Compounds useful in HIV therapy

Abstract

To provide compounds, pharmaceutical compositions, and methods of use thereof in connection with individuals infected with HIV or HBV or having cancer.SOLUTION: The invention provides a compound represented by the formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof. Specifically, (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(methylenebis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamido)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) is presented, for example.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 773,563, filed on 30 November 2018 (the disclosure thereof is incorporated herein by reference in its entirety).

[0002] Field of Invention The present invention relates to compounds, pharmaceutical compositions, and methods of using them in relation to individuals infected with HIV, HBV, or cancer.

[0003] Sequence List This application was prepared on November 12, 2010, using Patent-In 3.5, and includes sequences listed in a 2KB electronic sequence listing titled PR66692_Seq_List (the contents and sequences thereof are incorporated herein by reference). [Background technology]

[0004] Human immunodeficiency virus type 1 (HIV-1) infection causes acquired immunodeficiency disease (AIDS). The number of HIV cases continues to rise, and it is currently estimated that more than 35 million people worldwide are infected with HIV (see, for example, http: / / www.sciencedirect.com / science / article / pii / S235230181630087X? via Dihub).

[0005] Currently, long-term suppression of viral replication using antiretroviral drugs is the only treatment option for HIV-1 infection. In fact, the U.S. Food and Drug Administration has approved 25 drugs across six different inhibitor classifications, which have been shown to significantly improve patient survival and quality of life. However, due to several issues, including but not limited to undesirable drug-drug interactions; drug-food interactions; non-compliance with therapy; drug resistance due to enzyme target mutations; and inflammation associated with immunological damage caused by HIV infection, further therapies are still considered necessary.

[0006] Currently, almost all HIV-positive patients are treated with a combination antiretroviral drug regimen called highly active antiretroviral therapy ("HAART"). However, HAART therapy is often complex because patients often need to be given different drug combinations daily to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the favorable effects of HAART on patient survival, drug resistance can still occur, and survival and quality of life are not normalized compared to uninfected individuals [Lohse Ann Intern Med 2007 146;87-95]. In fact, the incidence of several non-AIDS pathological conditions and mortality, such as cardiovascular disease, frailty, and neurocognitive impairment, is increased in HIV-infected subjects under HAART [Deeks Annu Rev Med 2011;62:141-155]. This increased incidence of non-AIDS pathological conditions / mortality is associated with, or potentially caused by, increased systemic inflammation related to immunological damage caused by HIV infection and residual HIV infection [Hunt J Infect Dis 2014][Byakagwa J Infect Dis 2014][Tenorio J Infect Dis 2014].

[0007] Modern antiretroviral therapy (ART) has the ability to effectively suppress HIV replication and improve the health outcomes of HIV-infected individuals, but it is thought that it cannot completely eliminate the HIV viral reservoir within the individual. The HIV genome can remain latent in most immune cells in the infected individual and may reactivate at any time. After interruption of ART, viral replication typically resumes within a few weeks. In a small number of individuals, the size of this viral reservoir is significantly reduced, and the recurrence of viral replication is delayed upon discontinuation of ART [Henrich TJ J Infect Dis 2013][Henrich TJ Ann Intern Med 2014]. In one case, the viral reservoir was eliminated during the treatment of leukemia, and no viral recurrence was observed during the follow-up period of several years [Hutter G N Engl J Med 2009]. These examples suggest the concept that reduction or elimination of the viral reservoir is possible and may lead to viral remission or cure. Therefore, methods to eliminate the viral reservoir by direct molecular means, including excision of the viral genome with the CRISPR / Cas9 system, or to induce reactivation of latent reservoirs during ART to eliminate latent cells have been pursued. It is thought that reversal of latency is necessary to make latently infected cells more susceptible to clearance.

[0008] SMACm (Second Mitochondrial Caspase Activator) mimes are a class of compounds that have recently entered clinical trials as potential cancer treatments. These drugs deplete and / or inhibit cellular inhibitors (cIAPs) of apoptotic proteins, which act as anti-apoptotic proteins, thereby promoting cell death in cancer cells. Antagonism and / or depletion of cIAPs also leads to activation of non-standard NF-κB signaling pathways, which may induce HIV expression and enable the elimination of HIV-infected cells. Furthermore, by antagonizing anti-apoptotic proteins, SMAC mimes can selectively promote cell death in cells infected with HIV [Campbell Cell Host Microbe 2018] or HBV [Ebert Proc Nat Acad Sci 2013].

[0009] In recent years, targeting of the non-standard NF-κB (ncNF-κB) pathway to reverse latency in cell line models has been reported. The ncNF-κB pathway is typically activated by ligation of a subset of TNF receptor family members. In the steady state, a ubiquitin ligase-active multimolecular complex consisting of TNF receptor-related factor 2 (TRAF2), TRAF3, and a cellular inhibitor of apoptosis protein-1 (cIAP1) associates with the cytoplasm of the unligated receptor and constitutively ubiquitinates and degrades NF-κB-induced kinase (NIK). During receptor ligation, cIAP1 ubiquitinates and autoubiquitinates TRAF3, leading to proteasomal degradation of TRAF3 and cIAP1, thereby deinhibiting NIK accumulation. NIK is constitutively active and, upon accumulation, phosphorylates inhibitors of κB kinase-α (IKKα) homodimers. Subsequently, the activated IKKα / IKKα homodimer phosphorylates the inactive p100 form of NFκB2, triggering ubiquitination by Skp1-Cul1-F-box ubiquitin ligase (SCFβTrCP) and proteasome cleavage of p100, releasing the active p52 subunit. p52 associates with RelB, and this heterodimer translocates into the nucleus, driving transcription from the κB promoter element. In addition to receptor ligation, ncNF-κB can be activated by signaling intermediates of the apoptotic cascade. Cleavage of the caspase-mediated mitochondrial activator II (SMAC) from the mitochondrial membrane exposes the N-terminal motif Ala-Val-Pro-Ile, which specifically binds to the baculoviral intermediate repeat (BIR) region of the IAP protein. Such BIR binding in cIAP1 / 2 activates the ubiquitin ligase activity of the TRAF2:TRAF3:cIAP complex, inducing autoubiquitination and degradation of cIAP1 / 2, NIK accumulation, and activation of the ncNF-κB pathway. Binding SMAC to the BIR domains of XIAP and ML-IAP antagonizes the caspase inhibitory activity of these molecules, which are often overexpressed in tumor cells, leading to enhanced apoptosis.Therefore, the Ala-Val-Pro-Ile motif of SMAC has attracted considerable attention in oncology, leading to the discovery of a classification of peptide mimes with SMAC-like activity, known as SMAC mimes (SMACm). SMACm are of interest because they potently activate the ncNF-κB pathway, do not induce apoptosis in non-tumor cells, and thus reverse HIV latency. For example, see Richard Dunham et.al., The SMAC Mimetic AZD5582 is a Potent HIV Latency Reversing Agent, bioRxiv, May. 2, 2018; doi: http: / / dx.doi.org / 10.1101 / 312447.

[0010] U.S. Patent No. 7,960,372 relates to a divalent diazo bicyclic SMAC mimetic that inhibits the activity of IAP. [Overview of the Initiative] [Means for solving the problem]

[0011] In one embodiment, the present invention relates to formula (I):

[0012] [ka] [In the formula, R, R', R'', and R''' are independently selected from H and CH3; X1 and X2 are independently selected from the group consisting of O and S; L is as follows:

[0013] [ka] JPEG0007884492000003.jpg213161JPEG0007884492000004.jpg47161 (in the formula, Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar 10 Ar 11, Ar 12 , Ar 13 , Ar 14 , Ar 15 , Ar 16 , Ar 17 , Ar 18 , Ar 19 , Ar 21 , Ar 22 , Ar 23 , Ar 24 , Ar 25 and Ar 26 are each independently selected from (C6-C 14 ); Alk, Alk2 and Alk3 are each independently the following:

[0014] [Chemical formula] and are selected from; R1 is C3-C6 cycloalkyl or C1-C6 heterocycle; R2 is -(CH2) a -, -(CH2) b -O--(CH2) c -, -(CH2) d -(C6-C 14 ) aryl-(CH2) e - and -(CH2) f -(C1-C6) heteroaryl-(CH2) g - and is selected from the group consisting of; R3 is -(CH2) h -; -(CH2) i -O--(CH2) j -, -(CH2) k -(C6-C 14 ) aryl-(CH2) l - and -(CH2) m' -(C1-C6) heteroaryl-(CH2) m'' - and is selected from the group consisting of; R4 is C3-C6 cycloalkyl, (C6-C 14 ) aryl or (CH2) n' -(C6-C 14 ) aryl-(CH2) n'' , (CH2)n''' -Alk-(CH2) n'''' (wherein n', n'', n''', and n'''' are independently selected from 1 to 8); R5 is a C3-C6 cycloalkyl group; R6 is (CH2) z ,

[0015] [ka] Selected from the group consisting of; a, b, c, d, e, f, g, h, i, j, k, l, m, m', m'', n, p, q, r, s, t, u, v, x, y, and z are each independently selected from 1 to 12. This linker is selected from the group consisting of the following: The present invention provides compounds having the structure described herein, or pharmaceutically acceptable salts or stereoisomers thereof.

[0016] In another embodiment, the present invention relates to formula (Ia):

[0017] [ka] [In the formula, R, R', R'', and R''' are independently selected from H and CH3; X1 and X2 are independently selected from the group consisting of O and S; L is as follows:

[0018] [ka] JPEG0007884492000009.jpg111160 (in the formula, Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar 10 Ar 11 Ar 12 Ar 13 Ar 14 Ar 15 Ar 16 Ar 17 Ar18 Ar 19 Ar 21 Ar 22 Ar 23 Ar 24 Ar 25 and Ar 26 These are, independently of each other, (C6-C 14 ) Selected from the arrow; Alk, Alk2, and Alk3 are each independent of the following:

[0019] [ka] Selected from; R1 is a C3-C6 cycloalkyl or C1-C6 heterocycle; R2 is -(CH2) a -,-(CH2) b -O--(CH2) c -,-(CH2) d -(C6-C 14 )Aryl-(CH2) e -and-(CH2) f -(C1-C6) heteroaryl-(CH2) g -Selected from the group consisting of; R3 is -(CH2) h -; -(CH2) i -O--(CH2) j -,-(CH2) k -(C6-C 14 )Aryl-(CH2) l -and-(CH2) m' -(C1-C6) heteroaryl-(CH2) m'' -Selected from the group consisting of; R4 is C3-C6 cycloalkyl, (C6-C 14 ) Aryl or (CH2) n' -(C6-C 14 )Aryl-(CH2) n'' , (CH2) n''' -Alk-(CH2) n'''' (wherein n', n'', n''', and n'''' are independently selected from 1 to 8); R5 is C3-C6 cycloalkyl; R6 is (CH2) z 、

[0020]

Chem.

[0021] In another aspect, the present invention relates to formula (Ib):

[0022]

Chem.

[0023]

Chem.

[0024] [Chemical formula] selected from; R1 is C3-C6 cycloalkyl or C1-C6 heterocycle; R2 is -(CH2) a -, -(CH2) b -O--(CH2) c -, -(CH2) d -(C6-C 14 ) aryl-(CH2) e - and -(CH2) f -(C1-C6) heteroaryl-(CH2) g - selected from the group consisting of; R3 is -(CH2) h -; -(CH2) i -O--(CH2) j -, -(CH2) k -(C6-C 14 ) aryl-(CH2) l - and -(CH2) m' -(C1-C6) heteroaryl-(CH2) m'' - selected from the group consisting of; R4 is C3-C6 cycloalkyl, (C6-C 14 ) aryl or (CH2) n' -(C6-C 14 ) aryl-(CH2) n'' , (CH2) n''' -Alk-(CH2) n'''' (where n', n'', n''' and n'''' are each independently selected from 1 to 8); R5 is C3-C6 cycloalkyl; R6 is (CH2) z ,

[0025] [ka] Selected from the group consisting of; a, b, c, d, e, f, g, h, i, j, k, l, m, m', m'', n, p, q, r, s, t, u, v, x, y, and z are each independently selected from 1 to 12. This linker is selected from the group consisting of the following: This relates to the compound, or its pharmaceutically acceptable salts or stereoisomers.

[0026] In another embodiment, the present invention relates to formula (II):

[0027] [ka] [In the formula, R, R', R'', and R''' are independently selected from H and CH3; X1 and X2 are independently selected from the group consisting of O and S; L' is the formula:

[0028] [ka] (In the formula, Ar 27 and Ar 28 These are, independently, C6-C 14 Selected from the alphabet, R7 is

[0029] [ka] , C6 aryl and -(CH2) 4-15 -Selected from the group consisting of; a' and b' are independently selected from 0 to 6. It is the linker. This relates to compounds represented by [the specified method / function].

[0030] In another embodiment, the present invention relates to formula (III):

[0031] [ka] [In the formula, R, R', R'', and R''' are independently selected from H and CH3; X1 and X2 are independently selected from the group consisting of O and S; L'' is the formula:

[0032] [ka] (In the formula, Ar 29 and Ar 30 It is independently, C6-C 10 Selected from the array, R8 is,

[0033] [ka] ,-(CH2) 6-15 -, ' -and-(CH2) d' -(C6-C 10 )Aryl-(CH2) e' -(In the formula, d' and e' are selected independently from a group consisting of 1 to 6.) It is the linker. This relates to compounds represented by [the specified method / function].

[0034] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound according to formula (I), (Ia), (Ib), (II), (III) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0035] In another embodiment, the present invention provides a method for treating or curing HIV infection in a subject, comprising the step of administering a compound of formula (I), (Ia), (Ib), (II), (III) or a pharmaceutically acceptable salt thereof to the subject.

[0036] In another embodiment, the present invention provides a method for depleting HIV-infected cells, comprising the step of administering a compound of formula (I), (Ia), (Ib), (II), (III) or a pharmaceutically acceptable salt thereof to a target.

[0037] In another embodiment, the present invention provides a method for depleting HIV-infected cells, comprising the step of administering a compound of formula (I), (Ia), (Ib), (II), (III) or a pharmaceutically acceptable salt thereof, and one or more additional agents active against HIV to the target. In a particular embodiment, these agents active against HIV are selected from the group consisting of antiretroviral agents, latency reversal agents, and agents for clearance therapy.

[0038] These and other embodiments are encompassed by the present invention as described herein. [Brief explanation of the drawing]

[0039] [Figure 1] Figure 1 is a graph comparing rodent pharmacokinetic (PK) data for several compounds of formula I with SMACm AZD5582 PK data. [Modes for carrying out the invention]

[0040] Herein, the subject matter of this disclosure is fully described below. However, many variations and other embodiments of the subject matter of this disclosure described herein will be recalled by those skilled in the art who are interested in the teachings presented in the above description. Therefore, it should be understood that the subject matter of this disclosure is not limited to the specific embodiments disclosed, and that variations and other embodiments are intended to be included within the scope of the appended claims. That is, the subject matter described herein encompasses all substitutes, variations, and equivalents. If one or more incorporated documents, patents, and similar materials differ from or conflict with this application, including but not limited to defined terms, usage of terms, and described technology, this application shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All publications, patent applications, patents, and other references cited herein are incorporated by reference throughout.

[0041] Apoptosis, a type of programmed cell death, plays a crucial role in maintaining homeostasis and regulating cell number in higher organisms. Abnormal apoptosis is involved in several diseases, including autoimmune disorders, degenerative diseases of the central nervous system, cancer, and viral infections, such as HIV. The family of inhibitory apoptotic proteins (IAPs) plays a key role in suppressing pro-apoptotic signaling in mammalian cells. SMACm, which mimics a key tetrapeptide sequence from a second mitochondrial caspase activator, has been shown to disrupt the binding of IAPs to their functional partners, restoring the apoptotic response to pro-apoptotic stimuli in cells. Since the early 2000s, considerable effort has been focused on designing and preparing SMAC mimics as IAP antagonists, particularly in promoting cell death in tumor cells, and more recently in reversing HIV latency. Such investigations have explored the activation of the non-standard NF-κB pathway (ncNF-κB) as a potential way in which SMAC mimics selectively deplete latent HIV cells. An early example of an SMAC mimetic is the monomeric SBI-0637142, prepared by researchers at the Sanford-Burnham Medical Research Institute. In HIV depletion studies, SBI-0637142 was found to be potent in cell line assays, but it did not show activity in p100-p52 conversion or HIV caRNA induction in primary cells. Much work has also been directed towards the development of divalent mimetic, which are covalent monomeric SMAC mimetics. AstraZeneca's AZD5582 and Medivir's Birinapant TL32711 are examples of dimeric SMAC mimetics. In HIV latency reversal studies, Birinapant TL32711 was not potent in jarcut, p100-p52 conversion, or HIV caRNA induction. Conversely, AZD5582 showed increased cell-associated HIV RNA expression in resting CD4+ T cells through jarcut assay experiments, p100-p52 conversion studies, and HIV and CaRNA induction (Sampey et al. bioRxiv 312447).However, AZD5582 may also exhibit resistance issues.

[0042] [ka]

[0043] Disclosed herein is a dimerized SMACm that, as a single agent, is considered sufficiently potent and effective to activate ncNF-κB in primary unmodified human cells and reverse HIV latency, exhibiting lower in-target toxicity compared to other dimerized SMACms such as AZD5582, and potentially favorable consideration for further development. In particular, the dimerized SMACm of the present invention can induce HIV RNA expression in unstimulated resting primary CD4+ T cells from HIV-infected donors whose viremia is completely suppressed by standard therapy. Other SMACms, specifically monomeric or dimerized molecules with unoptimized linkers, are not considered to have this effect in these cells, the major latent reservoir of persistent infection. Furthermore, the dimerized SMACm of the present invention enables clinically measurable reversal of latency in two animal models (SIV-infected, antiretroviral-suppressed rhesus monkeys and HIV-infected ART-suppressed humanized mice), as evidenced by intermittent plasmaviremia that appears transiently despite successful ongoing antiviral therapy.

[0044] It should be understood that the terms used herein are intended to describe only specific embodiments and are not intended to limit the scope of the invention. In this specification and the following claims, several terms are defined as having the following meanings:

[0045] As used herein, unless otherwise specified, “alkyl” refers to a monovalent saturated aliphatic hydrocarbyl group having 1 to 14 carbon atoms, in some embodiments 1 to 8 carbon atoms, or 1 to 6 carbon atoms. “(Cx-Cy)alkyl” refers to an alkyl group having x to y carbon atoms. The term “alkyl” includes, for example, linear and branched hydrocarbyl groups, such as methyl (CH3), ethyl (CH3CH2), n-propyl (CH3CH2CH2), isopropyl ((CH3)2CH), n-butyl (CH3CH2CH2CH2), isobutyl ((CH3)2CHCH2), sec-butyl ((CH3)(CH3CH2)CH), t-butyl ((CH3)3C), n-pentyl (CH3CH2CH2CH2CH2), and neopentyl ((CH3)3CCH2). For example, (C1-C 12 It should be noted that the description of alkyl also includes the range within this group, for example, (C1-C6) alkyl groups.

[0046] "Alkylene" or "alkylene" refers to a divalent saturated aliphatic hydrocarbyl group having 1 to 10 carbon atoms, and in some embodiments, 1 to 6 carbon atoms. u C v "(C) Alkylene" refers to an alkylene group having u to v carbon atoms. Alkylene groups include branched and linear hydrocarbyl groups. For example, "(C) 1- C6) Alkylene is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, etc. Therefore, the term "propylene" has the following structure:

[0047] [ka] This can be illustrated by the following three structures or more:

[0048] [ka] , p, or

[0049] [ka] This can be illustrated by any of the following: Furthermore, the term "(C 1- C6) Alkylene is intended to contain a branched hydrocarbyl group such as cyclopropylmethylene, which has the following structure:

[0050] [ka] This can be illustrated by the following.

[0051] "Alkynyl" or "alkyne" refers to a linear or branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include hydrocarbyl groups having one triple bond and one double bond. For example, (C2-C6) alkynyls are intended to include ethynyl, propynyl, and the like.

[0052] "Aryl" refers to an aromatic group consisting of 6 to 14 carbon atoms, which does not have a ring heteroatom and has a monocyclic ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl). In the case of polycyclic systems, including fused, bridging, and spirocyclic systems, which have aromatic and non-aromatic rings without a ring heteroatom, the term "aryl" or "Ar" applies when the bond site is at an aromatic carbon atom (for example, 5,6,7,8-tetrahydronaphthalene-2-yl is an aryl group whose bond site is at the 2-position of an aromatic phenyl ring). In one embodiment, a preferred bicyclic aryl system is given by formula:

[0053] [ka] It can be represented by:

[0054] For the purpose of clarity, other bonding sites, such as those at non-aromatic carbon atoms, are encompassed by "Aryl" or "Ar".

[0055] "Cycloalkyl" refers to a saturated or partially saturated cyclic group of 3 to 14 carbon atoms that does not have a ring heteroatom and is monocyclic or polycyclic, e.g., condensed, cross-linked, and spirocyclic systems. In the case of polycyclic systems having aromatic and non-aromatic rings without a ring heteroatom, the term "cycloalkyl" applies when the bond site is at a non-aromatic carbon atom (e.g., 5,6,7,8-tetrahydronaphthalene-5-yl). The term "cycloalkyl" also includes cycloalkenyl groups, e.g., cyclohexenyl. Examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups containing bicycloalkyl polycyclic systems include bicyclohexyl, bicyclopentyl, and bicyclooctyl. Two such bicycloalkyl polycyclic structures are exemplified below and their names are listed:

[0056] [ka] Bicyclohexyl, and

[0057] [ka] Bicyclohexyl.

[0058] (C u- C v "Cycloalkyl" refers to a cycloalkyl group having u to v carbon atoms.

[0059] "Spirocycloalkyl" is the following structure in which the group shown here, bonded to the bond marked with a wavy line, is replaced with a spirocycloalkyl group:

[0060] [ka] As illustrated by [example], this refers to a 3- to 10-membered cyclic substituent formed by the substitution of two hydrogen atoms at a common carbon atom in a cyclic ring structure or in an alkylene group having 2 to 9 carbon atoms.

[0061] "Condensed cycloalkyl" has the following structure in which the cycloalkyl group shown here contains the wavy-lined bond to the carbon atom substituted by the condensed cycloalkyl group:

[0062] [ka] As illustrated by [example], this refers to a 3- to 10-membered cyclic substituent formed by the substitution of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure.

[0063] "AUC" refers to the area under a plot of the plasma concentration (not the logarithmic scale) of a drug against time after drug administration.

[0064] "EC 50 " refers to the concentration of the drug that gives up to half the response. Sometimes, EC 50 Also, pEC 50 Scale (-logIC) 50 It is converted to ), and higher values ​​indicate exponentially greater potency.

[0065] "I C 50 " refers to the inhibitory concentration of up to half the maximum amount of the drug. Sometimes, IC 50 Also, pIC 50 Scale (-logIC) 50 It is converted to ), and higher values ​​indicate exponentially greater potency.

[0066] "Heteroaryl" refers to an aromatic group having 1 to 14 carbon atoms (preferably 1 to 12 carbon atoms, more preferably 2 to 12 carbon atoms) and 1 to 6 heteroatoms (more preferably 1 to 3 heteroatoms) selected from oxygen, nitrogen, and sulfur, unless otherwise specified, and includes monocyclic (e.g., imidazolyl) and polycyclic (e.g., benzimidazole-2-yl and benzimidazole-6-yl). In the case of polycyclic systems, including condensed, cross-linked, and spirocyclic systems having aromatic and non-aromatic rings, the term "heteroaryl" applies if there is at least one ring heteroatom and the bond site is on an atom of the aromatic ring (e.g., 1,2,3,4-tetrahydroquinoline-6-yl and 5,6,7,8-tetrahydroquinoline-3-yl). In some embodiments, the nitrogen and / or sulfur ring atoms(s) of the heteroaryl group are optionally oxidized to yield an N oxide (N→O), sulfinyl, or sulfonyl moiety. A prefix indicating the number of carbon atoms (e.g., C) x -C y ) refers to the total number of carbon atoms in the heteroaryl group, excluding the number of heteroatoms. This group also includes the entire range between x and y, for example, C1-C 14 is C2-C 14This includes C2-C9, etc. More specifically, the term heteroaryl is not limited to but includes pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyl, pyrrolyl, pyrazolyl, pyridadinyl, pyrimidinyl, purinyl, phthalazyl, naphthylpryidyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, indolidinyl, The compounds include dihydroindolyl, indazolyl, indolinyl, benzoxazolyl, quinolyl, isoquinolyl, quinolidyl, quinazolyl, tetrahydroquinolinyl, isoquinolyl, quinazolinyl, benzimidazolyl, benzoisoxazolyl, benzothienyl, benzopyridazinyl, pteridinyl, carbazolyl, carborinyl, phenanthridine, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, phthalimidyl, and tetrazole. In one embodiment, for example, a (C3-C9) heteroaryl spirocycle condensation system, more preferably a (C4-C6) heteroaryl, is present.

[0067] "Heterocyclic" or "heterocycle," or "heterocycloalkyl" or "heterocyclyl," unless otherwise specified, refers to a saturated or partially saturated cyclic group having 1 to 14 carbon atoms (preferably 1 to 12 carbon atoms, more preferably 2 to 12 carbon atoms) and 1 to 6 heteroatoms (more preferably 1 to 3 heteroatoms) selected from nitrogen, sulfur, phosphorus, or oxygen, including monocyclic and polycyclic systems, e.g., condensed, bridging, and spirocyclic systems. In the case of polycyclic systems having aromatic and / or non-aromatic rings, the terms "heterocyclic," "heterocycle," "heterocycloalkyl," or "heterocyclyl" apply if there is at least one ring heteroatom and the bond site is on an atom of the non-aromatic ring (e.g., 1,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl, and decahydroquinoline-6-yl). In one embodiment, the nitrogen, phosphorus, and / or sulfur atoms (or more) of the heterocyclic group are optionally oxidized to yield an N-oxide, phosfinanoxide, sulfinyl, or sulfonyl moiety. More specifically, heterocyclyls include, but are not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2-pyrrolidon-1-yl, morpholinyl, and pyrrolidinyl. A prefix indicating the number of carbon atoms (e.g., C) x -C y ) refers to the total number of carbon atoms in the heterocyclyl group, excluding the number of heteroatoms. This group also includes the entire range between x and y, for example, C1-C 12 is C2-C 12 This includes C2-C9 and the like. In one embodiment, for example, there is a (C3-C9) heterocyclic spiro ring condensation system, more preferably a (C4-C6) heterocycle.

[0068] Examples of heterocyclic and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indidine, isoindole, indole, dihydroindole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthidine, acridine, phenanthitol Examples include phosphorus, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine, thiomorpholine (also called thiamorpholine), piperidine, pyrrolidine, and tetrahydrofuranil.

[0069] In addition to the embodiments described herein, “condensed heterocyclic” or “condensed heterocycle” refers to the following structures in which the cycloalkyl group shown herein is bonded to a carbon atom substituted with a condensed heterocyclic group, as indicated by the wavy lines:

[0070] [ka] As illustrated by [example], this refers to a 3- to 9-membered cyclic substituent (more preferably 4- to 6 members) formed by the substitution of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure.

[0071] Spiro ring systems in formulas (I), (Ia), (Ib), (II), or (III) (for example, but not limited to R 2 and R 3 The embodiments formed from, but are not limited to, the following:

[0072] [ka] Includes.

[0073] When used herein, “compound” (singular or plural) and “chemical substance” (singular or plural) refer to the general formulas disclosed herein, the compounds encompassed by any subgenerals of those general formulas, and any form of compounds within the range of general and subgeneral formulas, such as racemates, stereoisomers, and tautomers of a compound (singular or plural).

[0074] The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and any oxidation form of nitrogen, for example, N(O){N + -O - This includes any oxidation form of sulfur, such as S(O) and S(O)2, and any quaternary form of basic nitrogen.

[0075] A "linker" ("L") refers to a substance (for example, a molecule) that connects two parts of a molecule.

[0076] "Polymorphism" refers to the existence of two or more clearly different phenotypes within the same population of a species in which multiple morphs or allomorphs occur. For a species to be classified as such, the allomorphs must simultaneously occupy the same habitat and belong to an arbitrary mating population (one resulting from random mating).

[0077] "Protein binding" refers to the binding of a drug to proteins in plasma, tissue membranes, red blood cells, and other components of blood.

[0078] "Protein shift" is determined in the absence and presence of human serum. 50 This refers to determining the joinality shift by comparing values.

[0079] A "racemate" refers to a mixture of enantiomers. In one embodiment of the present invention, the compounds of formulas I, Ia, Ib, II, and III, or their pharmaceutically acceptable salts, are enantiomerically enriched with respect to one enantiomer in which all the chiral carbons mentioned are in one stereoconfiguration. Generally, references to an enantiomerically enriched compound or salt are intended to indicate that the specified enantiomer constitutes more than 50% by weight of the total weight of all enantiomers of the compound or salt.

[0080] A “solvate” (singular or plural) of a compound refers to the compound as defined above, bound to a stoichiometric or non-stoichiometric amount of a solvent. Solvates of a compound include all forms of solvates of the compound. In certain embodiments, the solvent is volatile, non-toxic, and / or acceptable for administration to humans in trace amounts. A preferred solvate is water.

[0081] A "stereoisomer" (singular or plural) refers to a compound with one or more stereocenters that differ in chirality. Stereoiomers include enantiomers and diastereomers, such as the compounds of formulas (I), (Ia), (Ib), (II), and (III), as well as the linkers (L) of formulas (I) to (xiii) as described herein, and the linkers of formulas (II) and (III).

[0082] "Tautomers" refer to alternative forms of compounds with different proton positions, such as enol / keto and imine / enamine tautomers, or tautomers of heteroaryl groups containing ring atoms bonded to both the ring NH moiety and the ring=N moiety, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0083] The term "atropisomer" refers to a stereoisomer arising from an asymmetric axis. This can occur due to restricted rotation around a single bond, and the rotational impediment is high enough to allow for the complete isolation of a diastereomer or enantiomer species that is not stably interconvertible and to distinguish between the isomer species containing it. Those skilled in the art will understand the asymmetric R xIt is recognized that introducing a second chiral center into the core enables the formation of atropisomers. Furthermore, introducing a second chiral center into a given molecule containing atropisomers can cause the two chiral elements to combine to produce diastereomers and enantiomer stereochemical species. Interconversion between atropisomers may or may not be possible depending on the substitution around the Cx axis, and this may be temperature-dependent. In some cases, atropisomers may interconvert rapidly at room temperature but may not cleave under ambient conditions. Other situations may allow cleavage and isolation, but the interconversion may occur over periods ranging from seconds to hours or even days or months, resulting in a measurable decrease in optical purity over time. Still other species may be cleavable and isolated, resulting in stable species, as interconversion at ambient and / or high temperatures may be completely restricted. Where known, the cleaved atropisomers were named using helical nomenclature. This nomenclature considers only the two ligands with the highest priority before and after the axis. If the rotation priority from the front ligand 1 to the rear ligand 1 is clockwise, the spatial configuration is P; if it is counterclockwise, it is M.

[0084] "Pharmacologically acceptable salts" refer to pharmaceutically acceptable salts derived from various organic and inorganic counterions known in the art, and for illustrative purposes only, include sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium. If the molecule contains a basic functional group, examples include salts of organic or inorganic acids, such as hydrochlorides, hydrobroms, tartrates, mesylates, acetates, maleates, and oxalates. Preferred salts are those described in P. Heinrich Stahl and Camille G. Wermuth (eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.

[0085] "Patient" or "subject" refers to a mammal, including humans and non-human mammals.

[0086] "Treating" or "treating" a disease in a patient means: 1) preventing the onset of the disease in a patient who is predisposed or has not yet shown symptoms of the disease; 2) inhibiting the disease or stopping its onset; or 3) improving the disease or causing its regression.

[0087] As stated above, the “treatment” of a disability includes the prevention of the disability. Those skilled in the art will understand that “prevention” is not an absolute term. In medicine, “prevention” is understood to mean the prophylactic administration of drugs to substantially reduce the likelihood or severity of a disability or its biological manifestation, or to delay the onset of such a disability or its biological manifestation.

[0088] The terms “intermittent” or “intermittently,” as used herein, mean stopping and starting at regular or irregular intervals. As used herein, the term “viral infection” describes a disease state in which a virus invades healthy cells, uses the cell’s reproductive mechanisms to multiply or replicate, and ultimately lyses the cells, resulting in cell death, release of viral particles, and infection of other cells by newly produced progeny viruses. Latent infection by certain viruses is also a possible outcome of a viral infection.

[0089] As used herein, the term “treating a viral infection” means inhibiting the replication of a particular virus, inhibiting the transmission of a virus, and improving or reducing the symptoms of a disease caused by a viral infection. Treatment is considered “therapeutic” if it reduces the viral load and decreases mortality and / or pathological conditions. “Preventing a viral infection” means preventing a virus from becoming established in a host. Treatment is considered “preventive” if the subject has been exposed to the virus but does not become infected with the virus as a result of treatment.

[0090] As used herein, "latency" means a concept that describes 1) a dormant state of viral activity within a population of cells in which viral production, viral packaging, and host cell lysis do not occur or occur at a very low frequency, or 2) downregulation or absence of gene expression within infected cells.

[0091] As used herein, “reversing latent HIV infection” refers to a treatment that upregulates the expression of the integrated HIV genome within latently infected cells, such as a drug that activates a non-canonical NF-κB pathway, resulting in increased susceptibility of infected cells to virus-induced cell death or immunological clearance. As used herein, “depleting latent HIV infection” refers to the clearance of latently HIV-infected cells that may follow reversal of HIV latentness by a reagent such as one that activates a non-canonical NF-κB pathway.

[0092] In certain embodiments, latent HIV-infected cells are dormant CD4 + These are T cells.

[0093] Whenever a dashed line occurs adjacent to a single bond indicated by a solid line, the dashed line represents an optional double bond at that position. Similarly, whenever a dashed circle appears within a ring structure indicated by a solid line or a solid circle, the dashed circle represents one to three optional double bonds arranged according to their appropriate valencies, taking into account whether the ring has optional substitutions around the ring, as is known to those skilled in the art. For example, the dashed lines in the following structure may indicate either a double bond or a single bond at that position:

[0094] [ka]

[0095] When certain compounds or general formulas containing aromatic rings, such as aryl or heteroaryl rings, are depicted, it is understood by those skilled in the art that the specific aromatic positions of any of the double bonds are a mixture of equivalent positions, even if they are depicted in different positions for each compound or formula. For example, in the following two pyridine rings (A and B), the double bonds are depicted in different positions, but they are known to be the same structure and compound:

[0096] [ka]

[0097] The present invention includes compounds and pharmaceutically acceptable salts thereof. Therefore, the word "or" in the context of "compounds or pharmaceutically acceptable salts thereof" is understood to refer to either 1) the compound alone or the compound and its pharmaceutically acceptable salt (selectively), or 2) the compound and its pharmaceutically acceptable salt (combination).

[0098] Unless otherwise specified, the nomenclature of substituents not explicitly defined herein is obtained by naming the terminal portion of the functional group followed by the adjacent functional group toward the bond site. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)(alkyl)OC(O). x In terms such as "2", two R x The bases may be the same, or R x If it is defined that has two or more possible identities, it should be understood that they may be different. In addition, certain substituents are -R x R y It is depicted as such, but in this case, "-" indicates a bond adjacent to the parent molecule, R y is the terminal portion of the functional group. Similarly, it is understood that the above definition is not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art.

[0099] The present invention provides compounds of formulas (I), (Ia), (Ib), (II), and (III), as well as various forms of these compounds described herein (e.g., pharmaceutically acceptable salts). Any reference herein to compounds of formulas (I), (Ia), (Ib), (II), and (III) is not limiting, but it should be understood that it is clearly intended to include the compounds listed in Table 1.

[0100] In one embodiment, the present invention relates to formula (I):

[0101] [ka] [In the formula, R, R', R'', and R''' are independently selected from H and CH3; X1 and X2 are independently selected from the group consisting of O and S; L is as follows:

[0102] [ka] JPEG0007884492000039.jpg98160 (in the formula, Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar 10 Ar 11 Ar 12 Ar 13 Ar 14 Ar 15 Ar 16 Ar 17 Ar 18 Ar 19 Ar 21 Ar 22 Ar 23 Ar 24 Ar 25 and Ar 26 These are, independently of each other, (C6-C 14 ) Selected from the arrow; Alk, Alk2, and Alk3 are each independent of the following:

[0103] [ka] Selected from; R1 is a C3-C6 cycloalkyl or C1-C6 heterocycle; R2 is -(CH2) a -,-(CH2) b -O--(CH2) c -,-(CH2) d -(C6-C 14 )Aryl-(CH2) e -and-(CH2) f -(C1-C6) heteroaryl-(CH2) g - a group consisting of; more preferably selected from C2 heteroaryls; R3 is -(CH2) h -; -(CH2) i -O--(CH2) j -,-(CH2) k -(C6-C 14 )Aryl-(CH2) l -and-(CH2) m' -(C1-C6) heteroaryl-(CH2) m'' -Selected from the group consisting of; R4 is C3-C6 cycloalkyl, (C6-C 14 ) Aryl or (CH2) n' -(C6-C 14 )Aryl-(CH2) n'' , (CH2) n''' -Alk-(CH2) n'''' (wherein n', n'', n''', and n'''' are independently selected from 1 to 8); R5 is a C3-C6 cycloalkyl group; R6 is (CH2) z ,

[0104] [ka] Selected from the group consisting of; a, b, c, d, e, f, g, h, i, j, k, l, m, m', m'', n, p, q, r, s, t, u, v, x, y, and z are each independently selected from 1 to 12. This linker is selected from the group consisting of the following: The present invention provides compounds having the structure described herein, or pharmaceutically acceptable salts or stereoisomers thereof.

[0105] In another embodiment, the present invention relates to formula (Ia):

[0106] [ka] [In the formula, R, R', R'', and R''' are independently selected from H and CH3; X1 and X2 are independently selected from the group consisting of O and S; L is as follows:

[0107] [ka] JPEG0007884492000044.jpg102160 (in the formula, Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar 10 Ar 11 Ar 12 Ar 13 Ar 14 Ar 15 Ar 16 Ar 17 Ar 18 Ar 19 Ar 21 Ar 22 Ar 23 Ar 24 Ar 25 and Ar 26 These are, independently of each other, (C6-C 14 ) Selected from the arrow; Alk, Alk2, and Alk3 are each independent of the following:

[0108] [ka] Selected from; R1 is a C3-C6 cycloalkyl or C1-C6 heterocycle; R2 is -(CH2) a -,-(CH2) b -O--(CH2) c -,-(CH2) d -(C6-C 14 )Aryl-(CH2) e -and-(CH2) f -(C1-C6) heteroaryl-(CH2) g -Selected from the group consisting of; R3 is -(CH2) h -; -(CH2) i -O--(CH2) j -,-(CH2) k -(C6-C 14 )Aryl-(CH2) l -and-(CH2) m' -(C1-C6) heteroaryl-(CH2) m'' -Selected from the group consisting of; R4 is C3-C6 cycloalkyl, (C6-C 14 ) Aryl or (CH2) n' -(C6-C 14 )Aryl-(CH2) n'' , (CH2) n''' -Alk-(CH2) n'''' (wherein n', n'', n''', and n'''' are independently selected from 1 to 8); R5 is a C3-C6 cycloalkyl group; R6 is (CH2) z ,

[0109] [ka] Selected from the group consisting of; a, b, c, d, e, f, g, h, i, j, k, l, m, m', m'', n, p, q, r, s, t, u, v, x, y, and z are each independently selected from 1 to 12. This linker is selected from the group consisting of the following: This relates to the compound, or its pharmaceutically acceptable salts or stereoisomers.

[0110] In another embodiment, the present invention relates to formula (Ib):

[0111] [ka] [In the formula, R, R', R'', and R''' are independently selected from H and CH3; X1 and X2 are independently selected from the group consisting of O and S; L is as follows:

[0112] [ka] JPEG0007884492000049.jpg95160 (in the formula, Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar 10 Ar 11 Ar 12 Ar 13 Ar 14 Ar 15 Ar 16 Ar 17 Ar 18 Ar 19 Ar 21 Ar 22 Ar 23 Ar 24 Ar 25 and Ar 26 These are, independently of each other, (C6-C 14 ) Selected from the arrow; Alk, Alk2, and Alk3 are each independent of the following:

[0113] [ka] Selected from; R1 is a C3-C6 cycloalkyl or C1-C6 heterocycle; R2 is -(CH2) a -,-(CH2) b -O--(CH2) c -,-(CH2) d -(C6-C 14 )Aryl-(CH2) e -and-(CH2) f -(C1-C6) heteroaryl-(CH2) g -Selected from the group consisting of; R3 is -(CH2) h -; -(CH2) i -O--(CH2) j -,-(CH2) k -(C6-C 14 )Aryl-(CH2) l -and-(CH2) m' -(C1-C6) heteroaryl-(CH2) m'' -Selected from the group consisting of; R4 is C3-C6 cycloalkyl, (C6-C 14 ) Aryl or (CH2) n' -(C6-C 14 )Aryl-(CH2) n'' , (CH2) n''' -Alk-(CH2) n'''' (wherein n', n'', n''', and n'''' are independently selected from 1 to 8); R5 is a C3-C6 cycloalkyl group; R6 is (CH2) z ,

[0114] [ka] Selected from the group consisting of; a, b, c, d, e, f, g, h, i, j, k, l, m, m', m'', n, p, q, r, s, t, u, v, x, y, and z are each independently selected from 1 to 12. This linker is selected from the group consisting of the following: This relates to the compound, or its pharmaceutically acceptable salts or stereoisomers.

[0115] In various embodiments, in addition to the above, the variables a, b, c, d, e, f, g, h, i, j, k, l, m, m', m'', n, p, q, r, s, t, u, v, x, y, and z in formulas (I), (Ia), (Ib), (II), and (III) can each be independently selected from 1 to 8.

[0116] In various embodiments, at least one of R'' and R''' is CH3. Preferably, both R'' and R' are CH3.

[0117] Most preferably, R, R', R'', and R''' are each CH3.

[0118] In various embodiments, both X1 and X2 are O.

[0119] In various embodiments, both X1 and X2 are S.

[0120] In various embodiments, X1 is O and X2 is S.

[0121] In various embodiments, X1 is S and X2 is O.

[0122] In various embodiments, Alk, Alk2, and Alk3 are preferably as follows:

[0123] [ka] That is the case.

[0124] In various embodiments, Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar 10 Ar 11 Ar 21 Ar 22 Ar 23 Ar 24 Ar 25 and Ar 26 Each of these could be a C6 aryl compound.

[0125] In various embodiments, Ar 12 Ar 13 Ar 14 Ar 15 Ar 16 Ar 17 Ar 18 and Ar 19 Each of these may be a C9 aryl. In a preferred embodiment, the C9 aryl is as follows:

[0126] [ka] [In the formula, the nitrogen in NH is bonded to the compound bicyclic system (or more) through an amide bond, and R indicates a bond to the linker.] It is represented by [this].

[0127] In various embodiments, Ar 16 Ar 17 Ar 18 and Ar 19 Each of them is C 10 It is an aryl. In a preferred embodiment, C 10 Ariel said the following:

[0128] [ka] [In the formula, the nitrogen in NH is bonded to the compound bicyclic system (or more) through an amide bond, and R indicates a bond to the linker.] It is represented by [this].

[0129] In various embodiments, the linker is given by formula (i):

[0130] [ka] It is the linker.

[0131] Ar1 and Ar2 can each be independently selected from the C6-C9 aryl groups.

[0132] Preferably, with respect to formula (i), Ar1 is a C6 aryl. Alk is as follows:

[0133] [ka] In this embodiment, Ar2 is C6 aryl, m is 1, n is 1, p is 1, and q is 1. In one embodiment, X1 is S and X2 is S. In another embodiment, X1 is S and X2 is O.

[0134] In various embodiments, the linker is given by formula (ii):

[0135] [ka] It is the linker.

[0136] Ar3, Ar2, and Ar5 can each be independently selected from the C6-C9 aryl groups.

[0137] Preferably, with respect to formula (ii), Ar3 is C6 aryl, Ar4 is C6 aryl, r is 1, Ar4 is C6 aryl, s is 1, and Ar5 is C6 aryl. In one embodiment, X1 is O and X2 is O. In one embodiment, X1 is S and X2 is S.

[0138] In various embodiments, the linker is given by formula (iii):

[0139] [ka] [In the formula, Ar6 and Ar7 are each independently a C6-C9 aryl, most preferably each being a C6 aryl; R1 is preferably a C1-C6 heterocycle (e.g., a C4 heterocycle), and most preferably the following:

[0140] [ka] [is] It is the linker.

[0141] In various embodiments, the linker is given by equation (iv):

[0142] [ka] It is the linker.

[0143] Preferably, with respect to formula (iv), Ar8 is C 6-9 Aryl, more preferably C6 aryl, and Alk2 is as follows:

[0144] [ka] And Ar9 is the C6 aryl; C 6-9 It is an aryl, or more specifically, a C6 aryl.

[0145] In various embodiments, the linker is given by equation (v):

[0146] [ka] It is the linker.

[0147] Preferably, with respect to formula (v), Ar 10 C 6-9 Aryl, more preferably C6 aryl, Ar 11 Preferably C 6-9 It is an aryl, more preferably a C6 aryl, where R2 is -(CH2)-C 6-9 aryl-(CH2)-, (or -(CH2)-C6aryl-(CH2)-), -(CH2) 1-8 -(more preferably -(CH2)4-, -(CH2)3-, or -(CH2)6-) and -(CH2) 2-6 -O-(CH2) 2-6 -( far-(CH2) 2-4 -O-(CH2) 2-4) are selected from. In one embodiment, R2 is -(CH2)2-O-(CH2)2-. If R2 is a heteroaryl, it is preferably a C2 heteroaryl.

[0148] In various embodiments, the linker is given by formula (vi):

[0149] [ka] It is the linker.

[0150] Preferably, with respect to formula (vi), Ar 12 is C 6-9 It is an aryl, t is 1 to 4 (more t is 1), and Alk3 is as follows:

[0151] [ka] And u is 1 to 4 (fuu is 1), Ar 13 is C 6-9 It is an arrow. Most preferably, Ar 12 and Ar 13 Each of these is a C9 aryl, most preferably a C9 aryl, which is as follows:

[0152] [ka] [In the formula, the nitrogen in NH is bonded to the compound bicyclic system (or more) through an amide bond, and R indicates a bond to the linker.] It is expressed as follows.

[0153] In various embodiments, the linker is given by formula (vii):

[0154] [ka] It is the linker.

[0155] Preferably, with respect to formula (vii), Ar14 C 6-9 It is an aryl (more preferably a C9 aryl), and R3 is (CH2)1- 12 (For example, (CH2)4-6); -(CH2)1-6-O-(CH2)1-6-(For example, -(CH2) 2-4 -O-(CH2) 2-4 Selected from the group consisting of -), Ar 15 is a C9 aryl. More preferably, with respect to formula (vii), Ar 14 R3 is a C9 aryl compound, and R3 is -(CH2) 4-12 -,-(CH2) 2-4 -O-(CH2) 2-4 - Selected from the group consisting of these. In a preferred embodiment, Ar 14 and Ar 15 These are as follows:

[0156] [ka] [In the formula, the nitrogen in NH is bonded to the compound bicyclic system (or more) through an amide bond, and R indicates a bond to the linker.] This is a C9 aryl.

[0157] In various embodiments, the linker is given by equation (viii):

[0158] [ka] It is the linker.

[0159] Preferably, Ar 16 C 6-10 Aryl, more preferably C9 aryl or C 10 It is an aryl, and R4 is a C3-C6 cycloalkyl or (C6-C 14 ) Selected from the group consisting of aryls, Ar 17 C 6-10 Aryl, more preferably C9 aryl or C 10It is an aryl group. More preferably, R4 is a C6 cycloalkyl group, a C6 aryl group, a -CH2-C6 aryl-CH2 group, or

[0160] [ka] That is the case.

[0161] In various embodiments, the linker is given by equation (ix):

[0162] [ka] It is the linker.

[0163] Preferably, Ar 18 C 6-10 Aryl, more preferably C9 aryl or C 10 It is Aryl, Ar 19 C 6-10 Aryl, more preferably C9 aryl or C 10 It is Ariel.

[0164] In various embodiments, the linker is given by equation (x):

[0165] [ka] It is the linker.

[0166] Preferably, A 21 and A 22 Independently, C 6-9 Selected from aryl, v ranges from 1 to 6. More preferably in one embodiment, Ar 21 is C6 aryl, v is 1, Ar 22 is C6 aryl. In one embodiment, more preferably Ar 21 is a C6 aryl, v is 2, Ar 22 This is a C6 aryl compound.

[0167] In various embodiments, the linker is given by formula (xi):

[0168] [ka] It is the linker.

[0169] Preferably, Ar 23 C 6-9 It is an aryl, more preferably a C6 aryl, and R5 is a C3-C6 cycloalkyl, Ar 24 Preferably C 6-9 It is an aryl, more preferably a C6 aryl. Most preferably, R5 is a C6 cycloalkyl.

[0170] In another embodiment, the present invention relates to formula (II):

[0171] [ka] [In the formula, R, R', R'', and R''' are independently selected from H and CH3; X1 and X2 are independently selected from the group consisting of O and S; L' is the formula:

[0172] [ka] (In the formula, Ar 27 and Ar 28 These are, independently, C6-C 14 Selected from the alphabet, R7 is

[0173] [ka] , C6 aryl and -(CH2) 4-15 -( far-(CH2) 6-10 Selected from the group consisting of -); a' and b' are independently selected from 0 to 6. It is the linker. The compound is provided.

[0174] In various embodiments, R, R', R'', and R''' are each CH3.

[0175] In various embodiments, X1 and X2 are each O;

[0176] In various embodiments, Ar 27 and Ar 28 These are C6-C respectively. 10 Selected from aryls, each more preferably a C9 aryl. In various embodiments, the C9 aryl is of formula

[0177] [ka] [In the formula, the nitrogen in NH is bonded to the compound bicyclic system (or more) through an amide bond, and R indicates a bond to the linker.] It can be represented by: Most preferably, the C9 aryl is given by formula:

[0178] [ka] This is the C9 aryl.

[0179] In one embodiment, R, R', R'', and R'''' are each CH3, and X1 and X2 are each O; a' is 1, b' is 1, and R7 is as follows:

[0180] [ka] and; Ar 27 and Ar 28 These are the formulas:

[0181] [ka] Ar 27 and Ar28 That is the case.

[0182] In one embodiment, the present invention provides a compound of formula (II), wherein R, R', R'' and R''' are each CH3, X1 and X2 are each O and Ar 27 and Ar 28 These are the formulas:

[0183] [ka] Ar 27 and Ar 28 And a' is 1, b' is 1, and R7 is as follows:

[0184] [ka] It is conditional on the fact that it is not;

[0185] In various embodiments, equation (II) [wherein a' is 0, b' is 0, and R7 is -(CH2)] 6-15 -, (more-(CH2) 6-10 -) and R, R', R'' and R''' are each CH3, and X1 and X2 are each O, Ar 27 and Ar 28 Each of these is a compound of the formula [C9 aryl]. Preferably, the C9 aryl is of the formula

[0186] [ka] [In the formula, the nitrogen in NH is bonded to the compound bicyclic system (or more) through an amide bond, and R indicates a bond to the linker.] It is represented by: Most preferably, the C9 aryl is given by formula:

[0187] [ka] This is the C9 aryl.

[0188] In one embodiment, the present invention relates to formula (II) [wherein a' is 0, b' is 0, R7 is -(CH2)6-, R, R', R'' and R''' are each CH3, X1 and X2 are each O, Ar 27 and Ar 28 These are the formulas:

[0189] [ka] (In the formula, the nitrogen in NH is bonded to the compound bicyclic system (or more) through an amide bond, and R indicates a bond to the linker.) This provides a compound of a C9 aryl represented by [the given formula].

[0190] In one embodiment, the present invention provides a compound of formula (II), wherein R, R', R'' and R''' are each CH3, X1 and X2 are each O, and Ar 27 and Ar 28 These are the formulas:

[0191] [ka] Ar 27 and Ar 28 The conditions are that a' is 0, b' is 0, and R7 is not -(CH2)6-:

[0192] In another embodiment, the present invention relates to formula (III):

[0193] [ka] [In the formula, R, R', R'', and R''' are independently selected from H and CH3; X1 and X2 are independently selected from the group consisting of O and S; L'' is the formula:

[0194] [ka] (In the formula, Ar 29 and Ar 30 It is independently, C6-C 10 Selected from the array, R8 is,

[0195] [ka] ,-(CH2) 6-15 -, ' -and-(CH2) d' -(C6-C 10 )Aryl-(CH2) e' -(In the formula, d' and e' are selected independently from a group consisting of 1 to 6.) It is the linker. This provides compounds with the structure described above.

[0196] In one embodiment of the compound of formula (III), R, R', R'' and R''' are each CH3; X1 and X2 are each O, and Ar 29 and Ar 30 These are C6 aryl compounds, and R8 is as follows:

[0197] [ka] That is the case.

[0198] In one embodiment of the compound of formula (III), R, R', R'' and R''' are each CH3; X1 and X2 are each O, and Ar 29 and Ar 30 These are C6 aryl compounds, and R8 is -(CH2) ' -(C6)aryl-(CH2) ' - is

[0199] In one embodiment of the compound of formula (III), R, R', R'' and R''' are each CH3; X1 and X2 are each O, and Ar 29 and Ar 30These are C6 aryl compounds, and R8 is -(CH2)6-.

[0200] In formulas (II) and (III) above, any of the aryl groups may, in part, be substituted with any one of the following, but not limited to: (C1-C6)alkyl, (C1-C6)alkoxy, halo, oxo, haloalkyl, bihaloalkyl, trihaloalkyl, haloalkoxy, bihaloalkoxy, trihaloalkoxy, hydroxyl, amino, and amide. Furthermore, any of the aryl groups in formulas (I), (Ia), and (Ib) may also, in part, be substituted with the above.

[0201] Examples of compounds included by the present invention include, but are not limited to, those listed in Table 1 below:

[0202] [Table 1] JPEG0007884492000091.jpg241161JPEG0007884492000092.jpg220161JPEG00078844920 00093.jpg227161JPEG0007884492000094.jpg231161JPEG0007884492000095.jpg236161 JPEG0007884492000096.jpg213161JPEG0007884492000097.jpg202161JPEG00078844920 00098.jpg204161JPEG0007884492000099.jpg234161JPEG0007884492000100.jpg212161

[0203] In one embodiment, the present invention is as follows:

[0204] [ka] This relates to compounds selected from the group consisting of JPEG0007884492000102.jpg206161 and JPEG0007884492000103.jpg176161, and their pharmaceutically acceptable salts.

[0205] In one embodiment, the present invention is as follows:

[0206] [ka] The present invention provides compounds selected from the group consisting of the following; and pharmaceutically acceptable salts thereof.

[0207] pharmaceutically acceptable salts are also within the scope of the present invention with respect to all compounds 1 to 63 described herein. Most preferably, each of compounds 1 to 63 may generally exist as a hydrochloride salt (i.e., an HCl salt), for example, more specifically as a dihydrochloride salt, or (2HCl) salt. Any of compounds 1 to 63 existing as a single species, including their pharmaceutically acceptable salts, as well as any of these compounds in free base form, are within the scope of the present invention.

[0208] Specific examples of linkers (L) that can be used in accordance with the present invention are as follows:

[0209] [ka] Examples include those selected from the group consisting of JPEG0007884492000106.jpg224161, JPEG0007884492000107.jpg196161, JPEG0007884492000108.jpg211161, and JPEG0007884492000109.jpg30160.

[0210] According to one embodiment of the present invention, a pharmaceutical composition is provided comprising a compound of formula (I), (Ia), (Ib), (II), or (III) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In a further embodiment, the compound exists in an amorphous form. In a further embodiment, the pharmaceutical composition is in the form of a tablet. In a further embodiment, the compound exists as a spray-dried dispersion. In a further embodiment, the composition exists in the form of nanoparticles, for example, particles between 1 and 100 nanometers in size.

[0211] One embodiment of the present invention provides a method for treating HIV infection in a subject, comprising the step of administering a compound of formula (I), (Ia), (Ib), (II), or (III) or a pharmaceutically acceptable salt thereof to the subject.

[0212] One embodiment of the present invention provides a method for treating HIV infection in a subject, comprising the step of administering a pharmaceutical composition described herein to the subject.

[0213] Furthermore, the compounds of the present invention and the linker (L) can exist in specific geometric or stereoisomeric forms. The present invention intends to encompass all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures. Additional chiral carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0214] The optically active (R)- and (S)-isomers, as well as the d- and l-isomers, can be prepared using chiral synthons or chiral reagents, or they can be separated using conventional techniques. For example, if a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary agent, in which case the resulting diastereomer mixture is separated and the auxiliary groups are cleaved to obtain the pure, desired enantiomer. Alternatively, if the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, a diastereomer salt can be formed using a suitable optically active acid or base, and then the diastereomer thus formed can be separated by fractional crystallization or chromatographic means known in the art, after which the pure enantiomer can be recovered. Furthermore, the separation of enantiomers and diastereomers is often achieved using chromatography with a chiral stationary phase, sometimes in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0215] Another embodiment of the present invention provides compounds of formula I, Ia, Ib, II, or III, or pharmaceutically acceptable salts thereof, for use in medical therapy.

[0216] Another embodiment of the present invention provides compounds of formula I, Ia, Ib, II, or III, or pharmaceutically acceptable salts thereof, for use in the treatment of HIV infection.

[0217] In another embodiment of the present invention, a compound of formula I, Ia, Ib, II, or III is provided, wherein the compound or a salt of the compound is used in the manufacture of a pharmaceutical for use in the treatment of HIV infection in humans.

[0218] In one embodiment, the present invention provides a method for curing HIV infection in a subject, comprising the step of administering to the subject a compound of formula I, Ia, Ib, II, and III, and any compound of Table 1, together with a pharmaceutically acceptable salt thereof. “Curing” or “curing” the disease in a patient is used to indicate the eradication, cessation, restorative, or termination of human immunodeficiency virus or symptoms, or the progression of symptoms or the virus, for a specified period. For example, in one embodiment, “curing” or “curing” refers to a therapeutic administration or combination of administrations, either alone or in combination with one or more other compounds, that induces and maintains sustained virological control of human immunodeficiency virus (e.g., plasmaviremia at levels undetectable by polymerase chain reaction (PCR) testing, bDNA (branched-chain DNA) testing, or NASBA (nucleic acid sequence-based amplification) testing) for at least two years without other therapeutic intervention. The PCR, bDNA, and NASBA tests are carried out using techniques known and well-known to those skilled in the art. For example, the eradication, cessation, suspension, or termination of human immunodeficiency virus or its symptoms, or the progression of the symptoms or virus, may last for at least two years.

[0219] In one embodiment, the present invention provides a method for curing HIV infection in a subject, comprising the step of administering to the subject a pharmaceutical composition comprising compounds of formulas I, Ia, Ib, II, and III together with pharmaceutically acceptable salts thereof.

[0220] In one embodiment, the present invention provides the use of compounds of formulas I, Ia, Ib, II, and III, or pharmaceutically acceptable salts thereof, in the manufacture of a pharmaceutical for use in the treatment of HIV infection.

[0221] In one embodiment, the present invention provides compounds of formulas I, Ia, Ib, II, and III, or pharmaceutically acceptable salts thereof, for use in the treatment of HIV infection.

[0222] Compounds of formulas I, Ia, Ib, II, and III, in combination with one or more drugs useful for HIV therapy, may also be used in methods for curing HIV infection.

[0223] In one embodiment, a pharmaceutical formulation containing a compound of formula I, Ia, Ib, II, or III, or a salt thereof, is a formulation suitable for parenteral administration. In another embodiment, the formulation is a long-acting parenteral formulation. In a further embodiment, the formulation is a nanoparticle formulation.

[0224] The compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives may be used alone or in combination with other therapeutic agents. Accordingly, in other embodiments, a method for treating and / or preventing HIV infection in a subject may further include the administration of one or more additional pharmaceuticals active against HIV, in addition to the administration of compounds of formula I, Ia, Ib, II, or III.

[0225] In such embodiments, one or more additional agents active against HIV are selected from the group consisting of antiretroviral agents, latent reversal agents, and agents for clearance therapy.

[0226] In other embodiments, one or more additional agents active against HIV are selected from the group consisting of nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, adhesion and fusion inhibitors, integrase inhibitors, maturation inhibitors, CXCR4 and / or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyltransferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and neutralizing antibodies, as well as combinations thereof.

[0227] In certain embodiments, one or more additional drugs active against HIV include zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, and adefovir dipivoxil.dipivoxil), fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, caplavillin (ca Pravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir anavir), tipranavir, palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS-626529, 5-Helix, raltegravir, elvitegravir, dolutegravir, cabotegravir (ca Bitegravir, bictegravir, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, darunavir, vorinostat, panobinostat, romidepsin, valpronic acidThe following are selected from the group consisting of acid, mocetinostat, sodium corotonate, bryostatin, ingenol B, disulfiram, GS-9620, JQ1, iBET151, bortezomib, epigallocatechin gallate, salinosporamide A, carfilzomib, broad-spectrum neutralizing antibodies (bNAb), eCD4-Ig, CD4-Ig, and biaffinity retargeting (DART) proteins.

[0228] Accordingly, the compounds of the present invention of formula (I), (Ia), (Ib), (II), or (III), and any other pharmaceutically active agents may be administered together or separately, and if administered separately, the administration may be simultaneous or sequential in any order. The amounts of the compounds of the present invention of formula (I), (Ia), (Ib), (II), or (III), and the other pharmaceutically active agents, and the relative timing of administration, are selected to achieve the desired combined therapeutic effect. The administration of the compounds of the present invention of formula (I), (Ia), (Ib), (II), or (III), and their salts, solvates, or other pharmaceutically acceptable derivatives, in combination with other therapeutic agents may be (1) in a single pharmaceutical composition containing both compounds; or (2) in a combination of simultaneous administration in separate pharmaceutical compositions each containing one of the compounds. Alternatively, the combination may be administered sequentially and separately, with one therapeutic agent administered first and the other second, or vice versa. Such sequential administrations may be time-shortened or time-separated. The amounts of compound(s) of formula I, Ia, Ib, II, or III, or their salts, and other pharmaceutically active agents(s), and the relative timing of administration are selected to achieve the desired combination therapeutic effect.

[0229] Furthermore, the compounds of the present invention of formula (I), (Ia), (Ib), (II), or (III) may be used in combination with one or more other agents that may be useful in the treatment of HIV. These agents include antiretroviral agents, latent reversal agents, and agents for clearance therapy. Some examples of antiretroviral agents are provided below:

[0230] Nucleotide reverse transcriptase inhibitors, such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, erbucitabine, and similar drugs;

[0231] Non-nucleotide reverse transcriptase inhibitors (including drugs with antioxidant activity such as Immunocal and Oltipraz), e.g., nevirapine, delavirdine, efavirenz, loviride, Immunocal, Oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, and similar drugs;

[0232] Protease inhibitors, such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, and similar drugs;

[0233] Invasion, adhesion, and fusion inhibitors, such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068, and BMS-626529, 5-helix, and similar agents;

[0234] Integrase inhibitors, such as raltegravir, elvitegravir, dolutegravir, cabotegravir, bictegravir, and similar drugs;

[0235] Maturation inhibitors, e.g., PA-344 and PA-457, and similar drugs; and

[0236] CXCR4 and / or CCR5 inhibitors, such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), TAK449, and those disclosed in WO 02 / 74769, PCT / US03 / 39644, PCT / US03 / 39975, PCT / US03 / 39619, PCT / US03 / 39618, PCT / US03 / 39740, and PCT / US03 / 39732, and similar agents.

[0237] Further examples of how the compounds of the present invention can be used in combination with one or more agents useful for the prevention or treatment of HIV are found in Table 2.

[0238] [Table 2] JPEG0007884492000111.jpg242160JPEG0007884492000112.jpg63160

[0239] The present invention may be used in combination with other agents that induce HIV expression, such as latency reversal agents. Some, but not limited to, latency reversal agents include: histone deacetylase inhibitors (e.g., vorinostat, panobinostat, romidepsin), histone crotonyltransferase inhibitors (sodium corotonate), protein kinase C agonists (e.g., bryostatin, ingenol B), disulfiram, TLR7 agonists (e.g., GS-9620), and bromodomain inhibitors (e.g., JQ1, iBET151). Many of these agents are described in more detail below.

[0240] The present invention may be used in combination with other agents that induce HIV expression, such as agents for clearance therapy. Some examples of agents for clearance therapy, or immunological combinations for clearance, include, but are not limited to, neutralizing and broad-spectrum neutralizing antibodies (bNAbs), eCD4-Ig, CD4-Ig, and biaffinity retargeting (DART) proteins.

[0241] The range of combinations of the compounds of the present invention with HIV agents is not limited to those listed above, but in principle includes any combination with any pharmaceutical composition useful for the treatment and / or prevention of HIV. As described, in such combinations, the compounds of the present invention and other HIV agents may be administered separately or together. Furthermore, one agent may be administered before, simultaneously with, or after the administration of other agents(s).

[0242] The present invention may be used in combination with one or more agents useful as pharmacological enhancers, and with or without additional compounds for the prevention or treatment of HIV. Examples of such pharmacological enhancers (or pharmacokinetic enhancers) include, but are not limited to, ritonavir, GS-9350 (cobicistat), and SPI-452.

[0243] Ritonavir is a compound of 10-hydroxy-2-methyl-5-(1-methylethyl)-1-1[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecane-13-onic acid, 5-thiazolyl methyl ester, [5S-(5S * ,8R * ,10R * ,11R * It is available as Norvir from Abbott Laboratories (Abbott Park, Illinois). Ritonavir is an HIV protease inhibitor indicated in conjunction with other antiretroviral agents for the treatment of HIV infection. Ritonavir also inhibits P450-mediated drug metabolism and the P-glycoprotein (Pgp) cell transport system, thereby increasing the concentration of the active compound in the body.

[0244] GS-9350 (cobicistat) is a compound developed by Gilead Sciences (Foster City, California) as a pharmacological enhancer.

[0245] SPI-452 is a compound developed by Sequoia Pharmaceuticals (Gaithersburg, Maryland) as a pharmacological enhancer.

[0246] In one embodiment, the compound of formula I, Ia, Ib, II, or III is used in combination with ritonavir. In one embodiment, the combination is an oral fixed-dose combination. In another embodiment, the compound of formula I, Ia, Ib, II, or III is formulated as a long-acting parenteral injectable agent, and ritonavir is formulated as an oral composition. In one embodiment, there is a kit containing the compound of formula I, Ia, Ib, II, or III formulated as a long-acting parenteral injectable agent, and ritonavir formulated as an oral composition. In another embodiment, the compound of formula I, Ia, Ib, II, or III is formulated as a long-acting parenteral injectable agent, and ritonavir is formulated as an injectable composition. In one embodiment, there is a kit containing the compound of formula I, Ia, Ib, II, or III formulated as a long-acting parenteral injectable agent, and ritonavir formulated as an injectable composition.

[0247] In another embodiment of the present invention, the compound of formula I, Ia, Ib, II, or III is used in combination with GS-9350. In one embodiment, the combination is an oral fixed-dose combination. In another embodiment, the compound of formula I, Ia, Ib, II, or III is formulated as a long-acting parenteral injectable agent, and GS-9350 is formulated as an oral composition. In one embodiment, a kit is provided containing the compound of formula I, Ia, Ib, II, or III formulated as a long-acting parenteral injectable agent, and GS-9350 formulated as an oral composition. In another embodiment, the compound of formula I, Ia, Ib, II, or III is formulated as a long-acting parenteral injectable agent, and GS-9350 is formulated as an injectable composition. In one embodiment, there is a kit containing the compound of formula I, Ia, Ib, II, or III formulated as a long-acting parenteral injectable agent, and GS-9350 formulated as an injectable composition.

[0248] In one embodiment, a compound of formula I, Ia, Ib, II, or III is used in combination with SPI-452. In one embodiment, the combination is an oral fixed-dose combination. In another embodiment, a compound of formula I, Ia, Ib, II, or III is formulated as a long-acting parenteral injectable agent, and SPI-452 is formulated as an oral composition. In one embodiment, a kit is provided containing a compound of formula I, Ia, Ib, II, or III formulated as a long-acting parenteral injectable agent, and SPI-452 formulated as an oral composition. In another embodiment, a compound of formula I, Ia, Ib, II, or III is formulated as a long-acting parenteral injectable agent, and SPI-452 is formulated as an injectable composition. In one embodiment, a kit is provided containing a compound of formula I, Ia, Ib, II, or III formulated as a long-acting parenteral injectable agent, and SPI-452 formulated as an injectable composition.

[0249] In one embodiment of the present invention, a compound of formula I, Ia, Ib, II, or III is used in combination with a compound found in the previously filed PCT / CN2011 / 0013021 (incorporated herein by reference).

[0250] The other therapeutic agents described herein may be used in combination with the chemicals described herein, for example, in the amounts specified in the Physicians' Desk Reference (PDR), or in amounts otherwise determined by those skilled in the art.

[0251] Another embodiment of the present invention provides a method for treating a viral infection in a mammal at least partially mediated by a virus of the retrovirus family, the method comprising the step of administering a compound of formula I, Ia, Ib, II, or III to a mammal diagnosed with the viral infection or a mammal at risk of developing the viral infection.

[0252] Another embodiment of the present invention provides a method for treating a viral infection in a mammal at least partially mediated by a virus of the retrovirus family, the method comprising the step of administering a compound of formula I, Ia, Ib, II, or III to a mammal diagnosed with the viral infection or a mammal at risk of developing the viral infection, wherein the virus is the HIV virus. In some embodiments, the HIV virus is the HIV-1 virus.

[0253] Another embodiment of the present invention provides a method for treating a viral infection in a mammal at least partially mediated by a virus of the retrovirus family, comprising the steps of administering a compound of formula I, Ia, Ib, II, or III to a mammal diagnosed with the viral infection or a mammal at risk of developing the viral infection, further comprising administering one or more agents active against the HIV virus in a therapeutically effective amount.

[0254] In another embodiment of the present invention, a method is provided for treating a viral infection in a mammal at least partially mediated by a virus of the retrovirus family, the method comprising the step of administering a compound of formula I, Ia, Ib, II, or III to a mammal diagnosed with the viral infection or a mammal at risk of developing the viral infection, further comprising the administration of one or more agents active against the HIV virus in a therapeutically effective amount, wherein the agents active against the HIV virus are selected from nucleotide reverse transcriptase inhibitors; non-nucleotide reverse transcriptase inhibitors; protease inhibitors; entry, attachment, and fusion inhibitors; integrase inhibitors; maturation inhibitors; CXCR4 inhibitors; and CCR5 inhibitors.

[0255] In another embodiment, the present invention provides a method for depleting latent HIV-infected cells, comprising the step of administering a compound of formula (I), (Ia), (Ib), (II), or (III) or a pharmaceutically acceptable salt thereof to a target.

[0256] In various embodiments of the above method, Alk, Alk2, and Alk3 are each given by the formula:

[0257] [ka] It is represented by [this].

[0258] In various embodiments of the above method, Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar 10 Ar 11 Ar 21 Ar 22 Ar 23 Ar 24 Ar 25 and Ar 26 Each of these is a C6 aryl compound.

[0259] In various embodiments of the above invention, Ar 12 Ar 13 Ar 14 and Ar15 Ar 16 Ar 17 Ar 18 , and Ar 19 Each of these is a C9 aryl.

[0260] In various embodiments of the above invention, Ar 16 Ar 17 Ar 18 and Ar 19 Each of them is C 10 It is Ariel.

[0261] In various embodiments of the above invention, the linker (L) is as follows:

[0262] [ka] Selected from the group consisting of JPEG0007884492000115.jpg206160, JPEG0007884492000116.jpg206160, and JPEG0007884492000117.jpg129160.

[0263] In various embodiments of the above invention, the compound is selected from the group consisting of:

[0264] [Table 3] JPEG0007884492000119.jpg221160JPEG0007884492000120.jpg238160JPEG00078844920 00121.jpg238160JPEG0007884492000122.jpg242160JPEG0007884492000123.jpg233162 JPEG0007884492000124.jpg244161JPEG0007884492000125.jpg215161JPEG00078844920 00126.jpg240161JPEG0007884492000127.jpg223161JPEG0007884492000128.jpg116162

[0265] In various embodiments of the above method, preferably, in formulas (Ia) and (Ib), X1 and X2 are O, respectively.

[0266] In various embodiments of the above method, in the linker (L), Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar 10 Ar 11 Ar 20 Ar 21 Ar 22 Ar 23 , and Ar 24 Each of these is a C6 aryl compound.

[0267] In various embodiments of the above method, the linker (L) is selected from the group consisting of (i) and (v).

[0268] In various embodiments of the above method, m, n, p, and q are each 1, and each (CH2) in equation (v) 0-3 The group is represented by (CH2).

[0269] In various embodiments of the above method and compound, the linker (L) is as follows:

[0270] [ka] It is selected from the group consisting of the following.

[0271] In various embodiments of the above method, the linker (L) is selected from the group consisting of (vi) and (vii), and Ar 12 Ar 13 Ar 14 and Ar 15 Each of these is a C9 aryl.

[0272] In various embodiments of the above method, Ar 12 and Ar 14 Each of them is,

[0273] [ka] And Ar 13 and Ar 15 Each of them is,

[0274] [ka] In this case, the wavy line represents the connection point.

[0275] In various embodiments of the above method, the linker (L) is as follows:

[0276] [ka] It is selected from the group consisting of the following.

[0277] In one embodiment of the present invention, the present invention is given by formula:

[0278] [ka] The present invention relates to the compound (compound 13); or a pharmaceutically acceptable salt thereof. The present invention also includes pharmaceutical compositions comprising this compound, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients, including, for example, those described herein. The present invention also includes a method for treating HIV infection in a subject, comprising the step of administering this compound, or a pharmaceutically acceptable salt thereof, and a combination thereof, to the subject. The present invention also includes this compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection. The present invention also includes the use of this compound in the manufacture of a pharmaceutical for the treatment of HIV infection. The present invention also includes a method for depleting latent HIV-infected cells, comprising the step of administering this compound, or a pharmaceutically acceptable salt thereof, and a combination thereof, to the subject.

[0279] In one embodiment of the present invention, the present invention is given by formula:

[0280] [ka] The present invention relates to the compound (compound 20); or a pharmaceutically acceptable salt thereof. The present invention also includes pharmaceutical compositions comprising the compound, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients, including, for example, those described herein. The present invention also includes a method for treating HIV infection in a subject, comprising the step of administering the compound, or a pharmaceutically acceptable salt thereof, and a combination thereof, to the subject. The present invention also includes the compound, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection. The present invention also includes the use of the compound in the manufacture of a pharmaceutical for the treatment of HIV infection. The present invention also includes a method for depleting latent HIV-infected cells, comprising the step of administering the compound, or a pharmaceutically acceptable salt thereof, and a combination thereof, to the subject.

[0281] In various embodiments, a method for depleting latent HIV infection further includes the step of administering one or more additional agents active against HIV as disclosed above. For example, in various embodiments, one or more additional agents are selected from the group consisting of nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, adhesion and fusion inhibitors, integrase inhibitors, maturation inhibitors, CXCR4 and / or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyltransferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and antibodies for clearance therapy, as well as combinations thereof. In various embodiments, one or more additional drugs active against HIV include zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, and adefovir dipivoxil.dipivoxil), fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, caplavillin (ca Pravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir anavir), tipranavir, palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS-626529, 5-Helix, raltegravir, elvitegravir, dolutegravir, cabotegravir (ca Bitegravir, bictegravir, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, darunavir, vorinostat, panobinostat, romidepsin, valpronic acidThe following are selected from the group consisting of acid, mocetinostat, sodium corotonate, bryostatin, ingenol B, disulfiram, GS-9620, JQ1, iBET151, bortezomib, epigallocatechin gallate, salinosporamide A, carfilzomib, and neutralizing antibodies, eCD4-Ig, CD4-Ig, bNAb, DARTS, and IgA.

[0282] Compounds according to formulas I, Ia, Ib, II, and III, as well as their pharmaceutically acceptable salts, may be useful in the treatment of cancer and precancerous syndromes. Preferably, the present invention relates to brain cancer (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Banayan-Zonana syndrome, Cowden disease, Lhermit-Dacross disease, Wilms tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous cell carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia The present invention relates to a method for treating cancers selected from the group consisting of hematological diseases, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial carcinoma, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, oral cancer, gastrointestinal stromal tumors (GISTs), and testicular cancer.

[0283] Preferably, the present invention relates to a method for treating precancerous syndromes in mammals, including humans, the precancerous syndromes being selected from: cervical intraepithelial neoplasm, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, cutaneous nevi (premelanoma), prostatic intraepithelial (intraductal) neoplasm (PIN), ductal carcinoma in situ (DCIS), colorectal polyps, and severe hepatitis or cirrhosis.

[0284] Compounds of formulas (I), (Ia), (Ib), (II), and (III), and their pharmaceutically acceptable salts, may be co-administered with at least one other active agent known to be useful in the treatment of cancer or precancerous syndromes.

[0285] The term "co-administration," as used herein, means either simultaneous administration of a c-MYC inhibitor compound described herein with one or more additional activators known to be useful in the treatment of cancer, including chemotherapy and radiotherapy, or separate sequential administration. The term "additional activators," as used herein, includes any compound or therapeutic agent known to or exhibiting advantageous properties when administered to patients requiring cancer treatment. Preferably, if administration is not simultaneous, the compounds are administered within a short time interval. Furthermore, it is not relevant whether the compounds are administered in the same dosage form; for example, one compound may be administered by injection and another by oral administration.

[0286] Examples of additional active ingredients (one or more) (antineoplastic agents) for use in combination with or co-administered with the combination of the present invention are listed below. This list is not limiting. Additional antineoplastic agents are intended for use with the compounds of the present invention.

[0287] Typically, any antineoplastic agent active against the susceptible tumor being treated can be co-administered in the treatment of cancer according to the present invention. Examples of such agents can be found in *Cancer Principles and Practice of Oncology* by VT Devita and S. Hellman (eds.), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Those skilled in the art will be able to identify which combinations of agents are useful based on the drugs involved and the specific characteristics of the cancer. Typical antineoplastic agents useful in the present invention include, but are not limited to, antimicrotubule agents, e.g., diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents, e.g., nitrogen mustard, oxazaphosphorine, alkyl sulfonates, nitrosourea, and triazenes; antibiotics, e.g., anthracyclines, actinomycin, and bleomycin; topoisomerase II inhibitors, e.g., epipodophyllotoxin; antimetabolites, e.g., purines and pyrimidine analogs, and folic acid antagonists; topoisomerase I inhibitors, e.g., camptothecin; hormones and hormone analogs; signaling pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; apoptosis promoters; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.

[0288] Examples of further active ingredients (one or more) (antineoplastic agents) to be used in combination with or co-administered with the compounds of the present invention are chemotherapeutic agents.

[0289] Antimicrotubule agents or antimitotic agents are phase-specific drugs that are active against microtubules of tumor cells during the M phase or mitotic phase of the cell cycle. Examples of antimicrotubule agents include, but are not limited to, diterpenoids and vinca alkaloids.

[0290] Diterpenoids are phase-specific anticancer agents derived from natural sources that act during the G2 / M phase of the cell cycle. Diterpenoids are thought to stabilize the β-tubulin subunit of microtubules by binding to this protein. Subsequently, protein degradation is inhibited, mitosis is halted, and cell death occurs. Examples of diterpenoids, though not limited to them, include paclitaxel and its analog, docetaxel.

[0291] Paclitaxel, 5β,20-epoxy-1,2α,4,7β,10β,13α-hexa-hydroxytaxa-11-en-9-one 4,10-diaacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine, is a natural diterpene product isolated from the Pacific yew (Taxus brevifolia) and is commercially available as the injectable solution TAXOL®. It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. (J. Am. Chem, Soc., 93:2325. 1971), whose structure was characterized by chemical and X-ray crystallographic methods. One mechanism of its activity is related to paclitaxel's ability to bind to tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981). For an overview of the synthesis and anticancer activity of several paclitaxel derivatives, see DGI Kingston et al., Studies in Organic Chemistry vol. 26, titled "New trends in Natural Products Chemistry 1986", edited by Attaur-Rahman, PW Le Quesne (Elsevier, Amsterdam, 1986), pp. 219-235.

[0292] Paclitaxel is approved for clinical use in the United States for the treatment of refractory ovarian cancer (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann. inntem, Med., 111:273, 1989) and breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991). It is a potential candidate for the treatment of cutaneous neoplasms (Einzig et al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck cancers (Forastire et al., Sem. Oncol., 20:56, 1990). This compound also shows potential in the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750, 1994), lung cancer, and malaria. When patients are treated with paclitaxel, myelosuppression occurs in relation to the duration of administration exceeding the threshold concentration (50 nM) (Kearns, CM et. al., Seminars in Oncology, 3(6) p.16-23, 1995) (multiple cell lines, Ignoff, RJ et. al, Cancer Chemotherapy Pocket Guide, 1998).

[0293] Docetaxel, a trihydrate of (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytaxa-11-en-9-one 4-acetate 2-benzoate, is marketed as an injectable solution under the registered trademark TAXOTERE. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semi-synthetic derivative of paclitaxel (see previous section), prepared using 10-deacetyl-baccatin III, a natural precursor extracted from the needles of the European yew tree. The dose-limiting toxicity of docetaxel is neutropenia.

[0294] Vinca alkaloids are phase-specific antineoplastic agents derived from periwinkle. Vinca alkaloids act on the M phase (mitosis) of the cell cycle by specifically binding to tubulin. As a result, the bound tubulin molecules are unable to polymerize into microtubules. Mitosis is thought to be arrested at metaphase, followed by cell death. Examples of vinca alkaloids, though not limited to them, include vinblastine, vincristine, and vinorelbine.

[0295] Vinblastine, also known as vincaleicoblastine sulfate, is marketed as VELBAN® in an injectable solution. While it may be indicated as a second-line treatment for various solid tumors, it is primarily indicated for testicular cancer, as well as various lymphomas, such as Hodgkin's disease, and lymphocytic and histiocytic lymphomas. Bone marrow suppression is a dose-limiting side effect of vinblastine.

[0296] Vincristine, vincaleicoblastine, 22-oxo-sulfate, is marketed as ONCOVIN® in injectable solution. Vincristine is indicated for the treatment of acute leukemia and has also been found in treatment regimens for Hodgkin and non-Hodgkin lymphoma. Alopecia and neurological effects are the most common side effects of vincristine, with myelosuppression and gastrointestinal mucositis occurring to a lesser degree.

[0297] Vinorelbine, 3',4'-didehydro-4'-deoxy-C'-norvincalocoblastin[R-(R * ,R * Vinorelbine (NAVELBINE®), a semi-synthetic vinca alkaloid, is marketed as an injectable solution of vinorelbine tartrate. Vinorelbine is indicated as a monotherapy or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung cancer, advanced breast cancer, and hormone-refractory prostate cancer. Bone marrow suppression is the most common dose-limiting side effect of vinorelbine.

[0298] Platinum-coordinated complexes are non-specific anticancer agents that interact with DNA. Platinum complexes enter tumor cells, are aqualated, and form intra- and inter-strand crosslinks with DNA, causing biological effects detrimental to the tumor. Examples of platinum-coordinated complexes, though not limited to them, include cisplatin and carboplatin.

[0299] Cisplatin, cis-diaminedichloroplatin, is marketed as PLATINOL® in an injectable solution. Cisplatin is primarily indicated for the treatment of metastatic testicular and ovarian cancer, as well as advanced bladder cancer. The main dose-limiting side effects of cisplatin are nephrotoxicity, which can be controlled by hydration and diuresis, and ototoxicity.

[0300] Carboplatin, platinum, and diammine[1,1-cyclobutane-dicarboxylate(2-)-O,O'] are marketed as PARAPLATIN® injectable solutions. Carboplatin is primarily indicated as a first- and second-line treatment for advanced ovarian cancer. Bone marrow suppression is a dose-limiting toxicity of carboplatin.

[0301] Alkylating agents are non-phase anti-cancer-specific agents and potent electrophiles. Typically, alkylating agents form covalent bonds to DNA through alkylation via nucleophilic moieties of DNA molecules, such as phosphate groups, amino groups, sulfhydryl groups, hydroxyl groups, carboxyl groups, and imidazole groups. Such alkylation disrupts nucleic acid function and leads to cell death. Examples of alkylating agents, but not limited to, include nitrogen mustard, e.g., cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates, e.g., busulfan; nitrosourea, e.g., carmustine; and triazenes, e.g., dacarbazine.

[0302] Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate, is marketed as CYTOXAN® in injectable solution or tablet form. Cyclophosphamide is indicated as a monotherapy or in combination with other chemotherapy agents in the treatment of malignant lymphoma, multiple myeloma, and leukemia. Alopecia, nausea, vomiting, and leukopenia are the most common dose-limiting side effects of cyclophosphamide.

[0303] Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is marketed as ALKERAN® in injectable solution or tablet form. Melphalan is indicated for the palliative treatment of multiple myeloma and unresectable ovarian epithelial carcinoma. Bone marrow suppression is the most common dose-limiting side effect of melphalan.

[0304] Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is marketed as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphocytic leukemia, as well as malignant lymphomas, such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose-limiting side effect of chlorambucil.

[0305] Busulfan, 1,4-butanediol dimethanesulfonate, is marketed as MYLERAN® tablets. Busulfan is indicated for the palliative treatment of chronic myeloid leukemia. Bone marrow suppression is the most common dose-limiting side effect of busulfan.

[0306] Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea], is marketed as BiCNU® in single vials of lyophilized material. Carmustine is indicated for the palliative treatment of brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin lymphoma, either as a monotherapy or in combination with other drugs. Delayed myelosuppression is the most common dose-limiting side effect of carmustine.

[0307] Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, is marketed as a single vial of the material under the registered trademark DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and, in combination with other drugs, as a second-line treatment for Hodgkin's disease. Nausea, vomiting, and loss of appetite are the most common dose-limiting side effects of dacarbazine.

[0308] Antibiotic antineoplastic agents are non-specific drugs that bind to or intercalate with DNA. Typically, such action results in the cleavage of stable DNA complexes or strands, thereby disrupting the normal function of nucleic acids and leading to cell death. Examples of antibiotic antineoplastic agents, but not limited to, actinomycin (e.g., dactinomycin), anthrocyclines (e.g., daunorubicin and doxorubicin), and bleomycin.

[0309] Dactinomycin, also known as Actinomycin D, is marketed as an injectable drug under the registered trademark COSMEGEN. Dactinomycin is indicated for the treatment of Wilms' tumor and rhabdomyosarcoma. Nausea, vomiting, and loss of appetite are the most common dose-limiting side effects of dactinomycin.

[0310] Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxohexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naftacendione hydrochloride, is marketed as DAUNOXOME® in liposomal injection form or as CERUBIDINE® as an injectable preparation. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and progressive HIV-associated Kaposi's sarcoma. Myelosuppression is the most common dose-limiting side effect of daunorubicin.

[0311] Doxorubicin, (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxohexopyranosyl)oxy]-8-glycoyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naftacendione hydrochloride, is marketed as an injectable formulation under the names RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but it is also a useful component in the treatment of several solid tumors and lymphomas. Bone marrow suppression is the most common dose-limiting side effect of doxorubicin.

[0312] Bleomycin is a mixture of cytotoxic glycopeptide antibiotics isolated from the Streptomyces verticillus strain and is marketed as BLENOXANE®. Bleomycin is indicated as a monotherapy or in combination with other drugs for the palliative treatment of squamous cell carcinoma, lymphoma, and testicular cancer. Pulmonary and cutaneous toxicity are the most common dose-limiting side effects of bleomycin.

[0313] Examples of topoisomerase II inhibitors, though not limited to them, include epipodophyllotoxin.

[0314] Epipodophyllotoxin is a phase-specific antineoplastic agent derived from the mandrake plant. Typically, epipodophyllotoxin affects cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA, thereby inducing DNA strand breaks. These breaks accumulate, leading to cell death. Examples of epipodophyllotoxin include, but are not limited to, etoposide and teniposide.

[0315] Etoposide, 4'-demethyl-epipodophyllotoxin 9 [4,6-O-(R)-ethylidene-β-D-glucopyranoside], is marketed as an injectable solution or capsule under the registered trademark VePESID and is commonly known as VP-16. Etoposide is indicated for the treatment of testicular cancer and non-small cell lung cancer, either as a monotherapy or in combination with other chemotherapy agents. Myelosuppression is the most common side effect of etoposide. Leukopenia tends to occur more severely than thrombocytopenia.

[0316] Teniposide, 4'-demethyl-epipodophyllotoxin 9 [4,6-0-(R)-tenylidene-β-D-glucopyranoside], is marketed as an injectable solution under the registered trademark VUMON and is commonly known as VM-26. Teniposide is indicated for the treatment of acute leukemia in children, either as a monotherapy or in combination with other chemotherapy agents. Myelosuppression is the most common dose-limiting side effect of teniposide. Teniposide can induce both leukopenia and thrombocytopenia.

[0317] Antimetabolites are phase-specific antineoplastic agents that act during the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis, thereby limiting DNA synthesis. As a result, the S phase does not progress, and cell death occurs. Examples of antimetabolites include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.

[0318] 5-Fluorouracil, also known as 5-fluorouracil or 5-fluoro-2,4-(1H,3H)pyrimidinedione, is marketed as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and integration into both RNA and DNA. The result is typically cell death. 5-Fluorouracil is indicated as a monotherapy or in combination with other chemotherapeutic agents in the treatment of breast, colon, rectal, gastric, and pancreatic cancers. Myelosuppression and mucositis are dose-limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.

[0319] Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone, is marketed as CYTOSAR-U® and is commonly known as Ara-C. Cytarabine is thought to exhibit cell phase specificity in the S phase by inhibiting DNA elongation through terminal integration of cytarabine into growing DNA strands. Cytarabine is indicated as a monotherapy or in combination with other chemotherapeutic agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacitidine and 2',2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leukopenia, thrombocytopenia, and mucositis.

[0320] Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, is marketed as PURINETHOL®. Mercaptopurine exhibits cell phase specificity in the S phase by inhibiting DNA synthesis through a mechanism that has not yet been identified. Mercaptopurine is indicated for the treatment of acute leukemia, either as a monotherapy or in combination with other chemotherapy agents. Myelosuppression and gastrointestinal mucositis are expected side effects of high-dose mercaptopurine. A useful mercaptopurine analog is azathioprine.

[0321] Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is marketed as TABLOID®. Thioguanine exhibits cell phase specificity in the S phase by inhibiting DNA synthesis through a mechanism that has not yet been identified. Thioguanine is indicated for the treatment of acute leukemia, either as a monotherapy or in combination with other chemotherapeutic agents. Myelosuppression, including leukopenia, thrombocytopenia, and anemia, is the most common dose-limiting side effect of thioguanine administration. However, gastrointestinal side effects can occur, which may also be dose-limiting. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.

[0322] Gemcitabine, 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer), is marketed as GEMZAR®. Gemcitabine exhibits cell phase specificity in the S phase by blocking cell progression across the G1 / S boundary. Gemcitabine is indicated in combination with cisplatin for the treatment of locally advanced non-small cell lung cancer and as a monotherapy for locally advanced pancreatic cancer. Myelosuppression, including leukopenia, thrombocytopenia, and anemia, is the most common dose-limiting side effect of gemcitabine.

[0323] Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid, is marketed as methotrexate sodium. Methotrexate exerts a specific cell phase effect in the S phase by inhibiting DNA synthesis, repair, and / or replication through the inhibition of dihydrofolate reductase, which is required for the synthesis of purine nucleotides and thymidylic acid. Methotrexate is indicated as a monotherapy or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin lymphoma, and cancers of the breast, head, neck, ovaries, and bladder. Myelosuppression (leukopenia, thrombocytopenia, and anemia) and mucositis are expected side effects of methotrexate administration.

[0324] Camptothecin and its derivatives are available or under development as topoisomerase I inhibitors. The cytotoxic activity of camptothecin is thought to be related to its topoisomerase I inhibitory activity. Examples of camptothecin, but not limited to, include irinotecan, topotecan, and various optical forms of 7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin, as described below.

[0325] Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3',4',6,7]indolidino[1,2-b]quinoline-3,14(4H,12H)-dione hydrochloride is marketed as an injectable solution under the registered trademark CAMPTOSAR.

[0326] Irinotecan is a derivative of camptothecin that binds to the topoisomerase I-DNA complex along with its active metabolite SN-38. Cytotoxicity is thought to result from irreparable double-strand breaks caused by the interaction between the topoisomerase I:DNA:irinotecan or SN-38 ternary complex and replication enzymes. Irinotecan is indicated for the treatment of metastatic colorectal cancer. Dose-limiting side effects of irinotecan HCl include myelosuppression, including neutropenia, and glycemic effects, including diarrhea.

[0327] Topotecan HCl, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4',6,7]indolidino[1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is marketed as the injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin that binds to the topoisomerase I-DNA complex and prevents religation of single-strand breaks induced by topoisomerase I in response to twisting and straining of DNA molecules. Topotecan is indicated as a second-line treatment for metastatic ovarian cancer and small cell lung cancer. The dose-limiting side effect of topotecan HCl is myelosuppression, mainly neutropenia.

[0328] Hormones and hormone analogs are compounds useful in treating cancers in which there is a relationship between hormones (or hormones) and the growth and / or lack thereof of cancer.Examples of hormones and hormone analogs useful in cancer treatment include, but are not limited to, corticosteroids such as prednisone and prednisolone, which are useful in treating malignant lymphoma and acute leukemia in children; aminoglutethimides such as anastrozole, letrazole, vorazole, and exemestane, and other aromatase inhibitors, which are useful in treating adrenocortical carcinoma and hormone-dependent breast cancer containing estrogen receptors; progestins such as megestrol acetate, which are useful in treating hormone-dependent breast cancer and endometrial cancer; and flutamide, nilutamide, bicalutamide, and cyproterone acetate. Estrogen, androgen, and antiandrogen agents such as acetate; 5α-reductases such as finasteride and dutasteride, which are useful in the treatment of prostate cancer and benign prostatic hyperplasia; anti-estrogen agents such as tamoxifen, toremifene, raloxifene, droloxifene, and iodoxyfene, which are useful in the treatment of hormone-dependent breast cancer and other sensitive cancers; and selective estrogen receptor modulators (SERMSs) such as those described in U.S. Patents No. 5,681,835, No. 5,877,219, and No. 6,207,716; and for the treatment of prostate cancer, for example, goserelin acetate. Examples include gonadotropin-releasing hormone (GnRH) and its analogues that stimulate the release of luteinizing hormone (LH) and / or follicle-stimulating hormone (FSH), such as LHRH agonists and antagonists like acetate and luprolide.

[0329] Signaling pathway inhibitors are inhibitors that block or inhibit chemical processes that cause intracellular changes. As used herein, these changes are cell proliferation or differentiation. Useful signaling inhibitors in this invention include receptor tyrosine kinases, non-receptor tyrosine kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phosphatidylinositol-3 kinases, myo-inositol signaling, and Ras oncogene inhibitors.

[0330] Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in regulating cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases. Receptor tyrosine kinases are transmembrane proteins possessing an extracellular ligand-binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in regulating cell growth and are commonly referred to as growth factor receptors. For example, inappropriate or unregulated activation of many of these kinases, i.e., abnormal kinase growth factor receptor activity, due to overexpression or mutation, has been shown to result in unregulated cell growth. Therefore, abnormal activity of such kinases has been associated with malignant tissue growth. Consequently, inhibitors of such kinases may offer potential cancer treatment options. Examples of growth factor receptors include epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homologous domains (TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colony-stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptor, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptor, and RET proto-oncogene. Several growth receptor inhibitors are under development, including ligand antagonists, antibodies, tyrosine kinase inhibitors, and antisense oligonucleotides.Growth factor receptors and drugs that inhibit growth factor receptor function are described, for example, in Kath, John C., Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, FJ et al, "Growth factor receptors as targets," New Molecular Targets for Cancer Chemotherapy, edited by Workman, Paul and Kerr, David, CRC press 1994, London.

[0331] Preferably, the pharmaceutically active compounds of the present invention are used in combination with a VEGFR inhibitor, preferably 5-[[4-[(2,3-dimethyl-2H-indazole-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, preferably a monohydrochloride salt, which is disclosed and claimed in International Application No. PCT / US01 / 49367 (whose entire disclosure is incorporated herein by reference), with an international filing date of 19 December 2001, international publication number WO02 / 059110 and an international publication date of 1 August 2002, and which is the compound of Example 69. 5-[[4-[(2,3-dimethyl-2H-indazole-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide can be prepared as described in International Application No. PCT / US01 / 49367.

[0332] Preferably, 5-[[4-[(2,3-dimethyl-2H-indazole-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide is in the form of a monohydrochloride salt. This salt form can be prepared by those skilled in the art from the description in International Application No. PCT / US01 / 49367, with an international filing date of December 19, 2001.

[0333] 5-[[4-[(2,3-dimethyl-2H-indazole-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide is commercially available as a monohydrochloride salt and is known by the generic name pazopanib and the trade name Votrient®.

[0334] Pazopanib is related to the treatment of cancer and eye diseases / angiogenesis. Preferably, the present invention relates to the treatment of cancer and eye diseases / angiogenesis, preferably age-related macular degeneration, and the method comprises administering a compound of formula (I) alone or in combination with pazopanib.

[0335] Tyrosine kinases that are not growth factor receptor kinases are referred to as non-receptor tyrosine kinases. Examples of non-receptor tyrosine kinases for use in the present invention that are targets or potential targets of anticancer drugs include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (adhesion plaque kinase), Bruton's tyrosine kinase, and Bcr-Abl. Such non-receptor kinases, and drugs that inhibit the function of non-receptor tyrosine kinases, are described in Sinh, S. and Corey, SJ, (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 - 80; and Bolen, JB, Brugge, JS, (1997) Annual review of Immunology. 15: 371-404.

[0336] SH2 / SH3 domain blockers are drugs that disrupt SH2 or SH3 domain binding in a variety of enzymes or adapter proteins, including the PI3-K p85 subunit, Src family kinases, adapter molecules (Shc, Crk, Nck, Grb2), and Ras-GAP. The SH2 / SH3 domain as a target for anticancer drugs is discussed in Smithgall, TE (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.

[0337] Inhibitors of serine / threonine kinases, e.g., MAP kinase cascade blockers, e.g., Raf kinase (rafk), mitogen or extracellular regulatory kinase (MEK), and extracellular regulatory kinase (ERK) blockers; and protein kinase C family member blockers, e.g., PKC (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta) blockers; IκB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, PDK1, and TGF beta receptor kinases. Such serine / threonine kinases and their inhibitors are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, PA, and Harris, AL (1995), Cancer Treatment and Research. 78: 3-27; Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Patent No. 6,268,391; Pearce, LR et al. Nature Reviews Molecular Cell Biology This is described in (2010) 11, 9-22 and Martinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.

[0338] Preferably, the pharmaceutically active compounds of the present invention are used in combination with MEK inhibitors. Preferably, N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidine-1-yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate thereof, preferably a dimethyl sulfoxide solvate, which is disclosed and claimed in International Application No. PCT / JP2005 / 011082 (whose entire disclosure is incorporated herein by reference), with an international filing date of 10 June 2005; international publication number WO 2005 / 121142 and an international publication date of 22 December 2005. N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidine-1-yl]phenyl}acetamide can be prepared as described in U.S. Patent Publication No. US2006 / 0014768, published on January 19, 2006 (the full disclosure thereof is incorporated herein by reference).

[0339] Preferably, the pharmaceutically active compounds of the present invention are used in combination with B-Raf inhibitors. Preferably, N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazole-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT / US2009 / 042682, with an international filing date of 4 May 2009 (the full disclosure thereof is incorporated herein by reference). N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazole-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide can be prepared as described in International Application No. PCT / US2009 / 042682.

[0340] Preferably, the pharmaceutically active compounds of the present invention are used in combination with Akt inhibitors. Preferably, N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazole-5-yl)-2-francarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT / US2008 / 053269 (whose entire disclosure is incorporated herein by reference), with an international filing date of 7 February 2008; international publication number WO 2008 / 098104 and an international publication date of 14 August 2008. N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazole-5-yl)-2-francarboxamide is the compound of Example 224 and can be prepared as described in International Application No. PCT / US2008 / 053269.

[0341] Preferably, the pharmaceutically active compounds of the present invention are used in combination with Akt inhibitors. Preferably, N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazole-5-yl)-2-thiophenecarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT / US2008 / 053269 (whose entire disclosure is incorporated herein by reference), with an international filing date of 7 February 2008; international publication number WO 2008 / 098104 and an international publication date of 14 August 2008. N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazole-5-yl)-2-thiophenecarboxamide is the compound of Example 96 and can be prepared as described in International Application No. PCT / US2008 / 053269. Preferably, N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazole-5-yl)-2-thiophenecarboxamide is in the form of a hydrochloride salt. This salt form can be prepared by those skilled in the art from the description in International Application No. PCT / US2010 / 022323, with an international filing date of January 28, 2010.

[0342] Inhibitors of phosphatidylinositol-3 kinase family members, including PI3-kinase, ATM, DNA-PK, and Ku blockers, may also be useful in the present invention. Such kinases are discussed in Abraham, RT (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, CE, Lim, DS (1998), Oncogene 17 (25) 3301-3308; Jackson, SP (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545.

[0343] Furthermore, the present invention is of interest in myo-inositol signaling inhibitors, such as phospholipase C blockers and myo-inositol analogs. Such signaling inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy, edited by Paul Workman and David Kerr, CRC press 1994, London.

[0344] Another group of signaling pathway inhibitors are Ras oncogene inhibitors. Such inhibitors include farnesyltransferase, geranyl-geranyltransferase, and CAAX protease inhibitors, as well as antisense oligonucleotides, ribozymes, and immunotherapies. These inhibitors have been shown to block ras activation in cells containing wild-type mutant ras, thereby acting as antiproliferative agents. Ras oncogene inhibition has been discussed in Scharovsky, OG, Rozados, VR, Gervasoni, SI Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, MN (1998), Current Opinion in Lipidology. 9(2) 99-102; and BioChim. Biophys. Acta, (19899) 1423(3):19-30.

[0345] As mentioned above, antibody antagonists targeting receptor kinase ligand binding can also serve as signaling inhibitors. Examples of signaling pathway inhibitors in this group include the use of humanized antibodies against the extracellular ligand-binding domain of receptor tyrosine kinases. Examples include Imclone C225 EGFR-specific antibody (see Green, MC et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286); Herceptin® erbB2 antibody (see Tyrosine Kinase Signalling in Breast cancer: erbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CB VEGFR2-specific antibody (see Brekken, RA et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124).

[0346] Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention. Inhibitors of angiogenesis-related VEGFR and TIE2 have been discussed above in relation to signaling inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis is generally associated with erbB2 / EGFR signaling, as inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, mainly VEGF expression. Therefore, non-receptor tyrosine kinase inhibitors may be used in combination with the compounds of the present invention. For example, anti-VEGF antibodies that do not recognize VEGFR (receptor tyrosine kinase) but bind to its ligand; integrins (alpha) that inhibit angiogenesis. vSmall molecule inhibitors of beta-3), such as endostatin and angiostatin (non-RTK), may also prove useful in combination with the disclosed compounds. (See Bruns CJ et al (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).

[0347] The drugs used in immunotherapy regimens may also be useful in combination with compounds of formula (I). There are several immunological strategies for eliciting an immune response. These strategies generally fall under the realm of tumor vaccination. The effectiveness of immunological approaches can be greatly enhanced through combined inhibition of signaling pathways using small molecule inhibitors. Discussions of immunological / tumor vaccine approaches to erbB2 / EGFR can be found in Reilly RT et al. (2000), Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J, and Kipps TJ. (1998), Cancer Res. 58: 1965-1971.

[0348] The agents used in pro-apoptosis regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention. Proteins of the Bcl-2 family members block apoptosis. Therefore, upregulation of bcl-2 is associated with chemotherapy resistance. Studies have shown that epidermal growth factor (EGF) stimulates the anti-apoptotic member of the bcl-2 family (i.e., mcl-1). Thus, strategies designed to downregulate bcl-2 expression in tumors have demonstrated clinical benefit and are currently undergoing Phase II / III clinical trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such pro-apoptosis strategies using antisense oligonucleotide strategies against bcl-2 are discussed in Water JS et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et al. (1994), Antisense Res. Dev. 4: 71-79.

[0349] Cell cycle signaling inhibitors inhibit molecules involved in the regulation of the cell cycle. Their interactions with a family of protein kinases called cyclin-dependent kinases (CDKs) and a family of proteins called cyclins regulate cell cycle progression in eukaryotes. Cooperative activation and inactivation of different cyclin / CDK complexes are necessary for normal cell cycle progression. Several inhibitors of cell cycle signaling are under development. For example, examples of cyclin-dependent kinases, including CDK2, CDK4, and CDK6, and their inhibitors, are described, for instance, in Rosania et al., Exp. Opin. Ther. Patents (2000) 10(2):215-230. Furthermore, p21WAF1 / CIP1 has been described as a potent and versatile inhibitor of cyclin-dependent kinases (Cdk) (Ball et al., Progress in Cell Cycle Res., 3: 125 (1997)). Compounds known to induce p21WAF1 / CIP1 expression have been associated with tumor suppressor activity and inhibit cell proliferation (Richon et al., Proc. Nat Acad. Sci. USA 97(18): 10014-10019 (2000)) and are included as cell cycle signaling inhibitors. Histone deacetylase (HDAC) inhibitors have been associated with transcriptional activation of p21WAF1 / CIP1 (Vigushin et al., Anticancer Drugs, 13(1): 1-13 (Jan 2002)) and are suitable cell cycle signaling inhibitors for use in the combinations described herein.

[0350] Examples of such HDAC inhibitors include the following: 1. Vorinostat, including its pharmaceutically acceptable salts. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007). Vorinostat has the following chemical structure and name:

[0351] [ka] N-hydroxy-N'-phenyloctanediamide

[0352] 2. Romidepsin, including its pharmaceutically acceptable salts. Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85-93. Romidepsin has the following chemical structure and name:

[0353] [ka] (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propane-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricosa-16-ene-3,6,9,19,22-pentone

[0354] 3. Panobinostat, including its pharmaceutically acceptable salts. Drugs of the Future 32(4): 315-322 (2007). Panobinostat has the following chemical structure and name:

[0355] [ka] (2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indole-3-yl)ethyl]amino}methyl)phenyl]acrylamide

[0356] 4. Valproic acid, including its pharmaceutically acceptable salts. Gottlicher, et al., EMBO J. 20(24): 6969-6978 (2001). Valproic acid has the following chemical structure and name:

[0357] [ka] 2-Propylpentanoic acid

[0358] 5. Mocetinostat (MGCD0103), including its pharmaceutically acceptable salts. Balasubramanian et al., Cancer Letters 280: 211-221 (2009). Mocetinostat has the following chemical structure and name:

[0359] [ka] N-(2-aminophenyl)-4-[[(4-pyridine-3-ylpyrimidine-2-yl)amino]methyl]benzamide

[0360] Further examples of such HDAC inhibitors are found in the Bertrand European Journal of Medicinal Chemistry 45, (2010) 2095-2116, and in particular, the compounds listed in Table 3 are as follows.

[0361] [ka]

[0362] Proteasome inhibitors are drugs that block the action of proteasomes, which are cellular complexes that degrade proteins such as the p53 protein. Several proteasome inhibitors are commercially available or being studied in the treatment of cancer. Suitable proteasome inhibitors for use in the combinations described herein include the following:

[0363] 1. Bortezomib (Velcade®), including its pharmaceutically acceptable salts. Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304-11. Bortezomib has the following chemical structure and name:

[0364] [ka] [(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazine-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid

[0365] 2. Disulfiram, including its pharmaceutically acceptable salts. Bouma et al. (1998). J. Antimicrob. Chemother. 42 (6): 817-20. Disulfiram has the following chemical structure and name:

[0366] [ka] 1,1',1'',1'''-[disulfanediirbis(carbonothioylnitrilo)]tetraethane

[0367] 3. Epigallocatechin gallate (EGCG), including its pharmaceutically acceptable salts. Williamson et al., (December 2006), The Journal of Allergy and Clinical Immunology 118 (6): 1369-74. Epigallocatechin gallate has the following chemical structure and name.

[0368] [ka] [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl]3,4,5-trihydroxybenzoate

[0369] 4. Salinosporamide A, including its pharmaceutically acceptable salts. Feling et at., (2003), Angew. Chem. Int. Ed. Engl. 42 (3): 355-7. Salinosporamide A has the following chemical structure and name.

[0370] [ka] (4R,5S)-4-(2-chloroethyl)-1-((1S)-cyclohexa-2-enyl(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo3.2.0heptane-3,7-dione

[0371] 5. Carfilzomib, including its pharmaceutically acceptable salts. Kuhn DJ, et al, Blood, 2007, 110:3281-3290. Carfilzomib has the following chemical structure and name.

[0372] [ka] (S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropane-2-yl)-2-((S)-2-(2-morpholinoacetamide)-4-phenylbutanamide)pentanamide

[0373] 70-kilodalton heat shock protein (Hsp70) and 90-kilodalton heat shock protein (Hsp90) are families of ubiquitously expressed heat shock proteins. Hsp70 and Hsp90 are overexpressed in certain types of cancer. Several Hsp70 and Hsp90 inhibitors have been studied in cancer treatment. Suitable Hsp70 and Hsp90 inhibitors for use in the combination described herein include:

[0374] 1. Contains 17-AAG (geldanamycin) and its pharmaceutically acceptable salts. Jia W et al. Blood. 2003 Sep 1;102(5):1824-32. 17-AAG (geldanamycin) has the following chemical structure and name.

[0375] [ka] 17-(allylamino)-17-demethoxygeldanamycin

[0376] 2. Radicicol, including its pharmaceutically acceptable salts. (Lee et al., Mol Cell Endocrinol. 2002, 188, 47-54) Radicicol has the following chemical structure and name:

[0377] [ka] (1aR,2Z,4E,14R,15aR)-8-chloro-9,11-dihydroxy-14-methyl-15,15a-dihydro-1aH-benzo[c]oxyreno[2,3-k][1]oxacyclotetradecine-6,12(7H,14H)-dione

[0378] Inhibitors of Cancer Metabolism - Many tumor cells exhibit significantly different metabolisms from normal tissues. For example, the rate of glycolysis, the metabolic process that converts glucose to pyruvate, is increased, and the resulting pyruvate is reduced to lactate rather than being further oxidized in the mitochondria via the tricarboxylic acid (TCA) cycle. This effect is often observed even under aerobic conditions and is known as the Warburg effect.

[0379] Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a central role in tumor cell metabolism by reducing pyruvate to lactate, which can then be transported out of the cell. This enzyme has been shown to be upregulated in many tumor types. The glucose metabolic changes described in the Warburg effect are important for cancer cell growth and proliferation, and RNA-i-mediated knockdown of LDH-A has been shown to lead to reduced cell proliferation and tumor growth in xenograft models. DA Tennant et. al., Nature Reviews, 2010, 267. P. Leder, et. al., Cancer Cell, 2006, 9, 425.

[0380] High levels of fatty acid synthase (FAS) have been found in precancerous lesions. Pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance. Alli et al. Oncogene (2005) 24, 39-46. doi:10.1038

[0381] Inhibitors of cancer metabolism, including LDH-A inhibitors and fatty acid biosynthesis inhibitors (or FAS inhibitors), are suitable for use in combination with the compounds of the present invention.

[0382] In one embodiment, the claimed method for treating cancer of the present invention comprises co-administration of a compound of formula I, Ia, Ib, II, or III and / or a pharmaceutically acceptable salt thereof with at least one antineoplastic agent selected from the group consisting of antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormone analogs, signaling pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, apoptosis promoters, cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.

[0383] In one embodiment, the compounds of formulas I, Ia, and Ib are used as chemosensitizers that enhance tumor cell death.

[0384] In one embodiment, compounds of formula I, Ia, Ib, II, or III are used in combination as chemosensitizers that enhance tumor cell death.

[0385] In one embodiment, compounds of formula I, Ia, Ib, II, or III are used in combination with compounds that inhibit the activity of protein kinase R (PKR)-like ER kinase, PERK (PERK inhibitors).

[0386] Preferably, compounds of formulas I, Ia, Ib, II, and III and their pharmaceutically acceptable salts may be co-administered with at least one other active agent known to be a PERK kinase (EIF2K3) inhibitor for treating or reducing the severity of neurodegenerative diseases / injuries such as Alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lungs, chronic and acute diseases of the kidneys, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, traumatic brain injury, cognitive impairment, atherosclerosis, eye diseases, and arrhythmias, as well as in organ transplantation and in the transport of transplantable organs.

[0387] The terms "chemotherapeutic drug" or "chemotherapeutic agent" are used in their simple and ordinary sense and refer to a chemical composition or compound that has antineoplastic properties or the ability to inhibit cell growth or proliferation.

[0388] Furthermore, the compounds described herein, though not limited to, include immunostimulants (e.g., Calmette-Guéranbacillus (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g., 111 In, 90 Y, or 131 It can be co-administered with conventional immunotherapies, including anti-CD20 monoclonal antibodies conjugated with I, etc.

[0389] In further embodiments, the compounds described herein may be conjugated with antibodies against tumor antigens, but are not limited to these embodiments.47 Sc, 64 C 67 C, 89 Sr, 86 Y, 87 Y, and 212 It can be administered co-administered with conventional radiotherapy agents, including radionuclides such as Bi.

[0390] An example of the addition of further active ingredients (one or more) (antineoplastic agents) for use in combination with or co-administered with a compound is an anti-PD-L1 agent.

[0391] Anti-PD-L1 antibodies and methods for producing them are known in the art.

[0392] Such antibodies against PD-L1 may be polyclonal or monoclonal, and / or recombinant, and / or humanized.

[0393] Exemplary PD-L1 antibodies are disclosed below: U.S. Patent No. 8,217,149; No. 12 / 633,339; U.S. Patent No. 8,383,796; No. 13 / 091,936; U.S. Patent No. 8,552,154; No. 13 / 120,406; U.S. Patent Publication No. 20110280877; No. 13 / 068337; U.S. Patent Publication No. 20130309250; No. 13 / 892671; WO2013019906; WO2013079174; U.S. Patent Application No. 13 / 511,538 (filed August 7, 2012), which is the U.S. national phase of International Patent Application No. PCT / US10 / 58007 (filed in 2010); and U.S. Patent Application No. 13 / 478,511 (filed on May 23, 2012).

[0394] Additional exemplary antibodies against PD-L1 (also known as CD274 or B7-H1) and methods for their use are disclosed in U.S. Patent No. 7,943,743; U.S. 20130034559, WO2014055897, U.S. Patent No. 8,168,179; and U.S. Patent No. 7,595,048. PD-L1 antibodies are under development as immunomodulatory agents for the treatment of cancer.

[0395] In one embodiment, the antibody against PD-L1 is the antibody disclosed in U.S. Patent No. 8,217,149. In another embodiment, the anti-PD-L1 antibody comprises a CDR of the antibody disclosed in U.S. Patent No. 8,217,149.

[0396] In another embodiment, the antibody against PD-L1 is the antibody disclosed in U.S. Patent Application No. 13 / 511,538. In another embodiment, the anti-PD-L1 antibody comprises a CDR of the antibody disclosed in U.S. Patent Application No. 13 / 511,538.

[0397] In another embodiment, the antibody against PD-L1 is the antibody disclosed in U.S. Patent Application No. 13 / 478,511. In another embodiment, the anti-PD-L1 antibody comprises a CDR of the antibody disclosed in U.S. Patent Application No. 13 / 478,511.

[0398] In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1105). In another embodiment, the anti-PD-L1 antibody is MPDL3280A (RG7446). In yet another embodiment, the anti-PD-L1 antibody is MEDI4736.

[0399] An example of additional active ingredients (one or more) (antineoplastic agents) to be used in combination with or co-administered with the ATF4 pathway inhibitory compounds of the present invention is a PD-1 antagonist.

[0400] "PD-1 antagonist" refers to any chemical compound or biomolecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or NKT cells), and preferably also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or alternative names for PD-1 and its ligands include PDCD1, PD1, CD279, and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc, and CD273 for PD-L2. In any embodiment of the aspects or embodiments of the present invention in which a human individual is treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, preferably blocking the binding of both human PD-L1 and PD-L2 to human PD-1. The amino acid sequence of human PD-1 can be found at NCBI locus number: NP_005009. The amino acid sequences of human PD-L1 and PD-L2 can be found at NCBI locus numbers: NP_054862 and NP_079515, respectively.

[0401] A useful PD-1 antagonist in any aspect of the present invention is a monoclonal antibody (mAb) or an antigen-binding fragment thereof that specifically binds to PD-1 or PD-L1, preferably to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0402] Examples of mAbs that bind to human PD-1 and are useful in various aspects and embodiments of the present invention are described in US7,488,802, US7,521,051, US8,008,449, US8,354,509, US8,168,757, WO2004 / 004771, WO2004 / 072286, WO2004 / 056875, and US2011 / 0271358.

[0403] Specific anti-human PD-1 mAbs useful as PD-1 antagonists in any aspect or embodiment of the present invention include MK-3475, a humanized IgG4 mAb having the structure described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013) and containing the heavy and light chain amino acid sequences shown in Figure 6; nivolumab, a human IgG4 mAb having the structure described in WHO Drug Information, Vol. 27, No. 1, pp. 68-69 (2013) and containing the heavy and light chain amino acid sequences shown in Figure 7; humanized antibodies h409A11, h409A16, and h409A17 described in WO2008 / 156712; and AMP-514 developed by Medimmune.

[0404] Other PD-1 antagonists useful in any aspect and embodiment of the present invention include immunoadhesins that specifically bind to PD-1, preferably to human PD-1, such as fusion proteins containing an extracellular or PD-1 binding moiety of PD-L1 or PD-L2 fused to a constant region such as the Fc region of an immunoglobulin molecule. Examples of immunoadhesive molecules that specifically bind to PD-1 are described in WO2010 / 027827 and WO2011 / 066342. A specific fusion protein useful as a PD-1 antagonist in the therapeutic methods, pharmaceuticals and uses of the present invention is the PD-L2-FC fusion protein AMP-224 (also known as B7-DCIg), which binds to human PD-1.

[0405] Other examples of mAbs that bind to human PD-L1 and are useful in the therapeutic methods, pharmaceuticals, and uses of the present invention are described in WO2013 / 019906, W02010 / 077634 A1, and US8,383,796. Specific anti-human PD-L1 mAbs useful as PD-1 antagonists in the therapeutic methods, pharmaceuticals, and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, and MSB0010718C.

[0406] Keytruda / pembrolizumab is an anti-PD-1 antibody marketed by Merck for the treatment of lung cancer. The amino acid sequence and method of use of pembrolizumab are disclosed in U.S. Patent No. 8,168,757.

[0407] Opdivo / nivolumab is a fully human monoclonal antibody against the immunomodulatory, negatively immunomodulatory human cell surface receptor PD-1 (Programmed Death-1 or Programmed Cell Death-1 / PCD-1), marketed by Bristol Myers Squibb. Nivolumab binds to PD-1, an Ig superfamily transmembrane protein, and blocks its activation by its ligands, PD-L1 and PD-L2, resulting in T cell activation and a cell-mediated immune response against tumor cells or pathogens. Activated PD-1 negatively modulates T cell activation and effector function through the suppression of P13k / Akt pathway activation. Other names for nivolumab include BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence, method of use, and method of manufacturing of nivolumab are disclosed in U.S. Patent No. 8,008,449.

[0408] Examples of additional active ingredients (one or more) (antineoplastic agents) to be used in combination with or co-administered with the compounds of the present invention are immunomodulators.

[0409] As used herein, “immunomodulatory substance” refers to any substance, including monoclonal antibodies, that affects the immune system. The ICOS-binding protein of the present invention can be considered an immunomodulatory substance. Immunomodulatory substances can be used as antineoplastic agents for the treatment of cancer. Examples of immunomodulatory substances include, but are not limited to, anti-CTLA-4 antibodies, such as ipilimumab (YERVOY), and anti-PD-1 antibodies (Opdivo / nivolumab and Keytruda / pembrolizumab). Other examples of immunomodulatory substances include, but are not limited to, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies, and GITR antibodies.

[0410] Yervoy (ipilimumab) is a fully human CTLA-4 antibody marketed by Bristol Myers Squibb. The protein structure and methods of use of ipilimumab are described in U.S. Patents No. 6,984,720 and No. 7,605,238.

[0411] In another embodiment, the present invention provides compounds of Table 1 or formula (I), (Ia), (Ib), (II), or (III) as described herein, or pharmaceutically acceptable salts or prodrugs thereof, for use in the treatment of hepatitis B virus-related diseases, conditions, or disorders. The present invention provides compounds of Table 1 or pharmaceutically acceptable salts or prodrugs thereof, for use in the treatment of hepatitis B virus-related diseases, conditions, or disorders (which may be jaundice, liver cancer, hepatitis, hepatic fibrosis, cirrhosis, hepatic failure, diffuse hepatoinflammatory disease, hemophagocytic syndrome, or serum hepatitis).

[0412] In further embodiments, the compounds of the present invention of formula (I), (Ia), (Ib), (II), or (III), or pharmaceutically acceptable salts thereof, are selected from the group of compounds listed in Table 1. Furthermore, the present invention also encompasses each of these individual compounds and their pharmaceutically acceptable salts.

[0413] In another embodiment, a pharmaceutical composition is provided comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of formula I, Ia, Ib, II, or III or a pharmaceutically acceptable salt thereof.

[0414] In certain embodiments, the compound(s) of the present invention, or a pharmaceutically acceptable salt thereof, is selected from the compounds listed in Table 1. The compounds of the present invention can be supplied in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to a salt prepared from pharmaceutically acceptable inorganic and organic acids and bases. Therefore, the word “or” in the context of “compound or pharmaceutically acceptable salt thereof” is understood to refer to the compound or a pharmaceutically acceptable salt thereof (selectively), or the compound and a pharmaceutically acceptable salt thereof (combination).

[0415] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or other problems or complications. Those skilled in the art will understand that pharmaceutically acceptable salts of compounds according to formulas I, Ia, Ib, II, or III can be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in the form of a free acid or free base with a suitable base or acid, respectively.

[0416] Exemplary pharmaceutically acceptable salts of the compounds of the present invention include the following acids, for example, but not limited to: formic acid, acetic acid, propionic acid, benzoic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, maleic acid, malic acid, tartaric acid, citric acid, nitric acid (nitic), ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, isocitric acid, trifluoroacetic acid, pamoic acid, propionic acid, anthranilic acid, mesylic acid, It can be prepared from oxalacetic acid, oleic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, nicotinic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, phosphoric acid, phosphonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, sulfuric acid, salicylic acid, cyclohexylaminosulfonic acid, alginic acid (algenic), hydroxybutyric acid, galactaric acid, and galacturonic acid. Preferred pharmaceutically acceptable salts include salts of hydrochloric acid and trifluoroacetic acid.

[0417] Examples of pharmaceutically acceptable inorganic base salts of the compounds of the present invention include metal ions. More preferred metal ions include, but are not limited to, suitable alkali metal salts, alkaline earth metal salts, and other physiologically acceptable metal ions. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron trivalent, iron divalent, lithium, magnesium, manganese trivalent salts, manganese divalent, potassium, sodium, zinc, and their usual valencies. Exemplary base salts include aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Other exemplary base salts include ammonium, calcium, magnesium, potassium, and sodium salts. Further examples of exemplary base salts include, for example, hydroxides, carbonates, hydrides, and alkoxides, such as NaOH, KOH, Na2CO3, K2CO3, NaH, and potassium-t-butoxide.

[0418] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, such as trimethylamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine; substituted amines, such as naturally occurring substituted amines; cyclic amines; and quaternary ammonium cations. Examples of basic ion exchange resins include arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0419] All of the salts described above can be prepared by those skilled in the art from the corresponding compounds of the present invention by conventional means. For example, the pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture thereof; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The salts may be collected by filtration after settling from the solution, or recovered by evaporation of the solvent. The degree of ionization in the salts can vary from fully ionized to nearly unionized. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p.1418, and Berge, J. Pharm. Sci., 1977, 66, 1-19, or listed in Handbook of Pharmaceutical Salts; Properties, Selection and Use, 2nd edition, edited by P.H. Stahl and C.G. Wermuth, Stahl / Wermuth: Wiley-VCH / VHCA, 2011 (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html; its disclosure is incorporated herein by reference only with respect to the list of suitable salts).

[0420] Compounds of formula (I), (Ia), (Ib), (II), or (III) of the present invention may exist in both non-solvated and solvated forms. The term “solvate” is used herein to describe a molecular complex comprising the compound of the present invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term “hydrate” is used when the solvent is water. Examples of pharmaceutically acceptable solvates include hydrates and other solvates in which the solvent for crystallization may be isotope-substituted (e.g., D2O, d6-acetone, d6-DMSO).

[0421] Compounds of formula (I), (Ia), (Ib), (II), or (III) containing one or more chiral carbon atoms can exist as two or more stereoisomers. If a compound of formula (I), (Ia), (Ib), (II), or (III) contains an alkenyl or alkenylene group or a cycloalkyl group, geometric cis / trans (or Z / E) isomers are possible. If the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomerism ("tautomerism") may occur. A single compound can exhibit two or more types of isomerism.

[0422] The scope of the compounds of the claimed invention includes all stereoisomers, geometric isomers, and tautomers of the compounds of formula I, Ia, Ib, II, or III, for example, compounds exhibiting two or more types of isomerism, and one or more mixtures thereof. It also includes acid addition salts or base salts whose counterions are optically active, for example, D-lactate or L-lysine, or racemates, for example, DL-tartrate or DL-arginine.

[0423] The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0424] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC).

[0425] Alternatively, the racemic mixture (or racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or, if the compound of formula I, Ia, Ib, II, or III contains an acidic or basic moiety, with an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomer mixture may be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers may be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art.

[0426] The chiral compounds (and their chiral precursors) of the present invention may be obtained in an enantiomerically enriched form by chromatography, typically HPLC, on a resin having an asymmetric stationary phase and a mobile phase consisting of a hydrocarbon containing 0-50% isopropanol, typically 2-20%, and 0-5% alkylamine, typically 0.1% diethylamine, typically heptane or hexane. Concentration of the eluent yields an enriched mixture.

[0427] Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art [see, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel (Wiley, New York, 1994)].

[0428] The present invention includes all pharmaceutically acceptable isotope-labeled compounds of formula (I), (Ia), (Ib), (II), or (III), in which one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from that commonly found in nature.

[0429] Examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen isotopes, for example, 2 H and 3 H, an isotope of carbon, for example, 11 C, 13 C and 14 C, an isotope of chlorine, for example, 36 Cl, an isotope of fluorine, for example, 18 F, an isotope of iodine, for example, 123 I and 125 I. Isotopes of nitrogen, for example, 13 N and 15 N, an isotope of oxygen, for example, 15 O, 17 O and 18 O, an isotope of phosphorus, for example, 32 P, and sulfur isotopes, for example, 35 S is one example.

[0430] Certain isotope-labeled compounds of formulas (I), (Ia), (Ib), (II), or (III), for example, those incorporating radioactive isotopes, are useful for studying the tissue distribution of drugs and / or substrates. Radioactive isotope tritium, i.e., 3 H and carbon-14, that is, 14 C is particularly useful for this purpose, given its ease of implementation and readily available detection means.

[0431] Deuterium, that is, 2 Substitution with heavier isotopes, such as 1H, may offer certain therapeutic benefits stemming from greater metabolic stability, such as increased half-life or reduced dose requirements in vivo, and therefore may be preferable in some environments.

[0432] Isotope-labeled compounds of formula (I), (Ia), (Ib), (II), or (III) can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples and preparations, using appropriate isotope-labeled reagents instead of previously used unlabeled reagents.

[0433] The compounds of the present invention may be administered as prodrugs. Therefore, certain derivatives of the compounds of formula (I), (Ia), (Ib), (II), or (III), which themselves may have little or no pharmacological activity, can be converted into the compounds of formula (I), (Ia), (Ib), (II), or (III) as "prodrugs" when administered in or onto the body.

[0434] The administration of the chemical substances described herein may be via any of the acceptable modes of administration for similarly useful drugs, including, but not limited to, oral, sublingual, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, transvaginal, rectal, or intraocular. In some embodiments, oral or parenteral administration is used.

[0435] Pharmaceutical compositions or formulations include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, solutions, suspensions, suppositories, and aerosols. Chemicals can also be administered in sustained or controlled-release dosage forms, including depot injections, implant preparations, osmotic pumps, pills, and transdermal (e.g., electrotransport) patches, for extended and / or timed pulsed administration at a predetermined rate. In certain embodiments, the composition is provided in a unit dosage form suitable for a single dose of a precise amount. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as a depot injection or implant. Inert materials, such as biodegradable polymers or synthetic silicones, such as Silastic or silicone rubber, may be used for the implant.

[0436] Chemical substances can also be administered in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. Liposome preparations of tyrosine kinase inhibitors may also be used in the methods of the present invention. Liposome versions of tyrosine kinase inhibitors may be used to increase resistance to the inhibitor.

[0437] Chemical substances can also be delivered by using monoclonal antibodies as individual carriers to which compound molecules are bound.

[0438] Chemicals can also be prepared using soluble polymers as targetable drug carriers. Examples of such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, chemicals can be prepared using biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0439] The chemical substances described herein may be administered alone or, more typically, in combination with conventional pharmaceutical carriers, excipients, etc. (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, sodium croscarmellose, glucose, gelatin, sucrose, magnesium carbonate, etc.). If desired, the pharmaceutical composition may also contain small amounts of non-toxic adjuvants, such as wetting agents, emulsifiers, solubilizers, pH buffers, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, etc.). Generally, depending on the intended mode of administration, the pharmaceutical composition may contain about 0.005% to 95% by weight of the chemical substance; in certain embodiments, about 0.5% to 50% by weight. Practical methods for preparing such dosage forms are known or obvious to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0440] In certain embodiments, the composition takes the form of pills or tablets, and therefore, along with the active ingredient, the composition contains diluents, such as lactose, sucrose, dicalcium phosphate, etc.; lubricants, such as magnesium stearate, etc.; and binders, such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In other solid dosage forms, the powder, marme, solution, or suspension (e.g., in propylene carbonate, vegetable oil, or triglycerides) is encapsulated in gelatin capsules.

[0441] Liquid pharmaceutically administerable compositions can be prepared, for example, by dissolving or dispersing at least one chemical substance and an optional pharmaceutical adjuvant in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectable preparations can be prepared in conventional forms, such as liquid solutions or suspensions, emulsions, or solid forms suitable for dissolution or suspension in liquid before injection. The proportion of chemical substances contained in such parenteral compositions depends highly on their specific properties, as well as the activity of the chemical substances and the needs of the target. However, proportions of 0.01% to 10% of the active ingredient in the solution can be used, and this can be higher if the composition is a solid that is subsequently diluted to the above proportion. In certain embodiments, the composition contains about 0.2% to 2% of the active agent in the solution.

[0442] The pharmaceutical compositions of the chemical substances described herein may also be administered to the airways alone or in combination with an inert carrier such as lactose, as an aerosol or solution for nebulizer use, or as an ultrafine powder for blowing. In such cases, the particles of the pharmaceutical composition have a diameter of less than 50 μm, and in certain embodiments, less than 10 μm.

[0443] Generally, the chemical substances provided are administered in therapeutically effective doses by any of the acceptable modes of administration for drugs having similar utility. Dosage regimens utilizing the chemical substances described in this specification can be selected according to various factors, such as type, species, age, weight, sex, and type of disease being treated; severity (i.e., stage) of the disease to be treated; route of administration; patient's renal and hepatic function; and the specific compound or salt thereof used. Dosage regimens can be used, for example, to prevent, inhibit (completely or partially) or halt the progression of disease. The drugs may be administered more than once a day, for example, once or twice a day.

[0444] Intravenously or subcutaneously, the patient is administered the chemical described in the specification in a therapeutically effective dose sufficient to deliver approximately 0.001 to 200 mg per kilogram of the recipient's body weight per day; for example, approximately 0.005 to 100 mg / kg / day, or for example, approximately 0.005 to 1 mg / kg / day. Therefore, for administration to a 70 kg person, the dose range may be approximately 0.35 to 70 mg per day. Such amounts may be administered in several preferred ways, for example, over a long period in one go, or several times a day, as large amounts of low concentrations of the chemical. The amount may be administered on consecutive days, intermittent days, or a combination thereof, for one or more days per week (7 days). Alternatively, small amounts of high concentrations of the chemical may be administered over a short period, for example, continuously, intermittently, or a combination thereof, once daily for one or more days per week (7 days).

[0445] According to the present invention, the chemical substances described in the specification can be administered in continuous or intermittent doses. For example, intermittent administration of a chemical substance may mean administration 1 to 6 days per week, or it may mean cyclical administration (e.g., daily administration for 2 to 8 consecutive weeks, followed by a rest period of up to 1 week), or it may mean administration every other day. The composition may be administered cyclically with rest periods in between (e.g., a 2 to 8 week treatment with a rest period of up to 1 week between treatments).

[0446] Subcutaneous formulations can be prepared at a pH in the range of about 5 to about 12, following procedures well known in the art, and these include suitable buffers and isotonic agents.

[0447] Generally, chemical substances are administered as pharmaceutical compositions by one of the following routes: orally, systemically (e.g., transdermally, intranasally, or via suppositories), or parenterally (e.g., intramuscularly, intravenously, or subcutaneously). In certain embodiments, oral administration may be used with a convenient daily dose regimen that can be adjusted according to the degree of discomfort. The composition may take the form of tablets, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition. Another mode of administration of the chemical substance provided is inhalation.

[0448] The choice of formulation depends on various factors such as the mode of drug administration and the bioavailability of the drug substance. For inhalation delivery, the chemical can be formulated as a liquid solution, suspension, aerosol propellant, or dry powder and filled into a suitable dispensing device for administration. Several types of pharmaceutical inhalation devices exist: nebulizers, medium-dose inhalers (MDIs), and dry powder inhalers (DPIs). Nebulizer devices provide a high-speed airflow that atomizes the therapeutic agent (formulated in liquid form) as a mist delivered into the patient's airway. MDIs are typically formulations packaged with compressed gas. Upon operation, the device releases a measured amount of the therapeutic agent by the compressed gas, thus providing a reliable method for administering a set amount of medication. DPIs distribute the therapeutic agent in the form of a free-flowing powder, which can be dispersed by the device into the patient's inspiratory flow during breathing. To achieve a free-flowing powder, the therapeutic agent is formulated with excipients such as lactose. The measured amount of therapeutic agent is stored in capsule form and dispensed with each operation.

[0449] In recent years, pharmaceutical compositions have been developed for drugs exhibiting insufficient bioavailability based on the principle that bioavailability can be increased by increasing surface area, i.e., by decreasing particle size. For example, U.S. Patent No. 4,107,288 describes a pharmaceutical formulation having particles in the size range of 10 to 1,000 nm in which the active material is supported on a polymer crosslinking matrix. U.S. Patent No. 5,145,684 describes the manufacture of a pharmaceutical formulation in which a drug substance is pulverized into nanoparticles (average particle size of 400 nm) in the presence of a surface modifier, and then dispersed in a liquid medium to obtain a pharmaceutical formulation exhibiting significantly high bioavailability.

[0450] The compositions generally consist of at least one chemical substance described herein in combination with at least one pharmaceutically acceptable excipient. The acceptable excipient is non-toxic, aids administration, and does not adversely affect the therapeutic benefit of the at least one chemical substance described herein. Such excipient may be a gaseous excipient, which is generally available to those skilled in the art, in the case of any solid, liquid, semi-solid, or aerosol composition.

[0451] Examples of solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, and dried skim milk. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, such as petroleum, animal oil, vegetable oil, or synthetic oils, such as peanut oil, soybean oil, mineral oil, and sesame oil. Examples of liquid carriers for injectable solutions include water, physiological saline, aqueous dextrose, and glycol.

[0452] Compressed gases may be used to disperse the chemicals described herein in aerosol form. Suitable inert gases for this purpose include nitrogen and carbon dioxide. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E.W. Martin (Mack Publishing Company, 18th edition, 1990).

[0453] The amount of chemicals in a composition can vary within the entire range used by those skilled in the art. Typically, a composition contains at least one of the chemicals described herein in about 0.01 to 99.99 wt% on a weight percentage (wt%) basis, with the remainder being one or more preferred pharmaceutical excipients. In certain embodiments, at least one of the chemicals described herein is present at a level of about 1 to 80 wt%.

[0454] In various embodiments, the pharmaceutical compositions of the present invention include compounds of formula (I), (Ia), (Ib), (II), or (III), salts thereof, and combinations thereof.

[0455] The various modes of administration, dosages, and administration schedules described herein are merely examples of specific embodiments and should not be construed as limiting the broad scope of the present invention. Any rearrangement, variation, and combination of dosages and administration schedules are included within the scope of the present invention.

[0456] The compounds of the present invention may be prepared according to various schemes described below.

[0457] Synthesis method The synthesis methods for the provided chemicals use readily available starting materials and employ the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through standard optimization procedures.

[0458] Furthermore, the method of the present invention may utilize protecting groups to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for the protection and deprotection of specific functional groups, are well known in the art. For example, numerous protecting groups are described in TW Greene and GM Wuts, Protecting Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999 and the references cited therein.

[0459] Furthermore, the provided chemicals may contain one or more chiral centers, and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this specification unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0460] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce, or Sigma (St. Louis, Missouri, USA). Other compounds can be prepared by procedures or obvious modifications thereof described in standard reference books such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplement (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 4th edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0461] Unless otherwise stated, the reactions described herein are carried out under atmospheric pressure and generally within a temperature range of -78°C to 200°C. Furthermore, unless used in the examples or otherwise specified, reaction times and conditions are intended to be approximate, for example, carried out over a period of about 1 to about 24 hours at a temperature range of about -78°C to about 110°C, generally under atmospheric pressure, with the reaction carried out overnight for an average of about 16 hours.

[0462] The terms “solvent,” “organic solvent,” and “inert solvent” each refer to a solvent that is inert under the conditions of the reaction described therein, such as benzene, toluene, acetonitrile, tetrahydrofuranyl ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone ("NMP"), and pyridine.

[0463] The isolation and purification of the chemical substances and intermediates described herein can be carried out by any suitable separation or purification procedure, if desired, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography, or thick-layer chromatography, or a combination thereof. Specific descriptions of suitable separation and isolation procedures can be obtained by referring to the following examples herein. However, other equivalent separation or isolation procedures may also be used.

[0464] If desired, the (R)- and (S)-isomers can be separated by methods known to those skilled in the art, for example, by the formation of diastereoisomer salts or complexes that are separable by crystallization; for example, by the formation of diastereoisomer derivatives that are separable by crystallization, gas-liquid chromatography or liquid chromatography; by selective reaction of one enantiomer with an enantiomer-specific reagent, for example, by enzymatic oxidation or reduction followed by separation of the modified and unmodified enantiomers; or by gas-liquid chromatography or liquid chromatography in a chiral environment, such as on a chiral support such as silica having a bound chiral ligand or in the presence of a chiral solvent. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by asymmetric transformation to convert one enantiomer to the other. [Examples]

[0465] The following embodiments will help to more fully illustrate the methods of manufacturing and using the above invention. It is understood that these embodiments are not intended to limit the true scope of the invention, but rather are presented for illustrative purposes. In the following embodiments and the above composite scheme, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

[0466] aq. = water-based μL = microliter μM = micromolar concentration NMR = nuclear magnetic resonance Boc = tert-butoxycarbonyl Br = broad (wide width) Cbz = Benzyloxycarbonyl d = doublet (double line) Δ = Chemical shift °C = degrees Celsius DCM = Dichloromethane dd = double doublet DMAP = 4-(dimethylamino)pyridine DMEM = Dulbecco's modified Eagle medium DMF = N,N-dimethylformamide DMP = 2,2-dimethoxypropane DMSO = Dimethyl sulfoxide HCl = ethyl acetate ESI = Electrospray Ionization G or g = gram h or hr = time HCV = Hepatitis C virus HPLC = High-Performance Liquid Chromatography Hz = Hertz IU = International Unit I C 50 = Inhibitory concentration at 50% inhibition J = coupling constant (given in Hz unless otherwise specified) LHMDS = Lithium bis(trimethylsilyl)amide M = Multiplet (multiple lines) M = molar concentration M+H + = Parent peak of mass spectrum + H + Mg or mg = milligrams Min = minutes mL = milliliter mM = millimolar concentration Mmol = millimoles MS = Mass Spectrum Nm = nanomolar concentration ppm = parts per million p-TsOH = p-toluenesulfonic acid qs = sufficient amount S = Singlet (single line) RT = room temperature sat. = saturation T = Triplet (triple line) TBS-Cl = tert-butyldimethylsilyl chloride TFA = Trifluoroacetic acid

[0467] Equipment Description 1 ¹H NMR spectra were recorded using a Varian spectrometer. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in Hertz (Hz). Splitting patterns indicate apparent multiplicity and are represented as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), and br (broad).

[0468] Analytical low-resolution mass spectra (MS) were recorded using Waters (Acquity). The conditions described below were used. Instrument: Agilent 1200-6100 Scanning mode: Alternating positive / negative electrospray Scanning range: 100~1000 amu

[0469] LC conditions: LC-MS analysis was performed at 45°C using a HALO C-18, 4.6 × 50 mm, 2.7 μm, C18 column. A 1.0 μL sample was injected.

[0470] The gradient used was as follows: Mobile phase A: Water + 0.1% v / v formic acid Mobile phase B: Acetonitrile + 0.1% v / v formic acid

[0471] [Table 4]

[0472] UV detection was provided by the total absorbance signal at 214 nm and 254 nm scans.

[0473] Equipment: Shimadzu LCMS-2020 Scanning mode: Alternating positive / negative electrospray Scanning range: 100-2000 amu

[0474] LC conditions: LC-MS analysis was performed at 45°C using a HALO C-18, 4.6 × 50 mm, 2.7 μm, C18 column. A 1.0 μL sample was injected.

[0475] The gradient used was as follows: Mobile phase A: Water + 0.1% v / v formic acid Mobile phase B: Acetonitrile + 0.1% v / v formic acid

[0476] [Table 5]

[0477] UV detection was provided by the total absorbance signal at 214 nm and 254 nm scans.

[0478] Scheme and experimental procedure The following schemes and procedures illustrate methods by which the compounds of the present invention can be prepared. The specific solvents and reaction conditions mentioned are also illustrative and not intended to limit the scope. Compounds not described can be readily prepared by those skilled in the art using commercially available or readily available starting materials. The examples disclosed herein are for illustrative purposes only and are not intended to limit the compounds within the scope of the present invention.

[0479] The additional examples included, though not limited to those, were determined to have the configurations shown by spectroscopic methods well known to those skilled in the art, including 1D and 2D NMR methods. Compounds of formula (I), (Ia), (Ib), (II), or (III) can be synthesized, for example, according to schemes 1 to 6.

[0480] In one embodiment, the compound of formula 1.12 can be prepared as shown in Scheme 1. The bicyclic ring systems in formulas 1.5 and 1.6 can be formed using a four-component eucytic reaction of carboxylic acid 1.1, isocyanide 1.2, aldehyde 1.3, and ammonia, followed by acid deprotection and cyclization to obtain dipeptide 1.4. The compounds of formulas 1.5 and 1.6 can be synthesized using asymmetric eucytic synthesis by adding a chiral reagent such as chiral phosphoric acid (Jian Zhang, et al, Science, 2018, 361, 1087). Isocyanides (Isocyanide Chemistry: Application in Synthesis and Material Science, V. Nenajdenko, Wiley-VCH ed., 1st edition) can be synthesized, for example, by dehydration of formamide using phosphorus oxychloride, phosgene, diphosgene, toluenesulfonyl chloride, etc. Next, formamide can be prepared by formylation of amines with ethyl formate, mixed formic acid-acetic anhydride, formic acid / carbodiimide, or activated formic acid ester. The aldehyde of formula 1.3 (M. Vamos, et al, ACS Chem. Biol., 2013, 8, 725-732) can be prepared by dimethylation of 4,4-dimethoxybutanenitrile followed by reduction with DIBAL-H. The compound of formula 1.8 can be prepared by coupling Boc-N-methyl-L-Ala-OH 1.7 with the desired diastereoisomer 1.5 using standard amide coupling reagents such as T3P, HATU, HBTU, EDC / HOBt, and TBTU in the presence of a base such as a Hünig base or N-methylmorpholine in a suitable solvent such as DMF or DCM. The alkyne in formula 1.8 can be selectively reduced by hydrogenation in the presence of a Lindler catalyst or by an alternative method to obtain the alkene of formula 1.9. The alkene of formula 1.9 can be dimerized using Grubbs olefin metathesis to obtain the compound of formula 1.10.The olefin of formula 1.10 can be reduced by hydrogenation in the presence of a metal catalyst such as palladium-carbon or platinum to obtain the compound of formula 1.11, and the Boc protecting group in that compound can be removed under acidic conditions such as HCl or TFA.

[0481] [ka]

[0482] In another embodiment, the intermediate of formula 2.8 can be prepared according to scheme 2. Intermediate 2.8 is a versatile intermediate with respect to formulas I, Ia, Ib, II, or III by coupling with various diamines known to those skilled in the art. The bicyclic compound of formula 2.5 can be prepared by a four-component reaction of acid 2.1, isocyanide 2.2, aldehyde 2.3, and ammonia to obtain the dipeptide of formula 2.4. The compound of formula 2.5 can be prepared by treating the dipeptide 2.4 with acid, which can result in the formation of a bicyclic ring structure and an indoleamide (O. Kreye, et al, SYNLETT, 2007, pp. 3188-3192). The compounds of formulas 2.6 and 2.7 can be prepared by coupling Boc-N-methyl-L-Ala-OH 1.7 with compound 2.5 in a suitable solvent such as DMF or DCM, in the presence of a base such as a Hünig base or N-methylmorpholine, using standard amide coupling reagents such as T3P, HATU, HBTU, EDC / HOBt, or TBTU. The acid of formula 2.8 can be prepared by basic hydrolysis of the indoleamide of formula 2.6 in a solvent such as water or methanol, in the presence of sodium hydroxide or the like.

[0483] [ka]

[0484] In another embodiment, the intermediate of formula 3.7 can be prepared according to scheme 3. Intermediate 3.7 is a versatile intermediate for compounds of formula I, Ia, Ib, II, or III by coupling with various diamines known to those skilled in the art.

[0485] Scheme 3. The activated thioamidation reagent of formula 3.4 can be prepared as follows: The compound of formula 3.2 can be obtained by amide coupling of Boc-N-methyl-L-Ala-OH 1.7 with the diamine of formula 3.1 using mixed anhydride coupling conditions or alternative amide coupling conditions. The thioamide of formula 3.3 can be obtained by thiolation of amide 3.2 using phosphorus pentasulfide in a solvent such as THF in the presence of a base such as sodium carbonate. The nitrobenzotriazole reagent of formula 3.4 can be prepared by treating thioamide 3.3 with sodium nitrite in acetic acid in a solvent such as THF (M. Ashraf Shalaby, et al, J. Org. Chem. 1996, 61, p 9045-9048). The compounds of formulas 3.5 and 3.6 can be prepared by reacting indoleamide 2.5 with the activated thioacylation reagent of formula 3.4 in a solvent such as DCM or DMF, in the presence of a base such as a Hünig base or triethylamine. The separated diastereoisomers of formula 3.5 can be treated with an aqueous base such as sodium hydroxide in an alcohol solvent such as methanol to obtain the intermediate of formula 3.7.

[0486] [ka]

[0487] In another embodiment, the compounds of formulas 4.3 and 4.5 can be prepared according to scheme 4. The compounds of formulas 4.2 and 4.4 can be prepared by coupling intermediate 2.8 or 3.7 with diamine 4.1 in a solvent such as DMF, THF, or DCM, in the presence of a base such as a Hünig base or triethylamine, in the presence of a coupling reagent, or via an activated ester. Coupling reagents such as HATU, TBTU, BOP, PyBOP, DEPBT, EDC / HOBt, and EEDQ can be used in the coupling reaction, but are not limited to this list. The compounds of formulas 4.3 and 4.5 can be prepared by Boc deprotection of compounds 4.2 and 4.4 under acidic conditions such as HCl or TFA.

[0488] [ka]

[0489] Diamines for the coupling of intermediates 2.8 and 3.7 are readily available from commercial suppliers or can be manufactured within the art. Various examples are illustrated in Scheme 5, but are not limited to the types of chemicals or functional groups used in the linker. Diamines of formulas 5.3 and 5.5 can be prepared by bis-alkylation of amino alcohols 5.1 or 5.4, where X is a leaving group such as a halide, tosylate, or mesylate, in a solvent such as DMF or THF, in the presence of a base such as sodium hydride. Compounds of formulas 5.8 and 5.10 can be prepared by coupling of protected amino acids 5.6 and 5.9 under amide coupling conditions, followed by acid-deprotection.

[0490] [ka] [In the formula, a rectangular box

[0491] [ka] [is a linker]

[0492] In another embodiment, dimers of formulas 6.7, 6.8, 6.9, 6.10, and 6.11 can be prepared according to Scheme 6. Compounds of formulas 6.3, 6.4, 6.5, and 6.6 can be prepared by amide coupling of intermediates 2.8 and 3.7 with amines of formulas 6.1 and 6.2, where X and Y are linkers having functional groups at their terminal ends that can be used in further reactions. Examples of functional groups, but not limited to the list below, include protected amines, protected carboxylic acids, protected thiols, alkynes, alkenes, sulfonyl chlorides, azides, hydroxyls, halides, nitriles, and isocyanates. For example, if X contains an alkyne, alkene, amine, or alternative functional group that can further react via copper-mediated alkyne coupling, olefin metathesis, urea, or sulfamide formation to form homodimers, the monomers of formulas 6.3 and 6.5 can be dimerized to form dimers of formulas 6.7 and 6.11. For example, if X contains an amine and Y contains a carboxylic acid, sulfonyl chloride, or isocyanate, thereby forming an amide, sulfonamide, or urea; or for example, if X is an alkyne and Y is an azide, thereby forming a triazole; or if X contains a hydroxyl group and Y contains a halogen group, thereby forming an ether, the monomers of formulas 6.3, 6.4, 6.5, and 6.6 can be reacted with each other to form the heterodimers of formulas 6.8, 6.9, and 6.10. As those skilled in the art will know, the chemistry is not limited to the above list and other combinations are possible.

[0493] Intermediate I: (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid

[0494] [ka]

[0495] Step 1: (E)-1-(2-nitrostyryl)pyrrolidine To a solution of 1-methyl-2-nitrobenzene (50 g, 365 mmol) in N,N-dimethylformamide (200 mL), pyrrolidine (31.1 g, 438 mmol) and 1,1-dimethoxy-N,N-dimethylmethaneamine (52.2 g, 438 mmol) were added. The resulting mixture was stirred at 60°C. After 5 hours, the temperature was raised to 80°C and stirred for 17 hours. After cooling to room temperature, the mixture was partitioned between methyl tert-butyl ether (500 mL) and water (1 L). The aqueous phase was separated and extracted with methyl tert-butyl ether (500 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (E)-1-(2-nitrostyryl)pyrrolidine (80 g, crude) as a dark red oil. This was used in the next step without further purification.

[0496] Step 2: 1-(2,2-dimethoxyethyl)-2-nitrobenzene To a solution of (E)-1-(2-nitrostyryl)pyrrolidine (80 g, crude) in methanol (600 mL), trimethylchlorosilane (59.5 g, 550 mmol) was slowly added. The mixture was heated under reflux for 24 hours. At that point, the solution was cooled to room temperature and concentrated under vacuum to obtain the residue. This was partitioned between ethyl acetate (500 mL) and 5% citric acid aqueous solution (800 mL). The aqueous layer was extracted with ethyl acetate (2 × 300 mL). The combined organic layers were washed with 5% sodium bicarbonate aqueous solution (300 mL), followed by brine. The crude product was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1-(2,2-dimethoxyethyl)-2-nitrobenzene (79 g, crude) as a dark red oil, which was used in the next step without further purification.

[0497] Step 3: 2-(2,2-dimethoxyethyl)aniline To a solution of 1-(2,2-dimethoxyethyl)-2-nitrobenzene (79 g, 374.4 mmol) in methanol (1 L), palladium activated carbon (17.6 g) was added. The mixture was stirred at room temperature under 50 psi of hydrogen for 17 hours. The mixture was filtered through diatomaceous earth and rinsed with methanol. The filtrate was concentrated to obtain the crude product. The crude product was dissolved in methyl tert-butyl ether (500 mL) and filtered. The filtrate was concentrated to obtain 2-(2,2-dimethoxyethyl)aniline (60 g, 331.5 mmol, 88.5% yield) as a dark red oily substance. This was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.98 - 6.89 (m, 2H), 6.63 (dd, J = 7.9, 1.1 Hz, 1H), 6.51 (td, J = 7.4, 1.2 Hz, 1H), 4.80 (s, 2H), 4.55 (t, J = 5.6 Hz, 1H), 3.25 (s, 6H), 2.72 (d, J = 5.6 Hz, 2H).

[0498] Step 4: N-(2-(2,2-dimethoxyethyl)phenyl)formamide A solution of 2-(2,2-dimethoxyethyl)aniline (60 g, 331.5 mmol) and ethyl formate (36.8 g, 497.2 mmol) in dry tetrahydrofuran (400 mL) was slowly added with a solution of 1 M lithium bis(trimethylsilyl)amide (597 mL, 597 mmol). The mixture was stirred at room temperature for 12 hours, then refluxed for 18 hours. At that point, saturated ammonium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate (3 × 200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (6:1 v / v)] to obtain N-(2-(2,2-dimethoxyethyl)phenyl)formamide (58 g, 277.5 mmol, 83.7% yield) as a dark red oil. LC-MS (2.5 min formic acid): Rt = 1.354 min, m / z: 209.1 [M+1] +, 231.9 [M+Na] + .

[0499] Step 5: 1-(2,2-dimethoxyethyl)-2-isocyanobenzene To a solution of N-(2-(2,2-dimethoxyethyl)phenyl)formamide (58 g, 277.5 mmol) in 500 mL of dichloromethane at 0°C, triethylamine (143 g, 1415.3 mmol), followed by phosphorus oxychloride (63.9 g, 416.3 mmol), was added. The mixture was warmed to room temperature and stirred for 2 hours. At that point, it was poured into 300 mL of saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (3 × 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (20:1 v / v)] to obtain 1-(2,2-dimethoxyethyl)-2-isocyanobenzene (42 g, 218.5 mmol, 79.2% yield) as a light brown oily substance. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.57 - 7.27 (m, 4H), 4.61 (t, J = 5.6 Hz, 1H), 3.27 (s, 6H), 3.00 (d, J = 5.6 Hz, 2H). LCMS (2.5 min formic acid): Rt = 1.455 minutes, m / z: 192.0 (M+1) + .

[0500] Step 6: 4,4-Dimethoxy-2,2-dimethylbutanenitrile A solution of diisopropylamine (89.4 mL, 682 mmol) in tetrahydrofuran (1 L) at -10°C under nitrogen was mixed with a solution of 2.4 M n-butyllithium in hexane (288 mL, 682 mmol). After 30 minutes, the mixture was cooled to -78°C, and a solution of 4,4-dimethoxybutanenitrile (40 g, 310 mmol) in tetrahydrofuran (30 mL) was added. After 1 hour, methyl iodide (42.4 mL, 682 mmol) was added very slowly. The mixture was warmed to room temperature and stirred overnight. At this point, it was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3 × 400 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (30:1 v / v)] to obtain 4,4-dimethoxy-2,2-dimethylbutanenitrile (35 g, 223 mmol, 71.9% yield) as a pale yellow oil. 1 H-NMR (400 MHz, CDCl3) δ ppm 4.60 (t, J = 5.4 Hz, 1H), 3.36 (s, 6H), 1.83 (d, J = 5.4 Hz, 2H), 1.39 (s, 6H).

[0501] Step 7: 4,4-Dimethoxy-2,2-Dimethylbutanal To a solution of 4,4-dimethoxy-2,2-dimethylbutanenitrile (27 g, 172 mmol) in dichloromethane (800 mL), a solution of 1 M diisobutylaluminum hydride (189 mL, 189 mmol) in hexane was slowly added at -78°C for 3.5 hours. At this point, the mixture was warmed to room temperature and quenched with saturated ammonium chloride aqueous solution (400 mL) and Rochelle salt (400 mL). The aqueous phase was extracted with dichloromethane (2 × 400 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (30:1 v / v)] to obtain 4,4-dimethoxy-2,2-dimethylbutanal (13 g, 81.1 mmol, 47.1% yield) as a colorless oil. LC-MS (2.5 min formic acid): Rt = 1.453 min, m / z: 182.9 (M+Na) + .

[0502] Step 8: (4S,9aS)-4-amino-7-(1H-indole-1-carbonyl)-8,8-dimethylhexahydropyrrolo[2,1-b][1,3]thiazepine-5(2H)-one a. A mixture of N-(tert-butoxycarbonyl)-S-trityl-L-homocysteine ​​(11.8 g, 24.7 mmol), 1-(2,2-dimethoxyethyl)-2-isocyanobenzene (from step 5) (4.5 g, 23.5 mmol), 4,4-dimethoxy-2,2-dimethylbutanal (from step 7) (4.5 g, 28.2 mmol), and 7M ammonia in methanol (10 mL) in 2,2,2-trifluoroethanol (150 mL) was stirred at 100°C for 2 hours. At that point, it was quenched with 1M aqueous sodium hydroxide solution (200 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude tert-butyl((2S)-1-((1-((2-(2,2-dimethoxyethyl)phenyl)amino)-5,5-dimethoxy-3,3-dimethyl-1-oxopentan-2-yl)amino)-1-oxo-4-(tritylthio)butan-2-yl)carbamate (26 g, crude) as a brown solid. This was used in the next step without further purification. b. In step a, trifluoroacetic acid (20 mL) was slowly added to a solution of crude tert-butyl((2S)-1-((1-((2-(2,2-dimethoxyethyl)phenyl)amino)-5,5-dimethoxy-3,3-dimethyl-1-oxopentan-2-yl)amino)-1-oxo-4-(tritylthio)butan-2-yl)carbamate (26 g, crude) in dichloromethane (200 mL). The mixture was stirred at 40°C for 2 hours. The solvent was concentrated, and the crude product was purified by silica gel chromatography [dichloromethane / methanol (25:1 v / v)] to obtain (4S,9aS)-4-amino-7-(1H-indole-1-carbonyl)-8,8-dimethylhexahydropyrrolo[2,1-b][1,3]thiazepine-5(2H)-one (7.5 g, 21.0 mmol) as a granular solid. LCMS (2.5 min formic acid): Rt = 1.361 min, m / z: 357.9 (M+1) + .

[0503] Step 9: tert-butyl((S)-1-(((4S,7S,9aS)-7-(1H-indole-1-carbonyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (8.27 g, 43.1 mmol) was added to a solution of (4S,9aS)-4-amino-7-(1H-indole-1-carbonyl)-8,8-dimethylhexahydropyrrolo[2,1-b][1,3]thiazepine-5(2H)-one (14 g, 39.2 mmol), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (8.76 g, 43.1 mmol), 1-hydroxybenzotriazole (5.82 g, 43.1 mmol), and 4-methylmorpholine (11.88 g, 117.6 mmol) in tetrahydrofuran (400 mL). The mixture was stirred at room temperature for 3 hours. At that point, it was quenched with saturated sodium bicarbonate aqueous solution (300 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (2:1 v / v ~ 1:1 v / v)] to obtain tert-butyl((S)-1-(((4S,7R,9aS)-7-(1H-indole-1-carbonyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (5.2 g, 9.6 mmol, 24.5% yield) as a granular solid. The desired product, tert-butyl((S)-1-(((4S,7S,9aS)-7-(1H-indole-1-carbonyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (5.0 g, 9.2 mmol, 23.5% yield), was obtained as a pale yellow solid. LCMS (2.5 min formic acid): Rt = 1.740 min, m / z: 564.8 (M+1) + .

[0504] Step 10: (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid A solution of tert-butyl((S)-1-(((4S,7S,9aS)-7-(1H-indole-1-carbonyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (3.9 g, 7.19 mmol) in methanol (60 mL) was mixed with 1 M aqueous sodium hydroxide solution (60 mL). The mixture was stirred at room temperature for 24 hours. The volatile solvent was removed under reduced pressure. The remaining aqueous phase was washed with ethyl acetate (50 mL), and the pH of the aqueous phase was adjusted to pH 3 with citric acid. The aqueous phase was extracted with ethyl acetate (3 × 60 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (1:2 v / v)] to obtain (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (2 g, 4.51 mmol, 62.7% yield) as a white solid. LCMS (2.5 min formic acid): Rt = 1.493 min, m / z: 443.9 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 12.57 (s, 1H), 7.75 (d, J = 6.6 Hz, 1H), 5.46 (t, J = 7.2 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.43 (s, 1H), 3.98 (s, 1H), 3.17 - 3.11 (m, 1H), 2.88 (dd, J = 14.6, 3.0 Hz, 1H), 2.74 (s, 3H), 2.27 (dd, J = 12.9, 7.5 Hz, 1H), 2.12 - 2.10 (m, 1H), 1.80 (dd, J = 13.0, 7.1 Hz, 1H), 1.74- 1.68 (m, J = 11.2 Hz, 1H), 1.40 (s, 9H), 1.25 (d, J = 7.1 Hz, 3H), 1.09 (d, J = 10.6 Hz, 6H).

[0505] Intermediate II: (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanethioamide)-8,8,9a-trimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid

[0506] [ka]

[0507] Step 1: tert-butyl(S)-(1-((2-amino-5-nitrophenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a solution of N-(tert-butoxycarbonyl)-N-methyl-L-alanine (20.3 g, 100 mmol) in dry tetrahydrofuran (1.2 L), 4-methylmorpholine (20.2 g, 200 mmol) was added. The mixture was stirred at -20°C for 10 minutes, and then isobutylcarbonochloride (13.6 g, 100 mmol) was added dropwise. The mixture was stirred at -15°C for 2 hours and then warmed overnight to room temperature. The mixture was diluted with ethyl acetate (1.6 L) and washed sequentially with 1 M disodium hydrogen phosphate aqueous solution (1 L), 5% sodium bicarbonate aqueous solution (1 L), and brine (1 L). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (S)-tert-butyl(1-((2-amino-5-nitrophenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (30 g, 88.7 mmol, 88.7% yield) as a dark red oily substance. LCMS (2.5 min formic acid): Rt = 1.537 min, m / z: 360.9 (M+Na) + .

[0508] Step 2: tert-butyl(S)-(1-((2-amino-5-nitrophenyl)amino)-1-thioxopropan-2-yl)(methyl)carbamate Sodium carbonate (5.8 g, 55 mmol) was added to a solution of phosphorus(V) sulfide (24.4 g, 110 mmol) in dry tetrahydrofuran (1.6 L). The mixture was stirred at room temperature for 1 hour, and then cooled to 0°C. Tert-butyl(S)-(1-((2-amino-5-nitrophenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (40 g, 110 mmol) was added to the reaction. The mixture was stirred at room temperature for 3 hours. The solvent was concentrated under vacuum, diluted with ethyl acetate (1 L), and washed with 500 mL of 5% sodium bicarbonate aqueous solution and brine (500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain tert-butyl(S)-(1-((2-amino-5-nitrophenyl)amino)-1-thioxopropan-2-yl)(methyl)carbamate (33 g, 93.2 mmol, 84.7% yield) product as an orange solid. LC-MS (2.5 min formic acid): Rt = 1.602 min, m / z: 376.8 (M+Na) + .

[0509] Step 3: tert-butyl(S)-methyl(1-(6-nitro-1H-benzo[d][1,2,3]triazole-1-yl)-1-thioxopropan-2-yl)carbamate To a solution of tert-butyl(S)-(1-((2-amino-5-nitrophenyl)amino)-1-thioxopropan-2-yl)(methyl)carbamate (30 g, 84.6 mmol) in dried tetrahydrofuran (250 mL) and acetic acid (250 mL), sodium nitrite (9 g, 130.4 mmol) was added. The mixture was stirred at 0°C for 1.5 hours. This was then washed sequentially with water (3 × 500 mL), 5% sodium bicarbonate aqueous solution (2 × 500 mL), and brine (500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain tert-butyl(S)-methyl(1-(6-nitro-1H-benzo[d][1,2,3]triazole-1-yl)-1-thioxopropan-2-yl)carbamate (20 g, 54.8 mmol, 64.8% yield) as a brown oily substance, which was used in the next step without further purification.

[0510] Step 4: tert-butyl((S)-1-(((4S,7S,9aS)-7-(1H-indole-1-carbonyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-thioxopropan-2-yl)(methyl)carbamate Triethylamine (8.6 g, 84.6 mmol) was added at 0°C to a solution of (4S,9aS)-4-amino-7-(1H-indole-1-carbonyl)-8,8-dimethylhexahydropyrrolo[2,1-b][1,3]thiazepine-5(2H)-one (15 g, 42 mmol) and tert-butyl(S)-methyl(1-(6-nitro-1H-benzo[d][1,2,3]triazole-1-yl)-1-thioxopropan-2-yl)carbamate (20 g, 54.7 mmol) in dichloromethane (400 mL). The mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ethyl acetate / petroleum ether = 1 / 15) to obtain tert-butyl((S)-1-(((4S,7R,9aS)-7-(1H-indole-1-carbonyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-thioxopropan-2-yl)(methyl)carbamate) (3.0g, 5.37mmol, 25.5g) The desired diastereoisomer, tert-butyl((S)-1-(((4S,7S,9aS)-7-(1H-indole-1-carbonyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-thioxopropan-2-yl)(methyl)carbamate (3.9 g, 6.98 mmol, 29.4% yield), was obtained as a yellow oil from the 3.9 g solution (2.5 min formic acid): Rt = 1.905 min, m / z: 580.8 (M+Na) + .

[0511] Step 5: (4S,7S,9aS)-4-(2-((tert-butoxycarbonyl)(methyl)amino)ethanethioamide)-8,8,9a-trimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid To a solution of tert-butyl(2-(((4S,7S,9aS)-7-(1H-indole-1-carbonyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-2-thioxoethyl)(methyl)carbamate (1.5 g, 2.69 mmol) in methanol, 60 mL of 1 M sodium hydroxide aqueous solution was slowly added. The mixture was stirred overnight at room temperature. The volatile solvent was removed under reduced pressure, and the remaining solution was extracted with ethyl acetate (50 mL). The pH of the aqueous layer was adjusted to pH 4 with 20% citric acid aqueous solution, and then extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain (4S,7S,9aS)-4-(2-((tert-butoxycarbonyl)(methyl)amino)ethanethioamide)-8,8,9a-trimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (1 g, 21.8 mmol, 81% yield) as a brown oil. LCMS (2.5 min formic acid): Rt = 1.632 min, m / z: 481.8 (M+Na) + .

[0512] Example 1 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(methylenebis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0513] [ka]

[0514] Step 1: N,N'-(methylenebis(4,1-phenylene))diformamide To a solution of 4,4'-methylenedianiline (5 g, 25.2 mmol) in toluene (40 mL), formic acid (4.64 g, 100.8 mmol) was added. The mixture was stirred at 110 °C for 2 hours. The reaction product was concentrated. The crude product was washed with dichloromethane and filtered to obtain the desired product, N,N'-(methylenebis(4,1-phenylene))diformamide (4.7 g, 18.5 mmol, 73.4% yield), as a white solid. LC-MS (2.5 min formic acid): Rt = 1.165 min, m / z: 255.1 (M+1) + .

[0515] Step 2: Bis(4-isocyanophenyl)methane To a solution of N,N'-(methylenebis(4,1-phenylene))diformamide (4.7 g, 18.5 mmol) in 150 mL of dichloromethane at 0°C, triethylamine (19 g, 188.7 mmol) was added, followed by phosphorus oxychloride (8.5 g, 55.4 mmol). The mixture was warmed to room temperature and stirred for 2 hours. The reaction product was poured into 100 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (3 × 60 mL). The organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [dichloromethane / methanol (25:1 v / v)] to obtain bis(4-isocyanophenyl)methane (1.6 g, 7.3 mmol, 39.6% yield) as a white solid. LC-MS (2.5 min formic acid): Rt = 1.715 min, m / z: 218.9 (M+1) + .

[0516] Step 3: (4S,4'S,9aS,9a'S)-N,N'-(methylenebis(4,1-phenylene))bis(4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) A mixture of N-(tert-butoxycarbonyl)-S-trityl-L-homocysteine ​​(2.4 g, 5.04 mmol), bis(4-isocyanophenyl)methane (500 mg, 2.29 mmol), 4,4-dimethoxy-2,2-dimethylbutanal (954 mg, 5.95 mmol), and 7M ammonia in methanol (2 mL, 14 mmol) in 2,2,2-trifluoroethanol (10 mL) was stirred at 80°C for 30 minutes under microwave conditions. The mixture was quenched with 1M aqueous sodium hydroxide solution (20 mL) and extracted with ethyl acetate (3 × 15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude di-tert-butyl((2S,2'S)-((((methylenebis(4,1-phenylene))bis(azandiyl))bis(5,5-dimethoxy-3,3-dimethyl-1-oxopentane-1,2-diyl))bis(azandiyl))bis(1-oxo-4-(tritylthio)butane-1,2-diyl))dicarbamate (2.0 g, crude) as a brown solid. This was used in the next step without further purification. A solution of crude di-tert-butyl((2S,2'S)-((((methylenebis(4,1-phenylene))bis(azandiyl))bis(5,5-dimethoxy-3,3-dimethyl-1-oxopentane-1,2-diyl))bis(azandiyl))bis(1-oxo-4-(tritylthio)butane-1,2-diyl))dicarbamate (2g, crude) in dichloromethane (20mL) was slowly added to trifluoroacetic acid (5mL). The mixture was stirred at 40°C for 2 hours. The reaction product was concentrated and purified by silica gel chromatography [dichloromethane / methanol (6:1 v / v)] to obtain (4S,4'S,9aS,9a'S)-N,N'-(methylenebis(4,1-phenylene))bis(4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) (500 mg, 0.74 mmol) as a granular solid. LCMS (2.5 min formic acid): Rt = 1.263 min, m / z: 678.8 (M+1) + .

[0517] Step 4: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((methylenebis(4,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (342 mg, 1.782 mmol) was added to a solution of (4S,4'S,9aS,9a'S)-N,N'-(methylenebis(4,1-phenylene))bis(4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) (550 mg, 0.810 mmol), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (362 mg, 1.782 mmol), 1-hydroxybenzotriazole (241 mg, 1.782 mmol), and 4-methylmorpholine (491 mg, 4.860 mmol) in tetrahydrofuran (30 mL). The mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated sodium bicarbonate aqueous solution (25 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [dichloromethane / methanol (25:1 v / v)] to obtain an impure product, which was further purified by chiral HPLC to obtain the desired product, di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((methylenebis(4,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (55 mg, 0.052 mmol, 6.4% yield), as a white solid. LC-MS (2.5 min formic acid): Rt = 1.828 min, m / z: 425 [(M - 2Boc)+2]+ / 2.

[0518] Step 5: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(methylenebis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride To a solution of di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((methylenebis(4,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (55 mg, 0.052 mmol) in dichloromethane (6 mL), 4N hydrogen chloride (1.5 mL) in 1,4-dioxane was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the solid was dried under high vacuum to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(methylenebis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride (43 mg, 0.046 mmol, 88.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.08 (s, 2H), 9.27-9.24 (m, 2H), 8.87-8.84 (m, 2H), 8.80 (d, J= 6.8 Hz, 2H), 7.52 (d, J= 8.0 Hz, 2H), 7.14 (d, J= 8.0 Hz, 2H), 5.47 (t, J= 7.8 Hz, 2H), 4.71 (t, J= 9.4 Hz, 2H), 4.26 (s, 2H), 3.84 (s, 2H), 3.71-3.65 (m, 2H), 3.17 (t, J= 12.4Hz, 2H), 2.95-2.91 (m, 2H), 2.48-2.47 (m, 6H), 2.23-2.18 (m, 2H), 2.14-2.10 (m, 2H), 1.96-1.90 (m, 2H), 1.85-1.76 (m, 2H), 1.42 (s, 4H), 1.39 (d, J= 7.2 Hz, 6H), 1.09 (m, 6H), 1.02 (m, 6H). LCMS (2.5 min formic acid): Rt = 1.268 min, m / z: 848.9 (M+1) + .

[0519] Example 2: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(methylenebis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0520] [ka]

[0521] Step 1: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((methylenebis(4,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2diyl))bis(methylcarbamate) To a solution of (4S,4'S,9aS,9a'S)-N,N'-(methylenebis(4,1-phenylene))bis(4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) (Example 1, Step 3) (260 mg, 0.38 mmol) in 10 mL of dichloromethane at 0°C, triethylamine (116.3 mg, 1.15 mmol) was added. After 10 minutes, a solution of tert-butyl(S)-methyl(1-(6-nitro-1H-benzo[d][1,2,3]triazole-1-yl)-1-thioxopropan-2-yl)carbamate (321.9 mg, 0.88 mmol) in 5 mL of dichloromethane was added. The mixture was stirred at room temperature for a further 2 hours. The solvent was removed under reduced pressure to obtain a yellow syrup. The residue was purified by thin-layer chromatography [ethyl acetate / petroleum ether (1:4 v / v)] to obtain a yellow oily substance (200 mg, 0.18 mmol), which was further purified by chiral HPLC to obtain the title product (45 mg, 0.04 mmol, 10.9% yield). LCMS (2.5 min formic acid): Rt = 1.998 min, m / z: 980.6 (M - Boc +1) + .

[0522] Step 2: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(methylenebis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride To a solution of di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((methylenebis(4,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (45 mg, 0.042 mmol) in diethyl ether (2 mL), hydrogen chloride (4N in 1,4-dioxane, 1 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure and dried under high vacuum to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(methylenebis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride (22 mg, 0.025 mmol, 55% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.08-11.96 (m, 2H), 10.15 (s, 1H), 9.89 (s, 1H), 9.64 (s, 1H), 8.66 (s, 1H), 8.42 (s, 1H), 7.52 (d, J= 8.0 Hz, 2H), 7.14 (d, J= 8.0 Hz, 2H), 5.43 (t, J= 7.6 Hz, 2H), 5.16-5.08 (m, 2H), 4.29-4.20 (m, 4H), 3.84 (s, 2H), 3.72-3.67 (m, 2H), 3.22-3.16 (m, 2H), 3.01-2.98 (m, 2H), 2.49 (s, 6H), 2.25-2.21 (m, 4H), 2.00-1.92 (m, 4H), 1.46-1.43 (m, 6H), 1.11 (m, 6H), 1.02 (m, 6H). LCMS (2.5 min formic acid): Rt = 1.298 min, m / z: 880.6 (M+1) + .

[0523] Example 3 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(2,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0524] [ka]

[0525] Step 1: 2,2'-(ethane-1,2-diyl)dianiline To a solution of 1,2-bis(2-nitrophenyl)ethane (9.5 g, 34.9 mmol) in ethanol (200 mL), palladium-activated carbon (1 g) was added. The mixture was stirred at room temperature under hydrogen (1 atm) for 5 hours. The catalyst was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (1:1 v / v)] to obtain 2,2'-(ethane-1,2-diyl)dianiline (5 g, 23.6 mmol, 67.6% yield) as a yellow solid. LCMS (2.5 min formic acid): Rt = 1.336 min, 212.9 (M+1) + .

[0526] Step 2: N,N'-(ethane-1,2-diirbis(2,1-phenylene))diformamide To a solution of 2,2'-(ethane-1,2-diyl)dianiline (5 g, 23.6 mmol) in toluene (100 mL), formic acid (4.3 g, 94.4 mmol) was added. The mixture was stirred under reflux overnight. The mixture was concentrated under reduced pressure to obtain a crude product, which was washed with petroleum ether to obtain N,N'-(ethane-1,2-diylbis(2,1-phenylene))diformamide (5 g, 18.7 mmol, 79.2% yield) as a white solid.

[0527] Step 3: 1,2-Bis(2-isocyanophenyl)ethane To a solution of N,N'-(ethane-1,2-diylbis(2,1-phenylene))diformamide (2 g, 7.46 mmol) in dichloromethane (50 mL) at 0°C, triethylamine (7.5 g, 74.6 mmol) was added, followed by phosphorus oxychloride (3.4 g, 22.4 mmol). The mixture was warmed to room temperature and stirred for 4 hours. The reaction product was then poured into saturated sodium bicarbonate aqueous solution (50 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (4:1 v / v)] to obtain 1,2-bis(2-isocyanophenyl)ethane (1.5 g, 6.47 mmol, 86.7% yield) as a white solid. LC-MS (2.5 min formic acid): Rt = 1.763 min, m / z: 233.0 (M+1) + .

[0528] Step 4: (4S,4'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(2,1-phenylene))bis(4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) A mixture of N-(tert-butoxycarbonyl)-S-trityl-L-homocysteine ​​(4.1 g, 8.6 mmol), bis(4-isocyanophenyl)methane (1 g, 4.3 mmol), 4,4-dimethoxy-2,2-dimethylbutanal (1.45 g, 9.0 mmol), and 7M ammonia in methanol (2.4 mL, 16.8 mmol) in 2,2,2-trifluoroethanol (20 mL) was stirred at 80°C for 30 minutes under microwave conditions. The reaction mixture was quenched with 1M sodium hydroxide solution (40 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude di-tert-butyl((2S,2'S)-((((ethane-1,2-diylbis(2,1-phenylene))bis(azandiyl))bis(5,5-dimethoxy-3,3-dimethyl-1-oxopentane-1,2-diyl))bis(azandiyl))bis(1-oxo-4-(tritylthio)butane-1,2-diyl))dicarbamate (4.0 g, crude) as a brown solid. A solution of crude di-tert-butyl((2S,2'S)-((((ethane-1,2-diylbis(2,1-phenylene))bis(azandiyl))bis(5,5-dimethoxy-3,3-dimethyl-1-oxopentane-1,2-diyl))bis(azandiyl))bis(1-oxo-4-(tritylthio)butane-1,2-diyl))dicarbamate (4g, crude) was slowly added to a solution of crude di-tert-butyl((2S,2'S)-((((ethane-1,2-diyl))bis(5,5-dimethoxy-3,3-dimethyl-1-oxopentane-1,2-diyl))dicarbamate (4g, crude) in dichloromethane (50mL). Trifluoroacetic acid (10mL) was slowly added. The mixture was stirred at 40°C for 2 hours. The reaction product was concentrated and purified by silica gel chromatography [dichloromethane / methanol (6:1 v / v)] to obtain (4S,4'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(2,1-phenylene))bis(4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) (2.3 g, 3.32 mmol, 77.2% yield) as a yellow solid. LCMS (2.5 min formic acid): Rt = 1.317 min, m / z: 692.9 (M+1) + .

[0529] Step 5: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(2,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (580 mg, 3.04 mmol) was added to a solution of (4S,4'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(2,1-phenylene))bis(4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) (1 g, 1.44 mmol), N-(tert-butoxycarbonyl)-N-methyl-L-alanine (580 mg, 2.88 mmol), 1-hydroxybenzotriazole (430 mg, 3.17 mmol), and 4-methylmorpholine (580 mg, 5.76 mmol) in tetrahydrofuran (30 mL). The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (25 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (1:1 v / v)] to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(2,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (1.2 g, 1.13 mmol, 78.5% yield) as a beige solid. LC-MS (2.5 min formic acid): Rt = 1.910 min, m / z: 431.9 [(M-2Boc)+2] + / 2.

[0530] Step 6: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(2,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride To a solution of di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(2,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (90 mg, 0.085 mmol) in methanol (10 mL), 4N hydrogen chloride (5 mL) in 1,4-dioxane was added. The mixture was stirred at room temperature for 4 hours. Next, the mixture was concentrated and crystallized from ether and methanol to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(2,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride (15 mg, 0.016 mmol, 18.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.51 (s, 2H), 9.15 (s, 2H), 8.83-8.77 (m, 4H), 7.39-7.53 (m, 4H), 7.21-7.12 (m, 4H), 5.50 (t, J= 8.0 Hz, 2H), 4.74 (t, J= 9.6 Hz, 2H), 4.38 (s, 2H), 3.90-3.82 (m, 2H), 3.17-3.11 (m, 2H), 2.99-2.82 (m, 6H), 2.48 (m, 6H), 2.26-2.21 (m, 2H), 2.04-1.95 (m, 4H), 1.72-1.63 (m, 2H), 1.36 (d, J= 6.4 Hz, 6H), 1.14 (m, 6H), 1.12 (m, 6H). LCMS (2.5 min formic acid): Rt = 1.293 min, m / z: 862.9 (M+1) + .

[0531] Example 4 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(2,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0532] [ka]

[0533] Step 1: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(2,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) To a solution of (4S,4'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(2,1-phenylene))bis(4-amino-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) (300 mg, 0.44 mmol) in dichloromethane (20 mL) at 0°C, triethylamine (132 mg, 1.31 mmol) and tert-butyl(S)-methyl(1-(6-nitro-1H-benzo[d][1,2,3]triazole-1-yl)-1-thioxopropan-2-yl)carbamate (400 mg, 1.09 mmol) were added. The mixture was warmed to room temperature and stirred overnight. The mixture was washed with saturated sodium bicarbonate aqueous solution (15 mL) and brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(2,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (50 mg, 0.046 mmol, 10.5% yield) as a white solid. LC-MS (2.5 min formic acid): Rt = 2.173 min, m / z: 1116.6 (M+Na) + .

[0534] Step 2: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(2,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride To a solution of di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(2,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (50 mg, 0.046 mmol) in dichloromethane (5 mL), 4N hydrogen chloride (4 mL) in 1,4-dioxane was added. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated and dried under high vacuum to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(2,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride (35 mg, 0.036 mmol, 78.3% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (d, J= 6.8 Hz, 2H), 9.59 (s, 2H), 9.49 (s, 2H), 8.59 (s, 2H), 7.39-7.33 (m, 4H), 7.21-7.11 (m, 4H), 5.45 (t, J= 8.0 Hz, 2H), 5.18 (t, J= 8.2 Hz, 2H), 4.41 (s, 2H), 4.25-4.23 (m, 2H), 3.72-3.65 (m, 2H), 3.51-3.47 (m, 2H), 3.16 (t, J= 12.4 Hz, 2H), 2.93-2.88 (m, 2H), 2.50 (s, 6H), 2.28-2.16 (m, 4H), 2.06-2.00 (m, 2H), 1.84-1.75 (m, 2H), 1.41 (d, J = 6.4 Hz, 6H), 1.14 (m, 12H). LCMS (2.5 min formic acid): Rt = 1.389 min, m / z: 894.8 (M+1) + .

[0535] Example 5 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide)ditrifluoroacetate

[0536] [ka]

[0537] Step 1: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(4,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) To a solution of (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (intermediate I) (230 mg, 0.519 mmol) in 1,2-dichloroethane (20 mL), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (175 mg, 0.709 mmol), N,N-diisopropylethylamine (120 mg, 0.930 mmol), and 4,4'-(ethane-1,2-diyl)dianiline (50 mg, 0.236 mmol) were added. The mixture was stirred overnight at 50°C. The solvent was removed under reduced pressure, followed by purification by silica gel chromatography [petroleum ether / ethyl acetate (2:1 v / v)] to obtain the desired product, di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(4,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (100 mg, 0.094 mmol, 39.8% yield), as a yellow solid. LC-MS (2.5 min formic acid): Rt = 1.828 min, m / z: 432.0 {[(M-2Boc)+2] / 2} + .

[0538] Step 2: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide)ditrifluoroacetate To a solution of di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(4,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (100 mg, 0.094 mmol) in methanol (5 mL), 4N hydrogen chloride (5 mL) was added. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated and purified by preparative HPLC to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide)ditrifluoroacetate (64 mg, 0.059 mmol, 62.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (s, 2H), 8.94 (s, 2H), 8.80-8.78 (m, 4H), 7.50 (d, J= 8.0 Hz, 4H), 7.17 (d, J= 8.0 Hz, 4H), 5.49 (t, J= 7.6 Hz, 2H), 4.73 (t, J= 9.0 Hz, 2H), 4.24 (s, 2H), 3.89-3.83 (m, 2H), 3.21-3.15 (m, 2H), 3.12-3.09 (m, 2H), 2.80 (m, 2H), 2.50 (s, 6H), 2.24-2.20 (m, LCMS (2.5 min Formic acid): Rt = 1.284 min, m / z: 862.9 (M+1) + .

[0539] Example 6 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0540] [ka]

[0541] Step 1: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(4,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) To a solution of (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanethioamide)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (intermediate II) (141 mg, 0.312 mmol) in 1,2-dichloroethane (20 mL), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (105 mg, 0.423 mmol), N,N-diisopropylethylamine (72 mg, 0.564 mmol), and 4,4'-(ethane-1,2-diyl)dianiline (30 mg, 0.141 mmol) were added. The mixture was stirred overnight at 50°C. The solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (2:1 v / v)] followed by preparative HPLC to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(4,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (60 mg, 0.055 mmol, 39.0% yield) as a white solid. LCMS (2.5 min formic acid): Rt = 2.059 min.

[0542] Step 2: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride To a solution of di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-(((ethane-1,2-diylbis(4,1-phenylene))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (70 mg, 0.064 mmol) in methanol (5 mL), 3 mL of 4N hydrogen chloride was added. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-(ethane-1,2-diylbis(4,1-phenylene))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride (43 mg, 0.044 mmol, 68.8% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (d, J= 6.0 Hz, 2H), 10.95 (d, J= 6.8 Hz, 2H), 10.11-10.10 (m, 2H), 9.80 (s, 1H), 9.56 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 7.51 (d, J= 8.0 Hz, 4H), 7.15 (d, J= 8.4 Hz, 4H), 5.45 (q, J= 5.6 Hz, 2H), 5.18-5.09 (m, 2H), 4.29 (s, 2H), 4.24-4.21 (m, 2H), 3.22-3.17 (m, 2H), 3.02-2.99 (m, 2H), 2.80 (s, 2H), 2.50 (s, 6H), 2.26-2.22 (m, 4H), 2.02-1.91 (m, 4H), 1.46-1.43 (m, 6H), 1.12 (s, 6H), 1.04 (m, 12H). LCMS (2.5 min formic acid): Rt = 1.326 min, m / z: 895.1 (M+1) + .

[0543] Example 7 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0544] [ka]

[0545] Step 1: (1R,2R)-1-((tert-butoxycarbonyl)amino)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid Sodium carbonate was added to a solution of (1R,2R)-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylate hydrochloride (1.3 g, 5.71 mmol) in dioxane / water (1:1 v / v, 100 mL) to adjust the pH to 8. Then, di-tert-butyl dicarbonate (1.62 g, 7.42 mmol) was added. The mixture was stirred overnight at room temperature. Upon completion of the reaction, the pH of the mixture was adjusted to 4 with a 20% citric acid solution. The mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (3 / 2 v / v)] to obtain (1R,2R)-1-((tert-butoxycarbonyl)amino)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.3 g, 4.46 mmol, 78.1% yield) as a white solid. LCMS (2.5 min formic acid): Rt = 1.519 min, m / z: 289.9 (M-1) - .

[0546] Step 2: Di-tert-butyl((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))dicarbamate To a solution of (1R,2R)-1-((tert-butoxycarbonyl)amino)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (270 mg, 0.90 mmol) and piperazine (39.9 mg, 0.46 mmol) in N,N-dimethylformamide (12 mL) at -10°C, triethylamine (187.5 mg, 1.85 mmol) and diethyl cyanophosphonate (226.7 mg, 1.38 mmol) were slowly added. The mixture was stirred for 20 minutes. The mixture was then warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice water (50 mL) to obtain a precipitate, which was filtered and dried to obtain di-tert-butyl((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))dicarbamate (435 mg, 0.69 mmol, 68.7% yield) as a white solid. LCMS (2.5 min formic acid): Rt = 1.74 min, m / z: 532.7 (M - Boc + 1) + .

[0547] Step 3: Piperazine-1,4-diirbis(((1R,2R)-1-amino-1,2,3,4-tetrahydronaphthalene-2-yl)methanone) dihydrochloride To a solution of di-tert-butyl((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))dicarbamate (435 mg, 1.0 mmol) in dichloromethane (20 mL), 4N hydrogen chloride (2 mL) in 1,4-dioxane was slowly added. The mixture was stirred overnight at room temperature. The solvent was concentrated under reduced pressure to obtain crude piperazine-1,4-diylbis(((1R,2R)-1-amino-1,2,3,4-tetrahydronaphthalene-2-yl)methanone) dihydrochloride (402 mg) as a white solid. This was used in the reaction without further purification. LCMS (2.5 min formic acid): Rt = 1.07 min, m / z: 432.9 (M+1) + .

[0548] Step 4: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) Piperazine-1,4-diylbis(((1R,2R)-1-amino-1,2,3,4-tetrahydronaphthalene-2-yl)methanone) dihydrochloride (150 mg, 0.297 mmol), (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-8,8-dimethyl-5-oxooctahydropyrrolo[2 A solution of ,1-b][1,3]thiazepine-7-carboxylic acid (intermediate I) (319 mg, 0.68 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (200 mg, 1.02 mmol), 1-hydroxybenzotriazole (187 mg, 1.36 mmol), and N,N-diisopropylethylamine (269 mg, 2.04 mmol) was stirred overnight at room temperature. The reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layer was washed with brine, dried, filtered, and concentrated. The residue was purified by thin-layer chromatography [ethyl acetate / petroleum ether (2 / 1 v / v)] to obtain an impure product (93 mg) as a yellow oil. This material was further purified by preparative HPLC to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (64 mg, 0.05 mmol, 13.9% yield) as a white solid. LC-MS (3.0 min formic acid): Rt = 2.51 min, m / z: 1282.6 (M+1) + , 642.5 {[(M - 2Boc)+2] / 2} + .

[0549] Step 5: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride To a solution of di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (64 mg, 0.05 mmol) in dichloromethane (5 mL), hydrogen chloride (4N in 1,4-dioxane, 1 mL) was added. The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride (50 mg, 0.043 mmol, 84.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 2H), 8.00 (d, J= 8.8 Hz, 1H), 7.87 (d, J= 8.4 Hz, 1H), 7.31-7.25 (m, 2H), 7.19-7.07 (m, 6H), 5.50-5.45 (m, 2H), 5.40-5.34 (m, 2H), 4.70-4.64 (m, 2H), 3.78-3.65 (m, 6H), 3.62-3.59 (m, 2H), 3.49-3.47 (m, 2H), 3.22-3.11 (m, 4H), 3.08-3.03 (m, 4H), 2.93-2.91 (m, 2H), 2.76 (s, 4H), 2.43 (m, 6H), 2.17-2.20 (m, 2H), 2.10-2.01 (m, 4H), 1.94-1.88 (m, 2H), 1.76-1.58 (m, 2H), 1.35-1.32 (m, 6H), 1.03-1.00 (m, 12H). LCMS (2.5 min formic acid): Rt = 1.407 min, m / z: 1082.8 (M+1) + .

[0550] Example 8 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0551] [ka]

[0552] Step 1: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) Piperazine-1,4-diylbis(((1R,2R)-1-amino-1,2,3,4-tetrahydronaphthalene-2-yl)methanone) dihydrochloride (Example 7, Step 3) (150 mg, 0.297 mmol), (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanethioamide)-8,8-dimethyl-5-oxooctahydropyrrolo[ A solution of 2,1-b][1,3]thiazepine-7-carboxylic acid (intermediate II) (272.8 mg, 0.593 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (170.7 mg, 0.89 mmol), 1-hydroxybenzotriazole (160.5 mg, 1.188 mmol), and N,N-diisopropylethylamine (230.2 mg, 1.782 mmol) was stirred overnight at room temperature. The reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layer was washed with brine, dried, filtered, and concentrated. The residue was purified by thin-layer chromatography [ethyl acetate / petroleum ether (2 / 1 v / v)] to obtain an impure product (170 mg) as a yellow oil. This material was further purified by preparative HPLC to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (90 mg, 0.07 mmol, 23.6% yield) as a white solid. LC-MS (3.0 min formic acid): Rt = 2.75 min, m / z: 1315.6 (M+1) + .

[0553] Step 2: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride To a solution of di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (96 mg, 0.073 mmol) in dichloromethane (10 mL), hydrogen chloride (4N in 1,4-dioxane, 1 mL) was added. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(piperazine-1,4-dicarbonyl)bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride (60 mg, 0.05 mmol, 68.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.12-10.98 (m, 1H), 10.89-10.87 (m, 1H), 9.81 (s, 1H), 9.62 (s, 1H), 8.67 (s, 1H), 8.44-8.36 (m, 1H), 8.15-8.07 (m, 1H), 7.95-7.88 (m, 1H), 7.26-7.25 (m, 2H), 7.15-7.09 (m, 6H), 5.47-5.41 (m, 2H), 5.36-5.35 (m, 2H), 5.17-5.03 (m, 2H), 4.41-4.32 (m, 2H), 3.78-3.65 (m, 4H), 3.60-3.47 (m, 4H), 3.39 (s, 2H), 3.25-3.09 (m, 4H), 3.03-2.96 (m, 2H), 2.75 (s, 4H), 2.51 (s, 6H), 2.30-2.19 (m, 6H), 2.02 (s, 2H), 1.91 (s, 2H), 1.66-1.62 (m, 2H), 1.45-1.41 (m, 6H), 1.04 (s, 6H), 1.00 (s, 6H). LCMS (2.5 min Formic acid): Rt = 1.246 min, m / z: 1114.4 (M+1) + .

[0554] Example 9 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0555] [ka]

[0556] Step 1: Di-tert-butyl((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))dicarbamate To a solution of (1R,2R)-1-((tert-butoxycarbonyl)amino)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (114 mg, 0.39 mmol) and 1,4-phenylenedimethaneamine (26 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) at -10°C, triethylamine (79 mg, 0.78 mmol) and diethyl cyanophosphonate (96 mg, 0.59 mmol) were slowly added. The mixture was stirred for 20 minutes. The mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice water (50 mL) to obtain a precipitate, which was filtered and dried to obtain di-tert-butyl((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))dicarbamate (180 mg, 0.26 mmol, 67.4% yield) as a white solid. LCMS (2.5 min formic acid): Rt = 1.736 min, m / z: 704.8 (M+Na) + .

[0557] Step 2: (1R,1'R,2R,2'R)-N,N'-(1,4-phenylenebis(methylene))bis(1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide) dihydrochloride To a solution of di-tert-butyl((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))dicarbamate (180 mg, 0.26 mmol) in dichloromethane (10 mL), 4N hydrogen chloride (1 mL) in 1,4-dioxane was slowly added. The mixture was stirred at room temperature for 4 hours, and the solvent was removed under reduced pressure to obtain (1R,1'R,2R,2'R)-N,N'-(1,4-phenylenebis(methylene))bis(1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide) dihydrochloride (150 mg) as a white solid. This was used in the next step without further purification. LC-MS (2.5 min formic acid): Rt = 1.085 min, m / z: 482.9 (M+1) + .

[0558] Step 3: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (1R,1'R,2R,2'R)-N,N'-(1,4-phenylenebis(methylene))bis(1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide) dihydrochloride (150 mg, 0.27 mmol), (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-8,8-dimethyl-5-oxoctahydr in dichloromethane (10 mL) A solution of ropyrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (intermediate I) (240 mg, 0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (155.3 mg, 0.81 mmol), 1-hydroxybenzotriazole (146 mg, 1.08 mmol), and N,N-diisopropylethylamine (209.3 mg, 1.62 mmol) was stirred overnight at room temperature. The reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layer was washed with brine, dried, filtered, and concentrated. The residue was purified by thin-layer chromatography [ethyl acetate / petroleum ether (2:1 v / v)] to obtain the crude product (170 mg) as a yellow oil. This material was further purified by preparative HPLC to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-di Bis(azandiyl)bis(carbonyl)bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl)bis(azandiyl)bis(1-oxopropane-1,2-diyl)bis(methylcarbamate) (76 mg, 0.057 mmol, 21.1% yield) was obtained as a white solid. LCMS (2.5 min formic acid): Rt = 1.80 min, m / z: 566.9 {[M-2Boc)=2] / 2} + .

[0559] Step 4: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl) in dichloromethane (6 mL) A solution of bis(carbonyl)bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl)bis(azandiyl)bis(1-oxopropane-1,2-diyl)bis(methylcarbamate) (80 mg, 0.06 mmol) was mixed with hydrogen chloride (4N in 1,4-dioxane, 1 mL). The mixture was stirred overnight at room temperature. The mixture was concentrated and dried under high vacuum to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride (46.2 mg, 0.038 mmol, 60.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 2H), 8.86-8.85 (m, 2H), 8.78 (d, J= 6.8 Hz, 2H), 8.36 (t, J= 5.2 Hz, 2H), 7.94 (d, J= 9.2 Hz, 2H), 7.31-7.29 (m, 2H), 7.22 (s, 4H), 7.14-7.12 (m, 4H), 7.09-7.06 (m, 3H), 5.48 (t, J= 7.8 Hz, 2H), 5.43-5.30 (m, 2H), 4.72-4.67 (m, 2H), 4.38-4.33 (m, 2H), 4.14 (s, 2H), 4.08-4.03 (m, 2H), 3.91-3.86 (m, 2H), 3.21-3.15 (m, 2H), 2.96-2.87 (m, 4H), 2.82-2.68 (s, 4H), 2.47 (t, J= 4.4 Hz, 6H), 2.21-2.16 (m, 2H), 2.09-1.99 (m, 6H), 2.00-1.96 (m, 2H), 1.75-1.70 (m, 2H), 1.38 (d, J= 6.8 Hz, 6H), 1.03 (s, 6H), 1.00 (s, 6H). LCMS (2.5 min Formic acid): Rt = 1.453 min, m / z: 1133.7 (M+1) + , 1155.6 (M+Na) + .

[0560] Example 10 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide)

[0561] [ka]

[0562] Step 1: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (1R,1'R,2R,2'R)-N,N'-(1,4-phenylenebis(methylene))bis(1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide) dihydrochloride (Example 9, Step 2) (116 mg, 0.21 mmol) in dichloromethane (10 mL), (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanethioamide)-8,8-dimethyl-5 A solution of -oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (intermediate II) (201 mg, 0.44 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (120 mg, 0.63 mmol), 1-hydroxybenzotriazole (113 mg, 0.84 mmol), and N,N-diisopropylethylamine (279 mg, 2.16 mmol) was stirred overnight at room temperature. The reaction mixture was quenched with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layer was washed with brine, dried, filtered, and concentrated. The residue was subjected to thin-layer chromatography [ethyl acetate / petroleum ether (2 / 1 The product was purified by v / v) to obtain an impure product (110 mg) as a yellow oily substance, which was further purified by preparative HPLC to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4 -Tetrahydronaphthalene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (54 mg, 0.039 mmol, 18.9% yield) was obtained as a white solid. LCMS (3.0 min formic acid): Rt = 2.614 min, m / z: 1388 (M+Na) + .

[0563] Step 2: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl) in dichloromethane (5 mL) To a solution of bis(carbonyl)bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl)bis(azandiyl)bis(1-thioxopropane-1,2-diyl)bis(methylcarbamate) (54 mg, 0.04 mmol), hydrogen chloride (4 N in 1,4-dioxane, 1 mL) was added. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the mixture was diluted with water. The pH was adjusted to 8-9 with sodium bicarbonate, and the mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography [dichloromethane / methanol (8 / 1 v / v)] to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1R,1'R,2R,2'R)-(((1,4-phenylenebis(methylene))bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) (6 mg, 0.005 mmol, 13% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43-8.37 (m, 2H), 7.85-7.82 (m, 2H), 7.33-7.27 (m, 2H), 7.20 (s, 4H), 7.15-7.13 (m, 4H), 7.08-7.06 (m, 2H), 5.51-5.46 (m, 2H), 5.40-5.37 (m, 2H), 5.10-5.06 (m, 2H), 4.40-4.34 (m, 2H), 4.16 (s, 2H), 4.04-4.00 (m, 2H), 3.49-3.42 (m, 2H), 3.22-3.14 (m, 2H), 2.98-2.91 (m, 4H), 2.79-2.69 (m, 4H), 2.42-2.31 (m, 2H), 2.27-2.20 (m, 2H), 2.16 (m, 6H), 2.07-1.98 (m, 4H), 1.74-1.65 (m, 2H), 1.22-1.21 (m, 6H), 1.07-1.06 (m, 6H), 1.03-1.02 (m , 6H). LCMS (2.5 min formic acid): Rt = 1.52 min, 1164.7 (M+1) + .

[0564] Example 11 (4S,7S,9aS)-8,8-dimethyl-4-[(2S)-2-(methylamino)propanamide]-5-oxo-N-[(1R,2R)-2-{[(1rs,4rs)-4-[(1R,2R)-1-[(4S,7S,9aS)-8,8-dimethyl-4-[(2S)-2-(methylamino)propanamide]-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine-7-amide]-1,2,3,4-tetrahydronaphthalene-2-amide]cyclohexyl]carbamoyl}-1,2,3,4-tetrahydronaphthalene-1-yl]-octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide dihydrochloride

[0565] [ka]

[0566] Step 1: Di-tert-butyl((1R,1'R,2R,2'R)-((((1R,4R)-cyclohexane-1,4-diyl)bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))dicarbamate To a solution of (1R,2R)-1-((tert-butoxycarbonyl)amino)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (250 mg, 0.858 mmol) and (1r,4r)-cyclohexane-1,4-diamine (49 mg, 0.429 mmol) in N,N-dimethylformamide (10 mL) at -10°C, N,N-diisopropylethylamine (221 mg, 1.716 mmol) and diethyl cyanophosphonate (210 mg, 1.287 mmol) were slowly added. The mixture was stirred for 20 minutes. The mixture was then warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice water (100 mL) to obtain a precipitate, which was filtered to obtain di-tert-butyl((1R,1'R,2R,2'R)-((((1R,4R)-cyclohexane-1,4-diyl)bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))dicarbamate (240 mg, 0.363 mmol, 84.6% yield) as an orange solid. LCMS (2.5 min formic acid): Rt = 1.724 min, m / z: 628.8 (M+Na) + .

[0567] Step 2: (1R,1'R,2R,2'R)-N,N'-((1R,4R)-cyclohexane-1,4-diyl)bis(1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide) dihydrochloride To a solution of di-tert-butyl((1R,1'R,2R,2'R)-((((1R,4R)-cyclohexane-1,4-diyl)bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))dicarbamate (150 mg, 0.23 mmol) in dichloromethane (5 mL), 4N hydrogen chloride (0.5 mL) in 1,4-dioxane was slowly added. The mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure to obtain (1R,1'R,2R,2'R)-N,N'-((1R,4R)-cyclohexane-1,4-diyl)bis(1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide) dihydrochloride (130 mg, crude) as a yellow syrup. LC-MS (2.5 min formic acid): Rt = 1.122 min, m / z: 461.1 (M+1) + .

[0568] Step 3: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-((((1R,4R)-cyclohexane-1,4-diyl)bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (1R,1'R,2R,2'R)-N,N'-((1R,4R)-cyclohexane-1,4-diyl)bis(1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide) dihydrochloride (130 mg, 0.24 mmol) and (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-8,8-dimethyl-5-oxoocta in dichloromethane (10 mL). A solution of hydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (intermediate I) (216.2 mg, 0.49 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemethiozide (140.1 mg, 0.73 mmol), 1-hydroxybenzotriazole (131.7 mg, 0.97 mmol), and N,N-diisopropylethylamine (189 mg, 1.46 mmol) was stirred overnight at room temperature. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layer was washed with brine, dried, filtered, and concentrated. The residue was purified by thin-layer chromatography [ethyl acetate / petroleum ether (2 / 1 v / v)] to obtain the crude product (170 mg) as a yellow oil. This material was further purified by preparative HPLC to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-((((1R,4R)-cyclohexane-1,4-diyl)bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2, 1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (86 mg, 0.06 mmol, 26.8% yield) was obtained as a white solid. LCMS (2.5 min formic acid): Rt = 1.96 min, m / z: 555.9 {[M-2Boc)+2] / 2} + .

[0569] Step 4: (4S,7S,9aS)-8,8-dimethyl-4-[(2S)-2-(methylamino)propanamide]-5-oxo-N-[(1R,2R)-2-{[(1rs,4rs)-4-[(1R,2R)-1-[(4S,7S,9aS)-8,8-dimethyl-4-[(2S)-2-(methylamino)propanamide]-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine-7-amide]-1,2,3,4-tetrahydronaphthalene-2-amide]cyclohexyl]carbamoyl}-1,2,3,4-tetrahydronaphthalene-1-yl]-octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide dihydrochloride Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-((((1R,4R)-cyclohexane-1,4-diyl)bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(a To a solution of zandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (80 mg, 0.073 mmol), hydrogen chloride (4 N in 1,4-dioxane, 1 mL) was added. The reaction mixture was stirred overnight at room temperature. The solvent was concentrated under reduced pressure, and the solid was dried under high vacuum to obtain the title compound (62 mg, 0.052 mmol, 79.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.29 (s, 1H), 8.89-8.88 (m, 1H), 8.78 (d, J= 6.8 Hz, 2H), 7.90 (d, J= 9.2 Hz, 2H), 7.74 (d, J= 7.6 Hz, 2H), 7.28-7.26 (m, 2H), 7.12-7.05 (m, 6H), 5.46 (t, J= 7.6 Hz, 2H), 5.36-5.33 (m, 2H), 4.71-4.67 (m, 2H), 4.15 (s, 2H), 3.90 (s, 2H), 3.41-3.39 (m, 2H), 3.16 (t, J= 11.8 Hz, 2H), 2.96-2.92 (m, 2H), 2.79-2.64 (m, 6H), 2.48 (s, 6H), 2.19-2.11 (m, 4H), 2.01-1.94 (m, 6H), 1.78-1.68 (m, 6H), 1.40 (d, J= 6.8 Hz, 6H), 1.20-1.12 (m, 4H), 1.02 (s, 6H), 1.00 (s, 6H). LCMS (2.5 min formic acid): Rt = 1.280 min, m / z: 1110.8 (M+1) + .

[0570] Example 12 (4S,7S,9aS)-8,8-dimethyl-4-[(2S)-2-(methylamino)propanethioamide]-5-oxo-N-[(1R,2R)-2-{[(1rs,4rs)-4-[(1R,2R)-1-[(4S,7S,9aS)-8,8-dimethyl-4-[(2S)-2-(methylamino)propanethioamide]-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine-7-amide]-1,2,3,4-tetrahydronaphthalene-2-amide]cyclohexyl]carbamoyl}-1,2,3,4-tetrahydronaphthalene-1-yl]-octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide dihydrochloride

[0571] [ka]

[0572] Step 1: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-((((1R,4R)-cyclohexane-1,4-diyl)bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (1R,1'R,2R,2'R)-N,N'-((1R,4R)-cyclohexane-1,4-diyl)bis(1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide) dihydrochloride (Example 11, Step 2) (200 mg, 0.375 mmol) in dichloromethane (15 mL), (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanethioamide)-8,8-dimeth A mixture of ru-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (intermediate II) (413 mg, 0.901 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (216 mg, 1.125 mmol), 1-hydroxybenzotriazole (203 mg, 1.5 mmol), and N,N-diisopropylethylamine (290 mg, 2.25 mmol) was stirred at room temperature for 4 hours. The reaction mixture was poured into water (15 mL) and extracted with dichloromethane (2 × 10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.Next, the crude product was purified by preparative TLC [petroleum ether / ethyl acetate (1:2 v / v)], followed by preparative HPLC, and then di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-((((1R,4R)-cyclohexane-1,4-diyl)bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1- Diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (140 mg, 0.104 mmol, 28.0% yield) was obtained as a beige solid. LCMS (2.5 min formic acid): Rt = 2.115 min, m / z: 572.1 {[(M-2Boc)+2] / 2}. + .

[0573] Step 2: (4S,7S,9aS)-8,8-dimethyl-4-[(2S)-2-(methylamino)propanethioamide]-5-oxo-N-[(1R,2R)-2-{[(1rs,4rs)-4-[(1R,2R)-1-[(4S,7S,9aS)-8,8-dimethyl-4-[(2S)-2-(methylamino)propanethioamide]-5-oxo-octahydropyrrolo[2,1-b][1,3]thiazepine-7-amide]-1,2,3,4-tetrahydronaphthalene-2-amide]cyclohexyl]carbamoyl}-1,2,3,4-tetrahydronaphthalene-1-yl]-octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide dihydrochloride Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1R,1'R,2R,2'R)-((((1R,4R)-cyclohexane-1,4-diyl)bis(azandiyl))bis(carbonyl))bis(1,2,3,4-tetrahydronaphthalene-2,1-diyl))bis(azandiyl) in dichloromethane (5 mL) To a solution of diyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (140 mg, 0.104 mmol), 0.5 mL of 4N hydrogen chloride in 1,4-dioxane was added. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the mixture was dried under high vacuum to obtain the title compound (70 mg, 0.058 mmol, 55.3% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.04-11.00 (m, 2H), 10.91 (s, 2H), 8.67 (s, 1H), 8.43 (s, 1H), 7.97 (t, J= 8.4 Hz, 2H), 7.76-7.75 (m, 2H), 7.27-7.25 (m, 2H), 7.15-7.06 (m, 6H), 5.45-5.33 (m, 4H), 5.15-5.09 (m, 2H), 4.32 (s, 2H), 4.18 (d, J= 9.2 Hz, 2H), 3.51-3.47 (m, 2H), 3.22-3.17 (m, 2H), 3.07-3.00 (m, 2H), 2.79-2.66 (m, 6H), 2.48 (s, 6H), 2.33-2.18 (m, 4H), 2.05-1.94 (m, 6H), 1.79-1.74 (m, 6H), 1.45 (s, 6H), 1.24-1.14 (m, 4H), 1.04-1.03 (m, 6H), 1.00 (m, 6H). LCMS (2.5 min formic acid): Rt = 1.242 min, m / z: 1144.4 (M+1) + , 572.3 [(M+2) / 2] + .

[0574] Example 13 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0575] [ka]

[0576] Step 1: (1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-amine To a solution of (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (2 g, 13.4 mmol) in tetrahydrofuran (50 mL) at 0°C, sodium hydride (60%, dispersed in liquid paraffin) (0.59 g, 14.7 mmol) was added in small increments. The mixture was warmed to room temperature. Then, 3-bromopropa-1-yne (1.75 g, 14.7 mmol) was added, and the resulting mixture was heated to 70°C. This was stirred overnight at 70°C. The mixture was quenched with ice water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (3:2 v / v)] to obtain (1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-amine (1.2 g, 6.4 mmol, 47.8% yield) as a black oily substance. LCMS (ES, m / z): 187.1, 188.1 [M+H] + , retention time 0.942 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.36 - 7.29 (m, 1H), 7.22 - 7.13 (m, 3H), 4.25 (dd, J = 4.2, 2.4 Hz, 2H), 4.22 - 4.15 (m, 2H), 3.43 (t, J = 2.4 Hz, 1H), 2.93 (qd, J = 16.1, 3.5 Hz, 2H), 1.75 (s, 2H).

[0577] Step 2: tert-butyl((S)-1-(((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-(((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-amine (100 mg, 0.534 mmol) was added to a solution of (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (260 mg, 0.587 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (305 mg, 0.801 mmol), and N,N-diisopropylethylamine (138 mg, 1.068 mmol) in 1,2-dichloroethane (10 mL). The mixture was stirred overnight at 50°C. The solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (1:1 v / v)] and further purified by thin-layer chromatography [ethyl acetate / petroleum ether (3 / 2 v / v)] to obtain tert-butyl((S)-1-(((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-(((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (160 mg, 0.261 mmol, 48.9% yield). LC-MS (2.5 min formic acid): Rt = 1.662 min, m / z: 634.8 (M+Na) + .

[0578] Step 3: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) a. To a solution of tert-butyl((S)-1-(((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-(((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (160 mg, 0.261 mmol) and pyridine (124 mg, 1.566 mmol) in acetonitrile (7 mL), cupric acetate (57 mg, 0.313 mmol) was added. The mixture was stirred at 85°C for 1 hour. The mixture was cooled, concentrated, and diluted with ethyl acetate (15 mL). Aqueous ammonia solution (20-fold dilution, 15 mL) was added. The aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to thin-layer chromatography [ethyl acetate / petroleum ether (2 / 1 The compound was then purified by preparative HPLC to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (80 mg, 0.065 mmol, 50.2% yield) as a white solid. LC-MS (2.5 min formic acid): Rt = 1.853 min, m / z: 511.8 {[(M-2Boc)+2] / 2} + . b. To a solution of tert-butyl((S)-1-(((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-(((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (1.0 g, 1.63 mmol) and pyridine (775 mg, 9.79 mmol), cupric acetate (366 mg, 1.96 mmol) was added. The mixture was stirred at 85°C for 1 hour. The reaction mixture was cooled, concentrated, and diluted with ethyl acetate (100 mL). A 20-fold solution of ammonia (50 mL) was added. The aqueous phase was extracted with ethyl acetate (2 × 50 mL). The organic layers were combined and washed with brine. The layers were dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The residue was purified by chromatography on a silica gel column eluted with ethyl acetate / petroleum ether = 1 / 1 to obtain the crude product. Next, the crude product was purified by preparative HPLC to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (800 mg, 0.65 mmol, 80.2% yield) as a white solid. LCMS (ES, m / z): 1222.6, 512.2 [M / 2-Boc+H] + , retention time 1.735 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 6.5 Hz, 2H), 7.24 (ddd, J = 14.9, 8.9, 2.8 Hz, 8H), 5.48 (t, J = 7.9 Hz, 2H), 5.38 (dd, J = 8.7, 5.3 Hz, 2H), 4. 67 - 4.62 (m, 2H), 4.30 (m, 6H), 4.23 (s, 2H), 3.15 (t, J = 11.9 Hz, 2H), 3.03 (d, J = 4.4 Hz, 2H), 2.88 (d, J = 16.4 Hz, 2H), 2.73 (s, 6H), 2.26 - 2.17 (m, 2H), 2.16 - 2.05 (m, 6H), 1.76 (dt, J = 23.3, 10.1 Hz, 4H), 1.40 (s, 18H), 1.24 (d, J = 7.1 Hz, 6H), 1.07 (d, J = 14.9 Hz, 12H).

[0579] Step 4: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-(Hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(azandiyl))bis(cal) in dichloromethane (5 mL) A solution of bonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (80 mg, 0.065 mmol) was mixed with 1.5 mL of 4N hydrogen chloride in 1,4-dioxane. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the solid was dried under high vacuum to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride (55 mg, 0.050 mmol, 76.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.53-9.50 (m, 2H), 8.95-8.91 (m, 2H), 8.88 (d, J= 7.2 Hz, 2H), 8.00 (d, J= 8.8 Hz, 2H), 7.28-7.20 (m, 8H), 5.51 (t, J= 7.8 Hz, 2H), 5.38 (dd, J= 8.6, 5.4 Hz, 2H), 4.76-4.71 (m, 2H), 4.24-4.28 (m, 6H), 4.23 (s, 2H), 3.93-3.85 (m, 2H), 3.22-3.16 (m, 2H), 3.10-3.00 (m, 4H), 2.94-2.90 (m, 2H), 2.47 (t, J= 5.2 Hz, 6H), 2.29-2.14 (m, 4H), 1.87-1.79 (m, 4H), 1.42 (d, J= 6.8 Hz, 6H), 1.10 (s, 6H), 1.06 (s , 6H). LCMS (2.5 min formic acid): Rt = 1.328 min, m / z: 512.0 [(M+2) / 2] + .

[0580] Example 14 (4S,7S,9aS)-N-((1S,2R)-2-((6-(((1S,2R)-1-((4S,7S,9aS)-8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide)-2,3-dihydro-1H-inden-2-yl)oxy)hexa-2,4-diin-1-yl)oxy)-2,3-dihydro-1H-inden-1-yl)-8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide

[0581] [ka]

[0582] Step 1: tert-butyl((S)-1-(((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-(((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-thioxopropan-2-yl)(methyl)carbamate (1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-amine (224 mg, 1.197 mmol) was added to a solution of (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanethioamide)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (500 mg, 1.088 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (621 mg, 1.632 mmol), and N,N-diisopropylethylamine (309 mg, 2.393 mmol) in 1,2-dichloroethane (15 mL). The mixture was stirred overnight at 50°C. The mixture was concentrated and purified by silica gel chromatography [petroleum ether / ethyl acetate (3:2 v / v)] followed by preparative TLC [petroleum ether / ethyl acetate (2:3 v / v)] to obtain tert-butyl((S)-1-(((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-(((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-thioxopropan-2-yl)(methyl)carbamate (400 mg, 0.636 mmol, 58.5% yield). LC-MS (2.5 min formic acid): Rt = 1.812 min, m / z: 650.8 (M+Na) + .

[0583] Step 2: tert-butyl((S)-1-(((4S,7S,9aS)-7-(((1S,2R)-2-((6-(((1S,2R)-1-((4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanethioamide)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-ca Luboxamide)-2,3-dihydro-1H-inden-2-yl)oxy)hexa-2,4-diin-1-yl)oxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate 390 mg, 0.636 mmol) of tert-butyl((S)-1-(((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-(((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate in acetonitrile (15 mL), tert-butyl((S)-1-(((4S Cupric acetate (277 mg, 1.526 mmol) was added to a solution of (7S,9aS)-8,8-dimethyl-5-oxo-7-(((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-thioxopropan-2-yl)(methyl)carbamate (400 mg, 0.636 mmol) and pyridine (301 mg, 3.816 mmol). The mixture was stirred at 85°C for 40 minutes. After cooling, the solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate (20 mL) and aqueous ammonia solution (20-fold dilution, 20 mL). The aqueous phase was extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.The crude product was purified by preparative TLC [petroleum ether / ethyl acetate (2:3 v / v)] and preparative HPLC to obtain tert-butyl((S)-1-(((4S,7S,9aS)-7-(((1S,2R)-2-((6-(((1S,2R)-1-((4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanethioamide)-8,8-dimethyl-5-oxooctahydropyrrolo[ 2,1-b][1,3]thiazepine-7-carboxamide)-2,3-dihydro-1H-inden-2-yl)oxy)hexa-2,4-diin-1-yl)oxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopro Pan-2-yl)(methyl)carbamate (50 mg, 0.040 mmol, 6.29% yield) and di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(hexa-2,4-diin-1,6-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-di Bis(azandiyl)bis(carbonyl)bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl)bis(azandiyl)bis(1-thioxopropane-1,2-diyl)bis(methylcarbamate) (30 mg, 0.024 mmol, 3.77% yield) were both obtained as white solids.

[0584] Step 3: (4S,7S,9aS)-N-((1S,2R)-2-((6-(((1S,2R)-1-((4S,7S,9aS)-8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide)-2,3-dihydro-1H-inden-2-yl)oxy)hexa-2,4-diin-1-yl)oxy)-2,3-dihydro-1H-inden-1-yl)-8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide dihydrochloride tert-butyl((S)-1-(((4S,7S,9aS)-7-(((1S,2R)-2-((6-(((1S,2R)-1-((4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanethioamide)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide)-2,3-dihydro-1 in dichloromethane (5 mL) To a solution of H-inden-2-yl)oxy)hexa-2,4-diin-1-yl)oxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (50 mg, 0.040 mmol), 4N hydrogen chloride (0.5 mL) in 1,4-dioxane was added. The mixture was stirred overnight at room temperature. The mixture was concentrated and dried to obtain (4S,7S,9aS)-N-((1S,2R)-2-((6-(((1S,2R)-1-((4S,7S,9aS)-8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide)-2,3-dihydro-1H-inden-2-i (L)oxy)hexa-2,4-diin-1-yl)oxy)-2,3-dihydro-1H-inden-1-yl)-8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide dihydrochloride (20 mg, 0.018 mmol, 45% yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.03-10.93 (m, 2H), 9.74-9.58 (m, 1H), 9.28 (s, 1H), 8.86-8.84 (m, 2H), 8.65-8.45 (m, 1H), 8.11-8.05 (m, 1H), 8.02-8.00 (m, 1H), 7.27-7.18 (m, 8H), 5.52-5.43 (m, 2H), 5.40-5.37 (m, 2H), 5.17 (q, J= 6.4 Hz, 1H), 4.76-4.65 (m, 1H), 4.38-4.23 (m, 8H), 3.91-3.88 (m, 1H), 3.73-3.65 (m, 1H), 3.51-3.46 (m, 1H), 3.22-3.16 (m, 2H), 3.10-2.97 (m, 4H), 2.95-2.90 (m, 1H), 2.49 (s, 6H), 2.33-2.12 (m, 4H), 1.96-1.76 (m, 4H), 1.45 (d, J= 6.4 H, 3H), 1.41 (d, J= 6.8 H, 3H), 1.10-1.06 (m, 12H). LCMS (2.5 min formic acid): Rt = 1.643 minutes, m / z: 520.0 [(M+2) / 2] + .

[0585] Example 15 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0586] [ka] Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(azandiyl))bis(carbonyl))bis To a solution of (8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (Example 14, Step 2) (35 mg, 0.028 mmol), 4N hydrogen chloride (0.5 mL) in 1,4-dioxane was added. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the mixture was dried under high vacuum to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride (12 mg, 0.011 mmol, 39.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00-10.91 (m, 2H), 9.66-9.51 (m, 2H), 8.62-8.44 (m, 2H), 8.08 (dd, J= 13.9, 9.0 Hz, 2H), 7.28-7.18 (m, 8H), 5.46 (q, J= 9.3 Hz, 2H), 5.38 (dd. J= 8.6, 5.4 Hz, 2H), 5.17 (t, J= 10.2 Hz, 2H), 4.38-4.26 (m, 10H), 3.23-3.17 (m, 2H), 3.06-2.99 (m, 6H), 2.50 (s, 6H), 2.33-2.17 (m, 4H), 1.95-1.84 (m, 4H), 1.44 (d, J= 6.4 H, 6H), 1.10 (s, 6H), 1.08 (s , 6H). LCMS (2.5 min formic acid): Rt = 1.505 min, m / z: 1055.6 (M+1) + .

[0587] Example 16 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide)

[0588] [ka]

[0589] Step 1: (1S,2R)-1-isocyano-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-indene A suspension of (1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-amine (3.31 g, 17.68 mmol) was heated in ethyl formate (28.8 mL, 354 mmol) at 70°C for 21 hours. After cooling, the solvent was removed under reduced pressure to obtain crude formamide (3.71 g). To the suspension of crude formamide in dichloromethane (DCM) (35 mL) at 0°C, Et3N (12.32 mL, 88 mmol) was added, followed by POCl3 (2.471 mL, 26.5 mmol). After 2 hours, the crude product was poured into a mixture of DCM (150 mL) and saturated NaHCO3 aqueous solution (60 mL). The aqueous phase was separated and extracted with DCM (50 mL). The combined organic layers were washed with brine (40 mL), dried (Na2SO4), filtered, and concentrated. The crude product was absorbed onto Celite® and purified by silica gel chromatography [1-20% ethyl acetate in hexane] to obtain (1S,2R)-1-isocyano-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-indene, 0.15 ethyl acetate (solvate) (1.88 g, 8.93 mmol, 50.5% yield) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.99 (dd, J=16.4, 5.9 Hz, 1 H), 3.11 (dd, J=16.0, 6.2 Hz, 1 H), 3.53 (t, J=2.3 Hz, 1 H), 4.26 - 4.38 (m, 2 H), 4.44 (q, J=5.6 Hz, 1 H), 5.34 - 5.45 (m, 1 H), 7.28 - 7.38 (m, 3 H), 7.44 (d, J=7.0 Hz, 1 H); LCMS(ESI) m / z: 171.0 (M-(NC)) + .

[0590] Step 2: (4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxo-N-((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide and (4S,7R,9aS)-4-amino-8,8-dimethyl-5-oxo-N-((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide A mixture of N-(tert-butoxycarbonyl)-S-trityl-L-homocysteine ​​(2.05 g, 4.29 mmol), (1S,2R)-1-isocyano-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-indene, 0.15-ethyl acetate (solvate) (0.903 g, 4.29 mmol), 4,4-dimethoxy-2,2-dimethylbutanal (1.2 g, 7.49 mmol), and 7M ammonia in MeOH (1.226 mL, 8.58 mmol) in trifluoroethanol (16 mL) was heated at 80°C. After 1 hour, the solvent was removed under reduced pressure. The crude product was diluted with DCM (100 mL) and washed with 1N NaOH (15 mL). The aqueous layer was separated and extracted with ELISA (75 mL). The combined organic layers were washed with brine (30 mL), dried to (MgSO4), filtered, and concentrated to obtain a foamy substance. Dichloromethane (DCM) (20 mL) and TFA (4 mL, 51.9 mmol) were added to this material. The mixture was heated at 35-40°C. After 1 hour, TFA (2 mL) was added to the mixture and heated for 1.5 hours. The mixture was stirred overnight at room temperature. TFA (2 mL) was added and the mixture was heated at 50°C for 1 hour. The crude product was adsorbed onto Celite® and purified by C18 using an ISCO apparatus [20-30% ACN gradient, 0.1% formic acid] to obtain two fractions. The lyophilized fractions were individually diluted with HCl (150 mL), washed with saturated NaHCO3 aqueous solution (25 mL), dried to (Na2SO4), filtered, and concentrated. Two diastereoisomers were obtained. (4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxo-N-((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide (290.1 ​​mg, 15.8% yield) and (4S,7R,9aS)-4-amino-8,8-dimethyl-5-oxo-N-((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide (283.3 mg, 15.4%) were obtained, and both were isolated as foamy substances. Data on 7S diastereoisomers:1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (s, 3 H), 1.09 (s, 3 H), 1.67 - 1.82 (m, 2 H), 1.96 - 2.05 (m, 1 H), 2.23 (dd, J=12.9, 7.4 Hz, 1 H), 2.81 (dt, J=11.5, 2.6 Hz, 1 H), 2.96 - 3.17 (m, 3 H), 3.43 (t, J=2.3 Hz, 1 H), 3.68 (d, J=9.8 Hz, 1 H), 4.13 (t, J=2.5 Hz, 2 H), 4.16 - 4.19 (m, 1 H), 4.28 - 4.35 (m, 1 H), 5.27 - 5.43 (m, 2 H), 7.13 - 7.32 (m, 4 H), 7.81 (d, J=8.6 Hz, 1 H); LCMS(ESI) m / z: 428.3 (M+1) + . Data of the 7R diastereoisomer: 1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3 H), 1.31 (s, 3 H), 1.55 - 1.67 (m, 1 H), 1.69 (d, J=13.3 Hz, 1 H), 1.94 (br. s., 1 H), 2.00 - 2.06 (m, 1 H), 2.77 (dt, J=11.6, 2.8 Hz, 1 H), 2.97 (dd, J=16.4, 3.1 Hz, 1 H), 3.08 (dd, J=16.4, 5.5 Hz, 1 H), 3.14 - 3.24 (m, 1 H), 3.39 (t, J=2.1 Hz, 1 H), 3.69 (d, J=9.8 Hz, 1 H), 4.16 - 4.23 (m, ......​​​

[0591] Step 3: tert-butyl((S)-1-(((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-(((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate To a solution of (4S,7S,9aS)-4-amino-8,8-dimethyl-5-oxo-N-((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)octahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide (287 mg, 0.671 mmol) and Boc-N-Me-Ala-OH (205 mg, 1.007 mmol), Hünig base (0.586 mL, 3.36 mmol) was added, followed by dropwise addition of 50 wt% T3P in ethyl acetate (0.699 mL, 1.175 mmol). After 45 minutes, the mixture was diluted with 100 mL of ethyl alcohol, washed with 25 mL of saturated aqueous NaHCO3 solution, then with 25 mL of brine, dried, filtered, and concentrated. The crude product was adsorbed onto Celite® and purified by silica gel chromatography [20-80% ethyl alcohol in hexane] to obtain tert-butyl((S)-1-(((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-(((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (314.5 mg, 0.513 mmol, 76% yield) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.13 (s, 3 H), 1.20 (s, 3 H), 1.35 (d, J=7.0 Hz, 3 H), 1.48 (s, 9 H), 1.79 - 1.90 (m, 1 H), 1.97 - 2.12 (m, 1 H), 2.29 (dd, J=13.3, 7.0 Hz, 2 H), 2.50 (br. s., 1 H), 2.77 - 2.84 (m, 4 H), 3.04 - 3.16 (m, 2 H), 3.25 - 3.36 (m, 1 H), 4.10 (dd, J=15.6, 2.3 Hz, 1 H), 4.17 (dd, J=15.6, 2.3 Hz, 1 H), 4.32 (s, 1 H), 4.49 (q, J=5.1 Hz, 1 H), 4.55 (dd, J=10.0, 6.1 Hz, 1 H), 5.17 (dd, J=9.2, 7.6 Hz, 1 H), 5.54 (dd, LCMS(ESI) m / z: 613.4 (M+1) + .

[0592] Step 4: tert-butyl((S)-1-(((4S,7S,9aS)-7-(((1S,2R)-2-(allyloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate A suspension of tert-butyl((S)-1-(((4S,7S,9aS)-8,8-dimethyl-5-oxo-7-(((1S,2R)-2-(propa-2-in-1-yloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)octahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (51.5 mg, 0.084 mmol) and Lindler catalyst (12.8 mg, 6.01 μmol) was stirred in MeOH (10 mL) under hydrogen (1 atm) for 2.5 hours. The suspension was filtered through a 0.45 μm disk, and the filtrate was evaporated under reduced pressure to obtain tert-butyl((S)-1-(((4S,7S,9aS)-7-(((1S,2R)-2-(allyloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (51.4 mg, 0.071 mmol, 85% yield, 85% purity) as a membrane. LCMS (ESI) m / z: 615.4, 617.6 (M+1) A mixture of olefin and O-propyl (ratio 85:15 by proton NMR).

[0593] Step 5: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(((E / Z)-buta-2-ene-1,4-diyl)bis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) A mixture of tert-butyl((S)-1-(((4S,7S,9aS)-7-(((1S,2R)-2-(allyloxy)-2,3-dihydro-1H-inden-1-yl)carbamoyl)-8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-4-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (51.4 mg, 0.084 mmol) and Grubbs catalyst (trademark) second generation (6.39 mg, 7.52 μmol) was stirred in dichloromethane (DCM) (350 μl) under nitrogen at room temperature. After 1 day, the second batch of Grubbs catalyst (trademark) second generation (6.39 mg, 7.52 μmol) was added to the mixture. After 4 days, the crude mixture was purified by silica gel chromatography [20-100% phenylethylamine in hexane] to obtain a mixture of cis and trans isomers (10.9 mg, 21.8%) of the adduct. LC-MS (ESI) m / z: 1199.7 (M-1).

[0594] Step 6: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(((E / Z)-buta-2-ene-1,4-diyl)bis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropy A suspension of lolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (13 mg, 10.82 μmol) and palladium, 10 wt%, Degussa type E101 (1.151 mg, 1.082 μmol) on activated carbon was stirred in methanol (4 mL) under hydrogen (1 atm). After 1 day, the mixture was filtered through a 0.45 μm disk and subjected to hydrogenation conditions at 30 psi in MeOH. A fresh batch of Pd / C was added and the mixture was stirred under hydrogen at 50 psi. After 4 days, the suspension was filtered through a 0.45 μm disk and the solvent was evaporated under reduced pressure. The crude product was purified by C18 using ISCO equipment [50-90% ACN gradient, 0.1% formic acid] to di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-di Bis(azandiyl)bis(carbonyl)bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl)bis(azandiyl)bis(1-oxopropane-1,2-diyl)bis(methylcarbamate) (4.5 mg, 3.74 μmol, 34.6% yield) was obtained as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 1.08 (s, 3 H), 1.17 (s, 3 H), 1.35 (d, J=7.0 Hz, 3 H), 1.41 - 1.51 (m, 12 H), 1.75 - 1.86 (m, 1 H), 1.91 (dd, J=13.3, 9.4 Hz, 1 H), 2.13 - 2.29 (m, 2 H), 2.56 - 2.68 (m, 1 H), 2.80 (s, 3 H), 2.90 - 3.03 (m, 2 H), 3.14 (t, J=12.7 Hz, 1 H), 3.31 - 3.51 (m, 2 H), 4.14 (q, J=4.3 Hz, 1 H), 4.28 (s, 1 H), 4.51 (dd, J=10.2, 5.9 Hz, 1 H), 5.12 (t, J=8.4 Hz, 1 H), 5.46 (dd, J=8.2, 5.9 Hz, 1 H), 7.14 - 7.25 (m, 4 H), 7.29 (d, J=7.0 Hz, 1 H), 7.35 (d, J=4.3 Hz, 1 H); LCMS(ESI) m / z: 502.4 {[(M - 2Boc)+2] / 2} + .

[0595] Step 7: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(azandiyl))bis(carbonyl)) in dichloromethane (DCM) (1 mL) at room temperature. To a solution of s(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (4.5 mg, 3.74 μmol), hydrogen chloride (4 M in 1,4-dioxane) (0.2 mL, 0.800 mmol) was added. After 5 hours, the solvent was removed under reduced pressure. The crude product was purified by C18 using ISCO equipment [10-100% ACN gradient, 0.1% formic acid] to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) (2.8 mg, 2.73 μmol, 73.1% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 1.11 (s, 3 H), 1.17 (s, 3 H), 1.29 (d, J=7.0 Hz, 3 H), 1.53 (br. s., 2 H), 1.79 - 1.98 (m, 2 H), 2.16 - 2.32 (m, 2 H), 2.43 (s, 3 H), 2.72 (dd, J=14.8, 2.3 Hz, 1 H), 2.99 (d, J=4.7 Hz, 2 H), 3.14 (q, J=7.0 Hz, 1 H), 3.24 (t, J=12.9 Hz, 1 H), 3.33 - 3.43 (m, 1 H), 3.50 (d, J=9.0 Hz, 1 H), 4.18 (q, J=4.7 Hz, 1 H), 4.30 (s, 1 H), 4.59 (dd, J=10.1, 7.0 Hz, 1 H), 5.17 (t, J=8.4 Hz, 1 H), 5.45 (dd, J=8.4, 5.7 Hz, 1 H), 7.15 - 7.25 (m, 3 H), 7.29 - 7.39 (m, 2 H), 8.34 (d, J=6.6 Hz, 1 H); LCMS(ESI) m / z: 1003.5 (M+1) + .

[0596] Example 17 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0597] [ka]

[0598] Step 1: Butane-1,4-diirbis(4-methylbenzenesulfonate) To a solution of butane-1,4-diol (2 g, 22.19 mmol) and triethylamine (8.98 g, 48.82 mmol) in dichloromethane (100 mL), 4-dimethylaminopyridine (0.54 g, 4.44 mmol), followed by p-tosylloride (9.31 g, 48.82 mmol), was added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated. The crude product was purified by silica gel chromatography [petroleum ether / ethyl acetate (3:1 v / v)] to obtain butane-1,4-diirbis(4-methylbenzenesulfonate) (4 g, 10.04 mmol, 45.2% yield) as a white solid. LCMS (2.5 min formic acid): Rt = 1.731 min, m / z: 420.8 (M+Na) + .

[0599] Step 2: (1S,1'S,2R,2'R)-2,2'-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-inden-1-amine) To a solution of (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (749 mg, 5.02 mmol) in tetrahydrofuran (80 mL) at 0°C, sodium hydride (60%, dispersed in liquid paraffin) (221 mg, 5.52 mmol) was added in small increments. The mixture was warmed to room temperature. Then, butane-1,4-diirbis(4-methylbenzenesulfonate) (1 g, 2.51 mmol) was added. The resulting mixture was stirred overnight at 70°C. The reaction product was quenched with ice water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography [dichloromethane / methanol (10:1 v / v)] to obtain (1S,1'S,2R,2'R)-2,2'-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-inden-1-amine) (220 mg, 0.62 mmol, 24.7% yield) as a brown solid. LCMS (2.5 min formic acid): Rt = 1.206 min, m / z: (M+1) + .

[0600] Step 3: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (1S,1'S,2R,2'R)-2,2'-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-inden-1-amine) (130 mg, 0.369 mmol) and (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanethioamide)-8, To a mixture of 8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (intermediate II) (373 mg, 0.812 mmol), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (274 mg, 1.107 mmol) and N,N-diisopropylethylamine (190 mg, 1.476 mmol) were added. The resulting mixture was stirred overnight at 50°C. The reaction product was quenched with water (50 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine, dried, filtered, and concentrated. The residue was purified by thin-layer chromatography [ethyl acetate / petroleum ether (1 / 1 v / v)] followed by preparative HPLC to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (60 mg, 0.049 mmol, 13.3% yield) as a white solid. LC-MS (2.5 min formic acid): Rt = 2.154 min, m / z: 517.9 {[(M-2Boc)+2] / 2} + .

[0601] Step 4: (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride To a solution of di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-thioxopropane-1,2-diyl))bis(methylcarbamate) (60 mg, 0.049 mmol) in dichloromethane (5 mL), 4N hydrogen chloride (3 mL) in 1,4-dioxane was added. The mixture was stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure, and the solid was dried under high vacuum to obtain (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-(butane-1,4-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanethioamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride (30 mg, 0.027 mmol, 57.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.01 (s, 1H), 10.93 (s, 1H), 9.63 (s, 1H), 9.48 (s, 1H), 8.64 (s, 2H), 8.47 (s, 2H), 7.98-7.93 (m, 2H),7.24-7.20 (m, 8H), 5.46 (q, J= 8.8 Hz, 2H), 5.35-5.32 (m, 2H), 5.19-5.14 (m, 2H), 4.28-4.26 (m, 4H), 4.10-4.09 (m, 2H), 3.73-3.65 (m, 2H), 3.51-3.47 (m, 2H), 3.39-3.38 (m, 2H), 3.20-3.14 (m, 2H), 2.96-2.95 (m, 4H), 2.50 (s, 6H), 2.27-2.13 (m, 4H), 1.94-1.82 (m, 4H), 1.45 (s, 10H), 1.07 (m, 12H). LCMS (2.5 min formic acid): Rt = 1.408 min, m / z: 518.0 [(M+2) / 2] + .

[0602] Example 18 (4S,4'S,7S,7'S,9aS,9a'S)-N,N'-((1S,1'S,2R,2'R)-((oxybis(ethane-2,1-diyl))bis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(8,8-dimethyl-4-((S)-2-(methylamino)propanamide)-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxamide) dihydrochloride

[0603] [ka]

[0604] Step 1: (1S,1'S,2R,2'R)-2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(2,3-dihydro-1H-inden-1-amine) To a solution of (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (800 mg, 5.36 mmol) in dry tetrahydrofuran (20 mL), sodium hydride (60%, dispersed in liquid paraffin) (241 mg, 10.04 mmol) was slowly added in small amounts under nitrogen at 0°C. The mixture was stirred at room temperature for 30 minutes, and then oxybis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (1.0 g, 2.44 mmol) was added. The mixture was heated under reflux and stirred for 5 hours. The mixture was carefully quenched with water (150 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by thin-layer chromatography (dichloromethane / methanol (8:1 v / v)) to obtain (1S,1'S,2R,2'R)-2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(2,3-dihydro-1H-inden-1-amine) (410 mg, 1.11 mmol, 53% yield) as a yellow oil. LCMS (2.5 min formic acid): Rt = 1.107 min, m / z: 368.9 (M+1) + .

[0605] Step 2: Di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-((oxybis(ethane-2,1-diyl))bis(oxy))bis(2,3-dihydro-1H-inden-2,1-diyl))bis(azandiyl))bis(carbonyl))bis(8,8-dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7,4-diyl))bis(azandiyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (1S,1'S,2R,2'R)-2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(2,3-dihydro-1H-inden-1-amine) (100 mg, 0.27 mmol), (4S,7S,9aS)-4-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamide)-8,8- A solution of dimethyl-5-oxooctahydropyrrolo[2,1-b][1,3]thiazepine-7-carboxylic acid (intermediate 1) (252.8 mg, 0.57 mmol), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (201.3 mg, 0.81 mmol), and N,N-diisopropyl-ethylamine (140.3 mg, 1.09 mmol) was stirred overnight at 50°C. The solvent was removed under reduced pressure, and the residue was purified by thin-layer chromatography [ethyl acetate / petroleum ether (1 / 1 v / v)] to obtain the product (260 mg) as a yellow oil. This material was further purified by preparative HPLC to obtain di-tert-butyl((2S,2'S)-(((4S,4'S,7S,7'S,9aS,9a'S)-((((1S,1'S,2R,2'R)-((oxybis(ethane-2,1-diy...

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, R, R', R'', and R''' are independent of H and CH. 3 Selected from; X 1 and X 2 These are independently selected from the group consisting of O and S; L is given by the following formula: 【Chemistry 2】 or 【Transformation 3】 (In the formula, Ar 12 、 Ar 13 、 Ar 14 、 and Ar 15 are each independently selected from (C 6 -C 14 ) aryl; Alk 3 The following: 【Chemistry 4】 Selected from; R 3 is, -(CH 2 ) h -; -(CH 2 ) i -O--(CH 2 ) j -Selected from the group consisting of; (h, i, j, t, and u are each independently selected from 1 to 12.) This is a linker represented by [this symbol]. Compounds represented by, or their pharmaceutically acceptable salts or stereoisomers, However, the following 【Transformation 5】 Excluding compounds thereof, or their pharmaceutically acceptable salts.

2. L is as follows: 【Transformation 6】 The compound according to claim 1.

3. The compound according to claim 2, wherein t and u are independently selected from 1 to 6.

4. The compound according to claim 3, wherein t and u are independently selected from 1 to 4.

5. Alk 3 However, the following: 【Transformation 7】 The compound according to claim 2.

6. Alk 3 However, the following: 【Transformation 8】 The compound according to claim 2.

7. Ar 12 and Ar 13 However, each is independent of C 6-9 The compound according to claim 1, wherein it is an aryl compound.

8. Ar 12 and Ar 13 However, each is C 9 The compound according to claim 1, wherein it is an aryl compound.

9. Ar 12 and Ar 13 However, each is independent of (C 6 -C 9 ) Selected from the arrow, Alk 3 However, the following: 【Chemistry 9】 The compound according to claim 2, wherein t and u are each independently selected from 1 to 6.

10. Alk 3 However, the following: 【Chemistry 10】 The compound according to claim 9.

11. Ar 12 and Ar 13 However, each is C 9 The compound according to claim 9, wherein it is an aryl compound.

12. L is as follows: 【Chemistry 11】 The compound according to claim 1.

13. Ar 14 and Ar 15 However, each is independent of C 6-9 The compound according to claim 12, wherein it is an aryl compound.

14. Ar 14 and Ar 15 However, each is C 9 The compound according to claim 12, wherein it is an aryl compound.

15. R 3 However, -(CH 2 ) h - The compound according to claim 12.

16. The compound according to claim 12, wherein h is 4 to 6.

17. Linker (L) is as follows: 【Chemistry 12】 and 【Chemistry 13】 A compound according to claim 1, selected from the group consisting of the following.

18. Compounds selected from the following group, and pharmaceutically acceptable salts thereof. Table 1

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

20. The pharmaceutical composition according to claim 19, which is suitable for parenteral administration.

21. The pharmaceutical composition according to claim 19, in the form of a tablet.

22. The pharmaceutical composition according to claim 19, wherein the compound exists as a spray-dried dispersion.

23. The pharmaceutical composition according to claim 19 for use in the treatment of HIV infection.

24. Use of a compound according to any one of claims 1 to 18 in the manufacture of a pharmaceutical product for the treatment of HIV infection.

25. i) The compound according to any one of claims 1 to 18; and ii) One or more additional drugs that are active against HIV A combination that includes [something].

26. The combination according to claim 25, wherein one or more additional agents are selected from the group consisting of nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, adhesion and fusion inhibitors, integrase inhibitors, maturation inhibitors, CXCR4 and / or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyltransferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and antibodies for clearance therapy.

27. One or more additional drugs active against HIV include zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, and adefovir dipivoxil.dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine Ravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir Navir, tipranavir, palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS-626529, 5-Helix, raltegravir, elvitegravir, dolutegravir, cabotegravir (cab otegravir, bictegravir, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, darunavir, vorinostat, panobinostat, romidepsin, valpronic acidThe combination according to claim 25, selected from the group consisting of (acid), mocetinostat, sodium corotonate, bryostatin, ingenol B, disulfiram, GS-9620, JQ1, iBET151, bortezomib, epigallocatechin gallate, salinosporamide A, carfilzomib, and a neutralizing antibody.

28. A pharmaceutical composition for depleting latent HIV-infected cells, comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

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