Piperazine derivatives for HIV therapy

Abstract

The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, compositions thereof, and methods of using them for therapeutic treatments. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 USC §119(e) to U.S. Provisional Application No. 63 / 346,362, filed on May 27, 2022, the contents of which (including the drawings) are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to compounds, pharmaceutical compositions and methods of use thereof in connection with individuals infected with HIV, HBV or cancer.

[0004] Sequence Listing

[0005] This application contains a sequence listing that has been submitted in XML format and is hereby incorporated by reference in its entirety. The XML copy is named PU66990.xml, is approximately 6.04KB (6,187 bytes) in size, and was created on May 18, 2023. Background Art

[0006] Human immunodeficiency virus type 1 (HIV-1) infection leads to acquired immunodeficiency disease (AIDS). Currently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. In fact, the U.S. Food and Drug Administration has approved 25 drugs within 6 different inhibitor classes, which have been shown to significantly improve patient survival and quality of life. However, due to many problems, it is still believed that additional therapies are needed, including but not limited to adverse drug-drug interactions, drug-food interactions, non-compliance with therapy, drug resistance due to enzyme target mutations, and inflammation associated with immune damage caused by HIV infection.

[0007] Currently, almost all HIV-positive patients are treated with a regimen of a combination of antiretroviral drugs, known as highly active antiretroviral therapy ("HAART"). However, HAART therapy is often complicated because a combination of different drugs must be administered to the patient daily to avoid the rapid emergence of drug-resistant HIV-1 variants. Although HAART has a positive impact on patient survival, drug resistance can still occur, and patient survival and quality of life are not normalized compared to uninfected people [LohseAnn Intern Med 2007 146; 87-95]. In fact, the incidence of some non-AIDS morbidity and mortality (e.g., cardiovascular disease, frailty, and neurocognitive impairment) has increased in HAART-suppressed HIV-infected subjects [DeeksAnnu Rev Med 2011; 62: 141-155]. This increase in non-AIDS morbidity / mortality occurs in the context of, and may be caused by, elevated systemic inflammation associated with immune damage caused by HIV infection and residual HIV infection[Hunt J Infect Dis 2014][Byakagwa J Infect Dis 2014][Tenorio J Infect Dis 2014].

[0008] Modern antiretroviral therapy (ART) is effective in suppressing HIV replication and improving health outcomes for HIV-infected individuals, but it is not believed to completely eliminate the HIV reservoir within an individual. HIV genomes can remain latent in most immune cells of infected individuals and are susceptible to reactivation, such that viral replication typically resumes within weeks after ART is discontinued. In a few individuals, the size of this reservoir has been significantly reduced, and rebound of viral replication has been delayed after cessation of ART [Henrich TJ J Infect Dis 2013][Henrich TJ Ann Intern Med 2014]. In one case, the reservoir was eliminated during treatment of leukemia, and no viral rebound was observed during years of follow-up [Hutter GN Engl J Med 2009]. These examples suggest that the concept of reducing or eliminating the reservoir is possible and could lead to viral remission or cure. Therefore, methods of eliminating the reservoir by direct molecular means have been sought, including excision of the viral genome with the CRISPR / Cas9 system, or inducing reactivation of the latent reservoir during ART to eliminate latent cells. Reversal of latency is thought to be necessary to render latently infected cells susceptible to clearance.

[0009] SMACm (second mitochondrial derived caspase activator mimetic) is a class of compounds that have recently entered clinical trials as potential cancer treatments. The drug consumes and / or inhibits inhibitors of apoptosis proteins (cIAPs) that act as anti-apoptotic proteins, thereby promoting cell death of cancer cells. Antagonism and / or consumption of cIAPs also lead to activation of non-classical NF-kB signaling pathways, which may induce HIV expression and may enable HIV-infected cells to be eliminated. In addition, SMAC mimetics can selectively promote cell death infected by HIV by antagonizing anti-apoptotic proteins [Campbell CellHost Microbe 2018] or HBV [Ebert Proc Nat Acad Sci 2013].

[0010] Recently, targeting the non-canonical NF-κB (ncNF-κB) pathway has been reported to reverse latency in cell line models. The ncNF-κB pathway is typically activated by ligation of a subset of TNF receptor family members. In the steady state, a multimolecular complex with ubiquitin ligase activity consisting of TNF receptor-associated factor 2 (TRAF2), TRAF3, and cellular inhibitor of apoptosis protein 1 (cIAP1) binds to the cytoplasmic fraction of unligated receptors and constitutively ubiquitinates and degrades NF-κB-inducing kinase (NIK). Upon receptor ligation, cIAP1 ubiquitinates TRAF3 and autoubiquitinates, leading to proteasomal degradation of TRAF3 and cIAP1, which uninhibits NIK accumulation. NIK is constitutively active and, once accumulated, phosphorylates inhibitor of κB kinase-α (IKKα) homodimers. The activated IKKα / IKKα homodimer subsequently phosphorylates the inactive p100 form of NFκB2, leading to ubiquitination by the Skp1-Cul1-F-box ubiquitin ligase (SCFβTrCP) and proteasomal cleavage of p100, thereby releasing the active p52 subunit. p52 binds to RelB, and the heterodimer translocates into the nucleus to drive transcription of the κB promoter element. In addition to receptor ligation, ncNF-κB can be activated by signaling intermediates of the apoptotic cascade. Cleavage of the second mitochondrial activator of caspases (SMAC) from the mitochondrial membrane exposes the N-terminal motif Ala-Val-Pro-Ile, which specifically binds to the baculoviral intermediate repeat (BIR) domain of IAP proteins. This BIR binding in cIAP1 / 2 activates the ubiquitin ligase activity of the TRAF2:TRAF3:cIAP complex, thereby inducing autoubiquitination and degradation of cIAP1 / 2, NIK accumulation, and activation of the ncNF-κB pathway [Sampey bioRxiv2018][Nixon Nature 2020 ]Binding of 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.

[0011] Therefore, the discovery and development of new SMACm molecules represents a currently unmet medical need. Summary of the invention

[0012] The present invention relates to compounds according to formula (I):

[0013]

[0014] or a pharmaceutically acceptable salt thereof, wherein:

[0015] Each R 1 and R 2 -H or -CH 3 ;

[0016] Each R 3 -H or -CH 3 ;

[0017] Each R 4 -H, -F, -Cl, -CH 3 , -CF 3 、-CN、-OH、-OCH 3 、-C(O)N(CH 3 ) 2 、-CH(CH 3 ) 2 or -C(O)OCH 3 ;

[0018] Each R 5 -H, -F, -Cl, -Br, -CH 3 , -CHF 2 or -CF 3 ;

[0019] Each R 6 is -H, -F or -Cl;

[0020] Each R 7 is -H or -F;

[0021] Each W is -CH-, -CH 2 -, -O-, or -N-;

[0022] Each X is -CH 2 -, -O-, -NH-, or -NCH 3 -;

[0023] Each Y1 is -CH- or -C(O)-;

[0024] Each Y 2 -N-, -NH- or -NCH 3 -;

[0025] Each represents a single bond or a double bond, where Y 1 When it is -CH-, Y 2 is -N-, and represents a double bond and when Y 1 When it is -C(O)-, Y 2 -NH- or -NCH 3 -,and Represents a single bond;

[0026] each Z is -CH- or -N-; and

[0027] L is a linker selected from the following:

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034] in represents a connection point; and wherein n is an integer from 2 to 15, m is an integer from 1 to 5, p is an integer from 1 to 20, q is an integer from 2 to 15, s is an integer from 1 to 8, t is an integer from 2 to 15, w is an integer from 1 to 10, x is an integer from 2 to 15, y is an integer from 2 to 15, and z is an integer from 2 to 15.

[0035] Another aspect of the present invention provides a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0036] In another aspect, the present invention provides a method for treating HIV infection in a human, comprising administering to the human a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0037] In yet another aspect, the present invention provides use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in the preparation of a medicament for treating HIV infection.

[0038] In yet another aspect, the present invention provides a method for treating cancer and precancerous syndromes in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0039] In another aspect, the present invention provides a method for eliminating HIV-infected cells, comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0040] In yet another aspect, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more agents having anti-HIV activity. In certain aspects, these agents having anti-HIV activity are selected from antiretroviral agents, latency reversal agents, and agents used for elimination therapy.

[0041] In yet another aspect, the present invention provides a method for eliminating HIV infected cells, comprising administering to a subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and one or more other agents having anti-HIV activity. In certain aspects, these agents having anti-HIV activity are selected from antiretroviral agents, latency reversal agents, and agents for elimination therapy.

[0042] These and other aspects are encompassed by the invention described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 is a graph comparing rodent pharmacokinetic (PK) data for several compounds of Formula I with SMACm AZD5582 PK data; and

[0044] Figure 2 is a table summarizing the activity and selectivity of certain SMAC mimetics and other mimetics disclosed herein.

[0045] Detailed Description

[0046] definition

[0047] It should be understood that the terminology used herein is used to describe particular embodiments only and is not intended to limit the scope of the present disclosure.In this specification and the claims that follow, reference will be made to a number of terms which shall be defined to have the following meanings.

[0048] Unless otherwise indicated, "alkyl" refers to a saturated, straight-chain or branched hydrocarbon moiety having 1 to 6 carbon atoms. 1 -C 6 )alkyl" refers to an alkyl moiety containing 1 to 6 carbon atoms. As used herein, examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0049] Unless otherwise indicated, "alkylene" refers to a straight or branched chain divalent alkyl group having 1 to 6 carbon atoms. 1 -C 6 )" alkylene" refers to an alkylene group containing 1 to 6 carbon atoms. As used herein, examples of "alkylene" include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.

[0050] “Substituted alkylene” refers to an alkylene group having from 1 to 5 (in some embodiments, from 1 to 3 or from 1 to 2) substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkoxy, amino, substituted amino, quaternary amino, aminocarbonyl, imino, amidino, aminocarbonylamino, amidinocarbonylamino, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkyl Alkylthio, guanidino, substituted guanidino, halogen, hydroxyl, hydroxyamino, alkoxyamino, hydrazine, substituted hydrazine, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, oxo, thioketone, spirocycloalkyl, phosphate, phosphonate, phosphinate, phosphonamidite), phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, sulfate, sulfonate, sulfonyl, substituted sulfonyl, sulfonyloxy, sulfyl, thiocyanate, thiol, alkylthio and substituted alkylthio. It should be understood that the above definition is not intended to include unpermitted substitution patterns.

[0051] Unless otherwise specified, "alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms. For example, "C 1 -C 6 "Alkoxy" refers to a straight or branched alkoxy group containing 1 to 6 carbon atoms. As used herein, examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, prop-1-oxy, prop-2-oxy, but-1-oxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentyloxy and hexyloxy.

[0052] "Aryl" or "Ar" refers to an aromatic hydrocarbon ring. Unless otherwise indicated, "aryl" includes monocyclic, bicyclic and tricyclic ring systems having a total of 5 to 15 ring member atoms, wherein at least one ring system is aromatic, and wherein each ring in the system contains 3 to 7 member atoms. "Aryl" also includes ring systems in which an aryl ring (as defined above) is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is located on the aryl ring, and in this case, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. As used herein, examples of "alkoxy" include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl, and the like.

[0053] "Arylene" refers to a divalent aromatic hydrocarbon ring. Unless otherwise indicated, "arylene" includes monocyclic, bicyclic and tricyclic ring systems having a total of 5 to 15 ring member atoms, wherein at least one ring system is aromatic, and wherein each ring in the system contains 3 to 7 member atoms. "Arylene" also includes ring systems in which an aromatic ring (as defined above) is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment is located on the aryl ring, and in this case, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. As used herein, examples of "arylene" include, but are not limited to, or are derived from phenylene (para, meta, ortho), naphthalene, biphenyl, indole, triazole, and the like.

[0054] “Substituted arylene” refers to an arylene group substituted with 1 to 8 (in some embodiments, 1 to 5, 1 to 4, 1 to 3, or 1 to 2) substituents selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, quaternary amino, aminocarbonyl, imino, amidino, aminocarbonylamino, amidinocarbonylamino, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy substituted cycloalkylthio, guanidino, substituted guanidino, halogen, hydroxyl, hydroxyamino, alkoxyamino, hydrazine, substituted hydrazine, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, oxo, thioketone, spirocycloalkyl, phosphate, phosphonate, phosphinate, phosphonamidite), phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, sulfate, sulfonate, sulfonyl, substituted sulfonyl, sulfonyloxy, sulfyl, thiocyanate, thiol, alkylthio and substituted alkylthio. It should be understood that the above definition is not intended to include unallowed substitution patterns.

[0055] As used herein, "compound" refers to compounds encompassed by the general formulae disclosed herein, any subgenus of those general formulae, and any form of the compounds within the general formulae and subgenus, including racemates, stereoisomers, and tautomers of the compounds.

[0056] "Cyano" refers to a -C≡N functional group.

[0057] Unless otherwise indicated, "cycloalkylene" refers to a non-aromatic, saturated, cyclic, divalent hydrocarbon ring containing 3 to 7 member ring atoms. "Heterocycloalkylene" refers to a "cycloalkylene" in which at least one ring atom is a heteroatom. Examples of "cycloalkylene" used include or are derived from, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and piperidine.

[0058] “Substituted cycloalkylene” refers to a cycloalkylene group, as defined herein, having from 1 to 8, or from 1 to 5, or in some embodiments, from 1 to 3 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, quaternary amino, aminocarbonyl, imino, amidino, aminocarbonylamino, amidinocarbonylamino, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, The term "substituted cycloalkyl" refers to alkyl, cycloalkylthio, substituted cycloalkylthio, guanidine, substituted guanidine, halogen, hydroxyl, hydroxylamino, alkoxyamino, hydrazino, substituted hydrazino, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, oxo, thioketone, spirocycloalkyl, phosphate, phosphonate, phosphinate, phosphonamidite), phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, sulfate, sulfonate, sulfonyl, substituted sulfonyl, sulfonyloxy, sulfyl, thiocyanate, mercaptan, alkylthio and substituted alkylthio.Term "substituted cycloalkyl" includes substituted cycloalkenyl groups.It should be understood that the above definition is not intended to include substitution patterns that are not allowed.

[0059] "Halo" or "halogen" refers to fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br) or iodine (iodo, I).

[0060] "Heteroatom" refers to nitrogen, oxygen or sulfur.

[0061] "Latency" refers to a concept that describes: 1) a dormant state of viral activity within a cell population 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 in infected cells.

[0062] "Optionally" means that the subsequently described event may or may not occur, and includes events that occur and events that do not occur.

[0063] "Solvates" of a compound refer to those compounds wherein the compound is as defined above, combined with a stoichiometric or non-stoichiometric amount of a solvent. Solvates of a compound include all forms of solvates of the compound. In some embodiments, the solvent is volatile, non-toxic and / or acceptable for administration to humans in trace amounts. Suitable solvents include water.

[0064] "Stereoisomer" refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds of formula (I) contain at least one asymmetric center (also referred to as a chiral center or stereocenter), and therefore can exist as single enantiomers (also referred to as optical isomers), diastereomers or other stereoisomeric forms (e.g., epimers), or as mixtures thereof. Chiral centers (e.g., chiral carbon atoms) can also exist in substituents (e.g., alkyl groups), wherein the carbon atom is connected to four different groups. When the stereochemistry of the chiral center present in the compounds of the present invention or any other chemical structure shown herein is not specified, the structure is intended to cover any individual stereoisomers and all mixtures thereof.

[0065] "Tautomers" refer to alternative forms of compounds with different proton positions, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms connected to the ring-NH-part and the ring=N-part, such as pyrazole, imidazole, benzimidazole, triazole and tetrazole. The compounds of the present invention can exist in tautomeric forms. It should be understood that any reference to a named compound or a compound described by a structure is intended to cover all tautomers of such compounds. For example, in the embodiments disclosed herein, the compound can exist in a pyrrolopyridone or pyrrolohydroxypyridine tautomeric form, or in any stoichiometric combination of the respective tautomers:

[0066]

[0067] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt derived from a pharmaceutically acceptable counterion. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002. It should be understood that if the compound of formula (I) contains two or more basic moieties, the stoichiometry of the salt formation may include 1, 2 or more equivalents of acid (i.e., acid addition salts). Such salts will contain 1, 2 or more acid counterions, such as dihydrochlorides. Both stoichiometric and non-stoichiometric forms of pharmaceutically acceptable salts of compounds of formula (I) are included within the scope of the present invention, including substoichiometric salts, for example, where the counterion contains more than one acidic proton.Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), anoate), caprylate (octanoate), cinnamate, citrate, cyclaminate, digluconate, 2,5-dihydroxybenzoate, succinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), sodium ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,5-disulfonate (naphthalene disulfonate), naphthalene-2-sulfonate (naphthalene sulfonate), nicotinate, nitrate, oil

[0013] The invention also includes but is not limited to bisphenol A, bisphenol A, bisphenol B, bisphenol C, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A, bisphenol A

[0068] "Pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions and dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0069] "Reversal of HIV latency" refers to a treatment that upregulates expression of the integrated HIV genome in latently infected cells, such as an agent that activates the non-canonical NF-kB pathway, resulting in susceptibility of infected cells to virus-induced cell death or immune clearance. In certain embodiments, latently HIV-infected cells are resting CD4 + T cells. As used herein, "eliminating latent HIV infection" refers to the elimination of latent HIV infected cells, which may be after reversing HIV latency by an agent (e.g., an agent that activates a non-classical NF-kB pathway). In some embodiments, each of Compounds 1-112 is used to reverse HIV latency and / or eliminate latent HIV infection.

[0070] "Therapeutically effective amount" refers to any amount that results in treatment, cure or improvement of a disease, disorder or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject not receiving that amount. The term also includes within its scope an amount that effectively enhances normal physiological function. For therapeutic purposes, a therapeutically effective amount of a compound of formula (I) and a salt thereof may be administered as a raw chemical. In addition, the active ingredient may be present as a pharmaceutical composition.

[0071] "Treating a viral infection" means inhibiting the replication of a specific virus, inhibiting viral transmission, and ameliorating or alleviating the symptoms of a disease caused by a viral infection. If viral load is reduced, mortality and / or morbidity is reduced, then the treatment is considered "therapeutic." "Preventing a viral infection" means preventing a virus from taking root in the host. If a subject is exposed to a virus but does not become infected with the virus because of the treatment, then the treatment is considered "prophylactic."

[0072] If a dashed line appears next to a single bond represented by a solid line, the dashed line indicates the presence of an optional double bond at that position. appears on the key, then Indicates a point of attachment. For example, the two wavy lines in the structure below represent two different points of attachment to another chemical moiety, and the dashed line in the structure below can represent a double bond at that position or a single bond at that position:

[0073]

[0074] The subject matter of the present disclosure will now be described more fully below. However, benefiting from the teachings presented in the foregoing description, the technical personnel in the field of the subject matter of the present disclosure will think of many modifications and other embodiments of the subject matter of the present disclosure described herein. Therefore, it should be understood that the subject matter of the present disclosure is not limited to the specific embodiments disclosed, and the modifications and other embodiments are intended to be included in the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications and equivalents. If one or more of the incorporated documents, patents and similar materials are different from or contradictory to the present application, including but not limited to defined terms, term usage, described technology, etc., the present application shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those skilled in the art are generally understood. All publications, patent applications, patents and other references mentioned herein are incorporated by reference as a whole.

[0075] Apoptosis, a type of programmed cell death, plays an important role in maintaining homeostasis and regulating the number of cells in higher organisms. Abnormal apoptosis has been associated with a variety of diseases, including autoimmune disorders, degenerative diseases of the central nervous system, cancer, and viral infections such as HIV. The inhibitor of apoptosis protein (IAP) family plays a key role in inhibiting pro-apoptotic signaling in mammalian cells. SMACm, which mimics a key tetrapeptide sequence from the second mitochondrial-derived activator of caspases, has been shown to disrupt the binding of IAPs to their functional partners and restore the apoptotic response of cells to pro-apoptotic stimuli. Since the beginning of the 21st century, a large amount of work has focused on the design and preparation of SMAC mimetics as IAP antagonists, especially in promoting cell death in tumor cells and, more recently, in reversing HIV latency. SMAC mimetics bind to the BIR2 and BIR3 domains of IAP proteins, resulting in inhibition (in the case of XIAP) and enhancement of apoptosis, or activation of ubiquitin ligase activity (in the case of cIAP1 and cIAP2), leading to autoubiquitination and depletion of activated proteins. Since cIAP1 and 2 inhibit the ncNF-kB pathway, it was observed that activation of these proteins by SMACm would lead to activation of the ncNFkB transcription factor and result in kB-dependent gene expression. Such studies have explored activation of the non-canonical NF-kB pathway (ncNF-kB) as a potential approach for SMAC mimetics to selectively deplete latent HIV cells. An example of an early SMAC mimetic studied in the context of HIV is the monomeric SBI-0637142, prepared by researchers at Sanford–Burnham Medical Research Institute. In HIV depletion assays, SBI-0637142 was found to be effective in cell line assays but did not exhibit p100-p52 switching or HIV caRNA-induced activity in primary cells. Much work has also been devoted to the development of bivalent mimetics in the field of oncology, which are covalently linked monomeric SMAC mimetics. AstraZeneca's AZD5582 and Medivir's BirinapantTL32711 are examples of dimeric SMAC mimetics. In HIV latency reversal studies, Birinapant TL32711 was ineffective in Jurkat, p100-p52 switch, or HIV caRNA induction. In contrast, AZD5582 demonstrated increased cell-associated HIV RNA expression in resting CD4+ T cells by Jurkat assays, p100-p52 switch studies, and HIV cell-associated RNA induction (Sampey et al. bioRxiv 312447). However, AZD5582 also exhibited tolerability issues.

[0076] The IAP proteins targeted by SMAC mimetics for ncNF-kB activation are cIAP1 and cIAP2, and the bivalent molecules with the best linker have the most potent activity in depleting both molecules and activating ncNF-kB. This ncNF-kB activation activity likely occurs through the formation of an intermolecular ternary complex, where one bivalent SMAC mimetic interacts with one BIR domain in each of two different molecules of cIAP1 or cIAP2. XIAP is also bound and inhibited by SMAC mimetics, described in the literature as an intramolecular bond, where one bivalent SMAC mimetic interacts with the BIR2 and BIR3 domains of a single XIAP molecule. XIAP is thought to play no role in ncNF-kB activation by SMAC mimetics, and is therefore likely an off-target in the context of HIV latency reversal.

[0077]

[0078] The dimeric SMACm disclosed herein have sufficient potency and efficacy to activate ncNF-kB as a single agent and reverse HIV latency in primary, unmodified primary human cells, making them suitable for consideration for further development. Specifically, the dimeric SMACm of the disclosed compounds are optimized to favor BIR3 binding rather than BIR2, especially those domains within XIAP, which should favor intermolecular ternary complex formation between the two IAP proteins and, therefore, depletion of cIAP1 and cIAP2 rather than inhibition of XIAP. Other SMACm, particularly monomeric or dimeric molecules with unoptimized linkers or lacking such specificity for BIR3 rather than BIR2, are believed to be ineffective in reversing HIV latency in primary human CD4+T cells and may also inhibit XIAP, leading to potential off-target effects by enhancing unnecessary apoptosis.

[0079] The present invention provides compounds of formula (I), and various forms of these compounds described herein (e.g., pharmaceutically acceptable salts, tautomers and stereoisomers). It should be understood that any reference to compounds of formula (I) herein is also meant to include, but not limited to, those compounds listed in Table 1.

[0080] In some embodiments, the present invention provides compounds according to the structure of Formula (I):

[0081]

[0082] or a pharmaceutically acceptable salt thereof, or in other embodiments, a compound according to the structure of Formula (Ia) is provided:

[0083]

[0084] or a pharmaceutically acceptable salt or stereoisomer thereof;

[0085] in:

[0086] Each R 1 and R 2 -CH 3 ;

[0087] Each R 3 -H or -CH 3 ;

[0088] Each R 4 -H, -F, -Cl, -CH 3 , -CF 3 、-CN、-OH、-OCH 3 、-C(O)N(CH 3 ) 2 、-CH(CH 3 ) 2 or -C(O)OCH 3 ;

[0089] Each R 5 -H, -F, -Cl, -Br, -CH 3 , -CHF 2 or -CF 3 ;

[0090] Each R 6 is -H, -F or -Cl;

[0091] Each R 7 is -H or -F;

[0092] Each W is -CH-, -CH 2 -, -O-, or -N-;

[0093] Each X is -CH 2 -, -O-, -NH-, or -NCH 3 -;

[0094] Each Y 1 is -CH- or -C(O)-;

[0095] Each Y 2 -N-, -NH- or -NCH 3 -;

[0096] Each represents a single bond or a double bond, where Y 1 When it is -CH-, Y 2 is -N-, and represents a double bond and when Y 1When it is -C(O)-, Y 2 -NH- or -NCH 3 -,and Represents a single bond;

[0097] each Z is -CH- or -N-; and

[0098] L is a linker selected from the following:

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105] in represents a connection point; and wherein n is an integer from 2 to 15, m is an integer from 1 to 5, p is an integer from 1 to 20, q is an integer from 2 to 15, s is an integer from 1 to 8, t is an integer from 2 to 15, w is an integer from 1 to 10, x is an integer from 2 to 15, y is an integer from 2 to 15, and z is an integer from 2 to 15.

[0106] In some embodiments, each R 1 and R 2 -CH 3 In other embodiments, each R 1 and R 2 In other embodiments, each R 1 and R 2 are independently -H or -CH 3 .

[0107] In some embodiments, each X is -CH 2 -, each Z is -CH-, and each R 4 is -H.

[0108] In some embodiments, each Y 1 For -C(O)-, each Y 2 -NH- or -NCH 3 -, and each Represents a single bond.

[0109] In some embodiments, the compound is

[0110]

[0111] or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the compound is selected from

[0113]

[0114]

[0115] In some embodiments, L is a linker selected from:

[0116]

[0117]

[0118] in represents a connection point; and wherein n is an integer from 2 to 12, m is an integer from 1 to 3, and p is an integer from 1 to 12.

[0119] In some embodiments, the compound is

[0120]

[0121] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0122] In some embodiments, L is selected from:

[0123]

[0124] in represents a connection point; and wherein n is an integer from 2 to 8.

[0125] In some embodiments, the compound is selected from

[0126]

[0127] In some embodiments, L is selected from

[0128]

[0129]

[0130]

[0131] in represents a connection point; and wherein q is an integer from 2 to 8, s is an integer from 1 to 5, t is an integer from 2 to 8, w is an integer from 1 to 5, x is an integer from 2 to 8, and y is an integer from 2 to 8.

[0132] In some embodiments, the compound is

[0133]

[0134] In some embodiments, L is selected from

[0135]

[0136]

[0137] in represents a connection point; and wherein z is an integer from 2 to 8.

[0138] In some embodiments, the compound or a pharmaceutically acceptable salt or stereoisomer thereof is a heterodimer selected from:

[0139]

[0140] In other aspects, the present invention provides compounds according to the structure of formula (II):

[0141]

[0142] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

[0143] Each R 3 -H or -CH 3 ;

[0144] Each W is -CH-, -O-, or -N-; and

[0145] L is a linker selected from the following:

[0146]

[0147] in represents a connection point; and wherein t is 6 or 8, and x is 3 or 6.

[0148] Exemplary compounds encompassed by the present invention include, but are not limited to, the compounds in Table 1 below:

[0149] Table 1.

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232] For all compounds 1-190 described herein, pharmaceutically acceptable salts are also within the scope of the present invention. In some embodiments, each of compound 1-190 can generally exist as a hydrochloride (i.e., HCl salt), for example, more specifically, a dihydrochloride (2HCl). In some embodiments, compound 1-190 can generally exist as a mixture of monoacid, diacid acetate, trifluoroacetate, citrate, or monoacid and diacid acetate, trifluoroacetate, citrate. In some embodiments, the salt form of compound 1-190 can be a mixture of hydrohalide and dihydrohalide (i.e., monoacid and diacid) forms. In addition, any compound 1-190 present as a single species is also within the scope of the present invention, including its pharmaceutically acceptable salt, and the free base form of any of these compounds.

[0233] Specific examples of linking groups (L) that can be used according to the present invention include those selected from the following:

[0234]

[0235]

[0236]

[0237]

[0238]

[0239] in Represents a connection point.

[0240] In another embodiment of the present invention, there is provided a compound of Formula I or a pharmaceutically acceptable salt thereof for use in medical therapy.

[0241] In another embodiment of the present invention, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof for use in treating HIV infection.

[0242] In another embodiment of the present invention, there is provided a compound of formula I, wherein the compound or a salt of the compound is used in the manufacture of a medicament for treating HIV infection in humans.

[0243] In some embodiments, the present invention provides a method of curing HIV infection in a subject, comprising administering to the subject a compound of Formula I and any compound in Table 1 and a pharmaceutical salt thereof. "Cure" or "curing" a disease in a patient is used to mean eradicating, preventing, stopping or terminating the human immunodeficiency virus or symptoms, or the progression of symptoms or viruses within a specified period of time. For example, in one embodiment, "Cure" or "Curing" refers to a therapeutic administration or a combination of administrations that induces and maintains sustained viral control of the human immunodeficiency virus (levels of plasma viremia that are undetectable by, for example, polymerase chain reaction (PCR) testing, bDNA (branched DNA) testing, or NASBA (nucleic acid sequence-based amplification) testing) after at least two years without any other therapeutic intervention. The above-mentioned PCR, bDNA, and NASBA tests are performed using techniques known and familiar to those skilled in the art. For example, eradication, prevention, suspension, or termination of human immunodeficiency virus or symptoms, or the progression of symptoms or viruses, can be maintained for at least two years.

[0244] In some embodiments, the present invention provides a method of curing HIV infection in a subject, comprising administering to the subject a pharmaceutical composition comprising a compound of Formula I and a pharmaceutical salt thereof.

[0245] In some embodiments, the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for curing HIV infection.

[0246] In some embodiments, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in curing HIV infection.

[0247] Combinations of a compound of formula I and one or more agents used in HIV therapy may also be used in methods of curing HIV infection.

[0248] In one embodiment, the pharmaceutical formulation containing the compound of Formula I or its salt 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.

[0249] The compounds of the present invention and their salts, solvates or other pharmaceutically acceptable derivatives can be used alone or in combination with other therapeutic agents. Therefore, in other embodiments, the method of treating and / or preventing HIV infection in a subject further comprises administering one or more additional agents having anti-HIV activity in addition to administering a compound of Formula I.

[0250] In such embodiments, the one or more additional agents having anti-HIV activity are selected from antiretroviral agents, latency reversal agents, and agents used for elimination therapy.

[0251] In other embodiments, the one or more additional agents having anti-HIV activity are selected from the group consisting of nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, attachment and fusion inhibitors, integrase inhibitors, maturation inhibitors, CXCR4 and / or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyl transferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, neutralizing antibodies, and combinations thereof.

[0252] In certain embodiments, the one or more additional agents having anti-HIV activity are selected from zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, dipivoxil), fozivudine, todoxil, emtricitabine, alovudine, amdosovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranvir, 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, bictegravir, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, darunavir, vorinostat, panobinostat, romidepin, valproic acid, mocetinostat, sodium corotonate, bryostatin, ingenol B, disulforam, GS-9620, JQ1, iBET151, bortezomib, epigallocatechin gallate, salinosporamide A, carfilzomib, broadly neutralizing antibodies (bNAbs), eCD4-Ig, CD4-Ig, and dual affinity redirecting (DART) proteins.

[0253] Therefore, the compound of formula (I) of the present invention and any other pharmaceutically active agent can be administered together or separately, and when administered separately, administration can occur simultaneously or in any order. The amount of the compound of formula (I) of the present invention and other pharmaceutically active agents and the relative time of administration will be selected to achieve the desired combined therapeutic effect. The administration of the combination of the compound of formula (I) of the present invention and its salt, solvate or other pharmaceutically acceptable derivatives and other therapeutic agents can be combined by simultaneous administration in the following: (1) a single pharmaceutical composition including two compounds; or (2) a separate pharmaceutical composition each including one of the compounds. Alternatively, the combination can be administered separately in a sequential manner, wherein one therapeutic agent is first administered, and then other therapeutic agents are administered, and vice versa. This sequential administration can be close in time or distant in time. The amount of the compound of formula (I) or its salt and other pharmaceutically active agents and the relative time of administration will be selected to achieve the desired combined therapeutic effect.

[0254] In addition, the compounds of formula (I) of the present invention can be used in combination with one or more other agents that can be used to treat HIV. These agents may include antiretroviral agents, latency reversal agents, and agents for elimination therapy. The following provides examples of several antiretroviral agents:

[0255] Nucleotide reverse transcriptase inhibitors , such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdosovir, efavirenz, and similar agents;

[0256] Non-nucleotidyl reverse transcriptase inhibitors (including agents with antioxidant activity, such as immunocal, oltipraz, etc.), such as nevirapine, delavirdine, efavirenz, loviramide, immunocal, oltipraz, capravirine, risilin, GSK2248761, TMC-278, TMC-125, etravirine and similar agents;

[0257] Protease inhibitors , such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, becanavir, darunavir, atazanavir, tipravir, palinavir, rasinavir and similar agents;

[0258] Entry, attachment and fusion inhibitors, For example, Enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS-626529, 5-Helix and similar agents;

[0259] Integrase inhibitors , such as raltegravir, elvitegravir, dolutegravir, carditegravir, bictegravir and similar agents;

[0260] Maturation inhibitors , such as PA-344 and PA-457 and similar agents; and

[0261] CXCR4 and / or CCR5 inhibitors , such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK427,857), 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.

[0262] Further examples in which the compounds of the present invention can be used in combination with one or more agents for the prevention or treatment of HIV are shown in Table 2.

[0263] Table 2.

[0264]

[0265]

[0266]

[0267] The present invention can be used in combination with other agents that induce HIV expression (e.g., latency reversal agents). Several latency reversal agents include, but are not limited to, the following: histone deacetylase inhibitors (e.g., vorinostat, panobinostat, romidepsin), histone crotonyl transferase inhibitors (sodium corotonate), protein kinase C agonists (e.g., bryostatin, ingenol B), disulfiram, TLR7 agonists (e.g., GS-9620), bromodomain inhibitors (e.g., JQ1, iBET151). Many of these agents will be described in further detail below.

[0268] The present invention can be used in combination with other agents that induce HIV expression, such as agents for clearance therapy. Several examples of agents for clearance therapy or immunological combinations for clearance include, but are not limited to, the following: neutralizing antibodies and broadly neutralizing antibodies (bNAbs), eCD4-Ig, CD4-Ig, and dual affinity redirection (DART) proteins.

[0269] The scope of the combination of the compounds of the present invention with HIV agents is not limited to those described above, but in principle includes any combination with any pharmaceutical composition that can be used to treat and / or prevent HIV. As previously mentioned, in such combinations, the compounds of the present invention and other HIV agents can be administered alone or in combination. In addition, one agent can be administered before, simultaneously with, or after the administration of the other agent.

[0270] In some embodiments, the compounds of Formula I and Table 1 can be used in combination with one or more agents used as pharmacological enhancers, and with or without additional compounds for preventing or treating HIV. Examples of such pharmacological enhancers (or pharmacokinetic enhancers) include, but are not limited to, ritonavir, GS-9350 (cobicistat), and SPI-452.

[0271] Ritonavir is 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-oic acid, 5-thiazolylmethyl ester, [5S-(5S*,8R*,10R*,11R*)] and is commercially available from Abbott Laboratories in Abbott Park, Illinois as Norvir. Ritonavir is an HIV protease inhibitor used in combination with other antiretroviral agents to treat HIV infection. Ritonavir also inhibits P450-mediated drug metabolism as well as the P-glycoprotein (Pgp) cellular transport system, resulting in increased concentrations of the active compound in the organism.

[0272] GS-9350 (cobicistat) is a compound being developed by Gilead Sciences of Foster City California as a pharmacologic enhancer.

[0273] SPI-452 is a compound being developed by Sequoia Pharmaceuticals of Gaithersburg, Maryland, as a pharmacological enhancer.

[0274] In some embodiments, the compound of formula I 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 is formulated into a long-acting parenteral injection, and ritonavir is formulated into an oral composition. In one embodiment, the kit contains a compound of formula I formulated into a long-acting parenteral injection, and ritonavir formulated into an oral composition. In another embodiment, the compound of formula I is formulated into a long-acting parenteral injection, and ritonavir is formulated into an injectable composition. In one embodiment, the kit contains a compound of formula I formulated into a long-acting parenteral injection and ritonavir formulated into an injectable composition.

[0275] In some embodiments, the compound of formula I 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 is formulated as a long-acting parenteral injection, and GS-9350 is formulated as an oral composition. In one embodiment, a kit is provided, which contains a compound of formula I formulated as a long-acting parenteral injection and GS-9350 formulated as an oral composition. In another embodiment, the compound of formula I is formulated as a long-acting parenteral injection, and GS-9350 is formulated as an injectable composition. In one embodiment, a kit is provided, which contains a compound of formula I formulated as a long-acting parenteral injection and GS-9350 formulated as an injectable composition.

[0276] In some embodiments, the compound of formula I is used in combination with SPI-452. In one embodiment, the combination is an oral fixed dose combination. In other embodiments, the compound of formula I is formulated as a long-acting parenteral injection, and SPI-452 is formulated as an oral composition. In yet other embodiments, a kit is provided, which contains a compound of formula I formulated as a long-acting parenteral injection and SPI-452 formulated as an oral composition. In other embodiments, the compound of formula I is formulated as a long-acting parenteral injection, and SPI-452 is formulated as an injectable composition. In some embodiments, a kit is provided, which contains a compound of formula I formulated as a long-acting parenteral injection and SPI-452 formulated as an injectable composition.

[0277] In some embodiments, the compound of Formula I is used in combination with compounds present in previously filed PCT / CN2011 / 0013021, which is incorporated herein by reference.

[0278] The above-mentioned other therapeutic agents, when used in combination with the chemical entities described herein, can be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or in amounts determined by one skilled in the art.

[0279] In other embodiments, a method of treating a viral infection in a mammal mediated at least in part by a virus in the retroviral family of viruses is provided, the method comprising administering a compound of Formula I to a mammal that has been diagnosed with or is at risk of developing the viral infection.

[0280] In still other embodiments, a method of treating a viral infection in a mammal is provided, the viral infection being mediated at least in part by a virus in the retroviral family of viruses, the method comprising administering a compound of Formula I to a mammal that has been diagnosed with or is at risk of developing the viral infection, wherein the virus is HIV virus. In some embodiments, the HIV virus is HIV-1 virus.

[0281] In other embodiments, a method of treating a viral infection in a mammal that is mediated at least in part by a virus in the retroviral family of viruses is provided, the method comprising administering to a mammal that has been diagnosed with or is at risk of developing the viral infection a compound of Formula I, further comprising administering a therapeutically effective amount of one or more agents having anti-HIV viral activity.

[0282] In some embodiments, a method of treating a viral infection in a mammal is provided, the viral infection being mediated at least in part by a virus in the retroviral family of viruses, the method comprising administering a compound of Formula I to a mammal that has been diagnosed with or is at risk of developing the viral infection, and further comprising administering a therapeutically effective amount of one or more agents having anti-HIV viral activity, wherein the agents having anti-HIV viral activity 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.

[0283] In another aspect, a method of eliminating latent HIV-infected cells comprises administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0284] In various embodiments, the compound is selected from the compounds listed in Table 1. In some embodiments, the pharmaceutical composition comprises the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, including, for example, those described herein. In other embodiments, the method for treating HIV infection in a subject comprises administering the compound or a pharmaceutically acceptable salt thereof and a combination thereof to the subject. In still other embodiments, the compound of Formula I or Table 1 or a pharmaceutically acceptable salt thereof is used to treat HIV infection. Some embodiments also include the use of the compound in the manufacture of a medicament for treating HIV infection. Still other embodiments include a method for eliminating latent HIV-infected cells, comprising administering the compound or a pharmaceutically acceptable salt thereof and a combination thereof to the subject.

[0285] In various embodiments, the method of eliminating latent HIV infection further comprises administering to the subject one or more additional agents having anti-HIV activity as disclosed above. For example, in various embodiments, the one or more additional agents are selected from: nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, attachment and fusion inhibitors, integrase inhibitors, maturation inhibitors, CXCR4 and / or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyl transferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and antibodies for clearance therapy and combinations thereof. In various embodiments, the one or more additional agents having anti-HIV activity are selected from zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdosovir, efcitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, risvirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, becanavir, darunavir, atazanavir, vir, tipravir, 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, cardioverter-protective agent, bictegravir, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, darunavir, vorinostat, panobinostat, romidepsin, valproic 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.

[0286] The compounds according to formula I and their pharmaceutically acceptable salts can be used to treat cancer, precancerous syndromes. Suitably, the present invention relates to a method for treating a cancer selected from the group consisting of brain (neuroglioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilms tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovary, pancreas, adenocarcinoma, ductal adenocarcinoma, adenosquamous 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, Blast cell leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic 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, cheek cancer, oral cancer, GIST (gastrointestinal stromal tumor) and testicular cancer.

[0287] Suitably, the present invention relates to a method of treating a precancerous syndrome in a mammal, including a human, wherein the precancerous syndrome is selected from the group consisting of cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (premelanoma), prostatic intraepithelial (intraductal) neoplasia (PIN), ductal carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.

[0288] The compounds of formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in treating cancer or precancerous syndromes.

[0289] As used herein, the term "co-administration" refers to simultaneous administration or any manner of separate sequential administration of a c-MYC inhibitory compound described herein and a further active agent or agent known to be useful for treating cancer (including chemotherapy and radiation therapy). As used herein, the term further active agent or agent includes any compound or therapeutic agent that has known favorable properties or exhibits favorable properties when administered to a patient in need of cancer treatment. Preferably, if the administration is not simultaneous, the compounds are administered at a time close to each other. In addition, it is not important whether the compound is administered in the same dosage form, for example, one compound can be administered by injection and another compound can be administered orally.

[0290] Examples of further active ingredients (antineoplastic agents) for use in combination or co-administration with the combinations of the present invention are listed below. This list is non-limiting. It is contemplated that additional antineoplastic agents are used together with the compounds of the present invention.

[0291] Generally, any anti-tumor agent that is active against the susceptible tumor being treated can be co-administered in the treatment of cancer of the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology, 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers, by VT Devita and S. Hellman (eds.). Those skilled in the art will be able to discern which combinations of agents are useful based on the specific characteristics of the drugs and the cancers involved. Typical anti-tumor agents useful in the present invention include, but are not limited to, anti-microtubule agents, such as diterpenes and vinca alkaloids; platinum coordination complexes; alkylating agents, such as nitrogen mustards, oxazaphosphorus, alkyl sulfonates, nitrosoureas and triazenes; antibiotic agents, such as anthracyclines, actinomycins and bleomycins; topoisomerase II inhibitors, such as epipodophyllotoxin; antimetabolites, such as purine and pyrimidine analogs and antifolate compounds; topoisomerase I inhibitors, such as camptothecin; hormones and hormone analogs; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; pro-apoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and cancer metabolism inhibitors.

[0292] Examples of further active ingredients (antineoplastic agents) used or co-administered in combination with the compounds of the present invention are chemotherapeutic agents.

[0293] Anti-microtubule or anti-mitotic agents are phase-specific agents that target tumor cell microtubules during the M or mitotic phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.

[0294] Diterpenoids are derived from natural sources and are activated during the G 2 Diterpenoids are stage-specific anticancer agents that act at the M / M stage. It is believed that diterpenoids stabilize the protein by binding to the β-tubulin subunit of the microtubules. Subsequently, the breakdown of the protein appears to be inhibited, mitosis is arrested, and cell death ensues. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.

[0295] Paclitaxel, 5β,20-epoxy-1,2α,4,7β,10β,13α-hexa-hydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is available as an injectable solution It is commercially available. 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), who characterized its structure by chemical and X-ray crystallographic methods. One of its mechanisms of activity is related to the ability of paclitaxel 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 a review of the synthesis and anticancer activity of some paclitaxel derivatives, see: DGI Kingston et al., Studies in Organic Chemistry vol. 26, entitled "New trends in Natural Products Chemistry 1986", Attaur-Rahman, PW Le Quesne, Eds. (Elsevier, Amsterdam, 1986) pp 219-235.

[0296] Paclitaxel has been approved 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. Intem, Med., 111: 273, 1989) and for clinical use in the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83: 1797, 1991.). It is a potential candidate drug for the treatment of skin tumors (Einzig et al., Proc. Am. Soc. Clin. Oncol., 20: 46) and head and neck cancer (Forastire et al., Sem. Oncol., 20: 56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et al., Nature, 368: 750. 1994), lung cancer and malaria. Treatment of patients with paclitaxel can lead to bone marrow suppression (multiple cell lineages, Ignoff, RJ et al., Cancer Chemotherapy Pocket Guide , 1998), which is related to the duration of administration above the threshold concentration (50 nM) (Kearns, CM et al., Seminars in Oncology, 3(6) p.16-23, 1995).

[0297] Docetaxel, (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate; as injectable solution It is commercially available. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semisynthetic derivative of paclitaxel qv, prepared using the natural precursor 10-deacetyl-baccatin III extracted from the needles of the European yew tree. The dose-limiting toxicity of docetaxel is neutropenia.

[0298] Vinca alkaloids are stage-specific antitumor agents derived from the periwinkle plant. Vinca alkaloids work by specifically binding to tubulin in the M phase (mitosis) of the cell cycle. Therefore, the bound tubulin molecules cannot polymerize into microtubules. Mitosis is considered to stop in metaphase, followed by cell death. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine and vinorelbine.

[0299] Vinblastine, also known as vinblastine sulfate, is used as It is commercially available as an injectable solution. Although it has potential indications as a second-line therapy for various solid tumors, it is primarily used to treat testicular cancer and various lymphomas, including Hodgkin's disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is a dose-limiting side effect of vinblastine.

[0300] Vincristine, 22-oxo-vinblastine sulfate, is used as It is commercially available as an injectable solution. Vincristine is used to treat acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas. Alopecia and neurologic effects are the most common side effects of vincristine, and myelosuppression and gastrointestinal mucositis effects occur to a lesser extent.

[0301] Vinorelbine, 3',4'-didehydro-4'-deoxy-C'-norvinblastine [R-(R*,R*)-2,3-dihydroxysuccinate (1:2) (salt)], injectable solution as vinorelbine tartrate Vinorelbine is commercially available and is a semisynthetic vinca alkaloid. Vinorelbine is used as a single agent or in combination with other chemotherapeutic agents (e.g., cisplatin) to treat various solid tumors, particularly non-small cell lung cancer, advanced breast cancer, and hormone-refractory prostate cancer. Myelosuppression is the most common dose-limiting side effect of vinorelbine.

[0302] Platinum complexes are non-stage specific anticancer agents that can interact with DNA. Platinum complexes enter tumor cells, undergo hydration and form intra- and inter-chain crosslinks with DNA, producing adverse biological effects on tumors. Examples of platinum complexes include, but are not limited to, cisplatin and carboplatin.

[0303] Cisplatin, also known as cis-diamminedichloroplatinum, is used as It is commercially available as an injectable solution. Cisplatin is primarily used to treat metastatic testicular and ovarian cancer and advanced bladder cancer. The major dose-limiting side effects of cisplatin are nephrotoxicity (which can be controlled by hydration and diuresis) and ototoxicity.

[0304] Carboplatin, also known as diammine platinum [1,1-cyclobutane-dicarboxylic acid (2-)-O,O'], is used as It is commercially available as an injectable solution. Carboplatin is primarily used in the first-line and second-line treatment of advanced ovarian cancer. Myelosuppression is the dose-limiting toxicity of carboplatin.

[0305] Alkylating agents are non-phasic anticancer specific agents and strong electrophiles. Typically, alkylating agents form covalent bonds with DNA through nucleophilic moieties (e.g., phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups) of DNA molecules by alkylation. This alkylation can destroy nucleic acid function and lead to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.

[0306] Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxaphosphine-2-oxide monohydrate, as It is commercially available as an injectable solution or tablet. Cyclophosphamide is used as a single agent or in combination with other chemotherapeutic agents to treat malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting, and leukopenia are the most common dose-limiting side effects of cyclophosphamide.

[0307] Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, as It is commercially available as an injectable solution or tablet. Melphalan is used for the palliative treatment of multiple myeloma and unresectable epithelial ovarian cancer. Myelosuppression is the most common dose-limiting side effect of melphalan.

[0308] Chlorambucil, 4-[bis(2-chloroethyl)amino]phenylbutyric acid, as Tablets are commercially available. Chlorambucil is used for the palliative treatment of chronic lymphatic leukemia and malignant lymphomas (eg, lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease). Myelosuppression is the most common dose-limiting side effect of chlorambucil.

[0309] Busulfan, 1,4-butanediol dimethanesulfonate, is used as Tablets are commercially available.Busulfan is used for the palliative treatment of chronic myeloid leukemia. Myelosuppression is the most common dose-limiting side effect of busulfan.

[0310] Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, as a single vial of lyophilized material It is commercially available. Carmustine is used as a single agent or in combination with other agents for the palliative treatment of brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphoma. Delayed myelosuppression is the most common dose-limiting side effect of carmustine.

[0311] Dacarbazine, 5-(3,3-dimethyl-1-triazene)-imidazole-4-carboxamide, as single vial material is commercially available. Dacarbazine is used to treat metastatic malignant melanoma and in combination with other agents for second-line treatment of Hodgkin's disease. Nausea, vomiting, and anorexia are the most common dose-limiting side effects of dacarbazine.

[0312] Antibiotic antineoplastic drugs are non-stage specific agents that bind to or intercalate with DNA. Typically, this action results in stable DNA complexes or strand breaks, thereby disrupting the usual functions of nucleic acids and causing cell death. Examples of antibiotic antineoplastic drugs include, but are not limited to, actinomycins (e.g., dactinomycin), anthracyclines (e.g., daunomycin and doxorubicin), and bleomycin.

[0313] Dactinomycin, also known as actinomycin D, is available in injectable form as It is commercially available. Dactinomycin is used to treat Wilms' tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose-limiting side effects of dactinomycin.

[0314] Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyso-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride, as a liposomal injectable form Or as an injection It is commercially available. Daunorubicin is used for the treatment of acute non-lymphocytic leukemia and remission induction in advanced HIV-associated Kaposi's sarcoma. Myelosuppression is the most common dose-limiting side effect of daunorubicin.

[0315] Doxorubicin, (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyso-hexopyranosyl)oxy]-8-glycolyl, 7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthophenadione hydrochloride, as an injectable form or An injectable formulation is commercially available. Doxorubicin is primarily used to treat acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of certain solid tumors and lymphomas. Myelosuppression is the most common dose-limiting side effect of doxorubicin.

[0316] Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from strains of Streptomyces verticillium, is commercially available. Bleomycin is used as a single agent or in combination with other drugs for the palliative treatment of squamous cell carcinoma, lymphoma, and testicular cancer. Pulmonary and skin toxicity are the most common dose-limiting side effects of bleomycin.

[0317] Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.

[0318] Epipodophyllotoxins are phase-specific antitumor agents derived from the mandrake plant. Epipodophyllotoxins affect the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA. 2 The cells of the stage 1 can be damaged, thereby causing DNA strand breaks. The strand breaks can accumulate and the cells die. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

[0319] Etoposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene-β-D-pyranoglucopyranoside], as an injectable solution or capsule is commercially available and is commonly known as VP-16. Etoposide is used as a single agent or in combination with other chemotherapy agents to treat testicular cancer and non-small cell lung cancer. Myelosuppression is the most common side effect of etoposide. The incidence of leukopenia tends to be more severe than thrombocytopenia.

[0320] Teniposide, 4'-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene-β-D-glucopyranoside], as an injectable solution is commercially available and is commonly referred to as VM-26. Teniposide is used as a single agent or in combination with other chemotherapeutic agents to treat childhood acute leukemia. Myelosuppression is the most common dose-limiting side effect of teniposide. Teniposide can induce leukopenia and thrombocytopenia.

[0321] Antimetabolite tumor agents are stage-specific antitumor agents that act in 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. Therefore, the S phase will not proceed, followed by cell death. Examples of antimetabolite antitumor agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine.

[0322] 5-fluorouracil, 5-fluoro-2,4-(1H,3H)pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil results in inhibition of thymidylate synthesis and is also incorporated into RNA and DNA. The result is usually cell death. 5-fluorouracil is used as a single agent or in combination with other chemotherapeutic agents to treat breast cancer, colon cancer, rectal cancer, gastric cancer, and pancreatic cancer. Myelosuppression and mucositis are dose-limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (floxyuridine) and 5-fluorodeoxyuridine monophosphate.

[0323] Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone, is used as It is commercially available and is commonly referred to as Ara-C. It is believed that cytarabine inhibits DNA chain elongation by terminally incorporating cytarabine into growing DNA chains, thereby exhibiting cell stage specificity in the S phase. Cytarabine is used as a single agent or in combination with other chemotherapeutic agents to treat acute leukemias. Other cytidine analogs include 5-azacytidine and 2',2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces leukopenia, thrombocytopenia, and mucositis.

[0324] Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, as It is commercially available. Mercaptopurine exhibits cell stage specificity at the S phase by inhibiting DNA synthesis (through a currently undetermined mechanism). Mercaptopurine is used as a single agent or in combination with other chemotherapeutic agents to treat acute leukemia. The expected side effects of high doses of mercaptopurine are bone marrow suppression and gastrointestinal mucositis. A useful mercaptopurine analog is azathioprine.

[0325] Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, as It is commercially available. Thioguanine exhibits cell stage specificity in the S phase by inhibiting DNA synthesis (by a currently undetermined mechanism). Thioguanine is used as a single agent or in combination with other chemotherapeutic agents to treat acute leukemia. Myelosuppression (including leukopenia, thrombocytopenia and anemia) is the most common dose-limiting side effect of thioguanine administration. However, gastrointestinal side effects may occur and may be dose-limiting. Other purine analogs include pentostatin, erythron-hydroxy-nonyl-adenine, fludarabine phosphate and cladribine.

[0326] Gemcitabine, 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer), as is commercially available. Gemcitabine exhibits cell phase specificity in the S phase and blocks the progression of cells through the G1 / S boundary. Gemcitabine is used in combination with cisplatin to treat locally advanced non-small cell lung cancer and alone to treat locally advanced pancreatic cancer. Myelosuppression, including leukopenia, thrombocytopenia, and anemia, is the most common dose-limiting side effect of gemcitabine administration.

[0327] Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid, is commercially available as sodium methotrexate. Methotrexate exhibits cell stage effects at the S phase by inhibiting DNA synthesis, repair and / or replication by inhibiting dihydrofolate reductase, which is required for the synthesis of purine nucleotides and thymidylate. Methotrexate is used as a single agent or in combination with other chemotherapeutic agents to treat choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and cancers of the breast, head, neck, ovary, and bladder. Myelosuppression (leukopenia, thrombocytopenia, and anemia) and mucositis are expected side effects of methotrexate administration.

[0328] Camptothecins, including camptothecin and camptothecin derivatives, are available or under development as topoisomerase I inhibitors. The cytotoxic activity of camptothecins is believed to be related to their topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to, irinotecan, topotecan, and various optical forms of 7-(4-methylpiperazinyl-methylene)-10,11-ethylenedioxy-20-camptothecin described below.

[0329] Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinylpiperidinyl)carbonyloxy]-1H-pyrano[3',4',6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione hydrochloride, as an injectable solution It is commercially available.

[0330] Irinotecan is a derivative of camptothecin that binds to the topoisomerase I-DNA complex together with its active metabolite SN-38. It is believed that cytotoxicity occurs due to irreparable double-strand breaks caused by the interaction of the topoisomerase I:DNA:irinotecan or SN-38 ternary complex with the replicase. Irinotecan is suitable for the treatment of metastatic cancer of the colon or rectum. The dose-limiting side effects of irinotecan HCl are bone marrow suppression (including neutropenia) and GI effects (including diarrhea).

[0331] Topotecan HCl, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4',6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, as an injectable solution is commercially available. Topotecan is a derivative of camptothecin that binds to the topoisomerase I-DNA complex and prevents the religation of single-strand breaks caused by topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second-line treatment of metastatic ovarian cancer and small-cell lung cancer. The dose-limiting side effect of topotecan HCl is myelosuppression, primarily neutropenia.

[0332] Hormones and hormone analogs are useful compounds for treating cancer where there is a relationship between the hormone and the growth and / or non-growth of the cancer. Examples of hormones and hormone analogs that can be used for cancer treatment include, but are not limited to, adrenocortical steroids, such as prednisone and prednisolone, which are used to treat childhood malignant lymphomas and acute leukemias; aminoglutethimide and other aromatase inhibitors, such as anastrozole, letrazole, vorazole, and exemestane, which are used to treat adrenocortical carcinoma and hormone-dependent breast cancer containing estrogen receptors; progestins, such as megestrol acetate, which are used to treat hormone-dependent breast cancer and endometrial cancer; estrogens, androgens, and antiandrogens, such as flutamide, nilutamide, bicalutamide, cyproterone acetate, and 5α-reductase inhibitors, such as finasteride and dutamide; androstamide, which is used to treat prostate cancer and benign prostatic hyperplasia; antiestrogens, such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, and selective estrogen receptor modulators (SERMS), such as those described in U.S. Pat. Nos. 5,681,835, 5,877,219, and 6,207,716, which are used to treat hormone-dependent breast cancer and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and its analogs, which stimulate the release of luteinizing hormone (LH) and / or follicle stimulating hormone (FSH), which are used to treat prostate cancer, for example, LHRH agonists and antagonists, such as goserelin acetate and luprolide.

[0333] Signal transduction pathway inhibitors are inhibitors that block or inhibit chemical processes that cause changes in cells. As used herein, this change is cell proliferation or differentiation. Useful signal transduction inhibitors in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phosphatidylinositol-3 kinases, myo-inositol signaling and Ras oncogenes.

[0334] A variety of protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in a variety of proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly divided into receptor kinases and non-receptor kinases.

[0335] Receptor tyrosine kinases are transmembrane proteins with 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. Inappropriate or uncontrolled activation of many such kinases, i.e., abnormal kinase growth factor receptor activity (e.g., by overexpression or mutation) has been shown to lead to uncontrolled cell growth. Therefore, abnormal activity of such kinases is associated with malignant tissue growth. Therefore, inhibitors of such kinases can provide cancer treatment methods. Growth factor receptors include, for example, 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 homology domains (TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptor, Trk receptor (TrkA, TrkB and TrkC), ephrin (eph) receptor and RET proto-oncogene. Several growth receptor inhibitors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and antisense oligonucleotides. Growth factor receptors and agents 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. February 1997; and Lofts, FJ et al., "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.

[0336] Suitably, the pharmaceutically active compound of the invention is used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt thereof, suitably the monohydrochloride salt thereof, which is disclosed and claimed in International Application No. PCT / US01 / 49367, having an International Application Date of December 19, 2001, International Publication No. WO02 / 059110, and an International Publication Date of August 1, 2002, the entire disclosure of which is hereby incorporated herein by reference, and which is the compound of Example 69. 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide may be prepared as described in International Application No. PCT / US01 / 49367.

[0337] Suitably, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide is in the form of a monohydrochloride. Those skilled in the art can prepare the salt form according to the description of International Application No. PCT / US01 / 49367 (International Application Date is December 19, 2001).

[0338] 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide is marketed as the monohydrochloride salt and is generically known as pazopanib and traded under the name

[0339] Pazopanib is relevant to the treatment of cancer and ocular diseases / angiogenesis. Suitably, the invention relates to the treatment of cancer and ocular diseases / angiogenesis, suitably the treatment of age-related macular degeneration, the method comprising administering a compound of formula (I) alone or in combination with pazopanib.

[0340] Tyrosine kinases that are not growth factor receptor kinases are referred to as non-receptor tyrosine kinases. Non-receptor tyrosine kinases used in the present invention, which are targets or potential targets of anticancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Brutons tyrosine kinase and Bcr-Abl. Such non-receptor kinases and agents 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.

[0341] SH2 / SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins, including PI3-K p85 subunits, Src family kinases, adaptor 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.

[0342] Inhibitors of serine / threonine kinases include MAP kinase cascade blockers, including blockers of Raf kinase (rafk), mitogen or extracellular regulated kinase (MEK) and extracellular regulated kinase (ERK); and protein kinase C family member blockers, including blockers of the following: PKC (α, β, γ, ε, μ, λ, ι, ζ), IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, PDK1 and TGFβ receptor kinase. 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, P. A, and Harris, A. L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al. Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Pat. No. 6,268,391; Pearce, L. R. et al. Nature Reviews Molecular Cell. Biology (2010) 11, 9-22. and Martinez-Iacaci, L., et al., Int. J. Cancer (2000), 88(1), 44-52.

[0343] Suitably, the pharmaceutically active compounds of the invention are used in combination with a MEK inhibitor. Suitably, N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate thereof, suitably a dimethyl sulfoxide solvate thereof, which is disclosed and claimed in International Application No. PCT / JP2005 / 011082, International Application Date June 10, 2005; International Publication No. WO2005 / 121142, International Publication Date December 22, 2005, the entire disclosure of which is hereby incorporated herein by reference. N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide can be prepared as described in U.S. Patent Publication No. US2006 / 0014768 (published on January 19, 2006), the entire disclosure of which is hereby incorporated by reference herein.

[0344] Suitably, the pharmaceutically active compounds of the invention are used in combination with a B-Raf inhibitor. Suitably, N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof, is disclosed and claimed in International Application No. PCT / US2009 / 042682, filed May 4, 2009, the entire disclosure of which is hereby incorporated by reference. N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide may be prepared as described in International Application No. PCT / US2009 / 042682.

[0345] Suitably, the pharmaceutically active compounds of the present invention are used in combination with an Akt inhibitor. Suitably, N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT / US2008 / 053269, International Application Date February 7, 2008; International Publication No. WO 2008 / 098104, International Publication Date August 14, 2008, the entire disclosure of which is hereby incorporated herein by reference. N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide is the compound of Example 224 and can be prepared as described in International Application No. PCT / US2008 / 053269.

[0346] Suitably, the pharmaceutically active compounds of the present invention are used in combination with an Akt inhibitor. Suitably, N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT / US2008 / 053269, International Application Date February 7, 2008; International Publication No. WO 2008 / 098104, International Publication Date August 14, 2008, the entire disclosure of which is hereby incorporated herein by reference. 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 according to the description in International Application No. PCT / US2008 / 053269. Suitably, 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 hydrochloride. Those skilled in the art can prepare salt forms according to the description in International Application No. PCT / US2010 / 022323 (International Application Date is January 28, 2010).

[0347] Inhibitors of members of the phosphatidylinositol-3 kinase family, including blockers of PI3-kinase, ATM, DNA-PK and Ku, can also be used 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.

[0348] Also of interest to the present invention are 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 ed., Paul Workman and David Kerr, CRC press 1994, London.

[0349] Another group of signal transduction pathway inhibitors are inhibitors of Ras oncogenes. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyltransferase and CAAX protease as well as antisense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild-type mutant ras, thereby acting as antiproliferative agents. Ras oncogene inhibition is 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.

[0350] As described above, antibody antagonists to receptor kinase ligand binding can also act as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies to bind extracellular ligands to the domains of receptor tyrosine kinases. For example, Imclone C225 EGFR-specific antibody (see Green, MC et al., Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26 (4), 269-286); erbB2 antibody (see Tyrosine Kinase Signaling in Breast cancer: erbB Family Receptor Tyrosine Kinases, 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).

[0351] Non-receptor kinase angiogenesis inhibitors can also be used in the present invention. The inhibitors of angiogenesis-related VEGFR and TIE2 discussed above are related to signal transduction inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis is often associated with erbB2 / EGFR signaling, because inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, mainly VEGF expression. Therefore, non-receptor tyrosine kinase inhibitors can be used in combination with the compounds of the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (receptor tyrosine kinase), but bind to ligands; integrins (α v β 3 ) will inhibit angiogenesis; endostatin and angiostatin (non-RTK) have also been shown to be 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).

[0352] The agents used in immunotherapy regimens may also be used in combination with the compounds of formula (I). There are a variety of immunological strategies to generate immune responses. These strategies are generally in the field of tumor vaccination. The efficacy of immunological methods can be greatly enhanced by inhibiting signal transduction pathways using a combination of small molecule inhibitors. Discussions of immunological / tumor vaccine methods for 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.

[0353] The agents used in the pro-apoptotic scheme (e.g., bcl-2 antisense oligonucleotides) can also be used in the combination of the present invention. Members of the Bcl-2 protein family block apoptosis. Therefore, the upregulation of bcl-2 is related to chemoresistance. Studies have shown that epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e., mcl-1). Therefore, strategies aimed at downregulating bcl-2 expression in tumors have been shown to have clinical benefits and are currently in Phase II / III trials, i.e., Genta's G3139 bcl-2 antisense oligonucleotides. Such pro-apoptotic strategies for bcl-2 using antisense oligonucleotide strategies 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.

[0354] Cell cycle signaling inhibitors inhibit molecules involved in controlling the cell cycle. A family of protein kinases called cyclin-dependent kinases (CDKs) and their interactions with a family of proteins called cyclins control the progression of the entire eukaryotic cell cycle. The coordinated activation and inactivation of different cyclin / CDK complexes are necessary for the normal progression of the entire cell cycle. 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 in, for example, Rosania et al., Exp. Opin. Ther. Patents (2000) 10 (2): 215-230. In addition, p21WAF1 / CIP1 has been described as a potent and universal inhibitor of cyclin-dependent kinases (Cdks) (Ball et al., Progress in Cell Cycle Res., 3: 125 (1997)). Compounds that induce p21WAF1 / CIP1 expression are known to be associated with inhibition of cell proliferation and tumor suppressor activity (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 are 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 herein.

[0355] Examples of such HDAC inhibitors include:

[0356] 1. Vorinostat, including pharmaceutically acceptable salts thereof. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007).

[0357] Vorinostat has the following chemical structure and name:

[0358]

[0359] 2. Romidepsin, including pharmaceutically acceptable salts thereof.

[0360] Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85-93.

[0361] Romidepsin, which has the following chemical structure and name:

[0362]

[0363] (1S,4S,7Z,10S,16E,21R)-7-Ethylene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-

[0364] 5,8,20,23-Tetraazabicyclo[8.7.6]tricosane-16-ene-3,6,9,19,22-pentanone

[0365] 3. Panobinostat, including pharmaceutically acceptable salts thereof. Drugs of the Future 32(4):315-322(2007).

[0366] Panobinostat, which has the following chemical structure and name:

[0367]

[0368] (2E)-N-Hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide

[0369] 4. Valproic acid, including pharmaceutically acceptable salts thereof. Gottlicher, et al., EMBO J. 20(24): 6969-6978 (2001).

[0370] Valproic acid, which has the following chemical structure and name:

[0371]

[0372] 5. Mocetinostat (MGCD0103), including pharmaceutically acceptable salts thereof. Balasubramanian et al., Cancer Letters 280: 211-221 (2009).

[0373] Mocetinostat, which has the following chemical structure and name:

[0374]

[0375] N-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl]benzamide

[0376] Further examples of such HDAC inhibitors are included in Bertrand European Journal of Medicinal Chemistry 45, (2010) 2095-2116, in particular the compounds in Table 3 therein, as shown below.

[0377] Table 3.

[0378]

[0379] Proteasome inhibitors are drugs that block the action of the proteasome, a cellular complex that breaks down proteins such as the p53 protein. Several proteasome inhibitors are on the market or are being studied for the treatment of cancer. Suitable proteasome inhibitors for use in the combinations herein include:

[0380] 1. Bortezomib Including pharmaceutically acceptable salts thereof. Adams J, Kauffman M (2004), Cancer Invest 22(2):304–11.

[0381] Bortezomib has the following chemical structure and name.

[0382]

[0383] [(1R)-3-Methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propionyl}amino)butyl]boronic acid

[0384] 2. Disulfiram, including pharmaceutically acceptable salts thereof.

[0385] Bouma et al. (1998). J. Antimicrob. Chemother. 42(6):817–20.

[0386] Disulfiram has the following chemical structure and name.

[0387]

[0388] 1,1',1",1"'-[Disulfanediylbis(carbonylsulfonyl nitrogen)]tetraethane

[0389] 3. Epigallocatechin gallate (EGCG), including pharmaceutically acceptable salts thereof. Williamson et al., (December 2006), The Journal of Allergy and Clinical Immunology 118(6):1369–74.

[0390] Epigallocatechin gallate has the following chemical structure and name.

[0391]

[0392] [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl] 3,4,5-trihydroxybenzoate

[0393] 4. Salinosporamide A, including pharmaceutically acceptable salts thereof. Feling et al., (2003), Angew. Chem. Int. Ed. Engl. 42(3): 355–7.

[0394] Salinosporamide A has the following chemical structure and name.

[0395]

[0396] (4R,5S)-4-(2-chloroethyl)-1-((1S)-cyclohex-2-enyl(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo3.2.0heptane-3,7-dione

[0397] 5. Carfilzomib, including pharmaceutically acceptable salts thereof. Kuhn DJ, et al., Blood, 2007, 110: 3281-3290.

[0398] Carfilzomib has the following chemical structure and name.

[0399]

[0400] (S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide

[0401] 70 kilodalton heat shock protein (Hsp70) and 90 kilodalton heat shock protein (Hsp90) are a family of heat shock proteins that are commonly expressed. Hsp70 and Hsp90 are overexpressed in certain cancer types. Several Hsp70 and Hsp90 inhibitors are being studied in the treatment of cancer. Suitable Hsp70 and Hsp90 inhibitors for use in the combinations herein include:

[0402] 1.17-AAG (geldanamycin), including pharmaceutically acceptable salts thereof. Jia W et al. Blood. 2003 Sep 1; 102(5):1824-32 .

[0403] 17-AAG (geldanamycin) has the following chemical structure and name.

[0404]

[0405] 17-(Allylamino)-17-demethoxygeldanamycin

[0406] 2. Radicicol, including pharmaceutically acceptable salts thereof. (Lee et al., Mol Cell Endocrinol. 2002, 188, 47-54) Radicicol has the following chemical structure and name.

[0407]

[0408] (1aR,2Z,4E,14R,15aR)-8-Chloro-9,11-dihydroxy-14-methyl-15,15a-dihydro-1aH-benzo[c]oxirane[2,3-k][1]oxacyclotetradecane-6,12(7H,14H)-dione

[0409] Cancer Metabolism Inhibitors - Many tumor cells exhibit a metabolism that is significantly different from that of normal tissues. For example, the rate of glycolysis (the metabolic process that converts glucose to pyruvate) is increased, and the pyruvate produced is reduced to lactate rather than further oxidized in the mitochondria via the tricarboxylic acid (TCA) cycle. This effect often occurs even under aerobic conditions and is known as the Warburg effect.

[0410] Lactate dehydrogenase A (LDH-A) is an isoform of lactate dehydrogenase expressed in muscle cells, which plays a key role in tumor cell metabolism by performing the reduction of pyruvate to lactate, which is then exported outside the cell. The enzyme has been shown to be upregulated in many tumor types. Alterations in glucose metabolism described in the Warburg effect are critical for cancer cell growth and proliferation, and knocking down LDH-A using RNA-i has been shown to result in reduced cell proliferation and tumor growth in xenograft models.

[0411] DATennant et al., Nature Reviews, 2010, 267.

[0412] P. Leder, et al., Cancer Cell, 2006, 9, 425.

[0413] High levels of fatty acid synthase (FAS) are found in precancerous lesions. Pharmacological inhibition of FAS affects the expression of key oncogenes involved in cancer development and maintenance.

[0414] Alli et al. Oncogene (2005) 24, 39–46. doi:10.1038

[0415] Cancer metabolism inhibitors, 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.

[0416] In one embodiment, the cancer treatment methods of the present invention comprise co-administering a compound of Formula I and / or a pharmaceutically acceptable salt thereof and at least one anti-tumor agent, such as an anti-microtubule agent, a platinum coordination complex, an alkylating agent, an antibiotic agent, a topoisomerase II inhibitor, an antimetabolite, a topoisomerase I inhibitor, a hormone and a hormone analog, a signal transduction pathway inhibitor, a non-receptor tyrosine kinase angiogenesis inhibitor, an immunotherapeutic agent, a pro-apoptotic agent, a cell cycle signaling inhibitor; a proteasome inhibitor; and an anti-tumor agent selected from cancer metabolism inhibitors.

[0417] In one embodiment, the compounds of Formula I are used as chemosensitizers to enhance tumor cell killing.

[0418] In one embodiment, compounds of Formula I are used in combination as chemosensitizers to enhance tumor cell killing.

[0419] In one embodiment, the compounds of the formula I are used in combination with compounds that inhibit the activity of the protein kinase R (PKR)-like ER kinase PERK (PERK inhibitors).

[0420] Suitably, the compounds of Formula I and their pharmaceutically acceptable salts may be co-administered with at least one other active agent known to be an inhibitor of PERK kinase (EIF2K3) for the treatment or reduction of 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 liver disease, chronic and acute lung disease, chronic and acute kidney disease, chronic traumatic encephalopathy (CTE), neurodegenerative diseases, dementia, traumatic brain injury, cognitive impairment, atherosclerosis, eye diseases, arrhythmias, organ transplantation and transportation of transplanted organs.

[0421] "Chemistry" or "chemotherapeutic agent" are used in accordance with their ordinary, customary meaning and refer to a chemical composition or compound that possesses anti-tumor properties or the ability to inhibit cell growth or proliferation.

[0422] In addition, the compounds described herein can be co-administered with conventional immunotherapeutic agents, including but not limited to immunostimulants (e.g., bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, α-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., with 111 In, 90 Y or 131 I-conjugated anti-CD20 monoclonal antibody, etc.).

[0423] In further embodiments, the compounds described herein may be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as 47 Sc, 64 C 67 C. 89 Sr. 86 Y. 87 Y and 212 Bi, optionally conjugated to an antibody against a tumor antigen.

[0424] A further example of a further active ingredient or ingredients (anti-tumor agents) used in combination or co-administered with the compound is an anti-PD-L1 agent.

[0425] Anti-PD-L1 antibodies and methods for their preparation are known in the art.

[0426] Such antibodies to PD-L1 may be polyclonal or monoclonal, and / or recombinant, and / or humanized.

[0427] Exemplary PD-L1 antibodies are disclosed below:

[0428] U.S. Patent Nos. 8,217,149; 12 / 633,339;

[0429] U.S. Patent Nos. 8,383,796; 13 / 091,936;

[0430] U.S. Patent Nos. 8,552,154; 13 / 120,406;

[0431] U.S. Patent Publication Nos. 20110280877; 13 / 068337;

[0432] U.S. Patent Publication Nos. 20130309250; 13 / 892671;

[0433] WO2013019906;

[0434] WO2013079174;

[0435] U.S. Application No. 13 / 511,538 (filed August 7, 2012), which is the U.S. national phase of International Application No. PCT / US10 / 58007 (filed in 2010);

[0436] and

[0437] U.S. Application No. 13 / 478,511 (filed May 23, 2012).

[0438] Additional exemplary antibodies to PD-L1 (also known as CD274 or B7-H1) and methods of use are disclosed in U.S. Pat. No. 7,943,743; US20130034559, WO2014055897, U.S. Pat. No. 8,168,179; and U.S. Pat. No. 7,595,048. PD-L1 antibodies are being developed as immunomodulators for the treatment of cancer.

[0439] In one embodiment, the antibody to PD-L1 is an antibody disclosed in U.S. Patent No. 8,217, 149. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of the antibody disclosed in U.S. Patent No. 8,217,149.

[0440] In another embodiment, the antibody to PD-L1 is an antibody disclosed in U.S. Application No. 13 / 511,538. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of the antibody disclosed in U.S. Application No. 13 / 511,538.

[0441] In another embodiment, the antibody to PD-L1 is an antibody disclosed in application number 13 / 478,511. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of the antibody disclosed in US application number 13 / 478,511.

[0442] 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 another embodiment, the anti-PD-L1 antibody is MEDI4736.

[0443] Another example of further active ingredient(s) (anti-tumor agents) used in combination or co-administered with the ATF4 pathway inhibitory compounds of the present invention is a PD-1 antagonist.

[0444] "PD-1 antagonist" refers to any chemical compound or biological molecule 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 by immune cells. Alternative names or synonyms 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 aspect or embodiment of the present invention, in which a human individual is to be treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and preferably blocks the binding of human PD-L1 and PD-L2 to human PD-1. The human PD-1 amino acid sequence can be found in NCBI locus number: NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found in NCBI loci number: NP_054862 and NP_079515, respectively.

[0445] PD-1 antagonists that can be used in any aspect of the present invention include monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1, and preferably specifically bind to human PD-1 or human PD-L1. mAbs can be human antibodies, humanized antibodies, or chimeric antibodies, and can include human constant regions. In some embodiments, the human constant region is selected from 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 Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0446] Examples of mAbs that bind to human PD-1 and can be used in various aspects and embodiments of the invention are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004 / 004771, WO2004 / 072286, WO2004 / 056875 and US2011 / 0271358.

[0447] Specific anti-human PD-1 mAbs that can be used as PD-1 antagonists in various aspects and embodiments of the present invention include: MK-3475, a humanized IgG4 mAb having a structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013), and which comprises the heavy chain and light chain amino acid sequences shown in Figure 6; nivolumab, a human IgG4 mAb having a structure described in WHO Drug Information, Vol. 27, No. 1, pages 68-69 (2013), and which comprises the heavy chain and light chain amino acid sequences shown in Figure 7; humanized antibodies h409A11, h409A16 and h409A17, which are described in WO2008 / 156712, and AMP-514, which is being developed by Mediimmune.

[0448] Other PD-1 antagonists that can be used in any aspect and embodiment of the present invention include immunoadhesion that specifically binds to PD-1, and preferably specifically binds to human PD-1, for example, a fusion protein containing an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin molecule). Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010 / 027827 and WO2011 / 066342. Specific fusion proteins that can be used as PD-1 antagonists in the methods of treatment, medicaments, and uses of the present invention include AMP-224 (also known as B7 DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1.

[0449] Other examples of mAbs that bind to human PD-L1 and can be used in the methods of treatment, medicines and uses of the present invention are described in WO2013 / 019906, WO2010 / 077634A1 and US8383796. Specific anti-human PD-L1 mAbs that can be used as PD-1 antagonists in the methods of treatment, medicines and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C.

[0450] KEYTRUDA / pembrolizumab is an anti-PD-1 antibody marketed by Merck for the treatment of lung cancer. The amino acid sequence of pembrolizumab and methods of use thereof are disclosed in U.S. Patent No. 8,168,757.

[0451] Opdivo / Nivolumab is a fully human monoclonal antibody marketed by Bristol Myers Squibb that targets the negative immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1 / PCD-1) with immunoenhancing activity. Nivolumab activates T cells and cell-mediated immune responses against tumor cells or pathogens by binding to and blocking the activation of PD-1 (Ig superfamily transmembrane protein) through its ligands PD-L1 and PD-L2. Activated PD-1 negatively regulates T cell activation and effector function by inhibiting P13k / Akt pathway activation. Other names for nivolumab include: BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence of nivolumab and methods of its use and manufacture are described in U.S. Patent No. US8,008,449 In the public.

[0452] A further example of a further active ingredient or ingredients (anti-neoplastic agents) used in combination or co-administered with the compounds of the present invention is an immunomodulator.

[0453] As used herein, "immunomodulator" refers to any substance that affects the immune system, including monoclonal antibodies. The ICOS binding protein of the present invention can be regarded as an immunomodulator. Immunomodulators can be used as anti-tumor agents for the treatment of cancer. For example, immunomodulators 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 immunomodulators include but are not limited to OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies, and GITR antibodies.

[0454] 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. Patent Nos. 6,984,720 and 7,605,238.

[0455] In another embodiment, the present invention provides a compound of Table 1 or Formula (I) as described herein, or a pharmaceutically acceptable salt or prodrug thereof, for use in treating a disease, condition or disorder associated with hepatitis B virus. The present invention provides a compound of Table 1, or a pharmaceutically acceptable salt or prodrug thereof, for use in treating a disease, condition or disorder associated with hepatitis B virus. Wherein the disease, condition or disorder associated with hepatitis B virus can be jaundice, liver cancer, liver inflammation, liver fibrosis, cirrhosis, liver failure, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome or serum hepatitis.

[0456] In some embodiments, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof is selected from the group of compounds listed in Table 1. In addition, the present invention also encompasses each of these compounds alone and a pharmaceutically acceptable salt thereof.

[0457] In other embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0458] In some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts are selected from the compounds listed in Table 1. The compounds of the present invention can be provided in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases. Therefore, the word "or" in the context of "compound or its pharmaceutically acceptable salt" should be understood to refer to the compound or its pharmaceutically acceptable salt (alternatively), or the compound and its pharmaceutically acceptable salt (combination).

[0459] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and dosage forms suitable for contact with human and animal tissues without excessive toxicity, stimulation or other problems or complications within the scope of reasonable medical judgment. It will be appreciated by those skilled in the art that pharmaceutically acceptable salts of compounds according to Formula I can be prepared. These pharmaceutically acceptable salts can be prepared in situ during the final separation and purification of the compound, or by reacting the purified compound with a suitable base or acid in the form of a free acid or free base, respectively.

[0460] The compounds of the present invention can be prepared according to the following various schemes

[0461] Synthesis method

[0462] The synthetic methods for the provided chemical entities use the following general methods and procedures, using readily available starting materials. It should be understood that when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given; other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary with the specific reactants or solvents used, but those skilled in the art can determine such conditions through routine optimization procedures.

[0463] In addition, the method of the present invention can use a protecting group, which prevents some functional groups from experiencing undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, TW Greene and GM Wuts, Protecting Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999, and many protecting groups are described in the references cited therein.

[0464] In addition, the chemical entities provided may contain one or more chiral centers, and such compounds can be prepared or separated as pure stereoisomers, i.e., single enantiomers or diastereomers, or as stereoisomer enriched mixtures. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of this specification. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, the racemic mixture of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0465] 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 starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts 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 Supplements (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), or obvious modifications thereof.

[0466] Unless otherwise indicated to the contrary, the reactions described herein are carried out at atmospheric pressure, typically at a temperature range of -78°C to 200°C. In addition, unless used or otherwise indicated in the examples, reaction times and conditions should be approximate, for example, at about atmospheric pressure at a temperature range of about -78°C to about 110°C for a period of about 1 to about 24 hours; the average time for overnight reactions is about 16 hours.

[0467] The terms "solvent," "organic solvent," and "inert solvent" each refer to a solvent that is inert under the conditions of the reaction being described therewith, and include, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone ("NMP"), pyridine, and the like.

[0468] If desired, the separation and purification of the chemical entities and intermediates described herein can be achieved by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography or thick layer chromatography, or a combination of these procedures. Suitable separations and separation procedures can be specifically illustrated by reference to the examples below. However, other equivalent separations or separation procedures may also be used.

[0469] When desired, the (R)- and (S)-isomers can be separated by methods known to those skilled in the art, such as by forming diastereomeric salts or complexes, which can be separated, for example, by crystallization or the like; by forming diastereomeric derivatives, which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, such as enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, such as on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. Example

[0470] The following examples are used to more fully describe the mode of making and using the above invention. It should be understood that these embodiments are in no way used to limit the true scope of the present invention, but are only used for illustrative purposes. In the following examples and above synthetic schemes, the following abbreviations have the following meanings. If abbreviations are undefined, then they have their commonly accepted meanings.

[0471]

[0472]

[0473]

[0474]

[0475] Device Description

[0476] NMR Instruments and Data:

[0477] 1 H NMR spectra were recorded at 25 °C on the various instruments listed below, with all spectrometers operating at 400 MHz.

[0478] Bruker AVANCE NEO 400MHz / 54mm instrument (MRCA 400 / 54 / ASC, 16971)

[0479] Bruker AVANCE III 400MHz / 54mm UltraShield Plus, long retention time, instrument (BZH439'400'70I, D335 / 54-6776)

[0480] Bruker AVANCE III 400MHz / 54mm Ascend instrument (BZH 994'400'70I, D315'54-9223)

[0481] Varian 400MR 400MHz / 54mm instrument (MRCA 400 / 54 / ASC, MRYOO20874)

[0482] Bruker AVANCE III 400MHz / 54mm Ascend instrument (BZH 993'400'70I, D315'54-9213)

[0483] Bruker AVANCE III 400MHz / 54mm Ascend instrument (BZH 1157'400'70I, D315'54-9574)

[0484] Bruker AVANCE III 400MHz / 54mm Ascend instrument (BZH 1126'400'70I, D315'54-9527)

[0485] Bruker AVANCE NEO 400MHz / 54mm Ascend instrument (BZH1396'400'70I, D315'54-10089)

[0486] Bruker AVANCE NEO 400MHz / 54mm Ascend instrument (BZH1373'400'70I, D315'54-10026)

[0487] Varian 400MR 400MHz / 54mm instrument (MRCA 400 / 54 / ASC, 20609)

[0488] Varian 400MR 400MHz / 54mm instrument (MRCA 400 / 54 / ASC, 20188)

[0489] Data were processed and analyzed using Topspin2.1 software. If the number of assigned protons is less than the theoretical number of protons in the molecule, it is assumed that the apparently missing signals are masked by solvent and / or water peaks. In addition, if the spectrum is acquired in a proton NMR solvent, exchange of NH and / or OH protons with the solvent will occur, so such signals are usually not observed. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in Hertz (Hz). The splitting pattern describes the apparent multiplicity and is designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad peak). Chemical shifts are referenced to the solvent peak, in 1 In H NMR, CDCl 3 7.27ppm, DMSO-d 6 is 2.50, D 2 O is 4.79, and CD 3 The OD is 3.31ppm.

[0490] Description of analytical LC-MS system and methods used for final products:

[0491] In the following examples, the compounds were characterized by mass spectrometry using the system and operating conditions listed below. When atoms with different isotopes are present and a single mass is quoted, the mass of the compound quoted is the mass of the single isotope (i.e. 35 CI; 79 Br, etc.).

[0492] Instrument: Agilent 1200&6100B

[0493] Scan mode: alternating positive / negative electrospray

[0494] Scanning range: 100-1000amu

[0495] LC conditions: LCMS analysis was performed on a Kinetex C18 50*2.1 mm column (5 um particles). The gradient used was:

[0496] Mobile phase A: water + 0.037% v / v TFA

[0497] Mobile phase B: acetonitrile + 0.018% v / v TFA

[0498]

[0499] UV detection was provided by the summed absorbance signal scanned at 214 nm and 254 nm.

[0500] Analytical LC-MS System and Method Description for Intermediates:

[0501] Method A:

[0502] Instrument: Shimadzu LCMS-2020

[0503] Scan mode: positive electrospray ionization

[0504] Scanning range: 100-1000amu

[0505] LC conditions: LCMS analysis was performed on a Luna-C18 2.0*30 mm (3 μm particles) column. The gradient used was:

[0506] Mobile phase A: water + 0.037% v / v TFA

[0507] Mobile phase B: acetonitrile + 0.018% v / v TFA

[0508]

[0509] UV detection was provided by the summed absorbance signal scanned at 214 nm and 254 nm.

[0510] Method B:

[0511] Instrument: Agilent 1200&6110B

[0512] Scan mode: positive electrospray ionization

[0513] Scanning range: 100-1000amu

[0514] LC conditions: LCMS analysis was performed on an Xbridge Shield RP18 2.1*50mm (5um particles) column. The gradient used was:

[0515] Mobile phase A: 10 mM ammonium bicarbonate / water

[0516] Mobile phase B: acetonitrile

[0517]

[0518] UV detection was provided by the summed absorbance signal scanned at 214 nm and 254 nm.

[0519] Preparative LC-MS System and Method Description:

[0520] Method A:

[0521] Instrument: Waters Fractionlynx system

[0522] Hardware: 2767 Dual Loop Autosampler / Fraction Collector; 2525 Preparative Pump; CFO (Column Fluid Organizer) for column selection; RMA (Waters Reagent Manager) as make-up pump; Waters ZQ Mass Spectrometer; Waters 2996 Photodiode Array Detector.

[0523] Waters ZQ Mass Spectrometer:

[0524] Scan mode: alternating positive / negative electrospray

[0525] Scanning range: 100-2000amu

[0526] LC conditions: Preparative LCMS separation was performed on a HALO C-18, 4.6*50 mm, 2.7 μm, C18 column at 45°C. The gradient used was:

[0527] Mobile phase A: water + 0.1% v / v formic acid

[0528] Mobile phase B: acetonitrile + 0.1% v / v formic acid

[0529]

[0530] UV detection was provided by the summed absorbance signal scanned at 214 nm and 254 nm.

[0531] Method B:

[0532] Instrument: Agilent 1100 LC-MS preparative system:

[0533] Hardware: 1100 series “prepALS” autosampler; 1100 series “PrepPump” for preparative flow gradients and 1100 series “QuatPump” for pumping regulators in preparative flows; 1100 series “MWD” multi-wavelength detector; 1100 series “LC-MSDVL” detector; 2x “Prep-FC” fraction collectors; “Waters RMA” make-up pump; Agilent active splitter.

[0534] Agilent MS operating conditions: capillary voltage: 4000 V (3500 V on ES negative film); Fragmentor / gain: 150 / 1; drying gas flow: 12.0 L / min; gas temperature: 350°C; nebulizer pressure: 50 psig; scan range: 125-800 amu; ionization mode: positive electrospray or negative electrospray.

[0535] LC conditions: Preparative LCMS separation was performed on a HALO C-18, 4.6*50 mm, 2.7 μm, C18 column at 45°C. The gradient used was:

[0536] Mobile phase A: water + 0.1% v / v formic acid

[0537] Mobile phase B: acetonitrile + 0.1% v / v formic acid

[0538]

[0539]

[0540] UV detection was provided by the summed absorbance signal scanned at 214 nm and 254 nm.

[0541] Normal phase chromatography separation:

[0542] Silica gel chromatography was performed on a Biotage instrument using prepackaged disposable SiO 2 Stationary phase column, eluent flow rate range from 15 to 200 mL / min, UV detection (254 and 280 nm).

[0543] Protocol and Experimental Procedure

[0544] The following schemes and procedures illustrate how to prepare the compounds of the present invention. The specific solvents and reaction conditions mentioned are also illustrative only and are not intended to be limiting. The compounds not described are either commercially available or can be easily prepared by those skilled in the art using available starting materials. The examples disclosed herein are for illustrative purposes only and are not intended to limit the compounds of the scope of the present invention.

[0545] I. Preparation of bisphenol raw material:

[0546] Bisphenol-045, [1,1'-Biphenyl]-3,3'-diol synthesis.

[0547]

[0548] At 15°C in N 2(3-Hydroxyphenyl)boronic acid (658 mg, 4.77 mmol, 1.05 eq), 3-iodophenol (1.00 g, 4.55 mmol, 1 eq) and K 2 CO 3 (2.51 g, 18.2 mmol, 4 eq) in H 2 Pd / C (300 mg, 10% purity) was added to the solution in N O (50 mL) in one portion. 2 The mixture was stirred at 80°C for 2 h. LCMS indicated that phenol was completely consumed and the desired mass was detected. The mixture was filtered and the filtrate was acidified to pH = 4-5 by adding aqueous HCl (1.0 M). The mixture was extracted with EtOAc (50 mL*3) and the combined organic phases were washed with brine (30 mL) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound (897 mg, 4.82 mmol, quantitative yield) as a yellow oil.

[0549] LCMS (ES, m / z): 187.0 [M+H] + .

[0550] Bisphenol-046, [1,1'-Biphenyl]-3,4'-diol synthesis.

[0551]

[0552] At 15°C in N 2 (4-Hydroxyphenyl)boronic acid (1.32 g, 9.55 mmol, 1.05 eq), 3-iodophenol (2 g, 9.09 mmol, 1 eq) and K 2 CO 3 (5.03 g, 36.4 mmol, 4 eq) in H 2 O (100mL) was added with Pd / C (300mg, 10% purity) in one portion. The mixture was stirred at 80°C for 2h. LCMS showed that phenol was completely consumed and the desired mass was detected. The mixture was filtered and the filtrate was acidified to pH = 4-5 by adding HCl aqueous solution (1.0M). The mixture was extracted with EtOAc (50mL*3) and the combined organic phase was washed with brine (30mL). 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound (1.9 g, 10.2 mmol, quantitative yield) as a brown solid.

[0553] LCMS (ES, m / z): 185.0 [MH] - .

[0554] Bisphenol-055, 1,2- Bis(4-hydroxyphenyl)ethane-1,2-dione synthesis.

[0555]

[0556] 1,2-Bis(4-methoxyphenyl)ethane-1,2-dione (2.00 g, 7.40 mmol, 1 eq) was dissolved in HBr / AcOH (40 mL, 33% HBr) and H 2 O (15 mL). The reaction mixture was stirred at 140 ° C for 16 h, after which time LCMS indicated that the reaction was complete. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL * 3). The organic phases were combined, washed with water (50 mL * 3), and purified by Na 2 SO 4 Dry and filter. The filtrate was concentrated under vacuum to give the crude title compound (1.6 g, 6.61 mmol, 89% yield) as a red solid.

[0557] LCMS (ES, m / z): 241.0 [MH] - .

[0558] Bisphenol-139, 5-Fluorobenzene-1,3-diol synthesis.

[0559]

[0560] at -65°C in N 2 To a solution of 1-fluoro-3,5-dimethoxybenzene (1.50 g, 9.61 mmol, 1 eq) in DCM (50 mL) was added BBr dropwise over 1.5 h. 3 (5.53 g, 22.1 mmol, 2.13 mL, 2.3 eq) in DCM (50 mL). The reaction mixture was stirred at 15 °C for 10.5 h, after which LCMS indicated complete consumption of the starting material and formation of the desired mass of product. The mixture was cooled in an ice / water bath, 60 mL of methanol was slowly added, and the organic solvent was evaporated under vacuum. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was separated and purified by Na 2 SO 4 The reaction mixture was dried and evaporated to dryness to give the crude product 5-fluorobenzene-1,3-diol (1.2 g, 9.37 mmol, yield 97.6%) as a red solid.

[0561] LCMS (ES, m / z): 127.1 [MH] - .

[0562] Bisphenol-052, 4,4'-(Ethane-1,2-diyl)diphenol synthesis.

[0563]

[0564] Step 1 (of 2): 1,2-Bis(4-methoxyphenyl)ethane synthesis.

[0565] To a solution of 1,2-bis(4-methoxyphenyl)ethan-1-one (5 g, 19.5 mmol, 1 eq) in TFA (20 mL) was added Et 3 SiH (11.3 g, 97.5 mmol, 15.6 mL, 5 eq). The mixture was stirred at 20°C for 12 h. TLC (petroleum ether / ethyl acetate = 5:1, R f =0.88) showed that the reaction was complete. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (80 mL*3). 3 The combined organic layers were washed until pH = 8-9. The organic layer was washed with anhydrous Na 2 SO 4 Drying, filtering and concentration gave a mixture of solid and oil. The material was triturated with petroleum ether (50 mL), filtered and dried to give the title compound (4.4 g, 18.2 mmol, 93% yield) as a white solid.

[0566] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.11-6.92 (m, 4H), 6.79-6.63 (m, 4H), 3.70 (s, 6H), 2.75 (s, 4H).

[0567] Step 2 (of 2): 4,4'-(Ethane-1,2-diyl)diphenol synthesis.

[0568] To a solution of 1,2-bis(4-methoxyphenyl)ethane (4.40 g, 18.2 mmol, 1 eq) in DCM (100 mL) was added BBr at 0 °C. 3 (18.2 g, 72.6 mmol, 7.00 mL, 4 eq). The mixture was stirred at 20 °C for 16 h, after which LCMS indicated the reaction was complete. The reaction mixture was poured into water (200 mL) with stirring, and the separated aqueous layer was extracted with EtOAc (100 mL*3). The combined organic extracts were washed with water (50 mL*3) and purified by Na 2 SO 4 Drying and removal of the solvent under vacuum gave the title compound (3.84 g, 17.9 mmol, 98.7% yield) as a light yellow solid.

[0569] LCMS (ES, m / z): 213.1 [MH] - .

[0570] II. Preparation of dibromide starting materials:

[0571] Dibromo-190, 1,4-Bis(bromomethyl)-2,3,5,6-tetrafluorobenzene Synthesis 。

[0572]

[0573] A mixture of 1,2,4,5-tetrafluoro-3,6-dimethylbenzene (0.9 g, 5.05 mmol, 1 eq), NBS (2.70 g, 15.16 mmol, 3 eq) and BPO (184 mg, 758 umol, 0.15 eq) in DCM (40 mL) was stirred at 35 °C for 12 h under irradiation with a 150 W lamp. TLC (petroleum ether / ethyl acetate = 5:1, R f =0.61) indicating complete consumption of the starting material and formation of new spots. The reaction mixture was poured into H 2 O (50 mL) and extracted with DCM (50 mL * 2). The combined organic phase was washed with brine (50 mL) and 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 2:1) to give 1,4-bis(bromomethyl)-2,3,5,6-tetrafluorobenzene (1.40 g, 4.17 mmol, yield 82.5%) as a white solid.

[0574] 1 H NMR (400 MHz, chloroform-d) δ=4.52 (s, 4H).

[0575] III. Preparation of diamine linkers, Method AM:

[0576] Diamine Linker, Method A:

[0577] Connector_A-017, 1,3-phenylenebis(((R)-3-methylpiperazin-1-yl)methanone) synthesis.

[0578]

[0579] Step 1 (of 2): Di-tert-butyl 4,4'-isophthaloyl (2R,2'R)-bis(2-methylpiperazine-1-carboxylic acid ester) synthesis.

[0580] To a solution of (R)-tert-butyl 2-methylpiperazine-1-carboxylate (1.00 g, 5.20 mmol) in dichloromethane (30 mL) was slowly added triethylamine (1.12 g, 11.1 mmol) followed by slowly adding isophthaloyl chloride (0.50 g, 2.5 mmol). The mixture was stirred at room temperature overnight, concentrated to dryness, and purified by flash chromatography (SiO 2 , dichloromethane / methanol=15:1) to give the title compound (1.3 g, 2.4 mmol, 98% yield) as a white solid.

[0581] LCMS (ES, m / z): 553.8 [M+Na] + .

[0582] 1 H NMR (400MHz, DMSO) δppm 7.59-7.31 (m, 4H), 4.45-4.00 (m, 4H), 3.95-3.33 (m, 4H), 3.30-2.80 (m, 6H), 1.41 (s, 18H), 1.06 (d, J = 48Hz, 6H).

[0583] Step 2 (of 2): 1,3-phenylenebis(((R)-3-methylpiperazin-1-yl)methanone) synthesis.

[0584] To a solution of di-tert-butyl 4,4'-isophthaloyl (2R,2'R)-bis(2-methylpiperazine-1-carboxylate) (1.3 g, 2.4 mmol) in dichloromethane (10 mL) was added HCl (10 mL, 4 M in dioxane). The resulting mixture was stirred at room temperature overnight and concentrated to dryness to give the crude title compound (0.90 g, 2.2 mmol, 91% yield, 2HCl) as a white solid.

[0585] LCMS (ES, m / z): 330.9 [M+H] + .

[0586] Linker_A-167, 1,3-Bis(((R)-3-methylpiperazin-1-yl)sulfonyl)benzene synthesis.

[0587]

[0588] The title compound was prepared according to the two-step procedure of Method A from (R)-tert-butyl 2-methylpiperazine-1-carboxylate and benzene-1,3-disulfonyl dichloride.

[0589] LCMS (ES, m / z): 402.8 [M+H] + .

[0590] Diamine Linker Synthesis, Method B: Linker_D-192, (2S,2'S)-2,2'-(((5-methyl-1,3-phenylene) Bis(oxy)bis(methylene)dimorpholine synthesis.

[0591]

[0592] Step 1 (of 2): Di-tert-butyl 2,2'-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene)) (2S,2'S)-Bis(morpholine-4-carboxylate) synthesis.

[0593] At 0°C in N 2 To (S)-2-(hydroxymethyl)morpholine-4-carboxylic acid tert-butyl ester (500 mg, 2.30 mmol, 2.5 eq), 5-methylbenzene-1,3-diol (114 mg, 920 umol, 1 eq) and PPh 3 To a mixture of 1,4-diol (603 mg, 2.30 mmol, 2.5 eq) in THF (4 mL) was added DIAD (465 mg, 2.30 mmol, 447 uL, 2.5 eq) in one portion. The mixture was stirred at 60 °C for 12 h, after which LCMS indicated that the diol had been completely consumed and the target mass of product had been formed. The mixture was concentrated to dryness and purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to purify the residue. The impure product was re-purified by reverse phase MPLC (40 g ISCO reverse phase (C18) flash column; mobile phase: [water-ACN]; B%: 0-55% @ 30 mL / min) to give the title compound (410 mg, 784 umol, yield 43%) as a white solid.

[0594] LCMS (ES, m / z): 423.2 [M-Boc+H + ]

[0595] Step 2 (of 2): (2S,2'S)-2,2'-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene)) Dimorpholine synthesis.

[0596] To a solution of di-tert-butyl 2,2'-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene))(2S,2'S)-bis(morpholine-4-carboxylate) (410 mg, 784 umol, 1 eq) in EtOAc (1.5 mL) was added HCl / EtOAc (4M, 5 mL, 25 eq). The mixture was stirred at 15 °C for 2 h, after which LCMS indicated that the starting material was completely consumed and the target mass of product was formed. The reaction mixture was filtered to give the title compound (290 mg, 734 umol, 94% yield, 2HCl) as a yellow solid.

[0597] LCMS (ES, m / z): 323.3 [M+H] + .

[0598] Diamine Linker Synthesis, Method C:

[0599] Connector_D-061, 1,4-Bis(2-(4-(((S)-morpholin-2-yl)methoxy)phenyl)propan-2-yl)benzene synthesis.

[0600]

[0601] Step 1 (of 2): Di-tert-butyl 2,2'-((((1,4-phenylenebis(propane-2,2-diyl))bis(4,1-phenylene 1-(2-Methyl)- ... synthesis.

[0602] Two reactions were performed in parallel:

[0603] At 15°C in N 2 To a mixture of tert-butyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate (392 mg, 1.80 mmol, 2.5 eq) and 4,4′-(1,4-phenylenebis(propane-2,2-diyl))diphenol (250 mg, 722 umol, 1 eq) in toluene (4 mL) was added (tributylphosphoranylidene)acetonitrile (435 mg, 1.80 mmol, 2.5 eq). The mixture was heated at 80° C. under N 2 Stir for 12h under atmosphere. LCMS shows that diol has been completely consumed and the product of the desired mass is detected. The two reactions are combined and concentrated in vacuo. The residue is purified by column chromatography (SiO2, petroleum ether / ethyl acetate=1 / 0 to 0 / 1) to obtain an impure product. The material is re-purified by reversed-phase MPLC (80g ISCO reversed-phase (C18) fast column; mobile phase: [water-ACN]; B%: 0-60%@50mL / min) to obtain the title compound (280mg, 376umol, 26% yield, impure), which is a yellow oil.

[0604] TLC (petroleum ether / ethyl acetate=2:1): R f =0.33

[0605] LCMS (ES, m / z): 767.4 [M+Na] + .

[0606] Step 2 (of 2): 1,4-Bis(2-(4-(((S)-morpholin-2-yl)methoxy)phenyl)propan-2-yl)benzene synthesis.

[0607] To a solution of di-tert-butyl 2,2'-((((1,4-phenylenebis(propane-2,2-diyl))bis(4,1-phenylene))bis(oxy))bis(methylene))(2S,2'S)-bis(morpholine-4-carboxylate) (280 mg, 376 umol, 1 eq) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 2 mL). The mixture was stirred at 15 °C for 2 h. LCMS indicated that the starting material was completely consumed and the desired mass of product was detected. The resulting solid was filtered off to give the title compound (220 mg, 356 umol, 95% yield, 2HCl) as a white solid.

[0608] LCMS (ES, m / z): 545.3 [M+H] + .

[0609] Diamine Linker Synthesis, Method D:

[0610] Linker_D-147, Di-tert-butyl 2,2'-(((1,2-phenylenebis(methylene))bis(oxy))bis(methylene) (2S,2'S)-bis(morpholine-4-carboxylate) synthesis.

[0611]

[0612] Step 1 (of 2): Di-tert-butyl 2,2'-(((1,2-phenylenebis(methylene))bis(oxy))bis(methylene (2S,2'S)-bis(morpholine-4-carboxylate) synthesis.

[0613] NaH (197 mg, 4.93 mmol, 60% purity, 2.6 eq) was added to a solution of compound (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1.03 g, 4.74 mmol, 2.5 eq) in THF (10 mL) at 0°C, and the mixture was stirred at 0°C for 0.5 h. 1,2-Bis(bromomethyl)benzene (500 mg, 1.89 mmol, 255 uL, 1 eq) was added to the mixture and stirred at 60°C for 12 h. LCMS showed that the starting material was completely consumed and the desired mass of product was detected. 2 O (15 ml) was added to the mixture and the mixture was extracted with EtOAc (15 mL*2). The combined organic layers were washed with brine (15 mL) and purified by Na 2 SO 4 The filtrate was concentrated under reduced pressure to give the title compound (1.3 g, 2.42 mmol, quantitative yield) as a yellow oil.

[0614] LCMS (ES, m / z): 559.3 [M+Na] + .

[0615] Step 2 (total 2 steps): Connecting base_D-147, Di-tert-butyl 2,2'-(((1,2-phenylenebis(methylene))bis(oxy 1-(2-Methylene)-Bis(Morpholine-4-carboxylate)synthesis.

[0616] To a solution of di-tert-butyl 2,2'-(((1,2-phenylenebis(methylene))bis(oxy))bis(methylene))(2S,2'S)-bis(morpholine-4-carboxylate) (1 g, 1.86 mmol, 1 eq) in EtOAc (5 mL) was added HCl / EtOAc (4 M, 5 mL) at 15 °C. The mixture was stirred at 15 °C for 2 h. LCMS showed that the starting material was completely consumed and the desired mass of product was formed. The mixture was filtered and the filter cake was dried to give the title compound (604 mg, 1.48 mmol, 79% yield, 2HCl).

[0617] LCMS (ES, m / z): 337.2 [M+H] + .

[0618] Bisamine Linker Synthesis, Method E:

[0619] Linker_D-088, 1,6- Bis(((S)-morpholin-2-yl)methoxy)hexane-2,4-diyne synthesis.

[0620]

[0621] Step 1 (of 3): (S)-tert-butyl 2-((prop-2-yn-1-yloxy)methyl)morpholine-4-carboxylate synthesis.

[0622] NaH (276 mg, 6.90 mmol, 60% purity, 1.5 eq) was added to a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (1.00 g, 4.60 mmol, 1 eq) in THF (10 mL) at 0°C and the mixture was stirred at 15°C for 0.5 h. 3-Bromoprop-1-yne (1.21 g, 9.20 mmol, 2 eq) was added to the mixture and stirred at 15°C for 12 h. TLC indicated that a new product was formed and LCMS indicated that the desired mass was detected. Saturated NH 4 Cl aqueous solution (5 mL) was added to the mixture, and the mixture was extracted with EtOAc (5 mL*2). The combined organic layer was washed with brine (10 mL) and purified by Na 2 SO 4 The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=20 / 1 to 5 / 1) to give the title compound product (0.95 g, 3.72 mmol, yield 63%) as a yellow oil.

[0623] TLC (petroleum ether / ethyl acetate=5:1): R f =0.43

[0624] LCMS (ES, m / z): 156.1 [M-Boc+H] + .

[0625] Step 2 (of 3): Di-tert-butyl 2,2'-((hexane-2,4-diyn-1,6-diylbis(oxy))bis(methylene)) (2S,2'S)-Bis(morpholine-4-carboxylate) synthesis.

[0626] (S)-tert-butyl 2-((prop-2-yn-1-yloxy)methyl)morpholine-4-carboxylate (450 mg, 1.76 mmol, 1 eq), CuI (67 mg, 352 umol, 0.2 eq), NiCl 2 6H 2 A mixture of O (84 mg, 353 umol, 0.2 eq), TMEDA (82 mg, 705 umol, 106 uL, 0.4 eq) and TEA (892 mg, 8.81 mmol, 1.23 mL, 5 eq) in THF (5 mL) was stirred at 15 °C under aerobic conditions for 12 h. TLC showed that new products were formed. The reaction was concentrated in vacuo and the residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5:1 to 1:1) to give the title compound (0.76 g, 1.49 mmol, yield 38%) as an oil.

[0627] TLC (petroleum ether / ethyl acetate=2:1): R f =0.43

[0628] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 4.40-4.18 (m, 4H), 4.01-3.79 (m, 6H), 3.67-3.49 (m, 8H), 3.14-2.55 (m, 4H), 2.07-2.03 (m, 1H), 1.48 (s, 18H).

[0629] Step 3 (total 3 steps): Connecting base_D-088, 1,6-Bis(((S)-morpholin-2-yl)methoxy)hexane-2,4-diyne synthesis.

[0630] HCl / EtOAc (4M, 2mL, 5.35eq) was added to a solution of di-tert-butyl 2,2'-((hexamethylene-2,4-diyne-1,6-diylbis(oxy))bis(methylene))(2S,2'S)-bis(morpholine-4-carboxylate) (0.76g, 1.49mmol, 1eq) in EtOAc (6mL) at 15°C, and the mixture was stirred at 15°C for 12h. LCMS indicated conversion to the target mass of product. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (0.27g, 876umol, 59% yield) as a white solid.

[0631] LCMS (ES, m / z): 309.3 [M+H] + .

[0632] 1 H NMR (400 MHz, methanol-d 4 )δ=4.88(s,14H),4.38-4.26(m,4H),4.14-4.10(m,1H),4.08(d,J=3.3Hz,1H),3.94-3.87(m,2H),3. 86-3.78(m,2H),3.68-3.58(m,4H),3.36-3.32(m,2H),3.29-3.25(m,2H),3.19-3.11(m,2H),3.04(br t,J=12.0Hz,2H).

[0633] The following bisamine linkers were prepared from (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate according to Method B, C, D or E, as shown in Table 4:

[0634] Table 4.

[0635]

[0636]

[0637]

[0638]

[0639] Bisamine Linker Synthesis, Method F:

[0640] Linker_E-079, (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(morpholine-2-carboxamide) synthesis.

[0641]

[0642] Step 1 (of 2): Di-tert-butyl 2,2'-(((1,4-phenylenebis(methylene))bis(azanediyl))bis(carbonyl) (2S,2'S)-bis(morpholine-4-carboxylate) synthesis.

[0643] To a solution of (S)-4-(tert-butyloxycarbonyl)morpholine-2-carboxylic acid (2.00 g, 8.65 mmol, 2.2 eq), 1,4-phenylenediamine (535 mg, 3.93 mmol, 1 eq) in DCM (20 mL) was added DIEA (2.03 g, 15.7 mmol, 2.74 mL, 4 eq) and HATU (3.74 g, 9.83 mmol, 2.5 eq). The mixture was stirred at 20 °C for 12 h, after which LC-MS indicated conversion to the target mass of product. The reaction mixture was poured into saturated NH 4Cl aqueous solution (100 mL) and extracted with DCM (50 mL * 3). The combined organic phase was washed with brine (100 mL) and 2 SO 4 The residue was mixed with MeOH (20 ml) and H 2 O (20 ml) was triturated at 15° C. for 30 min. The mixture was filtered, and the filter cake was dried to give the title compound (2.2 g, 3.91 mmol, 99% yield) as a white solid.

[0644] LCMS (ES, m / z): 463.2 [M-Boc+H] + .

[0645] 1 H NMR (400 MHz, DMSO-d 6 )δ=8.37(br t,J=6.2Hz,2H),7.16(s,4H),4.24(br d,J=6.0Hz,4H),4.00(br d,J=11.6Hz,2H),3.89(dd,J=3.1,10.4Hz,4H),3.71(br d, J=13.0Hz, 2H), 3.48 (dt, J=2.5, 11.4Hz, 2H), 3.03-2.70 (m, 4H), 1.41 (s, 18H).

[0646] Step 2 (of 2): (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(morpholine-2-carboxamide) synthesis.

[0647] To a mixture of di-tert-butyl 2,2'-(((1,4-phenylenebis(methylene))bis(azanediyl))bis(carbonyl))(2S,2'S)-bis(morpholine-4-carboxylate) (0.20 g, 355 umol, 1 eq) in DCM (4 mL) was added HCl / dioxane (4 M, 4 mL) at 15 °C. The mixture was stirred at 15 °C for 1 hr. LCMS indicated that the starting material was consumed and the desired mass of product was formed. The mixture was filtered and the filter cake was dried to give the title compound (168 mg, 386 umol, quantitative yield, 2 HCl) as a white solid.

[0648] LCMS (ES, m / z): 363.2 [M+H] + .

[0649] According to Method F, the following diamine linkers were prepared from (2S)-4-tert-butoxycarbonylmorpholine-2-carboxylic acid and diamines, as shown in Table 5:

[0650] Table 5.

[0651]

[0652] Bisamine Linker Synthesis, Method G:

[0653] Linker_E-182, (2S,2'S)-N,N'-(Hexa-2,4-diyne-1,6-diyl)bis(morpholine-2-carboxamide) synthesis.

[0654]

[0655] Step 1 (of 3): (S)-tert-Butyl 2-(prop-2-yn-1-ylcarbamoyl)morpholine-4-carboxylate synthesis.

[0656] To a solution of (2S)-4-tert-butyloxycarbonylmorpholine-2-carboxylic acid (2.00 g, 8.65 mmol, 1 eq) and prop-2-yn-1-amine (524 mg, 9.51 mmol, 609 uL, 1.1 eq) in DCM (20 mL) was added DIEA (3.35 g, 25.9 mmol, 4.52 mL, 3 eq) and HATU (4.28 g, 11.2 mmol, 1.3 eq). The mixture was stirred at 20 °C for 12 h, after which the desired mass of product was detected by LC-MS. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1 / 0 to 0 / 1) to give the title compound (2.59 g, 9.65 mmol, quantitative yield) as a yellow solid.

[0657] TLC (petroleum ether / ethyl acetate = 1:1) R f =0.53

[0658] Step 2 (of 3). Di-tert-butyl 2,2'-((hexane-2,4-diyne-1,6-diylbis(azanediyl))bis(carbonyl) (2S,2'S)-bis(morpholine-4-carboxylate) synthesis.

[0659] (S)-2-(prop-2-yn-1-ylcarbamoyl)morpholine-4-carboxylic acid tert-butyl ester (1.00 g, 3.73 mmol, 1 eq), CuI (71 mg, 373 umol, 0.1 eq), NiCl 2 6H 2 A mixture of O (89 mg, 373 umol, 0.1 eq), TMEDA (86.6 mg, 745 umol, 112 uL, 0.2 eq) and TEA (1.89 g, 18.6 mmol, 2.59 mL, 5 eq) in THF (10 mL) was stirred at 15 ° C under aerobic conditions for 12 h. LC-MS showed that the starting material was consumed and the target mass of the product was formed. Water (30 ml) was added to the mixture, and the mixture was extracted with EtOAc (50 mL*2). The combined organic layer was washed with brine (10 mL) and purified by Na 2 SO 4Dry, filter, and concentrate under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 0:1) to give the title compound (690 mg, 1.29 mmol, yield 35%) as a yellow solid.

[0660] TLC (petroleum ether / ethyl acetate=1:1): R f =0.24

[0661] LCMS (ES, m / z): 435.2 [M-Boc+H] + .

[0662] 1 H NMR (400 MHz, chloroform-d) δ = 6.82-6.69 (m, 2H), 4.41-4.26 (m, 2H), 4.15 (d, J = 5.5 Hz, 4H), 3.99-3.87 (m, 5H), 3.65-3.51 (m, 2H), 2.97-2.82 (m, 2H), 2.81-2.66 (m, 2H), 1.61 (s, 1H), 1.52-1.32 (m, 18H).

[0663] Step 3 (total 3 steps): Connecting base_E-182, (2S,2'S)-N,N'-(hexane-2,4-diyne-1,6-diyl)bis(morphine) 2-Methyl-1-phenoxy-1-ol synthesis.

[0664] To a solution of di-tert-butyl 2,2'-((hexamethylene-1,6-diylbis(azanediyl))bis(carbonyl))(2S,2'S)-bis(morpholine-4-carboxylate) (200 mg, 374 umol, 1 eq) in EtOAc (2 mL) was added HCl / dioxane (4 M, 2 mL, 21 eq). The mixture was stirred at 20 ° C for 0.5 h. LC-MS showed that the starting material was consumed and the target mass of product was formed. The reaction mixture was filtered and the filter cake was dried to give the title compound (110 mg, 270 umol, 72.2% yield, 2HCl) as a white solid.

[0665] LCMS (ES, m / z): 335.2 [M+H] + .

[0666] Bisamine Linker Synthesis, Method H:

[0667] Connector_F-157, N1,N4-Bis(2-(piperidin-4-yl)ethyl)terephthalamide synthesis.

[0668]

[0669] Step 1 (total 2 steps): Connecting base_F-157-Boc, Di-tert-butyl 4,4'-((terephthaloylbis(azanediol) bis(ethane-2,1-diyl)bis(piperidine-1-carboxylate) synthesis.

[0670] To a solution of terephthalic acid (661 mg, 3.98 mmol, 1 eq) in DCM (80 mL) was added tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (2.00 g, 8.76 mmol, 2.2 eq), DIEA (2.06 g, 15.9 mmol, 2.77 mL, 4 eq) and HATU (3.78 g, 9.95 mmol, 2.5 eq). The mixture was stirred at 15 °C for 12 h. LC-MS showed that terephthalic acid was completely consumed and a major peak of the desired mass was detected. The mixture was concentrated to dryness and purified by column chromatography (SiO 2 , ethyl acetate / methanol=1 / 0 to 3 / 1) to give the title compound (5.19 g, 8.85 mmol, quantitative yield) as a white solid.

[0671] LCMS (ES, m / z): 609.6 [M+Na] + .

[0672] Step 2 (total 2 steps): Connecting base_F-157, N1,N4-Bis(2-(piperidin-4-yl)ethyl)terephthalamide synthesis.

[0673] To a solution of di-tert-butyl 4,4'-((terephthaloylbis(azanediyl))bis(ethane-2,1-diyl))bis(piperidine-1-carboxylate) (1.00 g, 1.70 mmol, 1 eq) in EtOAc (4 mL) was added HCl / EtOAc (4 M, 6 mL). The mixture was stirred at 15 °C for 1 h. LC-MS showed complete consumption of the starting material to form a major peak of the desired mass. The solid was filtered, washed with EtOAc (3*1 mL) and dried under high vacuum to give the title compound (480 mg, 731 umol, 61.3% yield, 2HCl) as a white solid.

[0674] LCMS (ES, m / z): 387.4 [M+H] + .

[0675] Diamine Linker Synthesis, Method I:

[0676] Connector_F-154, 1,1'-(1,4-phenylene)bis(N-methyl-N-(piperidin-4-ylmethyl)methanamine) synthesis.

[0677]

[0678] Step 1 (of 2): 4-[[[4-[[(1-tert-Butyloxycarbonyl-4-piperidinyl)methyl-methyl-amino]methyl]benzene tert-butyl]methyl-methyl-amino]methyl]piperidine-1-carboxylate synthesis.

[0679] To a solution of 1,4-bis(bromomethyl)benzene (262 mg, 995 umol, 1 eq) in acetonitrile (10 mL) was added tert-butyl 4-(methylaminomethyl)piperidine-1-carboxylate (500 mg, 2.19 mmol, 2.2 eq) and DIEA (514 mg, 3.98 mmol, 693 uL, 4 eq). The mixture was stirred at 15 °C for 14 h, after which LC-MS indicated that the starting material was completely consumed to form a product of the target mass. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO 2 , ethyl acetate / methanol) = 1:0 to 1:3) to give the title compound (360 mg, 644 umol, yield 65%) as a yellow oil.

[0680] TLC (ethyl acetate / methanol=10:1): R f =0.4

[0681] LCMS (ES, m / z): 559.6 [M+H] + .

[0682] Step 2 (of 2): N-methyl-1-[4-[[methyl(4-piperidinylmethyl)amino]methyl]phenyl]-N-(4-piperidinylmethyl)amino]methyl]phenyl (piperidinylmethyl)methylamine synthesis.

[0683] To a solution of 4-[[[4-[[(1-tert-butyloxycarbonyl-4-piperidinyl)methyl-methyl-amino]methyl]phenyl]methyl-methyl-amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (360mg, 644umol, 1eq) in EtOAc (4mL) was added HCl / EtOAc (4M, 4mL). The mixture was stirred at 15°C for 1hr. LC-MS showed that the starting material was completely consumed and the target mass of product was formed. The solid was filtered off, washed with EtOAc (3)*1mL) and dried under high vacuum to give the title compound (410mg, 950umol, quantitative yield, 2HCl) as a white solid.

[0684] LCMS (ES, m / z): 359.4 [M+H] + .

[0685] Diamine Linker Synthesis, Method J:

[0686] Connector_F-158, N1,N4-Dimethyl-N1,N4-bis(2-(piperidin-4-yl)ethyl)terephthalamide synthesis.

[0687]

[0688] Step 1 (of 2): Di-tert-butyl 4,4'-((terephthaloylbis(methylazanediyl))bis(ethane-2,1- Bis(piperidin-1-carboxylate) synthesis.

[0689] To a solution of Linker_F-157-Boc, di-tert-butyl 4,4'-((terephthaloylbis(azanediyl))bis(ethane-2,1-diyl))bis(piperidine-1-carboxylate) (1.00 g, 1.70 mmol, 1 eq) in DMF (5 mL) was added NaH (170 mg, 4.26 mmol, 60% purity, 2.5 eq) at 0°C. The mixture was stirred at 0°C for 0.5 h, then iodomethane (605 mg, 4.26 mmol, 265 uL, 2.5 eq) was added at 0°C. The mixture was stirred at 0°C for 0.5 h, then at 25°C for 1 hr. LC-MS showed that the starting material was completely consumed to form a single product of the target mass. The reaction mixture was washed with saturated NH 4 The mixture was quenched with aqueous Cl solution (15 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (10 mL) and purified by Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue, which was purified by column chromatography (SiO 2 , ethyl acetate / methanol=1 / 0 to 3 / 1) to give the title compound (165 mg, 268 umol, 16% yield) as a yellow oil.

[0690] LCMS (ES, m / z): 637.6 [M+Na] + .

[0691] Step 2 (total 2 steps): Connecting base_F-158, N1,N4-dimethyl-N1,N4-bis(2-(piperidin-4-yl)ethyl) Phthalic acid amide synthesis.

[0692] To a solution of di-tert-butyl 4,4'-((terephthaloylbis(methylazanediyl))bis(ethane-2,1-diyl))bis(piperidine-1-carboxylate) (165 mg, 268 umol, 1 eq) in EtOAc (2 mL) was added HCl / EtOAc (4 M, 3 mL). The mixture was stirred at 15 °C for 1 h. LC-MS showed that the starting material was completely consumed, forming a single peak of the target mass. The solid was filtered, washed with EtOAc (3*1 mL), and dried under high vacuum to give the title compound (117 mg, crude, 2HCl) as a white solid.

[0693] LCMS (ES, m / z): 415.4 [M+H] + .

[0694] Diamine Linker Synthesis, Method K:

[0695] Connector_F-159, N,N'-(1,4-phenylenebis(methylene))bis(2-(piperidin-4-yl)acetamide) synthesis.

[0696]

[0697] Step 1 (of 2): 4-[2-[[4-[[[2-(1-tert-Butyloxycarbonyl-4-piperidinyl)acetyl]amino]methyl]benzene tert-butyl]methylamino]-2-oxo-ethyl]piperidine-1-carboxylate synthesis.

[0698] To a solution of 2-(1-tert-butyloxycarbonyl-4-piperidinyl)acetic acid (2.00 g, 8.22 mmol, 2.2 eq) in DCM (5 mL) was added [4-(aminomethyl)phenyl]methylamine (509 mg, 3.74 mmol, 1 eq), DIEA (1.93 g, 14.9 mmol, 2.60 mL, 4 eq) and HATU (3.55 g, 9.34 mmol, 2.5 eq). The mixture was stirred at 15 °C for 12 hr. LC-MS indicated complete conversion to the target mass of product. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO 2 , ethyl acetate / methanol=1:0 to 3:1) to give the title compound (5.49 g, 9.36 mmol, quantitative yield) as a white solid.

[0699] TLC (ethyl acetate / methanol=10:1): R f =0.4

[0700] LCMS (ES, m / z): 587.6 [M+H] + .

[0701] Step 2 (total 2 steps): Connecting base_F-159, N,N'-(1,4-phenylenebis(methylene))bis(2-(piperidin-4-yl) Acetamide) synthesis.

[0702] To a solution of tert-butyl 4-[2-[[4-[[[2-(1-tert-butyloxycarbonyl-4-piperidinyl)acetyl]amino]methyl]phenyl]methylamino]-2-oxo-ethyl]piperidine-1-carboxylate (1.00 g, 1.70 mmol, 1 eq) in EtOAc (4 mL) was added HCl / EtOAc (4 M, 6 mL). The mixture was stirred at 15 °C for 1 h, after which LCMS indicated complete conversion to the target mass of product. The solid was filtered, washed with EtOAc (3)*1 mL) and dried under high vacuum to give the title compound (440 mg, 670 umol, 56.2% yield, 2HCl) as a white solid.

[0703] LCMS (ES, m / z): 387.4 [M+H] + .

[0704] Diamine Linker Synthesis, Method L:

[0705] Connector_F-161, 1,3-Bis(piperidin-4-ylmethoxy)benzene synthesis.

[0706]

[0707] Step 1 (of 2): Di-tert-butyl 4,4'-((1,3-phenylenebis(oxy))bis(methylene))bis(piperidin-1-yl) Formate) synthesis.

[0708] DIAD (939 mg, 4.64 mmol, 903 uL, 2.5 eq) was added to a mixture of benzene-1,3-diol (204 mg, 1.86 mmol, 310 uL, 1 eq), tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.00 g, 4.64 mmol, 2.5 eq) and PPh3 (1.22 g, 4.64 mmol, 2.5 eq) in THF (15 mL) at 0 °C, and then stirred at 60 °C for 12 h. LC-MS indicated that the starting material was completely consumed, forming a single peak of the target mass. The reaction mixture was purified by H 2 O (15 mL) and extracted with ethyl acetate (15 mL * 2). The combined organic layer was washed with brine (30 mL) and purified by Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1:0 to 3:1) to give the title compound (513 mg, 1.02 mmol, yield 54.7%) as a white solid.

[0709] LCMS (ES, m / z): 505.5 [M+H] + .

[0710] Step 2 (of 2): 1,3-Bis(piperidin-4-ylmethoxy)benzene synthesis.

[0711] To a solution of di-tert-butyl 4,4'-((1,3-phenylenebis(oxy))bis(methylene))bis(piperidine-1-carboxylate) (690 mg, 1.37 mmol, 1 eq) in EtOAc (4 mL) was added HCl / EtOAc (4M, 6 mL, 17.6 eq). The mixture was stirred at 15 °C for 1 h, after which LC-MS indicated complete consumption of the starting material to form a single peak of the target mass. The solid was filtered, washed with EtOAc (3*1 mL), and dried under high vacuum to give the title compound (400 mg, 1.31 mmol, 96.1% yield, 2HCl) as a white solid.

[0712] LCMS (ES, m / z): 305.3 [M+H] + .

[0713] Diamine Linker Synthesis, Method M:

[0714] Connector_F-164, 1,3-Bis(2,2-difluoro-2-(piperidin-4-yl)ethoxy)benzene synthesis.

[0715]

[0716] Step 1 (of 2): Di-tert-butyl 4,4'-((1,3-phenylenebis(oxy))bis(1,1-difluoroethane-2,1-diol) bis(piperidin-1-carboxylate) synthesis.

[0717] At 15°C in N 2 To a solution of tert-butyl 4-(1,1-difluoro-2-hydroxy-ethyl)piperidine-1-carboxylate (169 mg, 639 umol, 2.2 eq) and benzene-1,3-diol (32 mg, 290 umol, 48 uL, 1 eq) in toluene (5 mL) was added (tributylphosphino)acetonitrile (175 mg, 726 umol, 2.5 eq) under atmosphere. The mixture was stirred at 90 ° C for 12 h, after which LC-MS indicated that the starting material was completely consumed to form a single peak of the target mass. The mixture was concentrated to dryness and purified by column chromatography (SiO 2 The residue was purified by preparative HPLC (column: Phenomenex Luna C 18 200*40mm*10um; mobile phase: [water (0.2% FA)-ACN]; B%: 60-100%; 8min) to obtain the title compound (50mg, 83umol, yield 14%) as a yellow oil.

[0718] LCMS (ES, m / z): 605.4 [M+H] + .

[0719] Step 2 (2 steps in total). Connecting base_F-164, 1,3-Bis(2,2-difluoro-2-(piperidin-4-yl)ethoxy)benzene synthesis.

[0720] To a solution of di-tert-butyl 4,4'-((1,3-phenylenebis(oxy))bis(1,1-difluoroethane-2,1-diyl))bis(piperidine-1-carboxylate) (50 mg, 82.7 umol, 1 eq) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 1 mL). The mixture was stirred at 15 °C for 1 h, after which LC-MS indicated that the starting material was completely consumed to form a single peak of the target mass. The mixture was filtered and the filter cake was dried to give the title compound (31 mg, 64.9 umol, 78% yield, crude, 2HCl) as a yellow solid.

[0721] LCMS (ES, m / z): 405.2 [M+H] + .

[0722] The following bisamine linkers were prepared according to Methods H, I, J, K, L, or M as shown in Table 6.

[0723] Table 6.

[0724]

[0725]

[0726]

[0727] Diamine linker_G-079, (2R,2'R)-N,N'-(1,4-phenylenebis(methylene))bis(morpholine-2-carboxylate amine) synthesis.

[0728]

[0729] The title compound was prepared according to the two-step procedure of Method F from (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid and 1,4-phenylenediamine.

[0730] LCMS (ES, m / z): 362.9 [M+H] + .

[0731] Diamine linker_H-131, 1,3-Bis(((R)-morpholin-2-yl)methoxy)benzene ; and H-166, 1,4-Bis(((R)- (morpholin-2-yl)methoxy)butane synthesis.

[0732] The bisamine linkers H-131 and H-166 were prepared according to the two-step procedure of Methods B and D, respectively, except that (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate was used instead of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate. The characterization data of these bisamines are shown in Table 7.

[0733] Table 7.

[0734]

[0735] IV. Preparation of key intermediates:

[0736] Intermediate 1.5, Preparation of tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate .

[0737]

[0738] Step 1 (total 4 steps): Intermediate 1.2, ((Benzyloxy)carbonyl)-L-seryl-D-alanine methyl ester synthesis.

[0739] Two batches are run in parallel:

[0740] To a solution of D-alanine methyl ester (46.7 g, 334.4 mmol, 1 eq, HCl), (2S)-2-(benzyloxycarbonylamino)-3-hydroxy-propionic acid (80.0 g, 334 mmol, 1 eq) and EDCI (76.9 g, 401 mmol, 1.2 eq) in DCM (800 mL) was added DIEA (129.7 g, 1.00 mol, 174.8 mL, 3 eq). The mixture was stirred at 15 °C for 16 h. The two reactions were combined and concentrated under reduced pressure. The residue was washed with saturated NaHCO 3 Aqueous solution (1000 mL) and H 2 O (1000 mL), and then extracted with ethyl acetate (1000 mL * 3). The combined organic layer was washed with 2M HCl (1000 mL) and brine (1000 mL), and then filtered through Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to give the crude title compound (160 g, 493 mmol, yield 73.8%) as a white solid.

[0741] 1 H NMR (400MHz, chloroform-d) δppm 7.27-7.38 (m, 5H) 7.12 (br d, J = 5.90Hz, 1H) 6.02 (br d, J = 7.40Hz, 1H) 5.12 (s, 2H) 4.54 (br t, J = 7.34Hz, 1H) 4.28 (br s,1H)4.06(br d,J=9.41Hz,1H)3.71(s,4H)1.39(br d,J=6.78Hz,3H).

[0742] Step 2 (total 4 steps): Intermediate 1.3, (3S,6R)-3-(Hydroxymethyl)-6-methylpiperazine-2,5-dione synthesis.

[0743] Four batches were run in parallel:

[0744] Pd / C (5 g, 10% purity) and cyclohexene (205 mL) were added to a solution of ((benzyloxy)carbonyl)-L-seryl-D-alanine methyl ester (35 g, 108 mmol, 1 eq) in MeOH (310 mL). The mixture was stirred at 90 ° C for 12 h. The four reactions were combined for post-treatment. The reaction mixture was filtered and the filter cake was washed with hot MeOH (250*3 mL). The filtrate was concentrated under reduced pressure to give the title compound (51.0 g, 322 mmol, 74.7% yield) as a white solid.

[0745] 1 H NMR (400 MHz, DMSO-d 6)δppm 8.09(s,1H)7.90(br s,1H)5.11(t,J=5.26Hz,1H)3.92(d,J=7.02Hz,1H)3.71-3.78(m,1H)3.65 -3.71(m,1H)3.52(ddd,J=10.52,5.04,2.85Hz,1H)1.23(d,J=7.02Hz,3H).

[0746] Step 3 (total 4 steps): Intermediate 1.4, ((2R,5R)-5-Methylpiperazin-2-yl)methanol synthesis.

[0747] Four batches were run in parallel:

[0748] To a solution of (3S,6R)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione (12.5 g, 79.0 mmol, 1 eq) in THF (50 mL) was added BH 3 .THF (1M, 474mL, 474mmol, 6eq). The mixture was stirred at 70°C for 12h. The four reactions were combined for post-processing. The solution was cooled in ice, and then methanol (650ml) was gradually added, followed by 5MHCl (150ml). The mixture was heated at 70°C for 2h and then cooled to 25°C. The solid was filtered out and the filter cake was washed with THF (250mL*2) to give the title compound (60g, 295mmol, 93% yield, 2HCl) as a white solid.

[0749] 1 H NMR (400 MHz, DMSO-d 6 )δppm 10.05(br s,4H)5.59(br s,1H)3.30-3.86(m,6H)3.10(q,J=12.28Hz,2H)1.31(d,J=6.58Hz,3H).

[0750] Step 4 (total 4 steps): Intermediate 1.5, tert-Butyl (2R,5R)-5-(Hydroxymethyl)-2-methylpiperazine-1-carboxylate synthesis.

[0751] Three batches were run in parallel:

[0752] To a solution of ((2R,5R)-5-methylpiperazin-2-yl)methanol (20.0 g, 98.5 mmol, 1 eq, 2 HCl) in MeOH (200 mL) was added Boc 2O (49.4g, 226mmol, 52.0mL, 2.3eq) and TEA (29.9g, 295mmol, 41.1mL, 3eq). The mixture was stirred at 50°C for 12h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was dissolved in EtOH (100mL) and treated with NaOH (1.5M, 328mL, 5eq) at 90°C for 12h under stirring. The three reactions were combined for post-processing. The reaction mixture was concentrated under reduced pressure to remove EtOH and the pH was adjusted to ~9 with 1M HCl. The mixture was extracted with DCM (800mL*6) and the combined organic layers were purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to give the title compound as a white solid.

[0753] 1 H NMR (400 MHz, methanol-d 4 )δppm 4.04-4.16(m,1H)3.76(dd,J=14.03,1.75Hz,1H)3.47-3.55(m,1H)3.57-3.66(m,1H)3.47-3.55(m,1H)3.21(dd,J=14.03,4. 38Hz, 1H) 3.02 (dd, J = 13.15, 4.82Hz, 1H) 2.86-2.95 (m, 1H) 2.51 (dd, J = 12.94, 3.29Hz, 1H) 1.46 (s, 9H) 1.23 (d, J = 7.02Hz, 3H).

[0754] Intermediate 2.2, 2-(4-Fluorobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Preparation.

[0755]

[0756] Five batches were run in parallel:

[0757] In N 2 Pd(PPh 3 ) 4(4.58 g, 3.97 mmol, 0.03 eq) was added to a mixture of KOAc (19.5 g, 198 mmol, 1.5 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (36.9 g, 145 mmol, 1.1 eq) and 1-(bromomethyl)-4-fluorobenzene (25.0 g, 132 mmol, 16.3 mL, 1 eq) in toluene (460 mL). The mixture was stirred at 100 °C for 3 h. TLC (petroleum ether / ethyl acetate = 10:1) showed that the starting material was completely consumed and a new spot was formed. The five reactions were combined for post-processing. The reaction mixture was filtered and washed with H at 0 °C. 2 O (1500ml) to quench the mixture. The mixture was extracted with EtOAc (1000ml*3) and the combined organic phase was washed with brine (500ml) and then dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue is purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=300 / 1 to 0 / 1) to give the title compound (127 g, 538 mmol, yield 55.2%) as a yellow liquid.

[0758] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 7.18-7.02 (m, 2H), 6.98-6.88 (m, 2H), 2.32-2.21 (m, 2H), 1.25 (br s, 1H).

[0759] Intermediate 3.14, (2R,5R)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-(hydroxymethyl)-2-methylpiperidin-1-yl Tert-Butyl Oxazine-1-carboxylate Preparation.

[0760]

[0761] Step 1 (13 steps): Intermediate 3.2, 2- (5-Bromo-3-nitropyridin-2-yl)malonic acid dimethyl ester synthesis.

[0762] Two batches are run simultaneously:

[0763] At 0℃, K 2 CO 3 A suspension of (464 g, 3.36 mol, 3.02 eq) in DMF (1000 mL) was added dropwise with CH 2 (CO 2 Me) 2(220.4g, 1.67mol, 192mL, 1.50eq), then 5-bromo-2-chloro-3-nitropyridine (264g, 1.11mol, 1eq) was added in batches. The reaction mixture was warmed to 20°C and stirred for 18h. TLC (petroleum ether / ethyl acetate = 2:1) showed that the reaction was almost complete. The two reactions were combined for post-processing. The reaction mixture was poured into 2.0M HCl (6.2L) and extracted with EtOAc (3L*3). The combined organic layer was washed with LiCl (1.0M aqueous solution, 2L) and brine (2L), and the mixture was purified by Na 2 SO 4 Dry, filter, and concentrate in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 to 1:1) to give the title compound (832 g, crude) as a yellow oil (containing dimethyl malonate residues).

[0764] TLC (petroleum ether / ethyl acetate = 2:1) R f =0.52.

[0765] 1 H NMR (400MHz, chloroform-d) δ = 8.88 (d, J = 1.9 Hz, 1H), 8.63 (d, J = 1.9 Hz, 1H), 5.49 (s, 1H), 3.82 (s, 6H).

[0766] Step 2 (13 steps): Intermediate 3.3, Methyl 2-(5-bromo-3-nitropyridin-2-yl)acetate synthesis.

[0767] Two reactions were performed in parallel:

[0768] To dimethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (416 g, 1.25 mol, 1 eq) was added in H 2 O (600mL) was added with LiCl (265g, 6.24mol, 5eq). The reaction mixture was heated to reflux for 72h, after which TLC (petroleum ether / ethyl acetate = 2:1) showed that the starting material was completely consumed. The two reactions were combined for post-processing. The cooled reaction mixture was distributed between EtOAc (3000mL) and water (1000mL). The separated organic phase was purified by anhydrous Na 2 SO 4 Drying, filtration and concentration in vacuo gave the crude product as a brown oil. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50:1 to 20:1) to give the title compound (540 g, 1.96 mol, yield 77.1%) as a yellow oil.

[0769] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.85 (d, J = 2.00 Hz, 1H), 8.58 (d, J = 2.00 Hz, 1H), 4.29 (s, 2H), 3.73 (s, 3H).

[0770] Step 3 (13 steps): Intermediate 3.4, Methyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methylpropanoate synthesis.

[0771] Four reactions were performed in parallel:

[0772] To a solution of methyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (50.0 g, 182 mmol, 1 eq) in DMF (500 mL) was added NaH (16.0 g, 400 mmol, 60% purity, 2.2 eq) at 0°C. The mixture was stirred at 0°C for 30 min, and then MeI (64.5 g, 454 mmol, 28.3 mL, 2.5 eq) was added dropwise to the mixture at 0°C for one hour. The mixture was stirred at 20°C for 0.5 h, after which TLC (petroleum ether / ethyl acetate = 10: 1) indicated that the starting material was completely consumed and a new product was formed. The four reactions were combined for post-processing. The reaction was heated at 0°C with saturated NH 4 The mixture was quenched with aqueous Cl solution (3000 mL), and the resulting mixture was extracted with EtOAc (3000 mL*2). The combined organic phase was washed with brine (1000 mL) and dried over anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 4:1) to give the title compound (160 g, 528 mmol, yield 74.4%) as a yellow oil.

[0773] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.83 (d, J = 2.13 Hz, 1H), 8.37 (d, J = 2.13 Hz, 1H), 3.65 (s, 3H), 1.68 (s, 6H).

[0774] Step 4 (13 steps): Intermediate 3.5, 6-Bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyrrolidone Pyridine-2-one synthesis.

[0775] Two reactions were performed in parallel:

[0776] To a solution of methyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methylpropanoate (80.0 g, 264 mmol, 1 eq) in AcOH (1000 mL) was added iron powder (73.7 g, 1.32 mol, 5 eq). The mixture was stirred at 100 ° C for 1.5 h, after which TLC (petroleum ether / ethyl acetate = 2: 1) indicated that the starting material was completely consumed and a new spot was formed. The two reactions were combined for post-processing. The mixture was filtered and the filtrate was concentrated to dryness. The crude product was washed with saturated NaHCO 3 The solution was treated with aqueous solution (2000 mL) and then extracted with EtOAc (1500 mL*3). The combined organic phase was washed with brine (500 mL) and purified by Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to give the title compound (120 g, 498 mmol, 94.3% yield) as a yellow solid.

[0777] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 6H) 7.41 (d, J = 1.75 Hz, 1H) 8.28 (d, J = 1.75 Hz, 1H) 9.94 (br s, 1H).

[0778] Step 5 (13 steps): Intermediate 3.6, 6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine synthesis.

[0779] Three reactions were performed in parallel:

[0780] At 0°C in N 2 To a solution of 6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (45 g, 187 mmol, 1 eq) in THF (900 mL) was added NaBH 4 (35.3 g, 933 mmol, 5 eq) and BF 3 .Et 2 O (185 g, 1.30 mol, 161 mL, 7 eq). The mixture was stirred at 20 ° C for 12 h, after which TLC (petroleum ether / ethyl acetate = 2:1) showed that the starting material was completely consumed and a new product was formed. The three reactions were quenched with saturated NH 4 The mixture was quenched with aqueous Cl solution (300 mL) and extracted with EtOAc (1000 mL*2). The combined organic phase was washed with brine (500 mL) and dried over anhydrous Na 2 SO 4 Dry, filter, and concentrate in vacuo, combine the three residues, and analyze by column chromatography (SiO 2, petroleum ether / ethyl acetate = 10:1 to 5:1) to give the title compound (90.0 g, 396 mmol, yield 71.0%) as a white solid.

[0781] 1H NMR (400 MHz, chloroform-d) δ ppm 1.32 (s, 6H) 3.40 (s, 2H) 6.89 (d, J = 1.75 Hz, 1H) 7.88 (d, J = 1.75 Hz, 1H).

[0782] Step 6 (13 steps): Intermediate 3.7, 6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyrrolidone Tert-Butylpyridine-1-carboxylate synthesis.

[0783] Two reactions were performed in parallel:

[0784] At 0°C, 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (55.0 g, 242 mmol, 1 eq) and Boc 2 To a solution of 1H-12O (38.7 g, 315 mmol, 1.3 eq) in DCM (900 mL) was added DMAP (32.5 g, 266 mmol, 1.1 eq) in batches. The mixture was stirred at 30 °C for 12 h, after which TLC (petroleum ether / ethyl acetate = 2:1) indicated that the starting material was completely consumed. The two reactions were combined for post-processing. The mixture was filtered and the filtrate was concentrated to give the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 4:1) to give the title compound (101 g, 309 mmol, yield 67.8%) as a colorless oil.

[0785] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.15 (d, J=2.00 Hz, 1H), 3.74 (br s, 2H), 1.49-1.63 (m, 9H), 1.36 (s, 6H).

[0786] Step 7 (13 steps): Intermediate 3.8, 6-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3, 2-b]Pyridine-1-carboxylic acid tert-butyl ester synthesis.

[0787] Two reactions were performed in parallel:

[0788] To tert-butyl 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (50 g, 153 mmol, 1 eq) and 2-(4-fluorobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.5 g, 214 mmol, 1.4 eq) in dioxane (800 mL) and H2 O (80 mL) was added with K 2 CO 3 (52.8 g, 382 mmol, 2.5 eq) and Pd(dppf)Cl 2 (16.8 g, 22.9 mmol, 0.15 eq). 2 The mixture was stirred at 80°C for 12 h, after which TLC (petroleum ether / ethyl acetate = 3:1) indicated conversion to a new product. The two reactions were combined for post-processing. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 40:1 to 5:1) to give the title compound (64.0 g, 180 mmol, yield 58.8%) as a yellow oil.

[0789] LCMS (ES, m / z): 357.3 [M+H] + .

[0790] Step 8 (13 steps): Intermediate 3.9, 1- (tert-Butyloxycarbonyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3- Hydrogen-1H-pyrrolo[3,2-b]pyridine 4-oxide synthesis.

[0791] To a solution of tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (35.0 g, 98.2 mmol 1 eq) in DCM (600 mL) was added m-CPBA (25.9 g, 128 mmol, 85% purity, 1.3 eq) at 0°C. The mixture was stirred at 15°C for 4 h, after which LCMS indicated the formation of the desired mass of product. The reaction was heated to 40°C with saturated Na 2 SO 3 The mixture was quenched with aqueous solution (600 mL) and then extracted with DCM (100 mL*2). The combined organics were washed with 1N NaOH (300 mL*2) and brine (300 mL) and then purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to afford the title compound (34 g, 91.3 mmol, 95.7% yield) as a red oil.

[0792] LCMS (ES, m / z): 373.3 [M+H] + .

[0793] Step 9 (13 steps): Intermediate 3.10, 6-(4-Fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro- 1H-Pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester synthesis.

[0794] 1-(tert-Butyloxycarbonyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine 4-oxide (34.0 g, 91.3 mmol, 1 eq) was dissolved in Ac 2 The mixture in 4% 4-(4-(4-(4-(4-(4-(4-oxo-1-yl)-2-nitropropene))-1H-4-yl ... 2 O (1500 mL) for 1 h. The solid was filtered off and the filter cake was dried to obtain the title compound (32.0 g, 85.0 mmol, yield 94.1%) as a white solid.

[0795] LCMS (ES, m / z): 373.3 [M+H] + .

[0796] Step 10 (total 13 steps): Intermediate 3.11, 6-(4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyridine Pyrrol[3,2-b]pyridin-5-one synthesis.

[0797] Two reactions were performed in parallel:

[0798] To a solution of 6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (16 g, 43.0 mmol, 1 eq) in DCM (270 mL) was added HCl / dioxane (4 M, 270 mL, 25.1 eq), and the mixture was stirred at 15 ° C for 12 h, after which LCMS indicated that the starting material was completely consumed and the target mass of product was formed. The two reactions were combined for post-processing. The mixture was filtered and the filter cake was dried to give the title compound (26 g, 84.2 mmol, 100% yield, HCl) as a yellow solid.

[0799] LCMS (ES, m / z): 273.1 [M+H] + .

[0800] Step 11 (13 steps): Intermediate 3.12, 1- (2-Chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-1,2, 3,4-Tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one synthesis.

[0801] 6-(4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one (26.0 g, 84.2 mmol, 1 eq, HCl) and K were added under stirring at 0°C. 2 CO 3 (29.1 g, 210 mmol, 2.5 eq) in CH 3 To the mixture in CN (500 mL) was added dropwise 2-chloroacetyl chloride (11.9 g, 105 mmol, 8.40 mL, 1.3 eq) dissolved in CH 3 The mixture was warmed to 15 °C and stirred for 4 h, after which LCMS indicated complete consumption of the starting material and formation of the target mass of product. MeOH (200 mL) was added and the mixture was stirred at 20 °C for 0.5 h. The mixture was concentrated to dryness and the residue was purified by HPLC. 2 O (500 mL) and extracted with EtOAc (400 mL * 3). The combined organic phase was washed with brine (200 mL) and purified by Na 2 SO 4 The residue was dried, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=10 / 1 to 0 / 1) to give the title compound (23.0 g, 65.9 mmol, yield 72.4%) as a yellow solid.

[0802] LCMS (ES, m / z): 349.2 [M+H] + .

[0803] Step 12 (of 13): Intermediate 3.13, 1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)- 3,3-Dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-chloroethan-1-one synthesis.

[0804] To a solution of 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one (20.0 g, 57.3 mmol, 1 eq) and DIEA (18.5 g, 143 mmol, 25 mL, 2.5 eq) in DMF (300 mL) was added TBDMSCl (9.51 g, 63.1 mmol, 1.1 eq) at 0 °C. The mixture was stirred at 15 °C for 12 h, after which LCMS indicated complete consumption of the starting material and formation of a new product of the target mass. The reaction mixture was poured into saturated NH 4 Cl aqueous solution (200 mL) and extracted with EtOAc (200 mL * 3). The combined organic phase was washed with brine (200 mL) and 2 SO 4Dry, filter, and concentrate under reduced pressure to give a residue, which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 4:1) to give the title compound (20.2 g, 43.6 mmol, yield 76.1%) as a white solid.

[0805] LCMS (ES, m / z): 463.2 [M+H] + .

[0806] Step 13 (total 13 steps): Intermediate 3.14, (2R,5R)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6- (4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-(hydroxy tert-Butyl 2-methylpiperazine-1-carboxylate synthesis.

[0807] (2R,5R)-5-(hydroxymethyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (14.9 g, 64.8 mmol, 1.5 eq), 1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-chloroethan-1-one (20 g, 43.2 mmol, 1 eq), K 2 CO 3 A mixture of 1,4-dihydro- ... 2 , petroleum ether / ethyl acetate = 1:0 to 0:1) to give the title compound (26.5 g, 40.3 mmol, yield 93.4%) as a yellow solid.

[0808] LCMS (ES, m / z): 657.5 [M+H] + .

[0809] Intermediate 4.4, (2R,5R)-4-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrakis tert-Butyl (1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate ester Preparation.

[0810]

[0811] Step 1 (total 4 steps): Intermediate 4.1, 6-(4-Fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro- 1H-Pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester synthesis.

[0812] To a solution of tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (4 g, 10.7 mmol, 1 eq) in THF (50 mL) was added t-BuOLi (1.72 g, 21.5 mmol, 1.94 mL, 2 eq) and MeI (3.05 g, 21.5 mmol, 1.34 mL, 2 eq) and the reaction mixture was stirred at 80 °C for 12 h. LC-MS indicated complete consumption of the starting material to form the desired mass of product. The mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=10 / 1 to 0 / 1) to give the title compound (3.20 g, 8.28 mmol, yield 77.1%) as a yellow solid.

[0813] LCMS (ES, m / z): 387.1 [M+H] + .

[0814] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.13 (br s, 1H), 7.22 (br s, 1H), 6.95 (br s, 2H), 3.83 (s, 2H), 3.71-3.56 (m, 5H), 1.56-1.30 (m, 15H).

[0815] Step 2 (total 4 steps): Intermediate 4.2, 6-(4-Fluorobenzyl)-3,3,4-trimethyl-1,2,3,4-tetrahydro-5H-pyrrole 3,2-b]pyridin-5-one synthesis.

[0816] To a solution of 6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (3.20 g, 8.28 mmol, 1 eq) in DCM (30 mL) was added HCl / dioxane (4 M, 20 mL, 9.7 eq). The mixture was stirred at 25 ° C for 12 h, after which LC-MS indicated that the starting material was completely consumed and the target mass of product was formed. The mixture was concentrated in vacuo to give the title compound (2.67 g, crude, HCl) as a yellow oil.

[0817] LCMS (ES, m / z): 287.1 [M+H] + .

[0818] Step 3 (total 4 steps): Intermediate 4.3, 1-(2-Chloroacetyl)-6-(4-fluorobenzyl)-3,3,4-trimethyl-1,2, 3,4-Tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one synthesis.

[0819] 6-(4-Fluorobenzyl)-3,3,4-trimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one (2.67 g, 9.32 mmol, 1 eq, HCl) and K 2 CO 3 A mixture of (2.84g, 20.5mmol, 2.2eq) in MeCN (20mL) was treated dropwise with a solution of 2-chloroacetyl chloride (1.26g, 11.19mmol, 890uL, 1.2eq) in MeCN (5mL). The mixture was warmed to 25°C and stirred for 2h, after which LC-MS showed that the starting material was consumed and the target mass of product was formed. The reaction was quenched with MeOH (10mL) and the mixture was concentrated in vacuo. The residue was extracted with EtOAc (10mL*2), and the combined organic phase was washed with brine (20mL) and dried over anhydrous Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=10 / 1 to 0 / 1) to give the title compound (2.7 g, 7.44 mmol, yield 79.8%) as a white solid.

[0820] TLC (petroleum ether / ethyl acetate = 0:1) R f =0.43.

[0821] LCMS (ES, m / z): 363.1 [M+H] + .

[0822] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.13 (br s, 1H), 7.22 (br s, 1H), 6.95 (br s, 2H), 3.83 (s, 2H), 3.71-3.56 (m, 5H), 1.56-1.30 (m, 15H).

[0823] Step 4 (total 4 steps): Intermediate 4.4, (2R,5R)-4-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo (2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-(hydroxymethyl)-2-methylpiperidin-1-yl) Tert-Butyl Oxazine-1-carboxylate synthesis.

[0824] To a solution of 1-(2-chloroacetyl)-6-(4-fluorobenzyl)-3,3,4-trimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one (2.70 g, 7.44 mmol, 1 eq) and (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (2.23 g, 9.67 mmol, 1.3 eq) in THF (30 mL) was added DIEA (2.89 g, 22.3 mmol, 3.89 mL, 3 eq). The mixture was stirred at 80 °C for 12 h, after which LC-MS indicated that the starting material was consumed and a new product of the target mass was formed. The mixture was concentrated in vacuo and the residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give the title compound (3.5 g, 6.29 mmol, yield 58.3%) as a yellow solid.

[0825] LCMS (ES, m / z): 557.3 [M+H] + .

[0826] TLC (petroleum ether / ethyl acetate = 0:1) R f =0.10.

[0827] 1 H NMR (400MHz, chloroform-d) δ = 8.34 (s, 1H), 7.32-7.28 (m, 2H), 6.96 (t, J = 8.7Hz, 2H), 4.19-4.09 (m, 2H), 3.97-3.87 (m, 2H), 3.85-3.74(m,5H),3.64-3.55(m,5H),3.54-3.42(m,2H),3.29(dd,J=4.1,14.1Hz,1H),2.98-2.89(m,2H),2.63(br dd,J=5.1,12.1Hz,1H),1.47(s,12H),1.23(d,J=6.5Hz,3H).

[0828] Intermediate 5.3, (2R,5R)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3, tert-Butyl 2-(2-b]pyridin-1-yl)-2-oxoethyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate Preparation.

[0829]

[0830] Step 1 (total 3 steps): Intermediate 5.1, 6-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3, 2-b]pyridine synthesis.

[0831] A solution of 6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridine-1-carboxylic acid tert-butyl ester (1.50 g, 4.21 mmol) in dichloromethane (10 mL) was treated with HCl (4 M in dioxane, 10 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between saturated aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (3x60 mL). The combined organics were purified by Na 2 SO 4 Dry, filter, and evaporate in vacuo to afford the title compound (0.72 g, 2.81 mmol, 94% yield) as a light brown solid.

[0832] LCMS (ES, m / z): 257.1 [M+H] + .

[0833] 1 H NMR (400 MHz, CDCl 3 ): δppm 7.78(1H,s),7.26(2H,dd),6.99-6.94(2H,t),6.57(1H,d),3.81(2H,s),3.36(2H,s),1.34(6H,s).

[0834] Step 2 (total 3 steps): Intermediate 5.2, 2-Chloro-1-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyridine Pyridin-1-yl)ethan-1-one synthesis.

[0835] To a stirred suspension of 6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (500 mg, 1.95 mmol, HCl) in acetonitrile (10 mL) was added a solution of chloroacetyl chloride (287 mg, 2.53 mmol) in acetonitrile (1 mL) at 20 ° C. over 2 min, while the reaction temperature was maintained at 20 ° C. or below using an external ice-methanol bath. The resulting mixture was stirred at room temperature for 1.5 hours, concentrated, and the residue was diluted with methanol. The solution was stirred at room temperature for 5 min. Then 10% potassium carbonate solution was added. The mixture was extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (3: 1) to give the title compound (580 mg, 1.74 mmol, yield 89.2%) as a white solid.

[0836] LCMS (ES, m / z): 332.8 [M+H] + .

[0837] Step 3 (total 3 steps), intermediate 5.3, (2R,5R)-4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3- tert-Butyl (1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate ester synthesis.

[0838] Finely ground potassium iodide (578 mg, 3.48 mmol) was added to a mixture of (2R, 5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (481 mg, 2.09 mmol), 2-chloro-1-[6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-ethanone hydrochloride (580 mg, 1.74 mmol), potassium carbonate (960 mg, 6.96 mmol) and acetonitrile (30 mL) under nitrogen. The mixture was stirred at 20 ° C overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic phase was purified by Na 2 SO 4 Dry, filter and evaporate in vacuo to afford the title compound (760 mg, 1.44 mmol, 82.7% yield).

[0839] LCMS (ES, m / z): 526.8 [M+H] + .

[0840] Intermediate 6.2, (2R,5S)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-2-methyl tert-Butyl piperazine-1-carboxylate Preparation.

[0841]

[0842] Step 1 (total 2 steps): Intermediate 6.1, (2R,5S)-5-(((R)-4-((Benzyloxy)carbonyl)-2-methylpiperazine-1- 4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester synthesis.

[0843] To a solution of (2R,5R)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (10.0 g, 15.2 mmol, 1 eq) and DIEA (4.90 g, 38.1 mmol, 6.60 mL, 2.5 eq) in DCM (120 mL) was added MsCl (2.09 g, 18.3 mmol, 1.4 mL, 1.2 eq) dropwise at 0°C. The mixture was stirred at 15°C for 1 h, after which TLC (petroleum ether / ethyl acetate = 0:1) indicated that the starting material had been completely converted to a new product. Water (100 mL) was added to the mixture and extracted with DCM (50 mL*2). The combined organic phases were washed with brine (50 mL) and purified by Na 2 SO4 Drying, filtration and concentration under reduced pressure gave the intermediate product (11.2 g, crude) as a yellow oil.

[0844] A mixture of the intermediate product (11.2 g, 15.2 mmol, 1 eq), (R)-3-methylpiperazine-1-carboxylic acid benzyl ester (3.93 g, 16.8 mmol, 1.1 eq), KI (2.53 g, 15.2 mmol, 1 eq) and DIEA (5.91 g, 45.7 mmol, 7.96 mL, 3 eq) in MeCN (150 mL) was stirred at 80 ° C for 12 h. TLC indicated that the starting material was completely consumed and a new product was formed. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 2:1) to give the title compound (10.8 g, 12.3 mmol, yield 81.2%) as a yellow oil.

[0845] LCMS (ES, m / z): 873.8 [M+H] + .

[0846] Step 2 (total 2 steps): Intermediate 6.2, (2R,5S)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4- (fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl-5- tert-Butyl (((R)-2-methylpiperazin-1-yl)methyl)piperazine-1-carboxylate synthesis.

[0847] In N 2 To a solution of tert-butyl (2R,5S)-5-(((R)-4-((benzyloxy)carbonyl)-2-methylpiperazin-1-yl)methyl)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate (5.00 g, 5.73 mmol, 1 eq) in MeOH (250 mL) was added Pd / C (4.00 g, 10% purity) under atmosphere. The suspension was degassed and heated to 40 ℃. 2 The mixture was heated at 50 °C under H 2 (15 psi) for 12 h, after which LCMS showed complete consumption of the starting material and formation of the target mass of the product. The mixture was filtered and the filtrate was concentrated to give the crude title compound (3.5 g, 4.74 mmol, quantitative yield) as a yellow solid.

[0848] LCMS (ES, m / z): 739.5 [M+H] + A small peak corresponding to the TBS cleavage product at 625.4 [M+H] was also noted. + .

[0849] Intermediate 7.2, (2R,5S)-4-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrakis (((R)-2-methylpiperazin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-2-methylpiperazin-1-yl)methyl tert-Butyl piperazine-1-carboxylate Preparation.

[0850]

[0851] Step 1 (of 2): Intermediate 7.1 (2R,5S)-5-(((R)-4-((Benzyloxy)carbonyl)-2-methylpiperazine-1- 4-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b] tert-Butyl pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate synthesis.

[0852] To a solution of (2R,5R)-tert-butyl 4-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (500 mg, 898 umol, 1 eq) and TEA (136 mg, 1.35 mmol, 187 uL, 1.5 eq) in DCM (5 mL) was added MsCl (123 mg, 1.08 mmol, 83.4 uL, 1.2 eq) at 0°C. The mixture was stirred at 25°C for 0.5 h, after which TLC indicated that the starting material was converted to a new product. The reaction was heated to 40 ℃ with saturated NaHCO 3 The mixture was quenched with aqueous solution (20 mL) and then extracted with DCM (10 mL*2). The combined organic phase was washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Drying, filtering, and concentration in vacuo gave the intermediate product (500 mg, crude) as a yellow solid.

[0853] To a solution of the intermediate product (1.00 g, 1.74 mmol, 1 eq) and (R)-3-methylpiperazine-1-carboxylic acid benzyl ester (367 mg, 1.56 mmol, 0.9 eq) in MeCN (10 mL) were added DIEA (674 mg, 5.22 mmol, 909 uL, 3 eq) and KI (289 mg, 1.74 mmol, 1 eq). The mixture was stirred at 80 °C for 12 h, after which TLC (dichloromethane / methanol = 15:1, R f =0.23) indicated that the starting material was completely consumed and a major new product was formed. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and filtered. The filtrate was concentrated in vacuo to give the title compound (1.3 g, crude) as a yellow oil.

[0854] LCMS (ES, m / z): 773.5 [M+H] + .

[0855] Step 2 (total 2 steps): Intermediate 7.2, (2R,5S)-4-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo (((R)-2-methyl-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-2-methyl tert-Butyl piperazine-1-carboxylate synthesis.

[0856] In N 2 To a solution of tert-butyl (2R,5S)-5-(((R)-4-((benzyloxy)carbonyl)-2-methylpiperazin-1-yl)methyl)-4-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate (1 g, 1.29 mmol, 1 eq) in MeOH (5 mL) was added Pd / C (50 mg, 129 umol, 10% purity). The suspension was degassed under vacuum and heated to 40 % by volume. 2 The mixture was stirred at 25 °C under H 2 (15 psi) for 12 h after which LCMS showed complete consumption of the starting material and formation of one major peak of the desired mass. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (800 mg, crude) as a yellow solid.

[0857] LCMS (ES, m / z): 639.4 [M+H] + .

[0858] Intermediate 8.2, (2R,5S)-5-(((S)-3-aminopiperidin-1-yl)methyl)-4-(2-(5-((tert-butyldimethyl (4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxy tert-Butyl (2-(2-methylpiperazine-1-carboxylate) Preparation.

[0859]

[0860] Step 1 (total 2 steps): Intermediate 8.1, (2R,5S)-5-(((S)-3-(((Benzyloxy)carbonyl)amino)piperidine- 1-yl)methyl)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester synthesis.

[0861] MsCl (290 mg, 2.53 mmol) was added to a solution of (2R, 5R)-4-{2-[6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (760 mg, 1.45 mmol) and triethylamine (293 mg, 2.89 mmol) in dichloromethane (20 mL) at 0°C. The solution was allowed to warm to room temperature and stirred overnight under a nitrogen atmosphere. The mixture was distributed between aqueous ammonium chloride solution and dichloromethane, and the separated organic phase was dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1) to give an intermediate product (500 mg, 0.917 mmol, yield 63.7%) as a white solid.

[0862] The intermediate (2.24 g, 3.05 mmol, 1 eq), (S)-piperidin-3-ylcarbamic acid benzyl ester (785 mg, 3.35 mmol, 1.1 eq), DIEA (1.18 g, 9.14 mmol, 1.59 mL, 3 eq) and KI (506 mg, 3.05 mmol, 1 eq) were stirred in CH 3 The solution in CN (50 mL) was stirred at 80 °C for 12 h, after which LCMS showed the formation of the target mass of the product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1:0 to 1:3) to give the title compound (1.40 g, 1.60 mmol, yield 52.6%) as a yellow oil.

[0863] TLC (petroleum ether / ethyl acetate = 1:1) R f =0.43

[0864] LCMS (ES, m / z): 873.6 [M+H] + .

[0865] Step 2 (total 2 steps): Intermediate 8.2, (2R,5S)-5-(((S)-3-aminopiperidin-1-yl)methyl)-4-(2-(5- ((tert-Butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyrrolidone tert-Butyl (2-oxoethyl)-2-methylpiperazine-1-carboxylate synthesis.

[0866] In N 2 To a solution of tert-butyl (2R,5S)-5-(((S)-3-(((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate (950 mg, 1.09 mmol, 1 eq) in MeOH (50 mL) was added Pd / C (15 mg, 10% purity) 。 The suspension was degassed under vacuum and washed with H 2 The mixture was heated at 50 °C under H 2 (15 psi) for 12 h after which LCMS indicated the formation of the desired mass of product. The mixture was filtered and the filtrate was concentrated to give the crude title compound (0.64 g, 866 umol, 79% yield) as a yellow solid.

[0867] LCMS (ES, m / z): 739.5 [M+H] + A small peak corresponding to the TBS cleavage product at 625.4 [M+H] was also noted. + .

[0868] Intermediate 9.2, (2R,5S)-5-(((R)-3-aminopiperidin-1-yl)methyl)-4-(2-(5-((tert-butyldimethyl (4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxy tert-Butyl (2-(2-methylpiperazine-1-carboxylate) Preparation.

[0869]

[0870] Step 1 (total 2 steps): Intermediate 9.1, (2R,5S)-5-(((R)-3-(((Benzyloxy)carbonyl)amino)piperidine- 1-yl)methyl)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester synthesis.

[0871] MsCl (290 mg, 2.53 mmol) was added to a solution of (2R, 5R)-4-{2-[6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (760 mg, 1.45 mmol) and triethylamine (293 mg, 2.89 mmol) in dichloromethane (20 mL) at 0 ° C. The solution was allowed to warm to room temperature and stirred overnight under a nitrogen atmosphere. The mixture was distributed between aqueous ammonium chloride solution and dichloromethane, and the separated organic phase was dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1: 1) to give an intermediate product (500 mg, 0.917 mmol, yield 63.7%) as a white solid.

[0872] A mixture of the intermediate product (2.8 g, 3.81 mmol, 1 eq), (R)-piperidin-3-ylcarbamic acid benzyl ester (982 mg, 4.19 mmol, 1.1 eq), KI (632 mg, 3.81 mmol, 1 eq) and DIEA (1.48 g, 11.4 mmol, 1.99 mL, 3 eq) in MeCN (50 mL) was stirred at 80 ° C for 12 h, after which TLC indicated that the starting material was completely converted to the new product. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1:0 to 1:4) to give the title compound (2.02 g, 2.31 mmol, 60.7% yield) as a yellow oil.

[0873] LCMS (ES, m / z): 873.8 [M+H] + .

[0874] Step 2 (total 2 steps): Intermediate 9.2, (2R,5S)-5-(((R)-3-aminopiperidin-1-yl)methyl)-4-(2-(5- ((tert-Butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyrrolidone tert-Butyl (2-oxoethyl)-2-methylpiperazine-1-carboxylate synthesis.

[0875] In N 2To a solution of tert-butyl (2R,5S)-5-(((R)-3-(((benzyloxy)carbonyl)amino)piperidin-1-yl)methyl)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate (1.8 g, 2.06 mmol, 1 eq) in MeOH (120 mL) was added Pd / C (1.5 g, 10% purity) under atmosphere. The suspension was degassed and heated with H 2 Purge several times. 2 (15 psi) at 50°C for 12 h, after which LCMS indicated the formation of the desired mass of product. The mixture was filtered and the filtrate was concentrated to give the crude title compound (1.3 g, 1.76 mmol, 85.5% yield) as a yellow solid.

[0876] LCMS (ES, m / z): 739.5 [M+H] + A small peak corresponding to the TBS cleavage product at 625.4 [M+H] was also noted. + .

[0877] Intermediate 10.2, (S)-4-(((2S,5R)-4-(tert-Butyloxycarbonyl)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl 2-( ... (4-(2-Methyl)morpholine-2-carboxylic acid) Preparation.

[0878]

[0879] Step 1 (total 2 steps): Intermediate 10.1, (S)-4-(((2S,5R)-4-(tert-butyloxycarbonyl)-1-(2-(5-((tert-butyl (2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-yl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine) methyl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxylate synthesis.

[0880] MsCl (290 mg, 2.53 mmol) was added to a solution of (2R, 5R)-4-{2-[6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (760 mg, 1.45 mmol) and triethylamine (293 mg, 2.89 mmol) in dichloromethane (20 mL) at 0 ° C. The solution was allowed to warm to room temperature and stirred overnight under a nitrogen atmosphere. The mixture was distributed between aqueous ammonium chloride solution and dichloromethane, and the separated organic phase was dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1: 1) to give an intermediate product (500 mg, 0.917 mmol, yield 63.7%) as a white solid.

[0881] To a solution of the intermediate product (5.59 g, 7.61 mmol, 1 eq) in MeCN (100 mL) was added (S)-methyl morpholine-2-carboxylate (1.66 g, 9.13 mmol, 1.2 eq, HCl), DIEA (3.93 g, 30.4 mmol, 5.30 mL, 4 eq) and KI (1.26 g, 7.61 mmol, 1 eq). The mixture was stirred at 80 °C for 12 h, after which LC-MS indicated that the starting material was completely consumed and the target mass of product was formed. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give the methyl title compound (5.9 g, 7.53 mmol, yield 98%) as a yellow oil.

[0882] TLC (petroleum ether / ethyl acetate = 1:2) R f =0.6.

[0883] LCMS (ES, m / z): 784.7 [M+H] + .

[0884] Step 2 (total 2 steps): Intermediate 10.2, (S)-4-(((2S,5R)-4-(tert-butyloxycarbonyl)-1-(2-(6-(4-fluoro benzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)- 5-Methylpiperazin-2-yl)methyl)morpholine-2-carboxylic acid synthesis.

[0885] To a solution of (S)-methyl 4-(((2S,5R)-4-(tert-butyloxycarbonyl)-1-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxylate (5.9 g, 7.53 mmol, 1 eq) in THF (100 mL) was added NaOH (2 M, 7.53 mL, 2 eq). The mixture was stirred at 15 °C for 2 h, after which LCMS indicated that the starting material was consumed and the target mass of product was formed. The mixture was concentrated under reduced pressure to remove most of the THF. The reaction mixture was washed with H 2 The mixture was diluted with 1N HCl (10 mL) and 1N HCl was added to adjust the pH to 3 to 4. The mixture was filtered and the filter cake was dried to give the title compound (5.75 g, crude) as a yellow solid.

[0886] LCMS (ES, m / z): 656.5 [M+H] + .

[0887] Intermediate 11.3, Di-tert-butyl 5,5'-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis (Morpholine-2,4-diyl)bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(6-bromo-3,3-dimethyl-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate) Preparation.

[0888]

[0889] Step 1 (total 3 steps): Intermediate 11.1, 1-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b] Pyridin-1-yl)-2-chloroethane-1-one synthesis.

[0890] To a solution of 6-bromo-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridine (1.5 g, 6.61 mmol, 1 eq) in MeCN (20 mL) was added K 2 CO 3 (2.28 g, 16.5 mmol, 2.5 eq) and 2-chloroacetyl chloride (932 mg, 8.26 mmol, 656 uL, 1.25 eq) in MeCN (2 mL). The mixture was stirred at 25 ° C for 4 h, after which LCMS indicated complete conversion to the target mass of product. MeOH (10 mL) was added to the mixture and stirred at 20 ° C for 0.5 h. The mixture was concentrated to dryness and the residue was heated to 40 ° C. 2 The mixture was partitioned between 1% O (20 mL) and EtOAc (10 mL). The phases were separated and the aqueous phase was extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (10 mL) and purified by Na 2 SO 4 The product was dried, filtered, and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 1:2) to give the title compound (2.00 g, 6.59 mmol, 99% yield) as a white solid.

[0891] TLC (petroleum ether / ethyl acetate = 1:1) R f =0.7

[0892] LCMS (ES, m / z): 303.1, 305.1 [M+H] + .

[0893] Step 2 (total 3 steps): Intermediate 11.2, (2R,5R)-4-(2-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyridine tert-Butyl pyridin-1-yl)-2-oxoethyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate synthesis.

[0894] To a solution of 1-(6-bromo-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl)-2-chloro-ethanone (2.00 g, 6.59 mmol, 1 eq) in MeCN (50 mL) were added (2R,5R)-5-(hydroxymethyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.97 g, 8.56 mmol, 1.3 eq), K 2 CO 3(1.82 g, 13.18 mmol, 2 eq) and KI (1.09 g, 6.59 mmol, 1 eq). The mixture was stirred at 50 °C for 12 h, after which LCMS indicated complete conversion to the target mass product. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 1:2) to give the title compound (2.45 g, 4.93 mmol, yield 75%) as a yellow solid.

[0895] TLC (petroleum ether / ethyl acetate = 1:1) R f =0.5

[0896] LCMS (ES, m / z): 497.3, 499.3 [M+H] + .

[0897] Step 3 (total 3 steps): Intermediate 11.3, Di-tert-butyl 5,5'-(((2S,2'S)-((1,3-phenylenebis(oxy)) Bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(6-bromo-3,3-di methyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate synthesis.

[0898] To a solution of (2R,5R)-4-[2-(6-bromo-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxo-ethyl]-5-(hydroxymethyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.4 g, 4.82 mmol, 1 eq) in DCM (25 mL) was added DIEA (1.56 g, 12.1 mmol, 2.10 mL, 2.5 eq) and MsCl (829 mg, 7.24 mmol, 560 uL, 1.5 eq) at 0° C. The mixture was stirred at 15° C. for 0.5 h, after which TLC indicated complete consumption of the starting material and the formation of a new spot (SiO 2 , petroleum ether / ethyl acetate = 0:1, R f =0.7). By adding H 2 O (10 mL) to quench the reaction mixture, and then extract with DCM (10 mL * 3). The combined organic layer was washed with brine (10 mL) and purified by Na 2 SO 4 Drying, filtration, and concentration under reduced pressure gave the intermediate product as a yellow oil.

[0899] The intermediate product was dissolved in MeCN (50 mL) and treated with (2S)-2-[[3-[[(2S)-morpholin-2-yl]methoxy]phenoxy]methyl]morpholine (753 mg, 1.97 mmol, 1.00 eq, 2HCl), DIEA (1.53 g, 11.85 mmol, 2.06 mL, 6 eq) and KI (656 mg, 3.95 mmol, 2 eq). The mixture was stirred at 80 ° C for 12 h, after which LCMS showed complete conversion to the target mass product. The mixture was concentrated under reduced pressure and purified by column chromatography (SiO 2 , ethyl acetate / methanol=1:0 to 3:1) to give the title compound (1.27 g, 1.00 mmol, 50.6% yield) as a yellow solid.

[0900] TLC (ethyl acetate / methanol = 10:1) R f =0.5

[0901] LCMS(ES,m / z):1265.8,1267.8,1269.8[M+H] + .

[0902] V. Preparation of Example 1-190:

[0903] Scheme 1: General method for Examples 1-23.

[0904]

[0905] Embodiment 1,

[0906] 1,6-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methyl Piperazine-1-yl)hexane-1,6-dione.

[0907]

[0908] Step 1 of 2: Di-tert-butyl 5,5'-(((2R,2'R)-adipoylbis(2-methylpiperazine-4,1-diyl)) Bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl) 2-(2-(2-(2-(2-methylpiperazine)-1-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-yl Formate) The synthesis of.

[0909]

[0136] HATU (65.1 mg, 171 umol, 2.5 equiv) was added to a mixture of tert-butyl (2R,5S)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-2-methylpiperazin-1-yl)methyl)piperazine-1-carboxylate (Intermediate 6.2) (106 mg, 143 umol, 2.1 equiv), adipic acid (10 mg, 68.4 umol, 11.3 uL, 1 equiv) and DIEA (35.4 mg, 273 umol, 47.7 uL, 4 equiv) in DCM (2 mL) at 15 °C. The mixture was stirred at 15°C for 12 h, then LCMS indicated conversion to the target mass of product. The mixture was concentrated to dryness and the residue was purified by preparative TLC (ethyl acetate / MeOH=10 / 1) to give the target compound (100 mg, 63.0 umol) as a yellow oil.

[0910] LCMS (ES, m / z): 1589.1 [M+H] +

[0911] Step 2 of 2: 1,6-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl 1-Methylpiperazine-1-yl)hexane-1,6-dione The synthesis of.

[0912] A solution of di-tert-butyl 5,5'-(((2R,2'R)-adipoylbis(2-methylpiperazine-4,1-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate) (100 mg, 62.9 umol, 1 eq.) in HCl / EtOAc (4M, 2 mL) was stirred at 15°C for 1 h, then LCMS indicated conversion to the target mass of the product. The precipitate was filtered and the filter cake was dried to give the crude product. The material was purified by preparative HPLC (FA conditions; column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.2% FA)-ACN]; B%: 15%-50%, 9min) to give the target compound (38.5mg, 30.5umol, 48.4% yield, 99% purity, 2FA) as a white solid.

[0913] LCMS (ES, m / z): 1159.7 [M+H] +

[0914] 1 H NMR (400 MHz, methanol-d4) δ ppm 8.37-8.47 (m, 2H) 8.10-8.21 (m, 2H) 7.16-7.30 (m, 4H) 7.01 (td, J = 8.63, 3.25 Hz, 4H) 3.65-3.96 (m, 15H) 3.40-3.63 (m, 5H) 3.17-3.29 (m, 3H) 2.85-3.11 (m, 11H)

[0915] 2.76(br t,J=11.51Hz,2H)2.26-2.49(m,6H)1.97-2.23(m,4H)1.53(br s,4H)1.33-1.42(m,12H)1.26(d,J=6.50Hz,6H)1.03(br dd,J=19.26, 5.75Hz, 6H).

[0916] The following compounds (Examples 2-23) were prepared according to the same procedure as Example 1, replacing adipic acid with the appropriate dicarboxylic acid:

[0917] Embodiment 2,

[0918] 1,8-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- Tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazine- 1-yl)octane-1,8-dione

[0919]

[0920] LCMS (ES, m / z): 1187.8 [M+H] +

[0921] 1 H NMR (400MHz, CD3OD, 299K) δ (ppm) = 8.19 (br s, 2H), 7.29 (br s, 4H), 7.06 (brt, J = 7.7Hz, 4H), 4.72-4.40 (m, 2H), 4.27-4.00 (m, 10H), 3.94 (br s, 11H), 3.61 (br s, 4H), 3.36 (br d, J=7.8Hz, 7H), 3.28-2.82 (m, 11H), 2.56 (br s, 5H), 1.73 (br s, 4H), 1.51 (brs, 12H), 1.39 (br t, J=6.5Hz, 12H).

[0922] Embodiment 3,

[0923] 1,10-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- Tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazine- 1-yl)decane-1,10-dione

[0924]

[0925] LCMS (ES, m / z): 1215.8 [M+H] +

[0926] 1 H NMR (400MHz, methanol-d4) δ=7.93 (br d, J=11.0Hz, 2H), 7.24 (dd, J=5.6, 8.2Hz, 4H), 7.01 (t, J=8.8Hz, 4H), 3.99 (br d, J=8.3Hz, 3H), 3.90 (br d, J=9.5Hz, 3H), 3.83(br s, 4H), 3.80(br s, 5H), 3.76-3.59 (m, 5H), 3.59-3.37 (m, 7H), 3.30-3.20 (m, 5H), 3.20-2.85 (m, 10H), 2.57-2.45 (m, 4H), 1.69 (br s, 4H), 1.42 (br d, J=6.8Hz, 20H), 1.33 (br s, 9H), 1.24 (br d, J=5.8Hz, 3H).

[0927] Embodiment 4,

[0928] 1,14-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- Tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazine- 1-yl)tetradecane-1,14-dione

[0929]

[0930] LCMS (ES, m / z): 1271.9 [M+H] +

[0931] 1 H NMR (400 MHz, methanol-d 4)δ = 7.94 (broad doublet, J = 10.8 Hz, 2H), 7.24 (doublet of doublets, J = 5.6, 8.2 Hz, 4H), 7.01 (triplet, J = 8.7 Hz, 4H), 4.04 - 3.95 (multiplet, 3H), 3.90 (broad doublet, J = 10.1 Hz, 3H), 3.84 (broad singlet, 4H), 3.80 (broad singlet, 5H), 3.78 - 3.61 (multiplet, 5H), 3.53 (broad doublet, J = 6.2 Hz, 7H), 3.30 - 3.20 (multiplet, 5H), 3.20 - 2.89 (multiplet, 10H), 2.50 (broad triplet, J = 7.2 Hz, 4H), 1.67 (broad singlet, 4H), 1.42 (doublet, J = 6.5 Hz, 16H), 1.33 (broad singlet, 20H), 1.25 (broad doublet, J = 5.7 Hz, 4H).

[0932] Example 5,

[0933] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(ethane-1,2-diylbis(oxy)) Bis(acetyl)bis(2-methylpiperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[0934]

[0935] LCMS (ES, m / z): 596.6 [M / 2 + H] +

[0936] 1 1H NMR (400 MHz, methanol-d4) δ = 7.95 (broad singlet, 2H), 7.28 (broad singlet, 4H), 7.08 (broad singlet, 4H), 4.82 - 4.31 (multiplet, 6H), 4.12 - 3.67 (multiplet, 24H), 3.60 (broad singlet, 4H), 3.35 (broad singlet, 4H), 3.30 - 2.87 (multiplet, 12H), 1.50 - 1.24 (multiplet, 24H).

[0937] Example 6,

[0938] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-((oxybis(ethane-2,1-diyl)) Bis(oxy)bis(acetyl)bis(2-methylpiperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridine- 5-Keto)

[0939]

[0940] LCMS (ES, m / z): 618.6 [M / 2 + H] +

[0941] 1H NMR (400MHz, methanol-d4) δ = 7.94 (br s, 2H), 7.28-7.20 (m, 4H), 7.03 (s, 4H), 4.50-4.22 (m, 5H), 4.07-3.94 (m, 3H), 3.93-3.78 (m, 11H), 3.73 (br s, 12H), 3.59-3.46 (m, 5H), 3.44-3.32 (m, 4H), 3.25 (br d, J=13.4Hz, 4H), 3.20-2.84 (m, 10H), 1.42 (d, J=6.4Hz, 12H), 1.36-1.23 (m, 12H).

[0942] Embodiment 7,

[0943] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,2-phenylene)bis(acetyl)) Bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6- (4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[0944]

[0945] LCMS (ES, m / z): 604.6 [M / 2+H] +

[0946] 1 H NMR (400MHz, methanol-d4) δ = 8.52 (s, 2H), 8.14 (br d, J=4.4Hz, 2H), 7.24-7.16 (m, 4H), 7.16-7.09 (m, 2H), 7.00 (q, J=7.6Hz, 6H), 3.92-3.83 (m, 3H), 3.80 (br d, J=10.3Hz, 8H), 3.73-3.63(m, 7H), 3.61-3.34(m, 5H), 3.29-3.15(m, 5H), 3.11-2.67(m, 14H), 2.47(br s, 1H), 2.29(br d, J=3.8Hz, 1H), 2.18-1.98 (m, 4H), 1.36 (br d, J=15.5Hz, 12H), 1.25 (br d, J=5.9Hz, 6H), 1.03-0.94 (m, 6H).

[0947] Embodiment 8,

[0948] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,2-phenylenebis(oxy))bis (acetyl)bis(2-methylpiperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[0949]

[0950] LCMS (ES, m / z): 620.6 [M / 2+H] +

[0951] 1 H NMR (400 MHz, methanol-d4) δ = 8.54 (s, 2H), 8.15 (br t, J = 8.0 Hz, 2H),

[0952] 7.24-7.16(m, 4H), 7.04-6.89(m, 8H), 4.75(br d, J=4.8Hz, 6H), 3.92-3.73 (m, 13H), 3.69-3.58 (m, 2H), 3.35 (s, 2H), 3.25-3. 11(m, 4H), 3.08-2.78(m, 12H), 2.76-2.62(m, 2H), 2.54-1.90(m, 7H), 1.37(br d, J=5.6Hz, 12H), 1.21 (br s, 6H), 1.07-0.95 (m, 6H).

[0953] Embodiment 9,

[0954] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-isophthaloylbis(2-methylpiperazine-4,1-dicarboxylic acid) bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis(6-(4-fluorobenzyl)-3,3-dimethyl- 1,2,3,4-Tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[0955]

[0956] LCMS (ES, m / z): 590.5 [M / 2+H] +

[0957] 1 H NMR (400MHz, methanol-d4) δ = 8.80-8.33 (m, 2H), 8.27-8.08 (m, 2H), 7.60-7.53 (m, 1H), 7.45 (br d, J = 7.3Hz, 2H), 7.19 (br s, 5H), 6.97 (br s, 4H), 4.04-3.46 (m, 18H), 3.35 (s, 2H), 3.25-3.13 (m, 4H), 3.11-2.57 (m, 14H), 2.49-1.87 (m, 6H), 1.45-1.29 (m, 12H), 1.26 (br s, 6H), 1.12-0.89 (m, 6H).

[0958] Embodiment 10,

[0959] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,3-phenylene)bis(acetyl)) Bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6- (4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[0960]

[0961] LCMS (ES, m / z): 604.6 [M / 2+H]+

[0962] 1 H NMR (400MHz, methanol-d4) δ = 8.45 (s, 2H), 8.29-8.17 (m, 2H), 7.26-7.19 (m, 4H), 7.07-6.95 (m, 6H), 6.85-6.59 (m, 2H), 4.10-3.79 (m, 10H), 3. 77-3.45(m, 13H), 3.28-3.08(m, 8H), 3.07-2.90(m, 5H), 2.89-2.47(m, 7H), 2.23-2.03(m, 3H), 2.00-1.88(m, 2H), 1.38(s, 6H), 1.26(br d, J=6.0Hz, 7H), 1.20(br d, J=4.0Hz, 3H), 1.12 (s, 2H), 1.00-0.92 (m, 6H).

[0963] Embodiment 11,

[0964] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,3-phenylenebis(oxy))bis (acetyl)bis(2-methylpiperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[0965]

[0966] LCMS (ES, m / z): 620.6 [M / 2+H] +

[0967] 1 H NMR (400 MHz, methanol-d4) δ = 8.49 (s, 2H), 8.26-8.13 (m, 2H),

[0968] 7.22(br d, J=4.9Hz, 4H), 7.09-6.89(m, 5H), 6.51-6.21(m, 3H), 4.68(br d, J=9.0Hz, 4H), 4.04-3.42(m, 19H), 3.30-3.18(m, 6H), 3.15-2.87(m, 11H), 2.73(br t, J=11.9Hz, 2H), 2.53-2.35 (m, 2H), 2.24-2.00 (m, 4H), 1.43-1.38 (m, 6H), 1.37-1.30 (m, 6H), 1.25 (d, J=6.4Hz, 6H), 1.11-0.97 (m, 6H).

[0969] Embodiment 12,

[0970] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,4-phenylene)bis(acetyl)) Bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6- (4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[0971]

[0972] LCMS (ES, m / z): 604.6 [M / 2 + H] +

[0973] 1 H NMR (400 MHz, methanol-d4) δ = 8.46 (br s, 2H), 8.16 - 8.10 (m, 2H), 7.20 (br t, J = 6.2 Hz, 4H), 7.07 - 6.95 (m, 8H), 3.89 - 3.76 (m, 9H), 3.75 - 3.56 (m, 11H), 3.55 - 3.45 (m, 2H), 3.29 - 3.15 (m, 6H), 3.13 - 2.68 (m, 14H), 2.47 (br d, J = 6.6 Hz, 1H), 2.30 - 2.20 (m, 1H), 2.15 - 1.97 (m, 4H), 1.34 (br s, 6H), 1.26 (dd, J = 6.1, 10.0 Hz, 12H), 1.03 - 0.93 (m, 6H).

[0974] Example 13

[0975] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,4-phenylenebis(oxy))bis (acetyl)bis(2-methylpiperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[0976]

[0977] LCMS (ES, m / z): 620.6 [M / 2 + H] +

[0978] 1 H NMR (400 MHz, methanol-d4) δ = 8.44 (s, 2H), 8.20 - 8.12 (m, 2H), 7.21 (ddd, J = 2.8, 5.3, 8.4 Hz, 4H), 6.98 (q, J = 8.9 Hz, 4H), 6.79 - 6.66 (m, 4H), 4.73 - 4.59 (m, 4H), 4.01 - 3.42 (m, 19H), 3.29 - 3.20 (m, 4H), 3.17 - 3.02 (m, 3H), 3.02 - 2.84 (m, 8H), 2.74 (br t, J = 11.8 Hz, 2H), 2.45 (br d, J = 3.1 Hz, 2H), 2.24 - 2.01 (m, 4H), 1.39 (s, 6H), 1.32 (br d, J = 18.7 Hz, 6H), 1.26 (d, J = 6.4 Hz, 6H), 1.11 - 0.96 (m, 6H).

[0979] Embodiment 14,

[0980] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-((2E,2'E)-3,3'-(1,4-phenylene)bis(phenylene) (acryloyl)bis(2-methylpiperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[0981]

[0982] LCMS (ES, m / z): 616.5 [M / 2+H] +

[0983] 1 H NMR (400MHz, methanol-d4) δ = 8.47 (s, 2H), 8.16 (s, 2H), 7.65 (s, 4H), 7.60-7.52 (m, 2H), 7.23 (br s, 4H), 7.15 (br d, J=15.4Hz, 2H), 7.05-6.95(m, 4H), 3.91-3.77(m, 16H), 3.47(br s, 3H), 3.38(br d, J=11.7Hz, 2H), 3.30-3.10(m, 4H), 3.08-2.91(m, 9H), 2.79(br t, J=11.9Hz, 2H), 2.50(br s, 2H), 2.32-2.04 (m, 4H), 1.40 (d, J=5.3Hz, 12H), 1.27 (d, J=6.4Hz, 6H), 1.07 (br d, J=2.4Hz, 6H).

[0984] Embodiment 15,

[0985] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(methylmethazinediyl (methylazanediyl))bis(acetyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine oxazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3, 2-b]pyridin-5-one)

[0986]

[0987] LCMS (ES, m / z): 581.0 [M / 2+H] +

[0988] 1H NMR (400MHz, methanol-d4) δ=8.01 (s, 2H), 7.26 (dd, J=5.6, 8.0Hz, 4H), 7.06 (t, J=8.8Hz, 4H), 4.64-4.31 (m, 4H), 4.04-3.79(m, 13H), 3.79-3.59(m, 5H), 3.58-3.32(m, 12H), 3.30-3.16(m, 4H), 3.15-2.60(m, 11H), 1.42(br d, J=6.0Hz, 12H), 1.37-1.21 (m, 12H).

[0989] Embodiment 16,

[0990] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(pyrazine-2,5-dicarbonyl)bis(2-methylpiperidin oxazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3, 3-Dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[0991]

[0992] LCMS (ES, m / z): 591.5 [M / 2+H] +

[0993] 1 H NMR (400MHz, methanol-d4) δ = 8.78 (d, J = 4.4Hz, 2H), 8.47 (s, 2H), 8.16-8.10 (m, 2H), 7.21 (ddd, J =5.5, 8.5, 11.8Hz, 4H), 7.04-6.91(m, 4H), 4.04-3.94(m, 1H), 3.90-3.70(m, 14H), 3.64(br dd, J=2.8, 14.2Hz, 1H), 3.55-3.45(m, 3H), 3.41-3.32(m, 3H), 3.29-3.16(m, 4H), 3.08-2.84(m, 10H), 2.77(br t, J=11.7Hz, 2H), 2.64 (br s, 1H), 2.48 (br d, J=5.1Hz, 1H), 2.31-2.08 (m, 4H), 1.39 (s, 12H), 1.26 (dd, J=2.3, 6.1Hz, 6H), 1.11 (br d, J=6.2Hz, 3H), 0.97 (br d, J=6.2Hz, 3H).

[0994] Embodiment 17,

[0995] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-([2,2'-bipyridine]-3,3'-dicarbonyl)bis( (2-methylpiperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis(6-(4- fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[0996]

[0997] LCMS (ES, m / z): 629.7 [M / 2+H] +

[0998] 1 H NMR (400MHz, methanol-d4) δ = 9.03-8.69 (m, 2H), 8.32-7.88 (m, 4H), 7.82-7.42 (m, 2H), 7.32-6.78 (m, 8H), 4.8 3-4.40(m, 2H), 4.16-3.68(m, 20H), 3.65-3.43(m, 6H), 3.41-3.33(m, 4H), 3.28-2.53(m, 10H), 1.44(br s, 12H), 1.40-1.02 (m, 12H).

[0999] Embodiment 18,

[1000] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(naphthalene-2,6-dicarbonyl)bis(2-methylpiperazine- 4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3- dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1001]

[1002] LCMS (ES, m / z): 615.5 [M / 2+H] +

[1003] 1 H NMR (400MHz, methanol-d4) δ = 8.51 (s, 2H), 8.12-7.97 (m, 4H), 7.91 (s, 2H), 7.49 (br s, 2H), 7.23-6.66 (m, 8H), 4.09-3.90 (m, 2H), 3.89-3.66 (m, 13H), 3.53-3.36 (m, 4H), 3.29-3.19 (m, 4H), 3 .18-2.88(m, 11H), 2.87-2.63(m, 4H), 2.62-2.25(m, 3H), 2.19-2.06(m, 3H), 1.45-1.38(m, 12H), 1.24(br d, J=6.0Hz, 6H), 1.19-1.11 (m, 3H), 0.85 (br d, J=3.8Hz, 3H).

[1004] Embodiment 19,

[1005] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-terephthaloylbis(2-methylpiperazine-4,1-dicarboxylic acid) bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis(6-(4-fluorobenzyl)-3,3-dimethyl- 1,2,3,4-Tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1006]

[1007] LCMS (ES, m / z): 590.6 [M / 2+H] +

[1008] 1 H NMR (400MHz, methanol-d4) δ = 8.53 (s, 2H), 8.12 (br s, 2H), 7.40 (br s, 4H), 7.19 (br d, J=12.2Hz, 4H), 7.04-6.87 (m, 4H), 4.01-3.68 (m, 14H), 3.53-3.32 (m, 5H), 3.22 (brd, J=6.5Hz, 4H), 3.13 (br dd, J=2.6, 4.1Hz, 2H), 2.96 (br s, 8H), 2.83-2.65 (m, 3H), 2.62-2.21 (m, 3H), 2.18-2.06 (m, 3H), 1.39 (s, 12H), 1.23 (br d, J=6.0Hz, 6H), 1.12 (br d, J=3.5Hz, 3H), 0.90 (br s, 3H).

[1009] Embodiment 20,

[1010] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(4,4'-((E)-ethylene-1,2-diyl)bis(phenylene) bis(formyl)bis(2-methylpiperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1011]

[1012] LCMS (ES, m / z): 641.6 [M / 2+H] +

[1013] 1 H NMR (400MHz, methanol-d4) δ = 8.51 (s, 2H), 8.08 (br s, 2H), 7.68 (d, J = 8.2Hz, 4H), 7.38-7.29 (m, 6H), 7.26-6.81 (m, 8H), 4.08-3.7 0(m, 15H), 3.54-3.35(m, 5H), 3.30-3.11(m, 4H), 3.10-2.83(m, 10H), 2.76(br t, J=11.8Hz, 2H), 2.61-2.41 (m, 2H), 2.34-2.06 (m, 4H), 1.41 (d, J=8.8Hz, 12H), 1.25 (d, J=6.4Hz, 6H), 1.19-0.84 (m, 6H).

[1014] Embodiment 21,

[1015] 1,4-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- Tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazine- 1-methyl)butane-1,4-dione

[1016]

[1017] LCMS (ES, m / z): 566.6 [M / 2+H] +

[1018] 1 H NMR (400MHz, methanol-d4) δ = 8.46 (br s, 2H), 8.16 (br s, 2H), 7.28-7.19 (m, 4H), 7.00 (br t, J = 8.2Hz, 4H), 3.91-3.60 (m, 16H), 3.49 (br d, J=1.8Hz, 3H), 3.34(br s, 1H), 3.28(br d, J=6.2Hz, 3H), 3.08-2.86(m, 11H), 2.76(br t, J=11.7Hz, 2H), 2.64-2.38 (m, 6H), 2.25-2.03 (m, 4H), 1.38 (s, 12H), 1.26 (d, J=6.4Hz, 6H), 1.10-0.97 (m, 6H).

[1019] Embodiment 22,

[1020] 1,5-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- Tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazine- 1-yl)pentane-1,5-dione

[1021]

[1022] LCMS (ES, m / z): 573.6 [M / 2+H] +

[1023] 1 H NMR (400MHz, methanol-d4) δ = 8.38 (s, 2H), 8.23-8.13 (m, 2H), 7.27-7.17 (m, 4H), 7.07-6.96 (m, 4H), 4.05-3.70 (m, 13H), 3.70-3.42 (m, 6H), 3. 29-3.05(m, 6H), 3.04-2.80(m, 8H), 2.80-2.66(m, 3H), 2.55-2.25(m, 6H), 2.23-2.07(m, 2H), 2.06-1.88(m, 2H), 1.77(brs, 2H), 1.39(br) d, J=4.0Hz, 6H), 1.36-1.25 (m, 12H), 1.06 (br t, J=5.7Hz, 3H), 0.98 (brt, J=7.3Hz, 3H).

[1024] Embodiment 23,

[1025] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-([2,2'-bipyridine]-4,4'-dicarbonyl)bis( (2-methylpiperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis(6-(4- fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1026]

[1027] LCMS (ES, m / z): 629.5 [M / 2+H] +

[1028] 1 H NMR (400MHz, methanol-d4) δ = 8.77 (br d, J = 4.3Hz, 2H), 8.53 (br s, 2H), 8.34 (brs, 2H), 8.12 (br s, 1H), 8.04 (s, 1H), 7.39 (br s, 2H), 7.19 (br s, 2H), 7.10 (br s, 2H), 6.95 (br t, J=8.1Hz, 2H), 6.83 (br t, J=8.3Hz, 2H), 3.97-3.69 (m, 14H), 3.51-3.35 (m, 4H), 3.20 (br s, 6H), 3.08-2.67 (m, 12H), 2.60 (br s, 1H), 2.45 (br s, 1H), 2.30 (br s, 1H), 2.14 (br d, J=12.6Hz, 3H), 1.47-1.34 (m, 12H), 1.22 (br s, 6H), 1.14 (br d, J=5.8Hz, 3H), 0.91 (br s, 3H).

[1029] Scheme 2: General method for Examples 24-28.

[1030]

[1031] Embodiment 24,

[1032] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-octane-1,8-diylbis(2-methylpiperazine-4, 1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-di Methyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one) .

[1033]

[1034] Step 1 of 2: _ Di-tert-butyl 5,5'-(((2R,2'R)-octane-1,8-diylbis(2-methylpiperazine-4,1- bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyldimethylsilyl)oxy)-6- (4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl Piperazine-1-carboxylate) The synthesis of.

[1035] Tert-butyl (2R,5S)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-2-methylpiperazin-1-yl)methyl)piperazine-1-carboxylate (Intermediate 6.2) (149 mg, 202 umol, 2.2 equiv), 1,8-dibromooctane (25 mg, 91.9 umol, 17.0 uL, 1 equiv), KI (30.5 mg, 184 umol, 2 equiv) and DIEA (47.5 mg, 367 umol, 64.0 uL, 4 equiv) were stirred in CH 3 The mixture in CN (3 mL) was stirred at 45 °C for 24 h, after which LCMS indicated complete conversion to the target mass of product. The mixture was concentrated to dryness and the residue was purified by preparative TLC (petroleum ether / ethyl acetate / NH 3 .H2O=100:10:4) to give the target compound (86 mg, 54.1 umol, 58.9% yield) as a yellow oil.

[1036] LCMS (ES, m / z): 1589.1 [M+H] +

[1037] Step 2 of 2: 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-octane-1,8-diylbis(2-hydroxy-1-yl)- (2-methylpiperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis(6-(4- fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one) The synthesis of.

[1038] To a solution of di-tert-butyl 5,5'-(((2R,2'R)-octane-1,8-diylbis(2-methylpiperazine-4,1-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate) (86 mg, 54.1 umol, 1 eq) in EtOAc (1.5 mL) was added dropwise HCl / EtOAc (4 M, 1.5 mL) at 15°C. The mixture was stirred at 15°C for 2 h, after which LCMS indicated complete conversion to the target mass of product. The mixture was filtered to give the crude product. The material was purified by preparative HPLC (FA conditions; column: Phenomenex Luna C18

[1039] 200*40mm*10um; mobile phase: [water (0.2% FA)-ACN]; B%: 10%-50%, 8min) to obtain the target compound (28.6mg, 22.8umol, 42.2% yield, 100% purity, 2FA) as a white solid.

[1040] LCMS (ES, m / z): 580.6 [M / 2+H] +

[1041] 1 H NMR (400MHz, methanol-d4) δ = 8.52 (br s, 2H), 8.38 (s, 2H), 7.34 (dd, J = 5.6, 7.9Hz, 4H), 6.98 (t, J = 8.6Hz, 4H), 4.20 (br d, J=18.1Hz, 2H), 4.00 (d, J=14.2Hz, 2H), 3.93-3.79 (m, 4H), 3.78-3.64 (m, 4H), 3.56 (br d, J=17.6Hz, 2H), 3.44-3.33(m, 2H), 3.29-2.99(m, 9H), 2.99-2.92(m, 2H), 2.83-2.63(m, 4H), 2.51(br d, J=3.5Hz, 2H), 2.39-2.09 (m, 4H), 2.08-1.76 (m, 9H), 1.52 (d, J=19.8Hz, 12H), 1.27 (br d, J=6.3Hz, 6H), 1.12 (brd, J=5.8Hz, 8H), 1.03-0.72 (m, 10H).

[1042] Examples 25-28 were prepared according to the same procedure as Example 24, substituting 1,8-dibromooctane with the appropriate dibromide. The compounds of Examples 25-28 were found to have the characterization data described below.

[1043] Embodiment 25,

[1044] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-decane-1,10-diylbis(2-methylpiperazine-4, 1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-di Methyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1045]

[1046] LCMS (ES, m / z): 594.7 [M / 2+H] +

[1047] 1H NMR (400MHz, methanol-d4) δ = 8.54 (s, 2H), 8.28 (s, 2H), 7.37-7.25 (m, 4H), 6.99 (t, J = 8.8Hz, 4H), 4.07 (br d, J=17.4Hz, 2H), 3.97-3.60 (m, 12H), 3.23-2.89 (m, 12H), 2.75-2.48 (m, 6H), 2.3 6-1.70 (m, 14H), 1.50 (s, 6H), 1.43 (s, 6H), 1.40-1.34 (m, 1H), 1.27-1.03 (m, 27H).

[1048] Embodiment 26,

[1049] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-dodecane-1,12-diylbis(2-methylpiperazine- 4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3- dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1050]

[1051] LCMS (ES, m / z): 608.7 [M / 2+H] +

[1052] 1 H NMR (400MHz, methanol-d4) δ = 8.50 (s, 2H), 8.21 (s, 2H), 7.28 (dd, J = 5.5, 8.4Hz, 4H), 7. 00(t, J=8.8Hz, 4H), 3.98-3.84(m, 6H), 3.78(s, 3H), 3.75-3.67(m, 3H), 3.60(br s, 2H), 3.26 (br d, J=9.1Hz, 4H), 3.18-3.03 (m, 6H), 2.97 (br d, J=10.1Hz, 6H), 2.75 (br t, J=10.8Hz, 2H), 2.56-1.93(m, 14H), 1.48-1.34(m, 14H), 1.32-1.06(m, 30H).

[1053] Embodiment 27,

[1054] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(1,4-phenylenebis(methylene))bis(2-methyl 4-(6-(4-fluorobenzyl)piperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis ... 1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1055]

[1056]

[1057] LCMS (ES, m / z): 576.5 [M / 2+H] +

[1058] 1 H NMR (400MHz, methanol-d4) δ = 8.41 (s, 2H), 8.22 (s, 2H), 7.30-7.24 (m, 4H), 7.02-6. 93(m, 8H), 4.07-3.90(m, 4H), 3.83-3.68(m, 6H), 3.66-3.55(m, 4H), 3.42(br d, J=13.1Hz, 2H), 3.27-3.13(m, 8H), 3.08-2.90(m, 6H), 2.77-2.47(m, 6H), 2.35-2.19(m, 2H), 2.11-1.85(m, 6H), 1.70(br s, 2H), 1.41 (s, 6H), 1.29-1.22 (m, 12H), 1.00 (d, J=6.2Hz, 6H).

[1059] Embodiment 28,

[1060] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-((perfluoro-1,4-phenylene)bis(methylene)) Bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6- (4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1061]

[1062] LCMS (ES, m / z): 612.5 [M / 2+H] +

[1063] 1 H NMR (400MHz, methanol-d4) δ = 8.51 (s, 2H), 8.25 (s, 2H), 7.33 (dd, J = 5.5, 8.4Hz, 4H), 7.02 (br t, J = 8.8Hz, 4H), 4.58-4.52 (m, 2H), 4.16 (br d, J=17.6Hz, 2H), 3.98-3.90(m, 2H), 3.85-3.73(m, 6H), 3.60-3.45(m, 6H), 3.35(s, 2H), 3.19-2.89(m, 12H), 2.69-2.40(m, 6H), 2.20(br d, J=7.4Hz, 2H), 1.99-1.59 (m, 8H), 1.43 (s, 5H), 1.25 (br d, J=6.4Hz, 6H), 1.16-0.98 (m, 11H).

[1064] Scheme 3: General method for Examples 29-30.

[1065]

[1066] Embodiment 29,

[1067] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-([1,1'-biphenyl]-4,4'-disulfonyl) (2-methylpiperazine-4,1-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis(6-(4- fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one).

[1068]

[1069] Step 1 of 2: Di-tert-butyl 5,5'-(((2R,2'R)-([1,1'-biphenyl]-4,4'-disulfonyl)bis(2- Methylpiperazine-4,1-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyldimethylsilane (4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl 2-Methylpiperazine-1-carboxylate The synthesis of.

[1070] At 15 ℃ 4-(4-chlorosulfonylphenyl)benzenesulfonyl chloride (21.6 mg, 61.5 umol, 1 eq) was added to a mixture of (2R,5S)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-2-methylpiperazin-1-yl)methyl)piperazine-1-carboxylic acid tert-butyl ester (Intermediate 6.2) (100 mg, 135 umol, 2.2 eq) and DIEA (39.7 mg, 307 umol, 53.5 uL, 5 eq) in DCM (2 mL). The mixture was stirred at 35 °C for 2 h, and then LCMS indicated complete conversion to the target mass of the product. The mixture was concentrated to dryness and the crude product was analyzed by preparative TLC (SiO 2 , petroleum ether / ethyl acetate = 1:2) to obtain the target compound (85 mg, 48.4 umol, 78.7% yield) as a yellow solid.

[1071] LCMS (ES, m / z): 1757.0 [M+H] +

[1072] Step 2 of 2: 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-([1,1'-biphenyl]-4, 4'-disulfonyl)bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(ethyl Bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one) The synthesis of.

[1073] A solution of di-tert-butyl 5,5'-(((2R,2'R)-([1,1'-biphenyl]-4,4'-disulfonyl)bis(2-methylpiperazine-4,1-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate) (85 mg, 48.4 umol, 1 equiv) in HCl / EtOAc (3 M, 2 mL) was stirred at 15 °C for 1 h, after which LCMS indicated complete conversion to the target mass of the product. The precipitate was filtered and the filter cake was dried to give the target compound (28.1 mg, 19.8 umol, 41% yield, 98% purity, 2HCl) as a white solid.

[1074] LCMS (ES, m / z): 1327.6 [M+H] +

[1075] 1 H NMR (400 MHz, deuterium oxide) δ ppm 7.79 (br s, 2H) 7.60 (br s, 4H) 7.00-7.30 (m, 4H) 6.61-6.90 (m, 8H) 3.63-4.22 (m, 18H) 3.53 (br s, 4H) 2.94-3.40 (m, 18H) 2.22-2.85 (m, 2H) 1.12-1.50 (m, 24H).

[1076] Example 30 was prepared according to the same procedure as Example 29, replacing 4-(4-chlorosulfonylphenyl)benzenesulfonyl chloride with 4,4'-oxydibenzenesulfonyl chloride: Example 30 was found to have the characterization data described below.

[1077] Embodiment 30,

[1078] 2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(oxybis(4,1-phenylenesulfonyl))bis(2-methyl Piperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethylpiperazine- 5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one)

[1079]

[1080] LCMS (ES, m / z): 1343.7 [M+H] +

[1081] 1H NMR (400MHz, methanol-d4) δppm 8.04 (br s, 2H) 7.88 (br d, J = 2.50Hz, 4H) 7.18 (br s, 8H) 6.98 (br t, J=8.25Hz, 4H) 3.88-4.07 (m, 10H) 3.65-3.86 (m, 12H) 3.47-3.63 (m, 6H) 3.37 (br s, 4H) 2.98-3.29 (m, 10H) 1.42 (br d, J=6.00Hz, 18H) 1.35 (br d, J=6.00Hz, 6H)

[1082] Scheme 4: General method for Examples 31-34.

[1083]

[1084] Embodiment 31,

[1085] 1,14-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4, 5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin- (oxazine-1-yl)tetradecane-1,14-dione .

[1086]

[1087] Step 1 of 2: Di-tert-butyl 5,5'-(((2R,2'R)-tetradecanoylbis(2-methylpiperazine-4,1-diol) bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3, 4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate The synthesis of.

[1088] HATU (102 mg, 267 umol, 2.5 eq) was added to a mixture of tert-butyl (2R,5S)-4-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-2-methylpiperazin-1-yl)methyl)piperazine-1-carboxylate (Intermediate 7.2) (150 mg, 235 umol, 2.2 eq), tetradecanedioic acid (27.6 mg, 107 umol, 1 eq) and DIEA (55.2 mg, 427 umol, 74.3 uL, 4 eq) in DCM (2 mL) at 15° C. The mixture was stirred at 35° C. for 12 h, then LCMS indicated conversion to the desired mass of product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 150*30mm*5um; mobile phase:

[1089] [water (0.1% TFA)-MeOH]; B%: 62%-85%, 10 min) to give the title compound (45 mg, 30.0 umol, 28.1% yield) as a white solid.

[1090] LCMS (ES, m / z): 750.9 [M / 2+H] +

[1091] Step 2 of 2: 1,14-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl- 5-Oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl 1-Methylpiperazin-1-yl)tetradecane-1,14-dione The synthesis of.

[1092] A solution of di-tert-butyl 5,5'-(((2R,2'R)-adipoylbis(2-methylpiperazine-4,1-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate) (45 mg, 30.0 umol, 1 eq) in EtOAc was treated with HCl / EtOAc (4M, 2 mL) with stirring at 15°C for 1 h, then LCMS indicated conversion to the target mass of the product. The precipitate was filtered and the filter cake was dried to give the crude product. The material was purified by preparative HPLC (TFA conditions; column: Phenomenex Gemini-NX 150mm*30mm*5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 25%-45%, 12min) to give the target compound (19.2mg, 12.3umol, 41.1% yield, 98% purity, 2TFA) as a white solid.

[1093] LCMS (ES, m / z): 650.6 [M / 2+H] +

[1094] 1 H NMR (400 MHz, methanol-d 4)δppm 8.00-8.13(m,2H)7.24(dd,J=7.75,5.75Hz,4H)6.94-7.07(m,4H)3.74-4.02(m,14H)3.55-3 .72(m,10H)3.34-3.54(m,7H)3.11-3.29(m,7H)2.59-3.11(m,10H)2.37-2.53(m,4H)1.63(br t, J=12.76Hz, 4H) 1.54 (d, J=5.00Hz, 12H) 1.24-1.39 (m, 27H) 1.20 (br s, 2H)

[1095] Examples 32-34 According to the same procedure as in Example 31, tetradecanedioic acid was replaced with an appropriate dicarboxylic acid. The compounds of Examples 32-34 were found to have the characteristic data described below.

[1096] Embodiment 32,

[1097] 1,6-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4, 5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin- Oxazine-1-yl)hexane-1,6-dione

[1098]

[1099] LCMS (ES, m / z): 1187.8 [M+H] +

[1100] 1 H NMR (400 MHz, methanol-d 4 )δ=8.02(br d, J=4.5Hz, 2H), 7.26-7.22(m, 4H), 7.02(br t, J=8.6Hz, 4H), 4.04-3.96 (m, 3H), 3.95-3.78 (m, 12H), 3.74-3.64 (m, 10H), 3.61 -3.48(m, 6H), 3.29-3.21(m, 4H), 3.18-2.93(m, 11H), 2.67-2.50(m, 5H), 1.79(br s, 5H), 1.57-1.53 ​​(m, 12H), 1.34 (br s, 9H), 1.25 (br d, J=4.6Hz, 3H)

[1101] Embodiment 33,

[1102] 1,8-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4, 5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin- (oxazine-1-yl)octane-1,8-dione

[1103]

[1104] LCMS (ES, m / z): 1215.9 [M / 2+H] +

[1105] 1 H NMR (400 MHz, DMSO-d 6 )δppm 10.11(br s,2H)9.36-9.73(m,2H)8.01(br d, J=3.50Hz, 2H) 7.26 (dd, J=8.25, 5.75Hz, 4H) 6.98-7.15 (m, 4H) 3.81-3.97 (m, 11H) 3.58-3.78 (m, 20H) 3.53 (s, 6H) 2.85-3.21 (m, 11H) 2.40 (br s, 4H) 1.53 (br s, 4H) 1.43 (s, 12H) 1.16-1.37 (m, 16H).

[1106] Embodiment 34,

[1107] 1,10-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4, 5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin- Oxazine-1-yl)decane-1,10-dione

[1108]

[1109] LCMS (ES, m / z): 622.7 [M / 2+H] +

[1110] 1 H NMR (400 MHz, methanol-d 4 )δppm 7.89-8.11 (m, 2H) 7.18-7.31 (m, 4H) 7.02 (br t, J=8.50Hz, 4H) 4.41-4.72 (m, 2H) 4.10-4.33 (m, 2H) 3.77-4.09 (m, 14H) 3.70 (s, 8H) 3.59 (br s, 3H) 3.34-3.49 (m, 4H) 2.84-3.29 (m, 14H) 2.54 (br s, 4H) 1.70 (br s, 4H) 1.57 (d, J=6.50Hz, 12H) 1.26-1.48 (m, 21H).

[1111] Scheme 5: General method for Examples 35-36.

[1112]

[1113] Embodiment 35,

[1114] 2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-isophthaloylbis(2-methylpiperazine-4,1-diyl))bis (methylene)bis(3-methylpiperazine-6,1-diyl)bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyridine) pyridin-1-yl)ethan-1-one .

[1115]

[1116] Step 1 of 2: Di-tert-butyl 5,5'-(((2R,2'R)-isophthaloylbis(2-methylpiperazine-4,1-dicarboxylic acid) bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H- Pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate The synthesis of.

[1117] At 0 ° C, methanesulfonyl chloride (290mg, 2.53mmol) is added to a solution of (2R, 5R)-4-{2-[6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (760mg, 1.45mmol) and triethylamine (293mg, 2.89mmol) in dichloromethane (20mL). The solution is warmed to room temperature and stirred overnight under a nitrogen atmosphere. The mixture is distributed between aqueous ammonium chloride solution and dichloromethane and the organic phase is dried with sodium sulfate and evaporated in vacuo. The residue is purified by flash chromatography on silica gel, eluted with petroleum ether / ethyl acetate (1:1) to give an intermediate product (500mg, 0.917mmol, 63.7% yield) as a white solid.

[1118] Potassium iodide (91.4 mg, 0.550 mmol) and potassium carbonate (152 mg, 1.101 mmol) were added to a solution of the intermediate product (150 mg, 0.275 mmol) and 1,3-phenylenebis(((R)-3-methylpiperazine-1-yl)methanone) dihydrochloride (bisamine intermediate A-017) (55.5 mg, 0.138 mmol) in acetonitrile (20 ml). The resulting mixture was stirred at 70 ° C overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3*20 mL). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was sequentially passed through preparative TLC (petroleum ether / ethyl acetate=1:3) and then through preparative HPLC (column: Phenomenex Gemini C-18

[1119] 150mm*21.2mm*5um; mobile phase: [water-ACN]; B%: 5%-50%, 10min) to obtain the target compound (50mg, 0.037mmol, 26.9% yield) as a colorless oil.

[1120] LCMS (ES, m / z): 673.9 [M / 2+H] +

[1121] Step 2 of 2: 2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-isophthaloylbis(2-methylpiperidin oxazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(6-(4-fluorobenzyl)-

[1122] 3,3-Dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one) The synthesis of.

[1123] To a solution of di-tert-butyl 5,5'-(((2R,2'R)-isophthaloylbis(2-methylpiperazine-4,1-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate) (50 mg, 0.037 mmol) in dichloromethane (5 mL) was added 4M hydrochloric acid in dioxane (5 mL). The resulting mixture was stirred at room temperature for 4 h and then concentrated to dryness to give the title compound (10.5 mg, 0.008 mmol, 23.3% yield, 2HCl) as a white solid.

[1124] LCMS (ES, m / z): 1147.5 [M+H] + .

[1125] 1 H NMR (400MHz, DMSO-d6) δ10.00 (s, 2H), 9.41 (s, 2H), 8.24 (s, 2H), 8.16 (s, 2H), 7.61 (s, 4H), 7.35-7.25 (t, 4H), 7.15-7.03 (t, 4H) , 4.03-3.92(m, 12H), 3.78-3.52(m, 12H), 3.49-3.36(m, 6H), 3.32-3.14(m, 6H), 3.12-2.81(m, 6H), 1.35(s, 12H), 1.24(s, 12H).

[1126] Example 36 was prepared according to the same procedure as Example 35, substituting 1,3-phenylenebis(((R)-3-methylpiperazin-1-yl)methanone) dihydrochloride with 1,3-bis(((R)-3-methylpiperazin-1-yl)sulfonyl)benzene dihydrochloride. The compound of Example 36 was found to have the characterization data described below.

[1127] Embodiment 36,

[1128] 2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(1,3-phenylenedisulfonyl)bis(2-methylpiperazine-4, 1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3- dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one)

[1129]

[1130] LCMS (ES, m / z): 609.8 [M / 2+H] +

[1131] 1 H NMR (400MHz, DMSO)d ppmδ10.10 (s, 2H), 9.57 (s, 2H), 8.26 (s, 2H), 8.17 (s, 2H), 8.06 (s, 2H), 8.02 (s, 1H), 7.87 (s, 1H), 7.32 (dd, J=8.4, 5.6, 4H), 7.20–7.12 (m, 4H ), 4.12–3.93(m, 12H), 3.92–3.77(m, 4H), 3.59–3.36(m, 12H), 3.32–3. 13(m, 8H), 3.12–2.91(m, 6H), 1.39–1.30(m, 12H), 1.27–1.20(m, 12H).

[1132] Scheme 6: General method for Examples 37-42.

[1133]

[1134] Embodiment 37,

[1135] N1,N6-bis((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4, 5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl) Adipic acid amide .

[1136]

[1137] Step 1 of 2: Di-tert-butyl 5,5'-(((3S,3'S)-(adipoylbis(methazanediyl (azanediyl)))bis(piperidin-3,1-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyl) dimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- 2-( ... The synthesis of.

[1138] To a solution of tert-butyl (2R,5S)-5-(((S)-3-aminopiperidin-1-yl)methyl)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate (150 mg, 203 umol, 2.2 eq), adipic acid (13.5 mg, 92.3 umol, 15.3 uL, 1 eq) in DCM (2 mL) was added DIEA (47.7 mg, 369 umol, 64.3 uL, 4 eq) and HATU (87.7 mg, 231 umol, 2.5 eq). The mixture was stirred at 30 °C for 12 h, then LCMS indicated conversion to the target mass of the product. The reaction was concentrated in vacuo and the residue was purified by preparative TLC (SiO 2 , ethyl acetate / methanol = 10:1) to obtain the target compound (90 mg, 56.7 umol, 61.4% yield) as a yellow oil.

[1139] TLC (ethyl acetate / methanol = 10:1) R f =0.43

[1140] LCMS (ES, m / z): 1589.0 [M+H] +

[1141] Step 2 of 2: N1,N6-bis((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl- 5-Oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl 3-(4-(4-piperidin-3-yl)hexamethylenediamide The synthesis of.

[1142] To a solution of di-tert-butyl 5,5'-(((3S,3'S)-(adipoylbis(methylazanediyl))bis(piperidine-3,1-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate) (90 mg, 56.7 umol, 1 eq) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 2 mL, 141 eq). The mixture was stirred at 15 °C for 1 h, then LCMS indicated complete conversion to the target mass of the product. The reaction mixture was filtered to give the crude product. The crude material was purified by preparative HPLC (TFA conditions; column: Phenomenex LunaC18 100*30mm*5um; mobile phase: [water (0.1% TFA)-ACN]; B%: 10%-30%, 10 min) to give the target compound (24.1 mg, 17.3 umol, 30.4% yield, 99.3% purity, 2TFA) as a white solid.

[1143] LCMS (ES, m / z): 580.6 [M / 2+H] +

[1144] 1 H NMR (400 MHz, methanol-d 4)δ=8.15 (s, 2H), 7.23 (dd, J=5.5, 8.6Hz, 4H), 6.98 (t, J=8.8Hz, 4H), 4.01 (br d, J=11.0Hz, 3H), 3.89 (br d, J=10.5Hz, 3H), 3.85-3.76 (m, 7H), 3.70 (br s, 3H), 3.52 (br s, 3H), 3.31 (s, 5H), 3.29-3.05 (m, 10H), 3.01 (br d, J=11.4Hz, 2H), 2.74 (br s, 3H), 2.28-1.94 (m, 8H), 1.75 (br s, 2H), 1.57 (br s, 5H), 1.42 (d, J=4.4Hz, 12H), 1.29 (br d, J=6.6Hz, 6H).

[1145] Examples 38-42 were prepared according to the same procedure as Example 37, substituting adipic acid with the appropriate dicarboxylic acid. The compounds of Examples 38-42 were found to have the characterization data described below.

[1146] Embodiment 38,

[1147] N 1 ,N 8 -bis((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)octane Diamide

[1148]

[1149] LCMS (ES, m / z): 594.6 [M / 2+H] +

[1150] 1 H NMR (400MHz, methanol-d4) δ = 8.16 (s, 2H), 7.24 (dd, J = 5.5, 8.6Hz, 4H), 7.04-6.94 (m, 4H), 4.05-3.96 (m, 3H), 3.93-3.85 (m, 3H), 3.83 (br s, 3H), 3.78 (s, 4H), 3.67 (brs, 2H), 3.48 (br d, J=3.1Hz, 2H), 3.30-3.29 (m, 10H), 3.26-2.97 (m, 15H), 2.19-1.94 (m, 8H), 1.53 (br s, 4H), 1.42 (d, J=4.8Hz, 12H), 1.29 (br d, J = 6.1 Hz, 10H).

[1151] Embodiment 39,

[1152] N 1 ,N 10 -bis((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4, 5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl) Sebacic acid amide

[1153]

[1154] LCMS(ES, m / z): 608.6 [M / 2 + H] +

[1155] 1 H NMR(400 MHz, methanol-d4) δ = 8.18 (s, 2H), 7.25 (dd, J = 5.5, 8.6 Hz, 4H), 6.99 (t, J = 8.8 Hz, 4H), 4.03 (d, J = 11.0 Hz, 3H), 3.91 (br d, J = 10.5 Hz, 2H), 3.87 - 3.77 (m, 8H), 3.76 - 3.63 (m, 3H), 3.53 (br s, 2H), 3.43 (br s, 1H), 3.28 - 3.10 (m, 11H), 3.02 (br d, J = 14.0 Hz, 2H), 2.78 (br s, 4H), 2.23 - 1.94 (m, 8H), 1.77 (br s, 2H), 1.54 (br s, 5H), 1.42 (s, 12H), 1.40 - 1.33 (m, 3H), 1.30 (br d, J = 6.1 Hz, 6H), 1.23 (br s, 8H).

[1156] Example 40,

[1157] N 1 ,N 14 -bis((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4, 5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl) Tetradecanediamide

[1158]

[1159] LCMS(ES, m / z): 636.7 [M / 2 + H] +

[1160] 11H NMR (400 MHz, methanol-d4) δ = 8.20 (br s, 2H), 7.32 - 7.21 (m, 4H), 6.99 (t, J = 8.8 Hz, 4H), 4.03 (br d, J = 10.5 Hz, 4H), 3.90 (br d, J = 10.5 Hz, 3H), 3.86 (br s, 4H), 3.78 (s, 4H), 3.69 (br s, 3H), 3.58 - 3.32 (m, 4H), 3.29 - 3.07 (m, 13H), 3.00 (br s, 2H), 2.88 - 2.54 (m, 3H), 2.16 (br s, 8H), 1.80 (br s, 2H), 1.56 (br s, 5H), 1.45 - 1.39 (m, 12H), 1.29 (br d, J = 6.6 Hz, 6H), 1.22 (br d, J = 17.5 Hz, 15H).

[1161] Example 41,

[1162] 2,2'-(1,3-phenylene)bis(N-((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl- 5-Oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl 1-(4-(4-piperidin-3-yl)acetamide)

[1163]

[1164] LCMS (ES, m / z): 604.6 [M / 2 + H] +

[1165] 1 1H NMR (400 MHz, methanol-d4) δ = 8.07 (br s, 2H), 7.29 - 7.13 (m, 4H), 7.06 (br s, 4H), 6.88 (br s, 4H), 4.01 (br d, J = 11.0 Hz, 2H), 3.87 (br d, J = 10.8 Hz, 4H), 3.81 - 3.72 (m, 7H), 3.68 (br s, 5H), 3.55 - 3.36 (m, 9H), 3.26 - 3.07 (m, 12H), 3.04 - 2.64 (m, 3H), 2.18 - 1.91 (m, 5H), 1.82 - 1.46 (m, 5H), 1.41 (d, J = 6.4 Hz, 12H), 1.27 (br d, J = 5.5 Hz, 6H).

[1166] Example 42,

[1167] 2,2'-(1,4-phenylene)bis(N-((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl- 5-Oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl 1-(4-(4-piperidin-3-yl)acetamide)

[1168]

[1169] LCMS (ES, m / z): 604.6 [M / 2+H] +

[1170] 1 H NMR (400MHz, methanol-d4) δ = 8.18-7.97 (m, 2H), 7.24 (br s, 4H), 7.05 (br s, 4H), 6.87 (br s, 4H), 4.02 (br d, J = 10.6Hz, 2H), 3.87 (br d, J=11.0Hz, 4H), 3.80-3.73(m, 7H), 3.67(br s, 5H), 3.54-3.37(m, 9H), 3.16(br d, J=19.6Hz, 12H), 3.03-2.58 (m, 3H), 2.17-1.90 (m, 5H), 1.81-1.47 (m, 5H), 1.42 (d, J=5.4Hz, 12H), 1.28 (br d, J=5.5Hz, 6H).

[1171] Scheme 7: General method for Examples 43-48.

[1172]

[1173] Embodiment 43,

[1174] N1,N6-bis((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4, 5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl) Adipic acid amide .

[1175]

[1176] Step 1 of 2: Di-tert-butyl 5,5'-(((3R,3'R)-(adipoylbis(methylazanediyl))bis(piperidinyl- 3,1-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methyl 1-[4-(2-piperazine-1-carboxylate) The synthesis of.

[1177] To a solution of tert-butyl (2R,5S)-5-(((R)-3-aminopiperidin-1-yl)methyl)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate (120 mg, 162 umol, 2.3 eq.), adipic acid (10.3 mg, 70.6 umol, 11.7 uL, 1 eq.) in DCM (3 mL) was added DIEA (36.5 mg, 282 umol, 49.2 uL, 4 eq.) and HATU (67.1 mg, 177 umol, 2.5 eq.). The mixture was stirred at 15 °C for 2 h, then LCMS indicated conversion to the desired mass of the product. The reaction was concentrated in vacuo and the residue was analyzed by preparative TLC (SiO 2 , ethyl acetate / methanol=10:1) to afford the title compound (110 mg, 69.2 umol, 98% yield) as a yellow oil.

[1178] LCMS (ES, m / z): 1588.6 [M+H] +

[1179] Step 2 of 2: N1,N6-bis((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl- 5-Oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl 3-(4-(4-piperidin-3-yl)hexamethylenediamide The synthesis of.

[1180] To a solution of di-tert-butyl 5,5'-(((3R,3'R)-(adipoylbis(methylazanediyl))bis(piperidine-3,1-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate) (110 mg, 69.2 umol, 1 eq) in EtOAc (1.5 mL) was added HCl / EtOAc (4 M, 1.5 mL). The mixture was stirred at 15 °C for 2 h, then LCMS indicated complete conversion to the target mass of the product. The reaction mixture was filtered to give the crude product. The crude material was purified by preparative HPLC (FA conditions; column: Phenomenex Luna C18

[1181] 100*30mm*5um; mobile phase: [water (0.2% FA)-ACN]; B%: 5%-35%, 9min) to obtain the target compound (9.4mg, 7.37umol, 10.64% yield, 98% purity, 2FA) as a white solid.

[1182] LCMS (ES, m / z): 580.6 [M / 2+H] +

[1183] 1 H NMR (400MHz, methanol-d4) δ = 8.46 (s, 2H), 7.23 (br t, J = 6.4Hz, 4H), 7.03-6.93 (m, 4H), 3.96-3.62 (m, 13H), 3.50 (br d, J = 17.1Hz, 2H), 3.22 (br s, 3H), 3.29-3.11 (m, 1H), 3.06-2.93 (m, 4H), 2.89-2.60 (m, 9H), 2.13 (br s, 6H), 1.99-1.84 (m, 2H), 1.80-1.47 (m, 10H), 1.40 (br d, J=4.4Hz, 12H), 1.37-1.32 (m, 2H), 1.25 (br d, J=6.1Hz, 6H), 1.20-1.12 (m, 2H).

[1184] Examples 44-48 were prepared according to the same procedure as Example 43, substituting adipic acid with the appropriate dicarboxylic acid. The compounds of Examples 44-48 were found to have the characterization data described below.

[1185] Embodiment 44,

[1186] N 1 ,N 8 -bis((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)octane Diamide

[1187]

[1188] LCMS (ES, m / z): 594.6 [M / 2+H] +

[1189] 11H NMR (400 MHz, methanol-d4) δ = 8.41 (s, 2H), 7.23 (br t, J = 5.9 Hz, 4H), 7.03 - 6.93 (m, 4H), 3.97 - 3.57 (m, 13H), 3.51 (br d, J = 17.1 Hz, 2H), 3.23 (br s, 2H), 3.01 (br d, J = 10.5 Hz, 4H), 2.88 - 2.60 (m, 9H), 2.23 - 2.01 (m, 6H), 1.92 (br s, 2H), 1.82 - 1.44 (m, 10H), 1.40 (br d, J = 3.9 Hz, 12H), 1.29 (br s, 4H), 1.26 (br d, J = 5.7 Hz, 7H), 1.16 (br d, J = 11.0 Hz, 3H).

[1190] Example 45,

[1191] N 1 ,N 10 -bis((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4, 5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl) Sebacic acid amide

[1192]

[1193] LCMS (ES, m / z): 608.6 [M / 2 + H] +

[1194] 1 1H NMR (400 MHz, methanol-d4) δ = 8.12 (br s, 2H), 7.25 (br s, 4H), 7.02 (br t, J = 8.1 Hz, 4H), 4.11 - 3.95 (m, 4H), 3.89 (br d, J = 10.1 Hz, 3H), 3.82 (br d, J = 15.8 Hz, 6H), 3.76 (br s, 1H), 3.67 (br s, 3H), 3.52 (br s, 2H), 3.31 - 3.04 (m, 17H), 3.03 - 2.89 (m, 4H), 2.62 (br s, 1H), 2.19 (br s, 4H), 2.08 - 1.87 (m, 4H), 1.58 (br s, 7H), 1.42 (br d, J = 9.2 Hz, 12H), 1.33 (br d, J = 6.1 Hz, 6H), 1.29 (br s, 6H).

[1195] Example 46,

[1196] N 1 ,N 14 -bis((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4, 5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl) Tetradecanediamide

[1197]

[1198] LCMS(ES, m / z): 636.7 [M / 2 + H] +

[1199] 1 H NMR(400 MHz, methanol-d4) δ = 8.48 (s, 2H), 8.28 (s, 2H), 7.23 (br t, J = 5.9 Hz, 4H), 7.03 - 6.93 (m, 4H), 3.95 - 3.68 (m, 13H), 3.49 (br d, J = 17.5 Hz, 2H), 3.28 (br s, 2H), 3.20 (br s, 2H), 3.01 (br d, J = 12.3 Hz, 4H), 2.90 - 2.73 (m, 5H), 2.67 (br d, J = 8.3 Hz, 4H), 2.21 - 2.06 (m, 6H), 1.93 (br t, J = 10.3 Hz, 2H), 1.81 - 1.47 (m, 10H), 1.40 (br d, J = 3.1 Hz, 12H), 1.27 (br s, 19H), 1.25 (br s, 4H), 1.16 (br d, J = 11.4 Hz, 3H).

[1200] Example 47,

[1201] 2,2'-(1,3-phenylene)bis(N-((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl- 5-Oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl 1-(4-(4-piperidin-3-yl)acetamide)

[1202]

[1203] LCMS(ES, m / z): 604.6 [M / 2 + H] +

[1204] 1H NMR (400MHz, methanol-d4) δ = 8.42 (s, 2H), 8.25 (s, 2H), 7.24-7.11 (m, 8H), 6.96 (br t, J = 8.1Hz, 4H), 3.95-3.61 (m, 14H), 3.51 (br d, J=16.2Hz, 2H), 3.42 (s, 4H), 3.26 (br d, J=13.6Hz, 6H), 3.06-2.91 (m, 4H), 2.90-2.50 (m, 10H), 2.14 (br d, J=11.4Hz, 2H), 1.95 (br s, 2H), 1.74(br s, 2H), 1.62(br d, J=12.7Hz, 2H), 1.38 (br d, J=4.8Hz, 12H), 1.24 (br d, J=5.7Hz, 6H), 1.19 (br d, J=11.4Hz, 2H).

[1205] Embodiment 48,

[1206] 2,2'-(1,4-phenylene)bis(N-((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl- 5-Oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl 1-(4-(4-piperidin-3-yl)acetamide)

[1207]

[1208] LCMS (ES, m / z): 604.5 [M / 2+H] +

[1209] 1 H NMR (400MHz, methanol-d4) δ = 8.09 (s, 2H), 7.24-7.13 (m, 8H), 7.00-6.92 (m, 4H), 4.07-3.94 (m, 4H), 3.91-3.76(m, 8H), 3.75-3.57(m, 7H), 3.56-3.41(m, 7H), 3.40-3.33(m, 2H), 3.28(br s, 4H), 3.21-2.86 (m, 7H), 2.78-2.46 (m, 2H), 2.08-1.88 (m, 4H), 1.59 (br s, 4H), 1.40 (br d, J=4.8Hz, 13H), 1.33 (br d, J = 6.1 Hz, 6H).

[1210] Scheme 8: General method for Examples 49-113.

[1211]

[1212] Embodiment 49,

[1213] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((1,2-phenylenebis(methylene))bis(oxygen) bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one) .

[1214]

[1215] Step 1 of 2: Di-tert-butyl 5,5'-(((2S,2'S)-(((1,2-phenylenebis(methylene))bis(oxy bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-(tert-butyl (2,3-dihydro-1H-pyrrolo[3,2-b]pyridine)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine 1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate) The synthesis of.

[1216] To a solution of tert-butyl (2R,5R)-4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (0.80 g, 1.22 mmol, 1 eq) and DIEA (393 mg, 3.04 mmol, 530 uL, 2.5 eq) in DCM (10 mL) was added MsCl (167 mg, 1.46 mmol, 113 uL, 1.2 eq) dropwise at 0°C. The mixture was stirred at 15°C for 1 h. TLC (petroleum ether / ethyl acetate=0:1, R f =0.79) indicated that the starting material was completely converted into the new product. Water (60 mL) was added to the mixture, and then extracted with DCM (30 mL*2). The combined organic phase was washed with brine (60 mL) and washed with Na 2 SO 4 Drying, filtration, and concentration under reduced pressure gave the intermediate product (820 mg, crude) as a yellow oil.

[1217] To the intermediate product (198mg, 293umol, 2 equivalents), 1,2-bis((((S)-morpholine-2-yl)methoxy)methyl)benzene(connector_D-147) (60mg, 147umol, 1 equivalent, 2HCl) and DIEA (94.7mg, 733umol, 128uL, 5 equivalents) in MeCN (5mL) was added KI (48.7mg, 293umol, 2 equivalents). The mixture was stirred at 80 ° C for 12h, and then LCMS indicated the formation of the product of target mass. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by preparative TLC (petroleum ether / ethyl acetate / NH 3 .H 2 O=50:75:1, Rf=0.54) to give the title compound (115 mg, crude) as a yellow solid.

[1218] LCMS (ES, m / z): 1614.1 [M+H] +

[1219] Step 2 of 2: 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((1,2-phenylenebis( (Methylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1- bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyrrolidone)bis(acetyl) pyridin-5-one) The synthesis of.

[1220] To a mixture of di-tert-butyl 5,5'-(((2S,2'S)-(((1,2-phenylenebis(methylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))(2R,2'R,5S,5'S)-bis(4-(2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate) (110 mg, 68.15 umol, 1 eq) in EtOAc (1.5 mL) was added HCl / EtOAc (4 M, 1.5 mL) at 15°C. The mixture was stirred at 15°C for 2 h, after which LCMS indicated complete consumption of the starting material and formation of the target mass product. The mixture was filtered and the filter cake was dried to give a crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18, 75*30mm*3um; mobile phase: [water (0.04% HCl)-ACN]; B%: 5%-35%, 9min) to give the target compound (25.3mg, 20.1umol, 29.5% yield, 100% purity, 2HCl) as a white solid.

[1221] LCMS (ES, m / z): 593.5 [M / 2+H] +

[1222] 1 H NMR (400MHz, methanol-d4) δ = 7.98 (s, 2H), 7.33 (br dd, J=3.7, 5.2Hz, 2H), 7.23 (dd, J=3.4, 5.5Hz, 2H), 7.17 (dd, J=5.6, 8.3Hz, 4H), 7.01 (t, J=8.7Hz, 4H), 4.70-4.56 (m, 4H), 4.18 (br d, J=12.1Hz, 2H), 4.09-3.86 (m, 7H), 3.86-3.68 (m, 12H), 3.66-3.50 (m, 8H), 3.49-3. 38(m, 4H), 3.29-3.16(m, 7H), 3.15-2.97(m, 6H), 1.44(s, 12H), 1.32(d, J=6.5Hz, 6H).

[1223] Examples 50-113 were prepared according to the same procedure as Example 49, replacing 1,2-bis((((S)-morpholin-2-yl)methoxy)methyl)benzene with a suitable bisamine linker. The compounds of Examples 50-113 were found to have the characterization data described below.

[1224] Embodiment 50,

[1225] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(([1,1'-biphenyl]-4,4'-diylbis(oxygen) bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1226]

[1227] LCMS (ES, m / z): 617.6 [M / 2+H] +

[1228] 1 H NMR (400 MHz, methanol-d 4 )δ=8.54 (br s, 1H), 8.22 (s, 2H), 7.37 (br d, J=8.6Hz, 4H), 7.23 (dd, J=5.6, 8.2Hz, 4H), 6.97 (t, J=8.7Hz, 4H), 6.80 (br d, J=8.8Hz, 4H), 3.97-3.70(m, 16H), 3.63-3.43(m, 6H), 3.19-3.04(m, 6H), 2.97-2.83(m, 4H), 2.82-2.61(m, 8H), 2.13(br d, J=13.6Hz, 2H), 2.06-1.92(m, 4H), 1.36(s, 12H), 1.18(br d, J = 6.5 Hz, 6H).

[1229] Embodiment 51,

[1230] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(([1,1'-biphenyl]-3,3'-diylbis(oxygen) bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1231]

[1232] LCMS (ES, m / z): 617.5 [M / 2+H] +

[1233] 1 H NMR (400 MHz, methanol-d 4) δ = 8.54 (s, 2H), 8.17 (s, 2H), 7.34 - 7.11 (m, 8H), 7.06 (s, 2H), 6.96 (t, J = 8.8 Hz, 4H), 6.82 (dd, J = 2.1, 8.2 Hz, 2H), 3.96 - 3.68 (m, 18H), 3.64 - 3.57 (m, 2H), 3.49 - 3.34 (m, 4H), 3.28 - 3.17 (m, 4H), 3.09 - 2.93 (m, 4H), 2.84 (br t, J = 12.5 Hz, 4H), 2.76 - 2.62 (m, 4H), 2.16 (br d, J = 11.5 Hz, 2H), 2.05 - 1.95 (m, 4H), 1.37 (d, J = 15.3 Hz, 12H), 1.25 (d, J = 6.4 Hz, 6H).

[1234] Example 52,

[1235] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(([1,1'-biphenyl]-3,4'-diylbis(oxygen) bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1236]

[1237] LCMS(ES, m / z): 617.5 [M / 2 + H] +

[1238] 1 1H NMR (400 MHz, methanol - d 4 ) δ = 8.49 (br s, 2H), 8.18 (d, J = 10.0 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.32 - 7.08 (m, 6H), 7.05 - 6.88 (m, 5H), 6.86 - 6.69 (m, 3H), 3.97 - 3.89 (m, 2H), 3.87 - 3.71 (m, 15H), 3.67 - 3.56 (m, 3H), 3.49 - 3.35 (m, 4H), 3.25 (br d, J = 12.5 Hz, 4H), 3.07 - 2.94 (m, 4H), 2.89 - 2.63 (m, 8H), 2.17 (br d, J = 13.8 Hz, 2H), 2.08 - 1.94 (m, 4H), 1.44 - 1.29 (m, 12H), 1.26 (br d, J = 6.2 Hz, 6H).

[1239] Example 53,

[1240] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((methylenebis(4,1-phenylene))bis(oxygen) bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1241]

[1242] LCMS (ES, m / z): 624.5 [M / 2 + H] +

[1243] 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 8.53 (s, 2H) 8.15 (s, 2H) 7.19 (br dd, J = 8.03, 5.52 Hz, 4H) 6.89 - 7.06 (m, 8H) 6.72 (br d, J = 8.53 Hz, 4H) 3.66 - 3.95 (m, 21H) 3.54 - 3.62 (m, 2H) 3.35 - 3.44 (m, 4H) 3.22 (br d, J = 10.04 Hz, 4H) 2.97 (br d, J = 5.02 Hz, 4H) 2.59 - 2.87 (m, 8H) 2.16 (br d, J = 11.04 Hz, 2H) 1.88 - 2.06 (m, 4H) 1.36 (br d, J = 3.01 Hz, 11H) 1.24 (br d, J = 6.53 Hz, 6H).

[1244] Example 54,

[1245] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((Carbonylbis(4,1-phenylene))bis(oxy bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1246]

[1247] LCMS (ES, m / z): 631.5 [M / 2 + H] +

[1248] 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.19 (s, 2H), 7.71 (d, J = 8.8 Hz, 4H), 7.21 (dd, J = 5.4, 8.6 Hz, 4H), 7.02 - 6.89 (m, 8H), 3.99 (br dd, J = 5.8, 10.3 Hz, 2H), 3.92 - 3.84 (m, 4H), 3.83 - 3.58 (m, 14H), 3.44 (br t, J = 10.6 Hz, 4H), 3.16 (br d, J = 11.5 Hz, 4H), 2.99 - 2.77 (m, 8H), 2.76 - 2.62 (m, 4H), 2.16 (br d, J = 11.4 Hz, 2H), 2.01 (br t, J = 10.6 Hz, 4H), 1.38 (d, J = 7.0 Hz, 12H), 1.21 (br d, J = 6.4 Hz, 6H).

[1249] Embodiment 55,

[1250] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((oxybis(4,1-phenylene))bis(oxy bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1251]

[1252] LCMS (ES, m / z): 625.6 [M / 2+H] +

[1253] 1 H NMR (400 MHz, methanol-d 4 )δ=8.55(s, 1H), 8.18(s, 1H), 7.21(br dd, J=5.5, 8.3Hz, 4H), 7.02-6.91(m, 4H), 6.88-6.72(m, 8H), 3.91-3.70(m, 16H), 3.67(s, 4H), 3.46-3.34(m, 2H), 3.27(br d, J=10.3Hz, 2H), 3.22-3.07(m, 4H), 2.98-2.74(m, 8H), 2.74-2.59(m, 4H), 2.14(br d, J=11.3Hz, 2H), 2.05-1.91(m, 4H), 1.38(br d, J=2.5Hz, 12H), 1.20 (br d, J=6.4Hz, 6H).

[1254] Embodiment 56,

[1255] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((propane-2,2-diylbis(4,1-phenylene)) Bis(oxy)bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis (acetyl)bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1256]

[1257] LCMS (ES, m / z): 638.6 [M / 2+H] +

[1258] 1 H NMR (400 MHz, methanol-d 4) δ = 8.16 (s, 2H), 7.18 (dd, J = 5.5, 8.5 Hz, 4H), 7.08 (d, J = 8.8 Hz, 4H), 6.94 (t, J = 8.8 Hz, 4H), 6.71 (d, J = 8.9 Hz, 4H), 3.92 - 3.55 (m, 21H), 3.42 (brt, J = 10.9 Hz, 2H), 3.29 - 3.24 (m, 3H), 3.12 (br d, J = 10.9 Hz, 4H), 2.97 - 2.74 (m, 8H), 2.72 - 2.57 (m, 4H), 2.13 (br d, J = 11.0 Hz, 2H), 2.05 - 1.91 (m, 4H), 1.59 (s, 6H), 1.38 (d, J = 6.0 Hz, 12H), 1.18 (d, J = 6.4 Hz, 6H).

[1259] Example 57,

[1260] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((sulfonylbis(4,1-phenylene))bis(oxy bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1261]

[1262] LCMS (ES, m / z): 649.5 [M / 2 + H] +

[1263] 1 H NMR (400 MHz, methanol - d 4 ) δ = 8.53 (br s, 2H), 8.14 (s, 2H), 7.81 (d, J = 8.9 Hz, 4H), 7.16 (dd, J = 5.5, 8.5 Hz, 4H), 7.00 - 6.87 (m, 8H), 3.96 - 3.90 (m, 2H), 3.88 - 3.80 (m, 4H), 3.79 - 3.64 (m, 12H), 3.63 - 3.54 (m, 2H), 3.42 - 3.34 (m, 4H), 3.24 - 3.15 (m, 4H), 3.01 - 2.89 (m, 4H), 2.85 - 2.60 (m, 8H), 2.16 (br d, J = 10.5 Hz, 2H), 2.07 - 1.91 (m, 4H), 1.36 (d, J = 10.6 Hz, 12H), 1.22 (d, J = 6.5 Hz, 6H).

[1264] Example 58,

[1265] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((ethane-1,2-diylbis(4,1-phenylene) bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl) Bis(acetyl)bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1266]

[1267] LCMS (ES, m / z): 631.6 [M / 2+H] +

[1268] 1 H NMR (400 MHz, methanol-d4) δ = 8.53 (s, 2H), 8.15 (s, 2H), 7.20 (dd, J = 5.6, 8.3 Hz, 4H), 7.02-6.91 (m, 8H), 6.73-6.63 (m, 4H), 3.86-3.71 (m, 16H), 3.62-3.53 (m, 2H), 3.46-3.34 (m, 4H), 3.23 (br d, J=9.9Hz, 4H), 3.06-2.93 (m, 4H), 2.88-2.60 (m, 12H), 2.21-2.12 (m, 2H), 2.05-1.93 (m, 4H), 1.37 (d, J=5.3Hz, 12H), 1.24 (br d, J=6.1Hz, 6H).

[1269] Embodiment 59,

[1270] 1,2-Bis(4-(((S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3, 4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2- (methyl)methoxy)phenyl)ethane-1,2-dione

[1271]

[1272] LCMS (ES, m / z): 645.6 [M / 2+H] +

[1273] 1 H NMR (400 MHz, methanol-d 4 )δ=8.52(br s, 2H), 8.20-8.14 (m, 2H), 7.94-7.76 (m, 4H), 7.24-7.13 (m, 4H), 7.03- 6.87(m, 8H), 4.05-3.95(m, 2H), 3.91-3.70(m, 15H), 3.66-3.56(m, 2H), 3.45-3.34(m, 4H), 3.25-3.14(m, 4H), 3.04-2.96(m, 3H), 2.86-2.63(m, 8H), 2.22-2.14(m, 2H), 2.05-1.92(m, 4H), 1.42-1.31(m, 12H), 1.25(br d, J = 6.4 Hz, 6H).

[1274] Embodiment 60,

[1275] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((((1,3-phenylenebis(oxy))bis(4,1- phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridine- 5-Keto)

[1276]

[1277] LCMS (ES, m / z): 671.5 [M / 2+H] +

[1278] 1 H NMR (400 MHz, methanol-d 4 )δ=8.53(s, 2H), 8.16(s, 2H), 7.25-7.15(m, 5H), 7.00-6.81(m, 12H), 6.55(dd, J =2.4, 8.3Hz, 2H), 6.45 (t, J = 2.3Hz, 1H), 3.88-3.71 (m, 18H), 3.63-3.54 (m, 2H), 3.46-3.35(m, 4H), 3.28-3.20(m, 4H), 3.07-2.94(m, 4H), 2.85-2.63(m, 8H), 2.2 3-2.13 (m, 2H), 2.05-1.95 (m, 4H), 1.38 (d, J = 2.8Hz, 12H), 1.25 (d, J = 6.5Hz, 6H).

[1279] Embodiment 61,

[1280] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((((1,3-phenylenebis(propane-2,2-diyl)) Bis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperidin oxazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3, 2-b]pyridin-5-one)

[1281]

[1282] LCMS (ES, m / z): 697.7 [M / 2+H] +

[1283] 1 H NMR (400 MHz, methanol-d 4 )δ=8.08-8.01(m, 2H), 7.23-7.05(m, 10H), 7.03-6.94(m, 6H), 6.75(br d, J=8.6Hz, 4H), 4.19-3.58 (m, 26H), 3.55-3.39 (m, 4H), 3.29-2.95 (m, 16H), 1.56 (s, 12H), 1.47-1.38 (m, 12H), 1.30 (d, J=6.5Hz, 6H).

[1284] Embodiment 62,

[1285] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((((1,4-phenylenebis(propane-2,2-diyl)) Bis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperidin oxazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3, 2-b]pyridin-5-one)

[1286]

[1287] LCMS(ES, m / z): 697.6 [M / 2 + H] +

[1288] 1 H NMR(400 MHz, methanol-d4) δ = 8.53 (s, 2H), 8.17 - 8.12 (m, 2H), 7.17 (dd, J = 5.6, 8.1 Hz, 4H), 7.13 - 7.02 (m, 8H), 6.93 (br t, J = 8.7 Hz, 4H), 6.72 (br d, J = 8.6 Hz, 4H), 3.90 - 3.81 (m, 4H), 3.81 - 3.69 (m, 13H), 3.63 - 3.54 (m, 2H), 3.45 - 3.34 (m, 4H), 3.21 (br d, J = 10.6 Hz, 4H), 3.05 - 2.92 (m, 4H), 2.85 - 2.77 (m, 4H), 2.76 - 2.61 (m, 4H), 2.22 - 2.11 (m, 2H), 2.06 - 1.94 (m, 4H), 1.58 (s, 11H), 1.37 (br d, J = 7.4 Hz, 12H), 1.28 - 1.19 (m, 6H).

[1289] Example 63,

[1290] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1291]

[1292] LCMS(ES, m / z): 579.5 [M / 2 + H] +

[1293] 1 H NMR(400 MHz, methanol-d 4 ) δ = 8.03 - 7.99 (m, 2H), 7.27 - 7.21 (m, 4H), 7.09 - 7.03 (m, 4H), 4.29 - 4.24 (m, 4H), 4.13 - 4.05 (m, 2H), 4.00 - 3.94 (m, 2H), 3.89 - 3.39 (m, 25H), 3.27 - 3.17 (m, 8H), 3.12 - 2.98 (m, 6H), 2.94 - 2.81 (m, 3H), 1.42 (d, J = 7.9 Hz, 12H), 1.30 (d, J = 6.1 Hz, 6H).

[1294] Embodiment 64,

[1295] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((hexane-1,6-diylbis(oxy))bis(oxy) methyl))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6- (4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1296]

[1297] LCMS (ES, m / z): 583.4 [M / 2+H] +

[1298] 1 H NMR (400 MHz, methanol-d4) δ = 8.07-8.02 (m, 2H), 7.27-7.21 (m, 4H), 7.06 (t, J = 8.8 Hz, 4H), 4.12-4.03 (m, 2H), 3.99-3.94 (m, 2H), 3.91-3.84 (m, 3H), 3.82-3.78 (m, 6H), 3 .75-3.62(m, 6H), 3.53-3.36(m, 13H), 3.27-3.15(m, 8H), 3.11-3.00(m, 6H), 2.92 -2.90(m, 1H), 2.92-2.73(m, 3H), 1.48-1.40(m, 16H), 1.32-1.28(m, 6H), 1.26(br d, J=6.9Hz, 4H).

[1299] Embodiment 65,

[1300] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((1,4-phenylenebis(methylene))bis(oxygen) bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1301]

[1302] LCMS (ES, m / z): 593.5 [M / 2+H] +

[1303] 1H NMR (400 MHz, methanol-d4) δ = 8.03-7.95 (m, 2H), 7.25-7.12 (m, 8H), 7.03-6.94 (m, 4H), 4.51-4.42 (m, 4H), 4.14-4.03 (m, 2H), 3.99-3.92 (m, 2H), 3.90-3.82 (m, 2H), 3 .82-3.63(m, 14H), 3.63-3.55(m, 2H), 3.55-3.37(m, 7H), 3.27-3.15(m, 8H), 3. 14-2.97(m, 7H), 2.96-2.77(m, 4H), 1.46-1.36(m, 12H), 1.30(d, J=6.5Hz, 6H).

[1304] Embodiment 66,

[1305] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((methylenebis(2,1-phenylene))bis(oxygen) bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1306]

[1307] LCMS (ES, m / z): 624.6 [M / 2+H] +

[1308] 1 H NMR (400 MHz, methanol-d 4 )δ=8.59-8.50(m, 1H), 8.36-8.25(m, 2H), 7.27-6.99(m, 8H), 6.85-6.59(m, 8H), 3.96-3.64(m, 12H), 3.64-3.39(m, 12H), 3.16-3. 00 (m, 4H), 2.98-2.74 (m, 8H), 2.70-2.51 (m, 6H), 2.07-1.96 (m, 2H), 1.96-1.78 (m, 4H), 1.46-1.23 (m, 12H), 1.15 (d, J=6.4Hz, 5H).

[1309] Embodiment 67,

[1310] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(([1,1'-biphenyl]-2,2'-diylbis(oxygen) bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1311]

[1312] LCMS (ES, m / z): 617.6 [M / 2+H] +

[1313] 1H NMR (400 MHz, methanol-d 4 )δ=8.65-8.44(m, 2H), 8.16(s, 2H), 7.29-7.15(m, 8H), 7.03-6.86(m, 8H), 3.84 -3.77(m, 5H), 3.74-3.60(m, 6H), 3.54-3.48(m, 3H), 3.42-3.34(m, 2H), 3.27(br d, J=10.6Hz, 4H), 3.22-3.12(m, 4H), 3.10-2.91(m, 6H), 2.75(br d, J=11.0Hz, 2H), 2.70-2.57(m, 4H), 2.51-2.39(m, 2H), 2.12-2.02(m, 2H), 1.90-1.76(m, 4H), 1.33-1.17(m, 12H), 1.16-1.02(m, 6H).

[1314] Embodiment 68,

[1315] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((oxybis(2,1-phenylene))bis(oxy bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1316]

[1317] LCMS (ES, m / z): 625.5 [M / 2+H] +

[1318] 1 H NMR (400 MHz, methanol-d 4 )δ=7.99-7.88(m, 2H), 7.20-6.99(m, 12H), 6.93(br t, J=7.6Hz, 2H), 6.81-6.70(m, 2H), 4.14(br d, J=3.9Hz, 6H), 4.05-3.92 (m, 6H), 3.88-3.62 (m, 13H), 3.61-3.45 (m, 4H), 3.43 -3.33(m, 5H), 3.28-3.15(m, 6H), 3.08-2.84(m, 6H), 1.46-1.40(m, 12H), 1.33(br d, J=6.4Hz, 6H).

[1319] Embodiment 69,

[1320] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene) bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis(6-(4- fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1321]

[1322]

[1323] LCMS(ES, m / z): 1157.7 [M+H] +

[1324] 1 H NMR(400 MHz, CD 3 OD, 297K) δ(ppm) = 8.08 - 7.94 (m, 2H), 7.24 - 7.12 (m, 5H), 7.05 - 6.92 (m, 4H), 6.55 (dd, J = 2.3, 8.3 Hz, 2H), 6.49 - 6.38 (m, 1H), 4.18 - 4.09 (m, 2H), 4.08 - 3.93 (m, 8H), 3.88 (br d, J = 10.8 Hz, 3H), 3.82 - 3.71 (m, 10H), 3.71 - 3.61 (m, 2H), 3.56 - 3.43 (m, 4H), 3.42 - 3.35 (m, 2H), 3.22 (br d, J = 18.7 Hz, 6H), 3.15 - 2.98 (m, 7H), 2.97 - 2.72 (m, 3H), 1.41 (d, J = 13.4 Hz, 11H), 1.30 (br d, J = 6.5 Hz, 6H).

[1325] Example 70,

[1326] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,4-phenylenebis(oxy))bis(methylene) bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis(6-(4- fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1327]

[1328] LCMS(ES, m / z): 579.5 [M / 2 + H] +

[1329] 1 H NMR(400 MHz, methanol - d4) δ = 8.54 (s, 1H), 8.25 (s, 1H), 7.25 - 7.17 (m, 4H), 6.96 (t, J = 8.8 Hz, 4H), 6.55 (s, 4H), 3.92 - 3.72 (m, 14H), 3.38 - 3.38 (m, 1H), 3.69 - 3.36 (m, 7H), 3.29 - 3.14 (m, 6H), 3.03 - 2.65 (m, 12H), 2.13 (br d, J = 13.0 Hz, 2H), 2.05 - 1.92 (m, 4H), 1.49 - 1.33 (m, 12H), 1.25 (br d, J = 6.5 Hz, 6H).

[1330] Example 71,

[1331] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,2-phenylenebis(oxy))bis(methylene) bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis(6-(4- fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1332]

[1333] LCMS (ES, m / z): 579.6 [M / 2+H] +

[1334] 1 H NMR (400MHz, methanol-d4) δ = 8.53 (s, 2H), 8.14 (s, 2H), 7.19 (dd, J = 5.5, 8.4Hz, 4H), 6.96 (t, J = 8.8Hz, 4H), 6.86 (br d, J=2.4Hz, 4H), 3.91 (dd, J=5.6, 10.4Hz, 2H), 3.84-3.70 (m, 16H), 3.61-3.53 (m, 2H), 3.45 (br dd, J=9.0, 9.9Hz, 2H), 3.39-3.33(m, 2H), 3.27-3.19(m, 4H), 3.08-2.94(m, 4H), 2.85-2.6 0 (m, 8H), 2.15 (s, 2H), 2.06-1.93 (m, 4H), 1.33 (d, J = 15.6Hz, 12H), 1.26 (d, J = 6.5Hz, 6H).

[1335] Embodiment 72,

[1336] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((2-fluoro-1,3-phenylene)bis(oxy))bis (methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis (6-(4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1337]

[1338]

[1339] LCMS (ES, m / z): 588.5 [M / 2+H] +

[1340] 1 H NMR (400 MHz, methanol-d 4) δ = 8.54 (s, 2H), 8.21 (s, 2H), 7.22 (dd, J = 5.6, 8.3 Hz, 4H), 7.00 - 6.86 (m, 5H), 6.59 (t, J = 7.8 Hz, 2H), 3.95 - 3.68 (m, 18H), 3.57 (br dd, J = 4.3, 5.6 Hz, 2H), 3.44 - 3.33 (m, 4H), 3.23 - 3.12 (m, 4H), 3.03 - 2.91 (m, 4H), 2.84 (br d, J = 10.8 Hz, 2H), 2.78 - 2.61 (m, 6H), 2.13 (br d, J = 12.6 Hz, 2H), 1.96 (br t, J = 10.9 Hz, 4H), 1.38 (d, J = 9.5 Hz, 12H), 1.22 (d, J = 6.4 Hz, 6H).

[1341] Example 73,

[1342] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((5-fluoro-1,3-phenylene)bis(oxy))bis (methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis (6-(4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1343]

[1344] LCMS (ES, m / z): 588.6 [M / 2 + H] +

[1345] 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.54 (br s, 2H), 8.21 - 8.16 (m, 2H), 7.25 - 7.18 (m, 4H), 7.00 - 6.92 (m, 4H), 6.28 - 6.21 (m, 2H), 6.17 - 6.12 (m, 1H), 3.91 - 3.66 (m, 18H), 3.58 - 3.49 (m, 2H), 3.44 - 3.34 (m, 3H), 3.24 - 3.13 (m, 4H), 2.99 - 2.91 (m, 4H), 2.84 (br d, J = 11.3 Hz, 2H), 2.78 - 2.60 (m, 6H), 2.18 - 2.10 (m, 2H), 2.01 - 1.93 (m, 3H), 1.42 - 1.34 (m, 12H), 1.26 - 1.18 (m, 6H).

[1346] Example 74,

[1347] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((2,4-difluoro-1,3-phenylene)bis(oxy bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1348]

[1349] LCMS (ES, m / z): 597.6 [M / 2 + H] +

[1350] 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.55 (s, 1H), 8.17 (d, J = 13.6 Hz, 2H), 7.26 - 7.16 (m, 4H), 6.96 (dt, J = 1.9, 8.7 Hz, 4H), 6.84 - 6.64 (m, 2H), 4.03 - 3.68 (m, 18H), 3.67 - 3.51 (m, 3H), 3.42 - 3.34 (m, 2H), 3.29 - 3.24 (m, 1H), 3.23 - 3.06 (m, 4H), 2.93 (br s, 3H), 2.87 - 2.59 (m, 9H), 2.11 (br t, J = 11.9 Hz, 2H), 2.02 - 1.89 (m, 4H), 1.38 (dd, J = 4.1, 7.1 Hz, 12H), 1.20 (br d, J = 6.4 Hz, 6H).

[1351] Example 75,

[1352] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((4-fluoro-1,3-phenylene)bis(oxy))bis (methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl)bis (6-(4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1353]

[1354] LCMS (ES, m / z): 588.6 [M / 2 + H] +

[1355] 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.53 (s, 2H), 8.16 (d, J = 4.1 Hz, 2H), 7.20 (br t, J = 5.9 Hz, 4H), 7.03 - 6.89 (m, 5H), 6.52 (dd, J = 2.4, 7.0 Hz, 1H), 6.38 (td, J = 2.8, 5.9 Hz, 1H), 3.93 - 3.65 (m, 18H), 3.59 (br d, J = 8.9 Hz, 2H), 3.47 - 3.34 (m, 4H), 3.24 (br s, 4H), 3.08 - 2.91 (m, 4H), 2.87 - 2.59 (m, 8H), 2.17 (br d, J = 11.4 Hz, 2H), 2.06 - 1.93 (m, 4H), 1.37 (brdd, J = 2.9, 7.6 Hz, 12H), 1.25 (br d, J = 5.9 Hz, 6H).

[1356] Embodiment 76,

[1357] 3,5-Bis(((S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholin-2-yl)methyl (2-(2-oxy)benzonitrile

[1358]

[1359] LCMS (ES, m / z): 592.0 [M / 2+H] +

[1360] 1 H NMR (400 MHz, methanol-d 4 )δ=8.54 (s, 2H), 8.21 (s, 2H), 7.22 (dd, J=5.5, 8.4Hz, 4H), 6.95 (t, J=8.8Hz, 4H), 6.82 (d, J=2.1Hz, 2H), 6.60 (s, 1H), 4.01-3.59 (m, 19H), 3.53 (br d, J=5.5Hz, 2H), 3.42 (br t, J=10.7Hz, 3H), 3.27-3.15 (m, 4H), 3.00-2.81 (m, 6H), 2.78-2.61 (m, 6H), 2.16 (s, 2H), 1.96 (br d, J=10.9Hz, 4H), 1.39 (d, J=12.8Hz, 12H), 1.24 (br d, J=6.4Hz, 6H).

[1361] Embodiment 77,

[1362] 2,4-bis(((S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholin-2-yl)methyl (2-(2-oxy)benzonitrile

[1363]

[1364] LCMS (ES, m / z): 592.1 [M / 2+H] +

[1365] 1 H NMR (400 MHz, methanol-d 4)δ=8.53 (s, 2H), 8.17 (s, 2H), 7.48 (d, J=9.1Hz, 1H), 7.21 (dd, J=5.6, 8.3Hz, 4H), 6.9 6(t, J=8.7Hz, 4H), 6.64-6.45(m, 2H), 4.04-3.55(m, 20H), 3.51-3.34(m, 4H), 3.24(br s, 4H), 3.13-2.93 (m, 4H), 2.92-2.59 (m, 8H), 2.25-1.89 (m, 6H), 1.48-1.32 (m, 12H), 1.25 (br d, J=6.1Hz, 6H).

[1366] Embodiment 78,

[1367] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(([1,1'-biphenyl]-2,4-diylbis(oxy bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1368]

[1369] LCMS (ES, m / z): 617.5 [M / 2+H] +

[1370] 1 H NMR (400MHz, methanol-d4) δ = 8.54 (s, 2H), 8.16 (d, J = 10.8Hz, 2H), 7.46-7.12 (m, 10H), 6.94 (dt, J = 6.8, 8.7Hz, 4H), 6.56-6 .44(m, 2H), 3.98-3.52(m, 19H), 3.45-3.36(m, 4H), 3.27-3.03(m, 6H), 2.99-2.90(m, 3H), 2.87-2.61(m, 7H), 2.53(br dd, J=8.5, 13.4Hz, 1H), 2.20-2.09 (m, 2H), 2.05-1.87 (m, 4H), 1.37 (d, J=3.9Hz, 6H), 1.27-1.18 (m, 9H), 1.08 (s, 3H).

[1371] Embodiment 79,

[1372] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((2-methyl-1,3-phenylene)bis(oxy)) Bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis (6-(4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1373]

[1374] LCMS (ES, m / z): 586.5 [M / 2+H] +

[1375] 1 H NMR (400 MHz, methanol-d4) δ = 8.55 (s, 1H), 8.31-8.26 (m, 2H), 7.17 (dd, J = 5.6, 8.3 Hz, 4H), 7.04-6.96 (m, 1H), 6.85 (t, J = 8.7 Hz, 4H), 6.45 (d, J = 8.4 Hz, 1H), 3.94-3.3 .82(m, 6H), 3.81-3.60(m, 12H), 3.60-3.51(m, 2H), 3.50-3.33(m, 6H), 3.23-3 .00(m, 6H), 2.99-2.91(m, 2H), 2.88-2.80(m, 2H), 2.77-2.58(m, 6H), 2.13(br d, J=13.1Hz, 2H), 2.03-1.90 (m, 4H), 1.70 (s, 2H), 1.40 (s, 5H), 1.30 (s, 6H), 1.25-1.17 (m, 6H).

[1376] Embodiment 80,

[1377] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((1,3-phenylenebis(methylene))bis(oxygen) bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1378]

[1379] LCMS (ES, m / z): 593.6 [M / 2+H] +

[1380] 1 H NMR (400MHz, methanol-d4) δ = 8.00 (s, 2H), 7.28-7.14 (m, 8H), 7.01 (t, J = 8.6Hz, 4H), 4.50 (s, 4H), 4.17 (br d, J=12.4Hz, 2H), 4.05-3.89(m, 6H), 3.87-3.50(m, 21H), 3.49-3.37(m, 4H), 3.26(br d, J=8.6Hz, 7H), 3.16-3.02 (m, 6H), 1.44 (d, J=7.4Hz, 12H), 1.32 (d, J=6.4Hz, 6H).

[1381] Embodiment 81,

[1382] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((butane-1,4-diylbis(oxy))bis(oxy) methyl))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6- (4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1383]

[1384]

[1385] LCMS (ES, m / z): 569.5 [M / 2+H] +

[1386] 1 H NMR (400MHz, methanol-d4) δ = 8.02-7.97 (m, 2H), 7.28-7.19 (m, 4H), 7.05 (t, J = 8. 8Hz, 4H), 4.17-4.06 (m, 2H), 4.01-3.93 (m, 2H), 3.90-3.84 (m, 2H), 3.82-3 .64(m, 14H), 3.54-3.38(m, 12H), 3.29-3.18(m, 8H), 3.17-3.06(m, 4H), 3. 05-2.85(m, 6H), 1.59-1.48(m, 4H), 1.44-1.37(m, 12H), 1.34-1.25(m, 6H).

[1387] Embodiment 82,

[1388] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((pentane-1,5-diylbis(oxy))bis(oxy) methyl))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6- (4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1389]

[1390] LCMS (ES, m / z): 576.4 [M / 2+H] +

[1391] 1 H NMR (400MHz, methanol-d4) δ = 8.06-8.00 (m, 2H), 7.30-7.20 (m, 4H), 7.11-7.01 (m, 4H), 4.14-4.03 (m, 2H), 4.01-3.93 (m, 2H), 3.87 (br d, J=10.8Hz, 2H), 3.82-3.63 (m, 14H), 3.54-3.43 (m, 8H), 3.41-3.36 (m, 4H), 3.28-3.1 8(m, 9H), 3.12-3.00(m, 6H), 2.93-2.80(m, 3H), 1.52-1.39(m, 16H), 1.33-1.25(m, 8H).

[1392] Embodiment 83,

[1393] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((oxybis(ethane-2,1-diyl))bis(oxy bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(acetyl) bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1394]

[1395] LCMS (ES, m / z): 577.4 [M / 2+H] +

[1396] 1 H NMR (400MHz, methanol-d4) δ = 7.99 (s, 2H), 7.24 (dd, J = 5.4, 8.4Hz, 4H), 7.12-7.02 (m, 4H), 4.09 (br d, J=12.1Hz, 2H), 4.01-3.94(m, 2H), 3.92-3.82(m, 3H), 3.81-3.78(m, 7H), 3.76-3.68(m, 5H), 3.64(br d, J=13.5Hz, 2H), 3.59-3.47(m, 15H), 3.23(br t, J=11.9Hz, 8H), 3.15-3.06 (m, 4H), 3.05-2.98 (m, 2H), 2.90 (br s, 4H), 1.42 (d, J=7.6Hz, 12H), 1.30 (d, J=6.5Hz, 6H).

[1397] Embodiment 84,

[1398] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((pyridine-2,6-diylbis(methylene))bis (oxy)bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl)bis(ethyl Bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1399]

[1400] LCMS (ES, m / z): 594.0 [M / 2+H] +

[1401] 1 H NMR (400 MHz, methanol-d4) δ = 8.08-7.97 (m, 2H), 7.70-7.60 (m, 1H), 7.28 (br d, J = 7.9 Hz, 6H), 6.99 (br t, J=8.6Hz, 4H), 4.64-4.56 (m, 4H), 4.17-4.04 (m, 2H), 3.98-3.86 (m, 4H), 3.84-3.57 (m, 20H), 3.53-3.40 (m, 4H), 3.28-3.16 (m, 8H), 3.13-3.02 (m, 6H), 2.95-2.86 (m, 2H), 1.44-1.37 (m, 12H), 1.31-1.26 (m, 6H).

[1402] Embodiment 85,

[1403] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((((perfluoro-1,4-phenylene)bis(methylene) bis(methylene)bis(morpholine-2,4-diyl)bis(methylene)bis(3-methylpiperazine-6,1-diyl) Bis(acetyl)bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1404]

[1405] LCMS (ES, m / z): 629.5 [M / 2+H] +

[1406] 1 H NMR (400 MHz, methanol-d4) δ = 8.03-7.94 (m, 2H), 7.23-7.15 (m, 4H), 7.05-6.95 (m, 4H), 4.65 (br s, 4H), 4.09-4.00 (m, 2H), 3.97-3.91 (m, 2H), 3.86-3.83 (m, 2H), 3.80-3.70 (m, 10H), 3.67-3.53 (m, 8H), 3.52-3 .42(m, 4H), 3.23-3.11(m, 8H), 3.10-2.99(m, 6H), 2.89-2.71(m, 4H), 1.44-1.37(m, 12H), 1.30(d, J=6.5Hz, 6H).

[1407] Embodiment 86,

[1408] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((5-methyl-1,3-phenylene)bis(oxy)) Bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis (6-(4-Fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one)

[1409]

[1410] LCMS (ES, m / z): 586.5 [M / 2+H] +

[1411] 1 H NMR (400 MHz, methanol-d 4 )δ=8.0...

Claims

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Each R 1 and R 2 is -H or -CH3; Each R 3 is -H or -CH3; Each R 4 is -H, -F, -Cl, -CH3, -CF3, -CN, -OH, -OCH3, -C(O)N(CH3)2, -CH(CH3)2 or -C(O)OCH3; Each R 5 is -H, -F, -Cl, -Br, -CH3, -CHF2 or -CF3; Each R 6 is -H, -F or -Cl; Each R 7 is -H or -F; each W is -CH-, -CH2-, -O- or -N-; each X is -CH2-, -O-, -NH- or -NCH3-; Each Y 1 is -CH- or -C(O)-; Each Y 2 is -N-, -NH- or -NCH3-; each represents a single bond or a double bond, when Y 1 When it is -CH-, Y 2 Yes-N-And represents a double bond, and when Y 1 When it is -C(O)-, Y 2 is -NH- or -NCH3-, and represents a single bond; each Z is -CH-, -CF-, or -N-; and L is a linker selected from the following wherein n is an integer from 2 to 15, m is an integer from 1 to 5, p is an integer from 1 to 20, q is an integer from 2 to 15, s is an integer from 1 to 8, t is an integer from 2 to 15, w is an integer from 1 to 10, x is an integer from 2 to 15, y is an integer from 2 to 15 and z is an integer from 2 to 15.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 In each case -CH3.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each X is -CH2-, each Z is -CH- and each R 4 Yes -H.

4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein each Y 1 is -C(O)-, each Y 2 is -NH- or -NCH3- and each Represents a single bond.

5. A compound which is or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein L is a linker selected from the following: wherein n is an integer from 2 to 12, m is an integer from 1 to 3 and p is an integer from 1 to 12.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein L is selected from: wherein n is an integer from 2 to 8.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein L is selected from wherein q is an integer from 2 to 8, s is an integer from 1 to 5, t is an integer from 2 to 8, w is an integer from 1 to 5, x is an integer from 2 to 8 and y is an integer from 2 to 8.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is selected from wherein z is an integer from 2 to 8.

14. A compound selected from 1,6-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)hexane-1,6-dione; 1,8-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)octane-1,8-dione; 1,10-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)decane-1,10-dione; 1,14-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)tetradecane-1,14-dione; 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(ethane-1,2-diylbis(oxy))bis(acetyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-((oxybis(ethane-2,1-diyl))bis(oxy))bis(acetyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,2-phenylene)bis(acetyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,2-phenylenebis(oxy))bis(acetyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-isophthaloylbis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,3-phenylene)bis(acetyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,3-phenylenebis(oxy))bis(acetyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,4-phenylene)bis(acetyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(1,4-phenylenebis(oxy))bis(acetyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-((2E,2'E)-3,3'-(1,4-phenylene)bis(acryloyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(methylmethazanediyl)bis(acetyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(pyrazine-2,5-dicarbonyl)bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-([2,2'-bipyridine]-3,3'-dicarbonyl)bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(naphthalene-2,6-dicarbonyl)bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-terephthaloylbis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(4,4'-((E)-ethylene-1,2-diyl)bis(benzoyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,4-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)butane-1,4-dione; 1,5-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)pentane-1,5-dione; 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-([2,2'-bipyridine]-4,4'-dicarbonyl)bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-octane-1,8-diylbis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-decane-1,10-diylbis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-dodecane-1,12-diylbis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(1,4-phenylenebis(methylene))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-((perfluoro-1,4-phenylene)bis(methylene))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-([1,1'-biphenyl]-4,4'-disulfonyl)bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(oxybis(4,1-phenylenesulfonyl))bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one); 1,14-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)tetradecane-1,14-dione; 1,6-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)hexane-1,6-dione; 1,8-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)octane-1,8-dione; 1,10-bis((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)decane-1,10-dione; 2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-isophthaloylbis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one); 2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-(1,3-phenylenedisulfonyl)bis(2-methylpiperazine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one); N1,N6-bis((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)adipamide; N1,N8-bis((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)octanediamide; N1,N10-bis((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)decanamide; N1,N14-bis((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)tetradecanediamide; 2,2'-(1,3-phenylene)bis(N-((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)acetamide); 2,2'-(1,4-phenylene)bis(N-((S)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)acetamide); N1,N6-bis((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)adipamide; N1,N8-bis((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)octanediamide; N1,N10-bis((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)decanamide; N1,N14-bis((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)tetradecanediamide; 2,2'-(1,3-phenylene)bis(N-((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)acetamide); 2,2'-(1,4-phenylene)bis(N-((R)-1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-3-yl)acetamide); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((1,2-phenylenebis(methylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(([1,1'-biphenyl]-4,4'-diylbis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(([1,1'-biphenyl]-3,3'-diylbis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(([1,1'-biphenyl]-3,4'-diylbis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((methylenebis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((carbonylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((oxybis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((propane-2,2-diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((sulfonylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((ethane-1,2-diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,2-bis(4-(((S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholin-2-yl)methoxy)phenyl)ethane-1,2-dione; 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((((1,3-phenylenebis(oxy))bis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((((1,3-phenylenebis(propane-2,2-diyl))bis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((((1,4-phenylenebis(propane-2,2-diyl))bis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((hexane-2,4-diyne-1,6-diylbis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((hexane-1,6-diylbis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((1,4-phenylenebis(methylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((methylenebis(2,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(([1,1'-biphenyl]-2,2'-diylbis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((oxybis(2,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,4-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,2-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((2-fluoro-1,3-phenylene)bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((5-fluoro-1,3-phenylene)bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((2,4-difluoro-1,3-phenylene)bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one) 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((4-fluoro-1,3-phenylene)bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 3,5-bis(((S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholin-2-yl)methoxy)benzonitrile; 2,4-bis(((S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholin-2-yl)methoxy)benzonitrile; 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(([1,1'-biphenyl]-2,4-diylbis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((2-methyl-1,3-phenylene)bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((1,3-phenylenebis(methylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((butane-1,4-diylbis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((pentane-1,5-diylbis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((oxybis(ethane-2,1-diyl))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((pyridine-2,6-diylbis(methylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((((perfluoro-1,4-phenylene)bis(methylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((2-bromo-1,3-phenylene)bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((2-chloro-1,3-phenylene)bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((4-chloro-1,3-phenylene)bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); (2S,2'S)-N,N'-(hexane-1,6-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-((1S,4S)-cyclohexane-1,4-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(hexane-2,4-diyn-1,6-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); 1,1'-(2,2'-((3R,3'R,6R,6'R)-((propane-1,3-diylbis(piperidin-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); N1,N3-bis((1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)methyl)-N1,N3-dimethylisophthalamide; N1,N4-bis((1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)methyl)-N1,N4-dimethylterephthalamide; N-((1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)methyl)-4-(2-(((1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)methyl)(methyl)amino)-2-oxoethyl)-N-methylbenzamide; N-((1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)methyl)-3-(2-(((1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)methyl)(methyl)amino)-2-oxoethyl)-N-methylbenzamide; 2,2'-(1,4-phenylene)bis(N-((1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)methyl)-N-methylacetamide); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((((1,4-phenylenebis(methylene))bis(methylmethazanediyl))bis(methylene))bis(piperidin-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); N1,N4-bis((1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)methyl)terephthalamide; 2,2'-(1,4-phenylene)bis(N-((1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)methyl)acetamide); N1,N4-bis(2-(1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)ethyl)terephthalamide; N1,N4-bis(2-(1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)ethyl)-N1,N4-dimethylterephthalamide; N,N'-(1,4-phenylenebis(methylene))bis(2-(1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)acetamide); N,N'-(1,4-phenylenebis(methylene))bis(2-(1-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)piperidin-4-yl)-N-methylacetamide); 1,1'-(2,2'-((3R,3'R,6R,6'R)-((((1,3-phenylenebis(oxy))bis(methylene))bis(piperidin-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-((((1,3-phenylenebis(oxy))bis(ethane-2,1-diyl))bis(piperidine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-((((1,3-phenylenebis(oxy))bis(propane-3,1-diyl))bis(piperidine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-((((1,3-phenylenebis(oxy))bis(1,1-difluoroethane-2,1-diyl))bis(piperidine-4,1-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); (2R,2'R)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-((butane-1,4-diylbis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3,4-trimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((methylenebis(4,1-phenylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3,4-trimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((hexane-2,4-diyne-1,6-diylbis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3,4-trimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((1,4-phenylenebis(methylene))bis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3,4-trimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(piperazine-1,4-dicarbonyl)bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); (2S,2'S)-N,N'-(octane-1,8-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(Decan-1,10-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,3-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(piperazine-1,4-diylbis(propane-3,1-diyl))bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(hexane-1,6-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-N-methylmorpholine-2-carboxamide); (2S,2'S)-N,N'-(propane-1,3-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(butane-1,4-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(butane-1,4-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-N-methylmorpholine-2-carboxamide); (2S,2'S)-N,N'-(ethane-1,2-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-N-(1-((S)-4- (((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carbonyl)piperidin-4-yl)morpholine-2-carboxamide; (2S,2'S)-N,N'-(propane-1,3-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-N-methylmorpholine-2-carboxamide); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(1,4-diazepane-1,4-dicarbonyl)bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); (S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-N-((1-((S)-4- (((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carbonyl)piperidin-4-yl)methyl)-N-methylmorpholine-2-carboxamide; (S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-N-((1-((S)-4- (((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carbonyl)piperidin-4-yl)methyl)morpholine-2-carboxamide; (S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-N-(2-(4-((S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carbonyl)piperazin-1-yl)ethyl)morpholine-2-carboxamide; (S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-N-(3-((S)-4- (((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamido)propyl)-N-methylmorpholine-2-carboxamide; (2S,2'S)-N,N'-(pentane-1,5-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(2-hydroxypropane-1,3-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(oxybis(ethane-2,1-diyl))bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(2,2-dimethylpropane-1,3-diyl)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,3-phenylene)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(2-methyl-1,3-phenylene)bis(4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); 1-[6-(4-fluorophenoxy)-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-[(2R,5R)-2-[[(2S)-2-[[3-[[(2S)-4-[[(2R,5R)-1-[2-[6-(4-fluorophenoxy)-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]-5-methyl-piperazin-2-yl]methyl]morpholin-2-yl]methoxy]phenoxy]methyl]morpholin-4-yl]methyl]-5-methyl-piperazin-1-yl]ethanone; -[6-(4-Fluoroanilino)-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-[(2R,5R)-2-[[(2S)-2-[[3-[[(2S)-4-[[(2R,5R)-1-[2-[6-(4-Fluoroanilino)-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]-5-methyl-piperazin-2-yl]methyl]morpholin-2-yl]methoxy]phenoxy]methyl]morpholin-4-yl]methyl]-5-methyl-piperazin-1-yl]ethanone; 2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(6-((4-fluorophenyl)(methyl)amino)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one); 2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one); 2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(3,3-dimethyl-6-(pyridin-3-ylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one); 2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(6-(4-chlorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one); 2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(3,3-dimethyl-6-(4-methylbenzyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one); 2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(3,3-dimethyl-6-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one); 2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(6-benzyl-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one); 2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(1-(6-(4-fluoro-2-methoxybenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one); Dimethyl 6,6'-(((2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1,6-diyl))bis(methylene))bis(3-fluorobenzoate); 1-[6-[(4-bromophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-[(2R,5R)-2-[[(2S)-2-[[3-[[(2S)-4-[[(2R,5R)-1-[2-[6-[(4-bromophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]-5-methyl-piperazin-2-yl]methyl]morpholin-2-yl]methoxy]phenoxy]methyl]morpholin-4-yl]methyl]-5-methyl-piperazin-1-yl]ethanone; 6-(4-fluorobenzyl)-1-(2-((2R,5R)-2-(((R)-4-(2-(1-(3-((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-4-yl)ethyl)-2-methylpiperazin-1-yl)methyl)-5-methylpiperazin-1-yl)acetyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one; 6-(4-fluorobenzyl)-1-(2-((2R,5R)-2-(((R)-4-((1-(2-((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)-5-methylpiperazin-1-yl)acetyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one; 6-(4-fluorobenzyl)-1-(2-((2R,5R)-2-(((R)-4-((1-(3-((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)-3-oxopropyl)-1H-1,2,3-triazol-4-yl)methyl)-2-methylpiperazin-1-yl)methyl)-5-methylpiperazin-1-yl)acetyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one; 6-(4-fluorobenzyl)-1-(2-((2R,5R)-2-(((R)-4-(2-(1-(4-((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)-4-oxobutyl)-1H-1,2,3-triazol-4-yl)ethyl)-2-methylpiperazin-1-yl)methyl)-5-methylpiperazin-1-yl)acetyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one; 6-(4-fluorobenzyl)-1-(2-((2R,5R)-2-(((R)-4-(2-(1-(5-((R)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)-5-oxopentyl)-1H-1,2,3-triazol-4-yl)ethyl)-2-methylpiperazin-1-yl)methyl)-5-methylpiperazin-1-yl)acetyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one; (S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-N-(2-((R)-4- (((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)-2-oxoethyl)morpholine-2-carboxamide; (S)-4-(((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-N-(4-((R)-4- (((2R,5R)-1-(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)-3-methylpiperazin-1-yl)-4-oxobutyl)morpholine-2-carboxamide; (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-chlorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-bromobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(3,3-dimethyl-6-(4-methylbenzyl)-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-chloro-2-hydroxybenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(2,4-dichlorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-(difluoromethyl)benzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(3,3-dimethyl-5-oxo-6-(2,4,6-trifluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-chloro-2-methylbenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-chloro-2-methoxybenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-chloro-2-(trifluoromethyl)benzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-chloro-2-cyanobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-chloro-2-(dimethylcarbamoyl)benzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(2-isopropylbenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(3,3-dimethyl-5-oxo-6-(2,3,4,5-tetrafluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(3,3-dimethyl-5-oxo-6-(2,4,5-trifluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(3,3-dimethyl-5-oxo-6-((perfluorophenyl)methyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(2,4-difluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(3,3-dimethyl-5-oxo-6-(2,3,4-trifluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(2-cyano-4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(3,3-dimethyl-5-oxo-6-(2,4,6-trichlorobenzyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-fluorophenoxy)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-chlorophenoxy)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-(4-bromophenoxy)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(3,3-dimethyl-5-oxo-6-(p-tolyloxy)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(3,3-dimethyl-5-oxo-6-phenoxy-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); (2S,2'S)-N,N'-(1,4-phenylenebis(methylene))bis(4-(((2R,5R)-1-(2-(6-benzyl-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)morpholine-2-carboxamide); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(2,4-dichlorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(3,3-dimethyl-6-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); 6,6'-(((2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1,6-diyl))bis(methylene))bis(3-chlorobenzonitrile); and 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-((1,3-phenylenebis(oxy))bis(methylene))bis(morpholine-2,4-diyl))bis(methylene))bis(3-methylpiperazine-6,1-diyl))bis(acetyl))bis(6-(2,4-difluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one); or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

16. A method for treating HIV infection in a human, comprising administering to the human a therapeutically effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15.

17. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 for use in treating HIV infection.

18. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating HIV infection.

19. A method for treating cancer and precancerous syndromes in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15.

20. A method for eliminating latent HIV-infected cells in a human body, comprising administering to the human a therapeutically effective amount of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15.

21. A combination comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and one or more agents effective against HIV.

22. The combination of claim 21, wherein the one or more agents effective against HIV are selected from nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, attachment and fusion inhibitors, integrase inhibitors, maturation inhibitors, CXCR4 and / or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyl transferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors and antibodies for clearance therapy.

23. A method of treating HIV infection in a human comprising administering to said human a therapeutically effective amount of a combination according to claim 21 or claim 22.

24. A method of eliminating latent HIV infected cells in a human, comprising administering to said human a therapeutically effective amount of a combination according to claim 21 or claim 22.

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