Piperazine derivatives useful for the treatment of HIV

Abstract

The present invention relates to a compound of formula (I) [Chemical formula 1] JPEG2025518076000381.jpg70170, or a pharmaceutically acceptable salt thereof, a composition thereof, and a method for therapeutic treatment using the same.

Description

Cross - Reference to Related Applications

[0001] This application claims the benefit of priority under 35 U.S.C.§119(e) to U.S. Provisional Patent Application No. 63 / 346,362, filed on May 27, 2022, the content of which is hereby incorporated by reference in its entirety, including the drawings.

Technical Field

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

[0003] Sequence Listing This application contains a sequence listing submitted in XML format, which is hereby incorporated by reference in its entirety. The XML copy is named PU66990.xml, is approximately 6.04 KB (6,187 bytes) in size, and was created on May 18, 2023.

Background Art

[0004] Human immunodeficiency virus type 1 (HIV - 1) infection leads to the development of acquired immune deficiency disease (AIDS). Currently, long - term suppression of viral replication using antiretroviral drugs is the only option for treating HIV - 1 infection. In fact, the U.S. Food and Drug Administration has approved 25 drugs across six different inhibitor classifications, which have been shown to significantly improve patient survival and quality of life. However, additional therapies are still needed due to several problems including, but not limited to, unwanted drug - drug interactions; drug - food interactions; non - adherence to treatment; drug resistance due to mutations in enzyme targets; and inflammation associated with immunological damage caused by HIV infection.

[0005] Currently, almost all HIV-positive patients are being treated with a regimen of antiretroviral drugs called highly active antiretroviral therapy (HAART). However, HAART therapy is often complex because patients must often be administered combinations of different drugs daily in order to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the beneficial effects of HAART on patient survival rates, drug resistance can still occur, and survival rates and quality of life have not been normalized compared to those of uninfected individuals [Lohse Ann Intern Med 2007;146:87-95]. In fact, the morbidity and mortality rates of several non-AIDS conditions, such as cardiovascular disease, frailty, and cognitive neuroscience impairment, are increasing in HIV-infected subjects who are suppressed on HAART [Deeks Annu Rev Med 2011;62:141-155]. This increased non-AIDS morbidity / mortality occurs in the context of increased systemic inflammation associated with immunological damage caused by HIV infection and residual HIV infection, potentially caused thereby [Hunt J Infect Dis 2014][Byakagwa J Infect Dis 2014][Tenorio J Infect Dis 2014].

[0006] Modern antiretroviral therapy (ART) has the ability to efficiently suppress HIV replication and improve the health outcomes of individuals infected with HIV, but it is considered impossible to completely eliminate the HIV viral reservoirs within an individual. The HIV genome can remain latent in the majority of immune cells in the infected individual and can be reactivated at any time, typically within a few weeks after ART interruption, allowing viral replication to resume. In a handful of individuals, the size of this viral reservoir has been significantly reduced, and when ART is interrupted, the rebound of viral replication is delayed [Henrich TJ J Infect Dis 2013][Henrich TJ Ann Intern Med 2014]. In one case, the viral reservoir was eliminated during the treatment of leukemia, and viral rebound was not observed during several years of follow-up [Hutter G N Engl J Med 2009]. These examples suggest the concept that the reduction or elimination of the viral reservoir may be possible and may cause viral quiescence or cure. Therefore, direct molecular means, including excision of the viral genome with the CRISPR / Cas9 system, have been pursued to eliminate the viral reservoir or to induce reactivation of the latent reservoir during ART, resulting in the removal of latent cells. The reversal of latency is considered necessary to make latently infected cells more susceptible to clearance.

[0007] SMACm (second mitochondria-derived activator of caspase mimetic) is a class of compounds that has recently entered clinical trials as a potential cancer treatment. The drug depletes and / or inhibits cellular inhibitor of apoptosis proteins (cIAPs), which act as anti-apoptotic proteins, thereby promoting cancer cell death. Antagonism and / or depletion of cIAPs also causes activation of the non-canonical NF-kB signaling pathway, which can induce HIV expression and enable the removal of HIV-infected cells. Additionally, SMAC mimetics can selectively promote the cell death of cells infected with HIV [Campbell Cell Host Microbe 2018] or HBV [Ebert Proc Nat Acad Sci 2013] by antagonizing anti-apoptotic proteins.

[0008] Recently, targeting of the non-canonical NF-kB (ncNF-κB) pathway, which reverses latency in cell line models, has been reported. The ncNF-κB pathway is typically activated by ligation of a subset of TNF receptor family members. In the steady state, a multi-molecular complex with ubiquitin ligase activity consisting of TNF receptor-associated factor 2 (TRAF2), TRAF3, and cellular inhibitor of apoptosis protein-1 (cIAP1) associates with the cytoplasmic portion of the unligated receptor and constitutively ubiquitinates and degrades NF-κB-inducing kinase (NIK). Upon receptor ligation, cIAP1 ubiquitinates TRAF3 and also auto-ubiquitinates, causing proteasomal degradation of TRAF3 and cIAP1, thereby de-repressing NIK accumulation. NIK is constitutively active and, when accumulated, phosphorylates the inhibitor of the κB kinase-α (IKKα) homodimer. The activated IKKα / IKKα homodimer then phosphorylates the inactive p100 form of NFκB2, causing ubiquitination by the Skp1-Cul1-F-box ubiquitin ligase (SCFβTrCP) and proteasomal cleavage of p100, releasing the active p52 subunit. p52 associates with RelB, and this heterodimer translocates into the nucleus to drive transcription from κB promoter elements. In addition to receptor ligation, ncNF-κB can be activated by signaling intermediates of the apoptotic cascade. Cleavage of the second mitochondria-derived activator of caspase (SMAC) from the mitochondrial membrane exposes an N-terminal motif Ala-Val-Pro-Ile that specifically binds to the baculovirus IAP repeat (BIR) domain of IAP proteins. Such BIR binding in cIAP1 / 2 activates the ubiquitin ligase activity of the TRAF2:TRAF3:cIAP complex, inducing auto-ubiquitination and degradation of cIAP1 / 2, NIK accumulation, and activation of the ncNF-κB pathway [Sampey bioRxiv 2018][Nixon Nature 2020].The binding of SMAC to the BIR domains of XIAP and ML-IAP antagonizes the caspase inhibitory activities of these molecules, which are often overexpressed in tumor cells, and causes a synergistic effect on apoptosis.

Summary of the Invention

[0009] Therefore, the discovery and development of novel SMACm molecules represent unmet medical needs.

[0010] The present invention relates to a compound of formula (I):

[0011]

Chemical Formula

[0012] or a pharmaceutically acceptable salt thereof. (Wherein, each R 1 and R 2 is -H or -CH 3 , each R 3 is -H or -CH 3 , each R 4 is -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 , each R 5 is -H, -F, -Cl, -Br, -CH 3 , -CHF 2 or -CF 3 , each R 6 is -H, -F or -Cl, each R 7 is -H or -F, each W is -CH-, -CH 2 -, -O- or -N-. Each X is -CH 2 -, -O-, -NH- or -NCH 3 -, and each Y 1 is -CH- or -C(O)-, and each Y 2 is -N-, -NH- or -NCH 3 -, and each

[0013]

Chemical formula

[0014] represents a single bond or a double bond, and when Y 1 is -CH-, Y 2 is -N-, and

[0015]

Chemical formula

[0016] represents a double bond, and when Y 1 is -C(O)-, Y 2 is -NH- or -NCH 3 -, and

[0017]

Chemical formula

[0018] represents a single bond, and each Z is -CH- or -N-, and L is

[0019]

Chemical formula

[0020] wherein, "

[0021]

Chemical formula

[0022] " indicates the attachment point, 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), or a pharmaceutically acceptable salt thereof.

[0023] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0024] 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 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.

[0025] In yet another aspect, the present invention provides the use of 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, in the manufacture of a medicament for treating HIV infection.

[0026] In yet another aspect, the present invention provides a method for treating cancer and pre-cancerous syndromes, comprising administering to a human in need thereof a therapeutically effective amount of 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.

[0027] In another aspect, the present invention provides a method for depleting HIV-infected cells, comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0028] In a further aspect, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceuticals active against HIV. In certain aspects, these pharmaceuticals active against HIV are selected from the group consisting of antiretroviral agents, latency reversing agents, and agents for clearance therapy.

[0029] In yet another aspect, the present invention provides a method for depleting HIV-infected cells, comprising administering to a subject a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, and one or more additional agents active against HIV. In certain aspects, these pharmaceuticals active against HIV are selected from the group consisting of antiretroviral agents, latency reversing agents, and agents for clearance therapy.

[0030] These and other aspects are encompassed by the present invention as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0031]

Figure 1

Figure 2

[0032] Definitions The technical terms used herein are for the purpose of merely explaining the detailed embodiments and are not intended to limit the scope of the present disclosure. In this specification and the following claims, several terms are referred to which are defined to have the following meanings.

[0033] "Alkyl" refers to a saturated straight-chain or branched hydrocarbon moiety having from 1 to 6 carbon atoms, unless otherwise specified. The term "(C 1 ~C 6 )alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl and hexyl.

[0034] "Alkylene" refers to a straight-chain or branched-chain divalent alkyl radical having from 1 to 6 carbon atoms, unless otherwise specified. The term "(C 1 ~C 6 )alkylene" refers to an alkylene containing from 1 to 6 carbon atoms. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, etc.

[0035] "Replacement alkylene" refers to alkylene having from 1 to 5 substituents selected from alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkoxy, amino, substituted amino, quaternary amino, aminocarbonyl, imino, amidino, aminocarbonylamino, amidinocarbonylamino, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyl oxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azide, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, hydroxyamino, alkoxyamino, hydrazino, substituted hydrazino, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, oxo, thione, spirocycloalkyl, phosphate, phosphonate, phosphinate, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, sulfate, sulfonate, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiocyanate, thiol, alkylthio and substituted alkylthio. In some embodiments, it refers to alkylene having from 1 to 3 substituents, or in some embodiments from 1 to 2 substituents. It is understood that the above definitions are not intended to include unacceptable substitution patterns.

[0036] "Alkoxy", unless otherwise specified, refers to a linear or branched alkoxy group having from 1 to 6 carbon atoms. For example, "C 1 ~C 6"Alkoxy" means a linear or branched alkoxy group containing 1 to 6 carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propan-1-oxy, propan-2-oxy, butan-1-oxy, butan-2-oxy, 2-methylpropan-1-oxy, 2-methylpropan-2-oxy, pentyloxy and hexyloxy.

[0037] "Aryl" or "Ar" refers to an aromatic hydrocarbon ring. "Aryl", unless otherwise specified, includes monocyclic, bicyclic and tricyclic ring systems having a total of 5 to 15 ring member atoms, with at least one ring system being aromatic and each ring in the system containing 3 to 7 member atoms. "Aryl" also includes ring systems in which the aryl ring defined above is condensed with one or more carbocyclic or heterocyclic groups and the radical or point of attachment is on the aryl ring. In such examples, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Examples of "aryl" as used herein include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl, etc.

[0038] "Arylene" refers to a divalent aromatic hydrocarbon ring. "Arylene", unless otherwise specified, includes monocyclic, bicyclic and tricyclic ring systems having a total of 5 to 15 ring member atoms, with at least one ring system being aromatic and each ring in the system containing 3 to 7 member atoms. "Arylene" also includes ring systems in which the aryl ring defined above is condensed with one or more carbocyclic or heterocyclic groups and the radical or point of attachment is on the aryl ring. In such examples, the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Examples of "arylene" as used herein include, but are not limited to, phenylene (para, meta, ortho), naphthalene, biphenyl, indole, triazole, etc., or those derived therefrom.

[0039] "Replacement arylene" refers to arylene 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, aminocarbonyl oxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azide, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, hydroxyamino, alkoxyamino, hydrazino, substituted hydrazino, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, oxo, thione, spirocycloalkyl, phosphate, phosphonate, phosphinate, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, sulfate, sulfonate, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiocyanate, thiol, alkylthio and substituted alkylthio. It is understood that the above definitions are not intended to include unacceptable substitution patterns.

[0040] As used herein, "compound(s)" refers to compounds encompassed by the general formulas disclosed herein, any subgenus of such general formulas, as well as any forms of the compounds within the general and sub-formulas, including racemates, stereoisomers and tautomers of the compound(s).

[0041] "Cyano" refers to the -C≡N functional group.

[0042] "Cycloalkylene" refers to a non-aromatic saturated cyclic divalent hydrocarbon ring containing 3 to 7 ring atoms, unless otherwise specified. "Heterocycloalkylene" refers to "cycloalkylene" in which at least one ring atom is a heteroatom. Examples of "cycloalkylene" used include, but are not limited to, those containing or derived from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and piperidine.

[0043] "Replacement cycloalkylene" refers to cycloalkylene as defined herein having from 1 to 8, or from 1 to 5, or in some embodiments, from 1 to 3 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, aminocarbonyl oxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azide, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, hydroxyamino, alkoxyamino, hydrazino, substituted hydrazino, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, oxo, thione, spirocycloalkyl, phosphate, phosphonate, phosphinate, phosphonamidate, phosphorodiamidate, phosphoramidate monoester, cyclic phosphoramidate, cyclic phosphorodiamidate, phosphoramidate diester, sulfate, sulfonate, sulfonyl, substituted sulfonyl, sulfonyloxy, thioacyl, thiocyanate, thiol, alkylthio and substituted alkylthio. The term "substituted cycloalkyl" includes substituted cycloalkenyl groups. It is understood that the above definitions are not intended to include unacceptable substitution patterns.

[0044] "Halo" or "halogen" refers to fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br) or iodine (iodo, I).

[0045] "Heteroatom" refers to nitrogen, oxygen or sulfur.

[0046] "Latent period" means 1) a state of inactivity of the virus within a population of cells where virus production, virus packaging and host cell lysis do not occur or occur at very low frequency, or 2) a concept that explains downregulation or absence of gene expression in infected cells.

[0047] "Optionally" means that the event(s) described hereinafter may or may not occur, including both the event(s) that occur and the event(s) that do not occur.

[0048] "Solvate(s)" of a compound refers to a compound as defined above that is bound to 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.

[0049] "Stereoisomer" refers to a compound in which the chirality of one or more stereocenters is different. Stereoisomers include enantiomers and diastereoisomers. The compounds of formula (I) contain at least one asymmetric center (also referred to as a chiral center or a stereocenter) and thus may exist as individual enantiomers (also known as optical isomers), diastereoisomers or other stereoisomers, such as epimers, or mixtures thereof. A chiral center, such as a chiral carbon atom, may also be present in a substituent, such as an alkyl group, where the carbon atom is attached to four different groups. Where the stereochemistry of a chiral center present in a compound of the invention or any other chemical structure exemplified herein is not specified, the structure is intended to embrace any individual stereoisomer and also all mixtures thereof.

[0050] "Tautomers" refer to different forms of a compound where the position of a proton is different, such as enol-keto and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms attached to both a ring-NH- moiety and a ring=N- moiety, such as pyrazole, imidazole, benzimidazole, triazole and tetrazole. The compounds of the present invention may exist in tautomeric forms. Any reference to a named or structurally depicted compound is to be understood as intended to encompass all tautomers of such a compound. For example, in the embodiments disclosed herein, the compound may exist in pyrrolopyridone or pyrrolohydroxypyridine tautomeric forms, or in any stoichiometric combination of the tautomers:

[0051]

Chemical formula

[0052] 。

[0053] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable salts derived from pharmaceutically acceptable counterions. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002. When the compound of formula (I) contains two or more basic moieties, it is understood that the stoichiometric salt form may contain one, two or more equivalents of acid (i.e., acid addition salts). Such salts, for example, dihydrochloride salts, may contain one, two or more acid counterions. The stoichiometric and non-stoichiometric forms of the pharmaceutically acceptable salts of the compound of formula (I) are included within the scope of the present invention, which includes, for example, semi-stoichiometric salts in which the counterion contains more than one acidic proton. Representative pharmaceutically acceptable acid addition salts are 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, hydrogen tartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprylate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, dicosuccinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edsylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisinate (2,5-dihydroxybenzoate), glucoheptonate (glceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-Di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicylate, pamoate (embonate), pantothenate, pectinate, persulfate, phenyl acetate, phenylethyl barbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, basic acetate, succinate, sulfamate, sulfate, tannate, tartrate, theocurate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate and valerate, including but not limited to them.,

[0054] "Pharmaceutically acceptable" refers to compounds (including salts), materials, compositions and dosage forms that are suitable for use in contact with human and animal tissues within the scope of medical common sense, without excessive toxicity, irritation or other problems or complications, and commensurate with a reasonable benefit / risk ratio.,

[0055] "Reversing HIV latency" refers to a treatment that upregulates the expression of the HIV genome integrated into latently infected cells, for example, activating the non-canonical NF-kB pathway and agents that cause the sensitivity of infected cells to virus-induced cell death or immunological clearance. In certain embodiments, latently HIV-infected cells are resting CD4 +It is a T cell. As used herein, "depleting latent HIV infection" refers to the clearance of cells latently infected with HIV that may follow the reversal of HIV latency by a reagent, such as one that activates the non-canonical NF-kB pathway. In some embodiments, each of Compounds 1-112 can be used for the reversal of HIV latency and / or the depletion of latent HIV infection.

[0056] "Therapeutically effective amount" means any amount that, compared to a corresponding subject not receiving such amount, results in an improved treatment, alleviation or remission of a disease, disorder or side effect, or a decrease in the rate at which the disease or disorder progresses. This term also includes within its scope amounts effective to improve normal physiological functions. For use in therapy, a therapeutically effective amount of a compound of formula (I), and its salts, can be administered as the raw chemical substance. Additionally, the active ingredient can be presented as a pharmaceutical composition.

[0057] "Treating a viral infection" means inhibiting the replication of a particular virus, inhibiting viral transmission, and alleviating or mitigating the symptoms of a disease caused by a viral infection. Treatment is considered "therapeutic" if a decrease in the viral load, mortality and / or morbidity is observed. "Preventing a viral infection" means preventing the virus from establishing itself in a host. Treatment is considered "preventive" if the subject is exposed to the virus but does not become infected as a result of the treatment.

[0058] When a dashed line appears adjacent to a single bond represented by a solid line, the dashed line always represents an optional double bond at that position. The wavy line "

[0059]

Chemical formula

[0060] " appears across a bond, it always means "

[0061] [Chemistry]

[0062] " refers to the attachment point. For example, the two wavy lines in the following structure refer to two different attachment points to additional chemical moieties, and the dashed line in the following structure may refer to a double bond at that position, or a single bond at that position:

[0063] [Chemistry]

[0064] .

[0065] The subject matter disclosed herein is described in more detail below. However, many modifications and other embodiments of the subject matter disclosed herein will come to the mind of those skilled in the art who are related to the subject matter disclosed herein and who have the benefit of the teachings presented in the foregoing description. Accordingly, it is to be understood that the subject matter disclosed herein is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein covers all substitutes, modifications, and equivalents. If one or more of the incorporated documents, patents, and similar materials are different from or conflict with this application, including defined terms, the use of terms, the described techniques, etc., this application shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0066] Apoptosis, a type of programmed cell death, plays an important role in maintaining homeostasis and regulating cell numbers in higher organisms. Aberrant apoptosis is involved in several diseases, such as autoimmune disorders, neurodegenerative diseases, cancer, and viral infections, including HIV. The family of inhibitor of apoptosis proteins (IAP) plays an important role in suppressing pro-apoptotic signaling in mammalian cells. SMACm, which mimics a critical tetrapeptide sequence from the second mitochondrial-derived activator of caspases, has been shown to interfere with the binding of IAP to its functional partners and restore the apoptotic response to pro-apoptotic stimuli in cells. Since the early 2000s, significant efforts have been focused on the design and preparation of SMAC mimics as IAP antagonists, particularly in promoting cell death in tumor cells and, more recently, in reversing HIV latency. SMAC mimics bind to the BIR2 and BIR3 domains of IAP proteins, causing inhibition (in the case of XIAP) and enhancement of apoptosis, or activation of ubiquitin ligase activity (in the case of cIAP1 and cIAP2), which leads to autoubiquitinylation and depletion of the activated proteins. When cIAP1 and 2 suppress the ncNF-kB pathway, activation of these proteins by SMACm is observed, which results in activation of the ncNFkB transcription factor and kB-dependent gene expression. Such investigations have explored the activation of the non-canonical NF-kB pathway (ncNF-kB) as a potential way for SMAC mimics to selectively deplete latently infected HIV cells. An example of an early SMAC mimic studied with respect to HIV was the monomer SBI-0637142 prepared by researchers at the Sanford-Burnham Medical Research Institute. In HIV depletion assays, SBI-0637142 was found to be potent in cell line assays but did not exhibit activity in primary cells in p100-p52 conversion or HIV caRNA induction. In the field of oncology, much effort has also been directed towards the development of bivalent mimics, which are covalently linked monomeric SMAC mimics.AstraZeneca's AZD5582 and Medivir's birinapant TL32711 are examples of dimer SMAC mimetics. In HIV latency reversal studies, birinapant TL32711 was not potent in Jurkat p100-p52 conversion or HIV caRNA induction. In contrast, AZD5582 exhibited increased cell-associated HIV RNA expression in resting CD4+ T cells through Jurkat assay experiments, p100-p52 conversion studies, and HIV cell-associated RNA induction (Sampey et al., bioRxiv 312447). However, AZD5582 can also demonstrate tolerance issues.

[0067] The IAP proteins targeted by SMAC mimetics for ncNF-kB activation are cIAP1 and cIAP2, and the bivalent molecules possess the optimal linker with the most efficient activity when depleting these two molecules and activating ncNF-kB. This ncNF-kB activation activity likely occurs through the formation of intermolecular ternary complexes, 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, and when one bivalent SMAC mimetic interacts with both the BIR2 and BIR3 domains of a single molecule of XIAP, it is described in the literature as an intramolecular binding. Since XIAP is not thought to have a role in ncNF-kB activation by SMAC mimetics, it may be an off-target in the context of HIV latency reversal.

[0068] [Chemical formula]

[0069] As a single agent, a dimer SMACm that is potent and effective enough to activate ncNF-kB and reverse HIV latency in primary, unmodified primary human cells is disclosed herein, making the dimer SMACm suitable for further development. Specifically, the disclosed dimer SMACm of the compounds is optimized to favor BIR3 over BIR2 binding, such that such domains, especially within XIAP, should favor the formation of intermolecular ternary complexes between two IAP proteins, and thus favor the depletion of cIAP1 and cIAP2 over the inhibition of XIAP. Other SMACms with unoptimized linkers or lacking this specificity for BIR3 over BIR2, specifically monomeric or dimeric molecules, are not reported to have an HIV latency reversal effect in primary human CD4+ T cells, inhibit XIAP, and may cause potential off-target effects through the synergistic action of unwanted apoptosis.

[0070] The present invention provides compounds of formula (I), as well as various forms of these compounds as specified herein (e.g., pharmaceutically acceptable salts, tautomers, and stereoisomers). It should be understood that any reference to a compound of formula (I) herein clearly means including, but not limited to, the compounds specified in Table 1.

[0071] In some embodiments, the present invention relates to a compound of formula (I)

[0072]

Chemical formula

[0073] or a pharmaceutically acceptable salt thereof, or in other embodiments, a compound of formula (Ia)

[0074]

Chemical formula

[0075] To provide a compound of the structure according to or a pharmaceutically acceptable salt or stereoisomer thereof. (In the formula, Each R 1 and R 2 is -CH 3 and Each R 3 is -H or -CH 3 and Each R 4 is -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 and Each R 5 is -H, -F, -Cl, -Br, -CH 3 , -CHF 2 or -CF 3 and Each R 6 is -H, -F or -Cl, Each R 7 is -H or -F, Each W is -CH-, -CH 2 -, -O- or -N-, Each X is -CH 2 -, -O-, -NH- or -NCH 3 - and Each Y 1 is -CH- or -C(O)-, Each Y 2 is -N-, -NH- or -NCH 3 - and Each

[0076]

Chemical formula

[0077] represents a single bond or a double bond, and Y 1 When Y 2 is -CH-, Y

[0078]

Chemical formula

[0079] represents a double bond, and Y 1 When Y 2 is -C(O)-, Y 3 is -NH- or -NCH

[0080]

Chemical formula

[0081] represents a single bond, each Z is -CH- or -N-, L is

[0082]

Chemical formula

[0083] a linker selected from the group consisting of, "

[0084]

Chemical formula

[0085] " indicates the attachment point, 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.)

[0086] In some embodiments, each R 1 and R 2 is -CH 3 In other embodiments, each R 1 and R 2 is -H. In still other embodiments, each R 1 and R 2 is independently -H or -CH 3 .

[0087] In some embodiments, each X is -CH 2 -, each Z is -CH-, and each R 4 is -H.

[0088] In some embodiments, each Y 1 is -C(O)-, each Y 2 is -NH- or -NCH 3 -, and each

[0089]

Chemical formula

[0090] represents a single bond.

[0091] In some embodiments, the compound is

[0092]

Chemical formula

[0093] or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the compound is

[0095]

Chemical formula

[0096] selected from the group consisting of In some embodiments, L is

[0097]

Chemical formula

[0098] a linker selected from the group consisting of, “

[0099]

Chemical formula

[0100] ” indicates the attachment point, 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.

[0101] In some embodiments, the compound is

[0102]

Chemical formula

[0103] or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, L is

[0104]

Chemical formula

[0105] selected from the group consisting of “

[0106]

Chem.

[0107] " indicates the attachment point, and n is an integer from 2 to 8.

[0108] In some embodiments, the compound is

[0109]

Chem.

[0110] selected from the group consisting of

[0111] In some embodiments, L is

[0112]

Chem.

[0113] selected from the group consisting of, "

[0114]

Chem.

[0115] " indicates the attachment point, 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.

[0116] In some embodiments, the compound is

[0117]

Chem.

[0118] is.

[0119] In some embodiments, L is

[0120]

Chemical formula

[0121] selected from the group consisting of

[0122] 「

[0123]

Chemical formula

[0124] 」indicates the attachment point, and z is an integer from 2 to 8.

[0125] In some embodiments, the compound, or a pharmaceutically acceptable salt or stereoisomer thereof, is

[0126]

Chemical formula

[0127] a heterodimer selected from the group consisting of

[0128] In another aspect, the present invention provides a compound of formula (II):

[0129]

Chemical formula

[0130] or a pharmaceutically acceptable salt or stereoisomer thereof. (Wherein, each R 3is -H or -CH 3 and each W is -CH-, -O- or -N-; L is

[0131] [Chemical formula]

[0132] a linker selected from the group consisting of

[0133] "

[0134] [Chemical formula]

[0135] " indicates the attachment point, t is 6 or 8, and x is 3 or 6)

[0136] Exemplary compounds encompassed by the present invention include, but are not limited to, those in Table 1 below:

[0137] [Table 1] JPEG2025518076000053.jpg 244153 JPEG2025518076000054.jpg 243153 JPEG2025518076000055.jpg 247152 JPEG2025518076000056.jpg 250154 JPEG2025518076000057.jpg 239153 JPEG2025518076000058.jpg 229153 JPEG2025518076000059.jpg 229153 JPEG2025518076000060.jpg 234153 JPEG2025518076000061.jpg 245152 JPEG2025518076000062.jpg 250152 JPEG2025518076000063.jpg 235153 JPEG2025518076000064.jpg 250152 JPEG2025518076000065.jpg 250152 JPEG2025518076000066.jpg 215153 JPEG2025518076000067.jpg 255153 JPEG2025518076000068.jpg 255153 JPEG2025518076000069.jpg 255152 JPEG2025518076000070.jpg 255153 JPEG2025518076000071.jpg 213153 JPEG2025518076000072.jpg 255153 JPEG2025518076000073.jpg 255153 JPEG2025518076000074.jpg 255153 JPEG2025518076000075.jpg 255152 JPEG2025518076000076.jpg 245152 JPEG2025518076000077.jpg 255152 JPEG2025518076000078.jpg 255153 JPEG2025518076000079.jpg 255153 JPEG2025518076000080.jpg 255153 JPEG2025518076000081.jpg 226153 JPEG2025518076000082.jpg 214153 JPEG2025518076000083.jpg 250152 JPEG2025518076000084.jpg 240153 JPEG2025518076000085.jpg252154JPEG2025518076000086.jpg247153JPEG2025518076000087.jpg255153JPEG2025518076000088.jpg240153JPEG2025518076000089.jpg255153JPEG2025518076000090.jpg240153JPEG2025518076000091.jpg225152JPEG2025518076000092.jpg221153JPEG2025518076000093.jpg210153JPEG2025518076000094.jpg194153JPEG2025518076000095.jpg204153JPEG2025518076000096.jpg250152JPEG2025518076000097.jpg252154JPEG2025518076000098.jpg231153JPEG2025518076000099.jpg255153JPEG2025518076000100.jpg252153JPEG2025518076000101.jpg230153JPEG2025518076000102.jpg241153JPEG2025518076000103.jpg235153JPEG2025518076000104.jpg250152JPEG2025518076000105.jpg250152JPEG2025518076000106.jpg250152JPEG2025518076000107.jpg255153JPEG2025518076000108.jpg252153JPEG2025518076000109.jpg252153JPEG2025518076000110.jpg225153JPEG2025518076000111.jpg230153JPEG2025518076000112.jpg225153JPEG2025518076000113.jpg255153JPEG2025518076000114.jpg252153JPEG2025518076000115.jpg255153JPEG2025518076000116.jpg94152.

[0138] Pharmaceutically acceptable salts are also within the scope of the present invention with respect to all compounds 1-190 specified herein. In some embodiments, each of compounds 1-190 may generally exist as a hydrochloride (i.e., HCl salt), for example, more specifically as a dihydrochloride, (2HCl) salt. In some embodiments, compounds 1-190 may generally exist as a mixture of mono and di-acid acetates, trifluoroacetate, citrate forms. In some embodiments, the salt forms of compounds 1-190 may be a blend of hydrohalide and dihydrohalide forms (i.e., mono and di-acids). Any of compounds 1-190 existing as a single species containing those pharmaceutically acceptable salts, as well as any of these compounds in their free base forms, are also within the scope of the present invention.

[0139] Specific examples of the linker (L) that can be used according to the present invention are

[0140]

Chemical formula

[0141] including those selected from the group consisting of

[0142] 「

[0143]

Chemical formula

[0144] 」indicates the attachment point.

[0145] In another embodiment of the invention, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof for use in drug therapy.

[0146] In another embodiment of the invention, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of HIV infection.

[0147] In another embodiment of the 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 use in the treatment of HIV infection in humans.

[0148] In some embodiments, the present invention provides a method of curing HIV infection in a subject, the method comprising administering to the subject a compound of formula I, as well as any compound of Table 1, together with its pharmaceutically acceptable salts. "Curing" or "curing" a disease in a patient is used to indicate the eradication, arrest, cessation or termination of the human immunodeficiency virus or symptoms, or the progression of symptoms or the virus, for a defined period. By way of example, in one embodiment, "curing" or "curing" means sustained viral control of the human immunodeficiency virus (e.g., plasma viremia levels that cannot be detected by polymerase chain reaction (PCR) testing, branched DNA (bDNA) testing or nucleic acid sequence-based amplification (NASBA) testing) after at least 2 years, alone or in combination with one or more other compounds, without any other therapeutic intervention. The above PCR, bDNA and NASBA tests are performed using techniques known to and well known to those of skill in the art. By way of example, the eradication, arrest, cessation or termination of the human immunodeficiency virus or symptoms, or the progression of symptoms or the virus, can be sustained for at least 2 years.

[0149] In some embodiments, the present invention provides a method of curing HIV infection in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a compound of formula I together with its pharmaceutically acceptable salts.

[0150] 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 use in the cure of HIV infection.

[0151] In some embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the cure of HIV infection.

[0152] The compound of formula I, and combinations of one or more agents useful in the treatment of HIV, may also be used in methods for curing HIV infection.

[0153] In one embodiment, the pharmaceutical formulation containing the compound of formula I or a salt thereof is a formulation adapted for parenteral administration. In another embodiment, the formulation is a long-acting parenteral formulation. In a further embodiment, the formulation is a nanoparticle formulation.

[0154] The compounds and salts of the present invention, their solvates or other pharmaceutically acceptable derivatives may be used alone or in combination with other therapeutic agents. Thus, in other embodiments, a method for treating and / or preventing HIV infection in a subject may further comprise administering one or more additional anti-HIV active pharmaceuticals in addition to the administration of a compound of formula I.

[0155] In such embodiments, the one or more additional anti-HIV active agents are selected from the group consisting of antiretroviral agents, latency reversing agents, and agents for clearance therapy.

[0156] In other embodiments, the one or more additional HIV-active agents 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 crotonyltransferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and neutralizing antibodies and combinations thereof.

[0157] In certain embodiments, the agent(s) active against one or more additional HIV are selected from the group consisting of zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, hydroxycarbamide, tenofovir, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, orchiprase, capravirine, raltegravir, elvitegravir, dolutegravir, cabotegravir, bictegravir, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, darunavir, vorinostat, panobinostat, romidepin, valpronic acid, mocetinostat, sodium corotonate, bryostatin, ingenol B, disulforam, GS-9620, JQ1, iBET151, bortezomib, epigallocatechin gallate, salinosporamide A, carfilzomib, broadly neutralizing antibody (bNAb), eCD4-Ig, CD4-Ig, and dual-affinity retargeting (DART) protein.

[0158] Accordingly, the compounds of the invention of formula (I), and any other pharmaceutically active agent(s), can be administered together or separately, and if administered separately, the administrations can occur simultaneously or sequentially in any order. The amounts of the compound of formula (I) of the invention and other pharmaceutically active agent(s), and the relative timing of administration, are selected to achieve the desired combined therapeutic effect. The combined administration of the compound of the invention of formula (I), and its salts, solvates or other pharmaceutically acceptable derivatives with other therapeutic agents can be (1) in a single pharmaceutical composition containing both compounds; or (2) in a combination by simultaneous administration in separate pharmaceutical compositions each containing one of the compounds. Alternatively, the combination can be administered separately in a sequential manner, with one therapeutic agent being administered first and the other second, or vice versa. Such sequential administrations can be close in time or separated in time. The amounts of the compound(s) of formula (I) or its salts, and other pharmaceutically active agent(s), and the relative timing of administration, are selected to achieve the desired combined therapeutic effect.

[0159] Furthermore, the compounds of the invention of formula (I) can be used in combination with one or more other agents that can be useful in the treatment of HIV. These agents can include antiretroviral agents, latency reversing agents and agents for clearance therapy. Some examples of antiretroviral agents are shown below:

[0160] Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine and similar agents;

[0161] Non-nucleotide reverse transcriptase inhibitors (agents having antioxidant activity, such as Immunocal, Orthoplas, etc.), such as nevirapine, delavirdine, efavirenz, loviride, Immunocal, Orthoplas, capravirine, rilpivirine, GSK2248761, TMC-278, TMC-125, etravirine and similar agents;

[0162] Protease inhibitors, such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir and similar agents;

[0163] Entry, attachment and fusion inhibitors, such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS-626529, 5-helix, and similar agents;

[0164] Integrase inhibitors, such as raltegravir, elvitegravir, dolutegravir, cabotegravir, bictegravir and similar agents;

[0165] Maturation inhibitors, such as PA-344 and PA-457, and similar agents; and

[0166] CXCR4 and / or CCR5 inhibitors, such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK427,857), TAK449, and those disclosed in WO02 / 74769, PCT / US03 / 39644, PCT / US03 / 39975, PCT / US03 / 39619, PCT / US03 / 39618, PCT / US03 / 39740 and PCT / US03 / 39732 and similar agents.

[0167] Further examples where the compounds of the present invention can be used in combination with one or more agents useful for the prevention or treatment of HIV are found in Table 2.

[0168]

Table 2

[0169] The present invention can be used in combination with other agents that induce HIV expression, such as latency reversing agents. Some latency reversing agents include, but are not limited to: histone deacetylase inhibitors (e.g., vorinostat, panobinostat, romidepsin), histone crotonyltransferase inhibitors (sodium crotonate), 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 are described in further detail below.

[0170] The present invention can be used in combination with other agents that induce HIV expression, such as agents for clearance therapy. Some examples of agents for clearance therapy, or immunological combinations for clearance, include, but are not limited to: neutralizing antibodies and broadly neutralizing antibodies (bNAb), eCD4-Ig, CD4-Ig, and bispecific affinity retargeting (DART) proteins.

[0171] The scope of the combination of the compounds of the present invention with HIV agents is not limited to those mentioned above, but in principle includes any combination with any pharmaceutical composition useful for the treatment and / or prevention of HIV. As mentioned above, in such combinations, the compounds of the present invention and other HIV agents may be administered separately or together. Further, one agent may be before, at the same time as, or after the administration of the other agent(s).

[0172] In some embodiments, the compounds of Formula I and Table 1 can be used in combination with one or more agents useful as pharmacological enhancers, and with or without additional compounds for preventing or treating HIV. Examples of such pharmacological enhancers (or pharmakinetic boosters) include, but are not limited to, ritonavir, GS-9350 (cobicistat), and SPI-452.

[0173] Ritonavir is 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5S*,8R*,10R*,11R*)], and is available as Norvir from Abbott Laboratories, Abbott Park, Illinois. Ritonavir is an HIV protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV infection. Ritonavir also inhibits P450-mediated drug metabolism, as well as the P-glycoprotein (Pgp) cellular transport system, thereby causing an increase in the concentration of active compounds in vivo.

[0174] GS-9350 (cobicistat) is a compound being developed as a pharmacological enhancer by Gilead Sciences, Foster City, California.

[0175] SPI-452 is a compound being developed as a pharmacological enhancer by Sequoia Pharmaceuticals, Gaithersburg, Maryland.

[0176] 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 as a long-acting parenteral injectable, and ritonavir is formulated as an oral composition. In one embodiment, the kit contains the compound of formula I formulated as a long-acting parenteral injectable and ritonavir formulated as an oral composition. In another embodiment, the compound of formula I is formulated as a long-acting parenteral injectable and ritonavir is formulated as an injectable composition. In one embodiment, the kit contains the compound of formula I formulated as a long-acting parenteral injectable and ritonavir formulated as an injectable composition.

[0177] 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 injectable, and GS-9350 is formulated as an oral composition. In one embodiment, a kit is provided that contains the compound of formula I formulated as a long-acting parenteral injectable and GS-9350 formulated as an oral composition. In another embodiment, the compound of formula I is formulated as a long-acting parenteral injectable and GS-9350 is formulated as an injectable composition. In one embodiment, a kit is provided that contains the compound of formula I formulated as a long-acting parenteral injectable and GS-9350 formulated as an injectable composition.

[0178] In some embodiments, the compounds of Formula I are used in combination with SPI-452. In one embodiment, the combination is an oral fixed-dose combination. In other embodiments, the compounds of Formula I are formulated as a long-acting parenteral implant, and SPI-452 is formulated as an oral composition. In still other embodiments, a kit is provided that contains a compound of Formula I formulated as a long-acting parenteral implant and SPI-452 formulated as an oral composition. In other embodiments, the compounds of Formula I are formulated as a long-acting parenteral implant, and SPI-452 is formulated as an injectable composition. In some embodiments, a kit is provided that contains a compound of Formula I formulated as a long-acting parenteral implant and SPI-452 formulated as an injectable composition.

[0179] In some embodiments, the compounds of Formula I are used in combination with compounds found in PCT / CN2011 / 0013021, which was previously filed and is incorporated herein by reference.

[0180] When used in combination with the chemical entities described herein, the other therapeutic agents above can be used, for example, in the amounts indicated in the Physicians’ Desk Reference (PDR) or in amounts otherwise determined by one of ordinary skill in the art.

[0181] In other embodiments, a method for treating a viral infection in a mammal, at least partially mediated by a virus in the retrovirus family, is provided, the method comprising administering a compound of Formula I to a mammal diagnosed with or at risk of developing the viral infection.

[0182] In yet other embodiments, there is provided a method for treating a viral infection in a mammal that is at least partially mediated by a virus in the retrovirus family of viruses, the method comprising administering a compound of Formula I to a mammal diagnosed with or at risk of developing said viral infection, wherein said virus is an HIV virus. In some embodiments, the HIV virus is an HIV-1 virus.

[0183] In other embodiments, there is provided a method for treating a viral infection in a mammal that is at least partially mediated by a virus in the retrovirus family of viruses, the method comprising administering a compound of Formula I to a mammal diagnosed with or at risk of developing said viral infection, and further comprising administering a therapeutically effective amount of one or more agents active against the HIV virus.

[0184] In some embodiments, there is provided a method for treating a viral infection in a mammal that is at least partially mediated by a virus in the retrovirus family of viruses, the method comprising administering a compound of Formula I to a mammal diagnosed with or at risk of developing said viral infection, and further comprising administering a therapeutically effective amount of one or more agents active against the HIV virus, wherein said agent active against the HIV virus is selected from the group consisting of 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.

[0185] In another aspect, there is provided a method of depleting latently HIV-infected cells, the method comprising administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0186] In various embodiments, the compound is selected from the group consisting of the compounds listed in Table 1. In some embodiments, a pharmaceutical composition comprising this compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient including, for example, those specified herein. In other embodiments, a method of treating HIV infection in a subject, the method comprising administering to the subject this compound or a pharmaceutically acceptable salt thereof, and a combination. In yet other embodiments, a compound of Formula I or Table 1 or a pharmaceutically acceptable salt thereof for use in the treatment of HIV infection. Some embodiments also include the use of this compound in the manufacture of a medicament for treating HIV infection. In yet other embodiments, a method of depleting latently HIV-infected cells, the method comprising administering to the subject this compound or a pharmaceutically acceptable salt thereof, and combinations thereof.

[0187] In various embodiments, the method of depleting latent HIV infection further comprises administering to the subject one or more additional agents that are active against HIV as disclosed hereinabove. By way of example, in various embodiments, the one or more additional agents are selected from the group consisting of nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, attachment and fusion inhibitors, integrase inhibitors, maturation inhibitors, CXCR4 and / or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyltransferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and antibodies for clearance therapy and combinations thereof.In various embodiments, the one or more additional agents active against HIV are selected from the group consisting of zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, hydroxycarbamide, tenofovir, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, orchiprase, capravirine, raltegravir, elvitegravir, dolutegravir, cabotegravir, bictegravir, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, darunavir, vorinostat, panobinostat, romidepsin, valproic acid, mocetinostat, sodium crotonate, 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.

[0188] Compounds according to formula I and pharmaceutically acceptable salts thereof may be useful for the treatment of cancer and pre-cancerous syndromes. Preferably, the present invention relates to methods for treating cancer selected from the group consisting of brain (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Banayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, epithelioma, medulloblastoma, head and neck cancer, kidney cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal carcinoma, adenoid squamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous 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 cancer, vulvar cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.

[0189] Suitably, the present invention is a method for treating precancerous syndromes in mammals including humans, wherein the precancerous syndrome is selected from cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, cutaneous nevi (melanoma in situ), prostatic intraepithelial (intraductal) neoplasia (PIN), ductal carcinoma in situ (DCIS), colorectal polyps, and severe hepatitis or cirrhosis.

[0190] The compounds of formula (I) and pharmaceutically acceptable salts thereof can be co-administered with at least one other active agent known to be useful in the treatment of cancer or precancerous syndromes.

[0191] As used herein, the term "co-administration" means any method of co-administration or separate sequential administration of the c-MYC inhibitory compounds described herein, and additional active agents or agents known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. As used herein, the term additional active agent or agent means any compound or therapeutic agent known or demonstrated to have advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administrations are not simultaneous, the compounds are administered at times very close to each other. Further, it is not a problem whether the compounds are administered in the same dosage form. For example, one compound can be administered by injection and another compound can be administered orally.

[0192] Examples of additional active ingredients or agents (antineoplastic agents) for use in combination with or co-administered with the combinations of the present invention are indicated below. This listing is non-limiting. Additional antineoplastic agents are contemplated for use with the compounds of the present invention.

[0193] Typically, any antineoplastic agent that is active against the sensitive tumor to be treated can be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology, V.T. Devita and S. Hellman (eds.), 6th Edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. One of ordinary skill in the art can identify which combinations of agents may be useful based on the detailed characteristics of the drugs and cancers involved. Typical antineoplastic agents useful in the present invention include microtubule inhibitors such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustard, oxazaphosphorine, alkyl sulfonate, nitrosourea and triazene; antibiotic preparations such as anthracyclins, actinomycin and bleomycin; topoisomerase II inhibitors such as epipodophyllotoxin; antimetabolites such as purine and pyrimidine analogs, and folic acid antagonist compounds; topoisomerase I inhibitors such as camptothecin; hormones and hormone analogs; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapy agents; pro-apoptotic agents; cell cycle signal transduction inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism, but are not limited thereto.

[0194] Examples of additional active ingredients or agents (antineoplastic agents) for use in combination with or co-administered with the compounds of the present invention are chemotherapeutic agents.

[0195] Microtubule inhibitors or antimitotic agents are cell cycle specific agents that are active against the microtubules of tumor cells during the M phase or mitosis of the cell cycle. Examples of microtubule inhibitors include, but are not limited to, diterpenoids and vinca alkaloids.

[0196] Diterpenoids derived from natural sources are in the G of the cell cycle 2It is a cell cycle-specific anticancer agent that acts in the M phase. Diterpenoids are thought to stabilize the β-tubulin subunit of microtubules by binding to this protein. Subsequently, protein degradation is inhibited, mitosis is arrested, and cell death is thought to follow. Examples of diterpenoids include, but are not limited to, paclitaxel and its analogue docetaxel.

[0197] Paclitaxel, the 5β,20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytaxa-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine, is a natural diterpenoid product isolated from the Pacific yew, Taxus brevifolia, and is commercially available as the injectable solution TAXOL (registered trademark). 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), and Wani et al. characterized its structure by chemical and X-ray crystallographic methods. One of its mechanisms of action relates to the ability of paclitaxel to bind to tubulin and thereby inhibit the growth of cancer cells. 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 D.G.I. Kingston et al., Studies in Organic Chemistry, Vol. 26, entitled "New trends in Natural Products Chemistry 1986", edited by Attaur-Rahman, P.W. Le Quesne (Elsevier, Amsterdam, 1986), pp. 219-235.

[0198] Paclitaxel is approved for clinical use in the treatment of refractory ovarian cancer in the United States (Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al., Ann. Intern. Med., 111:273, 1989), and also for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991). It is a potential candidate for the treatment of neoplasms in the skin (Einzig et al., Proc. Am. Soc. Clin. Oncol., 20:46), and head and neck cancer (Forastire et al., Sem. Oncol., 20:56, 1990). This 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 is associated with myelosuppression (multiple cell lineages, Ignoff, R.J. et al., Cancer Chemotherapy Pocket Guide, 1998) related to the duration of administration exceeding a threshold concentration (50 nM) (Kearns, C.M. et al., Seminars in Oncology, 3(6), 16 - 23, 1995).

[0199] Docetaxel, the (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester, trihydrate of 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytaxa-11-en-9-one 4-acetate 2-benzoate is marketed as an injectable solution under the trade name TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semi-synthetic derivative of paclitaxel q.v. prepared using the natural precursor 10-deacetyl-baccatin III extracted from the needles of European yew. The dose-limiting toxicity of docetaxel is neutropenia.

[0200] Vinca alkaloids are cell cycle-specific antineoplastic agents derived from the plant Catharanthus roseus. Vinca alkaloids act in the M phase (mitosis) of the cell cycle by specifically binding to tubulin. As a result, the bound tubulin molecules are unable to polymerize into microtubules. Mitosis is arrested in metaphase, followed by cell death. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.

[0201] Vinblastine, vincaleukoblastine sulfate, is marketed as VELBAN® injection. It may be indicated as a second-line treatment for various solid tumors, but is primarily indicated for the treatment of testicular cancer and Hodgkin's disease; as well as various lymphomas, including lymphocytic and histiocytic lymphomas. Myelosuppression is the dose-limiting side effect of vinblastine.

[0202] Vincristine, vincaleukoblastine, 22-oxo-, sulfate is marketed as ONCOVIN® injection. Vincristine is indicated for the treatment of acute leukemia and has also been found to be used in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas. Alopecia and neurological effects are the most common side effects of vincristine, with myelosuppression and gastrointestinal mucositis occurring on a smaller scale.

[0203] 3’,4’-Didehydro-4’-deoxy-C’-norbincaleukoblastine [R-(R * ,R *)-2,3-Dihydroxybutanedioate(1:2)(salt), vinorelbine, is commercially available as an injection solution of vinorelbine tartrate (NAVELBINE (registered trademark)) and is a semi-synthetic vinca alkaloid. Vinorelbine is indicated for the treatment of various solid tumors, particularly non-small cell lung cancer, advanced breast cancer, and hormone-refractory prostate cancer, either as a single agent or in combination with other chemotherapeutic agents, such as cisplatin. Myelosuppression is the most common dose-limiting side effect of vinorelbine.

[0204] Platinum coordination complexes are cell cycle non-specific anticancer agents that interact with DNA. Platinum complexes enter tumor cells, undergo aquation, and form cross-links with DNA within and between strands, causing harmful biological effects in tumors. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.

[0205] Cisplatin, cis-diamminedichloroplatinum, is commercially available as PLATINOL (registered trademark) as an injection solution. Cisplatin is mainly indicated for the treatment of metastatic testicular and ovarian cancers, as well as advanced bladder cancer. The main dose-limiting side effects of cisplatin are nephrotoxicity, which can be regulated by fluid replacement and diuresis, and ototoxicity.

[0206] Carboplatin, platinum, diammine [1,1-cyclobutane-dicarboxylate(2-)-O,O'] (Carboplatin, platinum, diammine [1,1-cyclobutane-dicarboxylate(2-)-O,O']) is commercially available as PARAPLATIN (registered trademark) as an injection solution. Carboplatin is mainly indicated for the first- and second-line treatment of advanced ovarian cancer. Myelosuppression is the dose-limiting toxicity of carboplatin.

[0207] Alkylating agents are non-cell cycle-specific anticancer agents and are powerful electrophiles. Typically, alkylating agents form covalent bonds to DNA by alkylation through nucleophilic moieties of the DNA molecule, such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation interferes with nucleic acid function and causes 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.

[0208] Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorin 2-oxide monohydrate, is commercially available as an injectable solution or tablets under the trademark CYTOXAN®. Cyclophosphamide is indicated for the treatment of malignant lymphoma, multiple myeloma, and leukemia, either as a single agent or in combination with other chemotherapeutic agents. Alopecia, nausea, vomiting, and leukopenia are the most common dose-limiting side effects of cyclophosphamide.

[0209] Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets under the trademark ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and inoperable epithelial ovarian cancer. Myelosuppression is the most common dose-limiting side effect of melphalan.

[0210] Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphocytic leukemia and malignant lymphoma, such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Myelosuppression is the most common dose-limiting side effect of chlorambucil.

[0211] Busulfan and 1,4-butanediol dimethanesulfonate are marketed as Myleran® tablets. Busulfan is indicated for palliative treatment of chronic myelogenous leukemia. Myelosuppression is the most common dose-limiting side effect of busulfan.

[0212] Carmustine, 1,3-bis(2-chloroethyl)-1-nitrosourea is marketed as a single vial of freeze-dried material as BiCNU®. Carmustine is indicated for palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease and non-Hodgkin's lymphoma. Delayed myelosuppression is the most common dose-limiting side effect of carmustine.

[0213] Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide is marketed as a single vial of material as DTIC-Dome®. Dacarbazine is indicated for treatment of metastatic malignant melanoma and as second-line treatment of Hodgkin's disease in combination with other agents. Nausea, vomiting and anorexia are the most common dose-limiting side effects of dacarbazine.

[0214] Antibiotic antineoplastic agents are non-cell cycle specific agents that bind to or intercalate with DNA. Typically, such action results in the formation of stable DNA complexes or strand breaks, thereby interfering with the normal function of nucleic acids and causing cell death. Examples of antibiotic antineoplastic agents include, but are not limited to, actinomycin, such as dactinomycin, anthrocyclins, such as daunorubicin and doxorubicin, and bleomycin.

[0215] Dactinomycin, also known as actinomycin D, is marketed in injectable form as Cosmegen®. Dactinomycin is indicated for treatment of Wilms' tumor and rhabdomyosarcoma. Nausea, vomiting and anorexia are the most common dose-limiting side effects of dactinomycin.

[0216] Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride is commercially available as a liposomal injection form under the name DAUNOXOME (registered trademark), or as an injection agent under the name CERUBIDINE (registered trademark). Daunorubicin is indicated for remission induction in the treatment of acute non-lymphocytic leukemia and advanced HIV-related Kaposi's sarcoma. Myelosuppression is the most common dose-limiting side effect of daunorubicin.

[0217] Doxorubicin, (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride is commercially available as an injection form under the names RUBEX (registered trademark) or ADRIAMYCIN RDF (registered trademark). Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose-limiting side effect of doxorubicin.

[0218] Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available under the name BLENOXANE (registered trademark). Bleomycin is indicated as a palliative treatment for squamous cell carcinoma, lymphoma, and testicular cancer, either as a single agent or in combination with other agents. Pulmonary toxicity and skin toxicity are the most common dose-limiting side effects of bleomycin.

[0219] Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.

[0220] Epipodophyllotoxin is a cell cycle-specific antineoplastic agent derived from the plant mandrake. Epipodophyllotoxin typically forms a ternary complex with topoisomerase II and DNA, causing DNA strand breaks, thereby affecting cells in the S and G 2 phases of the cell cycle. The strand breaks accumulate, followed by cell death. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

[0221] Etoposide, 4'-demethyl-epipodophyllotoxin 9 [4,6-O-(R)-ethylidene-β-D-glucopyranoside], is commercially available as an injection solution under the name VePESID® or as capsules and is commonly known as VP-16. Etoposide is indicated for the treatment of testicular cancer and non-small cell lung cancer, either as a single agent or in combination with other chemotherapeutic agents. Myelosuppression is the most common side effect of etoposide. The incidence of leukopenia tends to be more severe than that of thrombocytopenia.

[0222] Teniposide, 4'-demethyl-epipodophyllotoxin 9 [4,6-O-(R)-tenylidene-β-D-glucopyranoside], is commercially available as an injection solution under the name VUMON® and is commonly known as VM-26. Teniposide is indicated for the treatment of acute leukemia in children, either as a single agent or in combination with other chemotherapeutic agents. Myelosuppression is the most common dose-limiting side effect of teniposide. Teniposide can induce both leukopenia and thrombocytopenia.

[0223] Antimetabolite antineoplastic agents are cell cycle-specific antineoplastic agents that act on the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis, thereby limiting DNA synthesis. As a result, the S phase does not proceed and cell death follows. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine.

[0224] 5-Fluorouracil, 5-fluoro-2,4-(1H,3H)pyrimidinedione is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and incorporation into both RNA and DNA. The result is typically cell death. 5-Fluorouracil is indicated in the treatment of breast, colon, rectal, stomach, and pancreatic cancers, either as a single agent or in combination with other chemotherapeutic agents. Myelosuppression and mucositis are dose-limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.

[0225] Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2(1H)-pyrimidinone is commercially available as CYTOSAR-U® and is commonly known as Ara-C. Cytarabine is thought to exhibit cell cycle specificity for the S-phase by incorporating its terminus into the growing DNA strand and inhibiting DNA strand elongation. Cytarabine is indicated in the treatment of acute leukemia, either as a single agent or in combination with other chemotherapeutic agents. Other cytidine analogs include 5-azacytidine and 2’,2’-difluorodeoxycytidine (gemcitabine). Cytarabine induces leukopenia, thrombocytopenia, and mucositis.

[0226] Mercaptopurine, 1,7-dihydro-6H-purin-6-thione monohydrate is marketed as PURINETHOL (registered trademark). Mercaptopurine exhibits cell cycle specificity in the S-phase by inhibiting DNA synthesis through a mechanism not previously identified. Mercaptopurine is indicated in the treatment of acute leukemia as a single agent or in combination with other chemotherapeutic agents. Myelosuppression and gastrointestinal mucositis are expected side effects of high doses of mercaptopurine. A useful mercaptopurine analog is azathioprine.

[0227] Thioguanine, 2-amino-1,7-dihydro-6H-purin-6-thione is marketed as TABLOID (registered trademark). Thioguanine exhibits cell cycle specificity in the S-phase by inhibiting DNA synthesis through a mechanism not previously identified. Thioguanine is indicated in the treatment of acute leukemia as a single agent or in combination with other chemotherapeutic agents. Myelosuppression, including leukopenia, thrombocytopenia, and anemia, is the most common dose-limiting side effect of thioguanine administration. However, gastrointestinal side effects can occur and become dose-limiting. Other purine analogs include pentostatin, erythron-hydroxy-nonyl-adenine, fludarabine phosphate, and cladribine.

[0228] Gemcitabine, 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer) is marketed as GEMZAR (registered trademark). Gemcitabine exhibits cell cycle specificity by blocking the progression of cells in the S-phase and also through the G1 / S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and as a single agent in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leukopenia, thrombocytopenia, and anemia, is the most common dose-limiting side effect of gemcitabine administration.

[0229] Methotrexate, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid, is marketed as sodium methotrexate. Methotrexate specifically exhibits an S-phase cell phase effect by inhibiting DNA synthesis, repair, and / or replication through inhibition of dihydrofolic acid reductase, which is required for the synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapeutic agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin 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.

[0230] Camptothecin, including camptothecin and camptothecin derivatives, can be used or are in development as topoisomerase I inhibitors. Camptothecin cytotoxic activity is said to be related to its topoisomerase I inhibitory activity. Examples of camptothecin include, but are not limited to, irinotecan, topotecan, and various optical forms of 7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin described below.

[0231] Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3’,4’,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione hydrochloride, is marketed as the injectable solution CAMPTOSAR®.

[0232] Irinotecan is a derivative of camptothecin that binds to the topoisomerase I-DNA complex, along with its active metabolite SN-38. The cytotoxicity is thought to occur as a result of irreparable double-strand breaks caused by the interaction of the topoisomerase I:DNA:irinotecan or SN-38 ternary complex with the replicative enzymes. Irinotecan is indicated for the treatment of metastatic cancer of the colon or rectum. The dose-limiting side effects of irinotecan HCl are myelosuppression, including neutropenia, and GI effects, including diarrhea.

[0233] 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, is marketed as the injectable solution HYCAMTIN®. 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 in the DNA molecule. Topotecan is indicated for second-line treatment of metastatic cancers of the ovary and small cell lung cancer. The dose-limiting side effect of topotecan HCl is myelosuppression, mainly neutropenia.

[0234] Hormones and hormone analogs are compounds useful for treating cancers that are related to hormones and the growth and / or lack of growth of cancer. Examples of hormones and hormone analogs useful for treating cancer include adrenal corticosteroids, such as prednisone and prednisolone, useful for treating malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors, such as anastrozole, letrazole, vorazole, and exemestane, useful for treating adrenocortical carcinoma and estrogen receptor-containing hormone-dependent breast cancer; progestrins, such as megestrol acetate, useful for treating hormone-dependent breast cancer and endometrial cancer; estrogens, androgens, and antiandrogens, such as flutamide, nilutamide, bicalutamide, cyproterone acetate, and 5α-reductase, such as finasteride and dutasteride, useful for treating 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. Patent Nos. 5,681,835, 5,877,219, and 6,207,716, useful for treating hormone-dependent breast cancer and other sensitive cancers; gonadotropin-releasing hormone (GnRH) for treating prostate cancer, and its analogs that stimulate the release of luteinizing hormone (LH) and / or follicle-stimulating hormone (FSH), such as LHRH agonists and antagonists, such as goserelin acetate and luprolide, but not limited to these.

[0235] A signal transduction pathway inhibitor is an inhibitor that blocks or inhibits a chemical process that induces a change within a cell. As used herein, this change is cell growth or differentiation. Signal transduction inhibitors useful in the present invention include receptor tyrosine kinases, non-receptor tyrosine kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phosphatidylinositol-3 kinase, myo-inositol signal transduction, and inhibitors of the Ras oncogene.

[0236] Some protein tyrosine kinases catalyze the phosphorylation reaction of specific tyrosine residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.

[0237] Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand-binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are commonly referred to as growth factor receptors. For example, inappropriate or unregulated activation of many of these kinases by overexpression or mutation, i.e., abnormal kinase growth factor receptor activity, has been shown to result in unregulated cell growth. Thus, such abnormal activity of such kinases has been associated with malignant tissue growth. As a result, inhibitors of such kinases can provide methods for treating cancer. 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 receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET proto-oncogene. Some inhibitors of growth receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors, and antisense oligonucleotides. Agents that inhibit growth factor receptors and growth factor receptor function are described, for example, in Kath, John C., Exp. Opin. Ther. Patents (2000), 10(6):803-818; Shawver et al., DDT Vol. 2, No. 2, February 1997; and Lofts, F.J. et al., "Growth factor receptors as targets", New Molecular Targets for Cancer Chemotherapy, Workman, Paul and Kerr, David eds., CRC press 1994, London.

[0238] Preferably, the compound that is active as a medicament of the present invention is a VEGFR inhibitor, preferably 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide or a pharmaceutically acceptable salt thereof, preferably the monohydrochloride, which is used in combination with it, which is disclosed and claimed in International Application PCT / US01 / 49367 with an international filing date of December 19, 2001, and also in International Publication WO02 / 059110 with an international publication date of August 1, 2002 (International Publication Number WO02 / 059110 and an International Publication date of August 1, 2002), the entire disclosure of which is incorporated herein by reference, and this is the compound of Example 69. 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide can be prepared as described in International Application PCT / US01 / 49367.

[0239] Preferably, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide is in the form of the monohydrochloride. This salt form can be prepared by those skilled in the art from the description in International Application PCT / US01 / 49367 with an international filing date of December 19, 2001.

[0240] 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide is commercially available as the monohydrochloride and is known by the common name pazopanib and the trade name VOTRIENT®.

[0241] Pazopanib is associated with the treatment of cancer and ophthalmic diseases / angiogenesis. Preferably, the present invention relates to the treatment of cancer and ophthalmic diseases / angiogenesis, preferably age-related macular degeneration, and the method comprises administration of a compound of formula (I) alone or in combination with pazopanib.

[0242] Tyrosine kinases that are not growth factor receptor kinases are referred to as non-receptor tyrosine kinases. Non-receptor tyrosine kinases for use in the present invention, which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Bruton's tyrosine kinase and Bcr-Abl. Agents that inhibit the functions of such non-receptor kinases and non-receptor tyrosine kinases are described in Sinh, S. and Corey, S.J. (1999), Journal of Hematotherapy and Stem Cell Research 8(5):465-480; and Bolen, J.B., Brugge, J.S. (1997), Annual review of Immunology. 15:371-404.

[0243] SH2 / SH3 domain blockers are agents that interfere with SH2 or SH3 domain binding in a variety of enzymes or adapter proteins, including the PI3-K p85 subunit, Src family kinases, adapter molecules (Shc, Crk, Nck, Grb2) and Ras-GAP. The SH2 / SH3 domain as a target of anti-cancer drugs is discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3)125-132.

[0244] Inhibitors of serine / threonine kinases, including MAP kinase cascade blockers that include blockers of Raf kinase (rafk), mitogen or extracellular regulated kinases (MEK) and extracellular regulated kinases (ERK); and blockers of protein kinase C family members, including PKC (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta), IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, PDK1 and TGF beta receptor kinases. Such serine / threonine kinases and their inhibitors are described in Yamamoto, T., Taya, S., Kaibuchi, K. (1999), Journal of Biochemistry. 126(5) 799 - 803; Brodt, P, Samani, A. and Navab, R. (2000), Biochemical Pharmacology, 60. 1101 - 1107; Massague, J., Weis - Garcia, F. (1996) Cancer Surveys. 27:41 - 64; Philip, 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. Patent 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.

[0245] Suitably, the compound that is active as a medicament of the present invention is used in combination with a MEK inhibitor. Suitably, the entire disclosure of International Application No. PCT / JP2005 / 011082 with an international filing date of June 10, 2005; International Publication WO2005 / 121142 and an international publication date of December 22, 2005, which is incorporated herein by reference, discloses and claims 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, preferably a dimethyl sulfoxide solvate. 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 US Patent Publication US2006 / 0014768 published on January 19, 2006, the entire disclosure of which is incorporated herein by reference.

[0246] Suitably, the compound that is active as a medicament of the present invention is used in combination with a B-Raf inhibitor. Suitably, the entire disclosure of International Application No. PCT / US2009 / 042682 with an international filing date of May 4, 2009, which is incorporated herein by reference, discloses and claims 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. N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide can be prepared as described in International Application No. PCT / US2009 / 042682.

[0247] Suitably, the compound that is active as a medicament of the present invention is used in combination with an Akt inhibitor. Suitably, the entire disclosure of International Application No. PCT / US2008 / 053269, filed on February 7, 2008, with an international publication date of International Publication WO2008 / 098104 and an international publication date of August 14, 2008, which is incorporated herein by reference in its entirety, discloses and claims 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. 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.

[0248] Preferably, the compound that is active as a medicament of the present invention is used in combination with an Akt inhibitor. Preferably, the entire disclosure of International Application No. PCT / US2008 / 053269 with an international filing date of February 7, 2008; International Publication WO2008 / 098104 and an international publication date of August 14, 2008, which is incorporated herein by reference, discloses and claims 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. N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide is the compound of Example 96 and can be prepared as described in International Application No. PCT / US2008 / 053269. Preferably, N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide is in the form of a hydrochloride salt. This salt form can be prepared by those skilled in the art from the description in International Application No. PCT / US2010 / 022323 with an international filing date of January 28, 2010.

[0249] Inhibitors of phosphatidylinositol-3 kinase family members, including blockers of PI3-kinase, ATM, DNA-PK and Ku, may also be useful in the present invention. Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology. 8(3) pp. 412-418; Canman, C.E., Lim, D.S. (1998), Oncogene 17(25) pp. 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology. 29(7): 935-938; and Zhong, H. et al., Cancer res (2000), 60(6), pp. 1541-1545.

[0250] Myo-inositol signal transduction inhibitors, such as phospholipase C blockers and myo-inositol analogs, are also an object of the present invention. Such signal inhibitors are described in Powis, G. and Kozikowski A. (1994) New Molecular Targets for Cancer Chemotherapy, edited by Paul Workman and David Kerr, CRC press 1994, London.

[0251] Another group of signal transduction pathway inhibitors are inhibitors of the Ras oncogene. Such inhibitors include inhibitors of farnesyl transferase, geranylgeranyl transferase 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 and thereby act as antiproliferative agents. Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I., Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-298; Ashby, M.N. (1998), Current Opinion in Lipidology. 9(2) 99-102; and BioChim. Biophys. Acta, (19899) 1423(3): 19-30.

[0252] As mentioned above, antibody antagonists to receptor kinase ligand binding can also serve as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example, the Imclone C225 EGFR-specific antibody (see Green, M.C. et al., Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), pp. 269-286); Herceptin® erbB2 antibody (see Tyrosine Kinase Signaling in Breast cancer: erbB Family Receptor Tyrosine Kinases, Breast cancer Res., 2000, 2(3), pp. 176-183); and the 2CB VEGFR2-specific antibody (see Brekken, R.A. et al., Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, pp. 5117-5124).

[0253] Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention. Inhibitors of VEGFR and TIE2, which are associated with angiogenesis, have been discussed above with respect to signal transduction inhibitors (both receptors are receptor tyrosine kinases). Since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, mainly VEGF expression, angiogenesis is generally associated with erbB2 / EGFR signal transduction. Thus, non-receptor tyrosine kinase inhibitors can be used in combination with the compounds of the present invention. For example, an anti-VEGF antibody that does not recognize VEGFR (a receptor tyrosine kinase) but binds to the ligand; an integrin that inhibits angiogenesis (alpha v beta 3) small molecule inhibitors; endostatin and angiostatin (non-RTK) may also be proven 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).

[0254] Agents used in immunotherapy regimens may also be useful in combination with the compounds of formula (I). There are several immunological strategies for generating an immune response. These strategies generally lie in the area of tumor vaccine administration. The efficacy of immunological approaches can be significantly improved through combined inhibition of signaling pathways using small molecule inhibitors. Consideration of immunological / tumor vaccine approaches to erbB2 / EGFR can be found in Reilly RT et al. (2000), Cancer Res. 60:3569-3576; and Chen Y, Hu D, Eling DJ, Robbins J and Kipps TJ. (1998), Cancer Res. 58:1965-1971.

[0255] Agents used in a pro-apoptosis regimen (e.g., bcl-2 antisense oligonucleotides) can also be used in the combinations of the present invention. Proteins of members of the Bcl-2 family block apoptosis. Upregulation of bcl-2 is thus associated with chemoresistance. Studies have shown that epidermal growth factor (EGF) stimulates the anti-apoptotic member of the Bcl-2 family, namely mcl-1. Thus, strategies designed to downregulate the expression of bcl-2 in tumors have demonstrated clinical benefit and are currently in phase II / III trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such pro-apoptosis strategies using antisense oligonucleotide strategies against bcl-2 are discussed in Water JS et al. (2000), J. Clin. Oncol. 18:1812-1823 and Kitada S et al. (1994), Antisense Res. Dev. 4:71-79.

[0256] Cell cycle signaling inhibitors inhibit molecules involved in the control of the cell cycle. The interaction of a family of protein kinases called cyclin-dependent kinases (CDKs) and a family of proteins called cyclins controls progression through the eukaryotic cell cycle. Coordinated activation and inactivation of different cyclin / CDK complexes are required for normal progression through the cell cycle. Some inhibitors of cell cycle signaling are under development. For example, examples of cyclin-dependent kinases including CDK2, CDK4, and CDK6, and inhibitors thereof are described, for example, in Rosania et al., Exp. Opin. Ther. Patents (2000) 10(2):215-230. Further, p21WAF1 / CIP1 has been described as a potent and general inhibitor of cyclin-dependent kinases (Cdk) (Ball et al., Progress in Cell Cycle Res., 3:125 (1997)). Compounds known to induce the expression of p21WAF1 / CIP1 have been associated with the suppression of cell proliferation and also with tumor suppressor activity (Richon et al., Proc. Nat Acad. Sci. U.S.A. 97(18):10014-10019 (2000)) and are included as cell cycle signaling inhibitors. Histone deacetylase (HDAC) inhibitors have been associated with the transcriptional activation of p21WAF1 / CIP1 (Vigushin et al., Anticancer Drugs, 13(1):1-13 (January 2002)) and are cell cycle signaling inhibitors suitable for use in combination herein.

[0257] Examples of such HDAC inhibitors include the following:

[0258] 1. Vorinostat, including pharmaceutically acceptable salts thereof. Marks et al., Nature Biotechnology 25, 84-90 (2007); Stenger, Community Oncology 4, 384-386 (2007). Vorinostat has the following chemical structure and name:

[0259] [Chem.]

[0260] N-Hydroxy-N'-phenyl-octanediamide

[0261] 2. Romidepsin containing pharmaceutically acceptable salts thereof. Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85 - 93. Romidepsin has the following chemical structure and name:

[0262] [Chem.]

[0263] (1S,4S,7Z,10S,16E,21R)-7-Ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone

[0264] 3. Panobinostat containing pharmaceutically acceptable salts thereof. Drugs of the Future 32(4):315 - 322 (2007). Panobinostat has the following chemical structure and name:

[0265] [Chem.]

[0266] (2E)-N-Hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide

[0267] 4. Valproic acid, including pharmaceutically acceptable salts thereof. Gottlicher et al., EMBO J. 20(24):6969-6978 (2001). Valproic acid has the following chemical structure and name:

[0268] [Chemical formula]

[0269] 2-Propylvaleric acid

[0270] 5. Mosetinostat (MGCD0103), including pharmaceutically acceptable salts thereof. Balasubramanian et al., Cancer Letters 280:211-221 (2009). Mosetinostat has the following chemical structure and name:

[0271] [Chemical formula]

[0272] N-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl]benzamide

[0273] Further examples of such HDAC inhibitors are included in Bertrand European Journal of Medicinal Chemistry 45, (2010), 2095-2116, and in particular, the compounds in Table 3 are as indicated below.

[0274] [Table 3]

[0275] Proteasome inhibitors are drugs that block the action of the proteasome, a cellular complex that degrades 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 combination herein include the following:

[0276] 1. Bortezomib (Velcade®), including its pharmaceutically acceptable salts. Adams J, Kauffman M (2004), Cancer Invest 22(2):304-311.

[0277] Bortezomib has the following chemical structure and name.

[0278]

Chem.

[0279] [(1R)-3-Methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid

[0280] 2. Disulfiram, including its pharmaceutically acceptable salts. Bouma et al. (1998), J. Antimicrob. Chemother. 42(6):817-820. Disulfiram has the following chemical structure and name.

[0281]

Chem.

[0282] 1,1’,1’’,1’’’-[Disulfanediyldi(carbonothioylnitrilo)]tetraethane

[0283] Epigallocatechin gallate (EGCG) including its pharmaceutically acceptable salts. Williamson et al. (December 2006), The Journal of Allergy and Clinical Immunology 118(6):1369 - 1374. Epigallocatechin gallate has the following chemical structure and name.

[0284] [(2R,3R)-5,7 - Dihydroxy - 2-(3,4,5 - trihydroxyphenyl)chroman - 3 - yl] 3,4,5 - trihydroxybenzoate

[0285] [(2R,3R)-5,7 - Dihydroxy - 2-(3,4,5 - trihydroxyphenyl)chroman - 3 - yl] 3,4,5 - trihydroxybenzoate

[0286] Salinosporamide A including its pharmaceutically acceptable salts. Feling et al. (2003), Angew.Chem.Int.Ed., Engl. 42(3):355 - 357. Salinosporamide A has the following chemical structure and name.

[0287] [(4R,5S)-4-(2 - chloroethyl)-1 - ((1S)-cyclohex - 2 - enyl(hydroxy)methyl)-5 - methyl - 6 - oxa - 2 - azabicyclo[3.2.0]heptane - 3,7 - dione

[0288] (4R,5S)-4-(2 - chloroethyl)-1 - ((1S)-cyclohex - 2 - enyl(hydroxy)methyl)-5 - methyl - 6 - oxa - 2 - azabicyclo[3.2.0]heptane - 3,7 - dione

[0289] Carfilzomib including its pharmaceutically acceptable salts. Kuhn DJ et al., Blood, 2007, 110:3281 - 3290. Carfilzomib has the following chemical structure and name.

[0290] [(4R,5S)-4-(2 - chloroethyl)-1 - ((1S)-cyclohex - 2 - enyl(hydroxy)methyl)-5 - methyl - 6 - oxa - 2 - azabicyclo[3.2.0]heptane - 3,7 - dione

[0291] (S)-4-Methyl-N-((S)-4-methyl-1-((R)-2-methyloxirane-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamide)pentaamide

[0292] The 70-kilodalton heat shock protein (Hsp70) and the 90-kilodalton heat shock protein (Hsp90) are a family of ubiquitously expressed heat shock proteins. Hsp70 and Hsp90 are overexpressed in certain cancer types. Some Hsp70 and Hsp90 inhibitors are being studied for the treatment of cancer. Hsp70 and Hsp90 inhibitors suitable for use in combination herein include the following:

[0293] 1. 17-AAG (geldanamycin) including pharmaceutically acceptable salts thereof. Jia W et al., Blood. September 1, 2003; 102(5): 1824-1832. 17-AAG (geldanamycin) has the following chemical structure and name.

[0294]

Chemical formula

[0295] 17-(Allylamino)-17-demethoxygeldanamycin

[0296] 2. Radicicol (Lee et al., Mol Cell Endocrinol. 2002, 188, 47-54) including pharmaceutically acceptable salts thereof. Radicicol has the following chemical structure and name.

[0297]

Chemical formula

[0298] (1aR,2Z,4E,14R,15aR)-8-chloro-9,11-dihydroxy-14-methyl-15,15a-dihydro-1aH-benzo[c]oxiren[2,3-k][1]oxacyclotetradecine-6,12(7H,14H)-dione

[0299] Inhibitors of cancer metabolism - Many tumor cells exhibit metabolism that is significantly different from that of normal tissues. For example, the rate of glycolysis, a metabolic process that converts glucose to pyruvate, is increased, and the generated pyruvate is reduced to lactate without further oxidation in mitochondria via the tricarboxylic acid (TCA) cycle. This effect is often seen even under aerobic conditions and is known as the Warburg effect.

[0300] Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a central role in tumor cell metabolism by reducing pyruvate to lactate, after which lactate can be exported out of the cell. This enzyme has been shown to be upregulated in many tumor types. The changes in glucose metabolism described in the Warburg effect are important for cancer cell growth and proliferation, and knockdown of LDH-A using RNA-i has been shown to cause a decrease in cell proliferation and tumor growth in xenograft models. D.A. Tennant et al., Nature Reviews, 2010, page 267. P. Leder et al., Cancer Cell, 2006, 9, page 425.

[0301] High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions. Pharmacological inhibition of FAS affects the expression of important oncogenes involved in both cancer development and maintenance. Alli et al., Oncogene (2005) 24, pages 39 - 46. doi:10.1038

[0302] Inhibitors of LDH-A and inhibitors of fatty acid biosynthesis (or FAS inhibitors), which are inhibitors of cancer metabolism, are suitable for use in combination with the compounds of the present invention.

[0303] In one embodiment, the method for treating cancer of the claimed invention comprises co-administration of a compound of formula I and / or a pharmaceutically acceptable salt thereof, and at least one anti-neoplastic agent, such as a microtubule inhibitor, a platinum coordination complex, an alkylating agent, an antibiotic preparation, 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 immunotherapy agent, a pro-apoptotic agent, a cell cycle signal transduction inhibitor; a proteasome inhibitor; and an inhibitor of cancer metabolism, selected from the group consisting of.

[0304] In one embodiment, the compound of formula I is used as a chemosensitizer that improves tumor cell killing.

[0305] In one embodiment, the compound of formula I is used in combination as a chemosensitizer that improves tumor cell killing.

[0306] In one embodiment, the compound of formula I is used in combination with a PERK (PERK inhibitor), which is a compound that inhibits the activity of protein kinase R (PKR)-like ER kinase.

[0307] Preferably, the compounds of formula I and pharmaceutically acceptable salts thereof are administered concomitantly with at least one other active agent known to be an inhibitor of PERK kinase (EIF2K3) for treating or reducing the severity of neurodegenerative diseases / injuries such as Alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular diseases, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, traumatic brain injury, cognitive impairment, atherosclerosis, eye diseases, arrhythmia, and in organ transplantation and in the transport of organs for transplantation.

[0308] "Chemotherapeutic agent" or "chemotherapeutic drug" is used in its plain ordinary meaning and refers to a chemical composition or compound having the properties of an anti-neoplastic agent or the ability to inhibit cell growth or proliferation.

[0309] Furthermore, the compounds described herein can be co-administered with conventional immunotherapeutic agents including, but not limited to, immunostimulants (such as Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (such as anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR and anti-VEGF monoclonal antibodies), immunotoxins (such as anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.) and radioimmunotherapy (such as 111 In, 90 Y or 131 anti-CD20 monoclonal antibody conjugated to I, etc.).

[0310] In a further embodiment, the compounds described herein are optionally conjugated to a radionuclide directed against a tumor antigen, such as 47 Sc, 64 C,67 C, 89 Sr, 86 Y, 87 Y and 212 Bi, and is co-administered with conventional radiotherapy agents including, but not limited to, those.

[0311] Additional examples of further active ingredients or raw materials (antineoplastic agents) for use in combination with or co-administered with the compound are anti-PD-L1 agents.

[0312] Anti-PD-L1 antibodies and methods of making the same are known in the art.

[0313] Such antibodies against PD-L1 can be polyclonal or monoclonal, and / or recombinant, and / or humanized.

[0314] Exemplary PD-L1 antibodies are disclosed below: U.S. Patent No. 8,217,149; 12 / 633,339; U.S. Patent No. 8,383,796; 13 / 091,936; U.S. Patent No. 8,552,154; 13 / 120,406; U.S. Patent Application Publication No. 20110280877; 13 / 068337; U.S. Patent Application Publication No. 20130309250; 13 / 892671; WO2013019906; WO2013079174; U.S. Patent Application No. 13 / 511,538 (filed August 7, 2012), which is the U.S. national stage of International Application PCT / US10 / 58007 (filed 2010); and U.S. Patent Application No. 13 / 478,511 (filed May 23, 2012).

[0315] Additional exemplary antibodies to PD-L1 (also referred to as CD274 or B7-H1) and methods for using them are disclosed in U.S. Patent No. 7,943,743; US20130034559, WO2014055897, U.S. Patent No. 8,168,179 and U.S. Patent No. 7,595,048. PD-L1 antibodies are under development as immunomodulatory agents for treating cancer.

[0316] In one embodiment, the antibody to PD-L1 is the 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.

[0317] In another embodiment, the antibody to PD-L1 is the antibody disclosed in U.S. Patent Application No. 13 / 511,538. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of the antibody disclosed in U.S. Patent Application No. 13 / 511,538.

[0318] In another embodiment, the antibody to PD-L1 is the antibody disclosed in Application No. 13 / 478,511. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of the antibody disclosed in U.S. Patent Application No. 13 / 478,511.

[0319] 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.

[0320] Additional examples of additional active ingredients or agents (antineoplastic agents) for use in combination with or co-administered with the ATF4 pathway inhibiting compounds of the invention are PD-1 antagonists.

[0321] "PD-1 antagonist" means any 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 on immune cells. Alternative names or synonyms for PD-1 and its ligands are PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any embodiment of the aspects or embodiments of the invention in which a human individual is treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and preferably blocks the binding of both human PD-L1 and PD-L2 to human PD-1. The human PD-1 amino acid sequence can be found at NCBI locus No.: NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found at NCBI locus No.: NP_054862 and NP_079515, respectively.

[0322] PD-1 antagonists useful in any of the aspects of the invention include monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1, preferably specifically bind to human PD-1 or human PD-L1. The mAb can be a human antibody, a humanized antibody or a chimeric antibody, and can include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in a preferred embodiment, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab’-SH, F(ab’)2, scFv and Fv fragments.

[0323] Examples of mAbs that bind to human PD-1 and are useful in various aspects and embodiments of the present invention are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004 / 004771, WO2004 / 072286, WO2004 / 056875, and US2011 / 0271358.

[0324] In any of the aspects and embodiments of the present invention, specific anti-human PD-1 mAbs useful as PD-1 antagonists have the structures described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013), and are humanized IgG4 mAbs containing the heavy and light chain amino acid sequences shown in FIG. 6, MK-3475; human IgG4 mAbs having the structures described in WHO Drug Information, Vol. 27, No. 1, pp. 68-69 (2013), and containing the heavy and light chain amino acid sequences shown in FIG. 7, nivolumab; humanized antibodies h409A11, h409A16, and h409A17 described in WO2008 / 156712, and AMP-514 developed by Medimmune.

[0325] Other PD-1 antagonists useful in any of the aspects and embodiments of the present invention include immunoadhesions that specifically bind to PD-1, preferably specifically bind to human PD-1, for example, fusion proteins containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as 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 useful as PD-1 antagonists in the treatment methods, medicaments, and uses of the present invention are PD-L2-Fc fusion proteins, including AMP-224 (also known as B7-DCIg) that binds to human PD-1.

[0326] Other examples of mAbs that bind to human PD-L1 and are useful in the treatment methods, medicaments, and uses of the present invention are described in WO2013 / 019906, WO2010 / 077634A1, and US8383796. Specific anti-human PD-L1 mAbs useful as PD-1 antagonists in the treatment methods, medicaments, and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, and MSB0010718C.

[0327] Keytruda / pembrolizumab is an anti-PD-1 antibody sold by Merck for treating lung cancer. The amino acid sequence and method of use of pembrolizumab are disclosed in U.S. Patent No. 8,168,757.

[0328] Opdivo / nivolumab is a fully human monoclonal antibody sold by Bristol Myers Squibb directed against the negative immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1 / PCD-1) that has immune-enhancing activity. Nivolumab binds to PD-1, an Ig superfamily transmembrane protein, and blocks the activation of PD-1 by its ligands PD-L1 and PD-L2, resulting in T-cell activation and a cell-mediated immune response against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and effector functions through suppression of P13k / Akt pathway activation. Other names for nivolumab include BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence of nivolumab, as well as methods of use and preparation, are disclosed in U.S. Patent No. 8,008,449.

[0329] Additional examples of further active ingredients or agents (antineoplastic agents) for use in combination with or co-administered with the compounds of the present invention are immunomodulatory substances.

[0330] As used herein, "immunomodulatory substance" refers to any substance including monoclonal antibodies that affect the immune system. The ICOS-binding protein of the present invention may be a potential immune-regulatory factor. Immunomodulatory substances can be used as anti-neoplastic agents for treating cancer. For example, immune-regulatory factors 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 immunomodulatory substances include, but are not limited to, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies, and GITR antibodies.

[0331] Yervoy (ipilimumab) is a fully human CTLA-4 antibody sold by Bristol Myers Squibb. The protein structure and method of use of ipilimumab are described in U.S. Pat. Nos. 6,984,720 and 7,605,238.

[0332] In another embodiment, the present invention provides a compound of Table 1 or formula (I) described herein, or a pharmaceutically acceptable salt or prodrug thereof, for use in treating hepatitis B virus-related diseases, conditions or disorders. The present invention provides a compound of Table 1 or a pharmaceutically acceptable salt or prodrug thereof for use in treating hepatitis B virus-related diseases, conditions or disorders, and the hepatitis B virus-related diseases, conditions or disorders can be jaundice, liver cancer, hepatitis, liver fibrosis, cirrhosis, liver failure, diffuse hepatocyte inflammatory disease, hemophagocytic syndrome or serum hepatitis).

[0333] 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 specified in Table 1. Further, the present invention also includes each of these compounds individually, and their pharmaceutically acceptable salts.

[0334] In other embodiments, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0335] In some embodiments, the compound(s) of the invention or a pharmaceutically acceptable salt thereof is selected from the compounds set forth in Table 1. The compounds of the invention may be provided in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases. Thus, the word "or" with respect to "compound or a pharmaceutically acceptable salt thereof" is understood to refer to the compound or a pharmaceutically acceptable salt thereof (alternatively), or the compound and a pharmaceutically acceptable salt thereof (in combination).

[0336] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and dosage forms that are suitable for use within the scope of medical judgment, in contact with human and animal tissues, without excessive toxicity, irritation, or other problems or complications. Those skilled in the art will recognize that pharmaceutically acceptable salts of the compounds according to Formula I can be prepared. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the free acid or free base form of the purified compound with a suitable base or acid, respectively.

[0337] The compounds of the invention can be made according to the various schemes described below.

[0338] Synthetic Methods The methods for synthesizing the chemical entities shown use starting materials that are readily available using the following general methods and procedures. It is recognized that other process conditions may be used as well, unless otherwise specified, when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are shown. Optimal reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be determined by routine optimization procedures by those skilled in the art.

[0339] Furthermore, the method of the present invention may use a protecting group that prevents a functional group from undergoing an undesired reaction. Suitable protecting groups for various functional groups, as well as suitable conditions for the protection and deprotection of specific functional groups, are well known in the art. For example, numerous protecting groups are described in T.W. Greene and G.M. Wuts, Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, 1999 and the references cited therein.

[0340] Furthermore, the chemical entities shown may contain one or more chiral centers, and such compounds may be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereoisomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this specification unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, and the like.

[0341] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by the 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.

[0342] Unless otherwise specified, the reactions described herein are generally carried out at atmospheric pressure within a temperature range of -78°C to 200°C. Further, unless used in the Examples or otherwise specified, the reaction times and conditions are intended to be approximate values that occur over a temperature range of, for example, from about -78°C to about 110°C, at approximately atmospheric pressure, over a period of about 1 to about 24 hours; the reaction is left overnight for a period of about 16 hours on average.

[0343] The terms "solvent", "organic solvent" and "inerting solvent" each mean a solvent that is inert under the reaction conditions described in connection therewith, and include, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone ("NMP"), pyridine, and the like.

[0344] The isolation and purification of the chemical entities and intermediates described herein can, if necessary, be carried out 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. Specific illustrations of suitable separation and isolation procedures can be made by reference to the examples in the following text. However, other equivalent separation or isolation procedures may also be used.

[0345] If desired, the (R)- and (S)-isomers can be separated by methods known to those skilled in the art, for example, by formation of diastereoisomeric salts or complexes that can be separated by crystallization; by formation of diastereoisomeric derivatives that can be separated by, for example, crystallization, gas-liquid or liquid chromatography; by 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 by resolution in a chiral environment, such as on silica having a chiral support, e.g., a bonded chiral ligand, or by gas-liquid or liquid chromatography in the presence of a chiral solvent. Alternatively, a particular enantiomer can be synthesized by asymmetric synthesis using an optically active reagent, substrate, catalyst or solvent, or by converting one enantiomer to another by asymmetric transformation.

Examples

[0346] The following examples serve to more fully explain the methods of making and using the invention described above. It is understood that these examples are in no way intended to limit the true scope of the invention, but rather are presented for illustrative purposes. In the following examples and the synthetic schemes above, the following abbreviations have the following meanings. Abbreviations have the generally accepted meaning where not otherwise defined.

[0347]

Table A

[0348] Description of Equipment NMR Instrumentation and Data: 1 1H NMR spectra were recorded at 25 °C on all spectrometers operating at 400 MHz with the various instruments listed below. · Bruker AVANCE NEO 400MHz / 54mm instrument (MRCA 400 / 54 / ASC, 16971) · Bruker AVANCE III 400MHz / 54mm UltraShield Plus, long hold time instrument (BZH 439’400’70I, D335 / 54-6776) · Bruker AVANCE III 400MHz / 54mm Ascend instrument (BZH 994’400’70I, D315’54-9223) · Varian 400MR 400MHz / 54mm instrument (MRCA 400 / 54 / ASC, MRYOO20874) · Bruker AVANCE III 400MHz / 54mm Ascend instrument (BZH 993’400’70I, D315’54-9213) · Bruker AVANCE III 400MHz / 54mm Ascend instrument (BZH 1157’400’70I, D315’54-9574) · Bruker AVANCE III 400MHz / 54mm Ascend instrument (BZH 1126’400’70I, D315’54-9527) · Bruker AVANCE NEO 400MHz / 54mm Ascend instrument (BZH 1396’400’70I, D315’54-10089) · Bruker AVANCE NEO 400MHz / 54mm Ascend instrument (BZH 1373’400’70I, D315’54-10026) · Varian 400MR 400MHz / 54mm instrument (MRCA 400 / 54 / ASC, 20609) · Varian 400MR 400MHz / 54mm instrument (MRCA 400 / 54 / ASC, 20188)

[0349] Data was processed and analyzed using Topspin 2.1 software. If the number of assigned protons is less than the theoretical number of protons in the molecule, it is assumed that the apparent missing signal(s) is / are obscured by the solvent and / or water peak. Further, when the spectrum is obtained in a protic NMR solvent, exchange of NH and / or OH protons with the solvent occurs, and such signals are not usually observed. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in units of Hertz (Hz). Splitting patterns describe the apparent multiplicity and are denoted as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad). Chemical shifts are referenced to the solvent peak, which 1 In 1H NMR, CDCl 3 appears at 7.27 ppm, DMSO-d 6 appears at 2.50 ppm, D 2 O appears at 4.79 ppm and CD 3 OD appears at 3.31 ppm.

[0350] Description of the LC-MS system and method for analysis of the final product: In the following examples, the compounds were characterized by mass spectrometry using the systems and operating conditions presented below. Where atoms with different isotopes are present and a single mass is cited, the mass cited for the compound is the monoisotopic mass (i.e., 35 CI; 79 Br, etc.). Instrument: Agilent 1200 & 6100B Scan mode: Alternating positive / negative electrospray Scan range: 100 - 1000 amu LC conditions: LCMS analysis was performed on a Kinetex C18 50×2.1 mm column (5 μm particles). The gradient used was as follows: Mobile phase A: Water + 0.037% v / v TFA Mobile phase B: Acetonitrile + 0.018% v / v TFA Time %A %B Flow rate 0.00 min 95 5 1.0 ml / min 0.4 min 95 5 1.0 ml / min 3.0 min 5 95 1.0 ml / min 4.0 min 5 95 1.0 ml / min UV detection was indicated by the total absorbance signal at 214 nm and 254 nm scanning.

[0351] Description of LC-MS system and method for analysis of intermediate products: Method A: Instrument: Shimadzu LCMS-2020 Scan mode: Positive electrospray ionization Scan range: 100 - 1000 amu LC conditions: LCMS analysis was performed on a Luna-C18 2.0×30 mm (3 μm particles) column. The gradient used was as follows: Mobile phase A: Water + 0.037% v / v TFA Mobile phase B: Acetonitrile + 0.018% v / v TFA Time %A %B Flow rate 0.00 min 99.9.1 0.8 ml / min 0.10 min 90.0 10.0 0.8 ml / min 3.50 min 20.0 80.0 0.8 ml / min 3.80 min 90.0 10.0 1.2 ml / min 4.30 min 90.0 10.0 1.2 ml / min UV detection was indicated by the total absorbance signal at 214 nm and 254 nm scanning.

[0352] Method B: Equipment: Agilent 1200 & 6110B Scan mode: Positive electrospray ionization Scan range: 100 - 1000 amu LC conditions: LCMS analysis was performed on an Xbridge Shield RP18 2.1×50 mm (5 μm particles) column. The gradient used was as follows: Mobile phase A: 10 mM ammonium bicarbonate in water Mobile phase B: Acetonitrile Time %A %B Flow rate 0.00 min 90.0 10.0 1.0 ml / min 2.00 min 10.0 90.0 1.0 ml / min 2.48 min 10.0 90.0 1.0 ml / min 2.50 min 90.0 10.0 1.2 ml / min 3.00 min 90.0 10.0 1.2 ml / min UV detection was indicated by the total absorbance signal at 214 nm and 254 nm scanning.

[0353] Description of preparative LC - MS system and method: Method A: Equipment: Waters Fractionlynx system Hardware: 2767 Dual Loop Auto Sampler / Fraction Collector; 2525 Fraction Collector Pump; CFO (Column Fluid Organizer) for column selection; RMA (Waters Reagent Manager) as a make-up water pump; Waters ZQ Mass Spectrometer; Waters 2996 Photodiode Array Detector. Waters ZQ Mass Spectrometer: Scan Mode: Alternating positive / negative electrospray Scan Range: 100 - 2000 amu LC Conditions: Preparative LCMS separation was carried out at 45 °C on a Halo C-18, 4.6×50 mm, 2.7 μm, C18 column. The gradient used was as follows: Mobile Phase A: Water + 0.1% v / v formic acid Mobile Phase B: Acetonitrile + 0.1% v / v formic acid Time %A %B Flow Rate 0.00 min 95 5 1.5 ml / min 1.0 min 5 95 1.5 ml / min 2.0 min 5 95 1.5 ml / min 2.5 min 95 5 1.5 ml / min 3.0 min 95 5 1.5 ml / min UV detection was indicated by the total absorbance signal at 214 nm and 254 nm scanning.

[0354] Method B: Equipment: Agilent 1100 LC-MS Preparative System: Hardware: 1100 Series "prepALS" Auto Sampler; 1100 Series "PrepPump" for preparative flow gradient and 1100 Series "QuatPump" for delivering modifier in preparative flow; 1100 Series "MWD" Multi-Wavelength Detector; 1100 Series "LC-MSD VL" Detector; 2× "Prep-FC" Fraction Collector; "Waters RMA" Make-up Water Pump; Agilent Active Splitter. Agilent MS running conditions: Capillary voltage: 4000 V (3500 V in ES negative); 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: Electrospray positive or electrospray negative. 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 as follows: Mobile phase A: Water + 0.1% v / v formic acid Mobile phase B: Acetonitrile + 0.1% v / v formic acid Time %A %B Flow rate 0.00 min 95 5 1.5 ml / min 1.0 min 5 95 1.5 ml / min 2.0 min 5 95 1.5 ml / min 2.5 min 95 5 1.5 ml / min 3.0 min 95 5 1.5 ml / min UV detection was indicated by the total absorbance signal at 214 nm and 254 nm scanning.

[0355] Normal phase chromatography separation: Silica gel chromatography was performed on a pre-packed disposable SiO 2 stationary phase column, using an eluent flow rate in the range of 15 to 200 mL / min and UV detection (254 and 280 nm) on a Biotage instrument.

[0356] Scheme and experimental procedure The following scheme and procedure illustrate how the compounds of the present invention can be prepared. The specific solvents and reaction conditions mentioned are also illustrative and are not intended to be limiting. Compounds not described are readily prepared by those skilled in the art using commercially available or accessible starting materials. The examples disclosed herein are for illustrative purposes only and are not intended to limit the scope of the compounds of the present invention.

[0357] I. Preparation of Bis-Phenol Starting Materials: Synthesis of bis-phenol-045, [1,1'-biphenyl]-3,3'-diol.

[0358]

Chem.

[0359] H 2 To a solution of (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 O (50 mL) was added Pd / C (300 mg, purity 10%) at once at 15 °C under N 2 . The mixture was stirred at 80 °C for 2 h under N 2 . LCMS indicated that the 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 solution (1.0 M). The mixture was extracted with EtOAc (50 mL × 3), the combined organic phases were washed with brine (30 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (897 mg, 4.82 mmol, quantitative yield) as a yellow oil. LCMS (ES, m / z): 187.0 [M+H] + .

[0360] Synthesis of bis-phenol-046, [1,1'-biphenyl]-3,4'-diol.

[0361]

Chem.

[0362] H 2(4-Hydroxyphenyl)boronic acid (1.32 g, 9.55 mmol, 1.05 eq) in O (100 mL), 3-iodophenol (2 g, 9.09 mmol, 1 eq) and K 2 CO 3 (5.03 g, 36.4 mmol, 4 eq) solution was added Pd / C (300 mg, purity 10%) at 15 °C at once under N 2 . The mixture was stirred at 80 °C for 2 h. LCMS showed that the 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 solution (1.0 M). The mixture was extracted with EtOAc (50 mL × 3), the combined organic phases were washed with brine (30 mL), dehydrated with Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain the title compound (1.9 g, 10.2 mmol, quantitative yield) as a brown solid. LCMS (ES, m / z): 185.0 [M-H] - .

[0363] Synthesis of bis-phenol-055, 1,2-bis(4-hydroxyphenyl)ethane-1,2-dione.

[0364]

Chemical formula

[0365] 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, and then LCMS indicated that the reaction was complete. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with water (50 mL × 3) and Na 2 SO 4It was dehydrated and filtered. The filtrate was concentrated under vacuum to obtain the crude title compound (1.6 g, 6.61 mmol, 89% yield) as a red solid. LCMS (ES, m / z): 241.0 [M-H] - .

[0366] Synthesis of bis-phenol-139, 5-fluorobenzene-1,3-diol.

[0367]

Chemical Structure

[0368] To a solution of 1-fluoro-3,5-dimethoxybenzene (1.50 g, 9.61 mmol, 1 eq) in DCM (50 mL) was added dropwise a solution of BBr 3 (5.53 g, 22.1 mmol, 2.13 mL, 2.3 eq) in DCM (50 mL) at -65 °C over 1.5 h under N 2 . The reaction mixture was stirred at 15 °C for 10.5 h, and then LCMS indicated complete consumption of the starting material and formation of the product of the desired mass. 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 isolated, dehydrated with Na 2 SO 4 and evaporated to dryness to obtain the crude product 5-fluorobenzene-1,3-diol (1.2 g, 9.37 mmol, 97.6% yield) as a red solid. LCMS (ES, m / z): 127.1 [M-H] - .

[0369] Synthesis of bis-phenol-052, 4,4'-(ethane-1,2-diyl)diphenol.

[0370]

Chemical Structure

[0371] Step 1 of 2: Synthesis of 1,2-bis(4-methoxyphenyl)ethane.

[0372] To a solution of 1,2-bis(4-methoxyphenyl)ethan-1-one (5 g, 19.5 mmol, 1 eq) in TFA (20 mL), Et 3 SiH (11.3 g, 97.5 mmol, 15.6 mL, 5 eq) was added. The mixture was stirred at 20 °C for 12 h. TLC (petroleum ether / ethyl acetate = 5:1, R f = 0.88) indicated that the reaction was complete. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with satd. NaHCO 3 aq. to pH = 8 - 9. The organic layer was dehydrated with anhydrous Na 2 SO 4 filtered, and concentrated to give a mixture of solid and oil. This 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. 1 1H 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).

[0373] Step 2 of 2: Synthesis of 4,4'-(ethane-1,2-diyl)diphenol.

[0374] To a solution of 1,2-bis(4-methoxyphenyl)ethane (4.40 g, 18.2 mmol, 1 eq) in DCM (100 mL), BBr 3 (18.2 g, 72.6 mmol, 7.00 mL, 4 eq) was added at 0 °C. The mixture was stirred at 20 °C for 16 h, and then LCMS indicated that 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 Na 2 SO 4It was dehydrated and the solvent was removed under vacuum to obtain the title compound (3.84 g, 17.9 mmol, yield 98.7%) as a pale yellow solid. LCMS (ES, m / z): 213.1 [M-H] - .

[0375] II. Preparation of dibromide starting material: Synthesis of dibromide-190, 1,4-bis(bromomethyl)-2,3,5,6-tetrafluorobenzene.

[0376]

Chemical formula

[0377] 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 μmol, 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) indicated complete consumption of the starting material and formation of a new spot. The reaction mixture was poured into H 2 O (50 mL) and extracted with DCM (50 mL × 2). The combined organic phases were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 2:1) to obtain 1,4-bis(bromomethyl)-2,3,5,6-tetrafluorobenzene (1.40 g, 4.17 mmol, yield 82.5%) as a white solid. 1 1H NMR (400 MHz, chloroform-d) δ = 4.52 (s, 4H).

[0378] III. Preparation of bis-amine linker, Methods A - M: Bis-amine linker, Method A: Synthesis of Linker_A-017, 1,3-phenylenebis(((R)-3-methylpiperazin-1-yl)methanone).

[0379] [Chemical formula]

[0380] Step 1 of 2 steps: Synthesis of di-tert-butyl 4,4’-isophthaloyl(2R,2’R)-bis(2-methylpiperazine-1-carboxylate).

[0381] To a solution of tert-butyl (R)-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 isophthaloyl dichloride (0.50 g, 2.5 mmol). The mixture was stirred overnight at room temperature, concentrated to dryness, and purified by flash chromatography (SiO 2 , dichloromethane / methanol = 15:1) to obtain the title compound (1.3 g, 2.4 mmol, 98% yield) as a white solid. LCMS (ES, m / z): 553.8 [M+Na] + . 1 H NMR (400 MHz, 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 = 48 Hz, 6H).

[0382] Step 2 of 2 steps: Synthesis of 1,3-phenylenebis(((R)-3-methylpiperazin-1-yl)methanone).

[0383] 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 with HCl (10 mL, 4 M in dioxane). The resulting mixture was stirred overnight at room temperature and concentrated to dryness to obtain the crude title compound (0.90 g, 2.2 mmol, 91% yield, 2HCl) as a white solid. LCMS (ES, m / z): 330.9 [M+H] + .

[0384] Synthesis of Linker_A-167, 1,3-bis(((R)-3-methylpiperazin-1-yl)sulfonyl)benzene.

[0385]

Chem.

[0386] The title compound was prepared from tert-butyl (R)-2-methylpiperazine-1-carboxylate and benzene-1,3-disulfonyldichloride according to the two-step procedure of Method A. LCMS (ES, m / z): 402.8 [M+H] + .

[0387] Bis-amine linker synthesis, Method B: Synthesis of Linker_D-192, (2S,2’S)-2,2’-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene))dimorpholine.

[0388]

Chem.

[0389] Step 1 of the two steps: Synthesis of di-tert-butyl 2,2’-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene))(2S,2’S)-bis(morpholine-4-carboxylate).

[0390] (S)-tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylate (500 mg, 2.30 mmol, 2.5 eq), 5-methylbenzene-1,3-diol (114 mg, 920 μmol, 1 eq), and PPh 3 (603 mg, 2.30 mmol, 2.5 eq) in THF (4 mL), DIAD (465 mg, 2.30 mmol, 447 μL, 2.5 eq) was added all at once at 0 °C under N 2 . The mixture was stirred at 60 °C for 12 h, and then LCMS indicated complete consumption of the diol and formation of the product of the target mass. The mixture was concentrated to dryness, and the residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The crude product was repurified 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 μmol, 43% yield) as a white solid. LCMS (ES, m / z): 423.2 [M - Boc + H +

[0391] Step 2 of 2 steps: Synthesis of (2S,2’S)-2,2’-(((5-methyl-1,3-phenylene)bis(oxy))bis(methylene))dimorpholine.

[0392] 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 μmol, 1 eq) in EtOAc (1.5 mL) was added HCl / EtOAc (4 M, 5 mL, 25 eq). The mixture was stirred at 15 °C for 2 h, and then LCMS indicated complete consumption of the starting material and formation of the product of the target mass. The reaction mixture was filtered to give the title compound (290 mg, 734 μmol, 94% yield, 2HCl) as a yellow solid. LCMS (ES, m / z): 323.3 [M + H] + . ​

[0393] Bis-amine linker synthesis, method C: Synthesis of linker_D-061, 1,4-bis(2-(4-(((S)-morpholin-2-yl)methoxy)phenyl)propan-2-yl)benzene.

[0394] [Chemical formula]

[0395] Step 1 of 2 steps: Synthesis 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).

[0396] Two reactions were carried out in parallel. 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 μmol, 1 eq) in toluene (4 mL), (tributylphosphoranilidene)acetonitrile (435 mg, 1.80 mmol, 2.5 eq) was added at 15 °C under N 2 and the mixture was stirred at 80 °C for 12 h under N 2 LCMS indicated that the diol was completely consumed and the product of the desired mass was detected. The two reactions were combined and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give an impure product. This material was re-purified by reverse-phase MPLC (80 g ISCO reverse-phase (C18) flash column; mobile phase: [water-ACN]; B%: 0 - 60% @ 50 mL / min) to give the title compound (280 mg, 376 μmol, 26% yield, impure) as a yellow oil. TLC (petroleum ether / ethyl acetate = 2:1): R f = 0.33 LCMS (ES, m / z): 767.4 [M+Na] + .

[0397] Step 2 of 2: Synthesis of 1,4-bis(2-(4-(((S)-morpholin-2-yl)methoxy)phenyl)propan-2-yl)benzene.

[0398] To a solution of di-tert-butyl 2,2'-((((1,4-phenylene bis(propane-2,2-diyl))bis(4,1-phenylene))bis(oxy))bis(methylene))(2S,2'S)-bis(morpholine-4-carboxylate) (280 mg, 376 μmol, 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 product of the desired mass was detected. The resulting solid was filtered off to give the title compound (220 mg, 356 μmol, 95% yield, 2HCl) as a white solid. LCMS (ES, m / z): 545.3 [M+H] + .

[0399] Bis-amine linker synthesis, method D: Synthesis of linker_D-147, di-tert-butyl 2,2'-(((1,2-phenylene bis(methylene))bis(oxy))bis(methylene))(2S,2'S)-bis(morpholine-4-carboxylate).

[0400]

Chemical formula

[0401] Step 1 of 2: Synthesis of di-tert-butyl 2,2'-(((1,2-phenylene bis(methylene))bis(oxy))bis(methylene))(2S,2'S)-bis(morpholine-4-carboxylate).

[0402] NaH (197 mg, 4.93 mmol, purity 60%, 2.6 eq) was added to a solution of tert-butyl (S)-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 μL, 1 eq) was added to the mixture, and the mixture was stirred at 60 °C for 12 h. LCMS indicated that the starting material was completely consumed and the product of the desired mass was detected. H 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 Na 2 SO 4 was used for dehydration and filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (1.3 g, 2.42 mmol, quantitative yield) as a yellow oil. LCMS (ES, m / z): 559.3 [M+Na] + .

[0403] Step 2 of 2 steps: Synthesis of linker_D-147, di-tert-butyl 2,2'-(((1,2-phenylenebis(methylene))bis(oxy))bis(methylene))(2S,2'S)-bis(morpholine-4-carboxylate).

[0404] HCl / EtOAc (4M, 5 mL) was added 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) at 15 °C. The mixture was stirred at 15 °C for 2 h. LCMS indicated the complete consumption of the starting material and the formation of the product of the desired mass. The mixture was filtered, and the filter cake was dried to obtain the title compound (604 mg, 1.48 mmol, yield 79%, 2HCl). LCMS (ES, m / z): 337.2 [M+H] + .

[0405] Bis-amine linker synthesis, method E: Synthesis of linker_D-088, 1,6-bis(((S)-morpholin-2-yl)methoxy)hexa-2,4-diyne.

[0406] [Chemical formula]

[0407] Step 1 of 3 steps: Synthesis of tert-butyl (S)-2-((prop-2-yn-1-yloxy)methyl)morpholine-4-carboxylate.

[0408] NaH (276 mg, 6.90 mmol, purity 60%, 1.5 eq) was added to a solution of tert-butyl (S)-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 the mixture was stirred at 15 °C for 12 h. TLC indicated the formation of a new product, 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 layers were washed with brine (10 mL) and dried over Na 2 SO 4 , filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to obtain the title compound as a yellow oil (0.95 g, 3.72 mmol, yield 63%). TLC (petroleum ether / ethyl acetate = 5:1): R f = 0.43 LCMS (ES, m / z): 156.1 [M - Boc + H] + .

[0409] Step 2 of 3: Synthesis of di-tert-butyl 2,2’-((hexa-2,4-diyldiylbis(oxy))bis(methylene))(2S,2’S)-bis(morpholine-4-carboxylate).

[0410] A mixture of tert-butyl (S)-2-((prop-2-yn-1-yloxy)methyl)morpholine-4-carboxylate (450 mg, 1.76 mmol, 1 eq), CuI (67 mg, 352 μmol, 0.2 eq), NiCl 2 .6H 2 O (84 mg, 353 μmol, 0.2 eq), TMEDA (82 mg, 705 μmol, 106 μL, 0.4 eq) and TEA (892 mg, 8.81 mmol, 1.23 mL, 5 eq) in THF (5 mL) was stirred at 15 °C for 12 h under aerobic conditions. TLC indicated the formation of a new product. 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, 38% yield) as an oil. TLC (petroleum ether / ethyl acetate = 2:1): R f = 0.43 1 1H 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).

[0411] Step 3 of 3: Synthesis of linker_D-088, 1,6-bis(((S)-morpholin-2-yl)methoxy)hexa-2,4-diyne.

[0412] HCl / EtOAc (4 M, 2 mL, 5.35 eq) was added to a solution of di-tert-butyl 2,2'-((hexa-2,4-diyn-1,6-diylbis(oxy))bis(methylene))(2S,2'S)-bis(morpholine-4-carboxylate) (0.76 g, 1.49 mmol, 1 eq) in EtOAc (6 mL) at 15 °C, and the mixture was stirred at 15 °C for 12 h. LCMS indicated the conversion to the product of the target mass. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound (0.27 g, 876 μmol, 59% yield) as a white solid. LCMS (ES, m / z): 309.3 [M+H] + . 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 = 3.3 Hz, 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 = 12.0 Hz, 2H).

[0413] The following bis-amine linkers were prepared from tert-butyl (S)-2-(hydroxymethyl)morpholine-4-carboxylate according to methods B, C, D or E indicated in Table 4:

[0414]

Table 4

[0415] Bis-amine linker synthesis, method F: Synthesis of Linker_E-079, (2S,2’S)-N,N’-(1,4-phenylenebis(methylene))bis(morpholine-2-carboxamide).

[0416]

Chem.

[0417] Step 1 of 2 steps: Synthesis of di-tert-butyl 2,2’-(((1,4-phenylenebis(methylene))bis(azanediyl))bis(carbonyl))(2S,2’S)-bis(morpholine-4-carboxylate).

[0418] To a solution of (S)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (2.00 g, 8.65 mmol, 2.2 eq), 1,4-phenylenedimethanamine (535 mg, 3.93 mmol, 1 eq) in DCM (20 mL), DIEA (2.03 g, 15.7 mmol, 2.74 mL, 4 eq) and HATU (3.74 g, 9.83 mmol, 2.5 eq) were added. The mixture was stirred at 20 °C for 12 h, and then LC-MS indicated the conversion to the product of the target mass. The reaction mixture was poured into saturated NH 4 Cl aqueous solution (100 mL) and extracted with DCM (50 mL × 3). The combined organic phases were washed with brine (100 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was triturated with MeOH (20 ml) and H 2 O (20 ml) at 15 °C for 30 min. The mixture was filtered and the filter cake was dried to obtain the title compound (2.2 g, 3.91 mmol, 99% yield) as a white solid. LCMS (ES, m / z): 463.2 [M-Boc+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ = 8.37 (broad t, J = 6.2 Hz, 2H), 7.16 (s, 4H), 4.24 (broad d, J = 6.0 Hz, 4H), 4.00 (broad d, J = 11.6 Hz, 2H), 3.89 (dd, J = 3.1, 10.4 Hz, 4H), 3.71 (broad d, J = 13.0 Hz, 2H), 3.48 (dt, J = 2.5, 11.4 Hz, 2H), 3.03 - 2.70 (m, 4H), 1.41 (s, 18H).

[0419] Step 2 of 2 steps: Synthesis of (2S,2’S)-N,N’-(1,4-phenylenebis(methylene))bis(morpholine-2-carboxamide).

[0420] 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 μmol, 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 consumption of the starting material and formation of the desired mass product. The mixture was filtered and the filter cake was dried to afford the title compound (168 mg, 386 μmol, quantitative yield, 2HCl) as a white solid. LCMS (ES, m / z): 363.2 [M+H] + .

[0421] The following bis-amine linker was prepared from (2S)-4-tert-butoxycarbonylmorpholine-2-carboxylic acid and a diamine by Method F indicated in Table 5:

[0422]

Table 5

[0423] Bis-amine linker synthesis, Method G: Synthesis of Linker_E-182, (2S,2’S)-N,N’-(hexa-2,4-diyne-1,6-diyl)bis(morpholine-2-carboxamide).

[0424]

Chemical Structure

[0425] Step 1 of 3 steps: Synthesis of tert-butyl (S)-2-(prop-2-yn-1-ylcarbamoyl)morpholine-4-carboxylate.

[0426] To a solution of (2S)-4-tert-butoxycarbonylmorpholine-2-carboxylic acid (2.00 g, 8.65 mmol, 1 eq) and prop-2-yn-1-amine (524 mg, 9.51 mmol, 609 μL, 1.1 eq) in DCM (20 mL), DIEA (3.35 g, 25.9 mmol, 4.52 mL, 3 eq) and HATU (4.28 g, 11.2 mmol, 1.3 eq) were added. The mixture was stirred at 20 °C for 12 h, and then the product of the desired mass 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. TLC (petroleum ether / ethyl acetate = 1:1) R f = 0.53

[0427] Step 2 of 3 steps: Synthesis of di-tert-butyl 2,2’-((hexa-2,4-diyne-1,6-diylbis(azanediyl))bis(carbonyl))(2S,2’S)-bis(morpholine-4-carboxylate).

[0428] tert-Butyl (S)-2-(prop-2-yn-1-ylcarbamoyl)morpholine-4-carboxylate (1.00 g, 3.73 mmol, 1 eq), CuI (71 mg, 373 μmol, 0.1 eq), NiCl2 .6H 2 A mixture of O (89 mg, 373 μmol, 0.1 eq), TMEDA (86.6 mg, 745 μmol, 112 μL, 0.2 eq) and TEA (1.89 g, 18.6 mmol, 2.59 mL, 5 eq) was stirred at 15 °C for 12 h under aerobic conditions. LC-MS indicated the consumption of the starting materials and the formation of the product of the target mass. Water (30 ml) was added to the mixture, and the mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (10 mL), dehydrated with Na 2 SO 4 filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 0:1) to obtain the title compound (690 mg, 1.29 mmol, 35% yield) as a yellow solid. TLC (petroleum ether / ethyl acetate = 1:1): R f = 0.24 LCMS (ES, m / z): 435.2 [M - Boc + H] + . 1 1H 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).

[0429] Step 3 of 3 steps: Synthesis of Linker_E - 182, (2S,2’S)-N,N’-(hexa - 2,4 - diyne - 1,6 - diyl)bis(morpholine - 2 - carboxamide).

[0430] A solution of di-tert-butyl 2,2'-((hexa-2,4-diyldiylbis(azanediyl))bis(carbonyl))(2S,2'S)-bis(morpholine-4-carboxylate) (200 mg, 374 μmol, 1 eq) in EtOAc (2 mL) was treated with HCl / dioxane (4 M, 2 mL, 21 eq). The mixture was stirred at 20 °C for 0.5 h. LC-MS indicated consumption of the starting material and formation of the product of the desired mass. The reaction mixture was filtered and the filtered cake was dried to afford the title compound (110 mg, 270 μmol, 72.2% yield, 2HCl) as a white solid. LCMS (ES, m / z): 335.2 [M+H] + .

[0431] Bis-amine linker synthesis, method H: Synthesis of linker_F-157, N1,N4-bis(2-(piperidin-4-yl)ethyl)terephthalamide.

[0432]

Chemical formula

[0433] Step 1 of 2 steps: Synthesis of linker_F-157-Boc, di-tert-butyl 4,4'-((terephthaloyl bis(azanediyl))bis(ethane-2,1-diyl))bis(piperidine-1-carboxylate).

[0434] To a solution of terephthalic acid (661 mg, 3.98 mmol, 1 eq) in DCM (80 mL) were 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 indicated complete consumption of terephthalic acid and detection of one major peak of the desired mass. The mixture was concentrated to dryness and the residue was purified by column chromatography (SiO 2, Purified with ethyl acetate / methanol = 1 / 0 to 3 / 1) to obtain the title compound (5.19 g, 8.85 mmol, quantitative yield) as a white solid. LCMS (ES, m / z): 609.6 [M+Na] + .

[0435] Step 2 of 2 steps: Synthesis of linker_F-157, N1,N4-bis(2-(piperidin-4-yl)ethyl)terephthalamide.

[0436] To a solution of di-tert-butyl 4,4'-((terephthaloyl bis(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 and formation of one major peak of the desired mass. The solid was filtered, washed with EtOAc (3 × 1 mL), and dried under high vacuum to obtain the title compound (480 mg, 731 μmol, yield 61.3%, 2HCl) as a white solid. LCMS (ES, m / z): 387.4 [M+H] + .

[0437] Bis-amine linker synthesis, Method I: Synthesis of linker_F-154, 1,1'-(1,4-phenylene)bis(N-methyl-N-(piperidin-4-ylmethyl)methanamine).

[0438]

Chemical formula

[0439] Step 1 of 2 steps: Synthesis of tert-butyl 4-[[[4-[[(1-tert-butoxycarbonyl-4-piperidyl)methyl-methyl-amino]methyl]phenyl]methyl-methyl-amino]methyl]piperidine-1-carboxylate.

[0440] To a solution of 1,4-bis(bromomethyl)benzene (262 mg, 995 μmol, 1 eq) in MeCN (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 μL, 4 eq). The mixture was stirred at 15 °C for 14 h, after which LC-MS indicated complete consumption of the starting material and formation of the 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 afford the title compound (360 mg, 644 μmol, 65% yield) as a yellow oil. TLC (ethyl acetate / methanol = 10:1): R f = 0.4 LCMS (ES, m / z): 559.6 [M+H] + .

[0441] Step 2 of 2 steps: Synthesis of N-methyl-1-[4-[[methyl(4-piperidylmethyl)amino]methyl]phenyl]-N-(4-piperidylmethyl)methanamine.

[0442] To a solution of tert-butyl 4-[[[4-[[(1-tert-butoxycarbonyl-4-piperidyl)methyl-methyl-amino]methyl]phenyl]methyl-methyl-amino]methyl]piperidine-1-carboxylate (360 mg, 644 μmol, 1 eq) in EtOAc (4 mL) was added HCl / EtOAc (4 M, 4 mL). The mixture was stirred at 15 °C for 1 h. LC-MS indicated complete consumption of the starting material and formation of the product of the target mass. The solid was filtered off, washed with EtOAc (3 × 1 mL), and dried under high vacuum to afford the title compound (410 mg, 950 μmol, quantitative yield, 2HCl) as a white solid. LCMS (ES, m / z): 359.4 [M+H] + .

[0443] Bis-amine linker synthesis, method J: Synthesis of Linker_F-158, N1,N4-Dimethyl-N1,N4-bis(2-(piperidin-4-yl)ethyl)terephthalamide.

[0444] [Chemical formula]

[0445] Step 1 of 2 Steps: Synthesis of di-tert-butyl 4,4'-((terephthaloyl bis(methylazanediyl))bis(ethane-2,1-diyl))bis(piperidine-1-carboxylate).

[0446] To a solution of Linker_F-157-Boc, di-tert-butyl 4,4'-((terephthaloyl bis(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, purity 60%, 2.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then iodomethane (605 mg, 4.26 mmol, 265 μL, 2.5 eq) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h and then at 25 °C for 1 h. LC-MS showed complete consumption of the starting material and formation of a single product of the target mass. The reaction mixture was quenched with saturated NH 4 Cl aqueous solution (15 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , ethyl acetate / methanol = 1 / 0 to 3 / 1) to obtain the title compound (165 mg, 268 μmol, yield 16%) as a yellow oil. LCMS (ES, m / z): 637.6 [M+Na] + .

[0447] Step 2 of the two-step process: Synthesis of linker_F-158, N1,N4-dimethyl-N1,N4-bis(2-(piperidin-4-yl)ethyl)terephthalamide.

[0448] To a solution of di-tert-butyl 4,4'-((terephthaloyl bis(methylazanediyl))bis(ethane-2,1-diyl))bis(piperidine-1-carboxylate) (165 mg, 268 μmol, 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 indicated complete consumption of the starting material and formation of a single peak of the target mass. The solid was filtered, washed with EtOAc (3 × 1 mL), and dried under high vacuum to afford the title compound (117 mg, crude, 2HCl) as a white solid. LCMS (ES, m / z): 415.4 [M+H] + .

[0449] Bis-amine linker synthesis, method K: Synthesis of linker_F-159, N,N'-(1,4-phenylenebis(methylene))bis(2-(piperidin-4-yl)acetamide).

[0450]

Chemical formula

[0451] Step 1 of the two-step process: Synthesis of tert-butyl 4-[2-[[4-[[[2-(1-tert-butoxycarbonyl-4-piperidyl)acetyl]amino]methyl]phenyl]methylamino]-2-oxo-ethyl]piperidine-1-carboxylate.

[0452] A solution of 2-(1-tert-butoxycarbonyl-4-piperidyl)acetic acid (2.00 g, 8.22 mmol, 2.2 eq) in DCM (5 mL) was added to [4-(aminomethyl)phenyl]methanamine (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 h. LC-MS indicated complete conversion to the 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 3:1) to give the title compound (5.49 g, 9.36 mmol, quantitative yield) as a white solid. TLC (ethyl acetate / methanol = 10:1): R f = 0.4 LCMS (ES, m / z): 587.6 [M+H] + .

[0453] Step 2 of 2 steps: Synthesis of linker_F-159, N,N'-(1,4-phenylenebis(methylene))bis(2-(piperidin-4-yl)acetamide).

[0454] HCl / EtOAc (4 M, 6 mL) was added to a solution of tert-butyl 4-[2-[[4-[[[2-(1-tert-butoxycarbonyl-4-piperidyl)acetyl]amino]methyl]phenyl]methylamino]-2-oxo-ethyl]piperidine-1-carboxylate (1.00 g, 1.70 mmol, 1 eq) in EtOAc (4 mL). The mixture was stirred at 15 °C for 1 h, and then LCMS indicated complete conversion to the product of the target mass. The solid was filtered, washed with EtOAc (3 × 1 mL) and dried under high vacuum to give the title compound (440 mg, 670 μmol, yield 56.2%, 2HCl) as a white solid. LCMS (ES, m / z): 387.4 [M+H] + .

[0455] Bis-amine linker synthesis, method L: Synthesis of Linker_F-161, 1,3-bis(piperidin-4-ylmethoxy)benzene.

[0456]

Chemical formula

[0457] Step 1 of 2 steps: Synthesis of di-tert-butyl 4,4'-((1,3-phenylenebis(oxy))bis(methylene))bis(piperidine-1-carboxylate).

[0458] DIAD (939 mg, 4.64 mmol, 903 μL, 2.5 eq) was added to a mixture of benzene-1,3-diol (204 mg, 1.86 mmol, 310 μL, 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 N 2 under 0 °C, and then stirred at 60 °C for 12 h. LC-MS indicated complete consumption of the starting materials and formation of a single peak of the target mass. The reaction mixture was quenched with H 2 O (15 mL), extracted with ethyl acetate (15 mL × 2). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , 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 3:1) to give the title compound (513 mg, 1.02 mmol, yield 54.7%) as a white solid. LCMS (ES, m / z): 505.5 [M+H] + .

[0459] Step 2 of 2 steps: Synthesis of 1,3-bis(piperidin-4-ylmethoxy)benzene.

[0460] 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 to HCl / EtOAc (4 M, 6 mL, 17.6 eq). The mixture was stirred at 15 °C for 1 h, and then LC-MS indicated complete consumption of the starting material and formation of 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, yield 96.1%, 2HCl) as a white solid. LCMS (ES, m / z): 305.3 [M+H] + .

[0461] Bis-amine linker synthesis, method M: Synthesis of linker_F-164, 1,3-bis(2,2-difluoro-2-(piperidin-4-yl)ethoxy)benzene.

[0462]

Chemical formula

[0463] Step 1 of 2 steps: Synthesis of di-tert-butyl 4,4'-((1,3-phenylenebis(oxy))bis(1,1-difluoroethane-2,1-diyl))bis(piperidine-1-carboxylate).

[0464] To a solution of tert-butyl 4-(1,1-difluoro-2-hydroxy-ethyl)piperidine-1-carboxylate (169 mg, 639 μmol, 2.2 eq), benzene-1,3-diol (32 mg, 290 μmol, 48 μL, 1 eq) in toluene (5 mL), (tributylphosphoranilidene)acetonitrile (175 mg, 726 μmol, 2.5 eq) was added under N 2 atmosphere at 15 °C. The mixture was stirred at 90 °C for 12 h, and then LC-MS indicated complete consumption of the starting material and formation of a single peak of the target mass. The mixture was concentrated to dryness, and the residue was subjected to column chromatography (SiO2 , purified with petroleum ether / ethyl acetate = 1:0 to 0:1). The impure product was separated by preparative HPLC (column: Phenomenex Luna C 18 200×40mm×10μm; mobile phase: [water (0.2% FA)-ACN]; B%: 60-100%; 8 min) and re-purified to obtain the title compound (50 mg, 83 μmol, yield 14%) as a yellow oil. LCMS (ES, m / z): 605.4 [M+H] + .

[0465] Step 2 of the 2-step process. Synthesis of Linker_F-164, 1,3-bis(2,2-difluoro-2-(piperidin-4-yl)ethoxy)benzene.

[0466] 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 μmol, 1 eq) in EtOAc (1 mL) was added HCl / EtOAc (4 M, 1 mL). The mixture was stirred at 15 °C for 1 h, and then LC-MS indicated complete consumption of the starting material and formation of a single peak of the target mass. The mixture was filtered and the filter cake was dried to obtain the title compound (31 mg, 64.9 μmol, yield 78%, crude, 2HCl) as a yellow solid. LCMS (ES, m / z): 405.2 [M+H] + .

[0467] The following bis-amine linkers were prepared according to methods H, I, J, K, L or M indicated in Table 6.

[0468]

Table 6

[0469] Synthesis of Bis - amine linker_G - 079, (2R,2’R)-N,N’-(1,4 - phenylenebis(methylene))bis(morpholine - 2 - carboxamide).

[0470]

Chem.

[0471] The title compound was prepared from (R)-4-(tert - butoxycarbonyl)morpholine - 2 - carboxylic acid and 1,4 - phenylenedimethanamine according to the two - step procedure of Method F. LCMS (ES, m / z): 362.9 [M + H] + .

[0472] Synthesis of Bis - amine linker_H - 131, 1,3 - bis(((R)-morpholin - 2 - yl)methoxy)benzene; and H - 166, 1,4 - bis(((R)-morpholin - 2 - yl)methoxy)butane.

[0473] Bis - amine linkers H - 131 and H - 166 were prepared according to the two - step procedures of Methods B and D, respectively, except that tert - butyl (R)-2-(hydroxymethyl)morpholine - 4 - carboxylate was used instead of tert - butyl (S)-2-(hydroxymethyl)morpholine - 4 - carboxylate. The characterization data for these bis - amines are as shown in Table 7.

[0474]

Table 7

[0475] IV. Preparation of Important Intermediates: Preparation of Intermediate 1.5, tert - butyl (2R,5R)-5-(hydroxymethyl)-2 - methylpiperazine - 1 - carboxylate.

[0476]

Chem.

[0477] Step 1 out of 4 steps: Synthesis of Intermediate 1.2, Methyl ((benzyloxy)carbonyl)-L-seryl-D-alaninate.

[0478] Two batches were run in parallel. To a solution of methyl D-alaninate (46.7 g, 334.4 mmol, 1 eq, HCl), (2S)-2-(benzyloxycarbonylamino)-3-hydroxy-propanoic acid (80.0 g, 334 mmol, 1 eq), and EDCI (76.9 g, 401 mmol, 1.2 eq) in DCM (800 mL), DIEA (129.7 g, 1.00 mol, 174.8 mL, 3 eq) was added. The mixture was stirred at 15 °C for 16 h. The two reactions were combined and concentrated under reduced pressure. The residue was diluted with saturated NaHCO 3 aqueous solution (1000 mL) and H 2 O (1000 mL), then extracted with ethyl acetate (1000 mL × 3). The combined organic layers were washed with 2 M HCl (1000 mL) and brine (1000 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the crude title compound (160 g, 493 mmol, 73.8% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.27 - 7.38 (m, 5H) 7.12 (br d, J = 5.90 Hz, 1H) 6.02 (br d, J = 7.40 Hz, 1H) 5.12 (s, 2H) 4.54 (br t, J = 7.34 Hz, 1H) 4.28 (br s, 1H) 4.06 (br d, J = 9.41 Hz, 1H) 3.71 (s, 4H) 1.39 (br d, J = 6.78 Hz, 3H).

[0479] Step 2 out of 4 steps: Synthesis of Intermediate 1.3, (3S,6R)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione.

[0480] Four batches were run in parallel. To a solution of methyl ((benzyloxy)carbonyl)-L-seryl-D-alaninate (35 g, 108 mmol, 1 eq) in MeOH (310 mL) was added Pd / C (5 g, 10% purity) and cyclohexene (205 mL). The mixture was stirred at 90 °C for 12 h. Four reactions were combined for workup. The reaction mixture was filtered and the filter cake was washed with warm MeOH (250 × 3 mL). The filtrate was concentrated under reduced pressure to afford the title compound (51.0 g, 322 mmol, 74.7% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.09 (s, 1H) 7.90 (br s, 1H) 5.11 (t, J = 5.26 Hz, 1H) 3.92 (d, J = 7.02 Hz, 1H) 3.71 - 3.78 (m, 1H) 3.65 - 3.71 (m, 1H) 3.52 (ddd, J = 10.52, 5.04, 2.85 Hz, 1H) 1.23 (d, J = 7.02 Hz, 3H).

[0481] Step 3 of 4 steps: Synthesis of intermediate 1.4, ((2R,5R)-5-methylpiperazin-2-yl)methanol.

[0482] Four batches were run in parallel. 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 3THF (1 M, 474 mL, 474 mmol, 6 eq) was added at 20 °C. The mixture was stirred at 70 °C for 12 h. Four reactions were combined for workup. The solution was cooled in ice and then methanol (650 ml) and then 5 M HCl (150 ml) were added slowly. The mixture was heated at 70 °C for 2 h and then cooled to 25 °C. The solid was filtered off and the filter cake was washed with THF (250 mL × 2) to give the title compound (60 g, 295 mmol, 93% yield, 2HCl) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.05 (br s, 4H) 5.59 (br s, 1H) 3.30 - 3.86 (m, 6H) 3.10 (q, J = 12.28 Hz, 2H) 1.31 (d, J = 6.58 Hz, 3H).

[0483] Step 4 out of 4 steps: Synthesis of intermediate 1.5, tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate.

[0484] Three batches were run in parallel. To a solution of ((2R,5R)-5-methylpiperazin-2-yl)methanol (20.0 g, 98.5 mmol, 1 eq, 2HCl) in MeOH (200 mL), Boc 2 O (49.4 g, 226 mmol, 52.0 mL, 2.3 eq) and TEA (29.9 g, 295 mmol, 41.1 mL, 3 eq) were added. The mixture was stirred at 50 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOH (100 mL) and treated with NaOH (1.5 M, 328 mL, 5 eq) with stirring at 90 °C for 12 h. Three reactions were combined for workup. The reaction mixture was concentrated under reduced pressure to remove EtOH and the pH was adjusted to about 9 with 1 M HCl. The mixture was extracted with DCM (800 mL × 6) and the combined organic layers were dried over Na 2 SO 4 and filtered and concentrated under reduced pressure to give the title compound as a white solid. 1 1H NMR (400 MHz, methanol-d 4 ) δ ppm 4.04 - 4.16 (m, 1H) 3.76 (dd, J = 14.03, 1.75 Hz, 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, 4.38 Hz, 1H) 3.02 (dd, J = 13.15, 4.82 Hz, 1H) 2.86 - 2.95 (m, 1H) 2.51 (dd, J = 12.94, 3.29 Hz, 1H) 1.46 (s, 9H) 1.23 (d, J = 7.02 Hz, 3H).

[0485] Preparation of Intermediate 2.2, 2-(4-Fluorobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0486]

Chemical formula

[0487] Five batches were run in parallel. 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-dioxaborolane (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) under N 2 under. The mixture was stirred at 100 °C for 3 h. TLC (petroleum ether / ethyl acetate = 10:1) indicated complete consumption of the starting materials and formation of new spots. The five reactions were combined for workup. The reaction mixture was filtered and the mixture was H 2It was quenched with O(1500 ml) at 0 °C. The mixture was extracted with EtOAc (1000 ml × 3), and the combined organic phases were washed with brine (500 ml) and dried over anhydrous Na 2 SO 4 and filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 300 / 1 to 0 / 1) to give the title compound (127 g, 538 mmol, 55.2% yield) as a yellow liquid. 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).

[0488] Intermediate 3.14, Preparation 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.

[0489]

Chemical formula

[0490] Step 1 of 13 steps: Synthesis of intermediate 3.2, dimethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate.

[0491] Two batches were run in parallel. To a suspension of K 2 CO 3 (464 g, 3.36 mol, 3.02 eq) in DMF (1000 mL) was added CH 2 (CO 2 Me) 2(220.4 g, 1.67 mol, 192 mL, 1.50 eq) was added dropwise at 0 °C over 20 min, and then 5-bromo-2-chloro-3-nitropyridine (264 g, 1.11 mol, 1 eq) was added portionwise. The reaction mixture was warmed to 20 °C and stirred for 18 h. TLC (petroleum ether / ethyl acetate = 2:1) indicated that the reaction was almost complete. The two reactions were combined for workup. The reaction mixture was poured into 2.0 M HCl (6.2 L) and extracted with EtOAc (3 L × 3). The combined organic layers were washed with LiCl (1.0 M aqueous solution, 2 L) and brine (2 L), dehydrated with Na 2 SO 4 , filtered, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 20:1 to 1:1) to give the title compound (832 g, crude) as a yellow oil containing dimethyl malonate residue. TLC (petroleum ether / ethyl acetate = 2:1) R f = 0.52. 1 H NMR (400 MHz, 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).

[0492] Step 2 of 13 steps: Synthesis of Intermediate 3.3, Methyl 2-(5-bromo-3-nitropyridin-2-yl)acetate.

[0493] Two reactions were carried out in parallel. H 2A suspension of dimethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (416 g, 1.25 mol, 1 eq) in O (600 mL) was added to LiCl (265 g, 6.24 mol, 5 eq). The reaction mixture was heated to reflux for 72 h, and then TLC (petroleum ether / ethyl acetate = 2:1) indicated complete consumption of the starting material. Two reactions were combined for workup. The cooled reaction mixture was partitioned between EtOAc (3000 mL) and water (1000 mL). The isolated organic phase was dehydrated with anhydrous Na 2 SO 4 and filtered, and concentrated in vacuo to give 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, 77.1% yield) as a yellow oil. 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).

[0494] Step 3 of 13 steps: Synthesis of Intermediate 3.4, methyl 2-(5-bromo-3-nitropyridin-2-yl)-2-methylpropanoate.

[0495] Four reactions were run in parallel. 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, then MeI (64.5 g, 454 mmol, 28.3 mL, 2.5 eq) was added dropwise to the mixture at 0 °C over 1 h. The mixture was stirred at 20 °C for 0.5 h, and then TLC (petroleum ether / ethyl acetate = 10:1) indicated complete consumption of the starting material and formation of a new product. Four reactions were combined for workup. The reaction was quenched with saturated NH 4The solution was quenched with an aqueous solution of Cl (3000 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (3000 mL × 2). The combined organic matter was washed with brine (1000 mL) and dried over anhydrous Na 2 SO 4 filtered, and concentrated in vacuo. 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, 74.4% yield) as a yellow oil. 1 1H 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).

[0496] Step 4 of 13 steps: Synthesis of Intermediate 3.5, 6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

[0497] Two reactions were carried out in parallel. 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 complete consumption of the starting material and formation of one new spot. The two reactions were combined for workup. The mixture was filtered and the filtrate was concentrated to dryness. The crude product was treated with saturated aqueous NaHCO 3 (2000 mL), then extracted with EtOAc (1500 mL × 3). The combined organic phases were washed with brine (500 mL) and dried over Na 2 SO 4 filtered, and concentrated under reduced pressure to give the title compound (120 g, 498 mmol, 94.3% yield) as a yellow solid. 11H 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).

[0498] Step 5 out of 13 steps: Synthesis of Intermediate 3.6, 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine.

[0499] Three reactions were carried out in parallel. 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), NaBH 4 (35.3 g, 933 mmol, 5 eq) and BF 3 .Et 2 O (185 g, 1.30 mol, 161 mL, 7 eq) were added at 0 °C under N 2 . The mixture was stirred at 20 °C for 12 h, and then TLC (petroleum ether / ethyl acetate = 2:1) indicated complete consumption of the starting material and formation of a new product. The three reactions were quenched separately with saturated NH 4 Cl aqueous solution (300 mL) and extracted with EtOAc (1000 mL × 2). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The three residues were combined and purified 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. 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).

[0500] Step 6 of 13 steps: Synthesis of intermediate 3.7, tert-butyl 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate.

[0501] Two reactions were carried out in parallel. To a solution of 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (55.0 g, 242 mmol, 1 eq) and Boc 2 O (38.7 g, 315 mmol, 1.3 eq) in DCM (900 mL), DMAP (32.5 g, 266 mmol, 1.1 eq) was added portionwise at 0 °C. The mixture was stirred at 30 °C for 12 h, and then TLC (petroleum ether / ethyl acetate = 2:1) indicated complete consumption of the starting material. The two reactions were combined for workup. 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 afford the title compound (101 g, 309 mmol, 67.8% yield) as a colorless oil. 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).

[0502] Step 7 of 13 steps: Synthesis of intermediate 3.8, tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate.

[0503] Two reactions were carried out in parallel. Dioxane (800 mL) and H 2A solution of 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 O (80 mL) was added to 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). The mixture was stirred at 80 °C for 12 h under N 2 and then TLC (petroleum ether / ethyl acetate = 3:1) indicated conversion to the new product. The two reactions were combined for workup. 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, 58.8% yield) as a yellow oil. LCMS (ES, m / z): 357.3 [M+H] + .

[0504] Step 8 of 13 steps: Synthesis of Intermediate 3.9, 1-(tert-butoxycarbonyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine 4-oxide.

[0505] 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, purity 85%, 1.3 eq) at 0 °C. The mixture was stirred at 15 °C for 4 h and then LCMS indicated formation of the product of the desired mass. The reaction was quenched with saturated aqueous Na 2 SO 3It was quenched with (600 mL), and then extracted with DCM (100 mL × 2). The combined organic matter was washed with 1N NaOH (300 mL × 2) and brine (300 mL), and dehydrated with anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to obtain the title compound (34 g, 91.3 mmol, 95.7% yield) as a red oil. LCMS (ES, m / z): 373.3 [M+H] + .

[0506] Step 9 out of 13 steps: Synthesis of intermediate 3.10, tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate.

[0507] Ac 2 A mixture of 1-(tert-butoxycarbonyl)-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) in Ac 2 O (340 g, 315 mL) was stirred at 135 °C for 6 h, and then LCMS indicated complete consumption of the starting material. The reaction was cooled to ambient temperature, and the resulting solution was poured into ice water (2000 g). The resulting brown solid was collected by filtration, dissolved in MeOH (300 mL), and treated with NaOH (1 M, 408 mL) with stirring at 15 °C for 1 h. LCMS indicated consumption of the intermediate and detection of a new product of the desired mass. The mixture was concentrated to remove most of the MeOH under reduced pressure and treated with H LCMS (ES, m / z): 373.3 [M+H] + .

[0508] Step 10 out of 13 steps: Synthesis of Intermediate 3.11, 6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one.

[0509] Two reactions were carried out in parallel. 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 (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. Thereafter, LCMS indicated complete consumption of the starting material and formation of the product of the target mass. The two reactions were combined for workup. The mixture was filtered, and the filter cake was dried to obtain the title compound (26 g, 84.2 mmol, yield 100%, HCl) as a yellow solid. LCMS (ES, m / z): 273.1 [M+H] + .

[0510] Step 11 out of 13 steps: Synthesis of 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.

[0511] CH 3 To a mixture of 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 2 CO 3 (29.1 g, 210 mmol, 2.5 eq) in CH 3A solution of 2-chloroacetyl chloride (11.9 g, 105 mmol, 8.40 mL, 1.3 eq) dissolved in CN (40 mL) was added dropwise with stirring at 0 °C. 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 product of the target mass. 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 treated with H 2 O (500 mL) and extracted with EtOAc (400 mL × 3). The combined organic phases were washed with brine (200 mL), dried over Na 2 SO 4 , 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, 72.4% yield) as a yellow solid. LCMS (ES, m / z): 349.2 [M+H] + .

[0512] Step 12 of 13 steps: Synthesis of 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.

[0513] 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 a saturated aqueous solution of NH 4 Cl (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic phases were washed with brine (200 mL), dried over Na2 SO 4 It was dehydrated with SO, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain the title compound (20.2 g, 43.6 mmol, yield 76.1%) as a white solid. LCMS (ES, m / z): 463.2 [M+H] + .

[0514] Step 13 out of 13 steps: Synthesis of intermediate 3.14, 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.

[0515] A mixture of tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methyl-piperazine-1-carboxylate (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 (11.9 g, 86.4 mmol, 2 eq) and KI (7.17 g, 43.2 mmol, 1 eq) in MeCN (400 mL) was stirred at 50 °C for 12 h. Then TLC (petroleum ether / ethyl acetate = 3:1) indicated almost complete conversion of the starting material 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 0:1) to obtain the title compound (26.5 g, 40.3 mmol, yield 93.4%) as a yellow solid. LCMS (ES, m / z): 657.5 [M+H] + .

[0516] Preparation of Intermediate 4.4, tert-Butyl (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-Methylpiperazine-1-Carboxylate.

[0517]

Chemical formula

[0518] Step 1 of 4 Steps: Synthesis of Intermediate 4.1, tert-Butyl 6-(4-Fluorobenzyl)-3,3,4-Trimethyl-5-Oxo-2,3,4,5-Tetrahydro-1H-Pyrrolo[3,2-b]Pyridine-1-Carboxylate.

[0519] 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) were 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 and formation of the product of the desired mass. 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, 77.1% yield) as a yellow solid. LCMS (ES, m / z): 387.1 [M+H] + . 11H 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).

[0520] Step 2 of 4 steps: Synthesis of Intermediate 4.2, 6-(4-fluorobenzyl)-3,3,4-trimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one.

[0521] To a solution of tert-butyl 6-(4-fluorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate (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 complete consumption of the starting material and formation of the product of the target mass. The mixture was concentrated in vacuo to afford the title compound (2.67 g, crude, HCl) as a yellow oil. LCMS (ES, m / z): 287.1 [M+H] + .

[0522] Step 3 of 4 steps: Synthesis of 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.

[0523] 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 in MeCN (20 mL) 2 CO 3(2.84 g, 20.5 mmol, 2.2 eq) was added dropwise to a solution of 2-chloroacetyl chloride (1.26 g, 11.19 mmol, 890 μL, 1.2 eq) in MeCN (5 mL) with stirring at 0 °C. The mixture was warmed to 25 °C and stirred for 2 h, and then LC-MS indicated consumption of the starting material and formation of the product of the target mass. The reaction was quenched with MeOH (10 mL), and the mixture was concentrated in vacuo. The residue was extracted with EtOAc (10 mL × 2), and the combined organic phases were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to afford the title compound (2.7 g, 7.44 mmol, 79.8% yield) as a white solid. TLC (petroleum ether / ethyl acetate = 0:1) R f = 0.43. LCMS (ES, m / z): 363.1 [M+H] + . 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).

[0524] Step 4 of 4 steps: Synthesis of intermediate 4.4, tert-butyl (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-methylpiperazine-1-carboxylate.

[0525] 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 tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (2.23 g, 9.67 mmol, 1.3 eq) in THF (30 mL) was added to 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 consumption of the starting material and formation of a new product of the target mass. 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 afford the title compound (3.5 g, 6.29 mmol, 58.3% yield) as a yellow solid. LCMS (ES, m / z): 557.3 [M+H] + . TLC (petroleum ether / ethyl acetate = 0:1) R f = 0.10. 1 H NMR (400 MHz, chloroform-d) δ = 8.34 (s, 1H), 7.32 - 7.28 (m, 2H), 6.96 (t, J = 8.7 Hz, 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, 14.1 Hz, 1H), 2.98 - 2.89 (m, 2H), 2.63 (br dd, J = 5.1, 12.1 Hz, 1H), 1.47 (s, 12H), 1.23 (d, J = 6.5 Hz, 3H).

[0526] Preparation of Intermediate 5.3, tert-Butyl (2R,5R)-4-(2-(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.

[0527] [Chemical Formula]

[0528] Step 1 of 3 Steps: Synthesis of Intermediate 5.1, 6-(4-Fluorobenzyl)-3,3-Dimethyl-2,3-Dihydro-1H-Pyrrolo[3,2-b]Pyridine.

[0529] A solution of tert-Butyl 6-(4-Fluoro-Benzyl)-3,3-Dimethyl-2,3-Dihydro-Pyrrolo[3,2-b]Pyridine-1-Carboxylate (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 overnight at room temperature. The solvent was evaporated, and the residue was partitioned between saturated aqueous sodium bicarbonate (200 mL) and ethyl acetate (3 × 60 mL). The combined organics were dried over Na 2 SO 4 and filtered, then evaporated in vacuo to give the title compound (0.72 g, 2.81 mmol, 94% yield) as a light brown solid. LCMS (ES, m / z): 257.1 [M+H] + . 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).

[0530] Step 2 of 3 steps: Synthesis of Intermediate 5.2, 2-chloro-1-(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)ethan-1-one.

[0531] 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), a solution of chloroacetyl chloride (287 mg, 2.53 mmol) in acetonitrile (1 mL) was added dropwise at 20 °C over 2 min while maintaining a reaction temperature of less than 20 °C using an external ice-methanol bath. The resulting mixture was stirred at room temperature for 1.5 h, concentrated, and the residue was diluted with methanol. The solution was stirred at room temperature for 5 min, followed by the addition of 10% potassium carbonate solution. The mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate, and concentrated to dryness. The residue was purified by column chromatography on silica gel eluting with petroleum / ethyl acetate (3:1) to afford the title compound (580 mg, 1.74 mmol, 89.2% yield) as a white solid. LCMS (ES, m / z): 332.8 [M+H] + .

[0532] Step 3 of 3 steps: Synthesis of Intermediate 5.3, tert-butyl (2R,5R)-4-(2-(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.

[0533] Finely ground potassium iodide (578 mg, 3.48 mmol) was added under nitrogen 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). 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 dried over Na 2 SO 4 , filtered and evaporated in vacuo to give the title compound (760 mg, 1.44 mmol, 82.7% yield). LCMS (ES, m / z): 526.8 [M+H] + .

[0534] Preparation of Intermediate 6.2, 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.

[0535]

Chemical Structure

[0536] Step 1 of 2 steps: Synthesis of Intermediate 6.1, 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.

[0537] 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 (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 dropwise with MsCl (2.09 g, 18.3 mmol, 1.4 mL, 1.2 eq) at 0 °C. The mixture was stirred at 15 °C for 1 h, and then TLC (petroleum ether / ethyl acetate = 0:1) indicated complete conversion of the starting material to the new product. Water (100 mL) was added to the mixture, and it was extracted with DCM (50 mL × 2). The combined organic phases were washed with brine (50 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the intermediate (11.2 g, crude) as a yellow oil.

[0538] A mixture of the intermediate (11.2 g, 15.2 mmol, 1 eq), benzyl (R)-3-methylpiperazine-1-carboxylate (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 complete consumption of the starting material and formation of 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 2:1) to give the title compound (10.8 g, 12.3 mmol, yield 81.2%) as a yellow oil. LCMS (ES, m / z): 873.8 [M+H] + .

[0539] Step 2 of the two-step process: Synthesis of intermediate 6.2, 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.

[0540] 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, purity 10%) under N 2 atmosphere. The suspension was degassed and purged with H 2 . The mixture was stirred at 50 °C for 12 h under H 2 (15 psi), and then LCMS showed complete consumption of the starting material and formation of the product of the target mass. 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. LCMS (ES, m / z): 739.5 [M+H] + . A minor peak corresponding to the TBS cleavage product at 625.4 [M+H] + was also recorded.

[0541] Preparation of intermediate 7.2, 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.

[0542] [Chemical formula]

[0543] Step 1 of 2 Steps: Synthesis of Intermediate 7.1, 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.

[0544] To a solution of tert-butyl (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-methylpiperazine-1-carboxylate (500 mg, 898 μmol, 1 eq) and TEA (136 mg, 1.35 mmol, 187 μL, 1.5 eq) in DCM (5 mL) was added MsCl (123 mg, 1.08 mmol, 83.4 μL, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h, and then TLC indicated the conversion of the starting material to the new product. The reaction was quenched with saturated NaHCO 3 aqueous solution (20 mL), and then extracted with DCM (10 mL × 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated in vacuo to give the intermediate (500 mg, crude) as a yellow solid.

[0545] A solution of the intermediate product (1.00 g, 1.74 mmol, 1 eq) and benzyl (R)-3-methylpiperazine-1-carboxylate (367 mg, 1.56 mmol, 0.9 eq) in MeCN (10 mL) was added with DIEA (674 mg, 5.22 mmol, 909 μL, 3 eq) and KI (289 mg, 1.74 mmol, 1 eq). The mixture was stirred at 80 °C for 12 h, and then TLC (dichloromethane / methanol = 15:1, R f = 0.23) indicated the complete consumption of the starting material and the formation of a new main product. 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 afford the title compound (1.3 g, crude) as a yellow oil. LCMS (ES, m / z): 773.5 [M+H] + .

[0546] Step 2 of 2 steps: Synthesis of intermediate 7.2, 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.

[0547] 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 μmol, purity 10%) under N 2 under. The suspension was degassed under vacuum and purged with H 2 three times. The mixture was purged with H 2Stirred at 25 °C for 12 h under (15 psi), and then LCMS showed complete consumption of the starting material and formation of one main peak of the desired mass (LCMS complete consumption of starting material and formation of one main peak of desired mass). The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (800 mg, crude) as a yellow solid. LCMS (ES, m / z): 639.4 [M+H] + .

[0548] Preparation of Intermediate 8.2, 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.

[0549]

Chemical formula

[0550] Step 1 of 2 steps: Synthesis of Intermediate 8.1, 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.

[0551] 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 warmed to room temperature and stirred overnight under a nitrogen atmosphere. The mixture was partitioned between aqueous ammonium chloride solution and dichloromethane, and the isolated organic phase was dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to give the intermediate (500 mg, 0.917 mmol, 63.7% yield) as a white solid.

[0552] CH 3 A solution of the intermediate (2.24 g, 3.05 mmol, 1 eq), benzyl (S)-piperidin-3-ylcarbamate (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) in acetonitrile (50 mL) was stirred at 80 °C for 12 h, after which LCMS indicated the formation of the product of the target mass. 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, 52.6% yield) as a yellow oil. TLC (petroleum ether / ethyl acetate = 1:1) R f = 0.43 LCMS (ES, m / z): 873.6 [M+H] + .

[0553] Step 2 of the two-step process: Synthesis of intermediate 8.2, 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.

[0554] 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) under N 2 The suspension was degassed under vacuum and purged several times with H 2 The mixture was stirred at 50 °C for 12 h under H 2 (15 psi), and then LCMS indicated the formation of the product of the target mass. The mixture was filtered and the filtrate was concentrated to give the crude title compound (0.64 g, 866 μmol, 79% yield) as a yellow solid. LCMS (ES, m / z): 739.5 [M+H] + . A minor peak corresponding to the TBS cleavage product at 625.4 [M+H] + was also recorded.

[0555] Preparation of intermediate 9.2, 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.

[0556] [Chemical]

[0557] Step 1 of 2 Steps: Synthesis of Intermediate 9.1, 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.

[0558] MsCl (290 mg, 2.53 mmol) was added to a solution of tert-Butyl (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-carboxylate (760 mg, 1.45 mmol) and Triethylamine (293 mg, 2.89 mmol) in Dichloromethane (20 mL) at 0 °C. The solution was warmed to room temperature and stirred overnight under a nitrogen atmosphere. The mixture was partitioned between aqueous ammonium chloride solution and dichloromethane, and the isolated organic phase was dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with Petroleum ether / Ethyl acetate (1:1) to give the intermediate (500 mg, 0.917 mmol, 63.7% yield) as a white solid.

[0559] A mixture of the intermediate (2.8 g, 3.81 mmol, 1 eq), Benzyl (R)-piperidin-3-ylcarbamate (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 complete conversion of the starting material to the new product. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column chromatography (SiO2 , purified with petroleum ether / ethyl acetate = 1:0 to 1:4), to obtain the title compound (2.02 g, 2.31 mmol, yield 60.7%) as a yellow oil. LCMS (ES, m / z): 873.8 [M+H] + .

[0560] Step 2 of 2 steps: Synthesis of intermediate 9.2, 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.

[0561] To 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), Pd / C (1.5 g, purity 10%) was added under N 2 atmosphere. The suspension was degassed and purged several times with H 2 . The mixture was stirred at 50 °C for 12 h under H 2 (15 psi), and then LCMS indicated the formation of the product of the target mass. The mixture was filtered and the filtrate was concentrated to obtain the crude title compound (1.3 g, 1.76 mmol, yield 85.5%) as a yellow solid. LCMS (ES, m / z): 739.5 [M+H] + . A small peak corresponding to the TBS cleavage product of 625.4 [M+H] + was also recorded.

[0562] Preparation of Intermediate 10.2, (S)-4-(((2S,5R)-4-(tert-Butoxycarbonyl)-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-carboxylic Acid.

[0563] [Chemical Formula]

[0564] Step 1 of 2 Steps: Synthesis of Intermediate 10.1, Methyl (S)-4-(((2S,5R)-4-(tert-Butoxycarbonyl)-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.

[0565] 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 warmed to room temperature and stirred overnight under a nitrogen atmosphere. The mixture was partitioned between aqueous ammonium chloride solution and dichloromethane, and the isolated organic phase was dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate (1:1) to give the intermediate product (500 mg, 0.917 mmol, 63.7% yield) as a white solid.

[0566] To a solution of the intermediate (5.59 g, 7.61 mmol, 1 eq) in MeCN (100 mL) were added methyl (S)-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, and then LC-MS indicated complete consumption of the starting material and formation of the product of the target mass. 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 methyl, the title compound (5.9 g, 7.53 mmol, 98% yield) as a yellow oil. TLC (petroleum ether / ethyl acetate = 1:2) R f = 0.6. LCMS (ES, m / z): 784.7 [M+H] + .

[0567] Step 2 of 2 steps: Synthesis of Intermediate 10.2, (S)-4-(((2S,5R)-4-(tert-butoxycarbonyl)-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-carboxylic acid.

[0568] A solution of methyl (S)-4-(((2S,5R)-4-(tert-butoxycarbonyl)-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 with NaOH (2 M, 7.53 mL, 2 eq). The mixture was stirred at 15 °C for 2 h, and then LCMS indicated the consumption of the starting material and the formation of the product of the target mass. The mixture was concentrated to remove most of the THF under reduced pressure. The reaction mixture was diluted with H 2 O (10 mL), and 1N HCl was added to adjust the pH to 3 - 4. The mixture was filtered, and the filter cake was dried to obtain the title compound (5.75 g, crude) as a yellow solid. LCMS (ES, m / z): 656.5 [M+H] + .

[0569] Preparation of 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).

[0570]

Chemical formula

[0571] Step 1 of 3 steps: Synthesis of Intermediate 11.1, 1-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-chloroethan-1-one.

[0572] 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 with K 2 CO 3 (2.28 g, 16.5 mmol, 2.5 eq) and 2-chloroacetyl chloride (932 mg, 8.26 mmol, 656 μL, 1.25 eq) at 0 °C. The mixture was stirred at 25 °C for 4 h, and then LCMS indicated complete conversion to the product of the target mass. MeOH (10 mL) was added to the mixture and stirred at 20 °C for 0.5 h. The mixture was concentrated to dryness under reduced pressure, and the residue was partitioned between H 2 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), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1:0 to 1:2) to obtain the title compound (2.00 g, 6.59 mmol, yield 99%) as a white solid. TLC (petroleum ether / ethyl acetate = 1:1) R f = 0.7 LCMS (ES, m / z): 303.1, 305.1 [M+H] + .

[0573] Step 2 of 3 steps: Synthesis of intermediate 11.2, tert-butyl (2R,5R)-4-(2-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate.

[0574] 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) was added with tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methyl-piperazine-1-carboxylate (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, and then LCMS indicated complete conversion to the product of the target mass. 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 obtain the title compound (2.45 g, 4.93 mmol, 75% yield) as a yellow solid. TLC (petroleum ether / ethyl acetate = 1:1) R f = 0.5 LCMS (ES, m / z): 497.3, 499.3 [M+H] + .

[0575] Step 3 of 3 steps: Synthesis of 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).

[0576] A solution of tert-butyl (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-carboxylate (2.4 g, 4.82 mmol, 1 eq) in DCM (25 mL) was added with DIEA (1.56 g, 12.1 mmol, 2.10 mL, 2.5 eq) and MsCl (829 mg, 7.24 mmol, 560 μL, 1.5 eq) at 0 °C. The mixture was stirred at 15 °C for 0.5 h, and then TLC indicated the 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). The reaction mixture was quenched by the addition of H 2 O (10 mL), and then extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (10 mL), dehydrated with Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain the intermediate as a yellow oil.

[0577] The intermediate 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, and then LCMS indicated the complete conversion to the 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 3:1) to obtain the title compound (1.27 g, 1.00 mmol, yield 50.6%) as a yellow solid. TLC (ethyl acetate / methanol = 10:1) R f = 0.5 LCMS (ES, m / z): 1265.8, 1267.8, 1269.8 [M+H] + .

[0578] V. Preparation of Examples 1 to 190. Scheme 1: General method for Examples 1 to 23.

[0579] [Chemical formula]

[0580] [Example 1] 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.

[0581] [Chemical formula]

[0582] Step 1 of 2 steps: Synthesis 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)

[0583] HATU (65.1 mg, 171 μmol, 2.5 eq) 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 μmol, 2.1 eq), adipic acid (10 mg, 68.4 μmol, 11.3 μL, 1 eq) and DIEA (35.4 mg, 273 μmol, 47.7 μL, 4 eq) in DCM (2 mL) at 15 °C. The mixture was stirred at 15 °C for 12 h, after which LCMS indicated conversion to the product of the target mass. The mixture was concentrated to dryness and the residue was purified by preparative TLC (ethyl acetate / MeOH = 10 / 1) to afford the title compound (100 mg, 63.0 μmol) as a yellow oil. LCMS (ES, m / z): 1589.1 [M+H] +

[0584] Step 2 of 2: Synthesis of 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.

[0585] 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 μmol, 1 eq) in HCl / EtOAc (4 M, 2 mL) was stirred at 15 °C for 1 h, and then LCMS indicated the conversion to the product of the target mass. The precipitate was filtered off and the filter cake was dried to obtain the crude product. The material was purified by preparative HPLC (FA conditions; column: Phenomenex Luna C18 100×30 mm×5 μm; mobile phase: [water (0.2% FA)-ACN]; B%: 15% - 50%, 9 min) to give the title compound (38.5 mg, 30.5 μmol, yield 48.4%, purity 99%, 2FA) as a white solid. LCMS (ES, m / z): 1159.7 [M+H] + 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) 2.76 (br t, J = 11.51 Hz, 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 = 6.50 Hz, 6H) 1.03 (br dd, J = 19.26, 5.75 Hz, 6H).

[0586] The following compounds (Examples 2 to 23) were prepared according to the same procedure as Example 1, in which adipic acid was replaced with an appropriate bis-carboxylic acid:

[0587] [Example 2] 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

[0588] [Chemical formula]

[0589] LCMS (ES, m / z): 1187.8 [M+H] + 1 H NMR (400 MHz, CD3OD, 299K) δ (ppm) = 8.19 (br s, 2H), 7.29 (br s, 4H), 7.06 (br t, J = 7.7 Hz, 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 = 7.8 Hz, 7H), 3.28 - 2.82 (m, 11H), 2.56 (br s, 5H), 1.73 (br s, 4H), 1.51 (br s, 12H), 1.39 (br t, J = 6.5 Hz, 12H).

[0590] [Example 3] 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

[0591]

Chem.

[0592] LCMS (ES, m / z): 1215.8 [M+H] + 1 H NMR (400 MHz, methanol-d4) δ = 7.93 (br d, J = 11.0 Hz, 2H), 7.24 (dd, J = 5.6, 8.2 Hz, 4H), 7.01 (t, J = 8.8 Hz, 4H), 3.99 (br d, J = 8.3 Hz, 3H), 3.90 (br d, J = 9.5 Hz, 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 = 6.8 Hz, 20H), 1.33 (br s, 9H), 1.24 (br d, J = 5.8 Hz, 3H).

[0593] [Example 4] 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

[0594] [Chemical formula]

[0595] LCMS (ES, m / z): 1271.9 [M+H] + 1 1H NMR (400 MHz, methanol-d 4 ) δ = 7.94 (br d, J = 10.8 Hz, 2H), 7.24 (dd, J = 5.6, 8.2 Hz, 4H), 7.01 (t, J = 8.7 Hz, 4H), 4.04 - 3.95 (m, 3H), 3.90 (br d, J = 10.1 Hz, 3H), 3.84 (br s, 4H), 3.80 (br s, 5H), 3.78 - 3.61 (m, 5H), 3.53 (br d, J = 6.2 Hz, 7H), 3.30 - 3.20 (m, 5H), 3.20 - 2.89 (m, 10H), 2.50 (br t, J = 7.2 Hz, 4H), 1.67 (br s, 4H), 1.42 (d, J = 6.5 Hz, 16H), 1.33 (br s, 20H), 1.25 (br d, J = 5.7 Hz, 4H).

[0596] [Example 5] 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)

[0597] [Chemical formula]

[0598] LCMS (ES, m / z): 596.6 [M / 2+H] + 1 H NMR (400 MHz, methanol-d4) δ = 7.95 (br s, 2H), 7.28 (br s, 4H), 7.08 (br s, 4H), 4.82 - 4.31 (m, 6H), 4.12 - 3.67 (m, 24H), 3.60 (br s, 4H), 3.35 (br s, 4H), 3.30 - 2.87 (m, 12H), 1.50 - 1.24 (m, 24H).

[0599] [Example 6] 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)

[0600] [Chemical Structure]

[0601] LCMS (ES, m / z): 618.6 [M / 2+H] + 11H NMR (400 MHz, 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 = 13.4 Hz, 4H), 3.20 - 2.84 (m, 10H), 1.42 (d, J = 6.4 Hz, 12H), 1.36 - 1.23 (m, 12H).

[0602] [Example 7] 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)

[0603] [Chemical formula]

[0604] LCMS (ES, m / z): 604.6 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.52 (s, 2H), 8.14 (br d, J = 4.4 Hz, 2H), 7.24 - 7.16 (m, 4H), 7.16 - 7.09 (m, 2H), 7.00 (q, J = 7.6 Hz, 6H), 3.92 - 3.83 (m, 3H), 3.80 (br d, J = 10.3 Hz, 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 = 3.8 Hz, 1H), 2.18 - 1.98 (m, 4H), 1.36 (br d, J = 15.5 Hz, 12H), 1.25 (br d, J = 5.9 Hz, 6H), 1.03 - 0.94 (m, 6H).

[0605] [Example 8] 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)

[0606] [Chemical Structure]

[0607] LCMS (ES, m / z): 620.6 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.54 (s, 2H), 8.15 (br t, J = 8.0 Hz, 2H), 7.24 - 7.16 (m, 4H), 7.04 - 6.89 (m, 8H), 4.75 (br d, J = 4.8 Hz, 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 = 5.6 Hz, 12H), 1.21 (br s, 6H), 1.07 - 0.95 (m, 6H).

[0608] [Example 9] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-Isophthaloyl 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)

[0609] [Chemical Structure]

[0610] LCMS (ES, m / z): 590.5 [M / 2+H] + 11H NMR (400 MHz, 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 = 7.3 Hz, 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).

[0611] [Example 10] 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)

[0612] [Chemical formula]

[0613] LCMS (ES, m / z): 604.6 [M / 2+H] + 11H NMR (400 MHz, 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 = 6.0 Hz, 7H), 1.20 (br d, J = 4.0 Hz, 3H), 1.12 (s, 2H), 1.00 - 0.92 (m, 6H).

[0614] [Example 11] 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)

[0615] [Chemical Structure Diagram]

[0616] LCMS (ES, m / z): 620.6 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.49 (s, 2H), 8.26 - 8.13 (m, 2H), 7.22 (br d, J = 4.9 Hz, 4H), 7.09 - 6.89 (m, 5H), 6.51 - 6.21 (m, 3H), 4.68 (br d, J = 9.0 Hz, 4H), 4.04 - 3.42 (m, 19H), 3.30 - 3.18 (m, 6H), 3.15 - 2.87 (m, 11H), 2.73 (br t, J = 11.9 Hz, 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 = 6.4 Hz, 6H), 1.11 - 0.97 (m, 6H).

[0617] [Example 12] 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)

[0618] [Chemical Structure Diagram]

[0619] LCMS (ES, m / z): 604.6 [M / 2+H] + 11H 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).

[0620] [Example 13] 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)

[0621] [Chemical Structure]

[0622] LCMS (ES, m / z): 620.6 [M / 2+H] + 11H 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).

[0623] [Example 14] 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)

[0624] [Chemical Structure]

[0625] LCMS (ES, m / z): 616.5 [M / 2+H] + 11H NMR (400 MHz, 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 = 15.4 Hz, 2H), 7.05 - 6.95 (m, 4H), 3.91 - 3.77 (m, 16H), 3.47 (br s, 3H), 3.38 (br d, J = 11.7 Hz, 2H), 3.30 - 3.10 (m, 4H), 3.08 - 2.91 (m, 9H), 2.79 (br t, J = 11.9 Hz, 2H), 2.50 (br s, 2H), 2.32 - 2.04 (m, 4H), 1.40 (d, J = 5.3 Hz, 12H), 1.27 (d, J = 6.4 Hz, 6H), 1.07 (br d, J = 2.4 Hz, 6H).

[0626] [Example 15] 1,1'-(2,2'-(((3R,3'R,6R,6'R)-(((2R,2'R)-(2,2'-(methylazanediyl)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)

[0627] [Chemical Structure]

[0628] LCMS (ES, m / z): 581.0 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.01 (s, 2H), 7.26 (dd, J = 5.6, 8.0 Hz, 4H), 7.06 (t, J = 8.8 Hz, 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 = 6.0 Hz, 12H), 1.37 - 1.21 (m, 12H).

[0629] [Example 16] 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)

[0630] [Chemical Structure]

[0631] LCMS (ES, m / z): 591.5 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.78 (d, J = 4.4 Hz, 2H), 8.47 (s, 2H), 8.16 - 8.10 (m, 2H), 7.21 (ddd, J = 5.5, 8.5, 11.8 Hz, 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, 14.2 Hz, 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 = 11.7 Hz, 2H), 2.64 (br s, 1H), 2.48 (br d, J = 5.1 Hz, 1H), 2.31 - 2.08 (m, 4H), 1.39 (s, 12H), 1.26 (dd, J = 2.3, 6.1 Hz, 6H), 1.11 (br d, J = 6.2 Hz, 3H), 0.97 (br d, J = 6.2 Hz, 3H).

[0632] [Example 17] 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)

[0633] [Chemical formula]

[0634] LCMS (ES, m / z): 629.7 [M / 2+H] + 11H NMR (400 MHz, 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), 4.83 - 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).

[0635] [Example 18] 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)

[0636] [Chemical Structure]

[0637] LCMS (ES, m / z): 615.5 [M / 2+H] + 11H NMR (400 MHz, 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 = 6.0 Hz, 6H), 1.19 - 1.11 (m, 3H), 0.85 (br d, J = 3.8 Hz, 3H).

[0638] [Example 19] 1,1'-(2,2'-(((3R,3'R,6R,6'R)-(((2R,2'R)-terephthaloyl 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)

[0639] [Chemical Structure]

[0640] LCMS (ES, m / z): 590.6 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.53 (s, 2H), 8.12 (br s, 2H), 7.40 (br s, 4H), 7.19 (br d, J = 12.2 Hz, 4H), 7.04 - 6.87 (m, 4H), 4.01 - 3.68 (m, 14H), 3.53 - 3.32 (m, 5H), 3.22 (br d, J = 6.5 Hz, 4H), 3.13 (br dd, J = 2.6, 4.1 Hz, 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 = 6.0 Hz, 6H), 1.12 (br d, J = 3.5 Hz, 3H), 0.90 (br s, 3H).

[0641] [Example 20] 1,1'-(2,2'-(((3R,3'R,6R,6'R)-(((2R,2'R)-(4,4'-((E)-ethene-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)

[0642] [Chemical formula]

[0643] LCMS (ES, m / z): 641.6 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.51 (s, 2H), 8.08 (br s, 2H), 7.68 (d, J = 8.2 Hz, 4H), 7.38 - 7.29 (m, 6H), 7.26 - 6.81 (m, 8H), 4.08 - 3.70 (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 = 11.8 Hz, 2H), 2.61 - 2.41 (m, 2H), 2.34 - 2.06 (m, 4H), 1.41 (d, J = 8.8 Hz, 12H), 1.25 (d, J = 6.4 Hz, 6H), 1.19 - 0.84 (m, 6H).

[0644] [Example 21] 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

[0645] [Chemical Structure]

[0646] LCMS (ES, m / z): 566.6 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.46 (br s, 2H), 8.16 (br s, 2H), 7.28 - 7.19 (m, 4H), 7.00 (br t, J = 8.2 Hz, 4H), 3.91 - 3.60 (m, 16H), 3.49 (br d, J = 1.8 Hz, 3H), 3.34 (br s, 1H), 3.28 (br d, J = 6.2 Hz, 3H), 3.08 - 2.86 (m, 11H), 2.76 (br t, J = 11.7 Hz, 2H), 2.64 - 2.38 (m, 6H), 2.25 - 2.03 (m, 4H), 1.38 (s, 12H), 1.26 (d, J = 6.4 Hz, 6H), 1.10 - 0.97 (m, 6H).

[0647] [Example 22] 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

[0648] [Chemical Structure]

[0649] LCMS (ES, m / z): 573.6 [M / 2+H] + 11H NMR (400 MHz, 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 (br s, 2H), 1.39 (br d, J = 4.0 Hz, 6H), 1.36 - 1.25 (m, 12H), 1.06 (br t, J = 5.7 Hz, 3H), 0.98 (br t, J = 7.3 Hz, 3H).

[0650] [Example 23] 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)

[0651] [Chemical Structure]

[0652] LCMS (ES, m / z): 629.5 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.77 (br d, J = 4.3 Hz, 2H), 8.53 (br s, 2H), 8.34 (br s, 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 = 8.1 Hz, 2H), 6.83 (br t, J = 8.3 Hz, 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 = 12.6 Hz, 3H), 1.47 - 1.34 (m, 12H), 1.22 (br s, 6H), 1.14 (br d, J = 5.8 Hz, 3H), 0.91 (br s, 3H).

[0653] Scheme 2: General method for Examples 24 - 28.

[0654] [Chemical Structure]

[0655] [Example 24] 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)).

[0656] [Chemical Structure]

[0657] Step 1 of 2: Synthesis 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).

[0658] CH 3 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) (149 mg, 202 μmol, 2.2 eq), 1,8-dibromooctane (25 mg, 91.9 μmol, 17.0 μL, 1 eq), KI (30.5 mg, 184 μmol, 2 eq) and DIEA (47.5 mg, 367 μmol, 64.0 μL, 4 eq) in CN (3 mL) was stirred at 45 °C for 24 h. Then LCMS indicated complete conversion to the product of the target mass. 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 title compound (86 mg, 54.1 μmol, 58.9% yield) as a yellow oil. LCMS (ES, m / z): 1589.1 [M+H] +

[0659] Step 2 of 2: Synthesis of 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)).

[0660] 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 μmol, 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 product of the target mass. The mixture was filtered to give the crude product. This material was purified by preparative HPLC (FA conditions; column: Phenomenex Luna C18 200×40 mm×10 μm; mobile phase: [water (0.2% FA)-ACN]; B%: 10% - 50%, 8 min) to afford the title compound (28.6 mg, 22.8 μmol, yield 42.2%, purity 100%, 2FA) as a white solid. LCMS (ES, m / z): 580.6 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.52 (br s, 2H), 8.38 (s, 2H), 7.34 (dd, J = 5.6, 7.9 Hz, 4H), 6.98 (t, J = 8.6 Hz, 4H), 4.20 (br d, J = 18.1 Hz, 2H), 4.00 (d, J = 14.2 Hz, 2H), 3.93 - 3.79 (m, 4H), 3.78 - 3.64 (m, 4H), 3.56 (br d, J = 17.6 Hz, 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 = 3.5 Hz, 2H), 2.39 - 2.09 (m, 4H), 2.08 - 1.76 (m, 9H), 1.52 (d, J = 19.8 Hz, 12H), 1.27 (br d, J = 6.3 Hz, 6H), 1.12 (br d, J = 5.8 Hz, 8H), 1.03 - 0.72 (m, 10H).

[0661] Examples 25 to 28 were prepared according to the same procedure as Example 24, in which 1,8-dibromooctane was replaced with an appropriate dibromide. The compounds of Examples 25 to 28 were found to have the characterization data specified below.

[0662] [Example 25] 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)

[0663] [Chemical Structure]

[0664] LCMS (ES, m / z): 594.7 [M / 2+H] + 1 H NMR (400 MHz, methanol-d4) δ = 8.54 (s, 2H), 8.28 (s, 2H), 7.37 - 7.25 (m, 4H), 6.99 (t, J = 8.8 Hz, 4H), 4.07 (br d, J = 17.4 Hz, 2H), 3.97 - 3.60 (m, 12H), 3.23 - 2.89 (m, 12H), 2.75 - 2.48 (m, 6H), 2.36 - 1.70 (m, 14H), 1.50 (s, 6H), 1.43 (s, 6H), 1.40 - 1.34 (m, 1H), 1.27 - 1.03 (m, 27H).

[0665] [Example 26] 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)

[0666] [Chemical formula]

[0667] LCMS (ES, m / z): 608.7 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.50 (s, 2H), 8.21 (s, 2H), 7.28 (dd, J = 5.5, 8.4 Hz, 4H), 7.00 (t, J = 8.8 Hz, 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 = 9.1 Hz, 4H), 3.18 - 3.03 (m, 6H), 2.97 (br d, J = 10.1 Hz, 6H), 2.75 (br t, J = 10.8 Hz, 2H), 2.56 - 1.93 (m, 14H), 1.48 - 1.34 (m, 14H), 1.32 - 1.06 (m, 30H).

[0668] [Example 27] 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)

[0669] [Chemical Structure Diagram]

[0670] LCMS (ES, m / z): 576.5 [M / 2+H] + 11H NMR (400 MHz, 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 = 13.1 Hz, 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 = 6.2 Hz, 6H).

[0671] [Example 28] 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)

[0672] [Chemical Structure Diagram]

[0673] LCMS (ES, m / z): 612.5 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.51 (s, 2H), 8.25 (s, 2H), 7.33 (dd, J = 5.5, 8.4 Hz, 4H), 7.02 (br t, J = 8.8 Hz, 4H), 4.58 - 4.52 (m, 2H), 4.16 (br d, J = 17.6 Hz, 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 = 7.4 Hz, 2H), 1.99 - 1.59 (m, 8H), 1.43 (s, 5H), 1.25 (br d, J = 6.4 Hz, 6H), 1.16 - 0.98 (m, 11H).

[0674] Scheme 3: General method for Examples 29 - 30.

[0675]

Chemical Structure

[0676] [Example 29] 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).

[0677]

Chemical Structure

[0678] Step 1 of 2: Synthesis 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).

[0679] 4-(4-Chlorosulfonylphenyl)benzenesulfonyl chloride (21.6 mg, 61.5 μmol, 1 eq) 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) (100 mg, 135 μmol, 2.2 eq) and DIEA (39.7 mg, 307 μmol, 53.5 μL, 5 eq) in DCM (2 mL) at 15 °C. The mixture was stirred at 35 °C for 2 h, after which LCMS indicated complete conversion to the product of the target mass. The mixture was concentrated to dryness, and the crude product was purified by preparative TLC (SiO 2 , petroleum ether / ethyl acetate = 1:2) to give the title compound (85 mg, 48.4 μmol, 78.7% yield) as a yellow solid. LCMS (ES, m / z): 1757.0 [M+H] +

[0680] Step 2 of 2: Synthesis of 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).

[0681] 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 μmol, 1 eq) in HCl / EtOAc (3 M, 2 mL) was stirred at 15 °C for 1 h, and then LCMS indicated complete conversion to the product of the target mass. The precipitate was filtered off, and the filter cake was dried to give the title compound (28.1 mg, 19.8 μmol, yield 41%, purity 98%, 2HCl) as a white solid. LCMS (ES, m / z): 1327.6 [M+H] + 1 1H 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).

[0682] Example 30 was prepared according to the same procedure as Example 29, in which 4-(4-chlorosulfonylphenyl)benzenesulfonyl chloride was replaced with 4,4'-oxydibenzenesulfonyl chloride, and Example 30 was found to have the characterization data specified below.

[0683] [Example 30] 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)

[0684] [Chemical formula]

[0685] LCMS (ES, m / z): 1343.7 [M+H] + 1 1H NMR (400 MHz, methanol-d4) δppm 8.04 (br s, 2H) 7.88 (br d, J = 2.50 Hz, 4H) 7.18 (br s, 8H) 6.98 (br t, J = 8.25 Hz, 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 = 6.00 Hz, 18H) 1.35 (br d, J = 6.00 Hz, 6H)

[0686] Scheme 4: General method for Examples 31 to 34.

[0687] [Chemical formula]

[0688] [Example 31] 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.

[0689] [Chemical formula]

[0690] Step 1 of 2 steps: Synthesis of di-tert-butyl 5,5'-(((2R,2'R)-tetradecanedioylbis(2-methylpiperazine-4,1-diyl))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).

[0691] HATU (102 mg, 267 μmol, 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 μmol, 2.2 eq), tetradecanedioic acid (27.6 mg, 107 μmol, 1 eq) and DIEA (55.2 mg, 427 μmol, 74.3 μL, 4 eq) in DCM (2 mL) at 15 °C. The mixture was stirred at 35 °C for 12 h, after which LCMS indicated conversion to the product of the target mass. 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 150×30 mm×5 μm; mobile phase: [water (0.1% TFA)-MeOH]; B%: 62% - 85%, 10 min) to afford the title compound (45 mg, 30.0 μmol, yield 28.1%) as a white solid. LCMS (ES, m / z): 750.9 [M / 2+H] +

[0692] Step 2 of 2 steps: Synthesis of 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.

[0693] 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 μmol, 1 eq) in EtOAc was treated with HCl / EtOAc (4 M, 2 mL), stirred at 15 °C for 1 h, and then LCMS indicated conversion to the product of the target mass. The precipitate was filtered off and the filter cake was dried to obtain the crude product. The material was purified by preparative HPLC (TFA conditions; column: Phenomenex Gemini-NX 150 mm × 30 mm × 5 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 25% - 45%, 12 min) to give the title compound (19.2 mg, 12.3 μmol, yield 41.1%, purity 98%, 2TFA) as a white solid. LCMS (ES, m / z): 650.6 [M / 2+H] + 1 H NMR (400 MHz, methanol-d 4 ) δppm 8.00 - 8.13 (m, 2H) 7.24 (dd, J = 7.75, 5.75 Hz, 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 = 12.76 Hz, 4H) 1.54 (d, J = 5.00 Hz, 12H) 1.24 - 1.39 (m, 27H) 1.20 (br s, 2H)

[0694] Examples 32 to 34 were prepared according to the same procedure as Example 31, in which tetradecanedioic acid was replaced with an appropriate bis-carboxylic acid. The compounds of Examples 32 to 34 were found to have the characterization data specified below.

[0695] [Example 32] 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

[0696] [Chemical formula]

[0697] LCMS (ES, m / z): 1187.8 [M+H] + 1 H NMR (400 MHz, methanol-d 4 ) δ = 8.02 (br d, J = 4.5 Hz, 2H), 7.26 - 7.22 (m, 4H), 7.02 (br t, J = 8.6 Hz, 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 = 4.6 Hz, 3H)

[0698] [Example 33] 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

[0699]

Chem.

[0700] LCMS (ES, m / z): 1215.9 [M / 2+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.11 (br s, 2 H) 9.36 - 9.73 (m, 2 H) 8.01 (br d, J = 3.50 Hz, 2 H) 7.26 (dd, J = 8.25, 5.75 Hz, 4 H) 6.98 - 7.15 (m, 4 H) 3.81 - 3.97 (m, 11 H) 3.58 - 3.78 (m, 20 H) 3.53 (s, 6 H) 2.85 - 3.21 (m, 11 H) 2.40 (br s, 4 H) 1.53 (br s, 4 H) 1.43 (s, 12 H) 1.16 - 1.37 (m, 16 H).

[0701] [Example 34] 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

[0702]

Chem.

[0703] LCMS (ES, m / z): 622.7 [M / 2+H] + 1 1H NMR (400 MHz, methanol-d 4 ) δ ppm 7.89 - 8.11 (m, 2 H) 7.18 - 7.31 (m, 4 H) 7.02 (br t, J = 8.50 Hz, 4 H) 4.41 - 4.72 (m, 2 H) 4.10 - 4.33 (m, 2 H) 3.77 - 4.09 (m, 14 H) 3.70 (s, 8 H) 3.59 (br s, 3 H) 3.34 - 3.49 (m, 4 H) 2.84 - 3.29 (m, 14 H) 2.54 (br s, 4 H) 1.70 (br s, 4 H) 1.57 (d, J = 6.50 Hz, 12 H) 1.26 - 1.48 (m, 21 H).

[0704] Scheme 5: General method for Examples 35 - 36.

[0705] [Chemical Structure Diagram]

[0706] [Example 35] 2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-Isophthaloyl 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).

[0707] [Chemical Structure Diagram]

[0708] Step 1 of 2: Synthesis of di-tert-butyl 5,5’-(((2R,2’R)-isophthaloyl bis(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).

[0709] Methylsulfonyl chloride (290 mg, 2.53 mmol) was added at 0 °C 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). The solution was warmed to room temperature and stirred overnight under a nitrogen atmosphere. The mixture was partitioned between aqueous ammonium chloride solution and dichloromethane, the organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum / ethyl acetate (1:1) to give the intermediate (500 mg, 0.917 mmol, 63.7% yield) as a white solid.

[0710] To a solution of the intermediate product (150 mg, 0.275 mmol) and 1,3-phenylenebis(((R)-3-methylpiperazin-1-yl)methanone) dihydrochloride (bis-amine intermediate A-017) (55.5 mg, 0.138 mmol) in acetonitrile (20 mL) were added potassium iodide (91.4 mg, 0.550 mmol) and potassium carbonate (152 mg, 1.101 mmol). 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 combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The crude product was purified by preparative TLC (petroleum ether / ethyl acetate = 1:3) and then preparative HPLC (column: Phenomenex Gemini C-18 150 mm × 21.2 mm × 5 μm; mobile phase: [water-ACN]; B%: 5% - 50%, 10 min) to give the title compound (50 mg, 0.037 mmol, 26.9% yield) as a colorless oil. LCMS (ES, m / z): 673.9 [M / 2+H] +

[0711] Step 2 of 2 steps: Synthesis of 2,2'-((3R,3'R,6R,6'R)-(((2R,2'R)-isophthaloyl 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).

[0712] A solution of di-tert-butyl 5,5'-(((2R,2'R)-isophthaloyl bis(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 in vacuo to give the title compound (10.5 mg, 0.008 mmol, 23.3% yield, 2HCl) as a white solid. LCMS (ES, m / z): 1147.5 [M+H] + . 1 H NMR (400 MHz, 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).

[0713] Example 36 was prepared according to the same procedure as Example 35, replacing 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 set forth below.

[0714] [Example 36] 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)

[0715]

Chem.

[0716] LCMS (ES, m / z): 609.8 [M / 2+H] + 1 H NMR (400 MHz, DMSO) δ ppm δ 10.10 (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).

[0717] Scheme 6: General method for Examples 37 - 42.

[0718]

Chem.

[0719] [Example 37] 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.

[0720]

Chem.

[0721] Step 1 of 2 steps: Synthesis of di-tert-butyl 5,5'-(((3S,3'S)-(adipoylbis(azanediyl))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).

[0722] 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 μmol, 2.2 eq), adipic acid (13.5 mg, 92.3 μmol, 15.3 μL, 1 eq) in DCM (2 mL), DIEA (47.7 mg, 369 μmol, 64.3 μL, 4 eq) and HATU (87.7 mg, 231 μmol, 2.5 eq) were added. The mixture was stirred at 30 °C for 12 h, after which LCMS indicated conversion to the product of the target mass. The reaction was concentrated in vacuo and the residue was purified by preparative TLC (SiO 2 , ethyl acetate / methanol = 10:1) to give the title compound (90 mg, 56.7 μmol, 61.4% yield) as a yellow oil. TLC (ethyl acetate / methanol = 10:1) R f = 0.43 LCMS (ES, m / z): 1589.0 [M+H] +

[0723] Step 2 of 2: Synthesis of 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.

[0724] To a solution of di-tert-butyl 5,5'-(((3S,3'S)-(adipoylbis(azanediyl))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 μmol, 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, and then LCMS indicated complete conversion to the product of the target mass. The reaction mixture was filtered to obtain the crude product. The crude material was purified by preparative HPLC (TFA conditions; column: Phenomenex Luna C18 100×30 mm×5 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 10% - 30%, 10 min) to give the title compound (24.1 mg, 17.3 μmol, yield 30.4%, purity 99.3%, 2TFA) as a white solid. LCMS (ES, m / z): 580.6 [M / 2+H] + 1 1H NMR (400 MHz, methanol-d 4) δ = 8.15 (s, 2H), 7.23 (dd, J = 5.5, 8.6 Hz, 4H), 6.98 (t, J = 8.8 Hz, 4H), 4.01 (br d, J = 11.0 Hz, 3H), 3.89 (br d, J = 10.5 Hz, 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 = 11.4 Hz, 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 = 4.4 Hz, 12H), 1.29 (br d, J = 6.6 Hz, 6H).

[0725] Examples 38 - 42 were prepared according to the same procedure as Example 37, in which adipic acid was replaced with an appropriate bis - carboxylic acid. The compounds of Examples 38 - 42 were found to have the characterization data specified below.

[0726] [Example 38] 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)octanediamide

[0727] [Chemical Structure]

[0728] LCMS (ES, m / z): 594.6 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.16 (s, 2H), 7.24 (dd, J = 5.5, 8.6 Hz, 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 (br s, 2H), 3.48 (br d, J = 3.1 Hz, 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 = 4.8 Hz, 12H), 1.29 (br d, J = 6.1 Hz, 10H).

[0729] [Example 39] 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)decanediamide

[0730] [Chemical formula]

[0731] LCMS (ES, m / z): 608.6 [M / 2+H] + 11H 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).

[0732] [Example 40] 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

[0733] [Chemical formula]

[0734] LCMS (ES, m / z): 636.7 [M / 2+H] + 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).

[0735] [Example 41] 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)

[0736] [Chemical Structure]

[0737] LCMS (ES, m / z): 604.6 [M / 2+H] + 11H 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).

[0738] [Example 42] 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)

[0739] [Chemical Structure]

[0740] LCMS (ES, m / z): 604.6 [M / 2+H] + 11H NMR (400 MHz, 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 = 10.6 Hz, 2H), 3.87 (br d, J = 11.0 Hz, 4H), 3.80 - 3.73 (m, 7H), 3.67 (br s, 5H), 3.54 - 3.37 (m, 9H), 3.16 (br d, J = 19.6 Hz, 12H), 3.03 - 2.58 (m, 3H), 2.17 - 1.90 (m, 5H), 1.81 - 1.47 (m, 5H), 1.42 (d, J = 5.4 Hz, 12H), 1.28 (br d, J = 5.5 Hz, 6H).

[0741] Scheme 7: General method for Examples 43 - 48.

[0742] [Chemical Structure]

[0743] [Example 43] 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.

[0744] [Chemical Structure]

[0745] Step 1 of 2: Synthesis of di-tert-butyl 5,5'-(((3R,3'R)-(adipoylbis(azanediyl))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).

[0746] 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 μmol, 2.3 eq), adipic acid (10.3 mg, 70.6 μmol, 11.7 μL, 1 eq) in DCM (3 mL), DIEA (36.5 mg, 282 μmol, 49.2 μL, 4 eq) and HATU (67.1 mg, 177 μmol, 2.5 eq) were added. The mixture was stirred at 15 °C for 2 h, after which LCMS indicated conversion to the product of the target mass. The reaction was concentrated in vacuo and the residue was purified by preparative TLC (SiO 2 , ethyl acetate / methanol = 10:1) to afford the title compound (110 mg, 69.2 μmol, 98% yield) as a yellow oil. LCMS (ES, m / z): 1588.6 [M+H] +

[0747] Step 2 of 2: Synthesis of 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.

[0748] To a solution of di-tert-butyl 5,5'-(((3R,3'R)-(adipoylbis(azanediyl))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 μmol, 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, and then LCMS indicated complete conversion to the product of the target mass. The reaction mixture was filtered to obtain the crude product. The crude material was purified by preparative HPLC (FA conditions; column: Phenomenex Luna C18 100×30 mm×5 μm; mobile phase: [water (0.2% FA)-ACN]; B%: 5% - 35%, 9 min) to give the title compound (9.4 mg, 7.37 μmol, yield 10.64%, purity 98%, 2FA) as a white solid. LCMS (ES, m / z): 580.6 [M / 2+H] + 1 H NMR (400 MHz, methanol-d4) δ = 8.46 (s, 2H), 7.23 (br t, J = 6.4 Hz, 4H), 7.03 - 6.93 (m, 4H), 3.96 - 3.62 (m, 13H), 3.50 (br d, J = 17.1 Hz, 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 = 4.4 Hz, 12H), 1.37 - 1.32 (m, 2H), 1.25 (br d, J = 6.1 Hz, 6H), 1.20 - 1.12 (m, 2H).

[0749] Examples 44 to 48 were prepared according to the same procedure as Example 43, in which adipic acid was replaced with an appropriate bis-carboxylic acid. The compounds of Examples 44 to 48 were found to have the characterization data specified below.

[0750] [Example 44] 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)octanediamide

[0751] [Chemical formula]

[0752] LCMS (ES, m / z): 594.6 [M / 2+H] + 1 1H 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).

[0753] [Example 45] 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)decanediamide

[0754] [Chemical Structure]

[0755] LCMS (ES, m / z): 608.6 [M / 2+H] + 1 H 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).

[0756] [Example 46] 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

[0757] [Chemistry]

[0758] LCMS (ES, m / z): 636.7 [M / 2+H] + 1 1H 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).

[0759] [Example 47] 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)

[0760] [Chemistry]

[0761] LCMS (ES, m / z): 604.6 [M / 2+H] + 1 H NMR (400 MHz, methanol-d4) δ = 8.42 (s, 2H), 8.25 (s, 2H), 7.24 - 7.11 (m, 8H), 6.96 (br t, J = 8.1 Hz, 4H), 3.95 - 3.61 (m, 14H), 3.51 (br d, J = 16.2 Hz, 2H), 3.42 (s, 4H), 3.26 (br d, J = 13.6 Hz, 6H), 3.06 - 2.91 (m, 4H), 2.90 - 2.50 (m, 10H), 2.14 (br d, J = 11.4 Hz, 2H), 1.95 (br s, 2H), 1.74 (br s, 2H), 1.62 (br d, J = 12.7 Hz, 2H), 1.38 (br d, J = 4.8 Hz, 12H), 1.24 (br d, J = 5.7 Hz, 6H), 1.19 (br d, J = 11.4 Hz, 2H).

[0762] [Example 48] 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)

[0763] [Chemical Structure]

[0764] LCMS (ES, m / z): 604.5 [M / 2+H] + 11H NMR (400 MHz, 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 = 4.8 Hz, 13H), 1.33 (br d, J = 6.1 Hz, 6H).

[0765] Scheme 8: General method for Examples 49 - 113.

[0766] [Chemical Structure]

[0767] [Example 49] 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).

[0768] [Chemical Structure]

[0769] Step 1 of 2: Synthesis 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).

[0770] 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 μL, 2.5 eq) in DCM (10 mL) was added dropwise MsCl (167 mg, 1.46 mmol, 113 μL, 1.2 eq) 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 complete conversion of the starting material to the new product. Water (60 mL) was added to the mixture, which was then extracted with DCM (30 mL × 2). The combined organic phases were washed with brine (60 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give the intermediate (820 mg, crude) as a yellow oil.

[0771] A solution of the intermediate product (198 mg, 293 μmol, 2 eq) in MeCN (5 mL), 1,2-bis((((S)-morpholin-2-yl)methoxy)methyl)benzene (Linker_D-147) (60 mg, 147 μmol, 1 eq, 2HCl) and DIEA (94.7 mg, 733 μmol, 128 μL, 5 eq) was added to KI (48.7 mg, 293 μmol, 2 eq). The mixture was stirred at 80 °C for 12 h, and then LCMS indicated the formation of the product of the 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. LCMS (ES, m / z): 1614.1 [M+H] +

[0772] Step 2 of 2 steps: Synthesis of 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).

[0773] 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 μmol, 1 eq) in EtOAc (1.5 mL) was added with HCl / EtOAc (4 M, 1.5 mL) at 15 °C. The mixture was stirred at 15 °C for 2 h, and then LCMS indicated the complete consumption of the starting material and the formation of the product of the target mass. The mixture was filtered and the filter cake was dried to obtain the crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18, 75×30 mm×3 μm; mobile phase: [water (0.04% HCl)-ACN]; B%: 5% - 35%, 9 min) to give the title compound (25.3 mg, 20.1 μmol, yield 29.5%, purity 100%, 2HCl) as a white solid. LCMS (ES, m / z): 593.5 [M / 2+H] + 1 H NMR (400 MHz, methanol-d4) δ = 7.98 (s, 2H), 7.33 (br dd, J = 3.7, 5.2 Hz, 2H), 7.23 (dd, J = 3.4, 5.5 Hz, 2H), 7.17 (dd, J = 5.6, 8.3 Hz, 4H), 7.01 (t, J = 8.7 Hz, 4H), 4.70 - 4.56 (m, 4H), 4.18 (br d, J = 12.1 Hz, 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 = 6.5 Hz, 6H).

[0774] Examples 50 to 113 were prepared according to the same procedure as Example 49, in which 1,2-bis((((S)-morpholin-2-yl)methoxy)methyl)benzene was replaced with an appropriate bis-amine linker. The compounds of Examples 50 to 113 were found to have the characterization data specified below.

[0775] [Example 50] 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)

[0776] [Chemical Structure]

[0777] LCMS (ES, m / z): 617.6 [M / 2+H] + 1 H NMR (400 MHz, methanol-d 4) δ = 8.54 (br s, 1H), 8.22 (s, 2H), 7.37 (br d, J = 8.6 Hz, 4H), 7.23 (dd, J = 5.6, 8.2 Hz, 4H), 6.97 (t, J = 8.7 Hz, 4H), 6.80 (br d, J = 8.8 Hz, 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 = 13.6 Hz, 2H), 2.06 - 1.92 (m, 4H), 1.36 (s, 12H), 1.18 (br d, J = 6.5 Hz, 6H).

[0778] [Example 51] 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)

[0779] [Chemical Structure]

[0780] LCMS (ES, m / z): 617.5 [M / 2+H] + 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).

[0781] [Example 52] 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)

[0782] [Chemical Structure]

[0783] LCMS (ES, m / z): 617.5 [M / 2+H] + 1 H 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).

[0784] [Example 53] 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)

[0785] [Chemical Structure]

[0786] LCMS (ES, m / z): 624.5 [M / 2+H] + 1 H NMR (400 MHz, methanol-d 4) δ ppm 8.53 (s, 2 H) 8.15 (s, 2 H) 7.19 (br dd, J = 8.03, 5.52 Hz, 4 H) 6.89 - 7.06 (m, 8 H) 6.72 (br d, J = 8.53 Hz, 4 H) 3.66 - 3.95 (m, 21 H) 3.54 - 3.62 (m, 2 H) 3.35 - 3.44 (m, 4 H) 3.22 (br d, J = 10.04 Hz, 4 H) 2.97 (br d, J = 5.02 Hz, 4 H) 2.59 - 2.87 (m, 8 H) 2.16 (br d, J = 11.04 Hz, 2 H) 1.88 - 2.06 (m, 4 H) 1.36 (br d, J = 3.01 Hz, 11 H) 1.24 (br d, J = 6.53 Hz, 6 H).

[0787] [Example 54] 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)

[0788] [Chemical Structure]

[0789] LCMS (ES, m / z): 631.5 [M / 2+H] + 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).

[0790] [Example 55] 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)

[0791] [Chemical Structure]

[0792] LCMS (ES, m / z): 625.6 [M / 2+H] + 1 1H NMR (400 MHz, methanol-d 4) δ = 8.55 (s, 1H), 8.18 (s, 1H), 7.21 (br dd, J = 5.5, 8.3 Hz, 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 = 10.3 Hz, 2H), 3.22 - 3.07 (m, 4H), 2.98 - 2.74 (m, 8H), 2.74 - 2.59 (m, 4H), 2.14 (br d, J = 11.3 Hz, 2H), 2.05 - 1.91 (m, 4H), 1.38 (br d, J = 2.5 Hz, 12H), 1.20 (br d, J = 6.4 Hz, 6H).

[0793] [Example 56] 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)

[0794] [Chemical formula]

[0795] LCMS (ES, m / z): 638.6 [M / 2+H] + 1 1H 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 (br t, 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).

[0796] [Example 57] 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)

[0797] [Chemical Structure]

[0798] LCMS (ES, m / z): 649.5 [M / 2+H] + 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).

[0799] [Example 58] 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)

[0800] [Chemical Structure]

[0801] LCMS (ES, m / z): 631.6 [M / 2+H] + 11H 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 = 9.9 Hz, 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 = 5.3 Hz, 12H), 1.24 (br d, J = 6.1 Hz, 6H).

[0802] [Example 59] 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

[0803] [Chemical Structure]

[0804] LCMS (ES, m / z): 645.6 [M / 2+H] + 1 1H 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).

[0805] [Example 60] 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)

[0806] [Chemical formula]

[0807] LCMS (ES, m / z): 671.5 [M / 2+H] + 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, 8.3 Hz, 2H), 6.45 (t, J = 2.3 Hz, 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), 2.23 - 2.13 (m, 2H), 2.05 - 1.95 (m, 4H), 1.38 (d, J = 2.8 Hz, 12H), 1.25 (d, J = 6.5 Hz, 6H).

[0808] [Example 61] 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)

[0809] [Chemical formula]

[0810] LCMS (ES, m / z): 697.7 [M / 2+H] + 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 = 8.6 Hz, 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 = 6.5 Hz, 6H).

[0811] [Example 62] 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)

[0812] [Chemical Structure]

[0813] LCMS (ES, m / z): 697.6 [M / 2+H] + 11H 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).

[0814] [Example 63] 1,1'-(2,2'-(((3R,3'R,6R,6'R)-(((2S,2'S)-((Hexa-2,4-diyldiylbis(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)

[0815] [Chemical Structure]

[0816] LCMS (ES, m / z): 579.5 [M / 2+H] + 1 1H 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).

[0817] [Example 64] 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)

[0818] [Chemical Structure]

[0819] LCMS (ES, m / z): 583.4 [M / 2+H] + 11H 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 = 6.9 Hz, 4H).

[0820] [Example 65] 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)

[0821] [Chemical Structure]

[0822] LCMS (ES, m / z): 593.5 [M / 2+H] + 11H 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 = 6.5 Hz, 6H).

[0823] [Example 66] 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)

[0824] [Chemical Structure]

[0825] LCMS (ES, m / z): 624.6 [M / 2+H] + 1 1H 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 = 6.4 Hz, 5H).

[0826] [Example 67] 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)

[0827] [Chemical formula]

[0828] LCMS (ES, m / z): 617.6 [M / 2+H] + 1 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 = 10.6 Hz, 4H), 3.22 - 3.12 (m, 4H), 3.10 - 2.91 (m, 6H), 2.75 (br d, J = 11.0 Hz, 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).

[0829] [Example 68] 1,1'-(2,2'-(((3R,3'R,6R,6'R)-(((2S,2'S)-(((Oxydibis(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)

[0830] [Chemical formula]

[0831] LCMS (ES, m / z): 625.5 [M / 2+H] + 1 1H NMR (400 MHz, methanol-d 4) δ = 7.99 - 7.88 (m, 2H), 7.20 - 6.99 (m, 12H), 6.93 (br t, J = 7.6 Hz, 2H), 6.81 - 6.70 (m, 2H), 4.14 (br d, J = 3.9 Hz, 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 = 6.4 Hz, 6H).

[0832] [Example 69] 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)

[0833] [Chemical Structure]

[0834] LCMS (ES, m / z): 1157.7 [M+H] + 1 H NMR (400 MHz, CD 3OD, 297 K) 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).

[0835] [Example 70] 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)

[0836] [Chemical formula]

[0837] LCMS (ES, m / z): 579.5 [M / 2+H] + 11H 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).

[0838] [Example 71] 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)

[0839] [Chemical Structure Diagram]

[0840] LCMS (ES, m / z): 579.6 [M / 2+H] + 11H NMR (400 MHz, methanol-d4) δ = 8.53 (s, 2H), 8.14 (s, 2H), 7.19 (dd, J = 5.5, 8.4 Hz, 4H), 6.96 (t, J = 8.8 Hz, 4H), 6.86 (br d, J = 2.4 Hz, 4H), 3.91 (dd, J = 5.6, 10.4 Hz, 2H), 3.84 - 3.70 (m, 16H), 3.61 - 3.53 (m, 2H), 3.45 (br dd, J = 9.0, 9.9 Hz, 2H), 3.39 - 3.33 (m, 2H), 3.27 - 3.19 (m, 4H), 3.08 - 2.94 (m, 4H), 2.85 - 2.60 (m, 8H), 2.15 (s, 2H), 2.06 - 1.93 (m, 4H), 1.33 (d, J = 15.6 Hz, 12H), 1.26 (d, J = 6.5 Hz, 6H).

[0841] [Example 72] 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)

[0842] [Chemical Structure]

[0843] LCMS (ES, m / z): 588.5 [M / 2+H] + 1 1H 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).

[0844] [Example 73] 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)

[0845] [Chemical Structure]

[0846] LCMS (ES, m / z): 588.6 [M / 2+H] + 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).

[0847] [Example 74] 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)

[0848] [Chemical Structure]

[0849] LCMS (ES, m / z): 597.6 [M / 2+H] + 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).

[0850] [Example 75] 1,1'-(2,2'-((3R,3'R,6R,6'R)-(((2S,2'S)-(((4-Fluoro-1,3-phenylene)bis(oxy))bis(methylene))bis...

Claims

1. Formula (I): 【Chemical 1】 The compound of formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, Each R １ and R ２ is -H or -CH ３ and Each R ３ is -H or -CH ３ and Each R ４ is -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 and Each R ５ is -H, -F, -Cl, -Br, -CH ３ , -CHF ２ or -CF ３ and Each R ６ is -H, -F or -Cl, Each R ７ is -H or -F, Each W is -CH-, -CH ２ -, -O- or -N-, and Each X is -CH ２ -, -O-, -NH- or -NCH ３ - and Each Y １ is -CH- or -C(O)-, Each Y ２ is -N-, -NH- or -NCH ３ -. each [Chemical 2] represents a single bond or a double bond, and Y １ when it is -CH-, Y ２ is -N-, [Chemical Formula 3] represents a double bond, and Y １ is -C(O)-, then Y ２ is -NH- or -NCH ３ -, and 【Chemical 4】 represents a single bond, each Z is -CH-, -CF- or -N-, L is [Chemical Formula 5] [Chemical] [Chemical] 【Chem.】 【Chem.】 【Chem.】 a linker selected from the group consisting of 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, z is an integer from 2 to 15)

2. R in each case １ and R ２ are each —CH ３ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is

3. Each X is -CH ２ -, each Z is -CH-, each R ４ is -H, the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

4. Each Y １ is -C(O)-, and each Y ２ is -NH- or -NCH ３ -, and each 【Chemical Formula 6】 The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 3, wherein

5. 【Fig. 7】 represents a single bond.

6. The compound according to claim 1, wherein the compound is 【Chemical 8】 selected from the group consisting of

7. The compound or a pharmaceutically acceptable salt thereof according to claim 6, wherein L is 【Chemical Formula 9】 【Chem.】 a linker selected from the group consisting of n is an integer from 2 to 12, m is an integer from 1 to 3, p is an integer from 1 to 12.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is 【Chemical 10】 or a pharmaceutically acceptable salt thereof.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein L is 【Chemical Formula 11】 selected from the group consisting of n is an integer from 2 to 8.

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is 【Chemical Formula 12】 selected from the group consisting of

11. The compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein L is 【Chemical 13】 【Chem.】 【Chem.】 【Chem.】 selected from the group consisting of 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, y is an integer from 2 to 8.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is 【Chemical Formula 14】 as defined above.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is 【Chemical Formula 15】 selected from the group consisting of z is an integer from 2 to 8.

14. 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)-isophthaloyl 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-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'-(methylazanediyl))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)-terephthaloyl 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)-(4,4'-((E)-ethene-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)ethane-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)-isophthaloyl 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); 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)decanediamide; 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)decanediamide; 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)-((hexa-2,4-diyldiylbis(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-diyldiylbis(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'-(Hexa-2,4-diyne-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(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); 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(methylazanediyl))bis(methylene))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)); 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(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(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)-((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)-3,3,4-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'-(decane-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]morpholine-2-yl]methoxy]phenoxy]methyl]morpholine-4-yl]methyl]-5-methyl-piperazin-1-yl]ethenone; - [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]morpholine-2-yl]methoxy]phenoxy]methyl]morpholine-4-yl]methyl]-5-methyl-piperazin-1-yl]ethenone; 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]ethenone; 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-(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)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) A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising the 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 the step of administering to the human a therapeutically effective amount 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.

17. 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, for use in the treatment of 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 manufacture of a medicament for treating HIV infection.

19. A method for treating cancer and pre-cancerous syndromes in a human in need thereof, comprising administering to the human a therapeutically effective amount 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.

20. A method for depleting latently HIV-infected cells in a human, comprising administering to the human a therapeutically effective amount 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.

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 pharmaceuticals active against HIV.

22. The combination according to claim 21, wherein the one or more pharmaceuticals active against HIV 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 crotonyltransferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and antibodies for clearance therapy.

23. A method for treating HIV infection in a human, comprising administering to the human a therapeutically effective amount of the combination according to claim 21 or 22.

24. A method for depleting latently HIV-infected cells in a human, comprising administering to the human a therapeutically effective amount of the combination according to claim 21 or 22.

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