49)

[0498]

[0499] Step 1: tert-butyl methyl ((S)-1-oxo-1-(((3S,6S,8R,10aR)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-8-(vinyloxy)decahydropyrrolo[1,2-a]azocin-6-yl)amino)propan-2-yl)carbamate

[0500]

[0501] The above scheme shows that the starting material (1 g, 1.796 mmol, 1.0 equiv), ethoxyethylene (6.48 g, 90 mmol, 50 equiv), 1,10-phenanthroline (0.065 g, 0.359 mmol, 0.2 equiv) and Pd(OAc)2 (0.081 g, 0.359 mmol, 0.2 equiv) were dissolved in DCM (30 mL). The reaction mixture was stirred at 55 °C for 48 hours. H2O (100 mL) was added to the reaction mixture, followed by extraction with dichloromethane (50 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-5% methanol / dichloromethane to give the title compound (600 mg, 57.3%) as a colorless oil. LC / MS (ESI) m / z 583.4 [M+H] + .

[0502] Step 2: tert-Butyl ((S)-1-(((3S,6S,9S,10aR)-9-cyclopropyloxy-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0503]

[0504] Diiodomethane (1103 mg, 4.12 mmol, 4.0 equiv) and the intermediate obtained above (600 mg, 1.030 mmol, 1.0 equiv) were dissolved in DCM (5 mL). Diethylzinc (636 mg, 5.15 mmol, 5.0 equiv) was added to the reaction mixture at 0°C. The resulting mixture was stirred for 16 hours. Saturated NH4Cl (5 mL) was added to the reaction mixture, followed by extraction with dichloromethane (5 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-5% methanol / dichloromethane to give the title compound (300 mg, 48.8%) as a colorless oil. LC / MS (ESI) m / z 597.6[M+H] + .

[0505] Step 3: (3S,6S,9S,10aR)-9-cyclopropyloxy-N-((R)-6-fluoro-1,2,3,4-tetrahydronaphthalene-1-

[0506] 6-((S)-2-(methylamino)propionamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide

[0507]

[0508] According to the synthesis of Example 1, the title compound (40 mg) was obtained as a white solid. LC / MS (ESI) m / z 497.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.32(d,J=8.7Hz,1H),8.02(d,J=7.5Hz,1H),7.39–7.31(m,1H),7.19–7.02(m,3H) ,4.95(dd,J=12.3,8.0Hz,1H),4.87–4.74(m,1H),4.30(t,J=8.5Hz,1H),4.22–4.09(m,2H), 3.25(dq,J=9.2,3.1Hz,1H),2.93(q,J=6.8Hz,1H),2.82–2.64(m,2H),2.19(s,3H),2.15–2 .06(m,1H),2.04–1.80(m,9H),1.78–1.57(m,5H),1.09(d,J=6.8Hz,3H),0.53–0.32(m,4H).

[0509] Embodiment 29

[0510] (3S,6S,9S,10aR)-9-isopropoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 48)

[0511]

[0512] Step 1: tert-Butyl ((S)-1-(((3S,6S,9S,10aR)-9-isopropoxy-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0513]

[0514] The above scheme shows that the starting material (100 mg, 0.168 mmol, 1.0 equiv) and Pd / C (17.83 mg, 0.168 mmol, 1.0 equiv) were dissolved in MeOH (10 mL) under H2. The reaction mixture was stirred at 40 °C for 12 hours. The reaction mixture was filtered through celite and the filter cake was rinsed with MeOH (5 mL x 2). The organic layer was concentrated to give the title compound (40 mg, 39.9%) as a colorless oil. LC / MS (ESI) m / z 599.4 [M+H] + .

[0515] Step 2: (3S,6S,9S,10aR)-9-isopropoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0516]

[0517] According to the synthesis of Example 1, the title compound (10 mg) was obtained as a white solid. LC / MS (ESI) m / z 499.6 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.33(d,J=8.8Hz,1H),8.00(d,J=7.5Hz,1H),7.35(d,J=6.8Hz,1H),7.19–7.04( m,3H),4.94(d,J=4.2Hz,1H),4.86–4.74(m,1H),4.29(t,J=8.6Hz,1H),4.24–4.06(m,2H) ,3.57(dd,J=12.0,6.0Hz,1H),2.93(q,J=6.8Hz,1H),2.71(t,J=11.8Hz,2H),2.19(s,3H) ,2.16–1.78(m,10H),1.67(ddd,J=20.5,19.5,11.5Hz,5H),1.07(dd,J=11.7,6.0Hz,9H).

[0518] Embodiment 30

[0519] (3S,6S,7aS,8aR,9aR)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,7aR,8aS,9aR)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 101A and Compound No. 101B)

[0520]

[0521] Step 1: (3S,6S,9aR)-6-((tert-Butyloxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0522]

[0523] The raw materials shown in the above scheme were prepared according to the established scheme in Journal of Medicinal Chemistry (2010), Vol. 53, No. 17, pp. 6361-6367. The raw materials (0.3 g, 0.724 mmol, 1.0 equiv) and diazomethane (0.304 g, 7.24 mmol, 10 equiv) were dissolved in THF (10.00 mL) under argon to give a solution. The reaction mixture was cooled to -78°C with a dry ice / acetone bath. Pd(OAc)2 (0.049 g, 0.217 mmol, 0.3 equiv) was added to the reaction mixture in one portion. The reaction mixture was stirred at room temperature for 5 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-3% methanol / dichloromethane to give the title compound (0.26 g, 84%) as a colorless oil. LC / MS (ESI) m / z 429.3 [M+H] + .

[0524] Step 2: (3S,6S,9aR)-6-((tert-Butyloxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocine-3-carboxylic acid

[0525]

[0526] Under argon, the intermediate obtained above (0.26 g, 0.607 mmol, 1.0 equiv) and LiOH (0.073 g, 3.03 mmol, 5.0 equiv) were dissolved in water (2 mL) and THF (10 mL) to obtain a solution. The reaction mixture was stirred at room temperature for 16 hours. 1M HCl (5 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (0.205 g, 100%). LC / MS (ESI) m / z 339.3 [M+H] + .

[0527] Step 3: tert-Butyl ((3S,6S,9aR)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocin-6-yl)carbamate

[0528]

[0529] Under argon, the intermediate obtained above (0.205 g, 0.606 mmol, 1.0 equiv), (R)-1,2,3,4-tetrahydronaphthalene-1-amine (0.098 g, 0.666 mmol, 1.1 equiv), HATU (0.276 g, 0.727 mmol, 1.2 equiv) and DIPEA (0.157 g, 1.212 mmol, 2.0 equiv) were dissolved in DCM (20 mL) to give a solution. The reaction mixture was stirred at room temperature for 16 hours. H2O (30 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (0.283 g, 100%) as a colorless oil. LC / MS(ESI)m / z 468.4[M+H] + .

[0530] Step 4: (3S,6S,9aR)-6-amino-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocine-3-carboxamide

[0531]

[0532] Under argon, the intermediate obtained above (0.283 g, 0.605 mmol, 1.0 equiv) was dissolved in DCM (5 mL) and TFA (5 mL) to give a colored solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the title compound (0.222 g, 100%). LC / MS (ESI) m / z 368.3 [M+H] + .

[0533] Step 5: tert-butyl methyl ((2S)-1-oxo-1-(((3S,6S,9aR)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocin-6-yl)amino)propan-2-yl)carbamate

[0534]

[0535] Under argon, the intermediate obtained above (0.222 g, 0.604 mmol, 1.0 equiv), HATU (0.299 g, 0.785 mmol, 1.3 equiv), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (0.147 g, 0.725 mmol, 1.2 equiv) and DIEA (0.156 g, 1.208 mmol, 2.0 equiv) were dissolved in DCM (20 mL) to give a solution. The reaction mixture was stirred at room temperature for 16 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (0.334 g, 100%) as a colorless oil. LC / MS(ESI)m / z 553.4[M+H] + .

[0536] Step 6: (3S,6S,7aS,8aR,9aR)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,7aR,8aS,9aR)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocine-3-carboxamide

[0537]

[0538] According to the synthesis of Example 1, the crude product was purified by preparative HPLC to give the faster eluting isomer (peak 1, 40 mg) and the slower eluting isomer (peak 2, 12 mg) as a white solid. The absolute stereochemistry of the two cyclopropyl carbons has not yet been determined. LC / MS (ESI) m / z 453.3 [M+H] + .

[0539] Peak 1: 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.01(d,J=7.8Hz,1H),7.96(d,J=8.6Hz,1H),7.20(d,J=7.2Hz,1H),7.13(dd,J=10.6,4.0Hz,1H),7.09 –7.00(m,2H),4.96–4.86(m,1H),4.70(q,J=8.5Hz,1H),4.43(d,J=6.1Hz,1H),4.06(q,J=6.8Hz,1H),2.89(q,J= 6.8Hz,1H),2.71(td,J=17.0,9.2Hz,2H),2.17(s,3H),2.11–1.69(m,12H),1.58–1.44(m,1H),1.06(d,J=6.9Hz ,3H),0.84(dd,J=6.7,3.9Hz,1H),0.46(td,J=8.3,4.1Hz,1H),0.35–0.18(m,1H),-0.08(dd,J=9.8,4.9Hz,1H).

[0540] Peak 2: 1 H NMR (400 MHz, DMSO-d 6)δ(ppm)8.01(d,J=7.8Hz,1H),7.96(d,J=8.6Hz,1H),7.20(d,J=7.2Hz,1H),7.13(dd,J=10.6,4.0Hz,1H),7.09 –7.00(m,2H),4.96–4.86(m,1H),4.70(q,J=8.5Hz,1H),4.43(d,J=6.1Hz,1H),4.06(q,J=6.8Hz,1H),2.89(q,J= 6.8Hz,1H),2.71(td,J=17.0,9.2Hz,2H),2.17(s,3H),2.11–1.69(m,12H),1.58–1.44(m,1H),1.06(d,J=6.9Hz ,3H),0.84(dd,J=6.7,3.9Hz,1H),0.46(td,J=8.3,4.1Hz,1H),0.35–0.18(m,1H),-0.08(dd,J=9.8,4.9Hz,1H).

[0541] Embodiment 31

[0542] (3S,6S,8S,9S,10aR)-8-Hydroxy-9-methyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,8R,9R,10aR)-9-Hydroxy-8-methyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 98A and Compound No. 98B)

[0543]

[0544] Step 1: (1aS,3S,6S,8aR,9aR)-3-((tert-butoxycarbonyl)amino)-4-oxodecahydrocyclohexaspiro[2,3-d]pyrrolo[1,2-a]azocine-6-carboxylic acid benzyl ester

[0545]

[0546] The above scheme shows that the starting material (5.9 g, 14.23 mmol, 1.0 equiv), 1H-pyrazole (0.097 g, 1.423 mmol, 0.1 equiv), H2O2 (8.07 g, 71.2 mmol, 5.0 equiv) and methyltrioxorhenium (0.035 g, 0.142 mmol, 0.01 equiv) were dissolved in CF3CH2OH (60 mL) under argon to give a colored solution. The reaction mixture was stirred at room temperature for 12 hours. H2O (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-3% methanol / dichloromethane to give the title compound (5.7 g, 93%) as a colorless solid. LC / MS(ESI)m / z 431.3[M+H] + .

[0547] Step 2: (3S,6S,8S,9S,10aR)-6-amino-8-hydroxy-9-methyl-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0548]

[0549] Under argon, the intermediate obtained above (0.5 g, 1.161 mmol, 1.0 equiv) was dissolved in DCM (20 mL) to give a colored solution. The reaction mixture was cooled to 0 ° C with an ice / water bath. Trimethylaluminum (3.48 mmol, 3.0 equiv) was added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature for 72 hours. H2O (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (0.4 g, 99%). LC / MS (ESI) m / z 347.4 [M+H] + .

[0550] Step 3: (3S,6S,8S,9S,10aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-8-hydroxy-9-methyl-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0551]

[0552] Under argon, the intermediate obtained above (0.4 g, 1.155 mmol, 1.0 equiv), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (0.282 g, 1.386 mmol, 1.2 equiv), HATU (0.527 g, 1.386 mmol, 1.2 equiv) and DIEA (0.448 g, 3.46 mmol, 3.0 equiv) were dissolved in DCM (30 mL) to give a colored solution. The reaction mixture was stirred at room temperature for 16 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-3% methanol / dichloromethane to give the title compound (0.245 g, 39.9%) as a colored oil. LC / MS(ESI)m / z 532.7[M+H] + .

[0553] Step 4: (3S,6S,8S,9S,10aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-8-hydroxy-9-methyl-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0554]

[0555] The intermediate obtained above (0.245 g, 0.461 mmol, 1.0 equiv) and Pd / C (0.049 g, 0.461 mmol, 1.0 equiv) were dissolved in 2-propanol (15 mL) under H2 to give a colored suspension. The reaction mixture was stirred at 45 °C for 16 hours. The reaction mixture was filtered through celite and the filter cake was rinsed with dichloromethane. The reaction mixture was concentrated to give the title compound (0.203 g, 100%). LC / MS (ESI) m / z 442.6 [M+H] + .

[0556] Step 5: tert-butyl ((S)-1-(((3S,6S,8S,9S,10aR)-8-hydroxy-9-methyl-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0557]

[0558] Under argon, the intermediate obtained above (0.203 g, 0.460 mmol, 1.0 equiv), (R)-1,2,3,4-tetrahydronaphthalene-1-amine (0.088 g, 0.598 mmol, 1.3 equiv), HATU (0.227 g, 0.598 mmol, 1.3 equiv) and DIEA (0.149 g, 1.149 mmol, 2.5 equiv) were dissolved in DCM (15 mL) to give a colored solution. The reaction mixture was stirred at room temperature for 16 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (0.205 g, 78%) as a colored oil. LC / MS(ESI)m / z 571.5[M+H] + .

[0559] Step 6: (3S,6S,8S,9S,10aR)-8-Hydroxy-9-methyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,8R,9R,10aR)-9-Hydroxy-8-methyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0560]

[0561] Following the synthesis of Example 1, the crude product was purified by preparative HPLC to give the faster eluting isomer (peak 1, 6.8 mg) and the slower eluting isomer (peak 2, 4.5 mg) as a white solid. The absolute stereochemistry of the chiral hydroxyl and methyl-attached carbons has not been determined. LC / MS (ESI) m / z 471.4 [M+H] + .

[0562] Embodiment 32

[0563] (3S,6S,8S,9S,10aR)-8-ethoxy-9-methyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,8R,9R,10aR)-9-ethoxy-8-methyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 100A and Compound No. 100B)

[0564]

[0565] According to the synthesis of Example 12, the crude product was purified by preparative HPLC to give a faster eluting isomer (peak 1, 100A, 62 mg) and a slower eluting isomer (peak 2, 100B, 8 mg) as a white solid. LC / MS (ESI) m / z 498.4 [M+H] + .

[0566] 100A: 1 H NMR(400MHz, DMSO-d6)δ(ppm)8.32(d,J=8.7Hz,1H),8.19(d,J=9.2Hz,2H),7.37–7.31(m,1H),7.20 –7.03(m,3H),4.99–4.86(m,1H),4.78–4.65(m,1H),4.30(t,J=8.0Hz,2H),3.58–3.37(m,3H),3.15–

[0567] 3.07(m,1H),2.82–2.62(m,2H),2.27(s,3H),2.22–1.80(m,8H),1.80–1.57(m,3H),1 .57–1.39(m,2H),1.15(d,J=6.9Hz,3H),1.09(t,J=7.0Hz,3H),0.97(d,J=7.2Hz,3H).

[0568] 100B: 1H NMR(400MHz, DMSO-d6)δ(ppm)8.32(d,J=8.7Hz,1H),8.20(s,1H),8.10(d,J=7.5Hz,1H),7.38–7.29(m,1H) ,7.20–7.03(m,3H),4.99–4.89(m,1H),4.86–4.74(m,1H),4.31(t,J=8.3Hz,1H),4.26–4.17(m,1H),3.97– 3.86(m,1H),3.48–3.42(m,1H),3.34–3.28(m,1H),3.05(q,J=6.8Hz,1H),2.84–2.64(m,2H),2.23(s,3H), 2.14–1.79(m,8H),1.79–1.51(m,5H),1.12(d,J=6.8Hz,3H),1.06(t,J=7.0Hz,3H),0.96(d,J=6.8Hz,3H).

[0569] Embodiment 33

[0570] (3S,6S,7aS,8aR,9aR)-8,8-difluoro-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 102)

[0571]

[0572] Step 1: (3S,6S,7aS,8aR,9aR)-6-(1,3-dioxoisoindolin-2-yl)-8,8-difluoro-5-oxodecahydro-1H-cyclopropane[d]pyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0573]

[0574] The above scheme shows that the starting material (0.5 g, 1.125 mmol, 1.0 equiv), trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl) acetate (0.563 g, 2.250 mmol, 2.0 equiv) and sodium fluoride (0.047 g, 1.125 mmol, 1.0 equiv) were dissolved in toluene (10 mL) under argon to give a colored solution. The reaction mixture was stirred at 110°C for 12 hours. Saturated NaHCO3 (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-3% methanol / dichloromethane to give the title compound (0.2 g, 36.0%) as a colorless oil. LC / MS (ESI) m / z 495.3 [M+H] + .

[0575] Step 2: (3S,6S,7aS,8aR,9aR)-6-amino-8,8-difluoro-5-oxodecahydro-1H-cyclopropane[d]pyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0576]

[0577] Under argon, the intermediate obtained above (0.2 g, 0.404 mmol, 1.0 equiv) and hydrazine (0.049 g, 1.213 mmol, 3.0 equiv) were dissolved in MeOH (10 mL) to give a colored solution. The reaction mixture was stirred at room temperature for 2 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (0.147 g, 100%). LC / MS (ESI) m / z 365.3 [M+H] + .

[0578] Step 3: (3S,6S,7aS,8aR,9aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-8,8-difluoro-5-oxodecahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0579]

[0580] Under argon, the intermediate obtained above (0.147 g, 0.403 mmol, 1.0 equiv), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (0.107 g, 0.524 mmol, 1.3 equiv), HATU (0.230 g, 0.605 mmol, 1.5 equiv) and DIEA (0.156 g, 1.210 mmol, 3.0 equiv) were dissolved in DCM (15 mL) to give a colorless solution. The reaction mixture was stirred at room temperature for 16 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-3% methanol / dichloromethane to give the title compound (0.22 g, 99%) as a colorless oil. LC / MS(ESI)m / z 550.6[M+H] + .

[0581] Step 4: (3S,6S,7aS,8aR,9aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-8,8-difluoro-5-oxodecahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocine-3-carboxylic acid

[0582]

[0583] Under argon, the intermediate obtained above (0.22 g, 0.400 mmol, 1.0 equiv) and LiOH (0.048 g, 2.001 mmol, 5 equiv) were dissolved in water (2 mL) and THF (10 mL) to give a colorless solution. The reaction mixture was stirred at room temperature for 16 hours. 1M HCl (3 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the title compound (0.184 g, 100%). LC / MS (ESI) m / z 460.7 [M+H] + .

[0584] Step 5: tert-Butyl ((S)-1-(((3S,6S,7aS,8aR,9aR)-8,8-difluoro-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0585]

[0586] Under argon, the intermediate obtained above (0.184 g, 0.400 mmol, 1.0 equiv), (R)-1,2,3,4-tetrahydronaphthalene-1-amine (0.071 g, 0.481 mmol, 1.2 equiv), HATU (0.228 g, 0.601 mmol, 1.5 equiv) and DIEA (0.155 g, 1.201 mmol, 3.0 equiv) were dissolved in DCM (20 mL) to give a colored solution. The reaction mixture was stirred at room temperature for 16 hours. H2O (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL×2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-4% methanol / dichloromethane to give the title compound (0.07 g, 29.7%) as a colorless oil. LC / MS(ESI)m / z 589.4[M+H] + .

[0587] Step 6: (3S,6S,7aS,8aR,9aR)-8,8-difluoro-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydro-1H-cyclopropano[d]pyrrolo[1,2-a]azocine-3-carboxamide

[0588]

[0589] According to the synthesis of Example 1, the title compound (20 mg) was obtained as a white solid. LC / MS (ESI) m / z 489.4 [M+H] + .

[0590] Embodiment 34

[0591] (3S,6S,8R,10aS)-8-Acetamido-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,8S,10aS)-8-Acetamido-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 28A and Compound No. 28B)

[0592]

[0593] Step 1: tert-Butyl ((2S)-1-(((3S,6S,10aS)-8-acetamido-5-oxo-3-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0594]

[0595] The above scheme shows that the starting material (150 mg, 0.270 mmol, 1.0 equiv), DIPEA (52.3 mg, 0.405 mmol, 1.5 equiv) and acetyl chloride (22.25 mg, 0.283 mmol, 1.05 equiv) were dissolved in DCM (5 mL). The reaction was stirred for 2 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-5% MeOH / DCM to give the title compound (145 mg, 90%) as a colorless oil. LC / MS (ESI) m / z 599.0 [M+H] + .

[0596] Step 2: (3S,6S,8R,10aS)-8-Acetamido-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,8S,10aS)-8-Acetamido-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((S)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0597]

[0598] The crude product was purified by preparative HPLC following the synthesis of Example 1 to give the faster eluting isomer (peak 1, 5.6 mg, 4.6%) and the slower eluting isomer (peak 2, 18.4 mg, 15.2%) as a white solid. The absolute stereochemistry of the tertiary carbon has not been determined.

[0599] Peak 1: 1 H NMR (400 MHz, DMSO-d 6)δ(ppm)8.68(d,J=8.7Hz,1H),8.48(d,J=9.1Hz,1H),8.08(d,J=7.4Hz,1H),7.41–7. 34(m,1H),7.24–7.05(m,3H),5.05–4.96(m,1H),4.85–4.75(m,1H),4.40–4.16(m,3H ),3.41–3.36(m,1H),2.94(q,J=6.8Hz,1H),2.84–2.68(m,2H),2.21(s,3H),2.18–1. 97(m,5H),1.96–1.87(m,3H),1.86(s,3H),1.83–1.62(m,6H),1.10(d,J=6.8Hz,3H). LC / MS(ESI)m / z 499.0[M+H] + .

[0600] Peak 2: 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.31(d,J=8.7Hz,1H),8.06(d,J=7.7Hz,1H),7.81(d,J=6.8Hz,1H),7.40–7.33(m, 1H),7.19–7.06(m,3H),5.01–4.92(m,1H),4.91–4.84(m,1H),4.31(t,J=8.3Hz,1H),4.24–

[0601] 4.07(m,2H),3.41–3.38(m,1H),2.96(q,J=6.8Hz,1H),2.82–2.66(m,2H),2.21(s,3H),2. 16–1.96(m,4H),1.97–1.78(m,7H),1.77(s,3H),1.76–1.58(m,3H),1.11(d,J=6.8Hz,3H). LC / MS(ESI)m / z 499.0[M+H] + .

[0602] Embodiment 35

[0603] (3S,6S,10aR)-8,8-difluoro-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 59)

[0604]

[0605] Step 1: tert-Butyl ((3S,6S,10aR)-8,8-difluoro-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0606]

[0607] The intermediate shown (300 mg, 0.639 mmol, 1.0 eq) was dissolved in DCM (10 mL). BAST (1413 mg, 6.39 mmol, 10.0 eq) was added to the mixture at 0 ° C, the mixture was stirred at 45 ° C for 14 hours and cooled to room temperature. Water was added to the reaction mixture, followed by extraction with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-2% methanol / dichloromethane to give the title compound (150 mg, 47.8%) as a light yellow solid. LC / MS (ESI) m / z 492.5 [M+H] + .

[0608] Step 2-4: According to the synthesis of Example 13, the title compound (9.4 mg) was obtained as a white solid. LC / MS (ESI) m / z 477.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.38(d,J=8.6Hz,1H),8.23(d,J=7.1Hz,1H),7.37–7.30(m,1H),7.23–7.15(m,2H) ,7.15–7.08(m,1H),5.00–4.90(m,1H),4.86–4.74(m,1H),4.35(t,J=8.6Hz,1H),4.30–4.1 7(m,1H),3.40–3.36(m,1H),2.96(q,J=6.8Hz,1H),2.84–2.70(m,2H),2.40–2.28(m,1H),2 .23(s,3H),2.22–1.98(m,5H),1.96–1.78(m,4H),1.77–1.58(m,4H),1.14(d,J=6.9Hz,3H).

[0609] Embodiment 36

[0610] (3S,6S,8R,10aS)-8-(2-methoxyethyl)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,8S,10aS)-8-(2-methoxyethyl)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 66A and Compound No. 66B)

[0611]

[0612] Step 1: Ethyl (Z)-2-((3S,6S,10aS)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)octahydropyrrolo[1,2-a]azocine-8(5H)-ylidene)acetate

[0613]

[0614] Potassium 2-methylpropan-2-olate (0.303 g, 2.70 mmol, 1.5 equiv) and ethyl 2-(diethoxyphosphoryl)acetate (0.606 g, 2.70 mmol, 1.5 equiv) were dissolved in THF (10 mL). The reactants were stirred for 30 minutes. The raw material (1 g, 1.803 mmol, 1.0 equiv) was added to the reaction mixture. The resulting mixture was stirred for 12 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-50% PE / EA to give the title compound (1 g, 89%) as a colorless oil. LC / MS (ESI) m / z 625.6 [M+H] + .

[0615] Step 2: Ethyl 2-((3S,6S,10aS)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-8-yl)acetate

[0616]

[0617] The intermediate obtained above (1 g, 1.80 mmol, 1.0 equiv) and Pd / C (192 mg, 1.80 mmol, 1.0 equiv) were dissolved in MeOH (10 mL) under H2. The reactants were stirred at 40°C for 3 hours. The reaction mixture was filtered through celite and the filter cake was rinsed with MeOH. The organic layer was concentrated to give the title compound (0.7 g, 70%). LC / MS (ESI) m / z 627.6 [M+H] + .

[0618] Step 3: 2-((3S,6S,10aS)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-8-yl)acetic acid

[0619]

[0620] The intermediate obtained above (0.7 g, 1.117 mmol, 1.0 equiv) and LiOH (0.107 g, 4.47 mmol, 4.0 equiv) were dissolved in THF (5 mL) and water (5 mL). Then stirred at room temperature for 14 hours. The reaction mixture was adjusted to pH 7 with 1M HCl. The reaction mixture was diluted with ethyl acetate and then washed with H2O, saturated NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (600 mg, 90%) as a white solid. LC / MS (ESI) m / z 599.5 [M+H] + . Step 4: tert-Butyl ((2S)-1-(((3S,6S,10aS)-8-(2-hydroxyethyl)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0621]

[0622] The intermediate obtained above (600 mg, 1.002 mmol, 1.0 equiv) was dissolved in THF (10 mL). BH3·DMS (152 mg, 2.004 mmol, 2.0 equiv) was added to the reaction mixture at 0°C. The reactants were stirred for 2 hours. MeOH was added to the reaction mixture and then concentrated. The crude product was added to a silica gel column and eluted with 0%-5% MeOH / DCM to give the title compound (180 mg, 30.7%) as a white solid. LC / MS (ESI) m / z 585.6 [M+H]+ .

[0623] Step 5: tert-Butyl ((2S)-1-(((3S,6S,10aS)-8-(2-methoxyethyl)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0624]

[0625] The intermediate obtained above (180 mg, 0.308 mmol, 1.0 equiv) was dissolved in THF (10 mL). Sodium hydride (29.5 mg, 1.231 mmol, 4.0 equiv) was added to the reaction mixture at 0 ° C. The resulting mixture was stirred for 0.5 hours. Iodomethane (65.5 mg, 0.462 mmol, 1.5 equiv) was added to the reaction mixture. The mixture was stirred for 8 hours. H2O was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-5% MeOH / DCM to give the title compound (110 mg, 59.7%) as a white solid. LC / MS (ESI) m / z 599.8[M+H] + .

[0626] Step 6: (3S,6S,8R,10aS)-8-(2-methoxyethyl)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,8S,10aS)-8-(2-methoxyethyl)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0627]

[0628] The crude product was purified by preparative HPLC following the synthesis of Example 1 to give the faster eluting isomer (Peak 1, 38.6 mg) and the slower eluting isomer (Peak 2, 4 mg) as white solids.

[0629] Peak 1: LC / MS(ESI)m / z 499.9[M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ(ppm)8.30(d,J=8.7Hz,1H),7.98(d,J=7.6Hz,1H),7.40–7.33(m,1H),7.22–7.08(m,3H),5.00– 4.92(m,1H),4.91–4.83(m,1H),4.33(t,J=8.1Hz,1H),4.20(dd,J=11.7,6.9Hz,1H),3.45–3.38(m ,1H),3.32(t,J=7.2Hz,2H),3.22(s,3H),2.95(q,J=6.9Hz,1H),2.84–2.67(m,2H),2.22(s,3H),2 .19–1.99(m,3H),1.92–1.80(m,4H),1.77–1.58(m,8H),1.58–1.39(m,2H),1.11(d,J=6.8Hz,3H).

[0630] Peak 2: LC / MS(ESI)m / z 499.9[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.32(d,J=8.7Hz,1H),8.12(d,J=7.3Hz,1H),7.41–7.34(m,1H),7.21–7.09 (m,3H),5.00–4.90(m,1H),4.61–4.52(m,1H),4.35–4.21(m,2H),3.46–3.38(m,3H) ,3.25(s,3H),2.92(q,J=6.8Hz,1H),2.83–2.68(m,2H),2.22(s,3H),2.19–2.10(m, 1H), 2.08–1.84 (m, 5H), 1.82–1.59 (m, 7H), 1.54–1.29 (m, 4H), 1.13 (d, J = 6.8Hz, 3H).

[0631] Embodiment 37

[0632] (3S,6S,8R,10aS)-8-Ethyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0633] and (3S,6S,8S,10aS)-8-ethyl-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 95A and Compound No. 95B)

[0634]

[0635] Step 1: (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-8-ethyl-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0636]

[0637] The key intermediate II (1.0 g, 2.32 mmol, 1.0 equiv) was dissolved in ether (5 mL). Ethylmagnesium bromide (1.238 g, 9.29 mmol, 4.0 equiv) was added to the reaction mixture at 0°C. The reactants were stirred for 2 hours. Saturated NH4Cl was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with 0%-40% PE / EA to give the title compound (800 mg, 74.8%) as a colorless oil. LC / MS (ESI) m / z 461.7 [M+H] + .

[0638] Step 2: (3S,6S,10aS,Z)-6-((tert-butoxycarbonyl)amino)-8-ethylidene-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid benzyl ester

[0639]

[0640] The intermediate obtained above (800 mg, 1.737 mmol, 1.0 equiv) and Burgess reagent (1656 mg, 6.95 mmol, 4.0 equiv) were dissolved in toluene (10 mL). The reaction was stirred at 75 ° C for 2 hours and concentrated. The crude product was added to a silica gel column and eluted with 0%-40% PE / EA to give the title compound (600 mg, 78%) as a colorless oil. LC / MS (ESI) m / z 443.6 [M+H] + .

[0641] Step 3: (3S,6S,10aS)-6-((tert-butoxycarbonyl)amino)-8-ethyl-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0642]

[0643] The intermediate obtained above (600 mg, 1.356 mmol, 1.0 equiv) and Pd / C (289 mg, 2.71 mmol, 2.0 equiv) were dissolved in MeOH (40 mL) under H2. The reaction was stirred at 40 °C for 12 hours. The reaction mixture was filtered through celite and the filter cake was rinsed with MeOH. The organic layer was concentrated to give the title compound (480 mg, 100%) as a colorless oil. LC / MS (ESI) m / z 355.2 [M+H] + .

[0644] Step 4-7: According to the synthesis of Example 1, the crude product was purified by preparative HPLC to obtain a faster eluting isomer (peak 1, 28.2 mg) and a slower eluting isomer (peak 2, 98.5 mg) as a white solid. LC / MS (ESI) m / z 469.9 [M+H] + .

[0645] Peak 1: 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.29(d,J=8.7Hz,1H),7.99(d,J=7.7Hz,1H),7.36(dd,J=6.9,2.2Hz,1H),7.19–7.08(m,3H),4.99–

[0646] 4.93(m,1H),4.92–4.83(m,1H),4.33(t,J=8.1Hz,1H),4.25–4.16(m,1H ),3.44–3.40(m,1H),2.95(q,J=6.8Hz,1H),2.80–2.70(m,2H),2.22(s,3 H),2.15–1.98(m,3H),1.94–1.81(m,4H),1.78–1.58(m,7H),1.56–1.41 (m,2H),1.30–1.14(m,1H),1.11(d,J=6.8Hz,3H),0.85(t,J=7.3Hz,3H).

[0647] Peak 2: 1 H NMR (400 MHz, DMSO-d 6 )δ(ppm)8.33(d,J=8.7Hz,1H),8.13(d,J=7.2Hz,1H),7.38(dd,J=6.3,2.7Hz,1H),7.19–7.09(m,3H),4.99–

[0648] 4.19(m,1H),4.57(t,J=8.9Hz,1H),4.34–4.24(m,2H),3.44–3.40(m,1H),2.92(q,J=6.8Hz,1H),2.82–2.67(m,2H),2.22(s,3H),2.21– 2.10(m,1H),2.08–1.84(m,4H),1.81–1.59(m,6H),1.55–1.38(m,3H),1.39–1.19(m,3H),1.13(d,J=6.8Hz,3H),0.88(t,J=7.3Hz,3H).

[0649] Embodiment 38

[0650] (3S,6S,10aR)-9-(methoxymethyl)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide and (3S,6S,9R,10aR)-9-(methoxymethyl)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 43A and Compound No. 43B)

[0651]

[0652] Step 1: tert-Butyl ((3S,6S,10aR,Z)-9-(methoxymethylene)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0653]

[0654] Chloro(methoxymethyl)triphenyl-15-phosphane (917 mg, 2.67 mmol, 2.0 equiv) was dissolved in THF (15 mL). Potassium 2-methylpropan-2-ol (300 mg, 2.67 mmol, 2.0 equiv) was added to the reaction mixture at 0°C and Ar. The reaction mixture was stirred at 0°C for 30 minutes. The starting material (628 mg, 1.337 mmol, 1.0 equiv) was added and the mixture was stirred under Ar and 0°C for 3 hours. After 16 hours, water (60 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with PE / EA (2 / 1) to give the title compound (599 mg, 90%) as an off-white solid. LC / MS (ESI) m / z 489.5 [M+H] + .

[0655] Step 2: tert-Butyl ((3S,6S,10aR)-9-(methoxymethyl)-5-oxo-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0656]

[0657] The intermediate obtained above (256 mg, 0.514 mmol, 1.0 eq) was dissolved in ethyl acetate (15 mL). 10% Pd / C (1 g, 8.44 mmol, 16.41 eq) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 30 °C for 5 hours under H2. After concentration, the crude product was added to a silica gel column and eluted with PE / EA (1 / 1) to obtain the separated isomers, which were used in the following steps respectively: the faster eluting isomer (123 mg, 47.9% yield), LC / MS (ESI) m / z 500.5 [M+H] + ; Slower eluting isomer (113 mg, 44% yield), LC / MS (ESI) m / z 500.5 [M+H] + .

[0658] Step 3-5: According to the synthesis of Example 1, the title compounds 43A and 43B were obtained from each of the isomers obtained above after purification by preparative HPLC.

[0659] 43A, 38.2mg: LC / MS(ESI)m / z 486.0[M+H] + . 1H NMR(400MHz,DMSO-d6)δ(ppm)8.30(d,J=8.7Hz,1H),8.11(d,J=7.2Hz,1H),7.4 0–7.29(m,1H),7.22–7.06(m,3H),5.03–4.86(m,1H),4.62–4.49(m,1H),4.42–

[0660] 4.26(m,2H),3.24(s,3H),3.22–3.15(m,1H),3.14–3.07(m,1H),2.97–2.89(m,1H),2.82–2.68(m,2H),2.22(s,3H),2 .19–2.11(m,1H),2.10–1.81(m,6H),1.79–1.59(m,5H),1.54–1.34(m,2H),1.30–1.19(m,1H),1.12(d,J=6.8Hz,3H).

[0661] 43B, 22.2mg: LC / MS(ESI)m / z 486.0[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.29(d,J=8.6Hz,1H),7.93(d,J=7.7Hz,1H),7.3 7–7.24(m,1H),7.19–7.01(m,3H),5.03–4.87(m,1H),4.87–4.70(m,1H),4.36–

[0662] 4.27(m,1H),4.27–4.12(m,1H),3.23(s,3H),3.15–3.01(m,2H),3.00–2.86(m,1H),2.83–2.61(m, 2H), 2.18 (s, 3H), 2.15–1.94 (m, 3H), 1.90–1.50 (m, 11H), 1.41–1.22 (m, 1H), 1.08 (d, J = 6.8Hz, 3H).

[0663] Embodiment 39

[0664] (3S,6S,10aR)-8-ethoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-(4-phenyl-1,2,3-thiadiazol-5-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 71)

[0665]

[0666] Step 1: (3S,6S,10aR)-8-ethoxy-6-((S)-2-(methylamino)propionamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0667]

[0668] The above scheme shows that the starting material (500 mg, 1.098 mmol, 1.0 equiv) was dissolved in dioxane (5 mL) under nitrogen. A 4M HCl solution in dioxane (5 mL) was added to the reaction mixture at 25°C. The reaction mixture was stirred at 25°C for 3 hours. After concentration, a 7M NH3 solution in CH3OH was added. After concentration, the title compound (390 mg, 100%) was obtained as a white solid. LC / MS (ESI) m / z 356.3 [M+H] + .

[0669] Step 2: (3S,6S,10aR)-6-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)propionamido)-8-ethoxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0670]

[0671] The intermediate obtained above (390 mg, 1.097 mmol, 1.0 equiv) was dissolved in dioxane (15 mL) and water (3 mL). Na2CO3 (349 mg, 3.29 mmol, 3.0 equiv) and (9H-fluorene-9-yl)methyl chloroformate (426 mg, 1.646 mmol, 1.5 equiv) were added at 0°C. After 16 hours, water (60 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:10) to give the title compound (500 mg, 79%) as an off-white solid. LC / MS (ESI) m / z 578.4 [M+H] + .

[0672] Step 3: (9H-fluoren-9-yl)methyl((2S)-1-(((3S,6S,10aR)-3-(chlorocarbonyl)-8-ethoxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0673]

[0674] Under nitrogen, the intermediate obtained above (150 mg, 0.260 mmol, 1.0 equiv) was dissolved in CH2Cl2 (15 mL). Oxalyl chloride (65.9 mg, 0.519 mmol, 2.0 equiv) and N,N-dimethylformamide (0.949 mg, 0.013 mmol, 0.05 equiv) were added to the reaction mixture at 0°C. After stirring at 25°C for 5 hours, the reaction mixture was concentrated to give the title compound (155 mg, 100%) as an off-white solid.

[0675] Step 4: (9H-fluoren-9-yl)methyl((2S)-1-(((3S,6S,10aR)-8-ethoxy-5-oxo-3-((4-phenyl-1,2,3-thiadiazol-5-yl)carbamoyl)decahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0676]

[0677] Under nitrogen, 4-phenyl-1,2,3-thiadiazole-5-amine (55.3 mg, 0.312 mmol, 1.2 equiv) and pyridine (103 mg, 1.300 mmol, 5.0 equiv) were dissolved in CH2Cl2 (15 mL). The intermediate obtained above (155 mg, 0.260 mmol, 1.0 equiv) was added to the reaction mixture at 0°C. After stirring at 25°C for 16 hours, water (60 mL) was added to the reaction mixture, followed by extraction with dichloromethane (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:20) to give the title compound (80 mg, 41.8%) as an off-white solid. LC / MS (ESI) m / z 737.4[M+H] + .

[0678] Step 5: (3S,6S,10aR)-8-ethoxy-6-((S)-2-(methylamino)propionamido)-5-oxo-N-(4-phenyl-1,2,3-thiadiazol-5-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide

[0679]

[0680] Under nitrogen, the intermediate obtained above (80 mg, 0.109 mmol, 1.0 equiv) was dissolved in MeOH (10 mL). Piperidine (92 mg, 1.086 mmol, 10 equiv) was added to the reaction mixture at 25 °C. After stirring at 25 °C for 16 hours, the reaction mixture was concentrated and the crude residue was purified by preparative HPLC to give the title compound (10.6 mg, 18.97%) as a white solid. LC / MS (ESI) m / z 515.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.24 (d, J = 6.5 Hz, 1H), 8.20–8.02 (m, 1H), 7.57–7.44 (m, 2H), 7.44–7.30 (m, 1H), 4.87–4.67 (m, 2H), 4.28–4.16 ( m,1H),4.06–3.95(m,1H),3.43–3.38(m,2H),2.31(s,3H),2.25–1.79( m,8H),1.77–1.58(m,3H),1.17(d,J=6.8Hz,3H),1.12(t,J=6.9Hz,3H).

[0681] Embodiment 40

[0682] (3S,6S,10aR)-8-ethoxy-6-((S)-2-(methylamino)propionamido)-N-(2-(oxazol-2-yl)-4-phenylthiazol-5-yl)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 70)

[0683]

[0684] Step 1: 2-(Oxazol-2-yl)-4-phenylthiazol-5-amine

[0685]

[0686] Under nitrogen, 2-amino-2-phenylacetonitrile hydrochloride (2.61g, 15.45mmol, 1.0 equivalent) and oxazole-2-carboxaldehyde (1.5g, 15.45mmol, 1.0 equivalent) were dissolved in ethanol (15mL). At 25°C, sulfur (0.495g, 15.45mmol, 1.0 equivalent) and triethylamine (2.345g, 23.18mmol, 1.5 equivalent) were added to the reaction mixture. After stirring at 50°C for 1 hour, hydroxylamine (0.868g, 26.3mmol, 1.7 equivalent) was added at room temperature. The mixture was stirred at room temperature for 16 hours. After concentration, saturated NaHCO3 (aqueous solution) (60mL) was added, followed by extraction with ethyl acetate (15mL×3). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:20) to give the title compound (380 mg, 10.11%) as a yellow solid. LC / MS (ESI) m / z 244.0 [M+H] + .

[0687] Step 2-3: According to the synthesis of Example 39, the title compound (8.7 mg) was obtained as a white solid. LC / MS (ESI) m / z 581.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.30(s,1H),8.17–8.01(m,1H),7.91–7.70(m,2H),7.55–7.35(m,4H),4.90–4.73(m,1H),4.73–4.58(m,1H),4.33–4 .15(m,1H),3.97–3.81(m,1H),3.45–3.40(m,2H),3.11–2.97(m,1H),2.3 1–2.14(m,4H),2.15–1.80(m,6H),1.79–1.61(m,3H),1.18–1.06(m,6H).

[0688] Embodiment 41

[0689] (2S)-N-((3S,6S,10aR)-3-((3-acetyl-5-chloro-1H-indol-1-yl)methyl)-8-ethoxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)-2-(methylamino)propanamide (Compound No. 72)

[0690]

[0691] Step 1: tert-Butyl ((2S)-1-(((3S,6S,10aR)-8-ethoxy-3-(hydroxymethyl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0692]

[0693] The above scheme shows that the starting material (300 mg, 0.659 mmol, 1.0 equiv) was dissolved in THF (15 mL) under nitrogen. 1M BH3-THF (566 mg, 6.59 mmol, 10 equiv) was added at 0°C. The mixture was stirred at 0°C for 30 minutes and then at room temperature for 16 hours. Water (60 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:10) to give the title compound (130 mg, 44.7%) as an off-white solid. LC / MS (ESI) m / z 442.4[M+H] + .

[0694] Step 2: ((3S,6S,10aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-8-ethoxy-5-oxodecahydropyrrolo[1,2-a]azocin-3-yl)methyl 4-methylbenzenesulfonate

[0695]

[0696] Under nitrogen, the intermediate obtained above (130 mg, 0.294 mmol, 1.0 equiv) was dissolved in THF (15 mL). Sodium hydride (14.13 mg, 0.589 mmol, 2.0 equiv) was added at 0°C. The mixture was stirred at 0°C for 1 hour. 4-Methylbenzenesulfonyl chloride (112 mg, 0.589 mmol, 2.0 equiv) was added at 0°C. After stirring at room temperature for 16 hours, water (60 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:10) to give the title compound (80 mg, 45.6%) as an off-white solid. LC / MS (ESI) m / z 596.4[M+H] +Step 3: tert-Butyl ((2S)-1-(((3S,6S,10aR)-3-((3-acetyl-5-chloro-1H-indol-1-yl)methyl)-8-ethoxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0697]

[0698] Under nitrogen, the intermediate obtained above (80 mg, 0.134 mmol, 1.0 equiv) was dissolved in DMA (15 mL). Cs2CO3 (88 mg, 0.269 mmol, 2.0 equiv) and 1-(5-chloro-1H-indol-3-yl)ethan-1-one (52.0 mg, 0.269 mmol, 2.0 equiv) were added at 25 ° C. After stirring at 80 ° C for 16 hours, water (60 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:10) to give the title compound (28 mg, 33.8%) as an off-white solid. LC / MS (ESI) m / z 617.5 [M+H] + .

[0699] Step 4: (2S)-N-((3S,6S,10aR)-3-((3-acetyl-5-chloro-1H-indol-1-yl)methyl)-8-ethoxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)-2-(methylamino)propanamide

[0700]

[0701] According to the synthesis of Example 1, the title compound (3.0 mg) was obtained as a white solid. LC / MS (ESI) m / z 517.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ (ppm) 8.54 (s, 1H), 8.18 (d, J = 1.9 Hz, 1H), 8.12 (d, J = 6 .9Hz,1H),7.84(d,J=8.8Hz,1H),7.44–7.30(m,1H),4.93–4.81(m,1H),4.82– 4.69(m,1H),4.45–4.29(m,1H),4.27–4.12(m,2H),3.41–3.36(m,2H),3.06–2 .91(m,1H),2.46(s,3H),2.25(s,3H),2.12–1.56(m,11H),1.17–1.01(m,6H).

[0702] Embodiment 42

[0703] (S)-N-((3S,6S,8R,10aR)-8-ethoxy-3-(4-(4-fluorobenzoyl)thiazol-2-yl)-5-oxodecahydropyrrolo[1,2-a]azocine-6-yl)-2-(methylamino)propanamide (Compound No. 73)

[0704]

[0705] Step 1: tert-butyl ((S)-1-(((3S,6S,8R,10aR)-3-carbamoyl-8-ethoxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0706]

[0707] The above scheme shows that the raw material (500 mg, 1.098 mmol, 1.0 equiv) and di-tert-butyl dicarbonate (359 mg, 1.646 mmol, 1.5 equiv) were dissolved in CH2Cl2 (15 mL) under nitrogen. NH4HCO3 (260 mg, 3.29 mmol, 3.0 equiv) and pyridine (87 mg, 1.098 mmol, 1.0 equiv) were added to the reaction mixture at 25°C. After stirring for 16 hours at 25°C, water (60 mL) was added to the reaction mixture, followed by extraction with dichloromethane (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:20) to give the title compound (410 mg, 82%) as an off-white solid. LC / MS (ESI) m / z 455.4[M+H] + .

[0708] Step 2: tert-Butyl ((S)-1-(((3S,6S,8R,10aR)-3-carbamoylthio-8-ethoxy-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0709]

[0710] Under nitrogen, the intermediate obtained above (410 mg, 0.902 mmol, 1.0 equiv) was dissolved in THF (15 mL). Lawesson's reagent (182 mg, 0.451 mmol, 0.5 equiv) was added to the reaction mixture at 25 ° C. The reaction mixture was stirred at 25 ° C for 4 hours, then saturated NaHCO3 (aqueous solution) (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:20) to give the title compound (220 mg, 51.8%) as an off-white solid. LC / MS (ESI) m / z 471.4[M+H] + .

[0711] Step 3: 2-((3S,6S,8R,10aR)-6-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propionamido)-8-ethoxy-5-oxodecahydropyrrolo[1,2-a]azocin-3-yl)thiazole-4-carboxylic acid

[0712]

[0713] Under nitrogen, the intermediate obtained above (230 mg, 0.489 mmol, 1.0 equivalent) was dissolved in dioxane (15 mL). 3-Bromo-2-oxopropanoic acid (82 mg, 0.489 mmol, 1.0 equivalent) was added to the reaction mixture at 25 ° C. The reaction mixture was stirred at 80 ° C for 4 hours. Saturated NaHCO3 (aqueous solution) (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:20) to give the title compound (210 mg, 80%) as an off-white solid. LC / MS (ESI) m / z 539.4 [M+H] + .

[0714] Step 4: tert-butyl ((S)-1-(((3S,6S,8R,10aR)-8-ethoxy-3-(4-(methoxy(methyl)carbamoyl)thiazol-2-yl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0715]

[0716] The intermediate obtained above (210 mg, 0.390 mmol, 1.0 equiv) and NHMe(OMe)HCl (45.6 mg, 0.468 mmol, 1.2 equiv) were dissolved in CH2Cl2 (15 mL). 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (V) (222 mg, 0.585 mmol, 1.5 equiv) and DIPEA (252 mg, 1.949 mmol, 5.0 equiv) were added to the reaction mixture at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. Water (60 mL) was added to the reaction mixture, followed by extraction with dichloromethane (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:20) to give the title compound (190 mg, 84%) as an off-white solid. LC / MS (ESI) m / z 582.4 [M+H] + .

[0717] Step 5: tert-Butyl ((S)-1-(((3S,6S,8R,10aR)-8-ethoxy-3-(4-(4-fluorobenzoyl)thiazol-2-yl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0718]

[0719] Under nitrogen, the intermediate obtained above (247 mg, 0.425 mmol, 1.0 equiv) was dissolved in THF (15 mL). At -55 ° C, (4-fluorophenyl) magnesium bromide (508 mg, 2.55 mmol, 6.0 equiv) was added to the reaction mixture. The reaction mixture was stirred at -50 ° C for 1 hour and then at -15 ° C for 3 hours. Saturated NH4Cl (aqueous solution) (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with PE / EA (2: 1) to give the title compound (100 mg, 38.2%) as an off-white solid. LC / MS (ESI) m / z 617.4 [M+H] + .

[0720] Step 6: (S)-N-((3S,6S,8R,10aR)-8-ethoxy-3-(4-(4-fluorobenzoyl)thiazol-2-yl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)-2-(methylamino)propanamide

[0721]

[0722] According to the synthesis of Example 1, the title compound (11.5 mg) was obtained as a white solid. LC / MS (ESI) m / z 517.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.54 (s, 1H), 8.28–8.14 (m, 2H), 7.98 (d, J = 7.4Hz, 1H), 7.48–7.22 (m, 2H), 5.41–5.26 (m, 1H), 4.90–4.74 (m, 1H) ,4.39–4.18(m,1H),3.07–2.83(m,3H),2.42–2.27(m,2H),2.27–2.10( m,4H),1.94–1.59(m,8H),1.08(d,J=6.9Hz,3H),0.87(t,J=7.0Hz,3H).

[0723] Embodiment 43

[0724] (2S)-N-((3S,6S,10aR)-8-ethoxy-3-((6-fluoro-1H-indol-3-yl)methyl)-5-oxodecahydropyrrolo[1,2-a]azocine-6-yl)-2-(methylamino)propanamide (Compound 76)

[0725]

[0726] Step 1: (9H-fluoren-9-yl)methyl((S)-1-(((3S,6S,8R,10aR)-8-ethoxy-3-(6-fluoro-1H-indole-3-carbonyl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0727]

[0728] Under nitrogen, 6-fluoro-1H-indole (60.8 mg, 0.450 mmol, 2.0 equivalents) and ethylmagnesium bromide (59.9 mg, 0.450 mmol, 2.0 equivalents) were dissolved in toluene (15 mL). EtMgBr (3.0 N, 59.9 mg, 0.45 mmol, 2.0 equivalents) was added at 0 ° C. After 1 hour, the above scheme shows that a toluene (5 mL) solution of the raw material (134 mg, 0.225 mmol, 1.0 equivalents) was added at 0 ° C. After stirring at 25 ° C for 16 hours, saturated NH4Cl (aqueous solution) (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:20) to give the title compound (60 mg, 38.4%) as an off-white solid.

[0729] Step 2: (9H-fluoren-9-yl)methyl((S)-1-(((3S,6S,8R,10aR)-8-ethoxy-3-((6-fluoro-1H-indol-3-yl)methyl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

[0730]

[0731] Under nitrogen, the intermediate obtained above (60 mg, 0.086 mmol, 1.0 equiv) was dissolved in THF (15 mL). LiBH4 (9.40 mg, 0.432 mmol, 5.0 equiv) was added to the reaction mixture at 0 ° C. After stirring at 25 ° C for 4 hours, methanesulfonic acid (41.5 mg, 0.432 mmol, 5.0 equiv) was added at 0 ° C. After 16 hours at room temperature, water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (15 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was added to a silica gel column and eluted with CH3OH / DCM (1:20) to give the title compound (20 mg, 34.0%) as an off-white solid. LC / MS (ESI) m / z 681.6 [M+H] + .

[0732] Step 3: (2S)-N-((3S,6S,10aR)-8-ethoxy-3-((6-fluoro-1H-indol-3-yl)methyl)-5-oxodecahydropyrrolo[1,2-a]azocin-6-yl)-2-(methylamino)propanamide

[0733]

[0734] According to the synthesis of Example 1, the title compound (1.6 mg) was obtained as a white solid. LC / MS (ESI) m / z 459.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.88 (s, 1H), 8.07 (d, J = 7.4Hz, 1H), 7.77–7.58 (m ,1H),7.19(s,1H),7.17–6.98(m,1H),6.90–6.76(m,1H),4.91–4.74(m,1H),4.51 –4.30(m,1H),4.28–4.05(m,2H),3.43–3.38(m,2H),3.01–2.86(m,1H),2.69–2.5 3(m,1H),2.22(s,3H),2.07–1.69(m,10H),1.70–1.49(m,2H),1.15–0.96(m,6H).

[0735] Embodiment 44

[0736] (3S,6S,10aS)-6-((S)-2-(methylamino)propionamido)-5-oxo-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azocine-3-carboxamide (Compound No. 82)

[0737]

[0738] Step 1: Ethyl (3S,6S,10aS)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylate

[0739]

[0740] Commercially available material (100 mg, 0.284 mmol, 1.0 equiv) was dissolved in MeOH (15 mL) to give a solution. 10% Pd / C (100 mg, 0.844 mmol, 2.98 equiv) was added to the reaction mixture at 25 °C. The reaction mixture was stirred at 30 °C under H2 for 5 hours. After filtration and concentration, the crude residue was used without further purification (101 mg, 100%) as a yellow solid. LC / MS (ESI) m / z 355.2 [M+H] + .

[0741] Step 2: (3S,6S,10aS)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0742]

[0743] The intermediate obtained above (101 mg, 0.285 mmol, 1.0 equivalent) and lithium hydroxide hydrate (23.91 mg, 0.570 mmol, 2.0 equivalent) were dissolved in THF (6 mL) and water (6 mL). Under N2 protection, the reaction mixture was stirred at 25 ° C for 16 hours, then water (60 mL) and citric acid were added to the reaction mixture, followed by extraction with EA (15 mL×3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (93 mg, 100%) as an off-white solid. LC / MS (ESI) m / z 327.3 [M+H] + .

[0744] Step 3-6: According to the synthesis of Example 1, the title compound (57.4 mg) was obtained as a white solid. LC / MS (ESI) m / z 441.8 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ(ppm)8.28(d,J=8.7Hz,1H),7.95(d,J=7.7Hz,1H),7.37–7.25(m ,1H),7.15–7.02(m,3H),4.97–4.85(m,1H),4.81–4.65(m,1H),4.34–4.26(m,1H),4.23–

[0745] 4.12(m,1H),2.94–2.85(m,1H),2.78–2.60(m,2H),2.17(s,3H),2.12–1.88(m,4H),1.88–1.41(m,13H),1.07(d,J=6.9Hz,3H).

[0746] The products shown in Table 1 were prepared according to the representative protocols outlined in the above Examples with appropriate modifications.

[0747] Table 1

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764] Biological Examples

[0765] Embodiment 45:

[0766] Recombinant human cIAP1-BIR3 biochemical assay

[0767] The compounds disclosed herein were tested for blocking of human cIAP1-BIR3 protein (Catalog: APT-11-370, Reaction biology) and its peptides in a homogeneous time resolved fluorescence (HTRF) based assay.

[0768] cIAP1 BIR3 binding assays were performed using the HTRF Human cIAP1 BIR3 Binding Kit (Perkin Elmer) according to the manufacturer's instructions. Briefly, 5 μL of serial dilutions of the test compound (three-fold dilutions, 1 μM-0.152 nM) were added to a 384-well microplate, followed by 5 μL of human cIAP1 BIR3 GST-tagged protein. For blank control wells, 5 μL of diluent #9 (1X) and 5 μL of PROTAC Binding Buffer 2 were added to the wells (in duplicate). 10 μL of premixed LCL161-Red Ligand and GST Tb Cryptate Antibody Working Solution were then added to all wells. The plates were sealed and incubated at room temperature for 2 hours. HTRF signals were read on a TECAN multi-function microplate reader (cryptate emission measured at 620 nm, receptor emission measured at 665 nm). The IC of each compound was determined using GraphPad Prism software 50 .

[0769] IC of each compound 50 It was obtained by fitting the data to a four-parameter logistic equation using Dotmatics.

[0770] Cell proliferation assay

[0771] MDA-MB-231 and EVSA-T cells (10,000 cells / well) were seeded into 95 μL of culture medium (RPMI-1640 containing 10% FBS and MEM containing 10% FBS, respectively) in a 96-well plate (Corning, catalog number 3917). Various concentrations of compounds (0.0005 μM, 0.001 μM, 0.004 μM, 0.01 μM, 0.04 μM, 0.1 μM, 0.3 μM, 1.1 μM, 3.3 μM, 10 μM) were added to the wells. After 72 hours of treatment, 30 μL of Celltiter-Glo reagent (Promega, catalog number G7573) was added and incubated at room temperature for 15 minutes, and then the luminescent signal was measured with a microplate reader (Biotek, SynergyH1). The normalized IC fitted using the control-based normalization method 50 The dose-response curves of the inhibitors were analyzed by regression analysis.

[0772] In some cases, compounds were isolated and tested as a mixture of diastereomers. Data for some exemplary compounds are shown in Table 2 below.

[0773] Table 2

[0774]

[0775]

[0776]

[0777] Embodiment 46:

[0778] Pharmacokinetic parameters in CD-1 mice

[0779] The study was conducted in male CD-1 mice aged 6-10 weeks. Animals received a single intravenous injection of 2.0 mg / kg (0.4 mg / mL, 10% solutol 15 + 90% saline) and blood samples were collected from different groups at different time points (N=3 per group): Group 1 (0.083 hours, 1 hour, 8 hours), Group 2 (0.25 hours, 2 hours, 10 hours), Group 3 (0.5 hours, 4 hours, 24 hours). Animals received a single oral gavage of 10.0 mg / kg (1.0 mg / mL, 10% solutol 15 + 90% saline) and blood samples were collected from different groups at different time points (N=3 per group): Group 4 (pre-dose, 1 hour, 8 hours), Group 5 (0.25 hours, 2 hours, 10 hours), Group 6 (0.5 hours, 4 hours, 24 hours). Plasma concentrations of the compounds were determined using UPLC-MS / MS. The pharmacokinetic parameters are shown in Table 3 below.

[0780] Table 3. Pharmacokinetic characteristics of representative compounds in mice

[0781]

[0782] Having fully described the methods, compounds, and compositions herein, those skilled in the art will appreciate that the disclosure may be carried out over a broad 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.

[0783] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt or solvate thereof, in: R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and halogen; R2, R3, R4 and R5 may be the same or different and are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl, C3-C6 heterocycloalkyl, OR a 、C(O)R a and NR a R b ; and R a and R b Each is independently selected from the group consisting of H, benzylcarbonyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, and C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2, N(C1-C6 alkyl)2, and C1-C6 alkoxy; or R a and R b Together with the N atom to which they are attached, they form a 4-6 membered heterocyclyl group optionally substituted by one or more of deuterium, halogen, OH, NH2, N(C1-C6 alkyl)2 and C1-C6 alkoxy; or R2 and R3 or R4 and R5 together with the carbon to which they are attached form -C(=O)-, -C=CH, -C=C-C1-C6 heteroalkyl, or -C(=N-OH)- or C3-C6 carbocycle or C3-C6 heterocarbocycle; or One of R2 and R3 and one of R4 and R5, together with the carbon to which they are attached, form a C3-C6 carbocycle or a C3-C6 heterocarbocycle optionally substituted with one or more of deuterium, halogen, OH, NH2, N(C1-C6 alkyl)2, and C1-C6 alkoxy; R6 and R7 may be the same or different, each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; or R6 and R7 together with the carbon to which they are attached form -C(=O)- or C3-C6 carbocyclic ring; R8 is –X1-X2-R 10 Module, where X1 is a bond or -C(O)NH-; X2 is a bond or CHR c , where R c is selected from hydrogen, C1-C6 alkyl or phenyl optionally substituted by one or more halogens; and R 10 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered saturated or unsaturated carbocyclic group or optionally substituted by one or more R 11 A substituted 5-10 membered heterocyclic group, wherein each R 11 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkylcarbonyl, 5-6 membered heteroaryl, phenylcarbonyl or phenyl optionally substituted with one or more halogens; and R9 is selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl.

2. A compound of formula I: or a pharmaceutically acceptable salt or solvate thereof, in: R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and halogen; R2, R3, R4 and R5 may be the same or different and are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 heteroalkyl, C3-C6 heterocycloalkyl, OR a 、C(O)R a and NR a R b ; and R a and R b Each is independently selected from the group consisting of H, benzylcarbonyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkenyl, C1-C6 heteroalkyl and C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2 and C1-C6 alkoxy; or R2 and R3 or R4 and R5 together with the carbon to which they are attached form -C(=O)- or -C(=N-OH)- or C3-C6 carbocyclic ring or C3-C6 heterocarbocyclic ring; R6 and R7 may be the same or different, each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; or R6 and R7 together with the carbon to which they are attached form -C(=O)- or C3-C6 carbocyclic ring; R8 is –X1-X2-R 10 Module, where X1 is a bond or -C(O)NH-; X2 is a bond or CHR c , where R c is selected from hydrogen, C1-C6 alkyl or phenyl optionally substituted by one or more halogens; and R 10 is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 5-10 membered saturated or unsaturated carbocyclic group or optionally substituted by one or more R 11 A substituted 5-10 membered heterocyclic group, wherein each R 11 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkylcarbonyl, 5-6 membered heteroaryl, phenylcarbonyl or phenyl optionally substituted with one or more halogens; and R9 is selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl.

3. The compound according to claim 1 or 2, wherein R1 is selected from C1-C6 alkyl.

4. The compound according to any one of claims 1 to 3, wherein R1 is selected from methyl or ethyl, preferably methyl.

5. The compound according to any one of claims 1 to 4, wherein R2 is selected from OR a ; and R a Selected from the group consisting of H, benzylcarbonyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkenyl, C1-C6 heteroalkyl and C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2 and C1-C6 alkoxy; and R3, R4 and R5 are hydrogen.

6. The compound according to any one of claims 1 to 4, wherein R5 is selected from OR a ; and R a Selected from the group consisting of H, benzylcarbonyl, C1-C6 alkylcarbonyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C2-C6 alkenyl, C1-C6 heteroalkyl and C1-C6 alkyl optionally substituted with one or more of deuterium, halogen, OH, NH2 and C1-C6 alkoxy; and R2, R3 and R4 are hydrogen.

7. A compound according to any one of claims 1 to 6, wherein R a The group consisting of C1-C6 heteroalkyl and C1-C6 alkyl optionally substituted by one or more of deuterium, halogen, OH, NH2 and C1-C6 alkoxy.

8. A compound according to any one of claims 1 to 7, wherein R6 and R7 are each independently selected from the group consisting of: hydrogen and C1-C6 alkyl; or R6 and R7 together with the carbon to which they are attached form a C3-C6 carbocycle.

9. A compound according to any one of claims 1 to 8, wherein X1 is a bond; X2 is a bond; and R 10 Selected from optionally one or more R 11 Substituted 5-10 membered heteroaryl, wherein each R 11 Independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, phenylcarbonyl or phenyl optionally substituted with one or more halogens.

10. The compound according to claim 9, wherein R 10 Selected from: which is optionally replaced by one or more R 11 Substitute, where each R 11 Independently selected from the group consisting of phenylcarbonyl or phenyl optionally substituted with one or more halogens.

11. The compound according to claim 10, wherein R 10 Selected from:

12. A compound according to any one of claims 1 to 8, wherein X1 is a bond; X2 is CH2; and R 10 Selected from optionally one or more R 11 Substituted 5-10 membered heteroaryl, wherein each R 11 Independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkylcarbonyl.

13. The compound according to claim 12, wherein R 10 Selected from: It is optionally replaced by one or more R 11 Substitute, where each R 11 Independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl and C1-C6 alkylcarbonyl.

14. The compound according to claim 13, wherein R 10 Selected from:

15. A compound according to any one of claims 1 to 8, which has formula II: Where X2 is a bond or CHR c , where R c is selected from hydrogen, C1-C6 alkyl or phenyl optionally substituted by one or more halogens; and R 10 is selected from phenyl, 5-10 membered heteroaryl, 5-10 membered saturated or unsaturated carbocyclic group or optionally substituted by one or more R 11 A substituted 5-10 membered heterocyclic group, wherein each R 11 Independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 5-6 membered heteroaryl or phenyl optionally substituted with one or more halogens.

16. The compound according to claim 15, wherein the -X2-R 10 Modules are selected from: It is optionally replaced by one or more R 11 Substitute, where each R 11 Independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl.

17. The compound according to claim 16, wherein the -X2-R 10 Modules are selected from:

18. The compound according to claim 15, wherein the -X2-R 10 Modules are selected from: It is optionally replaced by one or more R 11 Substitute, where each R 11 are independently selected from the group consisting of: halogen or C1-C6 alkyl; X3 is -CH2- or -O-; and n is 0 or 1.

19. The compound according to claim 18, wherein the -X2-R 10 Modules are selected from:

20. The compound according to claim 15, wherein the -X2-R 10 Modules are selected from:

21. A compound according to any one of claims 1 to 20, wherein R9 is selected from C1-C6 alkyl, preferably methyl.

22. A compound according to any one of claims 1 to 21, wherein the compound has formula III:

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

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

25. A method for inhibiting IAP protein activity in a cell, the method comprising contacting the cell in which IAP protein activity needs to be inhibited with an effective amount of the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 24.

26. A method of treating a disease or condition in which inhibition of an IAP protein provides a benefit, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof; or a pharmaceutical composition according to claim 24.

27. The method of claim 26, wherein the disease or condition is cancer.

28. The method of claim 26, 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 diseases; vascular diseases, etc.

29. The method of claim 26, wherein the disease or condition is selected from the group consisting of HBV, autoimmune hemolytic anemia, autoimmune hepatitis, Bergey's disease or IgA nephropathy, celiac disease, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, graft-versus-host disease, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjögren's syndrome, systemic lupus erythematosus, type 1 diabetes, ulcerative colitis, vitiligo, and the like.

30. The method of claim 26, wherein the therapeutically effective amount of the compound is between about 0.01 mg / kg and 100 mg / kg per day.

31. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt or solvate thereof for use in inhibiting IAP protein activity in a cell.

32. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or solvate thereof, for use in treating a disease or condition in which inhibition of an IAP protein provides a benefit.

33. Use of the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition according to claim 24, in the preparation of a medicament for inhibiting the activity of an IAP protein in a cell.

34. Use of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to claim 24, in the preparation of a medicament for treating a disease or condition in which inhibition of an IAP protein provides a benefit.

35. A kit comprising a compound according to any one of claims 1-23 and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject in which inhibition of an IAP protein provides a benefit.

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