[go: up one dir, main page]

WO2025235719A1 - Dimeric smac mimetics useful in hiv therapy - Google Patents

Dimeric smac mimetics useful in hiv therapy

Info

Publication number
WO2025235719A1
WO2025235719A1 PCT/US2025/028330 US2025028330W WO2025235719A1 WO 2025235719 A1 WO2025235719 A1 WO 2025235719A1 US 2025028330 W US2025028330 W US 2025028330W WO 2025235719 A1 WO2025235719 A1 WO 2025235719A1
Authority
WO
WIPO (PCT)
Prior art keywords
bis
oxo
dimethyl
pyridin
methylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/028330
Other languages
French (fr)
Inventor
Christopher J. Aquino
Junghyun Lee Suh
Richard M. Dunham
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of North Carolina at Chapel Hill
ViiV Healthcare Co
Original Assignee
University of North Carolina at Chapel Hill
ViiV Healthcare Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of North Carolina at Chapel Hill, ViiV Healthcare Co filed Critical University of North Carolina at Chapel Hill
Publication of WO2025235719A1 publication Critical patent/WO2025235719A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala

Definitions

  • HAART highly active antiretroviral therapy
  • SMACm Synd Mitochondrial-derived Activator of Caspases mimetics
  • IAPi 15 inhibitors of the Inhibitor of Apoptosis Proteins
  • the drugs deplete and/or inhibit cellular inhibitor of apoptosis proteins (cIAP) that act as anti-apoptotic proteins, thereby promoting the cell death of cancer cells.
  • Antagonism and/or depletion of cIAP also leads to activation of the non-canonical NF-kB signaling pathway, that may induce HIV expression and may enable 20 elimination of HIV infected cells.
  • SMACm/IAPi may selectively promote the cell death of cells infected by HIV [Campbell Cell Host Microbe 2018] or HBV [Ebert Proc Nat Acad Sci 2013] by antagonizing anti-apoptotic proteins.
  • ncNF- ⁇ B non-canonical NF-kB pathway
  • the ncNF- ⁇ B pathway is typically activated by ligation of a 25 subset of TNF receptor family members.
  • a multimolecular 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 ubiquitinylates and degrades the NF- ⁇ B-inducing kinase (NIK).
  • TNF receptor-associated factor 2 TRAF2
  • cIAP1 cellular inhibitor of apoptosis protein-1
  • NIK is constitutively active and, once accumulated, phosphorylates the inhibitor of ⁇ B kinase- ⁇ (IKK ⁇ ) homodimer.
  • ncNF- ⁇ B can be activated by signaling intermediates of the apoptosis cascade.
  • Another aspect of the invention provides a pharmaceutical composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt thereof and a 30 pharmaceutically acceptable excipient.
  • the invention provides a method of treating an HIV infection in a human comprising administering to the human a therapeutically effective amount of a compound according to Formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition comprising a compound according to Formula (I) or a 35 pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the invention provides a use of a compound according to Formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, in the manufacture of a medicament for treating an HIV 5 infection.
  • the invention provides a method of treating cancer and pre- cancerous syndromes, in a human in need thereof, which comprises administering to the human a therapeutically effective amount of a compound according to Formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition comprising a compound 10 according to Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the invention provides a method of depleting HIV infected cells comprising administering to a subject a compound of Formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition comprising a compound according to 15 Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the invention provides a combination comprising a compound of Formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutical agents active against HIV.
  • these pharmaceutical agents active against HIV are selected 20 from the group consisting of anti-retroviral agents, latency reversing agents, and agents for clearance therapy.
  • the invention provides a method of depleting HIV infected cells comprising administering to a subject a compound of Formula (I), or pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition comprising a compound according to 25 Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and one or more additional agents active against HIV.
  • these pharmaceutical agents active against HIV are selected from the group consisting of anti-retroviral agents, latency reversing agents, and agents for clearance therapy.
  • Alkyl refers to a saturated, straight or branched hydrocarbon moiety having from 1 to 6 carbon atoms unless specified otherwise.
  • (C1-C6) alkyl refers to an alkyl moiety containing from 1 to 6 carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, and hexyl.
  • Alkylene refers to a straight or branched chain divalent alkyl radical having from 1 to 6 carbon atoms unless specified otherwise.
  • (C 1 -C 6 ) alkylene refers to an alkylene containing from 1 to 6 carbon atoms.
  • alkylene examples include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like. “Substituted alkylene” refers to an alkylene having from 1 to 5 and, in some embodiments, 10 1 to 3 or 1 to 2 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, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted 15 ary
  • Alkoxy refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms unless specified otherwise.
  • C 1 -C 6 alkoxy means a straight or branched alkoxy group containing from 1 to 6 carbon atoms.
  • alkoxy as used herein include, but are not limited to, methoxy, ethoxy, prop-1-oxy, prop-2-oxy, but-1-oxy, but-2-oxy, 2-methylprop-1-oxy, 2- 30 methylprop-2-oxy, pentoxy and hexyloxy.
  • Aryl or “Ar” refers to an aromatic hydrocarbon ring.
  • Aryl includes monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 15 ring member atoms unless specified otherwise, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms. “Aryl” also includes ring systems wherein the aryl ring, as defined 35 above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of 6 70226WO01 attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • alkoxy examples include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like.
  • 5 “Arylene” refers to a divalent aromatic hydrocarbon ring. “Arylene” includes monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 15 ring member atoms unless specified otherwise, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms.
  • “Arylene” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radicals or 10 points of attachment are on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • arylene as used herein include or are derived from, but are not limited to, phenylene (para, meta, ortho), naphthalene, biphenyl, indole, triazole, and the like.
  • “Substituted arylene” refers to an arylene substituted with 1 to 8 and, in some 15 embodiments, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 substituents selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, quaternary amino, aminocarbonyl, imino, amidino, aminocarbonylamino, amidinocarbonylamino, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, 20 aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxy
  • “Compound” and “compounds” as used herein refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae, including the racemates, stereoisomers, 35 and tautomers of the compound or compounds. 7 70226WO01 “ Cyano” refers to a ⁇ C N functional group. “Cycloalkylene” refers to a non-aromatic, saturated, cyclic divalent hydrocarbon ring containing 3 to 7 member ring atoms unless otherwise specified.
  • Heterocycloalkylene refers to a “cycloalkylene” wherein at least one ring atom is a heteroatom.
  • Examples of “cycloalkylene” as 5 used include or are derived from, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and piperidine.
  • “Substituted cycloalkylene” refers to a cycloalkylene, as defined herein, having from 1 to 8, or 1 to 5, or in some embodiments 1 to 3 substituents selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, 10 acylamino, acyloxy, amino, substituted amino, quaternary amino, aminocarbonyl, imino, amidino, aminocarbonylamino, amidinocarbonylamino, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl,
  • substituted cycloalkyl includes substituted cycloalkenyl groups. It is understood that the above 25 definition is not intended to include impermissible substitution patterns.
  • Halo or halogen refers to a fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br) or iodine (iodo, I).
  • Heteroatom refers to nitrogen, oxygen, or sulfur.
  • Latency means a concept describing 1) the dormant state of viral activity within a 30 population of cells, wherein viral production, viral packaging, and host cell lysis does not occur, or occurs at a very low frequency, or 2) the down-regulation or absence of gene expression within an infected cell.
  • “Optionally” means that the subsequently described event(s) may or may not occur and includes both event(s) that occur and event(s) that do not occur.
  • “Solvate” or “solvates” of a compound refer to those compounds, where compounds is as defined above, that are bound to a stoichiometric or non-stoichiometric amount of a solvent. Solvates of a compound include solvates of all forms of the compound. In some embodiments, solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. 5 Suitable solvents include water. “Stereoisomer” refers to compounds that differ in the chirality of one or more stereocenters.
  • Stereoisomers include enantiomers and diastereomers.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from pharmaceutically acceptable counterions. Suitable salts include those described in P. Heinrich Stahl, Camille G.
  • Reversing HIV latency refers to a treatment that upregulates the expression of integrated HIV genomes within latently infected cells, such as the agent that activates the non-canonical NF- kB pathway, leading to susceptibility of the infected cell to virally-induced cell death or immunologic clearance.
  • the latent HIV infected cells are resting CD4 + T20 cells.
  • “depleting latent HIV infection” refers to the clearance of latently HIV- infected cells that may follow the reversal of HIV latency by reagents such as those that activate the non-canonical NF-kB pathway.
  • each of compounds 1-117 may be used in reversing HIV latency and/or depleting latent HIV infection.
  • “Therapeutically effective amount” means any amount which, as compared to a 25 corresponding subject who has not received such amount, results in improved treatment, healing, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
  • therapeutically effective amounts of a compound of Formula (I), as well as salts thereof may be administered as the raw chemical. Additionally, the 30 active ingredient may be presented as a pharmaceutical composition.
  • Treating viral infections means to inhibit the replication of the particular virus, to inhibit viral transmission, and to ameliorate or alleviate the symptoms of the disease caused by the viral infection.
  • the treatment is considered “therapeutic” if there is a reduction in viral load, decrease in mortality and/or morbidity.
  • Preventing viral infections means to prevent the virus from 9 70226WO01 establishing itself in the host.
  • a treatment is considered “prophylactic” if the subject is exposed to the virus but does not become infected with the virus as a result of treatment. Wherever dashed lines occur adjacent to single bonds denoted by solid lines, then the dashed line represents an optional double bond at that position.
  • Apoptosis a type of programmed cell death, plays an important role in maintaining homeostasis and regulating the number of cells in higher organisms.
  • Abnormal apoptosis is 25 involved in a number of diseases, including autoimmune disorders, degenerative diseases of the Central Nervous System, cancer, and viral infections, such as HIV.
  • IAPs Inhibitor of Apoptosis Proteins
  • SMACm which mimic a critical tetrapeptide sequence from the second mitochondria-derived activator of caspase, have been shown to disrupt the binding of IAPs with 30 their functional partner and restore apoptotic response to proapoptotic stimuli in cells. Since the early 2000s, great effort has focused on the design and preparation of SMAC mimetics as IAP antagonists, particularly in promoting cell death in tumor cells and more recently in reversing HIV latency.
  • SMAC mimetics bind the BIR2 and BIR3 domains of IAP proteins, leading to inhibition 10 70226WO01 (in the case of XIAP) and potentiation of apoptosis, or activation of the ubiquitin ligase activities (in the case of cIAP1 and cIAP2), leading to autoubiquitinylation and depletion of the activated proteins.
  • cIAP1 and 2 suppress the ncNF-kB pathway, it is observed that the activation of these proteins by SMACm leads to activation of ncNFkB transcription factor and leads to kB-dependent 5 gene expression.
  • ncNF-kB non-canonical NF-kB pathway
  • Birinapant TL32711 are examples of dimeric SMAC mimetics. In HIV latency reversal studies, Birinapant TL32711 was not potent in Jurkat, p100-p52 conversion, or HIV caRNA induction. Conversely, AZD5582 15 exhibited an increase in 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 tolerability issues.
  • the IAP proteins targeted by SMAC mimetics for ncNF-kB activation are cIAP1 and cIAP2, with bivalent molecules possessing optimal linkers having the most efficient activity at 20 depleting these two molecules and activating ncNF-kB.
  • This ncNF-kB activating activity occurs perhaps through forming intermolecular ternary complexes wherein one bivalent SMAC mimetic interacts with one BIR domain in each of two different molecules of cIAP1 or cIAP2.
  • XIAP is also bound and inhibited by SMAC mimetics, described in the literature as an intramolecular bond where one bivalent SMAC mimetic interacts with both the BIR2 and BIR3 domains of a single 25 molecule of XIAP.
  • XIAP is not thought to have a role in ncNF-kB activation by SMAC mimetics and is therefore likely an off target in the HIV latency reversal context.
  • ant 11 r ncNF-kB reverse HIV latency in primary, unmodified primary human cells as single agents, 30 making them suitable for consideration for further development.
  • the dimeric 11 70226WO01 SMACm of the disclosed compounds may be optimized to favor binding of the BIR3 domain of cIAP1 and cIAP2 especially over the BIR3 domain within XIAP, which should favor intermolecular ternary complex formation between two cIAP proteins and therefore favor the depletion of cIAP1 and cIAP2 over inhibition of XIAP.
  • SMACm specifically monomeric 5 molecules or dimeric molecules with unoptimized linkers or lacking this specificity for BIR3 of cIAP1 and cIAP2
  • SMACm also monomeric 5 molecules or dimeric molecules with unoptimized linkers or lacking this specificity for BIR3 of cIAP1 and cIAP2
  • SMACm also monomeric 5 molecules or dimeric molecules with unoptimized linkers or lacking this specificity for BIR3 of cIAP1 and cIAP2
  • SMACm provides compounds of Formula (I), as well as various forms of these 10 compounds set forth herein (e.g., pharmaceutically acceptable salts, tautomers, and stereoisomers). It should be appreciated that any reference to the compounds of Formula (I) herein is clearly meant to also include, without limitation, those compounds set forth in Table 1.
  • the invention provides a compound of the structure according to Formula (I): 15 each R 1 and R 2 is -H or -CH 3 ; each R 3 is -H, -CH 3 , -CH 2 CH 3 , cyclopropyl, -CH 2 -OH, or -CH(OH)CH 3 ; 20 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 or -F; each R 6 is -H, -F, -Cl, -Br, -CN, -CH 3 , -CHF 2 , or -CF 3 ; each R 7 is -H; 25 each R 8 is -H, -F, -Cl, or
  • each R 1 and R 2 is independently -H or -CH 3 .
  • each R 1 and R 2 is -CH 3 .
  • each R 1 and R 2 is -H.
  • 30 one of each R 1 and R 2 is -H while the other of each R 1 and R 2 is -CH 3 .
  • each R 3 is -H, -CH 3 , -CH 2 CH 3 , cyclopropyl, -CH 2 -OH, or - CH(OH)CH 3 .
  • each R 3 may be -H, -CH 3 , or -CH 2 CH 3 such as -CH 3 or -CH 2 CH 3 .
  • R 3 is -H. In other embodiments, R 3 is -CH 3 . In even other embodiments, R 3 is -CH 2 CH 3 . In further embodiments, R 3 is cyclopropyl. In even further embodiments, R 3 is -CH 2 - 35 OH. In still other embodiments, R 3 is -CH(OH)CH3. 13 70226WO01 As indicated above, each R 4 is -H, -F, -Cl, -CH 3 , -CF 3 , -CN, -OH, -OCH 3 , -C(O)N(CH 3 ) 2 , - CH(CH3)2, or -C(O)OCH3.
  • each R 4 may be -H, -F, -Cl, or -CN. In some embodiments, each R 4 is -H. In other embodiments, each R 4 is -F. In even other embodiments, each R 4 is -Cl. In further embodiments, each R 4 is -CN. In even further embodiments, each R 4 is - 5 CH 3 . In other embodiments, each R 4 is -CF 3 . In other embodiments, each R 4 is -OH. In still other embodiments, each R 4 is -OCH 3 . In even other embodiments, each R 4 is -C(O)N(CH 3 ) 2 . In still even other embodiments, each R 4 is -CH(CH 3 ) 2 .
  • each R 4 is -C(O)OCH 3 .
  • each R 5 is -H or -F.
  • each R 5 is -H .
  • each R 5 is -F.
  • each R 6 is -H, -F, -Cl, -Br, -CN, -CH 3 , -CHF 2 , or -CF 3 .
  • each R 6 may be -H, -F, or -Cl, such as -F or -Cl.
  • each R 6 is -H.
  • each R 6 is -F.
  • each R 6 is -Cl.
  • each R 6 is -Br. In other further embodiments, each R 6 is -CN. In even further embodiments, each R 6 is -CH 3 . In other embodiments, each R 6 is -CHF 2 . In still other embodiments, each R 6 is -CF 3 . 15 As indicated above, each R 7 is -H. As indicated above, each R 8 is -H, -F, -Cl, or -CN. In some embodiments, each R 8 is -H. In other embodiments, each R 8 is -F. In even other embodiments, each R 8 is -Cl. In further embodiments, each R 8 is -CN.
  • each R 4 is -H
  • each R 5 is -H
  • each R 6 is -F
  • each R 7 is -H
  • each R 8 is -H
  • each R 4 is -F
  • each R 5 is -H
  • each R 6 is -F
  • each R 7 is -H
  • each R 8 is -H.
  • each R 4 is -H
  • each R 5 is -F
  • each R 6 is -F
  • each R 7 is -H
  • each R 8 is -H.
  • each R 4 is -H
  • each R 5 is -F
  • each R 6 is -F
  • each R 7 is -H
  • each R 8 is -F.
  • each R 4 is -Cl
  • each R 5 is -H
  • each R 6 is -Cl
  • each R 7 is -H
  • each R 8 is -H.
  • each R 4 is -CN
  • each R 5 is -H
  • each R 6 is -Cl
  • each R 7 is -H
  • each R 8 is -H.
  • each R 4 is -H
  • each R 5 is -H
  • each R 6 is -Cl
  • each R 7 is -H
  • each R 8 is -Cl.
  • each R 4 is -H
  • each R 5 is -H
  • each R 6 is -Cl
  • each R 7 is -H
  • each R 8 is -CN.
  • each R 9 is -H or -CH 3 .
  • each R 9 is -H.
  • each R 9 is -CH 3 .
  • each R 10 is -H or -CH 3 .
  • each R 10 is -CH 3 .
  • each X is -CH 2 - or -O-.
  • each X is -CH 2 -.
  • each X is -O-.
  • each Y 1 is -CH- or -C(O)-. In some embodiments, each Y 1 is -CH-. In other embodiments, each Y 1 is -C(O)-. As indicated above, each Y 2 is -N-, -NH-, or -NCH 3 -. In some embodiments, each Y 2 is - N-. In other embodiments, each Y 2 is -NH-. In even other embodiments, each Y 2 is -NCH 3 -. 5 In some embodiments, Y 1 is -CH- and Y 2 is -N- such that represents a double bond.
  • Y 1 is -C(O)- and Y 2 is -NH- or -NCH 3 - such that represents a single bond. In such instances, Y 2 is -NH- in some embodiments. In other embodiments, Y 2 is -NCH 3 -.
  • Z 1 is a C 1 -C 4 alkylene or a direct bond. In some embodiments, Z 1 is a C1-C4 alkylene, such as a C1-C3 alkylene, such as a C1-C2 alkylene. In other embodiments, Z 1 is a 10 direct bond. When Z 1 is a C 1 -C 4 alkylene, Z 1 is a C 1 alkylene in some embodiments.
  • Z 1 is a C 2 alkylene. In even other embodiments, Z 1 is a C 3 alkylene. In further embodiments, Z 1 is a C 4 alkylene. As indicated above, Z 2 is a C 1 -C 4 alkylene or a direct bond. In some embodiments, Z 2 is a C 1 -C 4 alkylene, such as a C 1 -C 3 alkylene, such as a C 1 -C 2 alkylene. In other embodiments, Z 2 is a 15 direct bond. When Z 2 is a C1-C4 alkylene, Z 2 is a C1 alkylene in some embodiments. In other embodiments, Z 2 is a C 2 alkylene.
  • Z 2 is a C 3 alkylene. In further embodiments, Z 2 is a C 4 alkylene.
  • W 1 is -(CH 2 ) n NHC(O)-, -C(O)NH(CH 2 ) n -, -O-, -C(O)-, -(CH 2 ) m -O-, - O-(CH 2 ) m -, or a direct bond where n is from 0 to 3 and m is from 1 to 4.
  • W 1 may be - 20 (CH 2 ) n NHC(O)-, -O-, -(CH 2 ) m -O-, or a direct bond.
  • W 1 is -(CH 2 ) n NHC(O)-.
  • n may be from 0 to 3, such as from 0 to 2, such as 0 in some embodiments, 1 in other embodiments, and 2 in further embodiments.
  • W 1 is - C(O)NH(CH 2 ) n -.
  • n may be from 0 to 3, such as from 0 to 2, such as 0 in some embodiments, 1 in other embodiments, and 2 in further embodiments.
  • W 1 is -O-.
  • W 1 is -C(O)-.
  • W 1 is -(CH 2 ) m -O-.
  • m may be from 1 to 4, such as from 1 to 3, such as from 1 to 2, such as 1 in some embodiments, 2 in other embodiments, 3 in further embodiments, and 4 in even further embodiments.
  • W 1 is -O-(CH 2 ) m -.
  • m may be from 1 to 4, such as from 1 to 3, such as from 1 to 2, such as 1 in some embodiments, 2 in 30 other embodiments, 3 in further embodiments, and 4 in even further embodiments.
  • W 1 is a direct bond.
  • W 2 is -(CH 2 ) n NHC(O)-, -C(O)NH(CH 2 ) n -, -O-, -C(O)-, -(CH 2 ) m -O-, - O-(CH 2 ) m -, or a direct bond where n is f be - C(O)NH(CH 2 ) n -, -O-, -O-(CH 2 ) m -, or a direct bond.
  • W 2 is -C(O)NH(CH 2 ) n -.
  • n may be from 0 to 3, such as from 0 to 2, such as 0 in some embodiments, 1 15 70226WO01 in other embodiments, and 2 in further embodiments.
  • W 2 is - (CH2)nNHC(O)-.
  • n may be from 0 to 3, such as from 0 to 2, such as 0 in some embodiments, 1 in other embodiments, and 2 in further embodiments.
  • W 2 is -O-.
  • W 2 is -C(O)-.
  • W 2 5 is -(CH 2 ) m -O-.
  • m may be from 1 to 4, such as from 1 to 3, such as from 1 to 2, such as 1 in some embodiments, 2 in other embodiments, 3 in further embodiments, and 4 in even further embodiments.
  • W 2 is -O-(CH 2 ) m -.
  • m may be from 1 to 4, such as from 1 to 3, such as from 1 to 2, such as 1 in some embodiments, 2 in other embodiments, 3 in further embodiments, and 4 in even further embodiments.
  • W 2 is a direct bond.
  • V 1 is an optionally substituted C 1 -C 4 alkylene, a heterocycloalkylene, an optionally substituted arylene, or a combination thereof.
  • V 1 is an optionally substituted C 1 -C 4 alkylene, such as an optionally substituted C 1 -C 3 alkylene, such as an optionally substituted C 1 -C 2 alkylene, such as an optionally substituted C 1 alkylene.
  • the C 1 -C 4 15 alkylene is a C1 alkylene in some embodiments.
  • the C1-C4 alkylene is a C2 alkylene.
  • the C 1 -C 4 alkylene is a C 3 alkylene.
  • the C 1 -C 4 alkylene is a C 4 alkylene.
  • the C 1 -C 4 alkylene may be unsubstituted in some embodiments.
  • V 1 may be a substituted C 1 -C 4 alkylene, such as a substituted C 1 -C 3 alkylene, such as a substituted C 1 -C 2 alkylene, such as a substituted C 1 alkylene.
  • Such 20 substitution(s) may be a lower alkyl substitution, such as a -CH 3 substitution in some embodiments.
  • V 1 may be a C 1 alkylene with a -CH 3 substitution in some embodiments.
  • V 1 is a heterocycloalkylene.
  • the heterocycloalkylene may be a 4 to 7 membered ring including at least one heteroatom, such as at least one N.
  • V 1 is a heterocycloalkylene including a 6 membered ring wherein one atom is a N 25 atom (e.g., piperidine based divalent radical).
  • V 1 as a heterocycloalkylene may be the following: .
  • V 1 is an optionally substituted arylene.
  • the optionally substituted arylene may be a 4 to 12 membered ring, such as a 5 to 10 membered ring.
  • the ring of V 1 may be fused such that it is formed from two or more rings.
  • the arylene may be a heteroarylene wherein at least one atom, such as at least two atoms, such as at least 3 atoms are a heteroatom, such as N.
  • V 1 may be an optionally substituted C 6 arylene in one embodiment.
  • V 1 may be a substituted C 6 arylene.
  • the C 6 arylene may have attachment points as the divalent radical through the para position.
  • V 1 may 16 70226WO01 be an optionally substituted 5 membered ring, such as one including at least one, such as at least two, such as at least three heteroatoms.
  • such heteroatom may be N (i.e., a C5 arylene including 3 N atoms - triazole based divalent radical, such as a 1H-1,2,3-triazol based divalent radical).
  • V 1 as an arylene may include the following . 5
  • the ring of V 1 may be fused suc ed from two or more rings.
  • the fused ring may be an 8 to 12 membered ring, such as a 9 to 10 membered ring.
  • V 1 may be an optionally substituted naphthalene.
  • V 1 may be an unsubstituted naphthalene.
  • V 1 may be an optionally substituted indole. In another embodiment, V 1 may be an 10 unsubstituted indole. Furthermore, V 1 may be a substituted arylene in some embodiments. In this regard, the arylene may include from 1-4, such as from 1-3, such as from 1-2, such as 1 or 2 substitutions. Such substitution may be halo, alkyl, cyano, or alkoxy. For instance, the halo substitution may be chloro in one embodiment. In another embodiment, the halo substitution may be fluoro. When the 15 substitution is alkyl, it may be a lower alkyl. For instance, the alkyl substitution may be methyl in one embodiment.
  • the alkyl substitution may be ethyl.
  • the substitution is alkoxy
  • the alkoxy substitution may be methoxy in one embodiment.
  • the alkoxy substitution may be ethoxy.
  • the substitution may be cyano.
  • V 1 may be a combination of any two or more of an optionally substituted C1-C4 alkylene, a heterocycloalkylene, or an optionally substituted arylene.
  • it may be a combination of optionally substituted C 1 -C 4 alkylene-heterocycloalkylene in one embodiment.
  • it may be a combination of heterocycloalkylene-C 1 -C 4 alkylene.
  • any of the aforementioned may be 30 substituted such as defined above.
  • Q 1 is an optionally substituted C 1 -C 4 alkylene or a direct bond.
  • Q 1 is a C 1 -C 4 alkylene, such as a C 1 -C 3 alkylene, such as a C 1 -C 2 alkylene.
  • Q 1 is a C 1 alkylene in some embodiments.
  • Q 1 is a C 2 alkylene.
  • Q 1 is a C3 alkylene.
  • Q 1 is a C4 alkylene.
  • Q 1 may be substituted, such as with a C 1 -C 3 alkyl, such as a C 1 -C 2 alkyl, such as a C 1 alkyl.
  • Q 1 is a direct bond.
  • the combination of Q 1 -V 1 is a combination of an optionally substituted C 1 -C 4 alkylene as defined herein and an optionally substituted arylene as 5 defined herein.
  • the combination may be presented as an optionally substituted C 1 -C 4 alkylene-optionally substituted arylene.
  • the combination of Q 1 -V 1 is, for example, an optionally substituted C 1 -C 4 alkylene as defined herein and a heterocycloalkylene as defined herein.
  • the combination may be presented as an optionally substituted C 1 - C4 alkylene-heterocycloalkylene.
  • V 2 is an optionally substituted C 1 -C 4 alkylene, such as an optionally substituted C 1 -C 3 alkylene, such as an optionally substituted C 1 -C 2 alkylene, such as an optionally substituted C 1 alkylene.
  • the C 1 -C 4 alkylene is a C 1 alkylene in some embodiments. In other embodiments, the C 1 -C 4 alkylene is a C 2 10 alkylene.
  • the C 1 -C 4 alkylene is a C 3 alkylene. In further embodiments, the C 1 -C 4 alkylene is a C 4 alkylene. Furthermore, the C 1 -C 4 alkylene may be unsubstituted in some embodiments. In other embodiments, V 2 may be a substituted C 1 -C 4 alkylene, such as a substituted C 1 -C 3 alkylene, such as a substituted C 1 -C 2 alkylene, such as a substituted C 1 alkylene. Such substitution(s) may be a lower alkyl substitution, such as a -CH 3 substitution in some embodiments.
  • V 2 may be a C 1 alkylene with a -CH 3 substitution in some embodiments.
  • V 2 is a heterocycloalkylene.
  • the heterocycloalkylene may be a 4 to 7 membered ring including at least one heteroatom, such as at least one N.
  • V 2 is a heterocycloalkylene including a 6 membered ring wherein one atom is a N atom (e.g., piperidine based divalent radical).
  • V 2 as a heterocycloalkylene may 20 include the following: .
  • V 2 is an optionally substituted arylene.
  • the optionally substituted arylene may be a 4 to 12 membered ring, such as a 5 to 10 membered ring.
  • the ring of V 2 may be fused such that it is formed from two or more rings.
  • the arylene may be a heteroarylene wherein at least one atom, such as at least two atoms, such as at least 3 atoms are a heteroatom, such as N.
  • V 2 may be an optionally substituted C 6 arylene in one embodiment.
  • V 2 may be a substituted C 6 arylene.
  • the C 6 arylene may have 5 attachment points as the divalent radical through the para position.
  • V 2 may be an optionally substituted 5 membered ring, such as one including at least one, such as at least two, such as at least three heteroatoms.
  • such heteroatom may be N (i.e., a C 5 arylene including 3 N atoms - triazole based divalent radical, such as a 1H-1,2,3-triazol based divalent radical).
  • V 2 as an arylene may include the followin . 10
  • the ring of V 2 may be fused suc d from two or more rings.
  • the fused ring may be an 8 to 12 membered ring, such as a 9 to 10 membered ring.
  • V 2 may be an optionally substituted naphthalene. In another embodiment, V 2 may be an unsubstituted naphthalene. In another embodiment, V 2 may be an optionally substituted indole. In another embodiment, V 2 may be an 15 unsubstituted indole. Furthermore, V 2 may be a substituted arylene in some embodiments. In this regard, the arylene may include from 1-4, such as from 1-3, such as from 1-2, such as 1 or 2 substitutions. Such substitution may be halo, alkyl, cyano, or alkoxy. For instance, the halo substitution may be chloro in one embodiment. In another embodiment, the halo substitution may be fluoro.
  • the 20 substitution when the 20 substitution is alkyl, it may be a lower alkyl.
  • the alkyl substitution may be methyl in one embodiment.
  • the alkyl substitution may be ethyl.
  • the substitution when the substitution is alkoxy, the alkoxy substitution may be methoxy in one embodiment.
  • the alkoxy substitution may be ethoxy.
  • the substitution may be cyano. 25
  • V 2 may be a combination of any two or more of an optionally substituted C 1 -C 4 alkylene, a heterocycloalkylene, or an optionally substituted arylene.
  • it may be a combination of optionally substituted C1-C4 alkylene-heterocycloalkylene in one embodiment.
  • it may be a combination of heterocycloalkylene-C1-C4 alkylene.
  • it may be a combination of optionally substituted C 1 -C 4 30 alkylene-optionally substituted arylene.
  • it may be a combination of optionally substituted arylene-optionally substituted C 1 -C 4 alkylene.
  • it may be a combination of heterocycloalkylene-optionally substituted arylene.
  • it may be a combination of optionally substituted arylene- 20 70226WO01 heterocycloalkylene.
  • Q 2 is an optionally substituted C 1 -C 4 alkylene or a direct bond.
  • Q 2 is a C 1 -C 4 alkylene, such as a C 1 -C 3 alkylene, such as a C 1 -C 2 alkylene.
  • Q 2 is a C 1 alkylene in some embodiments.
  • Q 2 is a C 2 alkylene.
  • Q 2 is a C 3 alkylene.
  • Q 2 is a C 4 alkylene.
  • Q 2 may be substituted, such as with a C 1 -C 3 alkyl, such as a C 1 -C 2 alkyl, such as a C 1 alkyl.
  • Q 2 is a direct bond.
  • the combination of V 2 -Q 2 is a combination of an 10 optionally substituted arylene as defined herein and an optionally substituted C 1 -C 4 alkylene as defined herein.
  • the combination may be presented as an optionally substituted arylene-optionally substituted C 1 -C 4 alkylene.
  • the combination of V 2 - Q 2 is, for example, a heterocycloalkylene as defined herein and an optionally substituted C 1 -C 4 alkylene as defined herein.
  • the combination may be presented as an 15 heterocycloalkylene-optionally substituted C1-C4 alkylene. Examples of such combinations may include, but are not limited to, the following: , 20 70226WO01 CN of a rticular e mbodiment, V2 may b . In another particular embodiment, V2 may be 5 .
  • L may be -(C ⁇ C) 2 - or a C 1 -C 8 alkylene. In some embodiments, L is -(C ⁇ C) 2 -. In other embodiments, L is a C 1 -C 8 alkylene. In even other embodiments, L is -C(O)NHCH 2 -. In still other embodiments, L is -NHC(O)CH2-. In further embodiments, L is an optionally substituted C5-C12 arylene including 15 from 0-3 heteroatoms. In even further embodiments, L is -C(O)NH-U-NHC(O)-. In other embodiments, L is - NHC(O)-U-C(O)NH-.
  • L is -C(O)NH-U-Ar 1 -U-NHC(O)-.
  • L is -NHC(O)-U-Ar 1 -U-C(O)NH-.
  • L may be -NHC(O)-U- C(O)NH- or -NHC(O)-U-Ar 1 -U-C(O)NH-.
  • U is a C 1 -C 4 alkylene or a direct 20 bond.
  • U is a direct bond.
  • U is a C 1 -C 4 alkylene.
  • U is a C 1 alkylene in some embodiments.
  • U is a C 2 alkylene. In even other embodiments, U is a C3 alkylene. In further embodiments, U is a C4 alkylene.
  • -Ar 1 - is a C 6 arylene. In one embodiment, such C 6 arylene is an unsubstituted C 6 arylene. Furthermore, such arylene may have attachment points as the divalent radical through the para 5 position.
  • L is -Ar 2 -Ar 3 -.
  • L may include the following: .
  • L is -Ar 4 -T-Ar 5 -.
  • L may include the following: .
  • L is -T-Ar 6 -T-, for instance wherein Ar 6 is ition.
  • L is -T-Ar -T- 10 Ar 8 -T-, for instance wherein Ar 7 and Ar 8 are bonded through the para position.
  • -T- is -O-, -CH 2 -, -C(CH 3 )(CH 3 )-, or -C(CF 3 )(CF 3 )-.
  • -T- may be -O-, - CH2-, or -C(CH3)(CH3)-.
  • -T- may be -O- in some embodiments.
  • -T- may be -CH 2 -. In even other embodiments, -T- may be -C(CH 3 )(CH 3 )-. In further embodiments, -T- may be -C(CF 3 )(CF 3 )-. Furthermore, -Ar 2 -, -Ar 3 -, -Ar 4 -, -Ar 5 -, and -Ar 6 - 15 are each a C 6 arylene. In some embodiments, any of the aforementioned C 6 arylenes may be an unsubstituted C 6 arylene.
  • L may be a C 2 -C 8 alkylene, such as a C 4 -C 8 alkylene.
  • L may be a C 2 alkylene.
  • L may be a C4 alkylene.
  • L may be a C6 alkylene.
  • L may be a C 8 alkylene.
  • L is an optionally substituted C 5 -C 12 arylene including from 0-3 heteroatoms.
  • the arylene may be a C 5 -C 6 arylene or a C 8 -C 10 arylene.
  • the arylene may be a C 5 arylene, C 6 arylene, or a C 10 arylene.
  • the C 6 arylene such as an unsubstituted C 6 arylene
  • the arylene may be fused such that it is formed from two or more rings.
  • the fused ring may be an 8 to 12 membered ring, such as a 9 to 10 membered ring.
  • L may be an optionally substituted naphthalene.
  • L may be an unsubstituted naphthalene.
  • the naphthalene may include any of the following: .
  • the arylene may be unsubstituted in some embodiments.
  • the C 5 -C 12 arylene may be substituted.
  • such arylene may include from 1 to 4, such as from 2 to 4, such as from 3 to 4, such as 4 substitutions.
  • substitution(s) 5 may be lower alkyl, such as methyl.
  • substitution(s) may be halo.
  • substitution(s) may be fluoro.
  • the arylene may have 2-4, such as 3-4, such as 4 fluoro substitutions.
  • the arylene may not include any heteroatoms.
  • the arylene may be a C5 10 arylene in one embodiment.
  • the arylene may be a C 6 arylene.
  • the C 5 -C 12 arylene may include from 1-3, such as from 2-3, such as 3 heteroatoms.
  • Such heteroatom(s) may be -O-, -S-, -N-, or a combination thereof. In one embodiment, such heteroatom(s) may be -N-.
  • L may be a C 5 arylene including 3 N atoms (e.g., triazole based divalent radical, such as a 1H-1,2,3-triazol based divalent radical).
  • L as an 15 .
  • rmula (I) has the formula as provided below:
  • the compound of Formula (I) has the formula as provided below: 24 70226WO01
  • the compound or pharmaceutically acceptable salt or stereoisomer thereof is selected from the group consisting of , , , 70226WO01 nd . In oth or stereoisomer thereof is selected from the group consisting of 5 and .
  • furth is selected from the group consisting of 26 70226WO01 , , , , , 70226WO01 , , , , and 70226WO01 .
  • furth ble salt or stereoisomer thereof is selected from the group consisting of 5 nd .
  • Furthe e a pharmaceutically acceptable salt of any of the compounds of any of the aforementioned formulae or compounds.
  • Exemplary compounds encompassed by the present invention include, without limitation, those in the following Table 1: 29 70226WO01 Table 1 Cmpd. # Compound Name Compound Structure N1,N10-bis((S)-5-((S)-2- 30 70226WO01 Cmpd.
  • each of compounds 1-117 may be present generically as hydrochloride (i.e., HCl salts), e.g., more specifically a dihydrochloride, (2 HCl) salt.
  • hydrochloride i.e., HCl salts
  • any of compounds 1-117 present as a single 5 species including pharmaceutically acceptable salts thereof, as well as any of these compounds in free base form.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy is provided.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating an HIV infection there is provided a compound of Formula (I) wherein the compound or salt of the compound is used in the manufacture of a medicament for use 5 in the treatment of an HIV infection in a human.
  • the invention provides a method of curing an HIV infection in a subject comprising administering to the subject a compound of Formula (I), as well as any compound of Table 1, along with pharmaceutically salts thereof.
  • “Cure” or “Curing” a disease in a patient is used to denote the eradication, stoppage, halt or end of the human immunodeficiency 10 virus or symptoms, or the progression of the symptoms or virus, for a defined period.
  • “cure” or “curing” refers to a therapeutic administration or a combination of administrations that alone or in combination with one or more other compounds induces and maintains sustained viral control (undetectable levels of plasma viremia by, e.g., a polymerase chain reaction (PCR) test, a bDNA (branched chain DNA) test or a NASBA (nucleic 15 acid sequence based amplification) test, ) of human immunodeficiency virus after a minimum of two years without any other therapeutic intervention.
  • PCR polymerase chain reaction
  • bDNA branched chain DNA
  • NASBA nucleic 15 acid sequence based amplification
  • the invention provides a method of curing an HIV infection in a subject comprising administering to the subject a pharmaceutical composition comprising a compound of Formula (I), along with pharmaceutically salts thereof.
  • the 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 curing an 25 HIV infection.
  • the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in curing an HIV infection.
  • Combinations of compounds of Formula (I), and one or more agents useful in HIV therapy may also be used in methods of curing an HIV infection.
  • the pharmaceutical formulation containing a compound of Formula (I), or a salt thereof is a formulation adapted for parenteral administration.
  • the formulation is a long-acting parenteral formulation.
  • the formulation is a nano-particle formulation.
  • the compounds of the present invention and their salts, solvates, or other pharmaceutically 35 acceptable derivatives thereof, may be employed alone or in combination with other therapeutic 58 70226WO01 agents.
  • the methods of treating and/or preventing an HIV infection in a subject may in addition to administration of a compound of Formula (I) further comprising administration of one or more additional pharmaceutical agents active against HIV.
  • the one or more additional agents active against HIV is selected 5 from the group consisting of anti-retroviral agents, latency reversing agents, and agents for clearance therapy.
  • the one or more additional agents active against HIV is selected from the group consisting of nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, attachment and fusion inhibitors, 10 integrase inhibitors, maturation inhibitors, CXCR4 and/or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyl transferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and neutralizing antibodies, and combinations thereof.
  • the one or more additional agents active against HIV is selected from the group consisting of zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, 15 adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, en
  • the compounds of the present invention of Formula (I) and any other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compounds of Formula (I) of the present invention and the other 30 pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the present invention of Formula (I) and salts, solvates, or other pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) 35 separate pharmaceutical compositions each including one of the compounds.
  • the 59 70226WO01 combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the amounts of the compound(s) of Formula (I) or salts thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in 5 order to achieve the desired combined therapeutic effect.
  • the compounds of the present invention of Formula (I) may be used in combination with one or more other agents that may be useful in the treatment of HIV. They agents may include anti-retroviral agents, latency reversing agents, and agents for clearance therapy.
  • Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents
  • Non-nucleotide reverse transcriptase inhibitors (including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, 15 oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, and similar agents
  • Protease inhibitors such as saquinavir,
  • Table 2 Further examples where the compounds of the present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV are found in Table 2.
  • Table 2 FDA Approval Brand N ame Generic Name Manufacturer 70226WO01 zalcitabine, 1992 Hivid dideoxycytidine, Roche ddC Pharmaceuticals cs s s cs 61 70226WO01 Roche 2003 Fuzeon Enfuvirtide, T-20 Pharmaceuticals & Trimeris expression, such as latency reversing agents.
  • latency reversing agents include, but are not limited to, the following: histone deacetylase inhibitors (e.g., vorinostat, panobinostat, romidepin), 5 histone crotonyl transferase inhibitors (sodium corotonate), protein kinase C agonists (e.g., bryostatin, ingenol B), disulfiram, TLR7 agonists (e.g., GS-9620), bromodomain inhibitors (e.g., JQ1, iBET151). Many of these agents are described in further detail below.
  • the present invention may be used in combination with other agents that induce HIV expression, such as agents for clearance therapy.
  • agents for clearance therapy 10 or of immunological combinations for clearance, include, but are not limited to, the following: neutralizing and broadly neutralizing antibodies (bNAb), eCD4-Ig, CD4-Ig, and dual-affinity re- targeting (DART) proteins.
  • bNAb neutralizing and broadly neutralizing antibodies
  • eCD4-Ig eCD4-Ig
  • CD4-Ig eCD4-Ig
  • DART dual-affinity re- targeting
  • the compounds of Formula (I) and Table 1 may be used in 20 combination with one or more agents useful as pharmacological enhancers as well as with or without additional compounds for the prevention or treatment of HIV.
  • agents useful as pharmacological enhancers include, but are not limited to, ritonavir, GS-9350 (cobicistat), and SPI-452.
  • Ritonavir is 10-hydroxy-2-methyl-5-(1-methyethyl)-1-1[2-(1-methylethyl)-4-thiazolyl]- 25 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 from Abbott Laboratories of Abbott Park, Illinois, as Norvir.
  • Ritonavir is an HIV protease inhibitor indicated with other antiretroviral agents for the treatment of HIV infection.
  • Ritonavir also inhibits P450 mediated drug metabolism as well as the 62 70226WO01 P-glycoprotein (Pgp) cell transport system, thereby resulting in increased concentrations of active compound within the organism.
  • GS-9350 cobicistat
  • 5 SPI-452 is a compound being developed by Sequoia Pharmaceuticals of Gaithersburg, Maryland, as a pharmacological enhancer.
  • a compound of Formula (I) is used in combination with ritonavir. In one embodiment, the combination is an oral fixed dose combination.
  • the compound of Formula (I) is formulated as a long-acting parenteral injection and ritonavir is 10 formulated as an oral composition.
  • a kit containing the compound of Formula (I) is formulated as a long-acting parenteral injection and ritonavir formulated as an oral composition.
  • the compound of Formula (I) is formulated as a long-acting parenteral injection and ritonavir is formulated as an injectable composition.
  • a kit containing the compound of Formula (I) is formulated as a long-acting parenteral injection and 15 ritonavir formulated as an injectable composition.
  • a compound of Formula (I) is used in combination with GS-9350.
  • the combination is an oral fixed dose combination.
  • the compound of Formula (I) is formulated as a long-acting parenteral injection and GS-9350 is formulated as an oral composition.
  • there is provided a kit containing the 20 compound of Formula (I) is formulated as a long-acting parenteral injection and GS-9350 formulated as an oral composition.
  • the compound of Formula (I) is formulated as a long-acting parenteral injection and GS-9350 is formulated as an injectable composition.
  • kits containing the compound of Formula (I) are formulated as a long-acting parenteral injection and GS-9350 formulated as an injectable composition.
  • a compound of Formula (I) is used in combination with SPI-452.
  • the combination is an oral fixed dose combination.
  • the compound of Formula (I) is formulated as a long-acting parenteral injection and SPI-452 is formulated as an oral composition.
  • there is provided a kit containing the compound of Formula (I) is formulated as a long-acting parenteral injection and SPI-452 30 formulated as an oral composition.
  • the compound of Formula (I) is formulated as a long-acting parenteral injection and SPI-452 is formulated as an injectable composition.
  • a kit containing the compound of Formula (I) is formulated as a long-acting parenteral injection and SPI-452 formulated as an injectable composition.
  • 63 70226WO01 a compound of Formula (I) is used in combination with compounds which are found in previously filed PCT/CN2011/0013021, which is herein incorporated by reference.
  • the above other therapeutic agents when employed in combination with the chemical 5 entities described herein, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of 10 developing said viral infection, a compound of Formula (I).
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), wherein said virus is an HIV virus.
  • the HIV virus is the HIV-1 virus.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a 20 therapeutically effective amount of one or more agents active against an HIV virus.
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of 25 a therapeutically effective amount of one or more agents active against the HIV virus, wherein said agent active against HIV virus is selected from Nucleotide reverse transcriptase inhibitors; Non- nucleotide reverse transcriptase inhibitors; Protease inhibitors; Entry, attachment and fusion inhibitors; Integrase inhibitors; Maturation inhibitors; CXCR4 inhibitors; and CCR5 inhibitors.
  • a method of depleting latent HIV infected cells comprising administering 30 to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound is selected from the group consisting of those compounds listed in Table 1.
  • a pharmaceutical composition comprising this compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient including e.g., those set forth herein.
  • a method of treating an HIV 35 infection in a subject comprising administering to the subject this compound or a pharmaceutically 64 70226WO01 acceptable salt thereof, as well as combinations.
  • Some embodiments also include use of this compound, in the manufacture of a medicament for treating an HIV infection.
  • Still other embodiments include a method of depleting 5 latent HIV infected cells comprising administering to a subject this compound or a pharmaceutically acceptable salt thereof, as well as combinations thereof.
  • the method of depleting latent HIV infection further comprises administering to the subject one or more additional agents active against HIV as disclosed hereinabove.
  • the one or more additional agents is selected 10 from the group consisting of nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, attachment and fusion inhibitors, integrase inhibitors, maturation inhibitors, CXCR4 and/or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyl transferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and antibodies for clearance therapy, and combinations 15 thereof.
  • the one or more additional agents active against HIV is selected from the group consisting of zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdinee, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, 20 amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir,
  • the compounds according to Formula (I) and pharmaceutically acceptable salts thereof may be useful in the treatment of cancer, pre-cancerous syndromes.
  • the present invention relates to a method for treating cancers selected from the group consisting of brain (gliomas), 30 glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, 35 lymphoblast
  • the present invention relates to a method for treating pre-cancerous syndromes in a mammal, including a human, wherein the pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and 15 severe hepatitis or cirrhosis.
  • MGUS monoclonal gammapathy of unknown significance
  • MUS monoclonal gammapathy of unknown significance
  • myelodysplastic syndrome aplastic anemia
  • cervical lesions cervical lesions
  • skin nevi pre-melanoma
  • PIN prostatic intraepithleial (intraductal) neoplasia
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co- administered with at least one other active agent known to be useful in the treatment of cancer or pre-cancerous syndromes.
  • co-administration as used herein is meant either simultaneous administration 20 or any manner of separate sequential administration of a c-MYC inhibiting compound, as described herein, and a further active agent or agents, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment.
  • further active agent or agents, as used herein includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer.
  • the administration is 25 not simultaneous, the compounds are administered in a close time proximity to each other.
  • the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.
  • a further active ingredient or ingredients for use in 30 combination or co-administered with the presently invented combinations are indicated below. This list is non-limiting. Additional anti-neoplastic agents are contemplated for use with the presently invented compounds.
  • any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of 35 such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S.
  • Typical anti- neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule 5 agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti- folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal 10 analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.
  • Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle.
  • anti- microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.
  • Diterpenoids, which are derived from natural sources, are phase specific anti-cancer agents20 that operate at the G 2 /M phases of the cell cycle. It is believed that the diterpenoids stabilize the - tubulin subunit of the microtubules, by binding with this protein.
  • diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.
  • Paclitaxel has been 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.
  • D ocetaxel (2R,3S)- N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5 -20- epoxy-1,2 ,4,7 ,10 ,13 -hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE .
  • Docetaxel is indicated for the treatment of breast cancer.
  • Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared 15 using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.
  • Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is 20 believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine. V inblastine, vincaleukoblastine sulfate, is commercially available as VELBAN as an injectable solution.
  • Vinorelbine is indicated as a single 35 agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of 68 70226WO01 various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.
  • Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form 5 intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.
  • Cisplatin is primarily indicated in the treatment of metastatic testicular and 10 ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.
  • Carboplatin, platinum, diammine [1,1-cyclobutane-dicarboxylate(2-)-O,O’] is c ommercially available as PARAPLATIN as an injectable solution.
  • Carboplatin is primarily indicated in the first- and second-line treatment of advanced ovarian carcinoma.
  • Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death.
  • 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.
  • nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil
  • alkyl sulfonates such as busulfan
  • nitrosoureas such as carmustine
  • triazenes such as dacarbazine.
  • Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2- o xide monohydrate is commercially available as an injectable solution or tablets as CYTOXAN .
  • Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting, and leukopenia are the most common dose limiting side effects of cyclophosphamide.
  • Melphalan 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an 30 injectable solution or tablets as ALKERAN .
  • Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.
  • Chlorambucil 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available a s LEUKERAN tablets. Chlorambucil is indicated for the palliative treatment of chronic 35 lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular 69 70226WO01 lymphoma, and Hodgkin’s disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil. B usulfan, 1,4-butanediol dimethanesulfonate, is commercially available as MYLERAN TABLETS.
  • Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. 5 Bone marrow suppression is the most common dose limiting side effects of busulfan.
  • Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea is commercially available as single vials o f lyophilized material as BiCNU .
  • Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin’s disease, and non-Hodgkin’s lymphomas. Delayed myelosuppression is the most common dose limiting side 10 effects of carmustine.
  • dacarbazine 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, is commercially a vailable as single vials of material as DTIC-Dome .
  • dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin’s Disease. Nausea, vomiting, and anorexia are the most common dose limiting side 15 effects of dacarbazine.
  • Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids, leading to cell death.
  • antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as 20 daunorubicin and doxorubicin; and bleomycins.
  • Dactinomycin also known as Actinomycin D, is commercially available in injectable form a s COSMEGEN . Dactinomycin is indicated for the treatment of Wilm’s tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.
  • Daunorubicin (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy- -L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedione h ydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME or as an injectable as CERUBIDINE . Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi’s sarcoma.
  • Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute 70 70226WO01 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.
  • Bleomycin a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of S treptomyces verticillus, is commercially available as BLENOXANE .
  • Bleomycin is indicated as 5 a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas.
  • Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.
  • Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake 10 plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows.
  • Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.
  • E toposide, 4’-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene- -D-glucopyranoside], 15 is commercially available as an injectable solution or capsules as VePESID and is commonly known as VP-16.
  • Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.
  • Teniposide, 4’-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene- -D- glucopyranoside], is commercially available as an injectable solution as VUMON and is commonly known as VM-26.
  • Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide.
  • Teniposide can induce both leucopenia and 25 thrombocytopenia.
  • Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed, and cell death follows.
  • Examples of antimetabolite anti-neoplastic agents include, but are 30 not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine. 5-fluorouracil, 5-fluoro-2,4- (1H,3H) pyrimidinedione, is commercially available as fluorouracil.
  • 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death.
  • 5-fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of 35 carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis 71 70226WO01 are dose limiting side effects of 5-fluorouracil.
  • Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.
  • C ytarabine 4-amino-1- -D-arabinofuranosyl-2 (1H)-pyrimidinone
  • CYTOSAR-U is commercially available as CYTOSAR-U and is commonly known as Ara-C. It is believed that cytarabine 5 exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia.
  • Other cytidine analogs include 5-azacytidine and 2’,2’-difluorodeoxycytidine (gemcitabine).
  • Cytarabine induces leucopenia, thrombocytopenia, and mucositis.
  • 10 Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, is commercially available a s PURINETHOL .
  • Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at 15 high doses.
  • a useful mercaptopurine analog is azathioprine.
  • Thioguanine 2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available as T ABLOID .
  • Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism.
  • Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. 20
  • Myelosuppression including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting.
  • G emcitabine 2’-deoxy-2’, 2’-difluorocytidine monohydrochloride ( -isomer), is 25 commercially available as GEMZAR .
  • Gemcitabine exhibits cell phase specificity at S-phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer.
  • Methotrexate N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L-glutamic acid
  • Methotrexate sodium is commercially available as methotrexate sodium.
  • Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and 35 thymidylate.
  • Methotrexate is indicated as a single agent or in combination with other 72 70226WO01 chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin’s lymphoma, and carcinomas of the breast, head, neck, ovary, and bladder.
  • Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.
  • Camptothecins including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity.
  • camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino- methylene)-10,11-ethylenedioxy-20-camptothecin described below.
  • 10 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 commercially a vailable as the injectable solution CAMPTOSAR .
  • Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN- 38, to the topoisomerase I – DNA complex. It is believed that cytotoxicity occurs as a result of 15 irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for 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.
  • Topotecan HCl (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H- 20 pyrano[3’,4’,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is c ommercially available as the injectable solution HYCAMTIN .
  • Topotecan is a derivative of camptothecin which binds to the topoisomerase I – DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule.
  • Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell 25 lung cancer.
  • the dose limiting side effect of topotecan HCl is myelosuppression, primarily neutropenia.
  • Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer.
  • hormones and hormonal analogues useful in cancer treatment include, but are not 30 limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone 35 dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such 73 70226WO01 a s flutamide, nilutamide, bicalutamide, cyproterone acetate and 5 -reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-ester
  • LHRH agonists and antagagonists such as goserelin acetate and luprolide.
  • Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation.
  • Signal transduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myo-inositol signaling, and Ras 15 oncogenes.
  • Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl 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.
  • Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand 20 binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been 25 linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods.
  • Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor –I (IGFI) receptor, macrophage colony 30 stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene.
  • EGFr epidermal growth factor receptor
  • PDGFr platelet derived growth factor receptor
  • erbB2 erbB4
  • VEGFr vascular endothelial growth factor receptor
  • TIE-2 vascular endothelial growth factor receptor
  • TIE-2
  • inhibitors of growth receptors include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.
  • Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C., Exp. Opin. Ther. Patents 35 (2000) 10(6):803-818; Shawver et al DDT Vol 2, No.2 February 1997; and Lofts, F. J. et al, 74 70226WO01 “Growth factor receptors as targets”, New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.
  • the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- 5 pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001, International Publication Number WO02/059110 and an International Publication date of August 1, 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of10 Example 69.
  • a VEGFR inhibitor suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- 5 pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochlor
  • 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide can be prepared as described in International Application No. PCT/US01/49367.
  • 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide is in the form of a monohydrochloride salt. This salt form can be 15 prepared by one of skill in the art from the description in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001.
  • Tyrosine kinases which are not growth factor receptor kinases are termed non-receptor 25 tyrosine kinases.
  • Non-receptor tyrosine kinases for use in the present invention include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl.
  • Such non-receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S.
  • SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck, Grb2) and Ras-GAP.
  • SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods.34(3) 35 125-32.
  • Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).
  • IkB kinase family IKKa, 5 IKKb
  • PKB family kinases akt kinase family members
  • PDK1 and TGF beta receptor kinases IkB kinase family
  • Serine/Threonine kinases and inhibitors thereof 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. 10 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.
  • the pharmaceutically active compounds of the invention are used in combination with a MEK inhibitor.
  • 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 United States Patent Publication No. US 2006/0014768, Published January 19, 2006, the entire disclosure of which is hereby incorporated by reference.
  • the pharmaceutically active compounds of the invention are used in combination25 with a B-Raf inhibitor.
  • N- ⁇ 3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4- 30 yl]-2-fluorophenyl ⁇ -2,6-difluorobenzenesulfonamide can be prepared as described in International Application No. PCT/US2009/042682.
  • the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor.
  • N- ⁇ (1S)-2-amino-1-[(3,4- difluorophenyl)methyl]ethyl ⁇ -5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2- 5 furancarboxamide is the compound of example 224 and can be prepared as described in International Application No. PCT/US2008/053269.
  • the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor.
  • 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 15 example 96 and can be prepared as described in International Application No. PCT/US2008/053269.
  • 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.
  • the salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US2010/022323, having an International filing date of January 28, 2010.20 Inhibitors of Phosphotidylinositol-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) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology.29 (7):935-8; and Zhong, H.
  • Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues.
  • signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London. 30
  • Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene.
  • inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy.
  • Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., 35 Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science.7(4) 292-8; Ashby, M.N.
  • antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors.
  • This group of signal transduction pathway inhibitors includes the 5 use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases.
  • Imclone C225 EGFR specific antibody see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat.
  • Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention.
  • Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases).
  • Angiogenesis in general is 15 linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the compounds of the present invention.
  • anti- VEGF antibodies which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha v beta 3 ) that will inhibit angiogenesis; endostatin 20 and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds.
  • VEGFR the receptor tyrosine kinase
  • small molecule inhibitors of integrin alpha v beta 3
  • endostatin 20 and angiostatin non-RTK
  • Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of Formula (I).
  • immunologic strategies to generate an immune 25 response. These strategies are generally in the realm of tumor vaccinations.
  • the efficacy of immunologic approaches may be greatly enhanced through combined inhibition of signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are 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.
  • Agents used in proapoptotic regimens may also be used in the combination of the present invention.
  • Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance.
  • EGF epidermal growth factor
  • cyclin dependent kinases A 5 family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle.
  • CDKs cyclin dependent kinases
  • examples of cyclin dependent kinases, including CDK2, CDK4, and 10 CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.
  • p21WAF1/CIP1 has been described as a potent and universal inhibitor of cyclin-dependent kinases (Cdks) (Ball et al., Progress in Cell Cycle Res., 3: 125 (1997)).
  • Cdks cyclin-dependent kinases
  • Compounds that are known to induce expression of p21WAF1/CIP1 have been implicated in the suppression of cell proliferation and as having tumor suppressing activity (Richon 15 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 are implicated in the transcriptional activation of p21WAF1/CIP1 (Vigushin et al., Anticancer Drugs, 13(1): 1-13 (Jan 2002)), and are suitable cell cycle signaling inhibitors for use in combination herein.
  • HDAC inhibitors include: 20 1. Vorinostat, including pharmaceutically acceptable salts thereof. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007). Vorinostat has the following chemical structure and name: ide 25 2. Romidepsin, including pharmaceutically acceptable salts thereof. Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85-93.
  • Romidepsin has the following chemical structure and name: 70226WO01 (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23- tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone 3.
  • Panobinostat including pharmaceutically acceptable salts thereof.
  • 5 Panobinostat has the following chemical structure and name: (2E)-N-hydroxy-3-[4- methyl)phenyl]acrylamide 4.
  • Valproic acid including pharmaceutically acceptable salts thereof.
  • Valproic acid has the following chemical structure and name: -propy pentanoc ac d 5.
  • Mocetinostat (MGCD0103), including pharmaceutically acceptable salts thereof. Balasubramanian et al., Cancer Letters 280: 211-221 (2009). 15 Mocetinostat, has the following chemical structure and name: N H2 N-(2-Aminophen o]methyl] benzamide Further examples of such HDAC inhibitors are included in Bertrand European Journal of Medicinal Chemistry 45, (2010) 2095-2116, particularly the compounds of table 3 therein as 20 indicated below. 80 70226WO01 5 that break down proteins, like the p53 protein.
  • proteasome inhibitors are marketed or are 81 70226WO01 being studied in the treatment of cancer.
  • Suitable proteasome inhibitors for use in combination herein include: 1. Bortezomib (Velcade®), including pharmaceutically acceptable salts thereof. Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304–11. Bortezomib has the following 5 chemical structure and name. [(1R)-3-methyl-1-( ⁇ (2S)-3-phen ino]propanoyl ⁇ amino)butyl]boronic acid 2. Disulfiram, including pharmaceutically acceptable salts thereof. 10 Bouma et al. (1998). J. Antimicrob. Chemother.42 (6): 817–20.
  • Disulfiram has the following chemical structure and name. 1,1',1'',1''-[disulfanediylbis(car 3.
  • Epigallocatechin gallate (EGCG) including pharmaceutically acceptable salts 15 thereof. Williamson et al., (December 2006), The Journal of Allergy and Clinical Immunology 118 (6): 1369–74.
  • Epigallocatechin gallate has the following chemical structure and name. [(2R,3R)-5,7-dihydroxy-2-(3,4,5 l]3,4,5-trihydroxybenzoate 4.
  • Salinosporamide A including pharmaceutically acceptable salts thereof. Feling et 20 at., (2003), Angew. Chem. Int. Ed. Engl.42 (3): 355–7.
  • Salinosporamide A has the following chemical structure and name. 82 70226WO01 (4R,5S)-4-(2-chloroethyl)-1-((1S)-cyclo roxy)methyl) -5-methyl-6-oxa-2- azabicyclo3.2.0heptane-3,7-dione 5.
  • Carfilzomib including pharmaceutically acceptable salts thereof. Kuhn DJ, et al, Blood, 5 2007, 110:3281-3290.
  • Carfilzomib has the following chemical structure and name.
  • the 70 kilodalton heat shock proteins (Hsp70s) and 90 kilodalton heat shock proteins 10 (Hsp90s) are a families of ubiquitously expressed heat shock proteins. Hsp70s and Hsp90s are over expressed certain cancer types. Several Hsp70s and Hsp90s inhibitors are being studied in the treatment of cancer.
  • Suitable Hsp70s and Hsp90s inhibitors for use in combination herein include: 1. 17-AAG(Geldanamycin), including pharmaceutically acceptable salts thereof. Jia W et al. Blood.2003 Sep 1;102(5):1824-32. 17-AAG(Geldanamycin) has the following chemical 15 structure and name. O H N H 2 17-(Allylamino)-17-demethoxygel danamycin 2. Radicicol, including pharmaceutically acceptable salts thereof. (Lee et al., 83 70226WO01 Mol Cell Endocrinol.2002, 188,47-54). Radicicol has the following chemical structure and name.
  • Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a pivotal role in tumor cell metabolism by performing the reduction of pyruvate to lactate, which can then be exported out of the cell.
  • the enzyme has been shown to be upregulated in many tumor types.
  • the alteration of glucose metabolism described in the Warburg 15 effect is critical for growth and proliferation of cancer cells and knocking down LDH-A using RNA-i has been shown to lead to a reduction in cell proliferation and tumor growth in xenograft models.
  • FAS fatty acid synthase
  • the cancer treatment method of the claimed invention includes the co- administration a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule 30 agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, 84 70226WO01 immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.
  • anti-neoplastic agent such as one selected from the group consisting of anti-microtubule 30 agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitor
  • a compound of Formula (I) is used as a chemosensitizer to enhance tumor cell killing. 5 In one embodiment, a compound of Formula (I) is used in combination as a chemosensitizer to enhance tumor cell killing. In one embodiment, a compound of Formula (I) is used in combination with a compound that inhibits the activity of protein kinase R (PKR)-like ER kinase, PERK (PERK inhibitor).
  • PLR protein kinase R
  • PERK PERK inhibitor
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may 10 be co-administered with at least one other active agent known to be inhibitors of PERK kinase (EIF2K3) for treating or lessening the severity of neurodegenerative diseases/injury, such as Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular 15 disease, 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, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.
  • EIF2K3 PERK kina
  • “Chemotherapeutic” or “chemotherapeutic agent” is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. Additionally, the compounds described herein can be co-administered with conventional immunotherapeutic agents including, but not limited to, immunostimulants (e.g., Bacillus Calmette-25 Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.
  • immunostimulants e.g., Bacillus Calmette-25 Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.
  • monoclonal antibodies e.g., anti- CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies
  • immunotoxins e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.
  • radioimmunotherapy e.g., anti- CD20 monoclonal antibody conjugated to 111 In, 90 Y, or 131 I, etc.
  • the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as 47 Sc, 64 C 6 7 C, 89 Sr, 86 Y, 87 Y, and 212 Bi, optionally conjugated to antibodies directed against tumor antigens.
  • radionuclides such as 47 Sc, 64 C 6 7 C, 89 Sr, 86 Y, 87 Y, and 212 Bi
  • additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the compounds are anti-PD-L1 agents.
  • 35 Anti-PD-L1 antibodies and methods of making the same are known in the art. 85 70226WO01
  • Such antibodies to PD-L1 may be polyclonal or monoclonal, and/or recombinant, and/or humanized.
  • Exemplary PD-L1 antibodies are disclosed in: US Patent No.8,217,149; 12/633,339; 5 US Patent No.8,383,796; 13/091,936; US Patent No 8,552,154; 13/120,406; US patent publication No.20110280877; 13/068337; US Patent Publication No.20130309250; 13/892671; WO2013019906; 10 WO2013079174; US Application No.13/511,538 (filed August 7, 2012), which is the US National Phase of International Application No. PCT/US10/58007 (filed 2010); and US Application No.13/478,511 (filed May 23, 2012).
  • PD-L1 also referred to as CD274 or B7-H1
  • 15 methods for use are disclosed in US Patent No.7,943,743; US20130034559, WO2014055897, US Patent No.8,168,179; and US Patent No.7,595,048.
  • PD-L1 antibodies are in development as immuno-modulatory agents for the treatment of cancer.
  • the antibody to PD-L1 is an antibody disclosed in US Patent No. 8,217,149.
  • the anti-PD-L1 antibody comprises the CDRs of an antibody 20 disclosed in US Patent No.8,217,149.
  • the antibody to PD-L1 is an antibody disclosed in US Application No.13/511,538.
  • the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Application No.13/511,538.
  • the antibody to PD-L1 is an antibody disclosed in Application No. 25 13/478,511.
  • the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Application No.13/478,511.
  • the anti-PD-L1 antibody is BMS-936559 (MDX-1105).
  • the anti-PD-L1 antibody is MPDL3280A (RG7446).
  • the anti-PD-L1 antibody is MEDI4736.
  • PD-1 antagonist means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B 35 cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to 86 70226WO01 the immune-cell expressed PD-1.
  • PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2.
  • the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1.
  • Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP_005009.
  • Human PD-L1 and PD- L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.
  • 10 PD-1 antagonists useful in the any of the aspects of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD- 1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1.
  • the mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region.
  • the human constant region is selected from the 15 group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region.
  • the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab') 2 , scFv and Fv fragments.
  • mAbs that bind to human PD-1 are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004/004771, WO2004/072286, WO2004/056875, and US2011/0271358.
  • Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in any of the aspects and embodiments of the present invention include: MK-3475, a humanized IgG4 mAb with the 25 structure described in WHO Drug Information, Vol. 27, No.
  • immunoadhesion molecules that specifically bind to PD-1 are described in WO2010/027827 and WO2011/066342.
  • Specific fusion proteins useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1.
  • AMP-224 also known as B7-DCIg
  • Other examples of mAbs that bind to human PD-L1, and useful in the treatment method, medicaments and uses of the present invention, are described in WO2013/019906, W02010/077634 A1 and US8383796.
  • Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS- 936559, MEDI4736, MSB0010718C.
  • KEYTRUDA/pembrolizumab is an anti-PD-1 antibody marketed for the treatment of lung cancer by Merck.
  • the amino acid sequence of pembrolizumab and methods of using are disclosed in US Patent No.8,168,757.
  • Opdivo/nivolumab is a fully human monoclonal antibody marketed by Bristol Myers Squibb directed against the negative immunoregulatory human cell surface receptor PD-1 15 (programmed death-1 or programmed cell death-1/PCD-1) with immunopotentiation activity.
  • Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands PD-L1 and PD-L2, resulting in the activation of T-cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and effector function through the suppression of P13k/Akt pathway activation.
  • Other names for 20 nivolumab include: BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence for nivolumab and methods of using and making are disclosed in US Patent No. US 8,008,449.
  • immuno-modulators refer to any substance including monoclonal antibodies that affects the immune system.
  • the ICOS binding proteins of the present invention can be considered immune-modulators.
  • Immuno-modulators can be used as anti-neoplastic agents for the treatment of cancer.
  • immune-modulators include, but are not limited to, anti- CTLA-4 antibodies such as ipilimumab (YERVOY) and anti-PD-1 antibodies (Opdivo/nivolumab 30 and Keytruda/pembrolizumab).
  • immuno-modulators include, but are not limited to, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies and GITR antibodies.
  • Yervoy (ipilimumab) is a fully human CTLA-4 antibody marketed by Bristol Myers Squibb. The protein structure of ipilimumab and methods are using are described in US Patent 35 Nos.6,984,720 and 7,605,238. 88 70226WO01
  • this invention provides a compound of Table 1 described herein or a Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment of a hepatitis B virus-related disease, condition or disorder.
  • This invention provides a compound of Table 1 or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment of a 5 hepatitis B virus-related disease, condition or disorder.
  • the hepatitis B virus-related disease, condition or disorder may be jaundice, liver cancer, liver inflammation, liver fibrosis, liver cirrhosis, liver failure, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome or serum hepatitis).
  • the compound of the present invention of Formula (I) or 10 pharmaceutically acceptable salts thereof is selected from the group of compounds set forth in Table 1. Additionally, the present invention also encompasses each of these compounds individually and pharmaceutically acceptable salts thereof.
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of 15 Formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound(s) of the present invention, or a pharmaceutically acceptable salt thereof is chosen from the compounds set forth in Table 1.
  • the compounds of the present invention can be supplied in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refer to salts prepared from pharmaceutically 20 acceptable inorganic and organic acids and bases.
  • the word “or” in the context of “a compound or a pharmaceutically acceptable salt thereof” is understood to refer to either a compound or a pharmaceutically acceptable salt thereof (alternative), or a compound and a pharmaceutically acceptable salt thereof (in combination).
  • pharmaceutically acceptable refers to those compounds, 25 materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication.
  • pharmaceutically acceptable salts of compounds according to Formula (I) may be prepared.
  • These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification 30 of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Compounds of the invention may be made according to various schemes described below Synthetic Methods The methods of synthesis for the provided chemical entities employ readily available 35 starting materials using the following general methods and procedures. It will be appreciated that 89 70226WO01 where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization 5 procedures.
  • the methods of this invention may employ protecting groups which prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are 10 described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the provided chemical entities may contain one or more chiral centers and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures.
  • stereoisomers and enriched 15 mixtures are included within the scope of this specification, unless otherwise indicated.
  • Pure stereoisomers may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. 20
  • 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.
  • reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about - 78 C to about 110 C over a period of about 1 to about 24 hours; reactions left to run overnight 35 average a period of about 16 hours.
  • solvent each mean a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N- 5 methylpyrrolidone (“NMP”), pyridine and the like.
  • solvent solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N- 5 methylpyrrolidone (“NMP”), pyridine and the like.
  • THF tetrahydrofuranyl
  • DMF dimethylform
  • Isolation and purification of the chemical entities and intermediates described herein can be affected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.
  • the (R)- and (S)-isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which 15 may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a specific enantiomer 20 may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • EXAMPLES The following examples serve to more fully describe the manner of making and using the above-described invention. It is understood that these examples in no way serve to limit the true 25 scope of the invention, but rather are presented for illustrative purposes. In the examples and the synthetic schemes herein, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.
  • DCM dichloromethane 70226WO01
  • MPLC medium pressure liquid chromatography
  • MS mass spectrum Equipment Description NMR Instrumentation and data: 1H NMR spectra were recorded at 25°C on various instruments as listed below with all 5 spectrometers operating at 400 MHz.
  • Method B Instrument: Agilent 1200 & 6110B 20 Scan Mode: Positive Electrospray Ionization Scan Range: 100-1000 amu LC Conditions: The LCMS analysis was conducted on a Xbridge Shield RP182.1*50 mm, (5 um particles) column. The gradient employed was: Mobile Phase A: 10 mM ammonium bicarbonate in water 25 Mobile Phase B: Acetonitrile in in in in 95 70226WO01 UV detection provided by summed absorbance signal at 214 nm and 254 nm scanning.
  • Preparative LC-MS system and method description Method A: Instrument: Waters Fractionlynx system 5 Hardware: 2767 Dual Loop Autosampler/Fraction Collector; 2525 preparative pump; CFO (column fluidic organizer) for column selection; RMA (Waters reagent manager) as make up pump; Waters ZQ Mass Spectrometer; Waters 2996 Photo Diode Array detector. Waters ZQ Mass Spectrometer: Scan Mode: Alternating Positive/Negative Electrospray 10 Scan Range: 100-2000 amu LC Conditions: Preparative LCMS separations were conducted on a HALO C-18, 4.6*50 mm, 2.7 ⁇ m, C18 column at 45 0 C.
  • Method B Instrument: Agilent 1100 LC-MS preparative system: Hardware: 1100 series “prepALS” autosampler; 1100 series “PrepPump” for preparative flow 25 gradient and 1100 series “QuatPump” for pumping modifier in prep flow; 1100 series “MWD” Multi Wavelength Detector; 1100 series “LC-MSD VL” detector; 2 x "Prep-FC” fraction collector; “Waters RMA” make-up pump; Agilent Active Splitter.
  • Agilent MS running conditions Capillary voltage: 4000 V (3500 V on ES Negative); Fragmentor/Gain: 150/1; Drying gas flow: 12.0 L/min; Gas Temperature: 350 °C; Nebuliser 30 Pressure: 50 psig; Scan Range: 125-800 amu; Ionisation Mode: ElectroSpray Positive or ElectroSpray Negative.
  • LC Conditions Preparative LCMS separations were conducted on a HALO C-18, 4.6*50 mm, 2.7 ⁇ m, C18 column at 45 0 C.
  • Step 2 of 11 Synthesis of Intermediate 2.2, methyl 2-(5-bromo-3-nitropyridin-2-yl)acetate. Two reactions were carried out in parallel: To a suspension of dimethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (416 g, 1.25 mol, 1 eq) in H 2 O (600 mL) was added LiCl (265 g, 6.24 mol, 5 eq).
  • Step 7 of 11 Synthesis of Intermediate 2.7, tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3- dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate.
  • Step 8 of 11 Synthesis of Intermediate 2.8, 1-(tert-butoxycarbonyl)-6-(4-fluorobenzyl)-3,3- 35 dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine 4-oxide. 101 70226WO01
  • a solution of tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine- 1-carboxylate (35.0 g, 98.2 mmol 1 eq) in DCM (600 mL) was added m-CPBA (25.9 g, 128 mmol, 85% purity, 1.3 eq) at 0°C.
  • Step 9 of 11 Synthesis of Intermediate 2.9, tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate.
  • Step 2 of 4 Synthesis of Intermediate 11.2, tert-butyl 3,3-dimethyl-5-oxo-6- [(2,4,5- trifluorophenyl)methyl]-2,4-dihydropyrrolo[3,2-b]pyridine-1-carboxylate.
  • the mixture was quenched with H 2 O (50 mL), then extracted with EtOAc (50 mL * 2), and then the water phase was acidified with 1M HCl to pH 1-2.
  • the acidic aqueous phase was extracted with DCM (50 mL * 3) and the combined organic phase was washed 10 with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the crude product was purified by reversed-phase MPLC (column: C1820-35um 100A 60g; mobile phase: [water-MeOH]; B%: 0%-60%, 45mL/min) to give the title compound (650 mg, 2.10 mmol, 31.0% yield) as a yellow oil.
  • Step 6 of 6 Synthesis of Intermediate 21.6, tert-butyl ((S)-1-(((S)-3-(4-(2- azidoethoxy)phenyl)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropan-2-yl)amino)-1-oxop -2-yl)(methyl)carbamate.
  • Step 7 of 7 Synthesis of Intermediate 23.7, 2-(4-((S)-2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)propanamido)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropyl)phenoxy)acetic acid.
  • Step 3 of 4 Synthesis of Intermediate 31.3, 3,5-dichloro-4-iodophenol.
  • Step 1 of 7 Synthesis of Intermediate 38.1, 4-benzyl 3-(tert-butyl) (4S,5R)-5-methyl-1,2,3- oxathiazolidine-3,4-dicarboxylate 2,2-dioxide.
  • a mixture of SOCl 2 (12.5 g, 105 mmol, 7.62 mL, 1.30 eq) in CH 3 C mL) was degassed and purged with N 2 three times.
  • Benzyl (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-butanoate 25 g, 80.8 mmol, 1 eq) in CH 3 CN (180 mL) was added dropwise over 30 min at -40°C.
  • the reaction mixture was quenched by addition of H 2 O (200 mL), and then diluted with EtOAc (200 mL) and extracted with EtOAc (200 mL * 3). The combined organic phase was washed with saturated NaCl 20 aq.
  • Step 3 of 7 Synthesis of Intermediate 38.3, tert-butyl (4S,5R)-4-[5-[tert-20 butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-
  • 4S,5R)-3-tert-butoxycarbonyl-5-methyl-2,2-dioxo-oxathiazolidine-4-carboxylic acid (2.62 g, 9.31 mmol, 1.2 eq)
  • DIEA (3.01 g, 23.3 mmol, 4.06 mL, 3 eq) in DCM (80 mL) was added tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5- 25 yl]oxy]-dimethyl-silane (3 g
  • Step 4 of 7 Synthesis of Intermediate 38.4, tert-butyl N-[(1S,2S)-2-azido-1-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- 1-carbonyl]propyl]carbamate.
  • Step 5 of 7 Synthesis of Intermediate 38.5, 1-[(2S,3S)-2-amino-3-azido-butanoyl]-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one.
  • Step 7 of 7 Synthesis of Intermediate 38.7, tert-butyl N-[(1S)-2-[[(1S,2S)-2-azido-1-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- 1-carbonyl]propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate.
  • Step 4 of 8 Synthesis of Intermediate 40.4, tert-butyl N-[(1S)-1-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- 1-carbonyl]-5-(pent-4-ynoylamino)pentyl]carbamate.
  • Step 5 of 8 Synthesis of Intermediate 40.5, tert-butyl N-[(1S)-5-[[10-[[(5S)-5-(tert -butoxycarbonylamino)-6-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-6-oxo-hexyl]amino]-10-oxo-deca-4,6- diynoyl]amino]-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl- 2H-pyrrolo[3,2-b]pyridine-1-carbonyl]pentyl]carbamate.
  • Step 6 of 8 Synthesis of Intermediate 40.6, N,N'-bis[(5S)-5-amino-6-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-6-oxo- hexyl]deca-4,6-diynediamide.
  • Step 7 of 8 Synthesis of Intermediate 40.7, tert-butyl N-[(1S)-2-[[(1S)-5-[[10-[[(5S)-5-[[(2S)-2-25 (tert-butoxycarbonylamino)propanoyl]amino]-6-[6-[(4-fluoroph n l)m th l]-33-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-6-oxo-hexyl]amino ]- -oxo- eca- , - diynoyl]amino]-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]pentyl]amino]-1-methyl-2-oxo-ethyl
  • Step 8 of 8 Synthesis of Example 1, N1,N10-bis((S)-5-((S)-2-aminopropanamido)-6-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6- oxohexyl)deca-4,6-diynediamide.
  • Step 2 of 2 Synthesis of Example 2, N1,N10-bis((S)-5-((S)-2-aminobutanamido)-6-(6-(4-20 fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6- oxohexyl)deca-4,6-diynediamide.
  • Example 3 N1,N10-bis((S)-6-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-5-((S)-2-(methylamino)propanamido)-6-oxohexyl)deca-4,6- diynediamide.
  • Example 4 N1,N10-bis((S)-6-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-5-((S)-2-(methylamino)butanamido)-6-oxohexyl)deca-4,6- diynediami .
  • Example 5 N1,N10-bis((S)-5-((R)-2-aminopropanamido)-6-(6-(4-fluorobenzyl)-3,3-dimethyl- 5-oxo-2,3,4 hydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6-oxohexyl)deca-4,6-diynediamide.
  • Example 6 (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(4-((S)-2-aminopropanamido)-5-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5- 10 oxopenta nam de).
  • Step 2 of 7 Synthesis of Intermediate 45.2, (2S)-2-(tert-butoxycarbonylamino)-5-oxo-5- (prop-2-ynylamino)pentanoic acid.
  • Step 6 of 7 Synthesis of Intermediate 45.6, tert-butyl N-[(1S)-2-[[(1S)-4-[6-[[(4S)-4 -[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]-5-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-5-ox noyl]amino]hexa-2,4- diynylamino]-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]-4-oxo-butyl]amino]-1-methyl-2-oxo-ethyl]carbamate.
  • Step 7 of 7 Synthesis of Example 6, (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(4-((S)-2- aminopropanamido)-5-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-5-oxopentanamide).
  • Step 2 of 2 Synthesis of Example 7, (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(5-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-((S)-2- (methylamino)propanamido)-5-oxopentanamide).
  • Example 8 (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(4-((S)-2-aminobutanamido)-5-(6-(4-20 fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5- oxopentanamide).
  • Step 1 of 2 Synthesis of Intermediate 47.1, tert-butyl N-[(1S)-1-[[(1S)-4-[6-[[(4S)-4-[[(2S)-2-25 (tert-butoxycarbonylamino)butanoyl]amino]-5-[6-[(4-fl h l h l 33 di hyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo-penta noy]am no] exa- , -d ynyamino]-1- carbonyl]-4-oxo-butyl]carbamoyl]propyl]carbamate.
  • Example 9 The following final compounds were prepared according to the same procedure as Example 8: Examples 9 and 10. The compounds were found to have characterizing data as set forth below. 159 70226WO01 Example 9, (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(5-(6-(4-fluorobenzyl)-3,3-dimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-((S)-2-(methylamino)butanamido)-5- oxopentanamide).
  • Example 10 (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(5-(6-(4-fluorobenzyl)-3,3-dimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-((R)-2-(methylamino)propanamido)- 5-oxopentanamide).
  • Step 2 of 2 Synthesis of Example 11, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-aminopropanamide).
  • Step 1 of 2 Synthesis of Intermediate 51.1, tert-butyl N-[(1S)-2-[[(1S)-1- [[4-[6-[4-[(2S)-2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-20 propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,
  • Example 13 (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- 35 b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-aminobutanamide).
  • the mixture was 169 70226WO01 stirred at 15°C for 12.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass.
  • the mixture was filtered and the filter cake was dried to give the title compound (480 mg, 459 umol, 99.0% yield, 2 HCl) as a yellow oil.
  • Step 7 of 7 Synthesis of Example 19, (2S,2'S)-N,N'-((2S,2'S)-((octa-3,5-diyne-1,8- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- 35 (methylamino)propanamide).
  • Step 4 of 5 Synthesis of Intermediate 60.4, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((butane-1,4- diylbis(oxy))bis(4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- 35 diyl))bis(azanediyl))bis(1-oxopropane-2,1-diyl))bis(methylcarbamate).
  • Step 5 of 5 Synthesis of Example 21, (2S,2'S)-N,N'-((2S,2'S)-((butane-1,4-15 diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)propanamide).
  • Example 22 (2S,2'S)-N,N'-((2S,2'S)-((hexane-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- 5 fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide).
  • Step 2 of 2 Synthesis of Example 23, (S)-N-((S)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(4-((1-(2-(4-((S)-3-(6-(4-fluorobenzyl)-3,3-15 dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2- xopropyl)phenoxy)ethyl)-1H-1,2,3-triazol-4- yl)methoxy)phenyl)-1-oxopropan-2-yl)-2-(methylamino)propanamide.
  • Step 1 of 7 Synthesis of Intermediate 64.1, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(1- (prop-2-yn-1-yl)-1H-indol-3-yl)propanoate. 5 To a solution of methyl (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)propanoate in DMF (100 mL) was added t-BuOK (4.23 g, 37.7 mmol, 1.2 eq) at 0°C.
  • Step 3 of 7 Synthesis of Intermediate 64.3, (S)-tert-butyl (1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(1-(prop- 2-yn-1-yl)-1H-indol-3-yl)propan-2-yl)carbamate.
  • Step 4 of 7 Synthesis of Intermediate 64.4, tert-butyl N-[(1S)-1-[[1-[6-[3-[(2S)-2-(tert- butoxycarbonylamino)-3-[6-[(4-fluorophenyl)methyl]-3,3-di th l 5 xo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]indol-1 l - , - iynyl]indol-3- yl]methyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5 -oxo- , -dihydropyrrolo[3,2- 30 b]pyridin-1-yl]-2-oxo-ethyl]carbamate.
  • Step 5 of 7 Synthesis of Intermediate 64.5, 1,1'-((2S,2'S)-3,3'-(1,1'-(hexa-2,4-diyne-1,6- diyl)bis(1H-indole-3,1-diyl))bis(2-aminopropanoyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-2,3- dihydro-1H-pyrrolo[3,2-b]pyridin-5(4H)-one).
  • Step 7 of 7 Synthesis of Example 25, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(1H- indole-1,3-diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- 10 pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide).
  • the acidic aqueous phase was extracted 20 with DCM (4 x 200 mL) and the combined organic phase was 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 reversed-phase MPLC (column: C1820-35um 100A 330 g; mobile phase: [water- CH 3 CN], B%: 0%-60%, 80 mL/min) to give the title compound (17.6 g, 74.2% yield) as a yellow oil.
  • Step 2 of 6 Synthesis of Intermediate 68.2, tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl] oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-(prop-2- ynoxymethyl)ethyl]carbamate.
  • Step 4 of 6 Synthesis of Intermediate 68.4, 1-[(2S)-2-amino-3-[6-[(2S)-2-amino-3-[6-[(4- 5 fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo- propoxy]hexa-2,4-diynoxy]propanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2,4- dihydropyrrolo[3,2-b]pyridin-5-one.
  • Step 5 of 6 Synthesis of Intermediate 68.5, tert-butyl N-[(1S)-1-[[(1S)-1-[6-[(2S)-2-[[(2S)-2- [tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyrid y xo-propoxy]hexa-2,4- diynoxymethyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- 25 b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate.
  • Example 30 (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(3-(6-(4- fluorobenzyl)-3,3-di hyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- 30 oxopropane-1,2-diyl) )bis(2-(methylamino)propanamide).
  • the acidic aqueous phase was extracted with DCM (4 * 200 mL) and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under 10 reduced pressure to give a residue.
  • the residue was purified by reversed-phase MPLC (column: C1820-35um 100A 330g; mobile phase: [water-CH 3 CN], B%: 0%-60%, 80 mL/min) to give the desired compound (5.29 g, 20.56 mmol, 45.08% yield) as a yellow oil.
  • Step 2 of 6 Synthesis of Intermediate 71.2, tert-butyl N-[(1S,2R)-1- [5- [tert-butyl (dimethyl) silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]-2- prop-2-ynoxy-propyl]carbamate.
  • Step 1 of 8 Synthesis of Intermediate 75.1, methyl (2S)-2-(tert- butoxycarbonylamino) -3-(3- hydroxyphenyl)propanoate.
  • Step 5 of 8 Synthesis of Intermediate 75.5, di-tert-butyl ((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(3,1-phenylene))bis(3-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))dicarbamate.
  • Example 37 (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(3,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide).
  • Step 2 of 6 Synthesis of Intermediate 77.2, (S)-(9H-fluoren-9-yl)methyl (2-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxo-1- (piperidin-4-yl)ethyl)carbamate.
  • Step 4 of 6 Synthesis of Intermediate 77.4, 1,10-bis(4-((S)-1-amino-2-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)piperidin-1- 5 yl)decane-1,10-dione.
  • Step 2 of 4 Synthesis of Intermediate 78.2, 1-[(2S)-2-amino-2-[1-[4-[4-[(1S)-1-amino-2-[6- [(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo- ethyl]piperidine-1-carbonyl]phenyl]benzoyl] iperidyl]acetyl]-6-[(4-fluorophenyl)methyl]- 20 3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one.
  • Step 4 of 4 Synthesis of Example 39, (2S,2'S)-N,N'-((1S,1'S)-(([1,1'-biphenyl]-4,4'- dicarbonyl)bis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1-diyl))bis(2- (methylamino)butanamide).
  • Example 40 (2S,2'S)-N,N'-((1S,1'S)-(((perfluoro-1,4-phenylene)bis(methylene))bis(piperidine- 1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- 10 b]pyridin-1-yl)-2-oxoethane-1,1-diyl))bis(2-(methylamino)butanamide).
  • Step 2 of 4 Synthesis of Intermediate 79.2, 1,1'-((2S,2'S)-2,2'-(((perfluoro-1,4- phenylene)bis(methylene))bis(piperidine-1,4-diyl))bis(2-aminoacetyl))bis(6-(4-fluorobenzyl)- 3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrol in-5-one).
  • Step 3 of 4 Synthesis o f Intermediate 79.3, di-tert-butyl ((2S,2'S)-(((1S,1'S)-(((perfluoro-1,4- phenylene)bis(methylene))bis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1- diyl))bis(azanediyl))bis(1-oxobutane-1,2-diyl))bis(methylca 20 To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (22.83 mg, 105.10 umol, 2.1 eq), DIEA (25.87 mg, 200.18
  • Step 4 of 4 Synthesis of Example 40, (2S,2'S)-N,N'-((1S,1'S)-(((perfluoro-1,4- phenylene)bis(methylene))bis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1-diyl))bis(2- 35 (methylamino)butanamide).
  • Step 1 of 4 Synthesis of Intermediate 80.1, (S)-1-(2-amino-2-(1-(prop-2-yn-1-yl)piperidin-4- yl)acetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5(4H)-one.
  • Step 2 of 4 Synthesis of Intermediate 80.2, tert-butyl ((S)-1-(((S)-2-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxo-1-(1-(prop-2-yn-1- yl)piperidin-4-yl)ethyl)amino)-1-oxobutan-2-yl)(methyl)carbamate on
  • Step 4 of 4 Synthesis of Example 41, (2S,2'S)-N,N'-((1S,1'S)-(hexa-2,4-diyne-1,6-20 diylbis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-
  • Step 1 of 10 Synthesis of Intermediate 81.1, (R)-(2-((tert-butoxycarbonyl)amino) -3- 10 methoxy-3-oxopropyl)zinc(II) iodide.
  • Zinc powder (10.5 g, 161 mmol, 3.53 eq) was added to a rapidly stirring solution of 2% aqueous HCl (108 mL) and stirred for 3 minutes.
  • the aqueous solution was decanted and the zinc was washed in rapid succession with EtOH (70 mL), acetone (2 * 35 mL), and MTBE (120 mL).
  • EtOH 70 mL
  • acetone 2 * 35 mL
  • MTBE 120 mL
  • the zinc was rapidly filtered, transferred to a 250 mL round bottomed flask and dried at 80°C under 15 vacuum for 2 h.
  • the flask containing the zinc dust was backfilled with N 2 and DMF (80 mL) was added followed by 1,2-dibromoethane (1.71 g, 9.11 mmol, 688 uL, 0.2 eq).
  • the suspension was heated at 80°C for 30 minutes.
  • Step 7 of 10 Synthesi s o Intermedate 81.7, (S)-2-((S)-2-((tert-butoxycarbonyl)(methyl) amino)butanamido)-3-(4-(prop-2-yn-1-yloxy)naphthalen-1-yl)propanoic acid.
  • Step 9 of 10 Synthesis of Intermediate 81.9, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(naphthalene-4,1-diyl))bis(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4- fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate).
  • Step 10 of 10 Synthesis of Example 42, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(naphthalene-4,1-diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- 214 70226WO01 tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide).
  • Step 2 of 10 Synthesis of Intermediate 82.2, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4- hydroxy-2,3-dimethylphenyl)propanoate. 216 70226WO01
  • MeOH 50 mL
  • Pd/C 1.5 g, 10% purity
  • Step 3 of 10 Synthesis of Intermediate 82.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3- (2,3-dimethyl-4-(prop-2-yn-1-yloxy)phenyl)propanoate.
  • Step 4 of 10 Synthesis of Intermediate 82.4, (S)-2-((tert-butoxycarbonyl)amino)-3-(2,3- dimethyl-4-(prop-2-yn-1-yloxy)phenyl)propanoic acid.
  • Step 5 of 10 Synthesis of Intermediate 82.5, (S)-tert-butyl (1-(5-((tert-10 butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2,3-dimethyl-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)carbamate.
  • Step 7 of 10 Synthesis of Intermediate 82.7, (S)-2-amino-1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(2,3-dimethyl- 4-(prop-2-yn-1-yloxy)phenyl)propan-1-one.
  • Step 8 of 10 Synthesis of Intermediate 82.8, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2,3-dimethyl-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- 30 oxobutan-2-yl)(methyl)carbamate.
  • Step 9 of 10 Synthesis of Intermediate 82.9, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-15 diyne-1,6-diylbis(oxy))bis(2,3-dimethyl-4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane- 3,2-diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate).
  • Step 10 of 10 Synthesis of Example 43, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(2,3-dimethyl-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- 35 (methylamino)butanamide).
  • Step 3 of 9 Synthesis of Intermediate 83.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2- methoxy-4-(prop-2-yn-1-yloxy)phenyl)propanoate.
  • 3-bromoprop-1-yne (1.76 g, 11.8 mmol, 1.27 mL, 80% purity, 1.2 eq)
  • K 2 CO 3 (2.72 g, 19.7 mmol, 2 eq) in DMF (30 mL).
  • Step 4 of 9 Synthesis of Intermediate 83.4, (S)-methyl 2-amino-3-(2-methoxy-4-(prop-2-yn-1- 30 yloxy)phenyl)propanoate hydrochloride.
  • methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2-methoxy-4-prop-2-ynoxy- phenyl)propanoate (3.48 g, 9.58 mmol, 1 eq) in EtOAc (15 mL) was added HCl/EtOAc (4 M, 30 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass.
  • Step 5 of 9 Synthesis of Intermediate 83.5, (S)-methyl 2-((S)-2-((tert- butoxycarbonyl)(methyl) amino)butanamido)-3-(2-methoxy-4-(prop-2-yn-1- 10 yloxy)phenyl)propanoate.
  • Step 6 of 9 Synthesis of Intermediate 83.6, (S)-2-((S)-2-((tert-butoxycarbonyl)(methyl) amino)butanamido)-3-(2-methoxy-4-(prop-2-yn-1-yloxy)phenyl)propanoic acid.
  • Step 7 of 9 Synthesis of Intermediate 83.7, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2-methoxy-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- oxobutan-2-yl)(methyl)carbamate.
  • Step 8 of 9 Synthesis of Intermediate 83.8, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-diyne- 1,6-diylbis(oxy))bis(2-methoxy-4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-30 fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate).
  • Step 9 of 9 Synthesis of Example 44, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-10 diylbis(oxy))bis(2-methoxy-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin -3-oxopropane-1,2-diyl))bis(2- (meth ino)butanamide).
  • Step 2 of 10 Synthesis of Intermediate 84.2, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2- cyano-4-hydroxyphenyl)propanoate 227 70226WO01
  • methyl (2S)-3-(4-benzyloxy-2-cyano-phenyl)-2-(tert-butoxy carbonylamino)propanoate 8 g, 19.5 mmol, 1 eq
  • Pd/C 8 g, 10% purity
  • Step 3 of 10 Synthesis of Intermediate 84.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2- cyano-4-(prop-2-yn-1-yloxy)phenyl)propanoate. 15
  • Step 4 of 10 Synthesis of Intermediate 84.4, (S)-2-((tert-butoxycarbonyl)amino)-3-(2-cyano- 4-(prop-2-yn-1-yloxy)phenyl)propanoic acid.
  • Step 5 of 10 Synthesis of Intermediate 84.5, (S)-tert-butyl (1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2-cyano-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)carbamate.
  • Step 6 of 10 Synthesis of Intermediate 84.6, (S)-2-(2-amino-3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b idin-1-yl)-3-oxopropyl)-5-(prop-2-yn- 1-yloxy)benzonitrile.
  • Step 7 of 10 Synthesis of Intermediate 84.7, (S)-2-(2-amino-3-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- 10 b]pyridin-1-yl)-3-oxopropyl)-5-(prop-2-yn-1-yloxy)benzonitrile.
  • Step 8 of 10 Synthesis of Intermediate 84.8, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-30 b]pyridin-1-yl)-3-(2-cyano-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- oxobutan-2-yl)(methyl)carbamate.
  • Step 9 of 10 Synthesis of Intermediate 84.9, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-20 1-yl]-3-oxo-propyl]-3-cyano-phenoxy]hexa-2,4- yl]methyl]-2-[5-[tert- l]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- bamate.
  • Step 10 of 10 Synthesis of Example 45, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(2-cyano-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- 5 (methylamino)butanamide).
  • Step 3 of 10 Synthesis of Intermediate 85.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2- ethyl-4-(prop-2-yn-1-yloxy)phenyl)propanoate.
  • Step 4 of 10 Synthesis of Intermediate 85.4, (S)-2-((tert-butoxycarbonyl)amino)-3-(2-ethyl-4- (prop-2-yn-1-yloxy)phenyl)propanoic acid.
  • Step 5 of 10 Synthesis of Intermediate 85.5, (S)-tert-butyl (1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- 10 b]pyridin-1-yl)-3-(2-ethyl-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)carbamate.
  • Step 6 of 10 Synthesis of Intermediate 85.6, (S)-1-(2-amino-3-(2-ethyl-4-(prop-2-yn-1-25 yloxy)phenyl)propanoyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-5(4H)-one hydrochloride.
  • Step 7 of 10 Synthesis of Intermediate 85.7, (S)-2-amino-1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(2-ethyl-4- (prop-2-yn-1-yloxy)phenyl)propan-1-one.
  • Step 8 of 10 Synthesis of Intermediate 85.8, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2-ethyl-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- oxobutan-2-yl)(methyl)carbamate.
  • Step 9 of 10 Synthesis of Intermediate 85.9, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(2-ethyl-4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4- 5 fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methyl
  • Step 10 of 10 Synthesis of Example 46, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(2-ethyl-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide).
  • Step 2 of 9 Synthesis of Intermediate 86.2, methyl (2S)-2-(tert-butoxycarbonylamino)- 3-(4- hydroxy-2,6-dimethyl-phenyl)propanoate.
  • methyl (2S)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-(tert- butoxycarbonylamino)propanoate (6.4 g, 15.5 mmol, 1 eq) in MeOH (200 mL) was added Pd/C 15 (2.5 g, 10% purity) under N2 atmosphere.
  • Pd/C 15 2.5 g, 10% purity
  • Step 5 of 9 Synthesis of Intermediate 86.5, methyl (2S)-2-[[(2S)-2-[tert-butoxycarbonyl (methyl)amino]butanoyl]amino]-3-(2,6-dimethyl-4-prop-2-ynoxy-phenyl)propanoate.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a compound of Formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof.

Description

70226WO01 COMPOUNDS USEFUL IN HIV THERAPY CROSS REFERENCE TO RELATED APPLICATION The present application claims filing benefit of U.S. Provisional Patent Application No. 5 63/643,956 having a filing date of May 8, 2024, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION The present invention relates to compounds, pharmaceutical compositions, and methods of use thereof in connection with individuals infected with HIV, HBV, or cancer. 10 BACKGROUND OF THE INVENTION Human immunodeficiency virus type 1 (HIV-1) infection leads to the contraction of acquired immune deficiency disease (AIDS). Presently, long-term suppression of viral replication with antiretroviral drugs is the only option for treating HIV-1 infection. Indeed, the U.S. Food and Drug Administration has approved twenty-five drugs over six different inhibitor classes, which 15 have been shown to greatly increase patient survival and quality of life. However, additional therapies are still believed to be required due to a number of issues including, but not limited to undesirable drug-drug interactions; drug-food interactions; non-adherence to therapy; drug resistance due to mutation of the enzyme target; and inflammation related to the immunologic damage caused by the HIV infection. 20 Currently, almost all people living with HIV are treated with therapeutic regimens of antiretroviral drug combinations termed, highly active antiretroviral therapy (“HAART”). However, HAART therapies are often complex because a combination of different drugs must be administered often daily to the patient to avoid the rapid emergence of drug-resistant HIV-1 variants. Despite the positive impact of HAART on patient survival, drug resistance can still occur 25 and the survival and quality of life are not normalized as compared to uninfected persons [Lohse Ann Intern Med 2007146;87-95]. Indeed, the incidence of several non-AIDS morbidities and mortalities, such as cardiovascular disease, frailty, and neurocognitive impairment, are increased in HAART-suppressed, HIV-infected subjects [Deeks Annu Rev Med 2011;62:141-155]. This increased incidence of non-AIDS morbidity/mortality occurs in the context of, and is potentially 30 caused by, elevated systemic inflammation related to the immunologic damage caused by HIV infection and residual HIV infection [Hunt J Infect Dis 2014][Byakagwa J Infect Dis 2014][Tenorio J Infect Dis 2014]. Modern antiretroviral therapy (ART) has the ability to effectively suppress HIV replication and improve health outcomes for HIV-infected persons, but is believed to not be capable of 1 70226WO01 completely eliminating HIV viral reservoirs within the individual. HIV genomes can remain latent within mostly immune cells in the infected individual and may reactivate at any time, such that after interruption of ART, virus replication typically resumes within weeks. In a handful of individuals, the size of this viral reservoir has been significantly reduced and upon cessation of 5 ART, the rebound of viral replication has been delayed [Henrich TJ J Infect Dis 2013][Henrich TJ Ann Intern Med 2014]. In a small number of cases, the viral reservoir was eliminated during treatment of leukemia and no viral rebound was observed during several years of follow-up [Hutter G N Engl J Med 2009] [Gupta The Lancet HIV 2020]. These examples suggest the concept that reduction or elimination of the viral reservoir may be possible and can lead to viral remission or 10 cure. As such, ways have been pursued to eliminate the viral reservoir, by direct molecular means, including excision of viral genomes with CRISPR/Cas9 systems, or to induce reactivation of the latent reservoir during ART so that the latent cells are eliminated. It is believed that reversal of latency is required to make latently infected cells vulnerable to clearance. SMACm (Second Mitochondrial-derived Activator of Caspases mimetics), also known as 15 inhibitors of the Inhibitor of Apoptosis Proteins or IAPi, are a class of compounds that have recently entered clinical trials as potential cancer treatments. The drugs deplete and/or inhibit cellular inhibitor of apoptosis proteins (cIAP) that act as anti-apoptotic proteins, thereby promoting the cell death of cancer cells. Antagonism and/or depletion of cIAP also leads to activation of the non-canonical NF-kB signaling pathway, that may induce HIV expression and may enable 20 elimination of HIV infected cells. In addition, SMACm/IAPi may selectively promote the cell death of cells infected by HIV [Campbell Cell Host Microbe 2018] or HBV [Ebert Proc Nat Acad Sci 2013] by antagonizing anti-apoptotic proteins. Recently, the targeting of the non-canonical NF-kB (ncNF-κB) pathway to reverse latency in cell line models was reported. The ncNF-κB pathway is typically activated by ligation of a 25 subset of TNF receptor family members. In the steady state, a multimolecular complex with ubiquitin ligase activity consisting of TNF receptor-associated factor 2 (TRAF2), TRAF3, and cellular inhibitor of apoptosis protein-1 (cIAP1) associates with the cytoplasmic portion of the unligated receptor and constitutively ubiquitinylates and degrades the NF-κB-inducing kinase (NIK). Upon receptor ligation, cIAP1 ubiquitinylates TRAF3 and auto-ubiquitinylates, leading to 30 proteasomal degradation of TRAF3 and cIAP1, thereby disinhibiting NIK accumulation. NIK is constitutively active and, once accumulated, phosphorylates the inhibitor of κB kinase-α (IKKα) homodimer. The activated IKKα/IKKα homodimer then phosphorylates the inactive p100 form of NFκB2 leading to ubiquitinylation by Skp1-Cul1-F-box ubiquitin ligase (SCFβTrCP) and proteasomal cleavage of p100, releasing the active p52 subunit. p52 associates with RelB, and this 35 heterodimer translocates into the nucleus to drive transcription from κB promoter elements. In 2 70226WO01 addition to receptor ligation, ncNF-κB can be activated by signaling intermediates of the apoptosis cascade. Cleavage of the second mitochondrial activator of caspases (SMAC) from the mitochondrial membrane exposes the N-terminal motif Ala-Val-Pro-Ile, which binds specifically to the baculovirus intermediate repeat (BIR) domains of the IAP proteins. Such BIR binding in 5 cIAP1/2 activates the ubiquitin ligase activity of the TRAF2:TRAF3:cIAP complex, inducing autoubiquitinylation and degradation of cIAP1/2, NIK accumulation, and activation of the ncNF- κB pathway [Sampey bioRxiv 2018][Nixon Nature 2020]. Binding of SMAC to the BIR domains of XIAP and ML-IAP antagonizes the caspase inhibition activities of these molecules, often overexpressed in tumor cells, leading to potentiation of apoptosis. 10 Accordingly, the discovery and development of new SMACm/IAPi molecules represent a currently unmet medical need. SUMMARY OF THE INVENTION The present invention relates to compounds according to Formula (I): 15 each R1 and R2 is -H or -CH3; each R3 is -H, -CH3, -CH2CH3, cyclopropyl, -CH2-OH, or -CH(OH)CH3; each R4 is -H, -F, -Cl, -CH3, -CF3, -CN, -OH, -OCH3, -C(O)N(CH3)2, -CH(CH3)2, 20 or -C(O)OCH3; each R5 is -H or -F; each R6 is -H, -F, -Cl, -Br, -CN, -CH3, -CHF2, or -CF3; each R7 is -H; each R8 is -H, -F, -Cl, or -CN; 3 70226WO01 each R9 is -H or -CH3; each R10 is -H or -CH3; each X is -CH2- or -O-; each Y1 is -CH- or -C(O)-; 5 each Y2 is -N-, -NH-, or -NCH3-; each represents a single bond or a double bond, wherein when Y1 is -CH-, Y2 is -N- and represents a double bond and when Y1 is -C(O)-, Y2 is -NH- or -NCH3-, and represents a single bond; L is a linker selected from the group consisting of -(C≡C)2-, a C1-C8 alkylene, -10 C(O)NHCH2-, -NHC(O)CH2-, -C(O)NH-U-NHC(O)-, -NHC(O)-U-C(O)NH-, -C(O)NH-U-Ar1-U- NHC(O)-, -NHC(O)-U-Ar1-U-C(O)NH-, an optionally substituted C5-C12 arylene including from 0- 3 heteroatoms, -Ar2-Ar3-, -Ar4-T-Ar5-, -T-Ar6-T-, and -T-Ar7-T-Ar8-T- wherein -Ar1-, -Ar2-, -Ar3-, -Ar4-, -Ar5-, -Ar6-, -Ar7-, and -Ar8- are each a C6 arylene; -T- is -O-, -CH2-, -C(CH3)(CH3)-, or -C(CF3)(CF3)-; and 15 -U- is a C1-C4 alkylene or a direct bond; Z1 is a C1-C4 alkylene or a direct bond; Z2 is a C1-C4 alkylene or a direct bond; W1 is -(CH2)nNHC(O)-, -C(O)NH(CH2)n-, -O-, -C(O)-, -(CH2)m-O-, -O-(CH2)m-, or a direct bond where n is from 0 to 3 and m is from 1 to 4; 20 W2 is -(CH2)nNHC(O)-, -C(O)NH(CH2)n-, -O-, -C(O)-, -(CH2)m-O-, -O-(CH2)m-, or a direct bond where n is from 0 to 3 and m is from 1 to 4; V1 is an optionally substituted C1-C4 alkylene, a heterocycloalkylene, an optionally substituted arylene, or a combination thereof; V2 is an optionally substituted C1-C4 alkylene, a heterocycloalkylene, an optionally 25 substituted arylene, or a combination thereof; Q1 is an optionally substituted C1-C4 alkylene or a direct bond; and Q2 is an optionally substituted C1-C4 alkylene or a direct bond. Another aspect of the invention provides a pharmaceutical composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt thereof and a 30 pharmaceutically acceptable excipient. In another aspect, the invention provides a method of treating an HIV infection in a human comprising administering to the human a therapeutically effective amount of a compound according to Formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition comprising a compound according to Formula (I) or a 35 pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 4 70226WO01 In yet another aspect, the invention provides a use of a compound according to Formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition comprising a compound according to Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, in the manufacture of a medicament for treating an HIV 5 infection. In still another aspect, the invention provides a method of treating cancer and pre- cancerous syndromes, in a human in need thereof, which comprises administering to the human a therapeutically effective amount of a compound according to Formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition comprising a compound 10 according to Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In another aspect, the invention provides a method of depleting HIV infected cells comprising administering to a subject a compound of Formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition comprising a compound according to 15 Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In still aspect, the invention provides a combination comprising a compound of Formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutical agents active against HIV. In certain aspects, these pharmaceutical agents active against HIV are selected 20 from the group consisting of anti-retroviral agents, latency reversing agents, and agents for clearance therapy. In yet another aspect, the invention provides a method of depleting HIV infected cells comprising administering to a subject a compound of Formula (I), or pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition comprising a compound according to 25 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 pharmaceutical agents active against HIV are selected from the group consisting of anti-retroviral agents, latency reversing agents, and agents for clearance therapy. These and other aspects are encompassed by the invention as set forth herein. 30 DETAILED DESCRIPTION Definitions It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present disclosure. In this specification and in the claims that follow, reference will be made to a number of terms that shall 35 be defined to have the following meanings. 5 70226WO01 “Alkyl” refers to a saturated, straight or branched hydrocarbon moiety having from 1 to 6 carbon atoms unless specified otherwise. The term “(C1-C6) 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. 5 “Alkylene” refers to a straight or branched chain divalent alkyl radical having from 1 to 6 carbon atoms unless specified otherwise. The term “(C1-C6) 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, and the like. “Substituted alkylene” refers to an alkylene having from 1 to 5 and, in some embodiments, 10 1 to 3 or 1 to 2 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, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted 15 arylthio, azido, 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 20 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 25 understood that the above definition is not intended to include impermissible substitution patterns. “Alkoxy” refers to a straight or branched alkoxy group having from 1 to 6 carbon atoms unless specified otherwise. For example, “C1-C6 alkoxy” means a straight or branched alkoxy group containing from 1 to 6 carbon atoms. Examples of “alkoxy” as used herein include, but are not limited to, methoxy, ethoxy, prop-1-oxy, prop-2-oxy, but-1-oxy, but-2-oxy, 2-methylprop-1-oxy, 2- 30 methylprop-2-oxy, pentoxy and hexyloxy. “Aryl” or “Ar” refers to an aromatic hydrocarbon ring. “Aryl” includes monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 15 ring member atoms unless specified otherwise, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms. “Aryl” also includes ring systems wherein the aryl ring, as defined 35 above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of 6 70226WO01 attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Examples of “alkoxy” as used herein include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenanthridinyl and the like. 5 “Arylene” refers to a divalent aromatic hydrocarbon ring. “Arylene” includes monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 15 ring member atoms unless specified otherwise, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms. “Arylene” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radicals or 10 points of attachment are on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Examples of “arylene” as used herein include or are derived from, but are not limited to, phenylene (para, meta, ortho), naphthalene, biphenyl, indole, triazole, and the like. “Substituted arylene” refers to an arylene substituted with 1 to 8 and, in some 15 embodiments, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 substituents selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, quaternary amino, aminocarbonyl, imino, amidino, aminocarbonylamino, amidinocarbonylamino, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, 20 aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, hydroxyamino, alkoxyamino, hydrazino, substituted hydrazino, heteroaryl, substituted heteroaryl, heteroaryloxy, 25 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 30 sulfonyl, sulfonyloxy, thioacyl, thiocyanate, thiol, alkylthio, and substituted alkylthio. It is understood that the above definition is not intended to include impermissible substitution patterns. “Compound” and “compounds” as used herein refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae, including the racemates, stereoisomers, 35 and tautomers of the compound or compounds. 7 70226WO01 “Cyano” refers to a −C N functional group. “Cycloalkylene” refers to a non-aromatic, saturated, cyclic divalent hydrocarbon ring containing 3 to 7 member ring atoms unless otherwise specified. “Heterocycloalkylene” refers to a “cycloalkylene” wherein at least one ring atom is a heteroatom. Examples of “cycloalkylene” as 5 used include or are derived from, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and piperidine. “Substituted cycloalkylene” refers to a cycloalkylene, as defined herein, having from 1 to 8, or 1 to 5, or in some embodiments 1 to 3 substituents selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, 10 acylamino, acyloxy, amino, substituted amino, quaternary amino, aminocarbonyl, imino, amidino, aminocarbonylamino, amidinocarbonylamino, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, azido, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, 15 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 20 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 25 definition is not intended to include impermissible substitution patterns. “Halo” or “halogen” refers to a fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br) or iodine (iodo, I). “Heteroatom” refers to nitrogen, oxygen, or sulfur. “Latency” means a concept describing 1) the dormant state of viral activity within a 30 population of cells, wherein viral production, viral packaging, and host cell lysis does not occur, or occurs at a very low frequency, or 2) the down-regulation or absence of gene expression within an infected cell. “Optionally” means that the subsequently described event(s) may or may not occur and includes both event(s) that occur and event(s) that do not occur. 8 70226WO01 “Solvate” or “solvates” of a compound refer to those compounds, where compounds is as defined above, that are bound to a stoichiometric or non-stoichiometric amount of a solvent. Solvates of a compound include solvates of all forms of the compound. In some embodiments, solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. 5 Suitable solvents include water. “Stereoisomer” refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. “Tautomer” refers to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups 10 containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. “Pharmaceutically acceptable salt” refers 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 15 Use; 2002. “Reversing HIV latency” refers to a treatment that upregulates the expression of integrated HIV genomes within latently infected cells, such as the agent that activates the non-canonical NF- kB pathway, leading to susceptibility of the infected cell to virally-induced cell death or immunologic clearance. In certain embodiments, the latent HIV infected cells are resting CD4+ T20 cells. As used herein, “depleting latent HIV infection” refers to the clearance of latently HIV- infected cells that may follow the reversal of HIV latency by reagents such as those that activate the non-canonical NF-kB pathway. In some embodiments, each of compounds 1-117 may be used in reversing HIV latency and/or depleting latent HIV infection. “Therapeutically effective amount” means any amount which, as compared to a 25 corresponding subject who has not received such amount, results in improved treatment, healing, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of a compound of Formula (I), as well as salts thereof, may be administered as the raw chemical. Additionally, the 30 active ingredient may be presented as a pharmaceutical composition. “Treating viral infections” means to inhibit the replication of the particular virus, to inhibit viral transmission, and to ameliorate or alleviate the symptoms of the disease caused by the viral infection. The treatment is considered “therapeutic” if there is a reduction in viral load, decrease in mortality and/or morbidity. “Preventing viral infections” means to prevent the virus from 9 70226WO01 establishing itself in the host. A treatment is considered “prophylactic” if the subject is exposed to the virus but does not become infected with the virus as a result of treatment. Wherever dashed lines occur adjacent to single bonds denoted by solid lines, then the dashed line represents an optional double bond at that position. For example, the dashed line in the 5 structure below could either indicate a double bond at that position or a single bond at that position: . Detailed Description The presently disclosed subject matter will now be described more fully hereinafter. 10 However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to 15 be included within the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. Unless otherwise defined, all technical and scientific terms used herein have 20 the same meaning as commonly understood by one of ordinary skill in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Apoptosis, a type of programmed cell death, plays an important role in maintaining homeostasis and regulating the number of cells in higher organisms. Abnormal apoptosis is 25 involved in a number of diseases, including autoimmune disorders, degenerative diseases of the Central Nervous System, cancer, and viral infections, such as HIV. The family of Inhibitor of Apoptosis Proteins (IAPs) plays a key role in the suppression of proapoptotic signaling in mammalian cells. SMACm, which mimic a critical tetrapeptide sequence from the second mitochondria-derived activator of caspase, have been shown to disrupt the binding of IAPs with 30 their functional partner and restore apoptotic response to proapoptotic stimuli in cells. Since the early 2000s, great effort has focused on the design and preparation of SMAC mimetics as IAP antagonists, particularly in promoting cell death in tumor cells and more recently in reversing HIV latency. SMAC mimetics bind the BIR2 and BIR3 domains of IAP proteins, leading to inhibition 10 70226WO01 (in the case of XIAP) and potentiation of apoptosis, or activation of the ubiquitin ligase activities (in the case of cIAP1 and cIAP2), leading to autoubiquitinylation and depletion of the activated proteins. As cIAP1 and 2 suppress the ncNF-kB pathway, it is observed that the activation of these proteins by SMACm leads to activation of ncNFkB transcription factor and leads to kB-dependent 5 gene expression. Such investigations have explored the activation of the non-canonical NF-kB pathway (ncNF-kB) as a potential method by which SMAC mimetics selectively deplete latent HIV cells. An example of an early SMAC mimetic studied in the context of HIV is monomeric SBI- 0637142, prepared by researchers at the Sanford–Burnham Medical Research Institute. In HIV depletion tests, SBI-0637142 was found to be potent in cell line assays, but did not exhibit activity 10 in p100-p52 conversion or HIV caRNA induction in primary cells. Much work has also been directed to the development of bivalent mimetics in the oncology field, which are covalently linked monomeric SMAC mimetics. AstraZeneca’s AZD5582 and Medivir’s Birinapant TL32711 are examples of dimeric SMAC mimetics. In HIV latency reversal studies, Birinapant TL32711 was not potent in Jurkat, p100-p52 conversion, or HIV caRNA induction. Conversely, AZD5582 15 exhibited an increase in 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 tolerability issues. The IAP proteins targeted by SMAC mimetics for ncNF-kB activation are cIAP1 and cIAP2, with bivalent molecules possessing optimal linkers having the most efficient activity at 20 depleting these two molecules and activating ncNF-kB. This ncNF-kB activating activity occurs perhaps through forming intermolecular ternary complexes wherein one bivalent SMAC mimetic interacts with one BIR domain in each of two different molecules of cIAP1 or cIAP2. XIAP is also bound and inhibited by SMAC mimetics, described in the literature as an intramolecular bond where one bivalent SMAC mimetic interacts with both the BIR2 and BIR3 domains of a single 25 molecule of XIAP. XIAP is not thought to have a role in ncNF-kB activation by SMAC mimetics and is therefore likely an off target in the HIV latency reversal context. ant 11 r ncNF-kB, reverse HIV latency in primary, unmodified primary human cells as single agents, 30 making them suitable for consideration for further development. In particular, the dimeric 11 70226WO01 SMACm of the disclosed compounds may be optimized to favor binding of the BIR3 domain of cIAP1 and cIAP2 especially over the BIR3 domain within XIAP, which should favor intermolecular ternary complex formation between two cIAP proteins and therefore favor the depletion of cIAP1 and cIAP2 over inhibition of XIAP. Other SMACm, specifically monomeric 5 molecules or dimeric molecules with unoptimized linkers or lacking this specificity for BIR3 of cIAP1 and cIAP2, are not believed to have the HIV latency reversal effect in primary human CD4+ T cells and/or likely also inhibit XIAP, leading to potential off-target effects through potentiation of unwanted apoptosis. The invention provides compounds of Formula (I), as well as various forms of these 10 compounds set forth herein (e.g., pharmaceutically acceptable salts, tautomers, and stereoisomers). It should be appreciated that any reference to the compounds of Formula (I) herein is clearly meant to also include, without limitation, those compounds set forth in Table 1. In some embodiments, the invention provides a compound of the structure according to Formula (I): 15 each R1 and R2 is -H or -CH3; each R3 is -H, -CH3, -CH2CH3, cyclopropyl, -CH2-OH, or -CH(OH)CH3; 20 each R4 is -H, -F, -Cl, -CH3, -CF3, -CN, -OH, -OCH3, -C(O)N(CH3)2, -CH(CH3)2, or -C(O)OCH3; each R5 is -H or -F; each R6 is -H, -F, -Cl, -Br, -CN, -CH3, -CHF2, or -CF3; each R7 is -H; 25 each R8 is -H, -F, -Cl, or -CN; 12 70226WO01 each R9 is -H or -CH3; each R10 is -H or -CH3; each X is -CH2- or -O-; each Y1 is -CH- or -C(O)-; 5 each Y2 is -N-, -NH-, or -NCH3-; each represents a single bond or a double bond, wherein when Y1 is -CH-, Y2 is -N- and represents a double bond and when Y1 is -C(O)-, Y2 is -NH- or -NCH3-, and represents a single bond; L is a linker selected from the group consisting of -(C≡C)2-, a C1-C8 alkylene, -10 C(O)NHCH2-, -NHC(O)CH2-, -C(O)NH-U-NHC(O)-, -NHC(O)-U-C(O)NH-, -C(O)NH-U-Ar1-U- NHC(O)-, -NHC(O)-U-Ar1-U-C(O)NH-, an optionally substituted C5-C12 arylene including from 0- 3 heteroatoms, -Ar2-Ar3-, -Ar4-T-Ar5-, -T-Ar6-T-, and -T-Ar7-T-Ar8-T- wherein -Ar1-, -Ar2-, -Ar3-, -Ar4-, -Ar5-, -Ar6-, -Ar7-, and -Ar8- are each a C6 arylene; -T- is -O-, -CH2-, -C(CH3)(CH3)-, or -C(CF3)(CF3)-; and 15 -U- is a C1-C4 alkylene or a direct bond; Z1 is a C1-C4 alkylene or a direct bond; Z2 is a C1-C4 alkylene or a direct bond; W1 is -(CH2)nNHC(O)-, -C(O)NH(CH2)n-, -O-, -C(O)-, -(CH2)m-O-, -O-(CH2)m-, or a direct bond where n is from 0 to 3 and m is from 1 to 4; 20 W2 is -(CH2)nNHC(O)-, -C(O)NH(CH2)n-, -O-, -C(O)-, -(CH2)m-O-, -O-(CH2)m-, or a direct bond where n is from 0 to 3 and m is from 1 to 4; V1 is an optionally substituted C1-C4 alkylene, a heterocycloalkylene, an optionally substituted arylene, or a combination thereof; V2 is an optionally substituted C1-C4 alkylene, a heterocycloalkylene, an optionally 25 substituted arylene, or a combination thereof; Q1 is an optionally substituted C1-C4 alkylene or a direct bond; and Q2 is an optionally substituted C1-C4 alkylene or a direct bond. As indicated above, each R1 and R2 is independently -H or -CH3. In some embodiments, each R1 and R2 is -CH3. In other embodiments, each R1 and R2 is -H. In even other embodiments, 30 one of each R1 and R2 is -H while the other of each R1 and R2 is -CH3. As indicated above, each R3 is -H, -CH3, -CH2CH3, cyclopropyl, -CH2-OH, or - CH(OH)CH3. For instance, each R3 may be -H, -CH3, or -CH2CH3 such as -CH3 or -CH2CH3. In some embodiments, R3 is -H. In other embodiments, R3 is -CH3. In even other embodiments, R3 is -CH2CH3. In further embodiments, R3 is cyclopropyl. In even further embodiments, R3 is -CH2- 35 OH. In still other embodiments, R3 is -CH(OH)CH3. 13 70226WO01 As indicated above, each R4 is -H, -F, -Cl, -CH3, -CF3, -CN, -OH, -OCH3, -C(O)N(CH3)2, - CH(CH3)2, or -C(O)OCH3. For instance, each R4 may be -H, -F, -Cl, or -CN. In some embodiments, each R4 is -H. In other embodiments, each R4 is -F. In even other embodiments, each R4 is -Cl. In further embodiments, each R4 is -CN. In even further embodiments, each R4 is - 5 CH3. In other embodiments, each R4 is -CF3. In other embodiments, each R4 is -OH. In still other embodiments, each R4 is -OCH3. In even other embodiments, each R4 is -C(O)N(CH3)2. In still even other embodiments, each R4 is -CH(CH3)2. In further embodiments, each R4 is -C(O)OCH3. As indicated above, each R5 is -H or -F. In some embodiments, each R5 is -H . In other embodiments, each R5 is -F. 10 As indicated above, each R6 is -H, -F, -Cl, -Br, -CN, -CH3, -CHF2, or -CF3. For instance, each R6 may be -H, -F, or -Cl, such as -F or -Cl. In some embodiments, each R6 is -H. In other embodiments, each R6 is -F. In even other embodiments, each R6 is -Cl. In further embodiments, each R6 is -Br. In other further embodiments, each R6 is -CN. In even further embodiments, each R6 is -CH3. In other embodiments, each R6 is -CHF2. In still other embodiments, each R6 is -CF3. 15 As indicated above, each R7 is -H. As indicated above, each R8 is -H, -F, -Cl, or -CN. In some embodiments, each R8 is -H. In other embodiments, each R8 is -F. In even other embodiments, each R8 is -Cl. In further embodiments, each R8 is -CN. Regarding, each R4, each R5, each R6, each R7, and each R8, it should be understood that 20 any combination of the aforementioned substituents may be utilized. In some embodiments, each R4 is -H, each R5 is -H, each R6 is -F, each R7 is -H, and each R8 is -H. In other embodiments, each R4 is -F, each R5 is -H, each R6 is -F, each R7 is -H, and each R8 is -H. In even other embodiments, each R4 is -H, each R5 is -F, each R6 is -F, each R7 is -H, and each R8 is -F. In further embodiments, each R4 is -Cl, each R5 is -H, each R6 is -Cl, each R7 is -H, and each R8 is -H. In 25 even further embodiments, each R4 is -CN, each R5 is -H, each R6 is -Cl, each R7 is -H, and each R8 is -H. In still further embodiments, each R4 is -H, each R5 is -H, each R6 is -Cl, each R7 is -H, and each R8 is -Cl. In other further embodiments, each R4 is -H, each R5 is -H, each R6 is -Cl, each R7 is -H, and each R8 is -CN. As indicated above, each R9 is -H or -CH3. In some embodiments, each R9 is -H. In other 30 embodiments, each R9 is -CH3. As indicated above, each R10 is -H or -CH3. In some embodiments, each R10 is -H. In other embodiments, each R10 is -CH3. As indicated above, each X is -CH2- or -O-. In some embodiments, each X is -CH2-. In other embodiments, each X is -O-. 14 70226WO01 As indicated above, each Y1 is -CH- or -C(O)-. In some embodiments, each Y1 is -CH-. In other embodiments, each Y1 is -C(O)-. As indicated above, each Y2 is -N-, -NH-, or -NCH3-. In some embodiments, each Y2 is - N-. In other embodiments, each Y2 is -NH-. In even other embodiments, each Y2 is -NCH3-. 5 In some embodiments, Y1 is -CH- and Y2 is -N- such that represents a double bond. In other embodiments, Y1 is -C(O)- and Y2 is -NH- or -NCH3- such that represents a single bond. In such instances, Y2 is -NH- in some embodiments. In other embodiments, Y2 is -NCH3-. As indicated above, Z1 is a C1-C4 alkylene or a direct bond. In some embodiments, Z1 is a C1-C4 alkylene, such as a C1-C3 alkylene, such as a C1-C2 alkylene. In other embodiments, Z1 is a 10 direct bond. When Z1 is a C1-C4 alkylene, Z1 is a C1 alkylene in some embodiments. In other embodiments, Z1 is a C2 alkylene. In even other embodiments, Z1 is a C3 alkylene. In further embodiments, Z1 is a C4 alkylene. As indicated above, Z2 is a C1-C4 alkylene or a direct bond. In some embodiments, Z2 is a C1-C4 alkylene, such as a C1-C3 alkylene, such as a C1-C2 alkylene. In other embodiments, Z2 is a 15 direct bond. When Z2 is a C1-C4 alkylene, Z2 is a C1 alkylene in some embodiments. In other embodiments, Z2 is a C2 alkylene. In even other embodiments, Z2 is a C3 alkylene. In further embodiments, Z2 is a C4 alkylene. As indicated above, W1 is -(CH2)nNHC(O)-, -C(O)NH(CH2)n-, -O-, -C(O)-, -(CH2)m-O-, - O-(CH2)m-, or a direct bond where n is from 0 to 3 and m is from 1 to 4. For instance, W1 may be - 20 (CH2)nNHC(O)-, -O-, -(CH2)m-O-, or a direct bond. In some embodiments, W1 is -(CH2)nNHC(O)-. In such embodiments, n may be from 0 to 3, such as from 0 to 2, such as 0 in some embodiments, 1 in other embodiments, and 2 in further embodiments. In other embodiments, W1 is - C(O)NH(CH2)n-. In such embodiments, n may be from 0 to 3, such as from 0 to 2, such as 0 in some embodiments, 1 in other embodiments, and 2 in further embodiments. In even other 25 embodiments, W1 is -O-. In further embodiments, W1 is -C(O)-. In even further embodiments, W1 is -(CH2)m-O-. In such embodiments, m may be from 1 to 4, such as from 1 to 3, such as from 1 to 2, such as 1 in some embodiments, 2 in other embodiments, 3 in further embodiments, and 4 in even further embodiments. In other embodiments, W1 is -O-(CH2)m-. In such embodiments, m may be from 1 to 4, such as from 1 to 3, such as from 1 to 2, such as 1 in some embodiments, 2 in 30 other embodiments, 3 in further embodiments, and 4 in even further embodiments. In still other embodiments, W1 is a direct bond. As indicated above, W2 is -(CH2)nNHC(O)-, -C(O)NH(CH2)n-, -O-, -C(O)-, -(CH2)m-O-, - O-(CH2)m-, or a direct bond where n is f be - C(O)NH(CH2)n-, -O-, -O-(CH2)m-, or a direct bond. In some embodiments, W2 is -C(O)NH(CH2)n-. 35 In such embodiments, n may be from 0 to 3, such as from 0 to 2, such as 0 in some embodiments, 1 15 70226WO01 in other embodiments, and 2 in further embodiments. In other embodiments, W2 is - (CH2)nNHC(O)-. In such embodiments, n may be from 0 to 3, such as from 0 to 2, such as 0 in some embodiments, 1 in other embodiments, and 2 in further embodiments. In even other embodiments, W2 is -O-. In further embodiments, W2 is -C(O)-. In even further embodiments, W2 5 is -(CH2)m-O-. In such embodiments, m may be from 1 to 4, such as from 1 to 3, such as from 1 to 2, such as 1 in some embodiments, 2 in other embodiments, 3 in further embodiments, and 4 in even further embodiments. In other embodiments, W2 is -O-(CH2)m-. In such embodiments, m may be from 1 to 4, such as from 1 to 3, such as from 1 to 2, such as 1 in some embodiments, 2 in other embodiments, 3 in further embodiments, and 4 in even further embodiments. In still other 10 embodiments, W2 is a direct bond. As indicated above, V1 is an optionally substituted C1-C4 alkylene, a heterocycloalkylene, an optionally substituted arylene, or a combination thereof. In some embodiments, V1 is an optionally substituted C1-C4 alkylene, such as an optionally substituted C1-C3 alkylene, such as an optionally substituted C1-C2 alkylene, such as an optionally substituted C1 alkylene. The C1-C415 alkylene is a C1 alkylene in some embodiments. In other embodiments, the C1-C4 alkylene is a C2 alkylene. In even other embodiments, the C1-C4 alkylene is a C3 alkylene. In further embodiments, the C1-C4 alkylene is a C4 alkylene. Furthermore, the C1-C4 alkylene may be unsubstituted in some embodiments. In other embodiments, V1 may be a substituted C1-C4 alkylene, such as a substituted C1-C3 alkylene, such as a substituted C1-C2 alkylene, such as a substituted C1 alkylene. Such 20 substitution(s) may be a lower alkyl substitution, such as a -CH3 substitution in some embodiments. For instance, V1 may be a C1 alkylene with a -CH3 substitution in some embodiments. In other embodiments, V1 is a heterocycloalkylene. For instance, the heterocycloalkylene may be a 4 to 7 membered ring including at least one heteroatom, such as at least one N. In one embodiment, V1 is a heterocycloalkylene including a 6 membered ring wherein one atom is a N 25 atom (e.g., piperidine based divalent radical). For example, V1 as a heterocycloalkylene may be the following: . In e ve o e e odiments, V1 is an optionally substituted arylene. For instance, the optionally substituted arylene may be a 4 to 12 membered ring, such as a 5 to 10 membered ring. In one embodiment, the ring of V1 may be fused such that it is formed from two or more rings. In 30 addition, in one embodiment, the arylene may be a heteroarylene wherein at least one atom, such as at least two atoms, such as at least 3 atoms are a heteroatom, such as N. In this regard, V1 may be an optionally substituted C6 arylene in one embodiment. In a further embodiment, V1 may be a substituted C6 arylene. In this regard, the C6 arylene may have attachment points as the divalent radical through the para position. In another embodiment, V1 may 16 70226WO01 be an optionally substituted 5 membered ring, such as one including at least one, such as at least two, such as at least three heteroatoms. In one embodiment, such heteroatom may be N (i.e., a C5 arylene including 3 N atoms - triazole based divalent radical, such as a 1H-1,2,3-triazol based divalent radical). For example, V1 as an arylene may include the following . 5 As indicated, in one embodiment, the ring of V1 may be fused suc ed from two or more rings. For instance, the fused ring may be an 8 to 12 membered ring, such as a 9 to 10 membered ring. In this regard, in one embodiment, V1 may be an optionally substituted naphthalene. In another embodiment, V1 may be an unsubstituted naphthalene. In another embodiment, V1 may be an optionally substituted indole. In another embodiment, V1 may be an 10 unsubstituted indole. Furthermore, V1 may be a substituted arylene in some embodiments. In this regard, the arylene may include from 1-4, such as from 1-3, such as from 1-2, such as 1 or 2 substitutions. Such substitution may be halo, alkyl, cyano, or alkoxy. For instance, the halo substitution may be chloro in one embodiment. In another embodiment, the halo substitution may be fluoro. When the 15 substitution is alkyl, it may be a lower alkyl. For instance, the alkyl substitution may be methyl in one embodiment. In another embodiment, the alkyl substitution may be ethyl. When the substitution is alkoxy, the alkoxy substitution may be methoxy in one embodiment. In another embodiment, the alkoxy substitution may be ethoxy. In a further embodiment, the substitution may be cyano. 20 In addition, as indicated above, V1 may be a combination of any two or more of an optionally substituted C1-C4 alkylene, a heterocycloalkylene, or an optionally substituted arylene. For instance, it may be a combination of optionally substituted C1-C4 alkylene-heterocycloalkylene in one embodiment. In another embodiment, it may be a combination of heterocycloalkylene-C1-C4 alkylene. In a further embodiment, it may be a combination of optionally substituted C1-C4 25 alkylene-optionally substituted arylene. In another further embodiment, it may be a combination of optionally substituted arylene-optionally substituted C1-C4 alkylene. In an even further embodiment, it may be a combination of heterocycloalkylene-optionally substituted arylene. In another embodiment, it may be a combination of optionally substituted arylene- heterocycloalkylene. Furthermore, in certain embodiments, any of the aforementioned may be 30 substituted such as defined above. As indicated above, Q1 is an optionally substituted C1-C4 alkylene or a direct bond. In some embodiments, Q1 is a C1-C4 alkylene, such as a C1-C3 alkylene, such as a C1-C2 alkylene. For instance, Q1 is a C1 alkylene in some embodiments. In other embodiments, Q1 is a C2 alkylene. In even other embodiments, Q1 is a C3 alkylene. In further embodiments, Q1 is a C4 alkylene. In one 17 70226WO01 embodiment, Q1 may be substituted, such as with a C1-C3 alkyl, such as a C1-C2 alkyl, such as a C1 alkyl. In other embodiments, Q1 is a direct bond. In this regard in certain examples, the combination of Q1-V1 is a combination of an optionally substituted C1-C4 alkylene as defined herein and an optionally substituted arylene as 5 defined herein. In this regard, the combination may be presented as an optionally substituted C1-C4 alkylene-optionally substituted arylene. In even further embodiments, the combination of Q1-V1 is, for example, an optionally substituted C1-C4 alkylene as defined herein and a heterocycloalkylene as defined herein. In this regard, the combination may be presented as an optionally substituted C1- C4 alkylene-heterocycloalkylene. 10 Examples of such combinations may include, but are not limited to, the following: , 15 70226WO01 of particular 1 1 be 5 alkylene, an optionally substituted arylene, or a combination thereof. In some embodiments, V2 is an optionally substituted C1-C4 alkylene, such as an optionally substituted C1-C3 alkylene, such as an optionally substituted C1-C2 alkylene, such as an optionally substituted C1 alkylene. The C1-C4 alkylene is a C1 alkylene in some embodiments. In other embodiments, the C1-C4 alkylene is a C2 10 alkylene. In even other embodiments, the C1-C4 alkylene is a C3 alkylene. In further embodiments, the C1-C4 alkylene is a C4 alkylene. Furthermore, the C1-C4 alkylene may be unsubstituted in some embodiments. In other embodiments, V2 may be a substituted C1-C4 alkylene, such as a substituted C1-C3 alkylene, such as a substituted C1-C2 alkylene, such as a substituted C1 alkylene. Such substitution(s) may be a lower alkyl substitution, such as a -CH3 substitution in some embodiments. 15 For instance, V2 may be a C1 alkylene with a -CH3 substitution in some embodiments. In other embodiments, V2 is a heterocycloalkylene. For instance, the heterocycloalkylene may be a 4 to 7 membered ring including at least one heteroatom, such as at least one N. In one embodiment, V2 is a heterocycloalkylene including a 6 membered ring wherein one atom is a N atom (e.g., piperidine based divalent radical). For example, V2 as a heterocycloalkylene may 20 include the following: . In even other e mbodiments, V2 is an optionally substituted arylene. For instance, the optionally substituted arylene may be a 4 to 12 membered ring, such as a 5 to 10 membered ring. In one embodiment, the ring of V2 may be fused such that it is formed from two or more rings. In 19 70226WO01 addition, in one embodiment, the arylene may be a heteroarylene wherein at least one atom, such as at least two atoms, such as at least 3 atoms are a heteroatom, such as N. In this regard, V2 may be an optionally substituted C6 arylene in one embodiment. In a further embodiment, V2 may be a substituted C6 arylene. In this regard, the C6 arylene may have 5 attachment points as the divalent radical through the para position. In another embodiment, V2 may be an optionally substituted 5 membered ring, such as one including at least one, such as at least two, such as at least three heteroatoms. In one embodiment, such heteroatom may be N (i.e., a C5 arylene including 3 N atoms - triazole based divalent radical, such as a 1H-1,2,3-triazol based divalent radical). For example, V2 as an arylene may include the followin . 10 As indicated, in one embodiment, the ring of V2 may be fused suc d from two or more rings. For instance, the fused ring may be an 8 to 12 membered ring, such as a 9 to 10 membered ring. In this regard, in one embodiment, V2 may be an optionally substituted naphthalene. In another embodiment, V2 may be an unsubstituted naphthalene. In another embodiment, V2 may be an optionally substituted indole. In another embodiment, V2 may be an 15 unsubstituted indole. Furthermore, V2 may be a substituted arylene in some embodiments. In this regard, the arylene may include from 1-4, such as from 1-3, such as from 1-2, such as 1 or 2 substitutions. Such substitution may be halo, alkyl, cyano, or alkoxy. For instance, the halo substitution may be chloro in one embodiment. In another embodiment, the halo substitution may be fluoro. When the 20 substitution is alkyl, it may be a lower alkyl. For instance, the alkyl substitution may be methyl in one embodiment. In another embodiment, the alkyl substitution may be ethyl. When the substitution is alkoxy, the alkoxy substitution may be methoxy in one embodiment. In another embodiment, the alkoxy substitution may be ethoxy. In a further embodiment, the substitution may be cyano. 25 In addition, as indicated above, V2 may be a combination of any two or more of an optionally substituted C1-C4 alkylene, a heterocycloalkylene, or an optionally substituted arylene. For instance, it may be a combination of optionally substituted C1-C4 alkylene-heterocycloalkylene in one embodiment. In another embodiment, it may be a combination of heterocycloalkylene-C1-C4 alkylene. In a further embodiment, it may be a combination of optionally substituted C1-C4 30 alkylene-optionally substituted arylene. In another further embodiment, it may be a combination of optionally substituted arylene-optionally substituted C1-C4 alkylene. In an even further embodiment, it may be a combination of heterocycloalkylene-optionally substituted arylene. In another embodiment, it may be a combination of optionally substituted arylene- 20 70226WO01 heterocycloalkylene. Furthermore, in certain embodiments, any of the aforementioned may be substituted such as defined above. As indicated above, Q2 is an optionally substituted C1-C4 alkylene or a direct bond. In some embodiments, Q2 is a C1-C4 alkylene, such as a C1-C3 alkylene, such as a C1-C2 alkylene. For 5 instance, Q2 is a C1 alkylene in some embodiments. In other embodiments, Q2 is a C2 alkylene. In even other embodiments, Q2 is a C3 alkylene. In further embodiments, Q2 is a C4 alkylene. In one embodiment, Q2 may be substituted, such as with a C1-C3 alkyl, such as a C1-C2 alkyl, such as a C1 alkyl. In other embodiments, Q2 is a direct bond. In this regard in certain examples, the combination of V2-Q2 is a combination of an 10 optionally substituted arylene as defined herein and an optionally substituted C1-C4 alkylene as defined herein. In this regard, the combination may be presented as an optionally substituted arylene-optionally substituted C1-C4 alkylene. In even further embodiments, the combination of V2- Q2 is, for example, a heterocycloalkylene as defined herein and an optionally substituted C1-C4 alkylene as defined herein. In this regard, the combination may be presented as an 15 heterocycloalkylene-optionally substituted C1-C4 alkylene. Examples of such combinations may include, but are not limited to, the following: , 20 70226WO01 CN of articular embodiment, V2 may b . In another particular embodiment, V2 may be 5 . )2-, a C1-C8 alkylene, -C(O)NHCH2-, -NHC(O)CH2-, -C(O)NH-U-NHC(O)-, -NHC(O)-U-C(O)NH-, -C(O)NH- U-Ar1-U-NHC(O)-, -NHC(O)-U-Ar1-U-C(O)NH-, an optionally substituted C5-C12 arylene including from 0-3 heteroatoms, -Ar2-Ar3-, -Ar4-T-Ar5-, -T-Ar6-T-, and -T-Ar7-T-Ar8-T- wherein --10 Ar1-, -Ar2-, -Ar3-, -Ar4-, -Ar5-, -Ar6-, -Ar7-, and -Ar8- are each a C6 arylene, -T- is -O-, -CH2-, - C(CH3)(CH3)-, or -C(CF3)(CF3)-, and -U- is a C1-C4 alkylene or a direct bond. For instance, L may be -(C≡C)2- or a C1-C8 alkylene. In some embodiments, L is -(C≡C)2-. In other embodiments, L is a C1-C8 alkylene. In even other embodiments, L is -C(O)NHCH2-. In still other embodiments, L is -NHC(O)CH2-. In further embodiments, L is an optionally substituted C5-C12 arylene including 15 from 0-3 heteroatoms. In even further embodiments, L is -C(O)NH-U-NHC(O)-. In other embodiments, L is - NHC(O)-U-C(O)NH-. In still other embodiments, L is -C(O)NH-U-Ar1-U-NHC(O)-. In even further embodiments, L is -NHC(O)-U-Ar1-U-C(O)NH-. For instance, L may be -NHC(O)-U- C(O)NH- or -NHC(O)-U-Ar1-U-C(O)NH-. In such embodiments, U is a C1-C4 alkylene or a direct 20 bond. In some embodiments, U is a direct bond. In other embodiments, U is a C1-C4 alkylene. In 22 70226WO01 this regard, U is a C1 alkylene in some embodiments. In other embodiments, U is a C2 alkylene. In even other embodiments, U is a C3 alkylene. In further embodiments, U is a C4 alkylene. In addition, -Ar1- is a C6 arylene. In one embodiment, such C6 arylene is an unsubstituted C6 arylene. Furthermore, such arylene may have attachment points as the divalent radical through the para 5 position. In other embodiments, L is -Ar2-Ar3-. For example, L may include the following: . In still other embodiments, L is -Ar4-T-Ar5-. For example, L may include the following: . In other embodiments, L is -T-Ar6-T-, for instance wherein Ar6 is ition. In f 7 urther embodiments, L is -T-Ar -T- 10 Ar8-T-, for instance wherein Ar7 and Ar8 are bonded through the para position. In such embodiments, -T- is -O-, -CH2-, -C(CH3)(CH3)-, or -C(CF3)(CF3)-. For instance, -T- may be -O-, - CH2-, or -C(CH3)(CH3)-. In this regard, -T- may be -O- in some embodiments. In other embodiments, -T- may be -CH2-. In even other embodiments, -T- may be -C(CH3)(CH3)-. In further embodiments, -T- may be -C(CF3)(CF3)-. Furthermore, -Ar2-, -Ar3-, -Ar4-, -Ar5-, and -Ar6- 15 are each a C6 arylene. In some embodiments, any of the aforementioned C6 arylenes may be an unsubstituted C6 arylene. In embodiments wherein L is a C1-C8 alkylene, L may be a C2-C8 alkylene, such as a C4-C8 alkylene. For instance, in some embodiments, L may be a C2 alkylene. In other embodiments, L may be a C4 alkylene. In even other embodiments, L may be a C6 alkylene. In further 20 embodiments, L may be a C8 alkylene. In certain embodiments, L is an optionally substituted C5-C12 arylene including from 0-3 heteroatoms. The arylene may be a C5-C6 arylene or a C8-C10 arylene. For instance, the arylene may be a C5 arylene, C6 arylene, or a C10 arylene. In this regard, the C6 arylene, such as an unsubstituted C6 arylene, may be bonded through the para position. Furthermore, in certain 25 embodiments, the arylene may be fused such that it is formed from two or more rings. For instance, the fused ring may be an 8 to 12 membered ring, such as a 9 to 10 membered ring. In this regard, in one embodiment, L may be an optionally substituted naphthalene. In another embodiment, L may be an unsubstituted naphthalene. For instance, the naphthalene may include any of the following: . 23 70226WO01 In embodiments wherein L is an optionally substituted C5-C12 arylene including from 0-3 heteroatoms, the arylene may be unsubstituted in some embodiments. In other embodiments, the C5-C12 arylene may be substituted. For instance, such arylene may include from 1 to 4, such as from 2 to 4, such as from 3 to 4, such as 4 substitutions. In one embodiment, such substitution(s) 5 may be lower alkyl, such as methyl. In another embodiment, such substitution(s) may be halo. For instance, such substitution(s) may be fluoro. In one embodiment, the arylene may have 2-4, such as 3-4, such as 4 fluoro substitutions. In embodiments wherein L is an optionally substituted C5-C12 arylene including from 0-3 heteroatoms, the arylene may not include any heteroatoms. In this regard, the arylene may be a C5 10 arylene in one embodiment. In another embodiment, the arylene may be a C6 arylene. In other embodiments, the C5-C12 arylene may include from 1-3, such as from 2-3, such as 3 heteroatoms. Such heteroatom(s) may be -O-, -S-, -N-, or a combination thereof. In one embodiment, such heteroatom(s) may be -N-. For example, L may be a C5 arylene including 3 N atoms (e.g., triazole based divalent radical, such as a 1H-1,2,3-triazol based divalent radical). For instance, L as an 15 . rmula (I) has the formula as provided below: In other embodiments, the compound of Formula (I) has the formula as provided below: 24 70226WO01 For instance, in one embodiment, the compound or pharmaceutically acceptable salt or stereoisomer thereof is selected from the group consisting of , , , 70226WO01 nd . In oth or stereoisomer thereof is selected from the group consisting of 5 and . In furth , alt or stereoisomer thereof is selected from the group consisting of 26 70226WO01 , , , , , 70226WO01 , , , , and 70226WO01 . In furth ble salt or stereoisomer thereof is selected from the group consisting of 5 nd . Furthe e a pharmaceutically acceptable salt of any of the compounds of any of the aforementioned formulae or compounds. 10 Exemplary compounds encompassed by the present invention include, without limitation, those in the following Table 1: 29 70226WO01 Table 1 Cmpd. # Compound Name Compound Structure N1,N10-bis((S)-5-((S)-2- 30 70226WO01 Cmpd. # Compound Name Compound Structure 31 70226WO01 Cmpd. # Compound Name Compound Structure 32 70226WO01 Cmpd. # Compound Name Compound Structure (2R,2'R)-N,N'-((2S,2'S)- ((hexa-24-di ne-16- 33 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'-((2S,2'S)-((octa- 35-di ne-18- 34 70226WO01 Cmpd. # Compound Name Compound Structure (S)-N-((S)-1-(6-(4- fluorobenz l)-33-dimeth l- 35 70226WO01 Cmpd. # Compound Name Compound Structure 36 70226WO01 Cmpd. # Compound Name Compound Structure 37 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'-((2S,2'S)- ((hexa-24-di ne-16- 38 70226WO01 Cmpd. # Compound Name Compound Structure 39 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'-((2S,2'S)- 40 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'-((2S,2'S)- 41 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'-((2S,2'S)-(hexa- 24-di ne-16-di lbis(4- 42 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'-((2S,2'S)- 43 70226WO01 Cmpd. # Compound Name Compound Structure 44 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'-((2S,2'S,3S,3'S)- 45 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'- ((2S2'S3S3'S)- 46 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'- ((2S2'S3R3'R)-((((propane- 47 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'-((2S,2'S)- ((hexa-24-di ne-16- 48 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'-((2S,2'S)- ((hexa-24-di ne-16- 70226WO01 Cmpd. # Compound Name Compound Structure (2S)-N-[(1S,2S)-1-[6-[(4- fluorophen l)meth l]-33- 50 70226WO01 Cmpd. # Compound Name Compound Structure (2S)-N-[(1S,2S)-1-[6-[(4- fluorophen l)meth l]-33- 51 70226WO01 Cmpd. # Compound Name Compound Structure 4-[1-[(1S,2S)-3-[6-[(4- fluorophen l)meth l]-33- 99 100 101 52 70226WO01 Cmpd. # Compound Name Compound Structure (2S)-N-[(1S,2S)-1-[6-[(4- fluorophen l)meth l]-33- 53 70226WO01 Cmpd. # Compound Name Compound Structure (2S)-N-[(1S,2S)-1-[6-[(4- fluorophen l)meth l]-33- 54 70226WO01 Cmpd. # Compound Name Compound Structure N4-[2-[1-[(1S,2S)-3-[6-[(4- fluorophen l)meth l]-33- 55 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'-((2S,2'S)- (((((14- 56 70226WO01 Cmpd. # Compound Name Compound Structure (2S,2'S)-N,N'-((2S,2'S)- (((((22'-(14- all compounds 1-117 set forth herein. In some embodiments, each of compounds 1-117 may be present generically as hydrochloride (i.e., HCl salts), e.g., more specifically a dihydrochloride, (2 HCl) salt. Also, within the scope of the invention are any of compounds 1-117 present as a single 5 species, including pharmaceutically acceptable salts thereof, as well as any of these compounds in free base form. In another embodiment of the present invention, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy. 57 70226WO01 In another embodiment of the present invention, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating an HIV infection. In another embodiment of the invention, there is provided a compound of Formula (I) wherein the compound or salt of the compound is used in the manufacture of a medicament for use 5 in the treatment of an HIV infection in a human. In some embodiments, the invention provides a method of curing an HIV infection in a subject comprising administering to the subject a compound of Formula (I), as well as any compound of Table 1, along with pharmaceutically salts thereof. “Cure” or “Curing” a disease in a patient is used to denote the eradication, stoppage, halt or end of the human immunodeficiency 10 virus or symptoms, or the progression of the symptoms or virus, for a defined period. As an example, in one embodiment, “cure” or “curing” refers to a therapeutic administration or a combination of administrations that alone or in combination with one or more other compounds induces and maintains sustained viral control (undetectable levels of plasma viremia by, e.g., a polymerase chain reaction (PCR) test, a bDNA (branched chain DNA) test or a NASBA (nucleic 15 acid sequence based amplification) test, ) of human immunodeficiency virus after a minimum of two years without any other therapeutic intervention. The above PCR, bDNA and NASBA tests are carried out using techniques known and familiar to one skilled in the art. As an example, the eradication, stoppage, halt or end of the human immunodeficiency virus or symptoms, or the progression of the symptoms or virus, may be sustained for a minimum of two years. 20 In some embodiments, the invention provides a method of curing an HIV infection in a subject comprising administering to the subject a pharmaceutical composition comprising a compound of Formula (I), along with pharmaceutically salts thereof. In some embodiments, the 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 curing an 25 HIV infection. In some embodiments, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in curing an HIV infection. Combinations of compounds of Formula (I), and one or more agents useful in HIV therapy may also be used in methods of curing an HIV infection. 30 In one embodiment, the pharmaceutical formulation containing a 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 nano-particle formulation. The compounds of the present invention and their salts, solvates, or other pharmaceutically 35 acceptable derivatives thereof, may be employed alone or in combination with other therapeutic 58 70226WO01 agents. Therefore, in other embodiments, the methods of treating and/or preventing an HIV infection in a subject may in addition to administration of a compound of Formula (I) further comprising administration of one or more additional pharmaceutical agents active against HIV. In such embodiments, the one or more additional agents active against HIV is selected 5 from the group consisting of anti-retroviral agents, latency reversing agents, and agents for clearance therapy. In other embodiments, the one or more additional agents active against HIV is selected from the group consisting of nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, attachment and fusion inhibitors, 10 integrase inhibitors, maturation inhibitors, CXCR4 and/or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyl transferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and neutralizing antibodies, and combinations thereof. In certain embodiments, the one or more additional agents active against HIV is selected from the group consisting of zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, 15 adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS-20 626529, 5-Helix, 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 antibodies (bNAb), eCD4-Ig, CD4-Ig, and dual-affinity re- 25 targeting (DART) proteins. As such, the compounds of the present invention of Formula (I) and any other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds of Formula (I) of the present invention and the other 30 pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The administration in combination of a compound of the present invention of Formula (I) and salts, solvates, or other pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) 35 separate pharmaceutical compositions each including one of the compounds. Alternatively, the 59 70226WO01 combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time. The amounts of the compound(s) of Formula (I) or salts thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in 5 order to achieve the desired combined therapeutic effect. In addition, the compounds of the present invention of Formula (I) may be used in combination with one or more other agents that may be useful in the treatment of HIV. They agents may include anti-retroviral agents, latency reversing agents, and agents for clearance therapy. Several examples of anti-retroviral agents are provided below: 10 Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents; Non-nucleotide reverse transcriptase inhibitors (including an agent having anti-oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, 15 oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, and similar agents; Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, and similar agents; 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; 20 Integrase inhibitors such as raltegravir, elvitegravir, dolutegravir, cabotegravir, bictegravir and similar agents; Maturation inhibitors such as PA-344 and PA-457, and similar agents; and CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), TAK449, as well as those disclosed in WO 02/74769, PCT/US03/39644, 25 PCT/US03/39975, PCT/US03/39619, PCT/US03/39618, PCT/US03/39740, and PCT/US03/39732, and similar agents. Further examples where the compounds of the present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV are found in Table 2. 30 Table 2: FDA Approval Brand Name Generic Name Manufacturer 70226WO01 zalcitabine, 1992 Hivid dideoxycytidine, Roche ddC Pharmaceuticals cs s s cs 61 70226WO01 Roche 2003 Fuzeon Enfuvirtide, T-20 Pharmaceuticals & Trimeris expression, such as latency reversing agents. Several latency reversing agents include, but are not limited to, the following: histone deacetylase inhibitors (e.g., vorinostat, panobinostat, romidepin), 5 histone crotonyl transferase inhibitors (sodium corotonate), protein kinase C agonists (e.g., bryostatin, ingenol B), disulfiram, TLR7 agonists (e.g., GS-9620), bromodomain inhibitors (e.g., JQ1, iBET151). Many of these agents are described in further detail below. The present invention may be used in combination with other agents that induce HIV expression, such as agents for clearance therapy. Several examples of agents for clearance therapy, 10 or of immunological combinations for clearance, include, but are not limited to, the following: neutralizing and broadly neutralizing antibodies (bNAb), eCD4-Ig, CD4-Ig, and dual-affinity re- targeting (DART) proteins. The scope of combinations of compounds of this invention with HIV agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical 15 composition useful for the treatment and/or prevention of HIV. As noted, in such combinations the compounds of the present invention and other HIV agents may be administered separately or in conjunction. In addition, one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s). In some embodiments, the compounds of Formula (I) and Table 1 may be used in 20 combination with one or more agents useful as pharmacological enhancers as well as with or without additional compounds for the prevention or treatment of HIV. Examples of such pharmacological enhancers (or pharmakinetic boosters) include, but are not limited to, ritonavir, GS-9350 (cobicistat), and SPI-452. Ritonavir is 10-hydroxy-2-methyl-5-(1-methyethyl)-1-1[2-(1-methylethyl)-4-thiazolyl]- 25 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 from Abbott Laboratories of Abbott Park, Illinois, as Norvir. Ritonavir is an HIV protease inhibitor indicated with other antiretroviral agents for the treatment of HIV infection. Ritonavir also inhibits P450 mediated drug metabolism as well as the 62 70226WO01 P-glycoprotein (Pgp) cell transport system, thereby resulting in increased concentrations of active compound within the organism. GS-9350 (cobicistat) is a compound being developed by Gilead Sciences of Foster City California as a pharmacological enhancer. 5 SPI-452 is a compound being developed by Sequoia Pharmaceuticals of Gaithersburg, Maryland, as a pharmacological enhancer. In some embodiments, a 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 injection and ritonavir is 10 formulated as an oral composition. In one embodiment, a kit containing the compound of Formula (I) is formulated as a long-acting parenteral injection and ritonavir formulated as an oral composition. In another embodiment, the compound of Formula (I) is formulated as a long-acting parenteral injection and ritonavir is formulated as an injectable composition. In one embodiment, a kit containing the compound of Formula (I) is formulated as a long-acting parenteral injection and 15 ritonavir formulated as an injectable composition. In some embodiments, a compound of Formula (I) is used in combination with GS-9350. In one embodiment, the combination is an oral fixed dose combination. In another embodiment, the compound of Formula (I) is formulated as a long-acting parenteral injection and GS-9350 is formulated as an oral composition. In one embodiment, there is provided a kit containing the 20 compound of Formula (I) is formulated as a long-acting parenteral injection and GS-9350 formulated as an oral composition. In another embodiment, the compound of Formula (I) is formulated as a long-acting parenteral injection and GS-9350 is formulated as an injectable composition. In one embodiment, is a kit containing the compound of Formula (I) is formulated as a long-acting parenteral injection and GS-9350 formulated as an injectable composition. 25 In some embodiments, a compound of Formula (I) is used in combination with SPI-452. In one embodiment, the combination is an oral fixed dose combination. In other embodiments, the compound of Formula (I) is formulated as a long-acting parenteral injection and SPI-452 is formulated as an oral composition. In still other embodiments, there is provided a kit containing the compound of Formula (I) is formulated as a long-acting parenteral injection and SPI-452 30 formulated as an oral composition. In other embodiments, the compound of Formula (I) is formulated as a long-acting parenteral injection and SPI-452 is formulated as an injectable composition. In some embodiments, there is provided a kit containing the compound of Formula (I) is formulated as a long-acting parenteral injection and SPI-452 formulated as an injectable composition. 63 70226WO01 In some embodiments, a compound of Formula (I) is used in combination with compounds which are found in previously filed PCT/CN2011/0013021, which is herein incorporated by reference. The above other therapeutic agents, when employed in combination with the chemical 5 entities described herein, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In other embodiments, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of 10 developing said viral infection, a compound of Formula (I). In still other embodiments, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), wherein said virus is an HIV virus. 15 In some embodiments, the HIV virus is the HIV-1 virus. In other embodiments, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a 20 therapeutically effective amount of one or more agents active against an HIV virus. In some embodiments, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the retrovirus family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of 25 a therapeutically effective amount of one or more agents active against the HIV virus, wherein said agent active against HIV virus is selected from Nucleotide reverse transcriptase inhibitors; Non- nucleotide reverse transcriptase inhibitors; Protease inhibitors; Entry, attachment and fusion inhibitors; Integrase inhibitors; Maturation inhibitors; CXCR4 inhibitors; and CCR5 inhibitors. In another aspect, a method of depleting latent HIV infected cells comprising administering 30 to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In various embodiments, the compound is selected from the group consisting of those 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 e.g., those set forth herein. In other embodiments, a method of treating an HIV 35 infection in a subject comprising administering to the subject this compound or a pharmaceutically 64 70226WO01 acceptable salt thereof, as well as combinations. In still other embodiments, a compound of Formula (I) or Table 1, or a pharmaceutically acceptable salt thereof, for use in treating an HIV infection. Some embodiments also include use of this compound, in the manufacture of a medicament for treating an HIV infection. Still other embodiments include a method of depleting 5 latent HIV infected cells comprising administering to a subject this compound or a pharmaceutically acceptable salt thereof, as well as combinations thereof. In various embodiments, the method of depleting latent HIV infection further comprises administering to the subject one or more additional agents active against HIV as disclosed hereinabove. As an example, in various embodiments, the one or more additional agents is selected 10 from the group consisting of nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, attachment and fusion inhibitors, integrase inhibitors, maturation inhibitors, CXCR4 and/or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyl transferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and antibodies for clearance therapy, and combinations 15 thereof. In various embodiments, the one or more additional agents active against HIV is selected from the group consisting of zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavudine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdinee, efavirenz, loviride, immunocal, oltipraz, capravirine, lersivirine, GSK2248761, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, 20 amprenavir, fosamprenavir, brecanavir, darunavir, atazanavir, tipranavir, palinavir, lasinavir, enfuvirtide, T-20, T-1249, PRO-542, PRO-140, TNX-355, BMS-806, BMS-663068 and BMS- 626529, 5-Helix, raltegravir, elvitegravir, dolutegravir,cabotegravir, bictegravir, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc, TAK449, didanosine, tenofovir, lopinavir, darunavir, vorinostat, panobinostat, romidepin, valpronic acid, mocetinostat, sodium corotonate, bryostatin, ingenol B, 25 disulforam, GS-9620, JQ1, iBET151, bortezomib, epigallocatechin gallate, salinosporamide A, carfilzomib, and neutralizing antibodies, eCD4-Ig, CD4-Ig, bNAb, DARTS and IgA. The compounds according to Formula (I) and pharmaceutically acceptable salts thereof may be useful in the treatment of cancer, pre-cancerous syndromes. Suitably the present invention relates to a method for treating cancers selected from the group consisting of brain (gliomas), 30 glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, 35 lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, 65 70226WO01 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 5 lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer. 10 Suitably the present invention relates to a method for treating pre-cancerous syndromes in a mammal, including a human, wherein the pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and 15 severe hepatitis or cirrhosis. The compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co- administered with at least one other active agent known to be useful in the treatment of cancer or pre-cancerous syndromes. By the term "co-administration" as used herein is meant either simultaneous administration 20 or any manner of separate sequential administration of a c-MYC inhibiting compound, as described herein, and a further active agent or agents, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active agent or agents, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is 25 not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally. Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in 30 combination or co-administered with the presently invented combinations are indicated below. This list is non-limiting. Additional anti-neoplastic agents are contemplated for use with the presently invented compounds. Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of 35 such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. 66 70226WO01 Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti- neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule 5 agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti- folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal 10 analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism. Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented compounds are chemotherapeutic 15 agents. Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti- microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids. Diterpenoids, which are derived from natural sources, are phase specific anti-cancer agents20 that operate at the G2/M phases of the cell cycle. It is believed that the diterpenoids stabilize the - tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel. Paclitaxel, 5 ,20-epoxy-1,2 ,4,7 ,10 ,13 -hexa-hydroxytax-11-en-9-one 4,10-diacetate 25 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL . It is a member of the taxane family of terpenes. It was first isolated in 1971 by Wani et al. J. Am. Chem, Soc., 93:2325.1971), who characterized its structure by chemical and X-ray crystallographic methods. One mechanism for its activity relates to paclitaxel's capacity 30 to bind tubulin, thereby inhibiting cancer cell growth. Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561-1565 (1980); Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem, 256: 10435-10441 (1981). For a review of 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”, Attaur-Rahman, P.W. Le Quesne, Eds. (Elsevier, 35 Amsterdam, 1986) pp 219-235. 67 70226WO01 Paclitaxel has been 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. lntem, Med., 111:273,1989) and for the treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst., 83:1797,1991.) It is a potential candidate for treatment of neoplasms in the 5 skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastire et. al., Sem. Oncol., 20:56, 1990). The compound also shows potential for the treatment of polycystic kidney disease (Woo et. al., Nature, 368:750.1994), lung cancer and malaria. Treatment of patients with paclitaxel results in bone marrow suppression (multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guide, 1998) related to the duration of dosing above a threshold 10 concentration (50nM) (Kearns, C.M. et. al., Seminars in Oncology, 3(6) p.16-23, 1995). Docetaxel, (2R,3S)- N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5 -20- epoxy-1,2 ,4,7 ,10 ,13 -hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE . Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared 15 using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia. Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is 20 believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine. Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas 25 including Hodgkin’s Disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is the dose limiting side effect of vinblastine. Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin’s and non-Hodgkin’s malignant 30 lymphomas. Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur. Vinorelbine, 3’,4’-didehydro -4’-deoxy-C’-norvincaleukoblastine [R-(R*,R*)-2,3- dihydroxybutanedioate (1:2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE ), is a semisynthetic vinca alkaloid. Vinorelbine is indicated as a single 35 agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of 68 70226WO01 various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine. Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form 5 intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin. Cisplatin, cis-diamminedichloroplatinum, is commercially available as PLATINOL as an injectable solution. Cisplatin is primarily indicated in the treatment of metastatic testicular and 10 ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity. Carboplatin, platinum, diammine [1,1-cyclobutane-dicarboxylate(2-)-O,O’], is commercially available as PARAPLATIN as an injectable solution. Carboplatin is primarily indicated in the first- and second-line treatment of advanced ovarian carcinoma. Bone marrow 15 suppression is the dose limiting toxicity of carboplatin. Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death. Examples 20 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. Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2- oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN . 25 Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting, and leukopenia are the most common dose limiting side effects of cyclophosphamide. Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an 30 injectable solution or tablets as ALKERAN . Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan. Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN tablets. Chlorambucil is indicated for the palliative treatment of chronic 35 lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular 69 70226WO01 lymphoma, and Hodgkin’s disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil. Busulfan, 1,4-butanediol dimethanesulfonate, is commercially available as MYLERAN TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. 5 Bone marrow suppression is the most common dose limiting side effects of busulfan. Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commercially available as single vials of lyophilized material as BiCNU . Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin’s disease, and non-Hodgkin’s lymphomas. Delayed myelosuppression is the most common dose limiting side 10 effects of carmustine. Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome . Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin’s Disease. Nausea, vomiting, and anorexia are the most common dose limiting side 15 effects of dacarbazine. Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids, leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as 20 daunorubicin and doxorubicin; and bleomycins. Dactinomycin, also known as Actinomycin D, is commercially available in injectable form as COSMEGEN . Dactinomycin is indicated for the treatment of Wilm’s tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin. 25 Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy- -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 injectable form as DAUNOXOME or as an injectable as CERUBIDINE . Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi’s sarcoma. 30 Myelosuppression is the most common dose limiting side effect of daunorubicin. Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy- -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 injectable form as RUBEX or ADRIAMYCIN RDF . Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute 70 70226WO01 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. Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus, is commercially available as BLENOXANE . Bleomycin is indicated as 5 a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin. Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins. Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake 10 plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide. Etoposide, 4’-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene- -D-glucopyranoside], 15 is commercially available as an injectable solution or capsules as VePESID and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia. 20 Teniposide, 4’-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene- -D- glucopyranoside], is commercially available as an injectable solution as VUMON and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and 25 thrombocytopenia. Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed, and cell death follows. Examples of antimetabolite anti-neoplastic agents include, but are 30 not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine. 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 is also incorporated into both RNA and DNA. The result typically is cell death. 5-fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of 35 carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis 71 70226WO01 are dose limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate. Cytarabine, 4-amino-1- -D-arabinofuranosyl-2 (1H)-pyrimidinone, is commercially available as CYTOSAR-U and is commonly known as Ara-C. It is believed that cytarabine 5 exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2’,2’-difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis. 10 Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL . Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at 15 high doses. A useful mercaptopurine analog is azathioprine. Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID . Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. 20 Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythron-hydroxy-nonyl-adenine, fludarabine phosphate, and cladribine. Gemcitabine, 2’-deoxy-2’, 2’-difluorocytidine monohydrochloride ( -isomer), is 25 commercially available as GEMZAR . Gemcitabine exhibits cell phase specificity at S-phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of 30 gemcitabine administration. Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L-glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and 35 thymidylate. Methotrexate is indicated as a single agent or in combination with other 72 70226WO01 chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin’s lymphoma, and carcinomas of the breast, head, neck, ovary, and bladder. Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration. 5 Camptothecins, including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino- methylene)-10,11-ethylenedioxy-20-camptothecin described below. 10 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 commercially available as the injectable solution CAMPTOSAR . Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN- 38, to the topoisomerase I – DNA complex. It is believed that cytotoxicity occurs as a result of 15 irreparable double strand breaks caused by interaction of the topoisomerase I : DNA : irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for 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. Topotecan HCl, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H- 20 pyrano[3’,4’,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN . Topotecan is a derivative of camptothecin which binds to the topoisomerase I – DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell 25 lung cancer. The dose limiting side effect of topotecan HCl is myelosuppression, primarily neutropenia. Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Examples of hormones and hormonal analogues useful in cancer treatment include, but are not 30 limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone 35 dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such 73 70226WO01 as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5 -reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such those described in U.S. Patent Nos. 5 5,681,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof which stimulate the release of leutinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide. 10 Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Signal transduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myo-inositol signaling, and Ras 15 oncogenes. Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl 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. Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand 20 binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been 25 linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor –I (IGFI) receptor, macrophage colony 30 stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene. Several inhibitors of growth receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C., Exp. Opin. Ther. Patents 35 (2000) 10(6):803-818; Shawver et al DDT Vol 2, No.2 February 1997; and Lofts, F. J. et al, 74 70226WO01 “Growth factor receptors as targets”, New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London. Suitably, the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2- 5 pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001, International Publication Number WO02/059110 and an International Publication date of August 1, 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of10 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 No. PCT/US01/49367. Suitably, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide is in the form of a monohydrochloride salt. This salt form can be 15 prepared by one of skill in the art from the description in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001. 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide is sold commercially as the monohydrochloride salt and is known by the generic name pazopanib and the trade name VOTRIENT®. 20 Pazopanib is implicated in the treatment of cancer and ocular diseases/angiogenesis. Suitably the present invention relates to the treatment of cancer and ocular diseases/angiogenesis, suitably age-related macular degeneration, which method comprises the administration of a compound of Formula (I) alone or in combination with pazopanib. Tyrosine kinases, which are not growth factor receptor kinases are termed non-receptor 25 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), Brutons tyrosine kinase, and Bcr-Abl. Such non-receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465 – 80; and Bolen, J.B., Brugge, J.S., 30 (1997) Annual review of Immunology.15: 371-404. SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods.34(3) 35 125-32. 75 70226WO01 Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, 5 IKKb), PKB family kinases, akt kinase family members, PDK1 and TGF beta receptor kinases. Such Serine/Threonine kinases and inhibitors thereof 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. 10 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. Suitably, the pharmaceutically active compounds of the invention are used in combination with a MEK inhibitor. Suitably, N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8- 15 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, suitably the dimethyl sulfoxide solvate, thereof, which is disclosed and claimed in International Application No. PCT/JP2005/011082, having an International filing date of June 10, 2005; International Publication Number WO 2005/121142 and an International Publication date of December 22, 2005, the entire disclosure of which is hereby20 incorporated by reference. N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl- 2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, can be prepared as described in United States Patent Publication No. US 2006/0014768, Published January 19, 2006, the entire disclosure of which is hereby incorporated by reference. Suitably, the pharmaceutically active compounds of the invention are used in combination25 with a B-Raf inhibitor. Suitably, N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3- thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof, which is disclosed and claimed, in International Application No. PCT/US2009/042682, having an International filing date of May 4, 2009, the entire disclosure of which is hereby incorporated by reference. N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4- 30 yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide can be prepared as described in International Application No. PCT/US2009/042682. Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor. Suitably, N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro- 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide or a pharmaceutically acceptable salt 35 thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, 76 70226WO01 having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference. N-{(1S)-2-amino-1-[(3,4- difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2- 5 furancarboxamide is the compound of example 224 and can be prepared as described in International Application No. PCT/US2008/053269. Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor. Suitably, N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4- chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide or a pharmaceutically acceptable salt 10 thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of February 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of August 14, 2008, the entire disclosure of which is hereby incorporated by reference. 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 15 example 96 and can be prepared as described in International Application No. PCT/US2008/053269. Suitably, N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4- chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide is in the form of a hydrochloride salt. The salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US2010/022323, having an International filing date of January 28, 2010.20 Inhibitors of Phosphotidylinositol-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) 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology.29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541- 25 1545. Also, of interest in the present invention are Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London. 30 Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O.G., Rozados, V.R., 35 Gervasoni, S.I. Matar, P. (2000), Journal of Biomedical Science.7(4) 292-8; Ashby, M.N. (1998), 77 70226WO01 Current Opinion in Lipidology.9 (2) 99 – 102; and BioChim. Biophys. Acta, (19899) 1423(3):19- 30. As mentioned above, antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the 5 use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example, Imclone C225 EGFR specific antibody (see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286); Herceptin erbB2 antibody (see Tyrosine Kinase Signaling in Breast cancer:erbB Family Receptor Tyrosine Kinases, Breast cancer Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody (see Brekken, R.A. 10 et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124). Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention. Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis in general is 15 linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the compounds of the present invention. For example, anti- VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alphav beta3) that will inhibit angiogenesis; endostatin 20 and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds. (See Bruns CJ et al (2000), Cancer Res., 60: 2926-2935; Schreiber AB, Winkler ME, and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469). Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of Formula (I). There are a number of immunologic strategies to generate an immune 25 response. These strategies are generally in the realm of tumor vaccinations. The efficacy of immunologic approaches may be greatly enhanced through combined inhibition of signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are 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. 30 Agents used in proapoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention. Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e., mcl-1). Therefore, strategies designed to downregulate the expression of bcl-2 in tumors have 35 demonstrated clinical benefit and are now in Phase II/III trials, namely Genta's G3139 bcl-2 78 70226WO01 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for 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. Cell cycle signaling inhibitors inhibit molecules involved in the control of the cell cycle. A 5 family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signaling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and 10 CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230. Further, p21WAF1/CIP1 has been described as a potent and universal inhibitor of cyclin-dependent kinases (Cdks) (Ball et al., Progress in Cell Cycle Res., 3: 125 (1997)). Compounds that are known to induce expression of p21WAF1/CIP1 have been implicated in the suppression of cell proliferation and as having tumor suppressing activity (Richon 15 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 are implicated in the transcriptional activation of p21WAF1/CIP1 (Vigushin et al., Anticancer Drugs, 13(1): 1-13 (Jan 2002)), and are suitable cell cycle signaling inhibitors for use in combination herein. Examples of such HDAC inhibitors include: 20 1. Vorinostat, including pharmaceutically acceptable salts thereof. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007). Vorinostat has the following chemical structure and name: ide 25 2. Romidepsin, including pharmaceutically acceptable salts thereof. Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85-93. Romidepsin, has the following chemical structure and name: 70226WO01 (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23- tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone 3. Panobinostat, including pharmaceutically acceptable salts thereof. Drugs of the Future 32(4): 315-322 (2007). 5 Panobinostat, has the following chemical structure and name: (2E)-N-hydroxy-3-[4- methyl)phenyl]acrylamide 4. Valproic acid, including pharmaceutically acceptable salts thereof. Gottlicher, et al., EMBO J.20(24): 6969-6978 (2001). 10 Valproic acid, has the following chemical structure and name: -propy pentanoc ac d 5. Mocetinostat (MGCD0103), including pharmaceutically acceptable salts thereof. Balasubramanian et al., Cancer Letters 280: 211-221 (2009). 15 Mocetinostat, has the following chemical structure and name: N H2 N-(2-Aminophen o]methyl] benzamide Further examples of such HDAC inhibitors are included in Bertrand European Journal of Medicinal Chemistry 45, (2010) 2095-2116, particularly the compounds of table 3 therein as 20 indicated below. 80 70226WO01 5 that break down proteins, like the p53 protein. Several proteasome inhibitors are marketed or are 81 70226WO01 being studied in the treatment of cancer. Suitable proteasome inhibitors for use in combination herein include: 1. Bortezomib (Velcade®), including pharmaceutically acceptable salts thereof. Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304–11. Bortezomib has the following 5 chemical structure and name. [(1R)-3-methyl-1-({(2S)-3-phen ino]propanoyl}amino)butyl]boronic acid 2. Disulfiram, including pharmaceutically acceptable salts thereof. 10 Bouma et al. (1998). J. Antimicrob. Chemother.42 (6): 817–20. Disulfiram has the following chemical structure and name. 1,1',1'',1'''-[disulfanediylbis(car 3. Epigallocatechin gallate (EGCG), including pharmaceutically acceptable salts 15 thereof. Williamson et al., (December 2006), The Journal of Allergy and Clinical Immunology 118 (6): 1369–74. Epigallocatechin gallate has the following chemical structure and name. [(2R,3R)-5,7-dihydroxy-2-(3,4,5 l]3,4,5-trihydroxybenzoate 4. Salinosporamide A, including pharmaceutically acceptable salts thereof. Feling et 20 at., (2003), Angew. Chem. Int. Ed. Engl.42 (3): 355–7. Salinosporamide A has the following chemical structure and name. 82 70226WO01 (4R,5S)-4-(2-chloroethyl)-1-((1S)-cyclo roxy)methyl) -5-methyl-6-oxa-2- azabicyclo3.2.0heptane-3,7-dione 5. Carfilzomib, including pharmaceutically acceptable salts thereof. Kuhn DJ, et al, Blood, 5 2007, 110:3281-3290. Carfilzomib has the following chemical structure and name. H O H O O (S)-4-methyl-N-((S)-1-(((S ntan-2-yl)amino)-1- oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide The 70 kilodalton heat shock proteins (Hsp70s) and 90 kilodalton heat shock proteins 10 (Hsp90s) are a families of ubiquitously expressed heat shock proteins. Hsp70s and Hsp90s are over expressed certain cancer types. Several Hsp70s and Hsp90s inhibitors are being studied in the treatment of cancer. Suitable Hsp70s and Hsp90s inhibitors for use in combination herein include: 1. 17-AAG(Geldanamycin), including pharmaceutically acceptable salts thereof. Jia W et al. Blood.2003 Sep 1;102(5):1824-32. 17-AAG(Geldanamycin) has the following chemical 15 structure and name. O H N H2 17-(Allylamino)-17-demethoxygel danamycin 2. Radicicol, including pharmaceutically acceptable salts thereof. (Lee et al., 83 70226WO01 Mol Cell Endocrinol.2002, 188,47-54). Radicicol has the following chemical structure and name. (1aR,2Z,4E,14R,15aR)-8-chloro-9 -15,15a-dihydro-1aH- 5 benzo[c]oxireno[2,3-k][1]oxacyclo e ra ec ne- , ( , )-dione Inhibitors of cancer metabolism - Many tumor cells show a markedly different metabolism from that of normal tissues. For example, the rate of glycolysis, the metabolic process that converts glucose to pyruvate, is increased, and the pyruvate generated is reduced to lactate, rather than being further oxidized in the mitochondria via the tricarboxylic acid (TCA) cycle. This effect is often 10 seen even under aerobic conditions and is known as the Warburg Effect. Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a pivotal role in tumor cell metabolism by performing the reduction of pyruvate to lactate, which can then be exported out of the cell. The enzyme has been shown to be upregulated in many tumor types. The alteration of glucose metabolism described in the Warburg 15 effect is critical for growth and proliferation of cancer cells and knocking down LDH-A using RNA-i has been shown to lead to a reduction in cell proliferation and tumor growth in xenograft models. D. A. Tennant et. al., Nature Reviews, 2010, 267. P. Leder, et. al., Cancer Cell, 2006, 9, 425. 20 High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions. Pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance. Alli et al. Oncogene (2005) 24, 39–46. doi:10.1038 Inhibitors of cancer metabolism, including inhibitors of LDH-A and inhibitors of fatty acid 25 biosynthesis (or FAS inhibitors), are suitable for use in combination with the compounds of this invention. In one embodiment, the cancer treatment method of the claimed invention includes the co- administration a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule 30 agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, 84 70226WO01 immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism. In one embodiment, a compound of Formula (I) is used as a chemosensitizer to enhance tumor cell killing. 5 In one embodiment, a compound of Formula (I) is used in combination as a chemosensitizer to enhance tumor cell killing. In one embodiment, a compound of Formula (I) is used in combination with a compound that inhibits the activity of protein kinase R (PKR)-like ER kinase, PERK (PERK inhibitor). Suitably, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may 10 be co-administered with at least one other active agent known to be inhibitors of PERK kinase (EIF2K3) for treating or lessening the severity of neurodegenerative diseases/injury, such as Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular 15 disease, 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, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. 20 "Chemotherapeutic" or "chemotherapeutic agent" is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells. Additionally, the compounds described herein can be co-administered with conventional immunotherapeutic agents including, but not limited to, immunostimulants (e.g., Bacillus Calmette-25 Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc. ), monoclonal antibodies (e.g., anti- CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc. ), and radioimmunotherapy (e.g., anti- CD20 monoclonal antibody conjugated to 111In, 90Y, or 131I, etc. ). 30 In a further embodiment, the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as 47Sc, 64C 67C, 89Sr, 86Y, 87Y, and 212Bi, optionally conjugated to antibodies directed against tumor antigens. Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the compounds are anti-PD-L1 agents. 35 Anti-PD-L1 antibodies and methods of making the same are known in the art. 85 70226WO01 Such antibodies to PD-L1 may be polyclonal or monoclonal, and/or recombinant, and/or humanized. Exemplary PD-L1 antibodies are disclosed in: US Patent No.8,217,149; 12/633,339; 5 US Patent No.8,383,796; 13/091,936; US Patent No 8,552,154; 13/120,406; US patent publication No.20110280877; 13/068337; US Patent Publication No.20130309250; 13/892671; WO2013019906; 10 WO2013079174; US Application No.13/511,538 (filed August 7, 2012), which is the US National Phase of International Application No. PCT/US10/58007 (filed 2010); and US Application No.13/478,511 (filed May 23, 2012). Additional exemplary antibodies to PD-L1 (also referred to as CD274 or B7-H1) and 15 methods for use are disclosed in US Patent No.7,943,743; US20130034559, WO2014055897, US Patent No.8,168,179; and US Patent No.7,595,048. PD-L1 antibodies are in development as immuno-modulatory agents for the treatment of cancer. In one embodiment, the antibody to PD-L1 is an antibody disclosed in US Patent No. 8,217,149. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody 20 disclosed in US Patent No.8,217,149. In another embodiment, the antibody to PD-L1 is an antibody disclosed in US Application No.13/511,538. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Application No.13/511,538. In another embodiment, the antibody to PD-L1 is an antibody disclosed in Application No. 25 13/478,511. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Application No.13/478,511. 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. 30 Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented ATF4 pathway inhibiting compounds are PD-1 antagonist. "PD-1 antagonist" means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B 35 cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to 86 70226WO01 the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any embodiments of the aspects or embodiments of the present invention in which a human 5 individual is to be treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP_005009. Human PD-L1 and PD- L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively. 10 PD-1 antagonists useful in the any of the aspects of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD- 1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments, the human constant region is selected from the 15 group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, 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. Examples of mAbs that bind to human PD-1, and useful in the various aspects and 20 embodiments of the present invention, are described in US7488802, US7521051, US8008449, US8354509, US8168757, WO2004/004771, WO2004/072286, WO2004/056875, and US2011/0271358. Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in any of the aspects and embodiments of the present invention include: MK-3475, a humanized IgG4 mAb with the 25 structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 6; nivolumab, a human IgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 1, pages 68-69 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 7; the humanized antibodies h409A11, h409A16 and h409A17, 30 which are described in WO2008/156712, and AMP-514, which is being developed by Medimmune. Other PD-1 antagonists useful in the any of the aspects and embodiments of the present invention include an immunoadhesion that specifically binds to PD-1, and preferably specifically binds to human PD-1, e.g., a fusion protein containing the extracellular or PD-1 binding portion 35 of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin 87 70226WO01 molecule. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010/027827 and WO2011/066342. Specific fusion proteins useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1. 5 Other examples of mAbs that bind to human PD-L1, and useful in the treatment method, medicaments and uses of the present invention, are described in WO2013/019906, W02010/077634 A1 and US8383796. Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS- 936559, MEDI4736, MSB0010718C. 10 KEYTRUDA/pembrolizumab is an anti-PD-1 antibody marketed for the treatment of lung cancer by Merck. The amino acid sequence of pembrolizumab and methods of using are disclosed in US Patent No.8,168,757. Opdivo/nivolumab is a fully human monoclonal antibody marketed by Bristol Myers Squibb directed against the negative immunoregulatory human cell surface receptor PD-1 15 (programmed death-1 or programmed cell death-1/PCD-1) with immunopotentiation activity. Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands PD-L1 and PD-L2, resulting in the activation of T-cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and effector function through the suppression of P13k/Akt pathway activation. Other names for 20 nivolumab include: BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence for nivolumab and methods of using and making are disclosed in US Patent No. US 8,008,449. Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the compounds of the invention are immuno- modulators. 25 As used herein “immuno-modulators” refer to any substance including monoclonal antibodies that affects the immune system. The ICOS binding proteins of the present invention can be considered immune-modulators. Immuno-modulators can be used as anti-neoplastic agents for the treatment of cancer. For example, immune-modulators include, but are not limited to, anti- CTLA-4 antibodies such as ipilimumab (YERVOY) and anti-PD-1 antibodies (Opdivo/nivolumab 30 and Keytruda/pembrolizumab). Other immuno-modulators include, but are not limited to, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies and GITR antibodies. Yervoy (ipilimumab) is a fully human CTLA-4 antibody marketed by Bristol Myers Squibb. The protein structure of ipilimumab and methods are using are described in US Patent 35 Nos.6,984,720 and 7,605,238. 88 70226WO01 In another embodiment, this invention provides a compound of Table 1 described herein or a Formula (I) or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment of a hepatitis B virus-related disease, condition or disorder. This invention provides a compound of Table 1 or a pharmaceutically acceptable salt or prodrug thereof, for use in the treatment of a 5 hepatitis B virus-related disease, condition or disorder. wherein the hepatitis B virus-related disease, condition or disorder may be jaundice, liver cancer, liver inflammation, liver fibrosis, liver cirrhosis, liver failure, diffuse hepatocellular inflammatory disease, hemophagocytic syndrome or serum hepatitis). In some embodiments, the compound of the present invention of Formula (I) or 10 pharmaceutically acceptable salts thereof, is selected from the group of compounds set forth in Table 1. Additionally, the present invention also encompasses each of these compounds individually and pharmaceutically acceptable salts thereof. In other embodiments, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of 15 Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the compound(s) of the present invention, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 1. The compounds of the present invention can be supplied in the form of a pharmaceutically acceptable salt. The terms "pharmaceutically acceptable salt" refer to salts prepared from pharmaceutically 20 acceptable inorganic and organic acids and bases. Accordingly, the word “or” in the context of “a compound or a pharmaceutically acceptable salt thereof” is understood to refer to either a compound or a pharmaceutically acceptable salt thereof (alternative), or a compound and a pharmaceutically acceptable salt thereof (in combination). As used herein, the term “pharmaceutically acceptable” refers to those compounds, 25 materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication. The skilled artisan will appreciate that pharmaceutically acceptable salts of compounds according to Formula (I) may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification 30 of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively. Compounds of the invention may be made according to various schemes described below Synthetic Methods The methods of synthesis for the provided chemical entities employ readily available 35 starting materials using the following general methods and procedures. It will be appreciated that 89 70226WO01 where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization 5 procedures. Additionally, the methods of this invention may employ protecting groups which prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are 10 described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein. Furthermore, the provided chemical entities may contain one or more chiral centers and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched 15 mixtures) are included within the scope of this specification, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. 20 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 may be prepared by procedures, or obvious modifications thereof, 25 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 Supplementals (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). 30 Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from -78 C to 200 C. Further, except as employed in the Examples or as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about - 78 C to about 110 C over a period of about 1 to about 24 hours; reactions left to run overnight 35 average a period of about 16 hours. 90 70226WO01 The terms "solvent," "organic solvent," and "inert solvent" each mean a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N- 5 methylpyrrolidone ("NMP"), pyridine and the like. Isolation and purification of the chemical entities and intermediates described herein can be affected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of 10 suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used. When desired, the (R)- and (S)-isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which 15 may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer 20 may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation. EXAMPLES The following examples serve to more fully describe the manner of making and using the above-described invention. It is understood that these examples in no way serve to limit the true 25 scope of the invention, but rather are presented for illustrative purposes. In the examples and the synthetic schemes herein, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning. ACN, AcCN, = acetonitrile 70226WO01 oC = degrees Celsius DCM = dichloromethane 70226WO01 MPLC = medium pressure liquid chromatography MS = mass spectrum Equipment Description NMR Instrumentation and data: 1H NMR spectra were recorded at 25°C on various instruments as listed below with all 5 spectrometers operating at 400 MHz. Bruker AVANCE NEO 400 MHz/54 mm instrument (MRCA 400/54/ASC, 16971) Bruker AVANCE III 400 MHz/54 mm UltraShield Plus, long hold time, instrument (BZH 439’400’70I, D335/54-6776) Bruker AVANCE III 400 MHz/54 mm Ascend instrument (BZH 994'400'70I, D315’54- 10 9223) Varian 400MR 400 MHz/54 mm instrument (MRCA 400/54/ASC, MRYOO20874) Bruker AVANCE III 400 MHz/54 mm Ascend instrument (BZH 993'400'70I, D315’54- 9213) 93 70226WO01 Bruker AVANCE III 400 MHz/54 mm Ascend instrument (BZH 1157'400'70I, D315’54- 9574) Bruker AVANCE III 400 MHz/54 mm Ascend instrument (BZH 1126'400'70I, D315’54- 9527) 5 Bruker AVANCE NEO 400 MHz/54 mm Ascend instrument (BZH 1396'400'70I, D315’54-10089) Bruker AVANCE NEO 400 MHz/54 mm Ascend instrument (BZH 1373'400'70I, D315'54- 10026) Varian 400MR 400 MHz/54 mm instrument (MRCA 400/54/ASC, 20609) 10 Varian 400MR 400 MHz/54 mm instrument (MRCA 400/54/ASC, 20188) The data were processed and analyzed using Topspin 2.1 software. Where the number of protons assigned is less than the theoretical number of protons in the molecule, it is assumed that the apparently missing signal(s) is/are obscured by solvent and/or water peaks. In addition, where spectra were obtained in protic NMR solvents, exchange of NH and/or OH protons with solvent 15 occurs and hence such signals are normally not observed. Chemical shifts are expressed in parts per million (ppm). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad). The chemical shifts are referenced to solvent peaks, which in 1H NMR appear at 7.27 ppm for CDCl3, 2.50 for DMSO-d6, 4.79 for D2O and 3.31 ppm for CD3OD. 20 Analytical LC-MS system and method description for final products: In the following examples, compounds were characterized by mass spectroscopy using the systems and operating conditions set out below. Where atoms with different isotopes are present and a single mass quoted, the mass quoted for the compound is the monoisotopic mass (i.e.35CI; 79Br, etc.). 25 Instrument: Agilent 1200 & 6100B Scan Mode: Alternating Positive/Negative Electrospray Scan Range: 100-1000 amu LC Conditions: The LCMS analysis was conducted on a Kinetex C1850*2.1 mm column (5 um particles). The gradient employed was: 30 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 35 3.0 min 5 95 1.0 ml/min 4.0 min 5 95 1.0 ml/min 94 70226WO01 UV detection provided by summed absorbance signal at 214 nm and 254 nm scanning. Analytical LC-MS system and method description for intermediate products: Method A: Instrument: Shimadzu LCMS-2020 5 Scan Mode: Positive Electrospray Ionization Scan Range: 100-1000 amu LC Conditions: The LCMS analysis was conducted on a Luna-C182.0*30mm (3 um particles) column. The gradient employed was: Mobile Phase A: Water + 0.037 % v/v TFA 10 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 15 3.80 min 90.0 10.0 1.2 ml/min 4.30 min 90.0 10.0 1.2 ml/min UV detection provided by summed absorbance signal at 214 nm and 254 nm scanning. Method B: Instrument: Agilent 1200 & 6110B 20 Scan Mode: Positive Electrospray Ionization Scan Range: 100-1000 amu LC Conditions: The LCMS analysis was conducted on a Xbridge Shield RP182.1*50 mm, (5 um particles) column. The gradient employed was: Mobile Phase A: 10 mM ammonium bicarbonate in water 25 Mobile Phase B: Acetonitrile in in in in in 95 70226WO01 UV detection provided by summed absorbance signal at 214 nm and 254 nm scanning. Preparative LC-MS system and method description: Method A: Instrument: Waters Fractionlynx system 5 Hardware: 2767 Dual Loop Autosampler/Fraction Collector; 2525 preparative pump; CFO (column fluidic organizer) for column selection; RMA (Waters reagent manager) as make up pump; Waters ZQ Mass Spectrometer; Waters 2996 Photo Diode Array detector. Waters ZQ Mass Spectrometer: Scan Mode: Alternating Positive/Negative Electrospray 10 Scan Range: 100-2000 amu LC Conditions: Preparative LCMS separations were conducted on a HALO C-18, 4.6*50 mm, 2.7 μm, C18 column at 450C. The gradient employed was: Mobile Phase A: Water + 0.1 % v/v Formic Acid Mobile Phase B: Acetonitrile + 0.1 % v/v Formic Acid 15 Time %A %B Flow Rate 0.00 min 95 5 1.5 ml/min 5 1.5 ml/min 5 1.5 ml/min 25 min 95 5 1.5 ml/min 5 5 1.5 ml/min d by su mmed absorbance signal at 214 nm and 254 nm scanning. Method B: Instrument: Agilent 1100 LC-MS preparative system: Hardware: 1100 series "prepALS" autosampler; 1100 series "PrepPump" for preparative flow 25 gradient and 1100 series "QuatPump" for pumping modifier in prep flow; 1100 series "MWD" Multi Wavelength Detector; 1100 series "LC-MSD VL" detector; 2 x "Prep-FC" fraction collector; "Waters RMA" make-up pump; Agilent Active Splitter. Agilent MS running conditions: Capillary voltage: 4000 V (3500 V on ES Negative); Fragmentor/Gain: 150/1; Drying gas flow: 12.0 L/min; Gas Temperature: 350 °C; Nebuliser 30 Pressure: 50 psig; Scan Range: 125-800 amu; Ionisation Mode: ElectroSpray Positive or ElectroSpray Negative. LC Conditions: Preparative LCMS separations were conducted on a HALO C-18, 4.6*50 mm, 2.7 μm, C18 column at 450C. The gradient employed was: Mobile Phase A: Water + 0.1 % v/v Formic Acid 96 70226WO01 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 5 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 provided by summed absorbance signal at 214 nm and 254 nm scanning. Normal Phase Chromatographic Separations: 10 Silica gel chromatography was performed on Biotage instruments using pre-packaged disposable SiO2 stationary phase columns with eluent flow rate range of 15 to 200 mL/min, UV detection (254 and 280 nm). Schemes and Experimental procedures The following schemes and procedures illustrate how compounds of the present invention 15 can be prepared. The specific solvents and reaction conditions referred to are also illustrative and are not intended to be limiting. Compounds not described are either commercially available or are readily prepared by one skilled in the art using available starting materials. The Examples disclosed herein are for illustrative purposes only and are not intended to limit the compounds of the scope of the invention. 20 Additional examples contained within were determined to have the shown configuration by spectroscopic methods well known to those skilled in the art including, but not limited to, 1D and 2D NMR methods. Compounds of Formula (I) can for example be synthesized according to the below schemes. I. Synthesis of synthetic intermediates. 25 Synthesis of Intermediate 1.1, 2-(4-fluorobenzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Five batches were carried out in parallel: 97 70226WO01 Pd(PPh3)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 N2. The mixture was stirred at 100°C for 3 h. 5 TLC (Petroleum ether/EtOAc = 10:1) indicated complete consumption of starting material and formation of new spots. The five reactions were combined for work-up. The reaction mixture was filtered and the mixture was quenched with H2O (1500 mL) at 0°C. The mixture was extracted with EtOAc (1000 mL * 3) and the combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column 10 chromatography (SiO2, Petroleum ether/EtOAc = 300:1 to 0:1) to give the title compound (127 g, 538 mmol, 55.2% yield) as a yellow liquid. 1H 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). 15 Synthesis of Intermediate 2.11, 5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine. Step 1 of 11: Synthesis of Intermediate 2.1, dimethyl 2-(5-bromo-3-nitropyridin-2- 20 yl)malonate. Two batches were carried out in parallel: 98 70226WO01 To a suspension of K2CO3 (464 g, 3.36 mol, 3.02 eq) in DMF (1000 mL) was added dropwise CH2(CO2Me)2 (220.4 g, 1.67 mol, 192 mL, 1.50 eq) over 20 min at 0 °C followed by portion-wise addition of 5-bromo-2-chloro-3-nitropyridine (264 g, 1.11 mol, 1 eq). The reaction mixture was allowed to warm to 20°C, and stirred for 18 h. TLC (Petroleum ether/EtOAc = 2:1) indicated the 5 reaction was almost complete. The two reactions were combined for work-up. The reaction mixture was poured into 2.0 M HCl (6.2 L) and extracted with EtOAc (3 L * 3). The combined organic phase was washed with LiCl (1.0 M aqueous solution, 2 L) and brine (2 L), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (Petroleum ether/EtOAc = 20:1 to 1:1) to give the 10 title compound (832 g, crude) as a yellow oil (containing dimethyl malonate residue). TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.52. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.88 (d, J=1.9 Hz, 1H), 8.63 (d, J=1.9 Hz, 1H), 5.49 (s, 1H), 3.82 (s, 6H). 15 Step 2 of 11: Synthesis of Intermediate 2.2, methyl 2-(5-bromo-3-nitropyridin-2-yl)acetate. Two reactions were carried out in parallel: To a suspension of dimethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (416 g, 1.25 mol, 1 eq) in H2O (600 mL) was added LiCl (265 g, 6.24 mol, 5 eq). The reaction mixture was heated at reflux for 72 h after which time TLC (Petroleum ether/EtOAc = 2:1) showed complete consumption of 20 starting material. The two reactions were combined for work-up. The cooled reaction mixture was partitioned between EtOAc (3000 mL) and water (1000 mL). The isolated organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product as a brown oil. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 50:1 to 20:1) to give the title compound (540 g, 1.96 mol, 77.1% yield) as a yellow oil. 25 1H NMR (400MHz, CHLOROFORM-d) δ ppm 8.85 (d, J=2.00 Hz, 1 H), 8.58 (d, J=2.00 Hz, 1 H), 4.29 (s, 2 H), 3.73 (s, 3 H). Step 3 of 11: Synthesis of Intermediate 2.3, methyl 2-(5-bromo-3-nitropyridin-2-yl)-2- methylpropanoate. 30 Four reactions were carried out 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 one hour. The mixture was stirred at 20°C for 0.5 h after which time TLC 35 (Petroleum ether/EtOAc = 10:1) indicated complete consumption of starting material and formation 99 70226WO01 of a new product. The four reactions were combined for work-up. The reaction was quenched with saturated aqueous NH4Cl (3000 mL) at 0°C and the resulting mixture was extracted with EtOAc (3000 mL * 2). The combined organics were washed with brine (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography 5 (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (160 g, 528 mmol, 74.4% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.83 (d, J=2.13 Hz, 1 H), 8.37 (d, J=2.13 Hz, 1 H), 3.65 (s, 3 H), 1.68 (s, 6 H). 10 Step 4 of 11: Synthesis of Intermediate 2.4, 6-bromo-3,3-dimethyl-1,3-dihydro-2H- pyrrolo[3,2-b]pyridin-2-one. 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 15 at 100°C for 1.5 h after which time TLC (Petroleum ether/EtOAc = 2:1) indicated complete consumption of starting material and formation of one new spot. The two reactions were combined for work-up. The mixture was filtered and the filtrate was concentrated to dryness. The crude product was treated with saturated aqueous NaHCO3 (2000 mL) and then extracted with EtOAc (1500 mL * 3). The combined organic phase was washed with brine (500 mL), dried over Na2SO4, 20 filtered, and concentrated under reduced pressure to give the title compound (120 g, 498 mmol, 94.3% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 6 H) 7.41 (d, J=1.75 Hz, 1 H) 8.28 (d, J=1.75 Hz, 1 H) 9.94 (br s, 1 H). 25 Step 5 of 11: Synthesis of Intermediate 2.5, 6-bromo-3,3-dimethyl-2,3-dihydro-1H- pyrrolo[3,2-b]pyridine. Th i arried 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) was added NaBH4 (35.3 g, 933 mmol, 5 eq) and BF3.Et2O (185 g, 30 1.30 mol, 161 mL, 7 eq) at 0°C under N2. The mixture was stirred at 20°C for 12 h after which time TLC (Petroleum ether/EtOAc = 2:1) indicated complete consumption of starting material and formation of a new product. The three reactions were quenched separately with saturated aqueous NH4Cl (300 mL) and extracted with EtOAc (1000 mL * 2). The combined organic phase was washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 35 The three residues were combined and purified by column chromatography (SiO2, Petroleum 100 70226WO01 ether/EtOAc = 10:1 to 5:1) to give the title compound (90.0 g, 396 mmol, 71.0% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 6 H) 3.40 (s, 2 H) 6.89 (d, J=1.75 Hz, 1 H) 7.88 (d, J=1.75 Hz, 1 H). 5 Step 6 of 11: Synthesis of Intermediate 2.6, tert-butyl 6-bromo-3,3-dimethyl-2,3-dihydro-1H- pyrrolo[3,2-b]pyridine-1-carboxylate. 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, 10 1 eq) and Boc2O (38.7 g, 315 mmol, 1.3 eq) in DCM (900 mL) was added DMAP (32.5 g, 266 mmol, 1.1 eq) in portions at 0°C. The mixture was stirred at 30°C for 12 h after which time TLC (Petroleum ether/EtOAc = 2:1) indicated complete consumption of the starting material. The two reactions were combined for work-up. The mixture was filtered and the filtrate was concentrated to give a crude product. The residue was purified by column chromatography (SiO2, Petroleum 15 ether/EtOAc = 1:0 to 4:1) to give the title compound (101 g, 309 mmol, 67.8% yield) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.15 (d, J=2.00 Hz, 1 H), 3.74 (br s, 2 H), 1.49 - 1.63 (m, 9 H), 1.36 (s, 6 H). 20 Step 7 of 11: Synthesis of Intermediate 2.7, tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3- dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. Two reactions were carried out in parallel: To a solu n 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- 25 dioxaborolane (50.5 g, 214 mmol, 1.4 eq) in dioxane (800 mL) and H2O (80 mL) was added K2CO3 (52.8 g, 382 mmol, 2.5 eq) and Pd(dppf)Cl2 (16.8 g, 22.9 mmol, 0.15 eq). The mixture was stirred at 80°C for 12 h under N2 after which time TLC (Petroleum ether/EtOAc = 3:1) indicated conversion to a new product. The two reactions were combined for work-up. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by column 30 chromatography (SiO2, Petroleum ether/EtOAc = 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]+. Step 8 of 11: Synthesis of Intermediate 2.8, 1-(tert-butoxycarbonyl)-6-(4-fluorobenzyl)-3,3- 35 dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine 4-oxide. 101 70226WO01 To a solution of tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine- 1-carboxylate (35.0 g, 98.2 mmol 1 eq) in DCM (600 mL) was added m-CPBA (25.9 g, 128 mmol, 85% purity, 1.3 eq) at 0°C. The mixture was stirred at 15°C for 4 h after which time LCMS indicated formation of a product of desired mass. The reaction was quenched with saturated 5 aqueous Na2SO3 (600 mL) and then extracted with DCM (100 mL * 2). The combined organics were washed with 1N NaOH (300 mL * 2) and brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (34 g, 91.3 mmol, 95.7% yield) as a red oil. LCMS (ES, m/z): 373.3 [M+H]+. 10 Step 9 of 11: Synthesis of Intermediate 2.9, tert-butyl 6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. 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 Ac2O (340 g, 315 mL) was stirred at 135°C for 6 h 15 after which time LCMS indicated complete consumption of 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 that the intermediate product was consumed and a new product of desired mass was detected. The mixture was concentrated to 20 remove most of the MeOH under reduced pressure and treated with H2O (1500 mL) with stirring at 15°C for 1 h. The solids were filtered off and the filter cake was dried to give the title compound (32.0 g, 85.0 mmol, 94.1% yield) as a white solid. LCMS (ES, m/z): 373.3 [M+H]+. 25 Step 10 of 11: Synthesis of Intermediate 2.10, 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridin-5(4H)-one. T l i f b l 6 4 fl ophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carboxylate (15 g, 40.3 mmol, 1 eq) in DCM (150 mL) was added HCl/dioxane (4 M, 150 mL) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete 30 consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (12.4 g, 40.3 mmol, 99.7% yield, HCl) as a yellow solid. LCMS (ES, m/z): 273.1 [M+H+]. 102 70226WO01 Step 11 of 11: Synthesis of Intermediate 2.11, 5-((tert-butyldimethylsilyl)oxy)-6-(4- fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine. To a solution of 6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydro-1H-pyrrolo[3,2-b]pyridin-5- one (8.7 g, 28.18 mmol, 1 eq, HCl) and imidazole (12.5 g, 183 mmol, 6.5 eq) in DCM (300 mL) 5 was added TBSCl (10.62 g, 70.4 mmol, 8.63 mL, 2.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h after which time TLC (Petroleum ether/EtOAc = 3:1) indicated complete consumption of starting material and formation of one new spot. The reaction mixture was added into saturated NH4Cl aq. (150 mL), extracted with DCM (100 mL * 2). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 10 the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 2:1) to give the title compound (15 g, quantitative yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1 ) LCMS (ES, m/z): 387.4 [M+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.14 (br dd, J = 5.6, 8.3 Hz, 2H), 6.99 - 6.92 (m, 2H), 15 6.62 (s, 1H), 3.93 - 3.68 (m, 2H), 3.31 (s, 2H), 1.31 - 1.25 (m, 6H), 0.95 (s, 9H), 0.32 (s, 6H) Synthesis of Intermediate 3.1, tert-butyl 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate 20 To a solution of tert-butyl 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- carboxylate (10 g, 30.56 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (9.31 g, 36.7 mmol, 1.2 eq), and KOAc (4.50 g, 45.8 mmol, 1.5 eq) in dioxane (150 mL), was added Pd(dppf)Cl2 (2.24 g, 3.06 mmol, 0.1 eq) under N2. The mixture was stirred at 100°C for 12 h under N2 after which time LC-MS indicated complete 25 consumption of starting material with formation of a peak of target mass. The reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was diluted with saturated NH4Cl (200 mL) and extracted with EtOAc (100 mL * 2). The combined organic phase was washed with brine (50 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced 103 70226WO01 pressure to give a residue. The residue was purified by flash chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (11.2 g, 29.9 mmol, 97.9% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.25 5 LCMS (ES, m/z): 293.1 [M+H]+ (boronic acid adduct). 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.55 - 8.32 (m, 2H), 3.72 (br s, 2H), 1.56 (br s, 9H), 1.41 - 1.26 (m, 18H) Synthesis of Intermediate 4.2, 6-(2,4-dichlorobenzyl)-3,3-dimethyl-2,3-dihydro-1H- 10 pyrrolo[3,2-b]pyridine hydrochloride Step 1 of 2: Synthesis of Intermediate 4.1, tert-butyl 6-(2,4-dichlorobenzyl)-3,3-dimethyl-2,3- dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. 15 To a solution of 1-(bromomethyl)-2,4-dichloro-benzene (1.54 g, 6.41 mmol, 1.2 eq), tert-butyl 3,3- dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrrolo[3,2-b]pyridine-1-carboxylate (2 g, 5.34 mmol, 1 eq), and K2CO3 (1.11 g, 8.02 mmol, 1.5 eq) in dioxane (50 mL) and H2O (5 mL), was added Pd(dppf)Cl2 (391 mg, 534 umol, 0.1 eq) under N2. The mixture was stirred at 80°C for 12 h under N2. LC-MS indicated complete conversion to a product of target mass. The 20 reaction was concentrated in vacuo to get a residue. The residue was purified by flash chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (965 mg, 2.37 mmol, 44.3% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.53 LCMS (ES, m/z): 407.2 [M+H]+ 25 Step 2 of 2: Synthesis of Intermediate 4.2, 6-(2,4-dichlorobenzyl)-3,3-dimethyl-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridine hydrochloride 6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b] 104 70226WO01 pyridine-1-carboxylate (500 mg, 1.23 mmol, 1 eq) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 5 mL). The mixture was stirred at 15°C for 2.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and filtered cake was concentrated under reduced pressure to give the title compound (400 mg, 1.16 5 mmol, 94.8% yield, HCl) as a yellow solid. LCMS (ES, m/z): 307.0 [M+H]+ Synthesis of Intermediate 5.4, 5-((tert-butyldimethylsilyl)oxy)-6-(2,4-dichlorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine 10 Step 1 of 4: Synthesis of Intermediate 5.1, tert-butyl 6-[(2,4-dichlorophenyl)methyl]-3,3- dimethyl-4-oxido-2H-pyrrolo[3,2-b]pyridin-4-ium-1-carboxylate. To a solution of tert-butyl 6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine 15 -1-carboxylate (965 mg, 2.37 mmol, 1 eq) in DCM (10 mL) was added m-CPBA (625 mg, 3.08 mmol, 85% purity, 1.3 eq) at 0°C, the mixture was stirred at 25°C for 4 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction was quenched with saturated Na2SO3 (20 mL) and then extracted with DCM (20 mL * 2). The combined organic phase was washed with 1N NaOH (20 mL * 2) and brine (20 mL), dried 20 over anhydrous Na2SO4, filtered, and concentrated to give the title compound (870 mg, 2.06 mmol, 86.8% yield) as a yellow oil. LCMS (ES, m/z): 423.2 [M+H]+ Step 2 of 4: Synthesis of Intermediate 5.2, tert-butyl 6-(2,4-dichlorobenzyl)-3,3-dimethyl-5- 25 oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. To a stirred solution of tert-butyl 6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-4-oxido-2H- pyrrolo[3,2-b]pyridin-4-ium-1-carboxylate (870 mg, 2.06 mmol, 1 eq) in DMF (10 mL), TFAA (4.32 g, 20.6 mmol, 2.86 mL, 10 eq) was added at 0°C. The mixture was stirred at 50°C for 3 h. LC-MS indicated complete consumption of starting material with formation of a single peak of 30 target mass. The reaction solution was cooled to 0°C and quenched with aqueous NaHCO3 until the pH = 7. The mixture was filtered and the filter cake was dried to give the title compound (741 mg, 1.75 mmol, 85.2% yield) as a yellow solid. 105 70226WO01 LCMS (ES, m/z): 423.2 [M+H]+ Step 3 of 4: Synthesis of Intermediate 5.3, 6-(2,4-dichlorobenzyl)-3,3-dimethyl-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridin-5(4H)-one. 5 To a solution of tert-butyl 6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carboxylate (741 mg, 1.75 mmol, 1 eq) in DCM (4 mL) was added HCl/dioxane (4 M, 8 mL). The mixture was stirred at 25°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (500 mg, 1.39 10 mmol, 79.4% yield, HCl) as a yellow solid. LCMS (ES, m/z): 323.1 [M+H]+ Step 4 of 4: Synthesis of Intermediate 5.4, 5-((tert-butyldimethylsilyl)oxy)-6-(2,4- dichlorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine. 15 To a solution of 6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-2,4-dihydro-1H-pyrrolo[3,2- b]pyridin-5-one (500 mg, 1.39 mmol, 1 eq, HCl) and imidazole (615 mg, 9.04 mmol, 6.5 eq) in DCM (10 mL) was added TBSCl (524 mg, 3.48 mmol, 426 uL, 2.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete conversion to a product of target mass. The reaction mixture was added into saturated NH4Cl (20 mL) and then extracted with DCM (20 mL * 20 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 2:1) to give the title compound (337 mg, 770 umol, 55.4% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.51 25 LCMS (ES, m/z): 437.2 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.38 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 1.8, 8.3 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.60 (s, 1H), 3.90 (s, 2H), 3.33 (s, 2H), 1.28 (s, 6H), 0.91 (s, 9H), 0.31 (s, 6H) 30 Synthesis of Intermediate 6.2, 6-(2,4-dichlorobenzyl)-3,3,4-trimethyl-2,3-dihydro-1H- pyrrolo[3,2-b]pyridin-5(4H)-one hydrochloride. 106 70226WO01 Boc N N HN NH Boc N N M I B Li O Step o : Synt ess o Intermed ate 6. , tert-buty 6-( , -dc orobenzy )-3,3, -trimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. 5 To a solution of tert-butyl 6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carboxylate (1 g, 2.36 mmol, 1 eq) in THF (15 mL) was added t- BuOLi (378 mg, 4.72 mmol, 426 uL, 2 eq) and MeI (671 mg, 4.72 mmol, 294 uL, 2 eq). The mixture was stirred at 60°C for 12 h. LC-MS indicated complete conversion to a product of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was 10 purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 0:1) to give the title compound (950 mg, 2.17 mmol, 91.9% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.35 LCMS (ES, m/z): 437.1 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.37 (br s, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 7.19 (br s, 15 1H), 3.95 (s, 2H), 3.64 (br d, J = 18.6 Hz, 5H), 1.51 - 1.32 (m, 15H) Step 2 of 2: Synthesis of Intermediate 6.2, 6-(2,4-dichlorobenzyl)-3,3,4-trimethyl-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridin-5(4H)-one hydrochloride. To a solution of tert-butyl 6-[(2,4-dichlorophenyl)methyl]-3,3,4-trimethyl-5-oxo-2H-pyrrolo[3,2- 20 b]pyridine-1-carboxylate (950 mg, 2.17 mmol, 1 eq) in EtOAc (8 mL) was added HCl/EtOAc (4 M, 8 mL). The mixture was stirred at 20°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (580 mg, 1.55 mmol, 71.5% yield, HCl) as a yellow solid. 25 LCMS (ES, m/z): 337.1 [M+H]+ 1 5 (s, 70226WO01 Synthesis of Intermediate 7.2, 5-chloro-2-((3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-6-yl)methyl)benzonitrile hydrochloride 5 Step 1 of 2: Synthesis of Intermediate 7.1, tert-butyl 6-[(4-chloro-2-cyano-phenyl) methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carboxylate. To a solution of tert-butyl 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H- pyrrolo[3,2-b]pyridine-1-carboxylate (2 g, 5.34 mmol, 1 eq), 2-(bromomethyl)-5-chloro - benzonitrile (1.48 g, 6.41 mmol, 1.2 eq), and K2CO3 (1.11 g, 8.02 mmol, 1.5 eq) in dioxane (40 10 mL) and H2O (4 mL), was added Pd(dppf)Cl2 (391 mg, 534 umol, 0.1 eq) under N2. The mixture was stirred at 80°C for 12 h under N2. LC-MS indicated complete conversion to a product of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (1.87 g, 4.70 mmol, 87.9% yield) as a yellow oil. 15 TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.45 LCMS (ES m/z): 3981 [M+H]+ H- o a sou on o er - u y -[( -c oro- -cyano-p eny )me y ]- , - me y- -pyrrolo[3,2-b] pyridine-1-carboxylate (1 g, 2.51 mmol, 1 eq) in EtOAc (8 mL) was added HCl/EtOAc (4 M, 8 mL). The mixture was stirred at 25°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was concentrated under reduced pressure to give the title compound (620 mg, 1.85 25 mmol, 73.8% yield, HCl) as a white solid. LCMS (ES, m/z): 298.1 [M+H]+ Synthesis of Intermediate 8.4, 2-[[5-[tert-butyl(dimethyl)silyl]oxy-3,3- dimethyl-1,2- dihydropyrrolo[3,2-b]pyridin-6-yl]methyl]-5-chloro-benzonitrile 108 70226WO01 Step 1 of 4: Synthesis of Intermediate 8.1, tert-butyl 6-[(4-chloro-2-cyano-phenyl) methyl]- 3,3-dimethyl-4-oxido-2H-pyrrolo[3,2-b]pyridin-4-ium-1-carboxylate. 5 To a solution of tert-butyl 6-[(4-chloro-2-cyano-phenyl)methyl]-3,3-dimethyl-2H-pyrrolo [3,2- b]pyridine-1-carboxylate (1.87 g, 4.70 mmol, 1 eq) in DCM (30 mL) was added m-CPBA (1.43 g, 7.05 mmol, 85% purity, 1.5 eq) at 0°C. The mixture was stirred at 40°C for 2 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction was quenched with saturated Na2SO3 (30 mL) and then extracted with DCM (40 mL * 2). 10 The combined organic phase was washed with 1N NaOH (30 mL * 2) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (1.81 g, 4.37 mmol, 92.9% yield) as a yellow oil. LCMS (ES, m/z): 414.2 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 7.75 - 7.47 (m, 4H), 4.08 (s, 2H), 3.80 - 3.70 (m, 3H), 15 1.60 (s, 6H), 1.54 (s, 9H) Step 2 of 4: Synthesis of Intermediate 8.2, tert-butyl 6-[(4-chloro-2-cyano-phenyl) methyl]- 3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridine-1-carboxylate. To a stirred solution of tert-butyl 6-[(4-chloro-2- o-phenyl)methyl]-3,3-dimethyl-4-oxido- 2H- 20 pyrrolo[3,2-b]pyridin-4-ium-1-carboxylate (1.8 g, 4.35 mmol, 1 eq) in DMF (20 mL), TFAA (9.13 g, 43.5 mmol, 6.05 mL, 10 eq) was added at 0°C. The mixture was stirred at 50°C for 3 h after which time TLC (Petroleum ether/EtOAc = 1:3) indicated complete consumption of starting material and formation of a new product. The reaction solution was cooled to 0°C and quenched with aqueous NaHCO3 until the pH = 7. The mixture was filtered and the filtrate was concentrated 25 under reduced pressure to give a residue. The residue was purified by flash chromatography (SiO2, l h A 1 11 i h il 1 2 4 l 4 ield) 1 - 70226WO01 Step 3 of 4: Synthesis of Intermediate 8.3, 5-chloro-2-[(3,3-dimethyl-5-oxo-2,4- dihydro-1H- pyrrolo[3,2-b]pyridin-6-yl)methyl]benzonitrile. To a solution of tert-butyl 6-[(4-chloro-2-cy 5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carboxylate (1 g, 2.42 mmol, 1 eq) in DCM (10 mL) was added 5 HCl/dioxane (4 M, 17.9 mL) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (796 mg, 2.27 mmol, 94.1% yield, HCl) as a yellow solid. LCMS (ES, m/z): 314.1 [M+H]+ 10 Step 4 of 4: Synthesis of Intermediate 8.4, 2-[[5-[tert-butyl(dimethyl)silyl]oxy-3,3- dimethyl- 1,2-dihydropyrrolo[3,2-b]pyridin-6-yl]methyl]-5-chloro-benzonitrile. To a solution of TBSCl (850 mg, 5.64 mmol, 691 uL, 2.5 eq) and imidazole (998 mg, 14.7 mmol, 6.5 eq) in DCM (20 mL) was added 5-chloro-2-[(3,3-dimethyl- 5-oxo-2,4-dihydro-1H-pyrrolo[3,2- 15 b]pyridin-6-yl)methyl]benzonitrile (790 mg, 2.26 mmol, 1 eq, HCl) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete conversion to a product of target mass. The residue was added into saturated NH4Cl (15 mL) and then extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash 20 chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (833 mg, 1.95 mmol, 86.3% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.45 LCMS (ES, m/z): 429.2 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 7.52 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 2.3, 8.4 Hz, 25 1H), 7.19 (s, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.67 (s, 1H), 3.95 (s, 2H), 3.26 (s, 2H), 1.20 (s, 6H), 0.88 - 0.76 (m, 9H), 0.29 - 0.18 (m, 6H) Synthesis of Intermediate 9.2, 5-chloro-2-((3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-6- H N O 30 70226WO01 Step 1 of 2: Synthesis of Intermediate 9.1, tert-butyl 6-(4-chloro-2-cyanobenzyl)-3,3,4- trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. To a solution of tert-butyl 6-[(4-chloro-2-cyano-phenyl)methyl]-3,3-dimethyl-5-oxo-2,4- 5 dihydropyrrolo[3,2-b]pyridine-1-carboxylate (600 mg, 1.45 mmol, 1 eq) in THF (10 mL) was added t-BuOLi (232 mg, 2.90 mmol, 261 uL, 2 eq) and MeI (412 mg, 2.90 mmol, 180 uL, 2 eq). The mixture was stirred at 60°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum 10 ether/EtOAc = 1:1) to give the title compound (570 mg, 1.33 mmol, 91.9% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.32 LCMS (ES, m/z): 428.2 [M+H]+ Step 2 of 2: Synthesis of Intermediate 9.2, 5-chloro-2-((3,3,4-trimethyl-5-oxo-2,3,4,5- 15 tetrahydro-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl)benzonitrile hydrochloride. To a solution of tert-butyl 6-[(4-chloro-2-cyano-phenyl)methyl]-3,3,4-trimethyl-5-oxo-2H- pyrrolo[3,2-b]pyridine-1-carboxylate (640 mg, 1.50 mmol, 1 eq) in EtOAc (6 mL) was added HCl/EtOAc (4 M, 8 mL). The mixture was stirred at 20°C for 4 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was 20 filtered and the filter cake was dried to give the title compound (340 mg, 933 umol, 62.4% yield, HCl) as a white solid. LCMS (ES, m/z): 328.1 [M+H]+ Synthesis of Intermediate 10.2, 3,3-dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-1,2- 25 dihydropyrrolo[3,2-b]pyridine. Step 1 of 2: Synthesis of Intermediate 10.1, tert-butyl 3,3-dimethyl-6-(2,4,5-trifluorobenzyl)- 2,3-dihydro -1H-pyrrolo[3,2-b]pyridine-1- carboxylate. 111 70226WO01 A mixture of tert-butyl 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,3-dihydro- 1H-pyrrolo[3,2-b]pyridine-1-carboxylate (2 g, 5.34 mmol, 1 eq), 1- (bromomethyl) -2,4,5-trifluoro- benzene (1.44 g, 6.41 mmol, 1.2 eq), K2CO3 (1.11 g, 8.02 mmol, 1.5 eq), Pd(dppf)Cl2 (391 mg, 534 umol, 0.1 eq) in dioxane (30 mL) H2O (3 mL) was degassed and purged with N2 three times, and 5 then the mixture was stirred at 80°C for 12 h under N2 atmosphere. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:0) to give the title compound (1 g, 2.55 mmol, 47.7% yield) as a yellow oil. 10 TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.50 LCMS (ES, m/z): 393.2 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.99 (br s, 1H), 7.02 - 6.79 (m, 2H), 3.88 (s, 2H), 3.74 (s, 2H), 1.54 (s, 9H), 1.37 (s, 6H) 15 Step 2 of 2: Synthesis of Intermediate 10.2, 3,3-dimethyl-6-[(2,4,5-trifluorophenyl) methyl]- 1,2- dihydropyrrolo[3,2-b]pyridine. To a solution of tert-butyl 3,3-dimethyl-6-(2,4,5-trifluorobenzyl)-2,3-dihydro-1H-pyrrolo [3,2- b]pyridine-1-carboxylate (1 g, 2.55 mmol, 1 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 10 mL). The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of 20 starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (670 mg, 2.04 mmol, 79.97% yield, HCl) as a yellow solid. LCMS (ES, m/z): 293.2 [M+H]+ 25 Synthesis of Intermediate 11.4, tert-butyl-[[3,3-dimethyl-6- [(2,4,5-trifluorophenyl)methyl]- 1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane Step 1 of 4: Synthesis of Intermediate 11.1, tert-butyl 3,3-dimethyl-4-oxido-6- [(2,4,5- 30 trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-4-ium-1-carboxylate. To a solution of tert-butyl 3,3-dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo [3,2-b] pyridine-1-carboxylate (1.35 g, 3.44 mmol, 1 eq) in DCM (15 mL) was added m-CPBA (1.05 g, 112 70226WO01 5.16 mmol, 85% purity, 1.5 eq). The mixture was stirred at 40°C for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction was quenched with saturated Na2SO3 (30 mL) and then extracted with DCM (20 mL * 3). The combined organic phase was washed with 1N NaOH (15 mL * 2) and brine (30 mL), dried 5 over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (1.38 g, 3.38 mmol, 98.2% yield) as a yellow oil. LCMS (ES, m/z): 409.1 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 7.64 (br s, 2H), 7.04 - 6.90 (m, 2H), 3.82 (s, 2H), 3.74 (s, 2H), 1.59 (s, 6H), 1 . , H) 10 Step 2 of 4: Synthesis of Intermediate 11.2, tert-butyl 3,3-dimethyl-5-oxo-6- [(2,4,5- trifluorophenyl)methyl]-2,4-dihydropyrrolo[3,2-b]pyridine-1-carboxylate. To a solution of tert-butyl 3,3-dimethyl-4-oxido-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo [3,2- b]pyridin-4-ium-1-carboxylate (1.37 g, 3.35 mmol, 1 eq) in DMF (15 mL) was added TFAA (7.05 15 g, 33.5 mmol, 4.67 mL, 10 eq) at 0°C. The mixture was stirred at 15°C for 3 h after which time TLC (Petroleum ether/EtOAc = 3:1) indicated complete consumption of starting material and formation of a new product. The reaction solution was cooled to 0°C and quenched with aqueous NaHCO3 until the pH = 7. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (SiO2, Petroleum 20 ether/EtOAc = 1:0 to 2:1) to give the title compound (1.07 g, 2.62 mmol, 78.1% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.24. LCMS (ES, m/z): 409.1 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 8.18 (br s, 1H), 7.64 (br s, 1H), 7.20 (br s, 2H), 3.79 25 (s, 2H), 3.70 (br s, 2H), 1.43 (s, 15H) Step 3 of 4: Synthesis of Intermediate 11.3, 3,3-dimethyl-6-[(2,4,5-trifluorophenyl) methyl]- 2,4-dihydro-1H-pyrrolo[3,2-b]pyridin-5-one. To a solution of tert-butyl 3,3-dimethyl-5-oxo-6-[(2,4,5-trifluorophenyl)methyl]- 2,4- 30 dihydropyrrolo[3,2-b]pyridine-1-carboxylate (1.07 g, 2.62 mmol, 1 eq) in DCM (10 mL) was added HCl/dioxane (4 M, 15 mL) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC- MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (748 mg, 2.17 mmol, 82.8% yield, HCl) as a yellow solid. 35 LCMS (ES, m/z): 309.2 [M+H]+ 113 70226WO01 1H NMR (400MHz, DMSO-d6) δ = 11.31 (br s, 1H), 7.54 (dt, J=6.9, 10.2 Hz, 1H), 7.41 (ddd, J=7.2, 9.2, 11.0 Hz, 1H), 7.30 (s, 1H), 4.69 (br s, 1H), 3.73 (s, 2H), 3.45 (s, 2H), 1.34 (s, 6H) Step 4 of 4: Synthesis of Intermediate 11.4, tert-butyl-[[3,3-dimethyl-6- [(2,4,5- 5 trifluorophenyl)methyl]-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane. To a solution of 3,3-dimethyl-6-[(2,4,5-trifluorophenyl) yl]- 2,4-dihydro-1H-pyrrolo [3,2- b]pyridin-5-one (720 mg, 2.09 mmol, 1 eq, HCl), and imidazole mg, 13.6 mmol, 6.5 eq) in DCM (15 mL) was added TBSCl (787 mg, 5.22 mmol, 639 uL, 2.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting 10 material with formation of a single peak of target mass. Saturated NH4Cl (20 mL) was added to the mixture and the mixture was extracted with DCM (20 mL* 2). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 2:1) to give the title compound (700 mg, 1.66 mmol, 79.3% yield) as a yellow oil. 15 TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.61 LCMS (ES, m/z): 423.2 [M+H]+ Synthesis of Intermediate 12.2, 3,3,4-trimethyl-6-[(2,4,5-trifluorophenyl)methyl]- 1,2- dihydropyrrolo[3,2-b]pyridin-5-one. Boc N Boc N HN N O 20 Step 1 of 2: Synthesis of Intermediate 12.1, tert-butyl 3,3,4-trimethyl-5-oxo-6- [(2,4,5- trifluorophenyl) methyl]-2H-pyrrolo[3,2-b]pyridine-1-carboxylate. To a solution of tert-butyl 3,3-dimethyl-5-oxo-6-(2,4,5-trifluorobenzyl)- 2,3,4,5-tetrahydro- 1H-25 pyrrolo[3,2-b]pyridine-1-carboxylate (890 mg, 2.18 mmol, 1 eq) in THF (15 mL) was added t- BuOLi (349 mg, 4.36 mmol, 392.91 uL, 2 eq) and MeI (619 mg, 4.36 mmol, 271.32 uL, 2 eq). The mixture was stirred at 60°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a peak of target mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum 114 70226WO01 ether/EtOAc = 1:0 to 2:1) to give the title compound (520 mg, 1.23 mmol, 56.49% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.34 LCMS (ES, m/z): 423.1 [M+H]+ 5 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.27 - 8.06 (m, 1H), 7.21 (br d, J = 6.9 Hz, 1H), 6.94 - 6.84 (m, 1H), 3.82 (s, 2H), 3.68 (br s, 2H), 3.61 (s, 3H), 1.54 - 1.39 (m, 15H) Step 2 of 2: Synthesis of Intermediate 12.2, 3,3,4-trimethyl-6-[(2,4,5-trifluorophenyl) methyl]- 1,2-dihydropyrrolo[3,2-b]pyridin-5-one. 10 To a solution of tert-butyl 3,3,4-trimethyl-5-oxo-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo [3,2- b]pyridine-1-carboxylate (520 mg, 1.23 mmol, 1 eq) in EtOAc (1.5 mL) was added HCl/EtOAc (4 M, 5 mL). The mixture was stirred at 20°C for 1 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give the title compound (440 mg, 1.23 mmol, 99.6% yield, 15 HCl) as a yellow oil. LCMS (ES, m/z): 323.2 [M+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 7.38 (s, 1H), 7.34 - 7.24 (m, 1H), 7.15 (dt, J = 6.8, 10.0 Hz, 1H), 3.84 (s, 2H), 3.64 (d, J = 4.4 Hz, 5H), 1.58 (s, 6H) 20 Synthesis of Intermediate 13.5, tert-butyl-[[6-[(2,4-difluorophenyl)methyl]- 3,3-dimethyl-1,2- dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane 70226WO01 Step 1 of 5: Synthesis of Intermediate 13.1, tert-butyl 6-[(2,4-difluorophenyl)methyl]- 3,3- dimethyl-2H -pyrrolo[3,2-b]pyridine-1-carboxylate. A mixture of tert-butyl 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-pyrrolo 5 [3,2-b]pyridine-1-carboxylate (2.5 g, 6.68 mmol, 1 eq), 1-(bromomethyl)-2,4-difluoro-benzene (1.80 g, 8.68 mmol, 1.12 mL, 1.3 eq), K2CO3 (1.38 g, 10.0 mmol, 1.5 eq), and Pd(dppf)Cl2 (488 mg, 668 umol, 0.1 eq) in dioxane (40 mL) and H2O (4 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 80°C for 12 h under N2 atmosphere. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The 10 mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (1.5 g, 4.01 mmol, 60.0% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.48 LCMS (ES, m/z): 375.3 [M+H]+ 15 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.01 (br s, 1H), 7.91 (br s, 1H), 7.19 - 7.08 (m, 1H), 6.86 - 6.75 (m, 2H), 3.91 (s, 2H), 3.73 (s, 2H), 1.53 (s, 9H), 1.36 (s, 6H) Step 2 of 5: Synthesis of Intermediate 13.2, tert-butyl 6-[(2,4-difluorophenyl)methyl]- 3,3- dimethyl-4-oxido-2H-pyrrolo[3,2-b]pyridin-4-ium-1-carboxylate. 20 To a solution of tert-butyl 6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo [3,2- b]pyridine-1-carboxylate (1.5 g, 4.01 mmol, 1 eq) in DCM (15 mL) was added m-CPBA (1.22 g, 6.01 mmol, 85% purity, 1.5 eq) at 0°C. The mixture was stirred at 40°C for 2 h after which time TLC (Petroleum ether/EtOAc = 3:1) indicated complete consumption of starting material and formation of a new product. The reaction was quenched with saturated Na2SO3 (20 mL) and then 25 extracted with DCM (20 mL * 2). The combined organic phase was washed with 1N NaOH (10 mL * 2) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound (1.3 g, 3.33 mmol, 83.1% yield) as a yellow oil. LCMS (ES, m/z): 391.2 [M+H]+ 30 Step 3 of 5: Synthesis of Intermediate 13.3, tert-butyl 6-[(2,4-difluorophenyl)methyl]- 3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridine-1-carboxylate. To a stirred solution of tert-butyl 6- [(2,4-difluorophenyl)methyl]-3,3-dimethyl-4- oxido-2H- pyrrolo[3,2-b]pyridin-4-ium-1-carboxylate (1.3 g, 3.33 mmol, 1 eq) in DMF (15 mL), TFAA (6.99 g, 33.3 mmol, 4.63 mL, 10 eq) was added at 0°C. The mixture was stirred at 50°C for 3 h after 35 which time TLC (Petroleum ether/EtOAc = 1:1) indicated complete consumption of starting 116 70226WO01 material and formation of a new product. The reaction solution was cooled to 0°C and quenched with aqueous NaHCO3 until the pH = 7. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (0.890 g, 2.28 mmol, 68.5% yield) as a yellow solid. 5 LCMS (ES, m/z): 391.2 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.54 (br s, 1H), 7.36 - 7.29 (m, 1H), 6.84 - 6.68 (m, 2H), 3.83 (s, 2H), 3.70 (br d, J = 6.1 Hz, 2H), 1.50 (br d, J = 18.9 Hz, 9H), 1.42 (s, 6H) Step 4 of 5: Synthesis of Intermediate 13.4, 6-[(2,4-difluorophenyl)methyl]-3,3- dimethyl-2,4- 10 dihydro-1H-pyrrolo[3,2-b]pyridin-5-one. To a solution of tert-butyl 6-[(2,4-difluorophenyl)methyl] -3,3-dimethyl-5-oxo-2,4- yridine-1-carboxylate (890 mg, 2.28 mmol, 1 eq) in DCM (10 mL) was added HCl/dioxane (4 M, 20 mL). The mixture was stirred at 15°C for 12 h after which time LC- MS indicated complete consumption of starting material with formation of a single peak of target 15 mass. The mixture was filtered and the filter cake was dried to give the title compound (650 mg, 1.99 mmol, 87.3% yield, HCl) as a yellow solid. LCMS (ES, m/z): 291.2 [M+H]+ Step 5 of 5: Synthesis of Intermediate 13.5, tert-butyl-[[6-[(2,4-difluorophenyl)methyl]- 3,3- 20 dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane. To a solution of 6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-2,4-dihydro-1H-pyrrolo [3,2- b]pyridin-5-one (650 mg, 1.99 mmol, 1 eq, HCl) in DCM (8 mL) was added imidazole (880 mg, 12.9 mmol, 6.5 eq) and TBSCl (749 mg, 4.97 mmol, 609 uL, 2.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting 25 material with formation of a single peak of target mass. Saturated NH4Cl (20 mL) was added to the mixture and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (Petroleum ether/EtOAc = 3:1) to give the title compound (650 mg, 1.61 mmol, 80.8% yield) as a yellow oil. 30 LCMS (ES, m/z): 405.3 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.13 - 7.06 (m, 1H), 6.84 - 6.70 (m, 2H), 6.66 (s, 1H), 3.81 (s, 2H), 3.32 (s, 2H), 1.27 (s, 6H), 0.95 (s, 9H), 0.33 - 0.30 (m, 6H) Synthesis of Intermediate 14.2, 6-(2,4-dichlorophenoxy)-3,3-dimethyl-2,3-dihydro-1H- 35 pyrrolo[3,2-b]pyridine hydrochloride 117 70226WO01 Cl Cl OH HCl HN N O Cl Step o : Synt ess o Intermed ate . , tert-buty 6-( , -d c orop enoxy)-3,3-dimethyl- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. 5 To a solution of tert-butyl 6-bromo-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carboxylate (3 g, 9.17 mmol, 1 eq), 2,4-dichlorophenol (1.79 g, 11.0 mmol, 1.2 eq), Cs2CO3 (5.97 g, 18.3 mmol, 2 eq) in dioxane (45 mL) was added CuI (873 mg, 4.58 mmol, 0.5 eq) and 2-(dimethylamino)acetic acid (945 mg, 9.17 mmol, 1 eq) under N2. The mixture was stirred at 110°C for 16 h under N2. LC-MS indicated complete consumption of starting material and desired mass was detected. The 10 reaction mixture was concentrated under reduced pressure to remove dioxane. The residue was diluted with EtOAc (20 mL), saturated NH4Cl aq. (40 mL) and extracted with EtOAc (40 mL * 2). The combined organic phase was washed with brine (40 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 5:1) to give the title compound (1.5 g, 3.66 15 mmol, 39.9% yield) as a yellow oil. LCMS (ES, m/z): 409.1 [M+H]+ Step 2 of 2: Synthesis of Intermediate 14.2, 6-(2,4-dichlorophenoxy)-3,3-dimethyl-2,3- dihydro-1H-pyrrolo[3,2-b]pyridine hydrochloride. 20 To a solution of tert-butyl 6-(2,4-dichlorophenoxy)-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1- carboxylate (1.5 g, 3.66 mmol, 1 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 12 mL) at 0°C. The mixture was stirred at 25°C for 12.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (720 mg, 2.08 mmol, 56.8% yield, HCl) as a green 25 solid. LCMS (ES, m/z): 309.1 [M+H]+ Synthesis of Intermediate 15.3, 5-chloro-2-((3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-6-yl)oxy)benzonitrile hydrochloride 118 70226WO01 CN Boc N Cl F N HCl HN N Boc N 2 2 B N N H O oc HCl/EtOAc O CN 3 Step 1 of 3: Synthesis of Intermediate 15.1, tert-butyl 6-hydroxy-3,3-dimethyl-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridine-1-carboxylate. 5 To a solution of tert-butyl 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H- pyrrolo[3,2-b]pyridine-1-carboxylate (500 mg, 1.34 mmol, 1 eq) in EtOAc (8 mL) was added H2O2 (1.68 g, 14.82 mmol, 1.42 mL, 30% purity, 11.1 eq). The mixture was stirred at 25°C for 1 h. LC- MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was cooled to 0°C and quenched by slowly adding saturated Na2S2O3 aq. The 10 aqueous layer was extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (350 mg, 1.32 mmol, 99.1% yield) as a yellow oil. LCMS (ES, m/z): 265.2 [M+H]+ 15 1H NMR (400MHz, CHLOROFORM-d) δ = 7.80 (d, J=2.2 Hz, 1H), 7.67 (br s, 1H), 3.75 (br s, 2H), 1.74 (br s, 3H), 1.57 (br s, 6H), 1.37 (s, 3H), 1.25 (s, 3H) Step 2 of 3: Synthesis of Intermediate 15.2, tert-butyl 6-(4-chloro-2-cyanophenoxy)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. 20 To a solution of tert-butyl 6-hydroxy-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carboxylate (400 mg, 1.51 mmol, 1 eq), 5-chloro-2-fluoro-benzonitrile (282 mg, 1.82 mmol, 1.2 eq) in DMF (8 mL) was added K2CO3 (418 mg, 3.03 mmol, 2 eq). The mixture was stirred at 80°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (15 mL * 2) was added to the mixture, and the mixture was extracted with EtOAc (20 mL * 25 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 5:1) to give the title compound (510 mg, 1.28 mmol, 84.28% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.46 30 LCMS (ES, m/z): 400.2 [M+H]+ 119 70226WO01 1H NMR (400MHz, CHLOROFORM-d) δ = 7.96 (br s, 1H), 7.78 (br s, 1H), 7.63 (br s, 1H), 7.45 (br d, J=6.9 Hz, 1H), 6.97 - 6.79 (m, 1H), 3.81 (br s, 2H), 1.53 (s, 9H), 1.40 (s, 6H) Step 3 of 3: Synthesis of Intermediate 15.3, 5-chloro-2-((3,3-dimethyl-2,3-dihydro-1H- 5 pyrrolo[3,2-b]pyridin-6-yl)oxy)benzonitrile hydrochloride. To a solution of tert-butyl 6-(4-chloro-2-cyano-phenoxy)-3,3-dimethyl-2H-pyrrolo[3,2-b] pyridine- 1-carboxylate (510 mg, 1.28 mmol, 1 eq) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 10 mL). The mixture was stirred at 25 °C for 12.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake 10 was dried to give the title compound (300 mg, 892 umol, 67.0% yield, HCl) as a white solid. LCMS (ES, m/z): 300.1 [M+H]+ Synthesis of Intermediate 16.1, (2S)-2-[tert-butoxycarbonyl(methyl)amino]-2-cyclopropyl- acetic acid. O O (S) 3 eq NaH, 8 eq MeI (S) OH 2-cyclopropyl-acetic acid (500 mg, 2.32 mmol, 1 eq) in THF (20 mL) was added NaH (279 mg, 6.97 mmol, 60% purity, 3 eq) at 0°C. The mixture was stirred at 0°C for 30 min and MeI (2.64 g, 18.6 mmol, 1.16 mL, 8 eq) was dropwise added to the mixture at 0°C, the mixture was stirred at 40°C for 2 h after which time LC-MS indicated 20 complete consumption of starting material with formation of a single peak of target mass. The mixture was added to ice H2O (30 mL), extracted with MTBE (20 mL * 2), and then the water phase was acidified with citric acid to pH = 4. The acidic aqueous phase was extracted with EtOAc (20 mL * 3) and the combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (530 mg, 2.31 mmol, 25 99.5% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3: 1) Rf = 0.33 LCMS (ES, m/z): 228.0 [M-H]-. 1H NMR (400 MHz, DMSO-d6) δ = 3.37 - 3.30 (m, 1H), 2.87 (s, 3H), 1.43 - 1.30 (m, 9H), 1.23 - 1.18 (m, 1H), 0.71 - 0.21 (m, 4H) 30 Synthesis of Intermediate 17.1, (2R)-3-benzyloxy-2-[tert-butoxycarbonyl(methyl)amino] propanoic acid. 120 70226WO01 O O (R) (R) O OH NaH, MeI O OH HN O THF0-15°C 12h N O panoic acid (2 g, 6.77 mmol, 1 eq) in THF (20 mL) was added NaH (894 mg, 22.4 mmol, 60% purity, 3.3 eq) in one portion at 0°C. The mixture was stirred at 0°C for 30 min and MeI (2.88 g, 20.3 mmol, 1.26 mL, 3 eq) was 5 added to the mixture, followed by addition of DMF (1 mL). The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was quenched with H2O (50 mL), then extracted with EtOAc (50 mL * 2), and then the water phase was acidified with 1M HCl to pH 1-2. The acidic aqueous phase was extracted with DCM (50 mL * 3) and the combined organic phase was washed 10 with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase MPLC (column: C1820-35um 100A 60g; mobile phase: [water-MeOH]; B%: 0%-60%, 45mL/min) to give the title compound (650 mg, 2.10 mmol, 31.0% yield) as a yellow oil. LCMS (ES, m/z): 308.1 [M-H]-. 15 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.37 - 7.32 (m, 5H), 4.63 - 4.56 (m, 2H), 3.91 (br s, 2H), 3.86 - 3.79 (m, 1H), 2.95 - 2.90 (m, 3H), 1.48 (s, 9H) no] mmol, 1 eq) in THF (30 mL) was added NaH (1.28 g, 32.00 mmol, 60% purity, 3.3 eq) in one portion at 0°C. The mixture was stirred at 0°C for 30 min and MeI (4.13 g, 29.1 mmol, 1.81 mL, 3 eq) was added to the mixture, followed by addition of DMF (1.5 mL). The mixture was stirred at 15°C for 25 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was quenched with H2O (50 mL), then extracted with EtOAc (50 mL * 2), then the water phase was acidified with 1M HCl to pH 1-2. The acidic aqueous phase was extracted with DCM (50 mL * 3) and the combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a 121 70226WO01 residue. The crude product was purified by reversed-phase MPLC (column: C1820-35um 100A 330g; mobile phase: [water-CH3CN], B%: 0%-70%, 70 mL/min) to give the title compound (2.2 g, 6.80 mmol, 70.2% yield) as a yellow oil. LCMS (ES, m/z): 224.2 [M-Boc+H]+. 5 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.30 (br d, J = 2.1 Hz, 5H), 4.83 (br d, J = 5.1 Hz, 1H), 4.61 (s, 1H), 4.47 (s, 1H), 4.32 (br t, J = 5.9 Hz, 1H), 3.01 (s, 3H), 1.49 (s, 9H), 1.25 (br s, 3H Synthesis of Intermediate 19.2, (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(prop-2-yn-1- yloxy)phenyl)propanoic acid OH O O 10 Step 1 of 2: Synthesis of Intermediate,19.1, (S)-methyl2-((tert-butoxycarbonyl)amino)-3-(4- (prop-2-yn-1-yloxy)phenyl)propanoate. A mixture of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate (10 g, 15 33.9 mmol, 1 eq), 3-bromoprop-1-yne (6.04 g, 40.6 mmol, 4.38 mL, 80% purity, 1.2 eq), and K2CO3 (9.36 g, 67.7 mmol, 2 eq) in DMF (150 mL), and was stirred at 25°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was diluted with EtOAc (100 mL). The organic phases were washed with 0.5 N HCl (100 mL), water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated 20 under reduced pressure to give the crude product. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 0:1) to give the title compound (11.2 g, 33.6 mmol, 99.22% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.4 LCMS (ES, m/z): 234.1 [M-Boc+H+]. 25 1H NMR (400MHz, CHLOROF M-d) δ = 7.05 (d, J=8.6 Hz, 2H), 6.94 - 6.86 (m, 2H), 4.99 (br d, J=7.9 Hz, 1H), 4.66 (d, J=2.4 Hz, 2H), 4.58 - 4.48 (m, 1H), 3.70 (s, 3H), 3.02 (dq, J=5.9, 13.8 Hz, 2H), 2.52 (t, J=2.4 Hz, 1H), 1.41 (s, 9H) Step 2 of 2: Synthesis of Intermediate 19.2, (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(prop-2- 30 yn-1-yloxy)phenyl)propanoic acid. 122 70226WO01 To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(prop-2-yn-1- yloxy)phenyl)propanoate (10 g, 30.0 mmol, 1 eq) in THF (250 mL) was added LiOH (1 M, 70 mL, 2.33 eq). The mixture was stirred at 25°C for 2h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated in 5 vacuo, dissolved in H2O (30 mL), then extracted with EtOAc (60 mL * 2), and then the water phase was acidified with 1M HCl to pH 3-4. The acidic aqueous phase was extracted with EtOAc (60 mL * 2), and the organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (11.51 g, 98.3% purity, quantitative yield) as a yellow oil. 10 LCMS (ES, m/z): 220.0 [M-Boc+H+]. Synthesis of Intermediate 20.3, tert-butyl ((S)-1-(((S)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn-1- yloxy)phenyl)propan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate 15 Step 1 of 3: Synthesis of Intermediate 20.1; (S)-tert-butyl (1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop- 2-yn-1-yloxy)phenyl)propan-2-yl)carbamate. 20 To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(prop-2-yn-1-yloxy)phenyl)propanoic acid (494 mg, 1.55 mmol, 1.2 eq) in DCM (15 mL) was added DIEA (667 mg, 5.16 mmol, 898 uL, 4 eq), tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5- yl]oxy]-dimethyl-silane (500 mg, 1.29 mmol, 1 eq) and HATU (638 mg, 1.68 mmol, 1.3 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete conversion to a product of 25 target mass. Saturated NH4Cl aq (40 mL) was added to the mixture, and the mixture was extracted with DCM (30 mL * 2). The combined organic phase was washed with brine (40 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (685.7 mg, 997 umol, 77.27% yield) as a yellow oil. 30 TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.43 LCMS (ES, m/z): 688.5 [M+H+]. 123 70226WO01 Step 2 of 3: Synthesis of Intermediate 20.2, (S)-1-(2-amino-3-(4-(prop-2-yn-1- yloxy)phenyl)propanoyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-5(4H)-one. To a solution of (S)-tert-butyl (1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl- 5 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn-1-yloxy)phenyl)propan-2- yl)carbamate (685 mg, 996 umol, 1 eq) in EtOAc (6 mL) was added HCl/dioxane (4 M, 6 mL) at 0°C. The mixture was stirred at 15°C for 24 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give the title compound (500 mg, 980.4 umol, 98.46% yield, HCl) as a 10 yellow oil. LCMS (ES, m/z): 474.4 [M+H+]. 1H NMR (400MHz, DMSO-d6) δ = 7.98 (s, 1H), 7.31 - 7.22 (m, 2H), 7.21 - 7.05 (m, 4H), 6.90 (d, J=8.5 Hz, 2H), 4.73 (d, J=2.3 Hz, 2H), 4.31 - 4.19 (m, 1H), 3.75 (br d, J=15.0 Hz, 2H), 3.51 (t, J=2.3 Hz, 1H), 3.08 (br dd, J=5.6, 13.2 Hz, 1H), 2.97 - 2.88 (m, 2H), 1.91 (s, 1H), 1.20 (s, 3H), 15 0.92 (s, 3H) Step 3 of 3: Synthesis of Intermediate 20.3, tert-butyl ((S)-1-(((S)-1-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn-1- yloxy)phenyl)propan-2-yl)amino)-1-oxopropan-2-yl)(me 20 To a solution of (S)-1-(2-amino-3-(4-(prop-2-yn-1-yloxy)phenyl)propanoyl)-6-(4-fluorobenzyl)- methyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5(4H)-one (355 mg, 696 umol, 1 eq, HCl) (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (170 mg, 835 umol, 1.2 eq) in DCM (15 mL) was added DIEA (360 mg, 2.78 mmol, 485 uL, 4 eq) and HATU (344 mg, 905 umol, 1.3 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of 25 starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (25 mL) was added and the mixture was extracted with DCM (30 mL * 2). The combined organic phase was washed with brine (25 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (247.1 mg, 375.10 umol, 53.89% yield) as a yellow oil. 30 TLC (Petroleum ether/EtOAc = 0 : 1) Rf = 0.46 LCMS (ES, m/z): 659.5 [M+H+]. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.44 - 8.37 (m, 1H), 7.26 - 7.22 (m, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 6.87 (d, J=8.4 Hz, 3H), 4.88 - 4.79 (m, 1H), 4.64 (d, J=2.3 Hz, 2H), 3.84 - 3.78 (m, 3H), 3.07 - 2.94 (m, 4H), 2.72 (s, 3H), 2.50 - 2.47 (m, 1H), 2.18 (s, 1H), 35 1.51 (s, 9H), 1.34 - 1.30 (m, 6H), 1.06 (s, 3H) 124 70226WO01 Synthesis of Intermediate 21.6, tert-butyl ((S)-1-(((S)-3-(4-(2-azidoethoxy)phenyl)-1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1- oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate Step 1 of 6: Synthesis of Intermediate 21.1, (S)-methyl 3-(4-(2-bromoethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate. To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate (10 g, 10 33.9 mmol, 1 eq) in 1,2-dibromoethane (40 mL) was added K2CO3 (31.8 g, 230 mmol, 6.8 eq) and 1,4,7,10,13,16-hexaoxacyclooctadecane (1 g, 3.78 mmol, 1.12e-1 eq). The mixture was stirred at 80°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into H2O (50 mL), then extracted with EtOAc (40 mL * 3). The combined organic phase was dried over Na2SO4, filtered and 15 concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (8.12 g, 20.2 mmol, 59.6% yield) as a white solid. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.63 LCMS (ES, m/z): 302.0 [M-Boc+H+]. 20 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.05 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.96 (br d, J = 7.7 Hz, 1H), 4.59 - 4.52 (m, 1H), 4.27 (t, J = 6.2 Hz, 2H), 3.72 (s, 3H), 3.64 (t, J = 6.3 Hz, 2H), 3.11 - 2.97 (m, 2H), 1.43 (s, 9H) Step 2 of 6: Synthesis of Intermediate 21.2, (S)-methyl 3-(4-(2-azidoethoxy)phenyl)-2-((tert- 25 butoxycarbonyl)amino)propanoate. 125 70226WO01 To a solution of (S)-methyl 3-(4-(2-bromoethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate (3 g, 7.46 mmol, 1 eq) in DMF (40 mL) was added NaN3 (620 mg, 9.54 mmol, 1.28 eq). The mixture was stirred at 50°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction 5 mixture was added into H2O (80 mL), then extracted with EtOAc (40 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.7 g, 7.41 mmol, 99.36% yield) as a yellow oil. LCMS (ES, m/z): 265.2 [M-Boc+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.05 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 10 4.98 (br d, J = 7.8 Hz, 1H), 4.58 - 4.51 (m, 1H), 4.12 (d, J = 5.4 Hz, 2H), 3.71 (s, 3H), 3.59 (t, J = 4.9 Hz, 2H), 3.11 - 2.96 (m, 2H), 1.42 (s, 9H) Step 3 of 6: Synthesis of Intermediate 21.3, (S)-3-(4-(2-azidoethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid. 15 To a solution of (S)-methyl 3-(4-(2-azidoethoxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate (2.81 g, 7.71 mmol, 1 eq) in THF (18 mL), MeOH (6 mL), and H2O (6 mL) was added lithium hydroxide (554 mg, 23.1 mmol, 3 eq). The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. 20 The residue was dissolved in H2O (40 mL), then extracted with EtOAc (20 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (20 mL * 3) and the combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.68 g, 7.65 mmol, 99.2% yield) as a yellow oil. 25 LCMS (ES, m/z): 251.2 [M-Boc+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.12 (br d, J = 8.3 Hz, 2H), 6.90 - 6.84 (m, 2H), 6.05 (br s, 1H), 4.94 (br d, J = 7.5 Hz, 1H), 4.58 (br d, J = 6.5 Hz, 1H), 4.14 - 4.09 (m, 2H), 3.59 (t, J = 4.9 Hz, 2H), 3.19 - 2.97 (m, 2H), 1.48 - 1.34 (m, 9H) 30 Step 4 of 6: Synthesis of Intermediate 21.4, (S)-tert-butyl (3-(4-(2-azidoethoxy)phenyl)-1-(5- ((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- To a solution of (S)-3-(4-(2-azidoethoxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (706.94 mg, 2.02 mmol, 1.3 eq) in DCM (15 mL) was added DIEA (802 mg, 6.21 mmol, 1.08 mL,35 4 eq), tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5- 126 70226WO01 yl]oxy]-dimethyl-silane (600 mg, 1.55 mmol, 1 eq) and HATU (885 mg, 2.33 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography 5 (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (890 mg, 1.24 mmol, 79.76% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.53 LCMS (ES, m/z): 719.5 [M+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.20 - 8.17 (m, 1H), 7.18 - 7.10 (m, 4H), 6.98 - 6.91 10 (m, 2H), 6.80 (d, J = 8.5 Hz, 2H), 5.34 (br d, J = 8.9 Hz, 1H), 4.70 - 4.61 (m, 1H), 4.07 (t, J = 5.0 Hz, 2H), 3.88 - 3.83 (m, 2H), 3.56 (t, J = 4.9 Hz, 2H), 3.12 (d, J = 10.1 Hz, 1H), 3.04 - 2.94 (m, 2H), 1.42 (s, 9H), 1.24 (s, 3H), 0.98 (s, 3H), 0.94 - 0.91 (m, 9H), 0.31 - 0.27 (m, 6H) Step 5 of 6: Synthesis of Intermediate 21.5, (S)-1-(2-amino-3-(4-(2-15 azidoethoxy)phenyl)propanoyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-5(4H)-one. To a solution of (S)-tert-butyl (3-(4-(2-azidoethoxy)phenyl)-1-(5-((tert-butyldimethylsilyl)oxy)-6- (4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropan-2- yl)carbamate (690 mg, 960 umol, 1 eq) in dioxane (6 mL) was added HCl/dioxane (4 M, 8 mL). 20 The mixture was stirred at 15°C for 1 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was blown to dryness by N2 stream to give the title compound (510 mg, 943 umol, 98.2% yield, HCl) as a yellow solid. LCMS (ES, m/z): 505.4 [M+H+]. 25 Step 6 of 6: Synthesis of Intermediate 21.6, tert-butyl ((S)-1-(((S)-3-(4-(2- azidoethoxy)phenyl)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropan-2-yl)amino)-1-oxop -2-yl)(methyl)carbamate. To a solution of (S)-1-(2-amino-3-(4-(2-azidoethoxy)phenyl)pro panoy )-6-(4-fluorobenzyl)-3,3- 30 dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5(4H)-one (610 mg, 1.13 mmol, 1 eq, HCl) in DCM (15 mL) was added DIEA (583 mg, 4.51 mmol, 786 uL, 4 eq), (2S)-2-[tert- butoxycarbonyl(methyl)amino]propanoic acid (344 mg, 1.69 mmol, 1.5 eq) and HATU (643 mg, 1.69 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction 35 mixture was concentrated under reduced pressure to give a residue. The residue was purified by 127 70226WO01 column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 0:1) to give the title compound (460 mg, 667 umol, 59.2% yield) as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.63 LCMS (ES, m/z): 690.5 [M+H+]. 5 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.36 (br s, 1H), 7.27 - 7.22 (m, 2H), 7.14 (d, J = 8.5 Hz, 2H), 6.94 (t, J = 8.6 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 4.90 - 4.78 (m, 1H), 4.16 - 4.11 (m, 2H), 3.86 - 3.75 (m, 3H), 3.57 (t, J = 4.9 Hz, 2H), 3.02 - 2.94 (m, 2H), 2.82 (s, 1H), 2.73 (s, 2H), 2.11 - 2.05 (m, 2H), 1.54 - 1.47 (m, 9H), 1.35 - 1.25 (m, 9H) 10 Synthesis of Intermediate 22.1, tert-butyl ((S)-1-(((S)-3-(4-(2-aminoethoxy)phenyl)-1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1- oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate F N F N B B NH2 To a solution of tert-butyl ((S)-1-(((S)-3-(4-(2-azidoethoxy)phenyl)-1-(6-(4-fluorobenzyl)-3,3-15 dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropan-2-yl)amino)-1- oxopropan-2-yl)(methyl)carbamate (180 mg, 261 umol, 1 eq) in MeOH (15 mL)/ NH3.H2O (5 mL) was added Pd/C (50 mg, 10% purity). The mixture was stirred at 15°C for 5 h under H2 (15 psi) atmosphere. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and concentrated under reduced 20 pressure to give the title compound (150 mg, 225.98 umol, 86.6% yield) as a white solid. LCMS (ES, m/z): 664.4 [M+H+]. Synthesis of Intermediate 23.7, 2-(4-((S)-2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)propanamido)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 25 128 70226WO01 HN N F O O OTBS OH OH OEt Br O OEt O Boc PhCH2Br, NaHCO3 O Pd/C, H2, OEt F 2.11 O NH O OEt Step 1 of 7: Synthesis of Intermediate 23.1, (S)-benzyl 2-((tert-butoxycarbonyl)amino)-3-(4- hydroxyphenyl)propanoate. 5 To a solution of (S)-2-((tert-butoxycarbonyl)ami 4-hydroxyphenyl)propanoic acid (10 g, 35.6 mmol, 1 eq), NaHCO3 (2.99 g, 35.6 mmol, 1.38 mL, 1 eq) in DMF (80 mL) was added bromomethylbenzene (6.08 g, 35.6 mmol, 4.22 mL, 1 eq) at 15°C. The mixture was stirred at 15°C for 12 h. LCMS showed desired mass was detected. The reaction mixture was added into H2O (100 mL), then extracted with EtOAc (50 mL * 2). The combined organic phase was washed with 10 brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 (br .3 - To a solution of (S)-benzyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)propanoate (8.2 g, 22.1 mmol, 1 eq) in DMF (100 mL) was added K2CO3 (9.15 g, 66.23 mmol, 3 eq) and ethyl 2- bromoacetate (7.37 g, 44.15 mmol, 4.88 mL, 2 eq). The mixture was stirred at 20°C for 12 h after which time TLC (Petroleum ether/EtOAc = 2:1) indicated complete consumption of starting 25 material and formation of one new spot. The reaction mixture was added into H2O (250 mL), and then extracted with EtOAc (150 mL * 3). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The 129 70226WO01 residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (9.5 g, 20.76 mmol, 94.05% yield) as a white solid. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.53 LCMS (ES, m/z): 358.1 [M-Boc+H+]. 5 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.40 - 7.34 (m, 3H), 7.33 - 7.29 (m, 2H), 6.95 (br d, J = 8.3 Hz, 2H), 6.77 (br d, J = 8.4 Hz, 2H), 5.21 - 5.07 (m, 2H), 4.97 (br d, J = 8.2 Hz, 1H), 4.58 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 3.07 - 2.92 (m, 2H), 1.42 (s, 9H), 1.30 (t, J = 7.2 Hz, 3H) Step 3 of 7: Synthesis of Intermediate 23.3, (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2- 10 ethoxy-2-oxoethoxy)phenyl)propanoic acid. To a solution of (S)-benzyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-ethoxy-2- oxoethoxy)phenyl)propanoate (3 g, 6.56 mmol, 1 eq) in EtOAc (50 mL) was added Pd/C (1 g, 284 umol, 10% purity). The mixture was stirred at 15°C for 12 h under H2 (15 psi) atmosphere. LC- MS indicated complete consumption of starting material with formation of a single peak of target 15 mass. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.4 g, 6.53 mmol, 99.6% yield) as a colorless oil. LCMS (ES, m/z): 268.2 [M-Boc+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.11 (br d, J = 7.9 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.94 (br s, 1H), 4.61 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 3.22 - 2.99 (m, 2H), 1.51 - 1.32 (m, 9H), 1.30 20 - 1.24 (m, 3H) Step 4 of 7: Synthesis of Intermediate 23.4, (S)-ethyl 2-(4-(2-((tert-butoxycarbonyl)amino)-3- (5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b] ridin-1- l)-3-oxo ro l) henox )acetate 25 To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(2-ethoxy-2-oxoethoxy)phenyl)propanoic acid (618 mg, 1.68 mmol, 1.3 eq), tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2- dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (500 mg, 1.29 mmol, 1 eq) in DCM (15 mL) was added DIEA (669 mg, 5.17 mmol, 901 uL, 4 eq) and HATU (738 mg, 1.94 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of 30 starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (920 mg, 1.25 mmol, 96.7% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.63 35 LCMS (ES, m/z): 736.4 [M+H+]. 130 70226WO01 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.20 - 7.09 (m, 5H), 6.98 - 6.92 (m, 2H), 6.79 (d, J = 8.5 Hz, 2H), 5.36 - 5.29 (m, 1H), 4.71 - 4.62 (m, 1H), 4.54 (s, 2H), 4.28 - 4.21 (m, 2H), 3.91 - 3.76 (m, 3H), 3.14 (d, J = 9.9 Hz, 1H), 3.02 - 2.94 (m, 2H), 1.42 (s, 9H), 1.29 - 1.24 (m, 6H), 0.99 - 0.91 (m, 12H), 0.31 - 0.27 (m, 6H) 5 Step 5 of 7: Synthesis of Intermediate 23.5, (S)-ethyl 2-(4-(2-amino-3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropyl)phenoxy)acetate hydrochloride. To a solution of (S)-ethyl 2-(4-(2-((tert-butoxycarbonyl)amino)-3-(5-((tert-butyldimethylsilyl)oxy)-10 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropyl)phenoxy)acetate (920 mg, 1.25 mmol, 1 eq) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 10.00 mL). The mixture was stirred at 15°C for 1 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give the title compound (690 mg, 1.24 15 mmol, 98.9% yield, HCl) as a yellow solid. LCMS (ES, m/z): 522.2 [M+H+]. 1H NMR (400 MHz, METHANOL-d4) δ = 7.27 - 7.24 (m, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.06 - 6.97 (m, 3H), 6.88 - 6.85 (m, 2H), 4.65 (s, 2H), 4.35 (dd, J = 6.5, 8.9 Hz, 2H), 4.21 - 4.15 (m, 2H), 3.81 (d, J = 2.9 Hz, 2H), 3.12 - 3.07 (m, 2H), 2.89 (d, J = 10.3 Hz, 1H), 1.31 - 1.22 (m, 9H) 20 Step 6 of 7: Synthesis of Intermediate 23.6, ethyl 2-(4-((S)-2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)propanamido)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropyl)phenoxy)acetate. To a solution of (S)-ethyl 2-(4-(2-amino-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- 25 tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropyl)phenoxy)acetate (300 mg, 538 umol, 1 eq, HCl) in DCM (6 mL) was added DIEA (278 mg, 2.15 mmol, 375 uL, 4 eq), (2S)-2-[tert- butoxycarbonyl(methyl)amino]propanoic acid (164 mg, 806 umol, 1.5 eq), and HATU (307 mg, 806 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction 30 mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (210 mg, 297 umol, 55.3% yield) as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.73 LCMS (ES, m/z): 607.4 [M-Boc+H+]. 35 131 70226WO01 Step 7 of 7: Synthesis of Intermediate 23.7, 2-(4-((S)-2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)propanamido)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropyl)phenoxy)acetic acid. To a solution of 4-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-(6- 5 (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropyl)phenoxy)acetate (210 mg, 297 umol, 1 eq) in THF (3 mL)/MeOH (1 mL)/H2O (1 mL) was added lithium hydroxide (21.4 mg, 891 umol, 3 eq). The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue 10 was dissolved in H2O (10 mL), then extracted with EtOAc (8 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (8 mL * 3) and the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (200 mg, 295 umol, 99.2% yield) as a yellow solid. 15 LCMS (ES, m/z): 679.5 [M+H+]. Synthesis of Intermediate 24.2, 1-[(2S)-2-amino-3-[4-[6-[4-[(2S)-2-amino- 3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo- propyl]phenoxy]hexa-2,4-diynoxy]phenyl]propanoyl]-6-[(4-fluorophenyl)methyl]-3,3- 20 dimethyl-2,4-dihydropyr b]pyridin-5-one. F F Boc N H OTBS N O O (S) NH Boc C O 1.2 eq. Cu(OAc)2, 6 eq.Py. O (S) NH O N HCl/EtOAc O (S) NH2 O N N ACN, 85oC N O ( N O N S) O EtOAc H H N (S) O F Step 1 of 2: Synthesis of Intermediate 24.1, tert-butyl N-[(1S)-1-[[4-[6-[4-[(2S)-2- (tert- butoxycarbonylamino)-3-[5-[tert-butyl(dimeth l) il l] xy-6-[(4-fluorophenyl)methyl]-3,3-25 dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo -propy ]phenoxy]hexa-2,4- diynoxy]phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamate. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2- 30 ynoxyphenyl)methyl]ethyl]carbamate (1.45 g, 2.11 mmol, 1 eq.) in CH3CN (60 mL) was added pyridine (1.00 g, 12.7 mmol, 1.02 mL, 6 eq.) and Cu(OAc)2 (459 mg, 2.53 mmol, 1.2 eq). The mixture was stirred at 85°C for 1 h under aerobic conditions. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction 132 70226WO01 mixture was filtered and the filtrate was added into NH3.H2O (30 mL), then extracted with EtOAc (30 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.53 g, 54.4% purity, quantitative yield) as a yellow oil. LCMS (ES, m/z): 1259.7 [M-TBS+H]+ 5 Step 2 of 2: Synthesis of Intermediate 24.2, 1-[(2S)-2-amino-3-[4-[6-[4-[(2S)-2-amino- 3-[6- [(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo- propyl]phenoxy]hexa-2,4-diynoxy]phenyl]propan luorophenyl)methyl]-3,3- dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one. 10 To a solution of tert-butyl N-[(1S)-1-[[4-[6-[4-[(2S)-2-(tert-butoxycarbonyl 3-[5- [tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 3-oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamate (1.53 g, 1.11 mmol, 1 eq.) in EtOAc (5 mL) was added HCl/dioxane (4 M, 10 mL). The mixture was stirred 15 at 25°C for 1 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give the title compound (1.1 g, 2 HCl, 93.1% purity, 97.3% yield) as a yellow solid. LCMS (ES, m/z): 945.4 [M+H]+ 20 Synthesis of Intermediate 25.1, 1-(benzyloxy)-4-bromonaphthalene BnBr, K2CO3 Bn To a solution of 4-bromonaphthalen-1-ol (9.5 g, 42.6 mmol, 1 eq) in CH3CN (200 mL) was added K2CO3 (7.06 g, 51.1 mmol, 1.2 eq) and bromomethylbenzene (8.74 g, 51.1 mmol, 6.07 mL, 1.2 eq). The mixture was stirred at 15°C for 12 h after which time TLC (Petroleum ether/EtOAc = 10:1) 25 indicated complete consumption of starting material and formation of one new spot. The reaction mixture was added into H2O (100 mL), then extracted with EtOAc (80 mL * 2). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 10:1) to give the title compound (12.4 g, 39.6 mmol, 92.9% yield) 30 as a white solid. TLC (Petroleum ether/EtOAc = 10:1) Rf = 0.63 133 70226WO01 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.38 (dd, J = 0.7, 8.3 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.67 - 7.61 (m, 2H), 7.57 - 7.50 (m, 3H), 7.47 - 7.37 (m, 3H), 6.77 (d, J = 8.3 Hz, 1H), 5.25 (s, 2H) 5 Synthesis of Intermediate 26.1, 1-(benzyloxy)-4-bromo-2,3-dimethylbenzene OH BnBr, K2CO3 OBn Br MeCN Br l (5 g, 24.9 mmol, 1 eq) in CH3CN (80 mL) was added K2CO3 (5.16 g, 37.3 mmol, 1.5 eq) and BnBr (6.38 g, 37.3 mmol, 4.43 mL, 1.5 eq). The mixture was stirred at 15°C for 12 h after which time TLC (Petroleum ether/EtOAc = 3:1) indicated 10 complete consumption of the starting material. Saturated NaHCO3 aq. (150 mL) was added to the mixture, and the mixture was extracted with EtOAc (150 mL * 2). The combined organic phase was washed with brine (150 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (5.15 g, 15 17.7 mmol, 71.1% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 3:1) 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.47 - 7.32 (m, 6H), 6.66 (d, J = 8.8 Hz, 1H), 5.05 (s, 2H), 2.39 (s, 3H), 2.28 (s, 3H) 20 Step 1 of 1: Synthesis of Intermediate 27.1, 4-(benzyloxy)-1-bromo-2-methoxybenzene. OH OBn BnBr, K2CO3 henol (9.5 g, 46.8 mmol, 1 eq) in CH3CN (150 mL) was added K2CO3 (9.70 g, 70.2 mmol, 1.5 eq), BnBr (12.0 g, 70.2 mmol, 8.34 mL, 1.5 eq). The mixture was stirred at 15°C for 12 h after which time TLC (Petroleum ether/EtOAc = 10:1) indicated 25 complete consumption of starting material and formation of a new product. The reaction mixture was added into H2O (200 mL), then extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 134 70226WO01 Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (13.3 g, 45.4 mmol, 95.0% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 10:1) Rf = 0.43 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.48 - 7.31 (m, 6H), 6.59 (d, J = 2.8 Hz, 1H), 6.48 5 (dd, J = 2.7, 8.7 Hz, 1H), 5.06 (s, 2H), 3.87 (s, 3H) was ated complete consumption of the starting material. Saturated NaHCO3 aq. (200 mL) was added to the mixture, and the mixture was extracted with EtOAc (200 mL * 2). The combined organic phase was washed with brine (200 mL), dried over Na2SO4 and filtered. The filtrate was concentrated 15 under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 2:1) to give the title compound (12 g, 41.7 mmol, 82.5% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.55 (d, J = 8.9 Hz, 1H), 7.47 - 7.35 (m, 5H), 7.23 (s, 1H), 7.08 (dd, J = 3.1, 8.9 Hz, 1H), 5.08 (s, 2H) 20 Synthesis of Intermediate 29.2, 4-(benzyloxy)-1-bromo-2-ethylbenzene B B K2CO3 NBS Bn Step 1 of 2: Synthesis of Intermediate 29.1, 1-(benzyloxy)-3-ethylbenzene. 25 To a solution of 3-ethylphenol (9.8 g, 80.2 mmol, 9.70 mL, 1 eq) and K2CO3 (11.09 g, 80.22 mmol, 1 eq) in CH3CN (100 mL) was added bromomethylbenzene (16.5 g, 96.3 mmol, 11.4 mL, 1.2 eq) at 15°C. The mixture was stirred at 15°C for 12 h after which time TLC (Petroleum ether/EtOAc = 5:1) indicated complete consumption of starting material and formation of one new spot. The reaction mixture was added into saturated NaHCO3 aq. (20 mL), then extracted with EtOAc (10 30 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered 135 70226WO01 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 10:1) to give the title compound (16.5 g, 77.7 mmol, 96.9% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 1:0) Rf = 0.28 5 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.55 - 7.36 (m, 5H), 7.28 (t, J = 7.8 Hz, 1H), 6.97 - as which al and formation of a new product. The reaction mixture was added into H2O (100 mL), then extracted with EtOAc (50 mL * 3), and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was 15 purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 10:1) to give the title compound (7.85 g, 30.0 mmol, 57.2% yield) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.52 - 7.32 (m, 6H), 6.91 (d, J = 3.0 Hz, 1H), 6.71 (dd, J = 3.0, 8.8 Hz, 1H), 5.06 (s, 2H), 2.74 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H) 20 Synthesis of Intermediate 30.1, 5-(benzyloxy)-2-bromo-1,3-dimethylbenzene OH BnBr, K2CO3 OBn Br Br To a solution of 4-bromo-3,5-dimethyl-phenol (15 g, 74.6 mmol, 1 eq) in CH3CN (150 mL) was added K2CO3 (12.4 g, 89.5 mmol, 1.2 eq), and bromomethylbenzene (15.3 g, 89.5 mmol, 10.63 mL, 1.2 eq). The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of 25 starting material with formation of a single peak of target mass. Saturated NH4Cl (100 mL) aq. was added to the mixture, and the mixture was extracted with EtOAc (80 mL * 2). The combined organic phase was washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 5:1) to give the title compound (16.8 g, 30 57.7 mmol, 77.3% yield) as a white solid. 44 - 70226WO01 Synthesis of Intermediate 31.4, 5-(benzyloxy)-1,3-dichloro-2-iodobenzene. Cl Cl Cl TEA,TIPSCl n-BuLi, I2, -78°C OH OTIPS I OTIPS Step 1 of 4: Synthesis of Intermediate 31.1, (3,5-dichlorophenoxy)triisopropylsilane. 5 To a solution of compound 3,5-dichlorophenol (10 g, 61.4 mmol, 1 eq) in THF (100 mL) was added TIPSCl (13.0 g, 67.5 mmol, 14.4 mL, 1.1 eq) and TEA (6.83 g, 67.5 mmol, 9.39 mL, 1.1 eq) at 15°C. The mixture was stirred at 15°C for 12 h under N2 after which time TLC (Petroleum ether/EtOAc = 5:1) indicated conversion to a new product. The residue was added into saturated NH4Cl aq. (150 mL), then extracted with EtOAc (100 mL * 3). The combined organic phase was 10 washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (19.5 g, 61.1 mmol, 99.53% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 5:1) Step 2 of 4: Synthesis of Intermediate 31.2, (3,5-dichloro-4-iodophenoxy)triisopropylsilane. 15 To a solution of (3,5-dichlorophenoxy)-triisopropyl-silane (19.5 g, 61.1 mmol, 1 eq) in THF (180 mL) was added n-BuLi (2.5 M, 56.2 mL, 2.3 eq) in five portions over 30 min at -78°C. The mixture was stirred for 60 min under N2. I2 (19.37 g, 76.33 mmol, 15.38 mL, 1.25 eq) dissolved in THF (150 mL) was added at -78°C. The mixture was stirred at 20°C for 0.5 h after which time TLC (Petroleum ether/EtOAc = 5:1) indicated complete consumption of starting material and 20 formation of a new product. No work-up. The crude product was used directly for the next Step without purification. The title compound (27 g, 60.6 mmol, 99.3% yield) was obtained as a yellow oil. Step 3 of 4: Synthesis of Intermediate 31.3, 3,5-dichloro-4-iodophenol. 25 To a solution of (3,5-dichloro-4-iodo-phenoxy)-triisopropyl-silane (27 g, 60.6 mmol, 1 eq) in THF (300 mL) was added TBAF (1 M, 424 mL, 7 eq) at 0°C in 30 min. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was dissolved in Na2SO3 (10% aq, 100 mL), then extracted with 137 70226WO01 EtOAc (100 mL * 2). The organic phase was washed with aq. H2SO4 (10%, 100 mL), and the organic phase was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 10:1) to give the title compound (11.7 g, 40.5 mmol, 66.8% yield) 5 as a yellow oil. TLC (Petroleum ether/EtOAc = 5: 1) Rf = 0.55 ro-2-iodobenzene. K2CO3 (4.07 g, 29.4 9 mL, 1.2 eq) at 15°C. The mixture was stirred at 15°C for 12 h after which time TLC (Petroleum ether/EtOAc = 1:0) indicated complete consumption of starting material and formation of one new spot. Saturated 15 NaHCO3 aq. (100 mL) was added to the mixture, and the mixture was extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:0) to give the title compound (8.8 g, 23.2 mmol, 78.9% yield) as a yellow oil. 20 TLC (Petroleum ether/EtOAc = 1:0) Rf = 0.40 1H NMR (400MHz CHLOROFORM-d) δ = 7.46 - 7.34 (m 5H) 7.09 - 6.98 (m 2H) 5.04 (s 2H) 31 g, .41 mL, 1.2 eq) dropwise at 0°C. The mixture was stirred at 15°C for 12 h after which time TLC (Petroleum ether/EtOAc = 10:1) indicated complete consumption of starting material and formation of one new spot. The reaction mixture was added into saturated NaHCO3 aq. (100 mL), then 30 extracted with EtOAc (50 mL * 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 50:1) to give the title compound (6.5 g, 21.7 mmol, 90.8% yield) as a yellow oil. 138 70226WO01 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.50 - 7.35 (m, 5H), 6.77 - 6.49 (m, 2H), 5.04 (s, 2H) Synthesis of Intermediate 33.1, 4-(benzyloxy)-1-iodo-2-methylbenzene. BnBr, K CO OH 2 3 OBn I MeCN I 5 To a sout on o - odo-3-met y-p eno ( 9 g, 81.2 mmol, 1 eq) and K2CO3 (11.22 g, 81.18 mmol, 1 eq) in CH3CN (200 mL) was added BnBr (16.66 g, 97.42 mmol, 11.57 mL, 1.2 eq) at 15°C. The mixture was stirred at 15°C for 12 h after which time TLC (Petroleum ether/EtOAc = 5:1) indicated complete consumption of starting material and formation of one new spot. Saturated NaHCO3 aq. (200 mL) was added to the mixture, and the mixture was extracted with EtOAc (200 mL * 2). The 10 combined organic phase was washed with brine (200 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (20 g, 61.7 mmol, 76.0% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.67 (d, J = 8.6 Hz, 1H), 7.47 - 7.32 (m, 5H), 6.92 (d, 15 J = 3.0 Hz, 1H), 6.57 (dd, J = 2.9, 8.7 Hz, 1H), 5.04 (s, 2H), 2.41 (s, 3H) Synthesis of Intermediate 34.2, dodeca-1,11-diyne. Si 20 Step 1 of 2: Synthesis of Intermediate 34.1, trimethyl(12-trimethylsilyldodeca-1,11- diynyl)silane. To a solution of ethynyl(trimethyl)silane (161 mg, 1.64 mmol, 227 uL, 3 eq) in THF (2 mL) was added n-BuLi (2.5 M, 656 uL, 3 eq) at -78°C. The reaction mixture was stirred for 30 min at -78°C and the mixture was stirred at 0°C for 50 min. The mixture was added to the 1,8-diiodooctane (200 25 mg, 546 umol, 1 eq) in THF (1 mL). The mixture was then treated with HMPA (1.57 g, 8.74 mmol, 1.54 mL, 16 eq). The mixture was stirred at 25°C for 12 h after which time TLC (Petroleum ether/EtOAc = 1:0) indicated conversion to a new product. 3 N HCl (20 mL) was added to the mixture and extracted with EtOAc (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced 30 pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum 139 70226WO01 ether/EtOAc = 1:0 to 1:1) to give the title compound (120 mg, 391 umol, 71.6% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 1:0) Rf = 0.52. 1H NMR (400 MHz, CHLOROFORM-d) δ = 2.22 - 2.18 (m, 4H), 1.54 - 1.47 (m, 4H), 1.39 - 1.29 5 (m, 8H), 0.19 - 0.09 (m, 18H). Step 2 of 2: Synthesis of Intermediate 34.2, dodeca-1,11-diyne. To a solution of trimethyl(12-trimethylsilyldodeca-1,11-diynyl) silane (120 mg, 391 umol, 1 eq) in THF (3 mL) was added TBAF (1 M, 1.37 mL, 3.5 eq). The mixture was stirred at 25°C for 12 h 10 after which time TLC (Petroleum ether/EtOAc = 1:0) indicated conversion to a new product. Water (10 mL) was added to the mixture which was then extracted with EtOAc (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. To the residue was added petroleum ether (5 mL) and the mixture was stirred 10 min. The mixture was filtered and the 15 filtrate was concentrated to give the title compound (30 mg, 185 umol, 47.2% yield) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 2.19 (dt, J = 2.6, 7.0 Hz, 4H), 1.94 (t, J = 2.6 Hz, 2H), 1.59 - 1.49 (m, 4H), 1.44 - 1.29 (m, 8H) 20 Synthesis of Intermediate 35.1, 1-[1-methyl-1-(4-prop-2-ynoxyphenyl)ethyl]-4-prop-2-ynoxy- benzene. Br To a solution of 4-[1-(4-hydroxyphenyl)-1-methyl-ethyl]phenol (3 g, 13.1 mmol, 1 eq) in acetone (100 mL) was added K2CO3 (10.9 g, 78.9 mmol, 6 eq) and 3-bromoprop-1-yne (4.89 g, 32.4 mmol, 25 3.54 mL, 80% purity, 2.5 eq). The mixture was stirred at 60°C for 12 h after which time TLC (Petroleum ether/EtOAc = 2:1) indicated complete consumption of starting material and formation of a new product. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue and crude product was added into H2O (50 mL) and then extracted with DCM (40 mL * 3). The combined organic phase was dried over Na2SO4, filtered 30 and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (2.68 g, 8.80 mmol, 67.0% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 2:1) Rf =0.43. 140 70226WO01 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.20 - 7.14 (m, 4H), 6.92 - 6.86 (m, 4H), 4.67 (d, J = 2.4 Hz, 4H), 2.52 (t, J = 2.4 Hz, 2H), 1.65 (s, 6H). Synthesis of Intermediate 36.1, 1-prop-2-ynoxy-4-(4-prop-2-ynoxyphenoxy)benzene. O Br O HO OH K2CO3, MeCN O O and K2CO3 (3.42 g, 24.7 , . q 3 p p y . 4 g, 21.8 mmol, 2.34 mL, 80% purity, 2.2 eq). The mixture was stirred at 80°C for 12 h after which time TLC (Petroleum ether/EtOAc = 5:1) indicated complete consumption of starting material and formation of a new 10 product. The mixture was concentrated under reduced pressure to give a residue. Water (20 mL) was added to the mixture which was then extracted with EtOAc (15 mL * 2). The combined organic phase was washed with brine (15 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (3.8 g, 15 crude) as an off-white oil. TLC (Petroleum ether/EtOAc = 5:1) Rf =0.64. 1H NMR (400MHz, CHLOROFORM-d) δ = 6.95 (s, 8H), 4.68 (d, J=2.4 Hz, 4H), 2.54 (t, J=2.3 Hz, 2H) 20 Synthesis of Intermediate 37.1, 1-prop-2-ynoxy-4-[(4-prop-2-ynoxyphenyl)methyl]benzene. Br To a solution of 4-[(4-hydroxyphenyl)methyl]phenol (2 g, 9.99 mmol, 1 eq), K2CO3 (3.45 g, 25.0 mmol, 2.5 eq) in CH3CN (30 mL) was added 3-bromoprop-1-yne (3.27 g, 22.0 mmol, 2.37 mL, 80% purity, 2.2 eq). The mixture was stirred at 80°C for 12 h after which time TLC (Petroleum 25 ether/EtOAc = 5:1) indicated complete consumption of starting material and formation of a new product. The mixture was concentrated under reduced pressure to give a residue. Water (20 mL) was added to the mixture which was then extracted with EtOAc (15 mL * 2). The combined organic phase was washed with brine (15 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column 30 chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (3.5 g, crude) as an off-white oil. 141 70226WO01 TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.57. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.12 (d, J=8.6 Hz, 4H), 6.94 - 6.91 (m, 4H), 4.68 (d, J=2.4 Hz, 4H), 3.90 (s, 2H), 2.53 (t, J=2.4 Hz, 2H) 5 Synthesis of Intermediate 38.7, tert-butyl N-[(1S)-2-[[(1S,2S)-2-azido-1-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- 1-carbonyl]propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate. 10 Step 1 of 7: Synthesis of Intermediate 38.1, 4-benzyl 3-(tert-butyl) (4S,5R)-5-methyl-1,2,3- oxathiazolidine-3,4-dicarboxylate 2,2-dioxide. A mixture of SOCl2 (12.5 g, 105 mmol, 7.62 mL, 1.30 eq) in CH3C mL) was degassed and purged with N2 three times. Benzyl (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-butanoate (25 g, 80.8 mmol, 1 eq) in CH3CN (180 mL) was added dropwise over 30 min at -40°C. The mixture 15 was stirred at -40°C for 60 min after which time pyridine (32.0 g, 404 mmol, 32.6 mL, 5.00 eq) was added. The mixture was stirred at 0°C for 1 h after which time TLC (Petroleum ether/EtOAc = 3:1) indicated complete consumption of starting material and formation of a new product. The reaction mixture was quenched by addition of H2O (200 mL), and then diluted with EtOAc (200 mL) and extracted with EtOAc (200 mL * 3). The combined organic phase was washed with saturated NaCl 20 aq. (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the 7 g, quantitative yield) as a yellow oil. To a solution of the intermediate product (28.6 g, 80.5 mmol, 1 eq) in CH3CN (200 mL) was added RuCl3 (334 mg, 1.61 mmol, 107 uL, 0.02 eq) at 0°C. To the mixture was added NaIO4 (25.8 g, 121 mmol, 6.69 mL, 1.5 eq) in H2O (200 mL). The mixture was stirred at 0°C for 2 h after which time TLC (Petroleum ether/EtOAc = 25 5:1) indicated complete consumption of starting material and formation of a new product. The reaction mixture was added into saturated NaHCO3 aq. (200 mL), then extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, 142 70226WO01 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 5:1) to give the title compound (20.8 g, 56.0 mmol, 69.6% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.28. 5 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.37 (s, 5H), 5.37 - 5.12 (m, 2H), 4.91 - 4.81 (m, 1H), 4.52 (br d, J = 5.4 Hz, 1H), 1.69 (d, J = 6.4 Hz, 3H), 1.54 - 1.43 (m, 9H) Step 2 of 7: Synthesis of Intermediate 38.2, (4S,5R)-3-tert-butoxycarbonyl-5-methyl-2,2- dioxo-oxathiazolidine-4-carboxylic acid. 10 To a solution of 4-benzyl 3-(tert-butyl) (4S,5R)-5-methyl-1,2,3-oxathiazolidine-3,4-dicarboxylate 2,2-dioxide (6 g, 16.2 mmol, 1 eq) in MeOH (120 mL) was added Pd/C (6 g, 10% purity) under N2 atmosphere at 0°C. The mixture was stirred at 0°C for 2 h under H2 (15 psi) after which time TLC (Petroleum ether/EtOAc = 5:1) indicated complete consumption of starting material and formation of a new product. The mixture was filtered and the filtrate was concentrated to give the title 15 compound (4.50 g, 16.0 mmol, 99.0% yield) as a yellow solid. 1H NMR (400MHz, CHLOROFORM-d) δ = 5.03 - 4.87 (m, 1H), 4.54 (br d, J=5.0 Hz, 1H), 1.55 (s, 9H), 1.47 (br s, 3H). Step 3 of 7: Synthesis of Intermediate 38.3, tert-butyl (4S,5R)-4-[5-[tert-20 butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- To a solution of (4S,5R)-3-tert-butoxycarbonyl-5-methyl-2,2-dioxo-oxathiazolidine-4-carboxylic acid (2.62 g, 9.31 mmol, 1.2 eq), DIEA (3.01 g, 23.3 mmol, 4.06 mL, 3 eq) in DCM (80 mL) was added tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5- 25 yl]oxy]-dimethyl-silane (3 g, 7.76 mmol, 1 eq), and HATU (4.43 g, 11.6 mmol, 1.5 eq) at 0°C .The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH4Cl aq. (30 mL), extracted with DCM (30 mL * 3). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to 30 give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 5:1) to give the title compound (1.27 g, 1.95 mmol, 25.1% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.70. LCMS (ES, m/z): 650.3 [M+H]+. 143 70226WO01 Step 4 of 7: Synthesis of Intermediate 38.4, tert-butyl N-[(1S,2S)-2-azido-1-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- 1-carbonyl]propyl]carbamate. To a solution of l (4S,5R)-4-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 5 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]-5-methyl-2,2-dioxo-oxathiazolidine-3- carboxylate (1.26 g, 1.94 mmol, 1 eq) in DMF (90 mL) was added NaN3 (0.5 g, 7.69 mmol, 3.97 eq) at 15°C. The mixture was stirred at 80°C for 4 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into H2O (180 mL), then extracted with EtOAc (90 mL * 3). The combined 10 organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (991 mg, 1.62 mmol, 83.4% yield) as a yellow oil. LCMS (ES, m/z): 613.3 [M+H]+. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.27 (s, 1H), 7.16 (dd, J=5.5, 8.5 Hz, 2H), 6.98 - 6.90 (m, 1H), 6.98 (br s, 1H) , 5.29 (br d, J=9.8 Hz, 1H), 4.53 - 4.36 (m, 1H), 4.02 (s, 2H), 3.89 - 3.83 15 (m, 2H), 1.46 - 1.41 (m, 12H), 1.34 (d, J=6.8 Hz, 6H), 0.94 - 0.92 (m, 9H), 0.31 (s, 6H). Step 5 of 7: Synthesis of Intermediate 38.5, 1-[(2S,3S)-2-amino-3-azido-butanoyl]-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one. To a solution of tert-butyl N-[(1S,2S)-2-azido-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- 20 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]propyl]carbamate (990 mg, 1.62 mmol, 1 eq) in EtOAc (8 mL) was added HCl/EtOAc (4 M, 10 mL) The mixture was stirred at 40°C for 1 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give the title compound (702 mg, 1.61 mmol, 99.9% yield, HCl) as a yellow 25 oil. LCMS (ES, m/z): 399.3 [M+H]+. Step 6 of 7: Synthesis of Intermediate 38.6, (2S,3S)-2-amino-3-azido-1-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 30 1-yl]butan-1-one. To a solution of 1-[(2S,3S)-2-amino-3-azido-butanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl- 2,4-dihydropyrrolo[3,2-b]pyridin-5-one (702 mg, 1.61 mmol, 1 eq, HCl) and imidazole (714 mg, 10.5 mmol, 6.5 eq) in DCM (15 mL) was added TBSCl (608 mg, 4.04 mmol, 494 uL, 2.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete 35 consumption of starting material with formation of a single peak of target mass. The residue was 144 70226WO01 added into saturated NH4Cl aq. (20 mL), extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (710 mg, 1.38 mmol, 85.8% yield) as a yellow 5 oil. TLC (EtOAc) Rf = 0.60. LCMS (ES, m/z): 513.3 [M+H]+. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.23 (s, 1H), 7.22 - 7.10 (m, 2H), 7.00 - 6.86 (m, 2H), 4.04 - 3.79 (m, 4H), 3.7 . 9 (m, 2H), 1.43 (br d, J=6.5 Hz, 3H), 1.34 (br d, J=1.1 Hz, 6H), 0.93 10 (s, 9H), 0.31 (s, 6H). Step 7 of 7: Synthesis of Intermediate 38.7, tert-butyl N-[(1S)-2-[[(1S,2S)-2-azido-1-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- 1-carbonyl]propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate. 15 To a solution of (2S,3S)-2-amino-3-azido-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]butan-1-one (550 mg, 1.07 mmol, 1 eq), DIEA (416 mg, 3.22 mmol, 561 uL, 3 eq) in DCM (15 mL) was added (2S)-2-[tert- butoxycarbonyl(methyl)amino]propanoic acid (240 mg, 1.18 mmol, 1.1 eq), and HATU (612 mg, 1.61 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS 20 indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH4Cl aq. (15 mL), extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 5:1) to give the title compound (650 mg, 25 931 umol, 86.8% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.50. LCMS (ES, m/z): 698.5 [M+H]+. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.18 (s, 1H), 7.16 (dd, J=5.5, 8.5 Hz, 2H), 7.00 - 6.88 (m, 2H), 4.78 (t, J=9.0 Hz, 1H), 4.61 (br s, 1H), 4.07 - 3.96 (m, 2H), 3.93 - 3.77 (m, 3H), 2.81 (s, 30 3H), 1.49 (s, 9H), 1.34 (d, J=7.5 Hz, 12H), 0.93 (s, 9H), 0.31 (s, 6H) Synthesis of Intermediate 39.1, tert-butyl N-[(1S)-2-[[(1S,2S)-2-azido-1-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridine-1- carbonyl]propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate. 145 70226WO01 Boc N HCl H2N O O N3 uorophenyl)methyl]-3,3-dimethyl- , -d ydropyrroo[3, -b]pyr dn-5-one (350 mg, 805 umo, eq, HCl), (2S)-2-[tert- butoxycarbonyl(methyl)amino]propanoic acid (245 mg, 1.21 mmol, 1.5 eq), and DIEA (312 mg, 5 2.41 mmol, 421 uL, 3 eq) in DCM (4 mL) was added T3P (512 mg, 805 umol, 479 uL, 50% purity, 1 eq) at 0°C. The mixture was stirred at 25°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was added to the mixture which was then extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The 10 filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 1:1) to give the title compound (280 mg, 480 umol, 59.6% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.47. LCMS (ES, m/z): 584.4 [M+H]+. 15 II. Synthesis of Final Compounds, Examples 1-91. Example 1, N1,N10-bis((S)-5-((S)-2-aminopropanamido)-6-(6-(4-fluorobenzyl)-3, 3-dimethyl- 5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6-oxohexyl)deca-4,6-diynediamide. 146 70226WO01 HN N OTBS Cbz H HN NH2 Boc N HO HN O Pd/C, 1M HCl, H2 O HN O LiOH HN O 2.11 (S) F M H N F Step 1 of 8: Synthesis of Intermediate 40.1, methyl (2S)-6-amino-2-(tert- butoxycarbonylamino)hexanoate. 5 Two batches were carried out in parallel: To a solution of methyl (2S)-6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoate (6 g, 15.2 mmol, 1 eq), HCl (2 M, 15.2 mL, 2 eq) in MeOH (100 mL) was added Pd/C (1 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25°C for 3 h. LC-MS indicated complete conversion to a 10 product of target mass. The two reactions were combined for work-up. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (7.81 g, 83.9% purity, 86.5% yield, HCl) as a colorless oil. LCMS (ES, m/z): 261.1 [M+H]+. 15 Step 2 of 8: Synthesis of Intermediate 40.2, methyl (2S)-2-(tert-butoxycarbonylamino)-6- (pent-4-ynoylamino)hexanoate. T3P (7.61 g, 23.9 mmol, 7.11 mL, 1 eq) was added to a mixture of methyl (2S)-6-amino-2-(tert- butoxycarbonylamino)hexanoate (7.81 g, 26.3 mmol, 1.1 eq, HCl), pent-4-ynoic acid (2.35 g, 23.9 mmol, 1 eq) and DIEA (12.4 g, 95.7 mmol, 16.7 mL, 4 eq) in DCM (100 mL) at 0°C and the 20 mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:4) to give the title compound (4.48 g, 99.6% purity, 55.0% yield) as a yellow oil. 147 70226WO01 LCMS (ES, m/z): 241.2 [M-Boc+H]+. Step 3 of 8: Synthesis of Intermediate 40.3, (2S)-2-(tert-butoxycarbonylamino)-6-(pent-4- ynoylamino)hexanoic acid. 5 To a solution of methyl (2S)-2-(tert-butoxyc nylamino)-6-(pent-4-ynoylamino)hexanoate (4.45 g, 13.1 mmol, 1 eq) in MeOH (10 mL)/THF (30 mL)/H2O (10 mL) was added LiOH (940 mg, 39.2 mmol, 3 eq) at 25°C. The mixture was stirred at 25°C for 2h. LC-MS indicated complete conversion to a product of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (10 mL), then extracted with EtOAc (40 mL * 2), 10 and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (4 * 40 mL) and the combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (3.53 g, 83.9% purity, 82.7% yield) as a yellow oil. LCMS (ES, m/z): 227.1 [M-Boc+H]+. 15 Step 4 of 8: Synthesis of Intermediate 40.4, tert-butyl N-[(1S)-1-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- 1-carbonyl]-5-(pent-4-ynoylamino)pentyl]carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-6-(pent-4-ynoylamino)hexanoic acid (2.03 g,20 6.21 mmol, 1.2 eq), tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2- b]pyridin-5-yl]oxy]-dimethyl-silane (2 g, 5.17 mmol, 1 eq), DIEA (1.34 g, 10.4 mmol, 1.80 mL, 2 eq) in DCM (30 mL) was added HATU (2.95 g, 7.76 mmol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction was concentrated under reduced pressure to 25 give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (2.87 g, 4.13 mmol, 79.8% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.43. LCMS (ES, m/z): 695.3 [M+H]+. 30 Step 5 of 8: Synthesis of Intermediate 40.5, tert-butyl N-[(1S)-5-[[10-[[(5S)-5-(tert -butoxycarbonylamino)-6-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-6-oxo-hexyl]amino]-10-oxo-deca-4,6- diynoyl]amino]-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl- 2H-pyrrolo[3,2-b]pyridine-1-carbonyl]pentyl]carbamate. 148 70226WO01 A mixture of tert-butyl N-[(1S)-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]-5-(pent-4-ynoylamino)pentyl]carbamate (2.67 g, 3.84 mmol, 1 eq), pyridine (1.82 g, 23.1 mmol, 1.86 mL, 6 eq), and Cu(OAc)2 (837.39 mg, 4.61 mmol, 1.2 eq) in CH3CN (30 mL) was stirred at 85°C for 1 h under air environment. LC-MS 5 indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the filtrate was added into saturated aq NH3.H2O (30 mL), then extracted with EtOAc (30 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.68 g, quantitative yield) as a yellow oil. LCMS (ES, m/z): 1159.7 [M+H]+. 10 Step 6 of 8: Synthesis of Intermediate 40.6, N,N'-bis[(5S)-5-amino-6-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-6-oxo- hexyl]deca-4,6-diynediamide. To a solution of tert-butyl N-[(1S)-5-[[10-[[(5S)-5-(tert-butoxycarbonylamino)-6-[5-[tert-15 butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 6-oxo-hexyl]amino]-10-oxo-deca-4,6-diynoyl]amino]-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]pentyl]carbamate (2.68 g, 1.93 mmol, 1 eq) in EtOAc (10 mL) was added HCl/dioxane (4 M, 15 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete conversion to a product of target mass. The 20 mixture was filtered and the filter cake was dried to give the title compound (2.1 g, quantitative yield, 2 HCl) as a yellow solid. LCMS (ES, m/z): 959.5 [M+H]+. Step 7 of 8: Synthesis of Intermediate 40.7, tert-butyl N-[(1S)-2-[[(1S)-5-[[10-[[(5S)-5-[[(2S)-2-25 (tert-butoxycarbonylamino)propanoyl]amino]-6-[6-[(4-fluoroph n l)m th l]-33-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-6-oxo-hexyl]amino ]- -oxo- eca- , - diynoyl]amino]-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]pentyl]amino]-1-methyl-2-oxo-ethyl]carbamate. To a solution of N,N'-bis[(5S)-5-amino-6-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- 30 dihydropyrrolo[3,2-b]pyridin-1-yl]-6-oxo-hexyl]deca-4,6-diynediamide (90 mg, 87.2 umol, 1 eq, 2 HCl), (2S)-2-(tert-butoxycarbonylamino)propanoic acid (36.3 mg, 192 umol, 2.2 eq), DIEA (56.4 mg, 436 umol, 75.95 uL, 5 eq) in DCM (3 mL) was added HATU (99.47 mg, 261.61 umol, 3 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under 149 70226WO01 reduced pressure to give a residue. The residue was purified by preparative TLC (EtOAc/Methanol = 5:1) to give the title compound (178 mg, quantitative yield) as a yellow solid. TLC (EtOAc/Methanol = 5:1) Rf = 0.75 LCMS (ES, m/z): 1302.6 [M+H]+. 5 Step 8 of 8: Synthesis of Example 1, N1,N10-bis((S)-5-((S)-2-aminopropanamido)-6-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6- oxohexyl)deca-4,6-diynediamide. To a solution of tert-butyl N-[(1S)-2-[[(1S)-5-[[10-[[(5S)-5-[[(2S)-2-(tert-10 butoxycarbonylamino)propanoyl]amino]-6-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-6-oxo-hexyl]amino]-10-oxo-deca-4,6-diynoyl]amino]-1-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridine-1- carbonyl]pentyl]amino]-1-methyl-2-oxo-ethyl]carbamate (122 mg, 93.7 umol, 1 eq) in EtOAc (1 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 25°C for 0.5 h. LC-MS 15 indicated complete conversion to a product of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875*30mm, 3um; mobile phase: [water(0.2%FA)-CH3CN], B%: 1%-30%, 8 min) to give the title compound (7.5 mg, 6.28 umol, 6.70% yield, 100% purity, 2FA) as a white solid. 20 LCMS (ES, m/z): 551.4 [M/2+H]+. 1H NMR (400MHz, METHANOL-d4) δ = 8.54 (br s, 1H), 8.17 (s, 2H), 7.25 (dd, J=5.5, 8.5 Hz, 4H) 699 (t, J=8.8 Hz, 4H), 4.19 (d, J=10.5 Hz, 2H), 3.95 (d, J=10.5 Hz, 2H), 3.80 (s, 4H), 3.72 (br d, J=7.0 Hz, 2H), 3.29 - 3.06 (m, 6H), 2.54 - 2.45 (m, 4H), 2.40 - 2.28 (m, 4H), 1.82 (br d, J=10.0 Hz, 2H), 1.71 (br d, J=9.8 Hz, 2H), 1.58 - 1.46 (m, 6H), 1.45 - 1.36 (m, 20H). 25 Example 2, N1,N10-bis((S)-5-((S)-2-aminobutanamido)-6-(6-(4-fluorobenzyl)-3,3-dimethyl-5- oxo-2,3,45 t t h d 1H l 32 b idi 1 l 6 h l d 46 di di id HCl O NH H2N O H (S) Boc N (S) OH O (S) O HN H F 70226WO01 Step 1 of 2: Synthesis of Intermediate 41.1, tert-butyl N-[(1S)-1-[[(1S)-5-[[10-[[(5S)-5-[[(2S)-2- (tert-butoxycarbonylamino)butanoyl]amino]-6-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-6-oxo-hexy - 5 diynoyl]amino]-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1 carbonyl]pentyl]carbamoyl]propyl]carbamate. , , ,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-6-oxo-hexyl]deca-4,6-diynediamide (188 mg, 196 umol, 1 eq, 2 HCl), (2S)-2-(tert-butoxycarbonylamino)butanoic acid (79.9 mg, 392.90 umol, 2 eq) in DCM (6 10 mL) was added DIEA (152. mg, 1.18 mmol, 205 uL, 6 eq), HOBt (79.6 mg, 589 umol, 3 eq) and EDCI (112.98 mg, 589.35 umol, 3 eq) at 0°C. The mixture was stirred at 40°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, DCM/MeOH/NH3.H2O = 10:1:1) to give the title compound (250 mg, 15 188 umol, 95.7% yield) as a yellow solid. TLC (DCM/Methanol/NH3.H2O = 10:1:1) Rf = 0.14 LCMS (ES, m/z): 1329.8 [M+H]+. Step 2 of 2: Synthesis of Example 2, N1,N10-bis((S)-5-((S)-2-aminobutanamido)-6-(6-(4-20 fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6- oxohexyl)deca-4,6-diynediamide. To a solution of tert-butyl N-[(1S)-1-[[(1S)-5-[[10-[[(5S)-5-[[(2S)-2-(tert- butoxycarbonylamino)butanoyl]amino]-6-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-6-oxo-hexyl]amino]-10-oxo-deca-4,6-diynoyl]amino]-1-[6-[(4-25 fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridine-1- carbonyl]pentyl]carbamoyl]propyl]carbamate (250 mg, 188.0 umol, 1 eq) in EtOAc (2 mL) was added HCl/dioxane (4 M, 2.00 mL). The mixture was stirred at 25°C for 0.5 h. LC-MS indicated complete conversion to a product of target mass. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex 30 Gemini-NX 150*30mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 10%-40%, 9 min) to give the title compound (53.8 mg, 39.64 umol, 21.1% yield, 100% purity, 2 TFA) as a white solid LCMS (ES, m/z): 565.5 [M/2+H]+. 1H NMR (400 MHz, METHANOL-d4) δ = 8.18 (s, 2H), 7.25 (dd, J = 5.6, 8.4 Hz, 4H), 6.98 (t, J = 8.8 Hz, 4H), 4.59 (s, 2H), 4.22 (d, J = 10.4 Hz, 2H), 3.95 (d, J = 10.4 Hz, 2H), 3.90 - 3.74 (m, 6H), 151 70226WO01 3.18 (br d, J = 8.9 Hz, 4H), 2.55 - 2.43 (m, 4H), 2.37 - 2.27 (m, 4H), 1.95 - 1.81 (m, 6H), 1.77 - 1.68 (m, 2H), 1.58 - 1.51 (m, 4H), 1.41 (d, J = 11.5 Hz, 16H), 1.00 (t, J = 7.5 Hz, 6H). The following final compounds were prepared according to the same procedure as Example 2: 5 Examples 3-5. The compounds were found to have characterizing data as set forth below. Example 3, N1,N10-bis((S)-6-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-5-((S)-2-(methylamino)propanamido)-6-oxohexyl)deca-4,6- diynediamide. O HCl NH H2N O O (S) N (S) HN (S) HN Boc OH O F H O N HN O F N O DCI, HOBT HCl/ dioxane H N E O F (S) N N N (S) 10 1H NMR (400 MHz, METHANOL-d4) δ = 8.16 (s, 2H), 7.25 (dd, J = 5.6, 8.4 Hz, 4H), 6.98 (t, J = 8.7 Hz, 4H), 4.59 (br t, J = 7.1 Hz, 2H), 4.20 (d, J = 10.4 Hz, 2H), 3.95 (d, J = 10.5 Hz, 2H), 3.87 (q, J = 6.8 Hz, 2H), 3.80 (s, 4H), 3.25 - 3.13 (m, 4H), 2.67 (s, 6H), 2.54 - 2.44 (m, 4H), 2.37 - 2.27 15 (m, 4H), 1.90 - 1.79 (m, 2H), 1.78 - 1.65 (m, 2H), 1.61 - 1.46 (m, 12H), 1.41 (d, J = 12.1 Hz, 14H). Example 4, N1,N10-bis((S)-6-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-5-((S)-2-(methylamino)butanamido)-6-oxohexyl)deca-4,6- diynediami . O HCl O NH H2N O N (S) (S) HN (S) Boc OH O F H HN O N HN O O H N O 20 1H NMR (400 MHz, METHANOL-d4) δ = 8.16 (s, 2H), 7.24 (dd, J = 5.5, 8.5 Hz, 4H), 6.98 (t, J = 8.8 Hz, 4H), 4.64 - 4.58 (m, 2H), 4.23 (d, J = 10.5 Hz, 2H), 3.96 (d, J = 10.4 Hz, 2H), 3.82 - 3.72 (m, 6H), 3.18 (br t, J = 6.8 Hz, 4H), 2.66 (s, 6H), 2.52 - 2.45 (m, 4H), 2.32 (br d, J = 7.3 Hz, 4H), 25 2.01 - 1.81 (m, 6H), 1.79 - 1.70 (m, 2H), 1.59 - 1.51 (m, 4H), 1.41 (d, J = 10.4 Hz, 15H), 0.97 (t, J = 7.5 Hz, 6H). Example 5, N1,N10-bis((S)-5-((R)-2-aminopropanamido)-6-(6-(4-fluorobenzyl)-3,3-dimethyl- 5-oxo-2,3,4 hydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6-oxohexyl)deca-4,6-diynediamide. 152 70226WO01 O NH2 HCl (R) HN O O O H2N H ( F (S) N R) H HN Boc OH HN O (S) H N N O O N N O EDCI, HOBT HCl/ dioxane N O H (S) , . , , . . , , . , .8 Hz, 4H), 4.53 (dd, J = 5.9, 8.3 Hz, 2H), 4.22 (d, J = 10.5 Hz, 2H), 3.98 - 3.91 (m, 4H), 3.80 (d, J = 8.4 5 Hz, 4H), 3.25 - 3.12 (m, 4H), 2.53 - 2.46 (m, 4H), 2.36 - 2.29 (m, 4H), 1.88 - 1.79 (m, 2H), 1.77 - 1.67 (m, 2H), 1.57 - 1.50 (m, 10H), 1.42 (d, J = 7.8 Hz, 16H). Example 6, (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(4-((S)-2-aminopropanamido)-5-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5- 10 oxopenta nam de). HN N OTBS HN O HO O O OH , DCM Step 1 of 7: Synthesis of Intermediate 45.1, methyl(2S)-2-(tert-butoxycarbonylamino)-5 -oxo- 5-(prop-2-ynylamino)pentanoate. 15 T3P (36.5 ol, 34.1 mL, 50% purity, 1.5 eq) was added to a mixture of (4S)-4-(tert- butoxycarbonylamino)-5-methoxy-5-oxo-pentanoic acid (10 g, 38.3 mmol, 1 eq), prop-2-yn-1- 153 70226WO01 amine (2.32 g, 42.1 mmol, 2.70 mL, 1.1 eq) and DIEA (9.89 g, 76.6 mmol, 13.3 mL, 2 eq) in DCM (150 mL) at 0°C and the mixture was stirred at 25°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was added into saturated NH4Cl aq. (100 mL), extracted with DCM (50 mL * 3). The 5 combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:4) to give the title compound (10.6 g, 59.8% purity, 92.5% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.64 10 LCMS (ES, m/z): 199.1 [M-Boc+H]+. Step 2 of 7: Synthesis of Intermediate 45.2, (2S)-2-(tert-butoxycarbonylamino)-5-oxo-5- (prop-2-ynylamino)pentanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-5-oxo-5-(prop-2-ynylamino) pentanoate 15 (10.5 g, 35.2 mmol, 1 eq) in THF (120 mL)/MeOH (40 mL)/H2O (40 mL) was added LiOH (2.53 g, 106 mmol, 3 eq) at 25°C. The mixture was stirred at 25°C for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (20 mL), then extracted with EtOAc (30 mL * 2), and then the water phase was acidified 20 with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (4 * 60 mL) and the combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (7.87 g, 83.9% purity, 78.6% yield) as a yellow oil. LCMS (ES, m/z): 185.2 [M-Boc+H]+. 25 Step 3 of 7: Synthesis of Intermediate 45.3, tert-butyl N-[(1S)-1-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- 1-carbonyl]-4-oxo-4-(prop-2-ynylamino)butyl]carbamate. To a solution of tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-30 b]pyridin-5-yl]oxy]-dimethyl-silane (2 g, 5.17 mmol, 1 eq), (2S)-2-(tert- butoxycarbonylamino)-5- oxo-5-(prop-2-ynylamino)pentanoic acid (1.77 g, 6.21 mmol, 1.2 eq), DIEA (1.34 g, 10.4 mmol, 1.80 mL, 2 eq) in DCM (30 mL) was added HATU (2.95 g, 7.76 mmol, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into 35 saturated NH4Cl aq (40 mL), then extracted with DCM (30 mL * 3). The combined organic phase 154 70226WO01 was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 0:1) to give the title compound (3.28 g, 73.6% purity, 97.0% yield) as a yellow oil. 5 TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.35 LCMS (ES, m/z): 653.4 [M+H]+. p ynthesis of Intermediate 45.4, tert-butyl N-[(1S)-4-[6-[[(4S)-4-(tert- butoxycarbonylamino)-5-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-10 dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-5-oxo-pentanoyl]amino]hexa-2,4-diynylamino]-1-[5- [tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2- b]pyridine-1-carbonyl]- bamate. A mixture of tert-butyl N-[(1S)-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]-4-oxo-4-(prop-2-ynylamino)butyl]carbamate 15 (3 g, 4.60 mmol, 1 eq), pyridine (2.18 g, 27.6 mmol, 2.23 mL, 6 eq), and Cu(OAc)2 (1.00 g, 5.51 mmol, 1.2 eq) in CH3CN (30 mL) was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH3.H2O aq. (40 mL), then extracted with EtOAc (30 mL * 3). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and 20 concentrated under reduced pressure to give the title compound (1.81 g, 76.9% purity, 60.3% yield) as a yellow oil. LCMS (ES, m/z): 1075.5 [M-2TBS+H]+ Step 5 of 7: Synthesis of Intermediate 45.5, (4S)-4-amino-N-[6-[[(4S)-4-amino-5-[6-[(4-25 fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo- pentanoyl]amino]hexa-2,4-diynyl]-5-[6-[(4-fluorophenyl)m e yl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo-pentanamide. To a solution of tert-butyl N-[(1S)-4-[6-[[(4S)-4-(tert-butoxycarbonylamino)-5- [5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-30 5-oxo-pentanoyl]amino]hexa-2,4-diynylamino]-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]-4-oxo-butyl]carbamate (1.8 g, 1.38 mmol, 1 eq) in EtOAc (8 mL) was added HCl/dioxane (4 M, 18.3 mL). The mixture was stirred at 20°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under 35 reduced pressure to give a residue. The residue was purified by reversed-phase MPLC (column: 155 70226WO01 C18, 20-35um, 100A, 120g; mobile phase: [water-MeOH; B%: 0%-90%, 50 mL/min) to give the title compound (1.00 g, 1.06 mmol, 94.7% purity, 76.8% yield, 2 HCl) as a yellow solid. LCMS (ES, m/z): 875.4 [M+H]+. 5 Step 6 of 7: Synthesis of Intermediate 45.6, tert-butyl N-[(1S)-2-[[(1S)-4-[6-[[(4S)-4 -[[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]-5-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-5-ox noyl]amino]hexa-2,4- diynylamino]-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]-4-oxo-butyl]amino]-1-methyl-2-oxo-ethyl]carbamate. 10 To a solution of (4S)-4-amino-N-[6-[[(4S)-4-amino-5-[6-[(4-fluorophenyl)methyl]-3, ethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo-pentanoyl]amino]hexa-2,4-diynyl]-5-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo- pentanamide (90 mg, 95.0 umol, 1 eq, 2 HCl), (2S)-2-(tert-butoxycarbonylamino)propanoic acid (37.73 mg, 199.39 umol, 2.1 eq), DIEA (61.4 mg, 475 umol, 82.7 uL, 5 eq) in DCM (4 mL) was 15 added HATU (108 mg, 285 umol, 3 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated complete conversion to a product of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 150*30mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 35%- 65%, 9 min) to give the title compound (40 mg, 34.6% yield) was obtained as a yellow oil. 20 LCMS (ES, m/z): 1217.5 [M+H]+. Step 7 of 7: Synthesis of Example 6, (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(4-((S)-2- aminopropanamido)-5-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-5-oxopentanamide). 25 To a solution of tert-butyl N-[(1S)-2-[[(1S)-4-[6-[[(4S)-4-[[(2S)-2-(tert- butoxycarbonylamino)propanoyl]amino]-5-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo-pentanoyl]amino]hexa-2,4-diynylamino]-1-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-4-oxo- butyl]amino]-1-methyl-2-oxo-ethyl]carbamate (40.00 mg, 32.86 umol, 1 eq) in MeOH (2 mL) was 30 added HCl/dioxane (4 M, 2 mL,). The mixture was stirred at 25°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 150*30mm, 5um; mobile phase: [water(0.2%FA)-CH3CN], B%: 15%-45%, 9 min) to give the title compound (8.0 mg, 7.21 umol, 35 22.0% yield, 100% purity, 2FA) as a yellow solid. 156 70226WO01 LCMS (ES, m/z): 509.4 [M/2+H]+. 1H NMR (400MHz, METHANOL-d4) δ = 8.26 - 8.07 (m, 2H), 7.23 (br d, J=5.6 Hz, 4H), 6.98 (br t, J=8.5 Hz, 4H), 4.18 - 4.05 (m, 2H), 4.04 - 3.91 (m, 5H), 3.86 - 3.75 (m, 5H), 3.29 - 3.22 (m, 4H), 2.49 (br s, 2H), 2.33 (br s, 2H), 2.11 (br s, 2H), 2.02 (br d, J=8.5 Hz, 2H), 1.55 - 1.46 (m, 6H), 1.44 5 - 1.30 (m, 12H). Example 7, (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(5-(6-(4-fluorobenzyl)-3,3-dimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-((S)-2-(methylamino)propanamido)- 5-oxopentanamide). N Boc NH HCl O O O Boc O O H2N O HN N HN HN HN H HN HN OH HN N O O HCl/ dioxane O ED I H BT F N O F Step 1 of 2: Synthesis of Intermediate 46.1, tert-butyl N-[(1S)-2-[[(1S)-5-[[10-[[(5S)-5-[[(2S)-2- (tert-butoxycarbonylamino)propanoyl]amino]-6-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-6-oxo-hexyl]amino]-10-oxo-deca-4,6- 15 diynoyl]amino]-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]pentyl]amino]-1-methyl-2-oxo-ethyl]carbamate. To a solution of (4S)-4-amino-N-[6-[[(4S)-4-amino-5-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihy 1-yl]-5-oxo-pentanoyl]amino]hexa-2,4-diynyl]-5-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo- 20 pentanamide (100 mg, 105.50 umol, 1 eq, 2 HCl), and (2S)-2-[tert- butoxycarbonyl(methyl)amino]propanoic acid (42.9 mg, 210.99 umol, 2 eq) in DCM (6 mL) was added DIEA (81.8 mg, 633 umol, 110.25 uL, 6 eq), HOBt (42.77 mg, 316.49 umol, 3 eq), and EDCI (60.67 mg, 316.49 umol, 3 eq) at 0°C. The mixture was stirred at 40°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. 25 The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, DCM/MeOH/NH3.H2O = 10:1:1) to give the title compound (102 mg, 69.2% purity, 77.6% yield) as a yellow oil. TLC (DCM/Methanol/NH3.H2O = 10:1:1) Rf = 0.5 LCMS (ES, m/z): 1245.6 [M+H]+. 30 Step 2 of 2: Synthesis of Example 7, (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(5-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-((S)-2- (methylamino)propanamido)-5-oxopentanamide). 157 70226WO01 To a solution of tert-butyl N-[(1S)-2-[[(1S)-4-[6-[[(4S)-4-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]propanoyl]amino]-5-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo-pentanoyl]amino]hexa-2,4-diynylamino]-1-[6- [(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-4- 5 oxo-butyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (102 mg, 81.90 umol, 1 eq) in EtOAc (2 mL)/MeOH (0.5 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 25 °C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 150*30mm, 10 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 5%-35%, 9 min) to give the title compound (21.6 mg, 16.58 umol, 20.3% yield, 97.8% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 523.4 [M/2+H]+. 1H NMR (400MHz, METHANOL-d4) δ = 8.27 - 8.06 (m, 2H), 7.31 - 7.18 (m, 4H), 6.98 (br t, J=8.6 Hz, 4H), 4.12 (br dd, J=10.4, 16.6 Hz, 2H), 4.05 - 3.92 (m, 4H), 3.91 - 3.82 (m, 4H), 3.79 (br 15 s, 4H), 3.69 - 3.54 (m, 1H), 3.35 (s, 1H), 2.89 (br s, 1H), 2.74 - 2.60 (m, 6H), 2.51 (br s, 1H), 2.34 (br d, J=6.0 Hz, 2H), 2.12 (br d, J=7.0 Hz, 2H), 1.98 (br s, 1H), 1.58 - 1.48 (m, 6H), 1.45 - 1.32 (m, 13H). Example 8, (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(4-((S)-2-aminobutanamido)-5-(6-(4-20 fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5- oxopentanamide). Boc NH NH2 HCl O O O O O O H H 2N HN HN HN HN N Boc OH HN HN HN HN F Step 1 of 2: Synthesis of Intermediate 47.1, tert-butyl N-[(1S)-1-[[(1S)-4-[6-[[(4S)-4-[[(2S)-2-25 (tert-butoxycarbonylamino)butanoyl]amino]-5-[6-[(4-fl h l h l 33 di hyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo-penta noy]am no] exa- , -d ynyamino]-1- carbonyl]-4-oxo-butyl]carbamoyl]propyl]carbamate. To a solution of (4S)-4-amino-N-[6-[[(4S)-4-amino-5-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-30 oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo-pentanoyl]amino]hexa-2,4-diynyl]-5-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo- pentanamide (100 mg, 105.50 umol, 1 eq, 2 HCl) in DMF (5 mL) was added DIEA (81.8 mg, 633 158 70226WO01 umol, 110 uL, 6 eq), HOBt (42.8 mg, 316.49 umol, 3 eq), (2S)-2-(tert- butoxycarbonylamino)butanoic acid (42.88 mg, 210.99 umol, 2 eq), and EDCI (60.7 mg, 317 umol, 3 eq) at 0°C. The mixture was stirred at 40°C for 12 h. LC-MS indicated complete conversion to a product of target mass. Water (8 mL) was added to the mixture, then extracted with EtOAc (10 mL 5 * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, DCM/Methanol/NH3.H2O = 10:1:1) to give the title compound (130 mg, 104 umol, 98.9% yield) as a yellow oil. TLC (DCM/Methanol/NH3.H2O = 10:1:1) Rf = 0.43 10 LCMS (ES, m/z): 1245.7 [M+H]+. Step 2 of 2: Synthesis of Example 8, (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(4-((S)-2- aminobutanamido)-5-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-5-oxopentanam 15 To a solution of tert-butyl N-[(1S)-1-[[(1S)-4-[6-[[(4S)-4-[[(2S)-2-(tert- butoxycarbonylamino)butanoyl]amino]-5-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-5-oxo-pentanoyl]amino]hexa-2,4-diynylamino]-1-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-4-oxo- butyl]carbamoyl]propyl]carbamate (130 mg, 104.38 umol, 1 eq) in EtOAc (1.5 mL) was added 20 HCl/dioxane (4 M, 3 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete conversion to a product of target mass. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*40mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 10%-38%, 8 min) to give the title compound (13.1 mg, 9.94 umol, 9.52% yield, 96.6% purity, 2 TFA) as an off-white solid. 25 LCMS (ES, m/z): 523.3 [M/2+H]+. 1H NMR (400 MHz, METHANOL-d4) δ = 8.22 - 8.12 (m, 2H), 7.29 - 7.19 (m, 4H), 6.98 (dt, J = 2.9, 8.8 Hz, 4H), 4.73 - 4.63 (m, 2H), 4.22 - 4.13 (m, 2H), 4.09 - 3.96 (m, 4H), 3.91 - 3.72 (m, 8H), 2.34 (br t, J = 6.3 Hz, 4H), 2.12 (qd, J = 6.8, 13.4 Hz, 2H), 1.99 (br dd, J = 8.2, 14.9 Hz, 2H), 1.93 - 1.81 (m, 4H), 1.46 - 1.34 (m, 12H), 1.07 - 0.96 (m, 6H). 30 The following final compounds were prepared according to the same procedure as Example 8: Examples 9 and 10. The compounds were found to have characterizing data as set forth below. 159 70226WO01 Example 9, (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(5-(6-(4-fluorobenzyl)-3,3-dimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-((S)-2-(methylamino)butanamido)-5- oxopentanamide). HCl O Boc O NH H2N N HN OH O O HN HN HN HN O EDCI HOBT HCl/ dioxane F 5 N ( z, N - ) = .5 ( r , J = . z, ), . ( , J = . z, ), 7.28 - 7.19 (m, 2H), 7.03 - 6.94 (m, 2H), 4.78 - 4.60 (m, 2H), 4.51 - 4.36 (m, 1H), 4.20 - 4.14 (m, 1H), 4.10 - 3.93 (m, 6H), 3.84 (s, 2H), 3.81 - 3.77 (m, 4H), 3.76 - 3.73 (m, 1H), 3.56 - 3.42 (m, 2H), 2.59 - 2.47 (m, 8H), 2.35 (br t, J = 5.9 Hz, 3H), 2.20 - 2.08 (m, 2H), 2.00 (br dd, J = 5.9, 12.6 10 Hz, 3H), 1.87 - 1.77 (m, 4H), 1.44 - 1.38 (m, 12H), 0.99 - 0.92 (m, 6H). Example 10, (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(5-(6-(4-fluorobenzyl)-3,3-dimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-((R)-2-(methylamino)propanamido)- 5-oxopentanamide). NH F 15 1H NMR (400 MHz, METHANOL-d4) δ = 8.18 - 8.12 (m, 2H), 7.28 - 7.19 (m, 4H), 7.02 - 6.95 (m, 4H), 4.69 - 4.57 (m, 2H), 4.16 (br d, J = 10.5 Hz, 2H), 4.05 - 3.99 (m, 4H), 3.90 - 3.74 (m, 8H), 2.69 - 2.62 (m, 6H), 2.34 (br t, J = 6.7 Hz, 4H), 2.19 - 2.07 (m, 2H), 2.04 - 1.91 (m, 2H), 1.55 - 1.49 20 (m, 6H), 1.44 - 1.37 (m, 12H). Example 11, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-aminopropanamide). 160 70226WO01 F Boc H F H HCl N O H O N (S) NH N O (S) Boc OH O (S) NH 2 O N ( NH N O O S) N O (S) DIEA, HATU, DCM, 25o O C O (S) O F tep o : ynt ess o nterme ate 5 . , tert- uty N-[( )- -[[( )- - [[ -[ -[ -[( )- - [[(2S)-2-(tert-butoxycarbonylamino)propanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3- 5 dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4- diynoxy]phenyl]methyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate. To a solution of 1-[(2S)-2-amino-3-[4-[6-[4-[(2S)-2-amino-3-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-10 diynoxy]phenyl]propanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2- b]pyridin-5-one (220 mg, 216 umol, 1 eq.2 HCl) in DCM (5 mL) were added (2S)-2-(tert- butoxycarbonylamino) propanoic acid (102 mg, 540 umol, 2.5 eq.), DIEA (223 mg, 1.73 mmol, 301 uL, 8 eq.) and HATU (329 mg, 864 umol, 4 eq.). The mixture was stirred at 25°C for 14 h after which time LC-MS indicated complete consumption of starting material with formation of a 15 single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 0:1) to give the title compound (200 mg, 155 umol, 89.6% purity, 71.9% yield) as an off-white solid. TLC (EtOAc) Rf = 0.2 LCMS (ES, m/z): 1287.7 [M+H]+. 20 Step 2 of 2: Synthesis of Example 11, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-aminopropanamide). To a solution of tert-butyl N-[(1S)-2-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2- (tert-25 butoxycarbonylamino)propanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[6- [(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo- ethyl]amino]-1-methyl-2-oxo-ethyl]carbamate (200 mg, 155 umol, 1 eq.) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 25°C for 1 h after which time LC-MS 161 70226WO01 indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18200*40mm*10um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 20%-60%, 8 min) to give the title compound (41.1 mg, 31.3 5 umol, 20.1% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 544.4 [M/2+H]+. 1H NMR (400MHz, METHANOL-d4) δ = 8.53 (s, 1H), 8.20 (s, 2H), 7.25 (dd, J=5.7, 8.2 Hz, 4H), 7.18 (br d, J=8.4 Hz, 4H), 6.99 (t, J=8.7 Hz, 4H), 6.84 (br d, J=8.4 Hz, 4H), 4.80 - 4.66 (m, 8H), 4.59 (br s, 2H), 3.91 (d, J=10.4 Hz, 2H), 3.85 - 3.70 (m, 6H), 3.07 - 2.95 (m, 6H), 1.41 (d, J=6.9 10 Hz, 6H), 1.27 (s, 6H), 0.97 (s, 6H) Example 12, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)propanamide). F F H O N N (S) (S) H HCl O Boc N Boc O N O O (S) NH OH 2 O (S) NH O N EDCI, HOBT O N F 15 Step 1 of 2: Synthesis of Intermediate 51.1, tert-butyl N-[(1S)-2-[[(1S)-1- [[4-[6-[4-[(2S)-2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-20 propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]amino]-1-methyl-2-oxo- ethyl]-N-methyl-carbamate. To a solution of 1-[(2S)-2-amino-3-[4-[6-[4-[(2S)-2-amino-3-[6 -[(4-fluorophenyl)methyl]- 3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-25 diynoxy]phenyl]propanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2- b]pyridin-5-one (200 mg, 196 umol, 1 eq., 2 HCl) in DMF (6 mL) was added DIEA (152 mg, 1.18 mmol, 205 uL, 6 eq.), HOBt (79.6 mg, 589 umol, 3 eq.), (2S)-2-[tert- butoxycarbonyl(methyl)amino]propanoic acid (79.9 mg, 393 umol, 2 eq), and EDCI (113 mg, 589 162 70226WO01 umol, 3 eq) at 0°C. The mixture was stirred at 40°C for 12 h. LCMS showed desired mass was detected. Water (8 mL) was added to the mixture, then extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative 5 TLC (SiO2, DCM/Methanol/TEA = 10:1:1) to give the title compound (239 mg, 182 umol, 63.1% purity, 92.5% yield) as a yellow solid. TLC (DCM/Methanol/TEA = 10:1:1) Rf = 0.60 LCMS (ES, m/z): 1315.6 [M+H]+ 10 Step 2 of 2: Synthesis of Example 12, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3 ropane-1,2-diyl))bis(2- (methylamino)propanamide). To a solution of tert-butyl N-[(1S)-2-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert-butoxycarbonyl15 (methyl)amino]propanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[6- [(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo- ethyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (239 mg, 182 umol, 1 eq.) in EtOAc (2 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 20°C for 0.5 h after which 20 time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C1875*30mm, 3um; mobile phase: [water(0.1% TFA)-CH3CN], B%: 10%-45%, 10 min) to give the title compound (79.2 mg, 58.8 umol, 32.4% yield, 99.8% purity, 2 TFA) as an off-white solid. 25 LCMS (ES, m/z): 558.4 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 8.19 (s, 2H), 7.28 - 7.16 (m, 8H), 7.00 (t, J=8.7 Hz, 4H), 6.85 (d, J=8.4 Hz, 4H), 4.82 - 4.68 (m, 6H), 3.93 (d, J=10.4 Hz, 2H), 3.86 - 3.75 (m, 6H), 3.12 - 2.97 (m, 6H), 2.61 (s, 6H), 1.50 (d, J=7.0 Hz, 6H), 1.28 (s, 6H), 1.00 (s, 6H) 30 The following final compounds were prepared according to the same procedure as Example 12: Examples 13-16. The compounds were found to have characterizing data as set forth below. Example 13, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- 35 b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-aminobutanamide). 163 70226WO01 F H O H N (S) HCl N O Boc OH F (S) NH2 H O (S) NH 2 O N O O N EDCI, HOBT NH HC O (S) O l/ dioxane O N N HN(S) O DIEA, DMF, 40oC EtOAc N O F 1 O O (S NH O (S) NH 2 ) O N F O F 164 70226WO01 Example 16, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-cyclopropyl-2-(methylamino)acetamide). F F H N OH HN HCl N O (S) (S) H N O F O F 70226WO01 b]pyridin-5-one (100 mg, 98.2 umol, 1 eq, 2 HCl), (2R)-3-benzyloxy-2-[tert- butoxycarbonyl(methyl)amino]propanoic acid (152 mg, 491 umol, 5 eq), DIEA (76.2 mg, 589 umol, 103 uL, 6 eq), and HOBt (39.8 mg, 295 umol, 3 eq) in DMF (3 mL) was added EDCI (56.5 mg, 295 umol, 3 eq) at 0 °C. The mixture was stirred at 40°C for 12 h after which time LC-MS 5 indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH4Cl (10 mL) and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (119 mg, 77.9 umol, 79.3% yield) 10 as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.54 LCMS (ES, m/z): 1528.9 [M+H]+ Step 2 of 2: Synthesis of Example 17, (2R,2'R)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-15 diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(3-hydroxy-2- (methylamino)propanamide). To a solution of (2R)-N-[(1S)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[[4-[6-[4-[(2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-20 5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2R)-3-hydroxy-2- (methylamino)propanoyl]amino]-3-oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-oxo- ethyl]-3-hydroxy-2-(methylamino)propanamide (70 mg, 45.8 umol, 1 eq) in DCM (3 mL) was added BCl3 (1 M, 458 uL, 10 eq) at -70 °C. The mixture was stirred at -70 °C for 1 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak 25 of target mass. MeOH (2 mL) was added to the mixture and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30mm, 3um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 20%-50%, 8 min) to give the title compound (23.1 mg, 16.8 umol, 36.7% yield, 100% purity, 2 TFA) as a pink solid. LCMS (ES, m/z): 574.3 [M/2+H]+ 30 1H NMR (400MHz, METHANOL-d4) δ = 8.17 (s, 2H), 7.27 - 7.22 (m, 4H), 7.19 (d, J=8.6 Hz, 4H), 7.03 - 6.98 (m, 4H), 6.86 (d, J=8.6 Hz, 4H), 4.81 - 4.69 (m, 6H), 4.69 - 4.65 (m, 2H), 3.99 - 3.73 (m, 14H), 3.02 (br d, J=9.8 Hz, 6H), 2.66 (s, 6H), 1.28 (s, 6H), 0.97 (s, 6H) The following final compound was prepared according to the same procedure as Example 17: 35 Example 18. The compound was found to have characterizing data as set forth below. 166 70226WO01 Example 18, (2R,2'R,3S,3'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(3-hydroxy-2-(methylamino)butanamide). O (R) OH F O (S) OH (S) N O F ( NH Cl H R) H H N O 18.1 O N O O (S) NH O 2 NH ED O (S) O N CI, HOBT BCl3 O N F - O F O F 70226WO01 indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (1.1 g, 3.17 mmol, 20.18% yield) was obtained as a white solid. 5 TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.36 LCMS (ES, m/z): 248.2 [M-Boc+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.04 (br d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 5.08 - 4.86 (m, 2H), 4.54 (br d, J = 7.5 Hz, 1H), 3.72 (s, 3H), 3.12 - 2.95 (m, 2H), 2.68 (dt, J = 2.5, 7.0 Hz, 2H), 2.50 (br s, 1H), 1.42 (s, 9H) 10 Step 2 of 7: Synthesis of Intermediate 58.2, (2S)-2-(tert-butoxycarbonylamino)-3- (4-but-3- ynoxyphenyl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-but-3-ynoxyphenyl) propanoate (870 mg, 2.50 mmol, 1 eq) in THF (9 mL)/H2O (3 mL) was added LiOH (179.92 mg, 7.51 mmol, 3 15 eq). The mixture was stirred at 20°C for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (15 mL), then extracted with EtOAc (15 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (15 mL * 3) and the combined organic 20 phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (640 mg, 1.92 mmol, 76.7% yield) as a yellow oil. LCMS (ES, m/z): 234.0 [M-Boc+H]+ Step 3 of 7: Synthesis of Intermediate 58.3, tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)25 silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(4-but-3- ynoxyphenyl)methyl]-2-oxo-ethyl]carbamate. T l i f 2S 2 b b l mino)-3-(4-but-3-ynoxyphenyl)propanoic acid (500 mg, .50 mmo, . eq) and tert-buty -[[6-[( -fluorophenyl)methyl]-3,3-dimethyl-1,2- dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (527 mg, 1.36 mmol, 1 eq) in DCM (5 mL) 30 was added DIEA (529 mg, 4.09 mmol, 712 uL, 3 eq) and T3P (1.30 g, 2.05 mmol, 1.22 mL, 50% purity, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (20 mL) was added to the mixture and the mixture was extracted with DCM (20 mL * 2). The combined organic phase was washed with brine (15 mL), dried over Na2SO4 and 35 filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was 168 70226WO01 purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (667 mg, 950 umol, 69.7% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.57 LCMS (ES, m/z): 702.5 [M+H]+ 5 1H NMR (400MHz, CHLOROFORM-d) δ = 8.19 (s, 1H), 7.20 - 7.09 (m, 4H), 6.95 (t, J=8.7 Hz, 2H), 6.78 (d, J=8.3 Hz, 2H), 5.35 (br d, J=9.0 Hz, 1H), 5.31 (s, 1H), 4.65 (q, J=7.7 Hz, 1H), 4.02 (t, J=7.0 Hz, 2H), 3.86 (br d, J=14.9 Hz, 2H), 3.10 (d, J=10.1 Hz, 1H), 2.98 (br d, J=7.2 Hz, 2H), 2.64 (dt, J=2.5, 7.0 Hz, 2H), 2.02 (t, J=2.5 Hz, 1H), 1.43 (s, 9H), 1.23 (s, 3H), 0.98 - 0.90 (m, 12H), 0.29 (d, J=8.8 Hz, 6H) 10 Step 4 of 7: Synthesis of Intermediate 58.4, tert-butyl N-[(1S)-1-[[4-[8-[4-[(2S)-2-(tert- butoxycarbonylamino)-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl] 5- diynoxy]phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- 15 dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamate. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(4-but-3-ynoxyphenyl)methyl]-2-oxo- ethyl]carbamate (660 mg, 940 umol, 1 eq) in CH3CN (4 mL) was added pyridine (446 mg, 5.64 mmol, 455 uL, 6 eq) and Cu(OAc)2 (205 mg, 1.13 mmol, 1.2 eq). The mixture was stirred at 85°C 20 for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH3 aq. (20 mL) and extracted with EtOAc (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (650 mg, 464 umol, 98.6% yield) as a yellow oil. 25 LCMS (ES, m/z): 1288.6 [M-TBS+H]+ Step 5 of 7: Synthesis of Intermediate 58.5, 1-[(2S)-2-amino-3-[4-[8-[4-[(2S)-2-amino-3- [6- [(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo- propyl]phenoxy]octa-3,5-diynoxy]phenyl]propanoyl]-6-[(4-fluorophenyl)methyl]-3,3- 30 dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one. To a solution of tert-butyl N-[(1S)-1-[[4-[8-[4-[(2S)-2-(tert-butoxycarbonylamino)-3- [5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 3-oxo-propyl]phenoxy]octa-3,5-diynoxy]phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamate (650 35 mg, 464 umol, 1 eq) in EtOAc (3 mL) was added HCl/dioxane (4 M, 5 mL). The mixture was 169 70226WO01 stirred at 15°C for 12.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (480 mg, 459 umol, 99.0% yield, 2 HCl) as a yellow oil. LCMS (ES, m/z): 973.5 [M+H]+ 5 1H NMR (400MHz, METHANOL-d4) δ = 8.90 (br d, J=5.3 Hz, 1H), 8.70 (tt, J=1.5, 7.9 Hz, 1H), 8.30 (s, 1H), 8.16 (br d 7.25 (dd, J=5.4, 8.5 Hz, 4H), 7.19 (d, J=8.6 Hz, 4H), 7.06 - 6.98 (m, 4H), 6.85 (d, J . , , .36 (dd, J=5.5, 10.0 Hz, 2H), 4.00 (t, J=6.4 Hz, 4H), 3.83 (d, J=5.3 Hz, 2H), 3.82 - 3.77 (m, 2H), 3.66 (s, 4H), 3.21 - 3.14 (m, 2H), 3.10 - 3.01 (m, 2H), 2.81 (d, J=10.4 Hz, 2H), 2.72 - 2.63 (m, 4H), 2.02 (d, J=3.5 Hz, 2H), 1.30 (s, 6H), 1.00 (s, 6H) 10 Step 6 of 7: Synthesis of Intermediate 58.6, tert-butyl N-[(1S)-2- [[(1S)-1-[[4-[8-[4-[(2S)-2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo- propyl]phenoxy]octa-3,5-diynoxy]phenyl]methyl]-2-[6-[(4-fluor enyl)methyl]-3,3-15 dimethyl-5-oxo-2,4-dihydropyrrolo[ ]amino]-1-methyl-2-oxo- ethyl]-N-methyl-carbamate. To a solution of 1-[(2S)-2-amino-3-[4-[8-[4-[(2S)-2-amino-3-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]octa-3,5- diynoxy]phenyl]propanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-20 b]pyridin-5-one (117 mg, 112 umol, 1 eq, 2 HCl), (2S)-2-[tert- butoxycarbonyl(methyl)amino]propanoic acid (50 mg, 246 umol, 2.2 eq) in DCM (3 mL) was added HATU (127 mg, 335 umol, 3 eq) and DIEA (72.3 mg, 559 umol, 97.4 uL, 5 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was 25 added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (35 mg, 26.05 umol, 23.30% yield) as a yellow oil. TLC (EtOAc) Rf = 0.57 30 LCMS (ES, m/z): 1343.6 [M+H]+. Step 7 of 7: Synthesis of Example 19, (2S,2'S)-N,N'-((2S,2'S)-((octa-3,5-diyne-1,8- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- 35 (methylamino)propanamide). 170 70226WO01 To a solution of tert-butyl N-[(1S)-2-[[(1S)-1-[[4-[8-[4-[(2S)-2-[[(2S)-2-[tert-butoxycarbonyl (methyl)amino]propanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]octa-3,5-diynoxy]phenyl]methyl]-2-[6- [(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo- 5 ethyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (35 mg, 26.1 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30mm, 3um; mobile 10 phase: [water(0.1%TFA)-CH3CN], B%: 20%-50%, 8 min) to give the title compound (22.6 mg, 16.5 umol, 63.3% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 572.3 [M/2+H]+. 1H NMR (400MHz, METHANOL-d4) δ = 8.18 (s, 2H), 7.25 (dd, J=5.5, 8.5 Hz, 4H), 7.17 (d, J=8.6 Hz, 4H), 7.01 (t, J=8.8 Hz, 4H), 6.80 (d, J=8.6 Hz, 4H), 4.72 (br t, J=8.0 Hz, 2H), 4.00 - 3.92 (m, 15 6H), 3.86 - 3.82 (m, 2H), 3.81 - 3.77 (m, 4H), 3.06 (d, J=10.4 Hz, 2H), 3.01 (br d, J=8.0 Hz, 4H), 2.67 - 2.62 (m, 4H), 2.61 (s, 6H), 1.50 (d, J=7.0 Hz, 6H), 1.29 (s, 6H), 1.02 (s, 6H) The following final compound was prepared according to the same procedure as Example 19: Example 20. The compound was found to have characterizing data as set forth below. 20 Example 20, (2S,2'S)-N,N'-((2S,2'S)-((octa-3,5-diyne-1,8-diylbis(oxy))bis(4,1-phenylene))bis(3- (6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). F HCl O NH H O H (S) (S) N (S NH2 O N O Boc N OH F O ) O (S) NH O N F 25 1H NMR (400MHz, METHANOL-d4) δ = 8.17 (s, 2H), 7.25 (dd, J=5.4, 8.6 Hz, 4H), 7.17 (d, J=8.6 Hz, 4H), 7.04 - 6.96 (m, 4H), 6.80 (d, J=8.6 Hz, 4H), 4.75 (br t, J=8.1 Hz, 2H), 4.02 - 3.93 (m, 6H), 3.79 (s, 4H), 3.73 (dd, J=5.3, 6.9 Hz, 2H), 3.09 (d, J=10.4 Hz, 2H), 3.02 (br d, J=8.1 Hz, 4H), 2.64 (br t, J=6.3 Hz, 4H), 2.59 (s, 6H), 1.98 - 1.83 (m, 4H), 1.29 (s, 6H), 1.01 (s, 6H), 0.96 (t, J=7.5 Hz, 30 6H). 171 70226WO01 Example 21, (2S,2'S)-N,N'-((2S,2'S)-((butane-1,4-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide). HN N F N OTBS Boc OH O N OH OH O Boc OH NH 211 O O F butoxycarbonyl)(methyl)amino)propanamido)-3-(4-hydroxyphenyl)propanoate. To a solution of (S)-methyl 2-amino-3-(4-hydroxyphenyl)propanoate (5 g, 25.6 mmol, 1 eq), (2S)- 2-[tert-butoxycarbonyl(methyl)amino] propanoic acid (5.73 g, 28.2 mmol, 1.1 eq), DIEA (6.62 g, 10 51.2 mmol, 8.92 mL, 2 eq) in DCM (150 mL) was added T3P (24.5 g, 38.4 mmol, 22.9 mL, 50% purity, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (100 mL) was added to the mixture, and the mixture was extracted with DCM (150 mL * 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4 and filtered. 15 The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromato ra h (SiO Petroleum ether/EtOAc = 1:0 to 1:1) to ive the title com ound (5.6 ), .88 hydroxyphenyl)propanoate (5.6 g, 14.7 mmol, 1 eq) in THF (60 mL)/MeOH (20 mL)/H2O (20 mL) 172 70226WO01 was added LiOH (1.06 g, 44.2 mmol, 3 eq). The mixture was stirred at 20°C for 14 h. LC-MS indicated complete conversion to a product of target mass. The mixture was concentrated in vacuo, dissolved in H2O (30 mL), then extracted with EtOAc (60 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (3 * 60 5 mL) and the combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (5.3 g, 14.46 mmol, 98.27% yield) as a colorless oil. LCMS (ES, m/z): 267.2 [M-Boc+H+]. 1H NMR (400MHz, CHLOROFORM-d) δ = 6.97 (d, J=8.4 Hz, 2H), 6.72 (br d, J=8.3 Hz, 2H), 10 4.87 - 4.86 (m, 1H), 4.85 - 4.75 (m, 1H), 4.85 - 4.75 (m, 1H), 4.88 - 4.74 (m, 1H), 4.86 - 4.56 (m, 1H), 4.72 (br s, 1H), 3.17 - 3.08 (m, 1H), 3.00 (br dd, J=6.8, 14.1 Hz, 1H), 2.65 (s, 3H), 1.47 (br s, 9H), 1.35 - 1.29 (m, 3H) Step 3 of 5: Synthesis of Intermediate 60.3, tert-butyl ((S)-1-(((S)-1-(5-((tert-15 butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)amino)-1-oxopropan-2- yl)(methyl)carbamate. To a solution of (S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3-(4- hydroxyphenyl)propanoic acid (948 mg, 2.59 mmol, 2 eq), tert-butyl-[[6-[(4-fluorophenyl)methyl] 20 -3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (500 mg, 1.29 mmol, 1 eq) in DCM (30 mL) was added DIEA (501.49 mg, 3.88 mmol, 675.86 uL, 3 eq) and HATU (738 mg, 1.94 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (50 mL) was added to the mixture, and the mixture was extracted with DCM 25 (60 mL * 2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 2:1) to give the title compound (665 mg, 904.80 umol, 69.95% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.67 30 LCMS (ES, m/z): 735.5 [M+H+]. Step 4 of 5: Synthesis of Intermediate 60.4, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((butane-1,4- diylbis(oxy))bis(4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- 35 diyl))bis(azanediyl))bis(1-oxopropane-2,1-diyl))bis(methylcarbamate). 173 70226WO01 Three batches were carried out in parallel: To a solution of tert-butyl ((S)-1-(((S)-1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(4-hydroxyphenyl)-1-oxopropan-2- yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (52.2 mg, 71.0 umol, 2.2 eq) in DMF (3 mL) was 5 added K2CO3 (4.46 mg, 32.3 umol, 1 eq) and 1,4-diiodobutane (10 mg, 32.3 umol, 4.24 uL, 1 eq). The mixture was stirred at 40°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Three reactions were combined for workup. Water (20 mL * 2) and saturated NH4Cl aq. (20 mL) was added to the mixture, and the mixture was extracted with EtOAc (25 mL * 2). The combined organic phase was washed with 10 brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (141 mg, 92.5 umol, 95.6% yield) as a yellow oil. LCMS (ES, m/z): 1195.7 [M-Boc-2TBS+H+]. Step 5 of 5: Synthesis of Example 21, (2S,2'S)-N,N'-((2S,2'S)-((butane-1,4-15 diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)propanamide). To a solution of di-tert-butyl ((2S,2'S)-(((2S,2'S)-((butane-1,4-diylbis(oxy))bis(4,1- phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-20 1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2-diyl))bis(azanediyl))bis(1-oxopropane-2,1- diyl))bis(methylcarbamate) (140 mg, 91.86 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a crude product. The crude product was purified by 25 preparative HPLC (column: Phenomenex Luna C18100*30mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 15%-45%,10 min) to give the title compound (23.1 mg, 17.5 umol, 19.0% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 548.3 [M/2+H+]. 1H NMR (400MHz, METHANOL-d4) δ = 8.17 - 8.12 (m, 2H), 7.18 - 7.11 (m, 4H), 7.08 (d, J=8.4 30 Hz, 4H), 6.95 - 6.87 (m, 4H), 6.66 (d, J=8.5 Hz, 4H), 4.85 - 4.74 (m, 2H), 4.33 (br s, 4H), 4.01 - 3.93 (m, 2H), 3.87 - 3.75 (m, 6H), 3.27 - 3.19 (m, 2H), 3.07 - 2.92 (m, 4H), 2.64 - 2.54 (m, 6H), 1.78 (br d, J=2.8 Hz, 4H), 1.52 - 1.42 (m, 5H), 1.52 - 1.42 (m, 1H), 1.25 - 1.19 (m, 6H), 1.05 - 0.99 (m, 6H) 174 70226WO01 The following final compound was prepared according to the same procedure as Example 21: Example 22. The compound was found to have characterizing data as set forth below. Example 22, (2S,2'S)-N,N'-((2S,2'S)-((hexane-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- 5 fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide). O F - - 70226WO01 fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4- (prop-2-yn-1-yloxy)phenyl)propan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (73.5 mg, 112 umol, 1 eq), and DIEA (14.4 mg, 112 umol, 19.4 uL, 1 eq) in THF (3 mL) was added CuI (14.9 mg, 78.1 umol, 0.7 eq). The mixture was degassed and purged with N2 three times, and then the 5 mixture was stirred at 15°C for 12 h under N2 atmosphere. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was quenched by addition NH4Cl (10 mL), and then diluted with DCM (5 mL) and extracted with DCM (10 mL *3). The combined organic phase was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound 10 (150 mg, 111 umol, 99.7% yield) as a yellow solid. LCMS (ES, m/z): 1349.8 [M+H+]. Step 2 of 2: Synthesis of Example 23, (S)-N-((S)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(4-((1-(2-(4-((S)-3-(6-(4-fluorobenzyl)-3,3-15 dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2- xopropyl)phenoxy)ethyl)-1H-1,2,3-triazol-4- yl)methoxy)phenyl)-1-oxopropan-2-yl)-2-(methylamino)propanamide. To a solution of tert-butyl N-[(1S)-2-[[(1S)-1-[[4-[[1-[2-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]propanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-20 oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]ethyl]triazol-4- yl]methoxy]phenyl]methyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl- carbamate (80 mg, 59.3 umol, 1 eq) in dioxane (1 mL) was added HCl/dioxane (4 M, 2 mL). The mixture was stirred at 15°C for 1 h after which time LC-MS indicated complete consumption of 25 starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(0.1%TFA)- CH3CN], B%: 15%-45%,9 min) to give the title compound (19.5 mg, 14.17 umol, 23.88% yield, 100% purity, 2 TFA) as a white solid. 30 LCMS (ES, m/z): 1148.5 [M+H+]. 1H NMR (400 MHz, METHANOL-d4) δ = 8.17 (s, 2H), 8.06 (s, 1H), 7.25 (dd, J = 5.6, 7.9 Hz, 4H), 7.17 (t, J = 8.6 Hz, 4H), 7.04 - 6.96 (m, 4H), 6.90 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 5.09 - 5.00 (m, 2H), 4.78 - 4.69 (m, 4H), 4.34 - 4.27 (m, 2H), 3.93 (dd, J = 10.4, 14.0 Hz, 2H), 3.86 - 3.76 (m, 6H), 3.06 (s, 2H), 3.03 - 2.96 (m, 4H), 2.59 (d, J = 3.4 Hz, 6H), 1.49 (dd, J = 3.3, 7.0 Hz, 35 6H), 1.27 (d, J = 9.3 Hz, 6H), 0.97 (s, 3H), 0.88 (s, 3H). 176 70226WO01 Example 24, (S)-N-((S)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-3-(4-(2-((2-(4-((S)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2-(methylamino)propanamido)-3- 5 F Step 1 of 2: Synthesis of Intermediate 63.1, tert-butyl N-[(1S)-2-[[(1S)-1-[[4-[2-[[2-[4-[(2S)-2-10 [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]py - propyl]phenoxy]acetyl]amino]ethoxy]phenyl]methyl]-2-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]amino]-1-methyl-2-oxo- ethyl]-N-methyl-carba 15 To a solution of tert -fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropan-2-yl)amino)-1- oxopropan-2-yl)(methyl)carbamate (117 mg, 177 umol, 1 eq) and 2-(4-((S)-2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)propanamido)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropyl)phenoxy)acetic acid (120 mg, 177 umol, 1 20 eq) in DMF (4 mL) was added DIEA (91.4 mg, 707 umol, 123 uL, 4 eq), HOBt (35.8 mg, 265 umol, 1.5 eq) and EDCI (50.8 mg, 265 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (10 mL) was added to the mixture, then extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (15 mL), then dried over Na2SO4, filtered and 25 concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100*40mm, 5um; mobile phase: [water(0.1%TFA)- CH3CN], B%: 40%-75%, 8 min) to give the title compound (40 mg, 30.2 umol, 17.1% yield) as a pink solid. LCMS (ES, m/z): 1325.8 [M+H+]. 30 Step 2 of 2: Synthesis of Example 24, (S)-N-((S)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(4-(2-((2-(4-((S)-3-(6-(4-fluorobenzyl)-3,3- 177 70226WO01 dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2- (methylamino)propanamido)-3-oxopropyl)phenoxy)ethyl)amino)-2-oxoethoxy)phenyl)-1- oxopropan-2-yl)-2-(methylamino)propanamide. To a solution of tert-butyl N-[(1S)-2-[[(1S)-1-[[4-[2-[[2-[4-[(2S)-2-[[(2S)-2-[tert- 5 butoxycarbonyl(methyl)amino]propanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo- propyl]phenoxy]acetyl]amino]ethoxy]phenyl]methyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl- 5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]-N- methyl-carbamate (35 mg, 26.4 umol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 2 mL). 10 The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(0.1%TFA)- CH3CN], B%: 15%-45%, 9 min) to give the title compound (7.9 mg, 5.64 umol, 21.33% yield, 15 96.4% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 1124.5 [M+H+]. 1H NMR (400 MHz, METHANOL-d4) δ = 8.19 (s, 2H), 7.28 - 7.14 (m, 8H), 7.05 - 6.97 (m, 4H), 6.91 - 6.78 (m, 4H), 4.78 - 4.69 (m, 2H), 4.42 (s, 2H), 4.04 - 3.93 (m, 4H), 3.90 - 3.76 (m, 6H), 3.71 - 3.49 (m, 2H), 3.12 (dd, J = 7.5, 10.1 Hz, 2H), 3.01 (br d, J = 7.4 Hz, 4H), 2.61 (d, J = 3.1 Hz, 20 6H), 1.50 (d, J = 7.0 Hz, 6H), 1.28 (s, 6H), 0.97 (d, J = 6.4 Hz, 6H). Example 25, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(1H-indole-1,3-diyl))bis(3-(6- (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl) 2-(methylamino)butanamide). 178 70226WO01 HN N OTBS F HN Boc N Br 2.11 Pyr. O F Step 1 of 7: Synthesis of Intermediate 64.1, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(1- (prop-2-yn-1-yl)-1H-indol-3-yl)propanoate. 5 To a solution of methyl (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)propanoate in DMF (100 mL) was added t-BuOK (4.23 g, 37.7 mmol, 1.2 eq) at 0°C. The mixture was stirred at 0°C for 0.5 h and the 3-bromoprop-1-yne (5.14 g, 34.6 mmol, 3.72 mL, 80% purity, 1.1 eq) dissolved in DMF (50 mL) was added dropwise to the mixture at 0°C and the mixture was stirred at 0°C for 1 h. The mixture was stirred at 40°C for 2 h after which time TLC (Petroleum ether/EtOAc 10 = 3:1) indicated complete consumption of starting material and formation of one new spot. The residue was added into H2O (150 mL), and extracted with EtOAc (50 mL * 4). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0: to 4:1) to give the title compound (6.19 g, 17.4 mmol, 55.3% yield) 15 as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.50 LCMS (ES, m/z): 357.1 [M+H+]. 1H NMR (400MHz, DMSO-d6) δ = 7.55 - 7.45 (m, 2H), 7.35 - 7.13 (m, 3H), 7.10 - 7.04 (m, 1H), 5.03 (d, J = 2.3 Hz, 2H), 4.72 (d, J = 2.3 Hz, 1H), 4.26 - 4.16 (m, 1H), 3.62 - 3.57 (m, 2H), 3.41 - 20 3.36 (m, 1H), 3.14 - 2.96 (m, 2H), 1.38 - 1.19 (m, 9H) Step 2 of 7: Synthesis of Intermediate 64.2, (S)-2-((tert-butoxycarbonyl)amino)-3-(1-ethyl- 1H-indol-3-yl)propanoic acid 179 70226WO01 To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(1-(prop-2-yn-1-yl)-1H-indol-3- yl)propanoate (5.15 g, 14.5 mmol, 1 eq) in THF (60 mL)/MeOH (20 mL)/H2O (20 mL) was added LiOH (1.04 g, 43.4 mmol, 3 eq) at 25°C. The mixture was stirred at 25°C for 2 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. 5 The mixture was concentrated in vacuo, dissolved in H2O (30 mL), then extracted with EtOAc (60 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH = 1-2. The acidic aqueous phase was extracted with DCM (3 * 60 mL) and the combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (4.75 g, 13.9 mmol, 95.9% yield) as a yellow oil. 10 LCMS (ES, m/z): 343.1 [M+H]. Step 3 of 7: Synthesis of Intermediate 64.3, (S)-tert-butyl (1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(1-(prop- 2-yn-1-yl)-1H-indol-3-yl)propan-2-yl)carbamate. 15 To a solution of tert-butyl-[[6-[(4-fluorophenyl)methyl]-3 imethyl-1,2-dihydropyrrolo[3,2- b]pyridin-5-yl]oxy]-dimethyl-silane (2.35 g, 6.08 mmol, 1 eq), (S)-2-((tert-butoxycarbonyl)amino)- 3-(1-ethyl-1H-indol-3-yl)propanoic acid (2.29 g, 6.69 mmol, 1.1 eq), DIEA (3.14 g, 24.32 mmol, 4.24 mL, 4 eq) in DCM (40 mL) was added HATU (5.78 g, 15.20 mmol, 2.5 eq) at 0°C. The mixture was stirred at 40°C for 12 h. LC-MS indicated complete conversion to a product of target 20 mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0: to 5:1) to give the title compoumd (2.8 g, 3.94 mmol, 64.8% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.6 LCMS (ES, m/z): 711.4 [M+H+]. 25 Step 4 of 7: Synthesis of Intermediate 64.4, tert-butyl N-[(1S)-1-[[1-[6-[3-[(2S)-2-(tert- butoxycarbonylamino)-3-[6-[(4-fluorophenyl)methyl]-3,3-di th l 5 xo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]indol-1 l - , - iynyl]indol-3- yl]methyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5 -oxo- , -dihydropyrrolo[3,2- 30 b]pyridin-1-yl]-2-oxo-ethyl]carbamate. To a solution of (S)-tert-butyl (1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(1-(prop-2-yn-1-yl)-1H-indol-3-yl)propan-2- yl)carbamate (2.7 g, 3.80 mmol, 1 eq) in CH3CN (60 mL) was added pyridine (1.80 g, 22.8 mmol, 1.84 mL, 6 eq) and Cu(OAc)2 (828 mg, 4.56 mmol, 1.2 eq). The mixture was stirred at 85°C for 1 35 h. LC-MS indicated complete consumption of starting material with formation of a single peak of 180 70226WO01 target mass. The reaction mixture was filtered and the filtrate was added into NH3.H2O (60 mL), then extracted with EtOAc (60 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.81 g, quantitative yield) as a yellow oil. LCMS (ES, m/z): 1191.7 [M+H+]. 5 Step 5 of 7: Synthesis of Intermediate 64.5, 1,1'-((2S,2'S)-3,3'-(1,1'-(hexa-2,4-diyne-1,6- diyl)bis(1H-indole-3,1-diyl))bis(2-aminopropanoyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-2,3- dihydro-1H-pyrrolo[3,2-b]pyridin-5(4H)-one). To a solution of tert-butyl N-[(1S)-1-[[1-[6-[3-[(2S)-2-(tert-butoxycarbonylamino)-3-[6-[(4-10 fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo- propyl]indol-1-yl]hexa-2,4-diynyl]indol-3-yl]methyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl- 5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamate (2.80 g, 2.35 mmol, 1 eq) in EtOAc (10 mL) was added HCl/dioxane (4 M, 18 mL). The mixture was stirred at 20°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a 15 single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18250*70 mm, 10 um; mobile phase: [water (0.05% NH3.H2O)-CH3CN], B%: 33-58%, 35 min) to give the title compound (800 mg, 807 umol, 34.3% yield) as a yellow solid. LCMS (ES, m/z): 991.5 [M+H+]. 20 1H NMR (400MHz, METHANOL-d4) δ = 8.22 (d, J = 7.9 Hz, 2H), 7.55 - 7.46 (m, 2H), 7.31 - 7.17 (m, 6H), 7.12 - 7.03 (m, 2H), 7.00 - 6.88 (m, 8H), 4.98 - 4.87 (m, 4H), 3.89 (dt, J = 4.5, 9.8 Hz, 2H), 3.80 - 3.69 (m, 4H), 3.51 (dd, J = 4.8, 10.4 Hz, 2H), 3.14 - 3.06 (m, 2H), 3.01 - 2.92 (m, 2H), 2.64 (t, J = 10.0 Hz, 2H), 1.06 (d, J = 9.8 Hz, 6H), 0.42 (s, 6H) 25 Step 6 of 7: Synthesis of Intermediate 64.6, di-tert-butyl ((2S,2'S)-(((2S,2'S)-(1,1'-(hexa-2,4- diyne-1,6-diyl)bis(1H-indole-3,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2-diyl))bis(azanediyl))bis(1- oxobutane-2,1-diyl))bis(methylcarbamate). To a solution of 1,1'-((2S,2'S)-3,3'-(1,1'-(hexa-2,4-diyne-1,6-diyl)bis(1H-indole-3,1-diyl))bis(2-30 aminopropanoyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin- 5(4H)-one) (150 mg, 151.34 umol, 1 eq) in DMF (3 mL) was added DIEA (117.36 mg, 908 umol, 158 uL, 6 eq), HOBt (61.4 mg, 454 umol, 3 eq), (2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoic acid (65.8 mg, 303 umol, 2 eq) and EDCI (87.0 mg, 454 umol, 3 eq) at 0°C. The mixture was stirred at 40°C for 12 h. LC-MS indicated complete 35 conversion to a product of target mass. Water (20 mL) was added to the mixture, then extracted 181 70226WO01 with EtOAc (20 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol/TEA = 100:2:8) to give the title compound (183 mg, 131.69 umol, 87.01% yield) as a yellow solid. 5 TLC (EtOAc/Methanol/TEA = 100:2:8) Rf = 0.55 LCMS (ES, m/z): 1389.8 [M+H+]. Step 7 of 7: Synthesis of Example 25, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(1H- indole-1,3-diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- 10 pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). To a solution of di-tert-butyl ((2S,2'S)-(((2S,2'S)-(1,1'-(hexa-2,4-diyne-1,6-diyl)bis(1H-indole-3,1- diyl))bis(1-(6-(4-fluorobenzyl ethyl-5-oxo-2,3,4,5 -pyrrolo[3,2-b]pyridin-1- yl)-1-oxopropane-3,2-diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate) (183 mg, 132 umol, 1 eq) in EtOAc (3 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was 15 stirred at 20°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water (0.1% TFA) - CH3CN], B%: 20% - 50%, 9 min) to give the title compound (20.5 mg, 14.24 umol, 10.8% yield, 98.431% purity, 2 20 TFA) as an off-white solid. LCMS (ES, m/z): 595.5 [M/2+H+]. 1H NMR (400MHz, METHANOL-d4) δ = 8.19 (s, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 7.28 - 7.22 (m, 4H), 7.17 (t, J = 7.6 Hz, 2H), 7.09 (s, 2H), 7.06 - 6.96 (m, 6H), 4.95 (br d, J = 7.6 Hz, 6H), 3.81 - 3.74 (m, 8H), 3.24 (br d, J = 8.3 Hz, 4H), 2.80 (d, J = 10.4 Hz, 2H), 2.63 (s, 25 6H), 1.98 - 1.87 (m, 4H), 1.15 (s, 6H), 0.98 (t, J = 7.5 Hz, 6H), 0.51 (s, 6H) The following final compounds were prepared according to the same procedure as Example 25: Examples 26-28. The compounds were found to have characterizing data as set forth below. 30 Example 26, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(1H-indole-1,3-diyl))bis(3-(6- (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide). 182 70226WO01 F F O NH H H (S) N (S) N O N O Boc OH O O (S) NH N O NH 2 N EDCI, HOBT HCl/ dioxane N N N N N HN (S) O F , O F = , , O F 70226WO01 (m, 8H), 4.98 - 4.92 (m, 6H), 3.80 - 3.74 (m, 6H), 3.28 (br s, 2H), 3.24 (br d, J = 7.5 Hz, 4H), 2.84 (br d, J = 10.1 Hz, 2H), 2.67 - 2.62 (m, 8H), 1.16 (s, 8H), 0.85 - 0.79 (m, 2H), 0.72 - 0.62 (m, 6H), 0.55 (s, 6H). 5 Example 29, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). HN N TBSO OTBS B N F O oc B HN OH r 211 B (S) N N (S) O N O HCl/dioxane c O H2N HN F Boc OH HN HN F HN HN F (S) O (S) O H (S) O N O DIEA H BTED I Cl/dioxane O N f Intermediate 68.1, (2S)-2-(tert-butoxycarbonylamino)-3-prop -2- To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-hydroxy-propanoic acid (20 g, 97.5 mmol, 1 eq) in DMF (800 mL) was added NaH (7.80 g, 195 mmol, 60% purity, 2 eq) portionwise at 0°C. The mixture was stirred at 0°C for 30 min and 3-bromoprop-1-yne (14.5 g, 97.5 mmol, 10.5 mL, 15 80% purity, 1 eq) was added dropwise at 0°C under N2. The mixture was stirred at 0°C for 2.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The resulting reaction mixture was quenched by the addition of H2O (200 mL) and the mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (400 mL) and acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted 20 with DCM (4 x 200 mL) and the combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase MPLC (column: C1820-35um 100A 330 g; mobile phase: [water- CH3CN], B%: 0%-60%, 80 mL/min) to give the title compound (17.6 g, 74.2% yield) as a yellow oil. 25 LCMS (ES, m/z): 144.2 [M-Boc+H]+ 84 70226WO01 1H NMR (400 MHz, CHLOROFORM-d) δ = 9.80 - 8.99 (m, 1H), 5.40 (br d, J = 8.3 Hz, 1H), 4.58 - 4.44 (m, 1H), 4.22 - 4.13 (m, 2H), 4.00 (br dd, J = 2.4, 9.1 Hz, 1H), 3.82 (dd, J = 3.4, 9.3 Hz, 1H), 2.47 (t, J = 2.4 Hz, 1H), 1.46 (s, 9H). 5 Step 2 of 6: Synthesis of Intermediate 68.2, tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl] oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-(prop-2- ynoxymethyl)ethyl]carbamate. To a solution of tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo [3,2-b] pyridine-5-yl]oxy]-dimethyl-silane (500 mg, 1.29 mmol, 1 eq), 5-((tert-butyldimethylsilyl)oxy)-6- 10 (4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (409 mg, 1.68 mmol, 1.3 eq), and DIEA (669 mg, 5.17 mmol, 901 uL, 4 eq) in DCM (40 mL) was added HATU (1.23 g, 3.23 mmol, 2.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (60 mL), then extracted with DCM (30 mL * 3). The 15 combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (599 mg, 979 umol, 75.7% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.60. 20 LCMS (ES, m/z): 612.4 [M+H]+ Step 3 of 6: Synthesis of Intermediate 68.3, tert-butyl N-[(1S)-1-[6-[(2S)-2-(tert- butoxycarbonylamino)-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propoxy]hexa-2,4-diynoxymethyl]-2-[5-[tert-25 butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-2-oxo-ethyl]carbamate. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl] - 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-(prop-2-ynoxymethyl)ethyl]carbamate (490 mg, 800 umol, 1 eq) in CH3CN (15 mL) was added pyridine (380 mg, 4.81 mmol, 388 uL, 6 eq) 30 and Cu(OAc)2 (175 mg, 961 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under aerobic conditions. LC-MS indicated complete conversion to a product of target mass. The reaction mixture was filtered. The filtrate was added into NH3.H2O (30 mL), then extracted with EtOAc (30 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (589 mg, 482 umol, quantitative yield) as a yellow oil. 185 70226WO01 LCMS (ES, m/z): 611.8 [M/2+H]+ , another peak of 1107.6 [M+H]+ corresponding to TBS cleaved product also noted. Step 4 of 6: Synthesis of Intermediate 68.4, 1-[(2S)-2-amino-3-[6-[(2S)-2-amino-3-[6-[(4- 5 fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo- propoxy]hexa-2,4-diynoxy]propanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2,4- dihydropyrrolo[3,2-b]pyridin-5-one. To a solution of tert-butyl N-[(1S)-1-[6-[(2S)-2-(tert-butoxycarbonylamino)-3-[5-[tert- butyl(dimethyl) silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-10 3-oxo-propoxy]hexa-2,4-diynoxymethyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamate (589 mg, 482 umol, 1 eq) in EtOAc (4 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to 15 give the title compound (414 mg, 478 umol, 99.2% yield, 2 HCl) as a yellow oil. LCMS (ES, m/z): 793.4 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 8.26 - 8.11 (m, 2H), 7.23 (dd, J = 5.5, 8.4 Hz, 4H), 7.04 - 6.91 (m, 4H), 4.52 (br t, J = 5.0 Hz, 2H), 4.36 - 4.23 (m, 4H), 4.08 - 3.95 (m, 4H), 3.93 - 3.84 (m, 4H), 3.35 (s, 4H), 1.42 (d, J = 9.6 Hz, 12H). 20 Step 5 of 6: Synthesis of Intermediate 68.5, tert-butyl N-[(1S)-1-[[(1S)-1-[6-[(2S)-2-[[(2S)-2- [tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyrid y xo-propoxy]hexa-2,4- diynoxymethyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- 25 b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate. To a solution of 1-[(2S)-2-amino-3-[6-[(2S)-2-amino-3 -[6-[(4-fluorophenyl)methyl]-3,3- dimethyl- 5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propoxy]hexa-2,4-diynoxy]propanoyl]-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one (180 mg, 208 umol, 1 eq, 2 HCl) in DMF (5 mL) was added DIEA (161 mg, 1.25 mmol, 217 uL, 6 eq), HOBt (84.3 mg, 30 624 umol, 3 eq), (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (90.3 mg, 416 umol, 2 eq) and EDCI (119 mg, 624 umol, 3 eq) at 0°C. The mixture was stirred at 40°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (8 mL) was added to the mixture, then extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under 35 reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, 186 70226WO01 EtOAc/Petroleum ether/TEA = 10:1:1) to give the title compound (120 mg, 100.73 umol, 48.45% yield) as a yellow solid. TLC (Petroleum ether/EtOAc/TEA = 10:1:1) Rf = 0.70. LCMS (ES, m/z): 1191.7 [M+H]+ 5 Step 6 of 6: Synthesis of Example 29, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6- diylbis(oxy))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2 hylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[6-[(2S)-2-[[(2S)-2- [tert-butoxycarbonyl (methyl)10 amino]butanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridin-1-yl]-3-oxo-propoxy]hexa-2,4-diynoxymethyl]-2-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl- carbamate (120 mg, 101 umol, 1 eq) in EtOAc (3 mL) was added HCl/dioxane (4 M, 3 mL). The mixture was stirred at 20°C for 0.5 h after which time LC-MS indicated complete consumption of 15 starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100*40mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN]; B%:1%-38%, 8 min) to give the title compound (57.2 mg, 46.29 umol, 45.96% yield, 98.673% purity, 2 TFA) as a yellow solid. 20 LCMS (ES, m/z): 496.3 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 8.27 - 8.12 (m, 2H), 7.23 (dd, J = 5.5, 8.4 Hz, 4H), 7.06 - 6.90 (m, 4H), 4.91 (br d, J = 6.3 Hz, 2H), 4.25 (s, 4H), 4.16 - 3.97 (m, 4H), 3.88 - 3.73 (m, 10H), 2.69 - 2.62 (m, 6H), 1.99 - 1.84 (m, 4H), 1.40 (d, J = 4.9 Hz, 12H), 1.03 - 0.93 (m, 6H) 25 The following final compounds were prepared according to the same procedure as Example 29: Examples 30 and 31. The compounds were found to have characterizing data as set forth below. Example 30, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(3-(6-(4- fluorobenzyl)-3,3-di hyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- 30 oxopropane-1,2-diyl) )bis(2-(methylamino)propanamide). O HN ( O HCl O S) HN N (S) O F 70226WO01 LCMS (ES, m/z): 482.3 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.17 (s, 2H), 7.24 (br dd, J = 5.6, 8.3 Hz, 4H), 6.97 (br t, J = 8.8 Hz, 4H), 4.25 (s, 5H), 4.13 - 4.00 (m, 4H), 3.95 - 3.81 (m, 4H), 3.81 - 3.73 (m, 7H), 2.67 (s, 6H), 1.51 (d, J = 7.0 Hz, 6H), 1.40 (d, J = 4.9 Hz, 12H). 5 Example 31, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-aminobutanamide). NH2 O ( O H O S) (S) O HCl HN Boc N OH HN HN F H2N F 10 1H NMR (400 MHz, METHANOL-d4) δ = 8.19 (s, 2H), 7.24 (br dd, J = 5.6, 8.3 Hz, 4H), 6.97 (t, J = 8.8 Hz, 4H), 4.75 - 4.51 (m, 2H), 4.24 (s, 4H), 4.08 (q, J = 10.4 Hz, 4H), 3.86 - 3.67 (m, 8H), 3.34 (br t, J = 6.4 Hz, 2H), 1.78 - 1.54 (m, 4H), 1.39 (s, 12H), 0.93 (t, J = 7.4 Hz, 6H). 15 Example 32, (2S,2'S)-N,N'-((2S,2'S,3R,3'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1- oxobutane-3,2-diyl))bis(2-aminopropanamide). F H2 20 Step 1 of 6: Synthesis of Intermediate 71.1, (2S,3R)-2-(tert-butoxycarbonylamino) -3- prop-2- ynoxy-butanoic acid. 88 70226WO01 To a solution of (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-butanoic acid (10 g, 45.6 mmol, 1 eq) in DMF (400 mL) was added NaH (3.65 g, 91.2 mmol, 60% purity, 2 eq) portionwise at 0°C. The mixture was stirred at 0°C for 30 min and 3-bromoprop-1-yne (6.78 g, 45.6 mmol, 4.91 mL, 80% purity, 1 eq) was added dropwise at 0°C under N2. The mixture was stirred at 0°C for 2.5 h. 5 LC-MS indicated complete conversion to a product of target mass. The resulting reaction mixture was quenched by the addition of 100 mL H2O, then the mixture was concentrated under reduced pressure to get a residue. The residue was dissolved in H2O (200 mL), acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (4 * 200 mL) and the combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under 10 reduced pressure to give a residue. The residue was purified by reversed-phase MPLC (column: C1820-35um 100A 330g; mobile phase: [water-CH3CN], B%: 0%-60%, 80 mL/min) to give the desired compound (5.29 g, 20.56 mmol, 45.08% yield) as a yellow oil. LCMS (ES, m/z): 158.2 [M-Boc+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 9.95 - 9.38 (m, 1H), 5.36 - 5.19 (m, 1H), 4.39 - 4.26 15 (m, 2H), 4.22 - 4.12 (m, 2H), 2.44 (t, J = 2.1 Hz, 1H), 1.45 (s, 9H), 1.26 (d, J = 6.1 Hz, 3H). Step 2 of 6: Synthesis of Intermediate 71.2, tert-butyl N-[(1S,2R)-1- [5- [tert-butyl (dimethyl) silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]-2- prop-2-ynoxy-propyl]carbamate. 20 To a solution of (2S,3R)-2-(tert-butoxycarbonylamino)-3-prop-2-ynoxy-butanoic acid (559 mg, 2.17 mmol, 1.2 eq), tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl -1,2-dihydropyrrolo [3,2- b] pyridine -5-yl]oxy]-dimethyl-silane (700 mg, 1.81 mmol, 1 eq) in DCM (10 mL) was added DIEA (468 mg, 3.62 mmol, 631 uL, 2 eq) and HATU (1.03 g, 2.72 mmol, 1.5 eq) at 0°C, the mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material 25 with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (1.18 g, quantitative yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.63. LCMS (ES, m/z): 626.3 [M+H]+ 30 Step 3 of 6: Synthesis of Intermediate 71.3, tert-butyl N-[(1S,2R)-2-[6-[(1R,2S)-2- (tert- butoxycarbonylamino)-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyri -yl]-1-methyl-3-oxo-propoxy]hexa-2,4-diynoxy]-1-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3, yridine-1- 35 carbonyl]propyl]carbamate. 89 70226WO01 Four batches were carried out in parallel: To a solution of tert-butyl N-[(1S,2R)-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl) methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]-2-prop-2-ynoxy-propyl]carbamate (295 mg, 471 umol, 1 eq) in CH3CN (5 mL) was added Cu(OAc)2 (34.2 mg, 188 umol, 0.4 eq) and 5 pyridine (14.9 mg, 188 umol, 15.2 uL, 0.4 eq) at 25°C. The mixture was heated and stirred at 80°C for 12 h under aerobic conditions. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Four reactions were combined for work-up. The reaction mixture was added into saturated NH4Cl aq. (80 mL), then extracted with EtOAc (80 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced 10 pressure to give the title compound (980 mg, 83.1% yield) as a yellow solid. LCMS (ES, m/z): 1021.5 [M+H]+ Step 4 of 6: Synthesis of Intermediate 71.4, 1-[(2S,3R)-2-amino-3-[6-[(1R,2S) -2-amino-3- [6- [(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-15 methyl-3-oxo-propoxy]hexa-2,4-diynoxy]butanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl- 2,4-dihydropyrrolo[3,2-b]pyridin-5-one. To a solution of tert-butyl N-[(1S,2R)-2-[6-[(1R,2S)-2-(tert-butoxycarbonylamino) -3-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 1-methyl-3-oxo-propoxy]hexa-2,4-diynoxy]-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- 20 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]propyl]carbamate (980 mg, 784 umol, 1 eq) in EtOAc (5 mL) was added HCl/dioxane (4 M, 10 mL). The mixture was stirred at 20°C for 1 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the filter cake was dried to give a crude product. The crude product was purified by reversed-phase MPLC (column: C1820- 25 35um 100A 330g; mobile phase: [water-CH3CN], B%: 0%-80%, 80 mL/min) to give the title compound (600 mg, 2FA, 83.9% yield) as a brown solid. LCMS (ES, m/z): 821.4 [M+H]+ Step 5 of 6: Synthesis of Intermediate 71.5, tert-butyl N-[(1S)-2-[[(1S,2R)-2- [6-[(1R,2S)-2 -30 [[(2S)-2- (tert-butoxycarbonylamino)propanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-3-oxo-propoxy]hexa-2,4- diynoxy]-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- mate. To a solution of 1-[(2S,3R)-2-amino-3-[6-[(1R,2S)-2-amino-3-[6-[(4-fluorophenyl)methyl] -3,3-35 dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-3-oxo-propoxy]hexa-2,4- 190 70226WO01 diynoxy]butanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5- one (80 mg, 87.6 umol, 1 eq, 2 FA), and (2S)-2-(tert-butoxycarbonylamino) propanoic acid (41.4 mg, 219 umol, 2.5 eq) in DCM (4 mL) was added DIEA (68.0 mg, 526 umol, 91.6 uL, 6 eq) and HATU (100 mg, 263 umol, 3 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS 5 indicated complete consumption of starting material with formation of a single peak of target mass. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/MeOH/NH3.H2O = 20:2:1) to give the title compound (140 mg, quantitative yield) as a yellow solid. TLC (EtOAc/Methanol NH3.H2O = 20:2:1) Rf = 0.63. 10 LCMS (ES, m/z): 1191.7 [M+H]+ Step 6 of 6: Synthesis of Example 32, (2S,2'S)-N,N'-((2S,2'S,3R,3'R)-(hexa-2,4-diyne-1,6- diylbis(oxy))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- propanamide). 15 (1R,2S)-2-[[(2S)-2-(tert- butoxycarbonylamino) propanoy ino]-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-3-oxo-propoxy]hexa-2,4-diynoxy]-1-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridine-1- carbonyl]propyl]amino]-1-methyl-2-oxo-ethyl]carbamate (140 mg, 120 umol, 1 eq) in EtOAc (1.5 20 mL) was added HCl/dioxane (4 M, 3.00 mL). The mixture was stirred at 20°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the filter cake was dried to give a crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm, 3um; mobile phase: [water(0.2%FA)-CH3CN], B%: 5%-35%, 8 min) to give the title 25 compound (21.7 mg, 20.09 umol, 16.69% yield, 97.683% purity, 2FA) as an off-white solid. LCMS (ES, m/z): 482.4 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.57 - 8.50 (m, 1H), 8.25 - 8.16 (m, 2H), 7.30 - 7.18 (m, 4H), 7.03 - 6.90 (m, 4H), 4.77 - 4.50 (m, 6H), 4.17 - 3.97 (m, 10H), 3.83 - 3.69 (m, 6H), 1.46 - 1.35 (m, 18H), 1.25 - 1.17 (m, 6H). 30 The following final compounds were prepared according to the same procedure as Example 32: Example 33 and 34. The compounds were found to have characterizing data as set forth below. 191 70226WO01 Example 33, (2S,2'S)-N,N'-((2S,2'S,3R,3'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1- oxobutane-3,2-diyl))bis(2-aminobutanamide). O O O H HN F (S) N Boc N H OH (S2 ) F O HN H2N HN 2 , F 15 1H NMR (400 MHz METHANOL-d4) δ = 823 - 820 (m 1H) 823 - 820 (m 1H) 725 - 719 (m, F H 70226WO01 Step 1 of 2: Synthesis of Intermediate 74.1, di-tert-butyl ((2S,5S,6R,15R,16S,19S)- 5,16-bis(6- (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1- carbonyl)-6,15-dimethyl-3,18-dioxo-7,14-dioxa-4,17-diazaicosa-9,11-diyne-2,19- diyl)bis(methylcarbamate). 5 To a solution of 1,1'-((2S,2'S,3R,3'R)-3,3'-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2 -aminobutanoyl)) bis(6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5(4H)-one) (150 mg, 168 umol, 1 eq, 2 HCl) in DMF (2 mL) was added DIEA (130 mg, 1.01 mmol, 175 uL, 6 eq), HOBt (68.0 mg, 503 umol, 3 eq), (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (68.2 mg, 335 umol, 2 eq) and EDCI (96.5 mg, 503 umol, 3 eq) at 0°C. The mixture was stirred at 40°C 10 for 6 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was added into H2O (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC ( SiO2 DCM/Methanol/TEA = 20:2:1) to give impure product. The crude product was 15 purified by preparative HPLC (TFA condition: column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN]; B%:53%-83%,9 min) to give the title compound (60 mg, 50.36 umol, 30.01% yield) as a yellow oil. TLC (Dichloromethane/Methanol/TEA = 20:2:1) Rf = 0.50. LCMS (ES, m/z): 1191.7 [M+H]+ 20 Step 2 of 2: Synthesis of Example 35, (2S,2'S)-N,N'-((2S,2'S,3R,3'R)-(hexa-2,4-diyne-1,6- diylbis(oxy))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2-( ylamino)propanamide). To a solution of di-tert-butyl ((2S,5S,6R,15R,16S,19S)- 5,16-bis(6- (4-fluorobenzyl)-3,3- dimethyl-25 5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridine-1-carbonyl)-6,15-dimethyl-3,18-dioxo-7,14- dioxa-4,17-diazaicosa-9,11-diyne-2,19-diyl)bis(methylcarbamate) (60 mg, 50.4 umol, 1 eq) in EtOAc (2 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue 30 was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 12%-42%,9 min) to give the title compound (9 mg, 7.38 umol, 14.66% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 496.4 [M/2+H]+ 193 70226WO01 1H NMR (400 MHz, METHANOL-d4) δ = 8.18 (s, 2H), 7.23 (dd, J = 5.6, 8.4 Hz, 4H), 6.96 (br t, J = 8.7 Hz, 4H), 4.78 (br d, J = 3.5 Hz, 4H), 4.09 - 3.96 (m, 10H), 3.79 (s, 4H), 2.67 (s, 6H), 1.53 (d, J = 6.9 Hz, 6H), 1.45 (s, 6H), 1.39 (s, 6H), 1.23 (br d, J = 6.3 Hz, 6H). 5 Example 36, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(3,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)propanamide). HN N Pyr. HCl O (S) N Boc NH N H N Boc OH F F 2N (S) O O (S) O EDCI, HOB O O O O ) O T (S) (S 40oC 10 Step 1 of 8: Synthesis of Intermediate 75.1, methyl (2S)-2-(tert- butoxycarbonylamino) -3-(3- hydroxyphenyl)propanoate. To a solution of methyl (2S)-2-amino-3-(3-hydroxyphenyl)propanoate (10.5 g, 45.3 mmol, 1 eq, HCl), NaHCO3 (11.4 g, 136 mmol, 5.29 mL, 3 eq) in THF (200 mL)/H2O (40 mL) was added (Boc)2O (10.9 g, 49.8 mmol, 11.4 mL, 1.1 eq) at 0°C . The mixture was stirred at 20°C for 12 h. 15 LC-MS indicated complete conversion to a product of target mass. Water (80 mL) was added to the mixture, then extracted with EtOAc (60 mL * 3). The combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (13.11 g, 44.39 mmol, 97.95% yield) as a colorless oil. 20 TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.55. + (br , 70226WO01 Step 2 of 8: Synthesis of Intermediate 75.2, methyl (2S)-2-(tert-butoxycarbonylamino)- 3-(3- prop-2-ynoxyphenyl)propanoate. A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-hydroxyphenyl)propanoate (13.1 g, 5 44.4 mmol, 1 eq), 3-bromoprop-1-yne (6.33 g, 53.2 mmol, 4.59 mL, 1.2 eq), and K2CO3 (12.3 g, 88.71 mmol, 2 eq) in DMF (120 mL) was stirred at 20°C for 12 h . LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was added into NH4Cl aq. (120 mL), and extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and 10 concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (12.82 g, 38.45 mmol, 86.69% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.60. LCMS (ES, m/z): 234.2 [M+H]+ 15 Step 3 of 8: Synthesis of Intermediate 75.3, (2S)-2-(tert-butoxycarbonylamino) -3-(3-prop-2 - ynoxyphenyl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-prop-2-ynoxyphenyl)propanoate (12.8 g, 38.4 mmol, 1 eq) in THF (180 mL), MeOH (60 mL), and H2O (60 mL) was added LiOH 20 (2.76 g, 115 mmol, 3 eq) at 20°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (100 mL), then extracted with EtOAc (80 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (80 * 4 mL) and 25 the combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (12.1 g, 38.0 mmol, 98.9% yield) as a yellow oil. LCMS (ES, m/z): 318.0 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 7.26 - 7.21 (m, 1H), 6.92 - 6.81 (m, 3H), 4.96 (br d, J 30 = 7.6 Hz, 1H), 4.72 - 4.57 (m, 3H), 3.26 - 3.00 (m, 2H), 2.54 (t, J = 2.2 Hz, 1H), 1.43 (s, 9H) Step 4 of 8: Synthesis of Intermediate 75.4, tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl) silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-p lo[3,2-b]pyridin-1-yl]-2-oxo-1-[(3- prop-2-ynoxyphenyl)methyl]ethyl]carbamate. 195 70226WO01 To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(3-prop-2-ynoxyphenyl)propanoic acid (991 mg, 3.10 mmol, 1.2 eq), tert-butyl-[[6-[(4-fluorophenyl) methyl]-3,3-dimethyl-1,2-dihydropyrrolo [3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (1 g, 2.59 mmol, 1 eq), DIEA (668 mg, 5.17 mmol, 901 uL, 2 eq) in DCM (20 mL) was added T3P (2.47 g, 3.88 mmol, 2.31 mL, 50% purity, 1.5 eq) at 5 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH4Cl aq. (40 mL), then extracted with DCM (30 mL * 3). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc 10 = 1:0 to 2:1) to give the title compound (570 mg, 828.59 umol, 64.06% yield) and the title compound-TBS (539 mg, 939.59 umol, 72.64% yield) as yellow solid. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.60. LCMS (ES, m/z): 688.5 [M+H]+ 15 Step 5 of 8: Synthesis of Intermediate 75.5, di-tert-butyl ((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(3,1-phenylene))bis(3-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))dicarbamate. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(3-prop-2- 20 ynoxyphenyl)methyl]ethyl]carbamate (570 mg, 828 umol, 1 eq) in CH3CN (12 mL) was added Cu(OAc)2 (181 mg, 994 umol, 1.2 eq) and pyridine (393 mg, 4.97 mmol, 401 uL, 6 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the filtrate was added into NH3.H2O (20 mL), then extracted with EtOAc 25 (30 mL * 3), then dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (569 mg, 414 umol, 99.97% yield) as a yellow oil. LCMS (ES, m/z): 1259.7 [M-TBS+H]+ Step 6 of 8: Synthesis of Intermediate 75.6, 1,1'-((2S,2'S)-3,3'-((hexa-2,4-diyne-1,6-30 diylbis(oxy))bis(3,1-phenylene))bis(2-aminopro )bis(6-(4-fluorobenzyl)-3,3-dimethyl- To a solution of tert-butyl N-[(1S)-1-[[3-[6-[3-[(2S)-2-(tert-butoxycarbonylamino)-3 -[5-[tert-butyl (dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3- oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- 35 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamate (569 196 70226WO01 mg, 414.18 umol), in EtOAc (10 mL) was added HCl/dioxane (4 M, 15.0 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (843 mg, 828 umol, 99.9% yield, 2 HCl) as a yellow solid. 5 LCMS (ES, m/z): 473.6 [M/2+H]+ Step 7 of 8: Synthesis of Intermediate 75.7, tert-butyl N-[(1S)-2-[[(1S)-1-[[3-[6-[3-[(2S)-2- [[(2S)-2-[tert-butoxycarbonyl (methyl)amino]propanoyl]amino]-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-10 propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[6-[(4-fluorophenyl)methyl]-3,3- dimeth dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]amino]-1-methyl-2-oxo- ethyl]-N-methyl-carbamate. To a 1-[(2S)-2-amino-3-[3-[6-[3-[(2S)-2-amino-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo -2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-15 diynoxy]phenyl]propanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2- b]pyridin-5-one (120 mg, 118 umol, 1 eq, 2 HCl) in DMF (4 mL) was added DIEA (91.4 mg, 707 umol, 123 uL, 6 eq), HOBt (47.8 mg, 354 umol, 3 eq), (2S)-2-[tert- butoxycarbonyl(methyl)amino]propanoic acid (47.9 mg, 236 umol, 2 eq) and EDCI (67.8 mg, 354 umol, 3 eq) at 0°C. The mixture was stirred at 40°C for 12 h. LC-MS indicated complete 20 consumption of starting material with formation of a single peak of target mass. Water (20 mL) was added to the mixture, then extracted with EtOAc (20 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (93 mg, 70.70 umol, 59.97% yield) as a yellow oil. 25 TLC (EtOAc/Methanol = 10:1) Rf = 0.50. LCMS (ES, m/z): 1316.7 [M+H]+ Step 8 of 8: Synthesis of Example 36, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(3,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-30 tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)propan de). To a solution of tert-but yl N-[(1S)-2-[[(1S)-1-[[3-[6-[3-[(2S)-2-[[(2S)-2-[tert-butoxycarbonyl (methyl)amino]propanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[6-35 [(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo- 197 70226WO01 ethyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (93 mg, 70.7 umol, 1 eq) in EtOAc (3 mL) was added HCl/dioxane (4 M, 4 mL) dropwise at 20°C. The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a crude product. The 5 crude product was purified by preparative HPLC (column: Phenomenex Luna C18100*40mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 18%-45%, 8 min) to give the title compound (40.5 mg, 29.56 umol, 41.81% yield, 98.039% purity, 2 TFA) as an off-white solid. LCMS (ES, m/z): 558.4 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 8.21 (s, 2H), 7.32 - 7.15 (m, 6H), 7.07 - 6.79 (m, 10H), 10 4.82 - 4.56 (m, 6H), 3.96 (d, J = 10.4 Hz, 2H), 3.89 - 3.75 (m, 6H), 3.12 (d, J = 10.4 Hz, 2H), 3.04 (br d, J = 7.8 Hz, 4H), 2.59 (s, 6H), 1.50 (d, J = 7.0 Hz, 6H), 1.34 - 1.23 (m, 6H), 1.01 (s, 6H) The following final compound was prepared according to the same procedure as Example 36: Example 37. The compound was found to have characterizing data as set forth below. 15 Example 37, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(3,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). O O HN O H HN HCl (S) Boc N OH N (S) H2N N NH N F F O F 20 1H NMR (400MHz, METHANOL-d4) δ = 8.21 (s, 2H), 7.33 - 7.16 (m, 6H), 7.06 - 6.78 (m, 10H), 4.81 (br t, J = 8.0 Hz, 2H), 4.74 - 4.58 (m, 4H), 3.98 (d, J = 10.3 Hz, 2H), 3.86 - 3.69 (m, 6H), 3.14 (d, J = 10.3 Hz, 2H), 3.05 (br d, J = 7.9 Hz, 4H), 2.57 (s, 6H), 2.02 - 1.74 (m, 4H), 1.29 (s, 6H), 1.06 - 0.91 (m, 12H). 25 Example 38, (2S,2'S)-N,N'-((1S,1'S)-(decanedioylbis(piperidine-1,4-diyl))bis(2-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2- oxoethane-1,1-diyl))bis(2-(methy )butanamide). 198 70226WO01 HN N OTBS Fmoc O Fmoc F Fmoc HN F HN OH HN O O Fmoc HO 2.11 O O O N HN F Step 1 of 6: Synthesis of Intermediate 77.1, (S)-tert-butyl 4-(1-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-2-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- 5 dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)piperidine-1-carboxylate. To a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(1-(tert- butoxycarbonyl)piperidin-4-yl)acetic acid (2.5 g, 5.20 mmol, 1 eq) and tert-butyl-[[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (2.61 g, 6.76 mmol, 1.3 eq) in DCM (50 mL) was added HATU (2.97 g, 7.80 mmol, 1.5 eq) and10 DIEA (2.02 g, 15.61 mmol, 2.72 mL, 3 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC- MS indicated complete consumption of starting material with formation of a single peak of target CM and s 7.4 .4 z, 70226WO01 Step 2 of 6: Synthesis of Intermediate 77.2, (S)-(9H-fluoren-9-yl)methyl (2-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxo-1- (piperidin-4-yl)ethyl)carbamate. 5 To a solution of (S)-tert-butyl 4-(1-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1- yl)-2-oxoethyl)piperidine-1-carboxylate (4.4 g, 5.18 mmol, 1 eq) in EtOAc (15 mL) was added HCl/EtOAc (4 M, 30 mL, 23.16 eq) at 0°C. The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak 10 of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase MPLC (column: 330g Agela C18; mobile phase: [water- MeOH-HCl]; B%: 30-60% 25min; 60% 20 min, 70 mL/min) to give the title compound (3.4 g, 5.07 mmol, 97.8% yield, HCl) as a yellow oil. LCMS (ES, m/z): 635.3 [M+H+]. 15 1H NMR (400MHz, DMSO-d6) δ = 8.93 (br d, J=9.3 Hz, 1H), 8.52 (br d, J=9.6 Hz, 1H), 8.05 (s, 1H), 7.88 (br d, J=7.4 Hz, 2H), 7.70 (br dd, J=3.9, 7.1 Hz, 2H), 7.39 (dt, J=4.1, 7.3 Hz, 2H), 7.32 - 7.21 (m, 4H), 7.10 (br t, J=8.8 Hz, 2H), 4.30 (br d, J=7.0 Hz, 2H), 4.23 - 4.13 (m, 2H), 4.02 - 3.94 (m, 1H), 3.89 (br d, J=10.5 Hz, 1H), 3.80 - 3.68 (m, 3H), 3.34 - 3.13 (m, 1H), 2.92 - 2.64 (m, 3H), 2.02 (br d, J=8.8 Hz, 1H), 1.86 (br d, J=12.6 Hz, 1H), 1.67 (br d, J=12.3 Hz, 1H), 1.52 - 1.36 (m, 20 2H), 1.29 - 1.22 (m, 5H), 1.12 (br d, J=18.0 Hz, 1H) Step 3 of 6: Synthesis of Intermediate 77.3, bis((9H-fluoren-9-yl)methyl) ((1S,1'S)-(1,1'- decanedioylbis(piperidine-4,1-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1-diyl))dicarbamate. 25 Two batches were carried out in parallel: To a solution of decanedioic acid (34 mg, 168 umol, 1 eq) in DMF (3 mL) was added DIEA (109 mg, 841 umol, 146 uL, 5 eq) and HATU (128 mg, 336 umol, 2 eq) at 0°C. The mixture was stirred 2 h, then (S)-(9H-fluoren-9-yl)methyl (2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamatehydrochloride 30 (248 mg, 370 umol, 2.2 eq, HCl) was added to the mixture. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Two reactions were combined for work up. H2O (15 mL * 2) was added to the mixture, and the mixture was extracted with DCM (20 mL * 3). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the 35 title compound (600 mg, quantitative yield) as a white solid. 200 70226WO01 LCMS (ES, m/z): 1435.6 [M+H+]. Step 4 of 6: Synthesis of Intermediate 77.4, 1,10-bis(4-((S)-1-amino-2-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethyl)piperidin-1- 5 yl)decane-1,10-dione. To a solution of bis((9H-fluoren-9-yl)methyl) ((1S,1'S)-(1,1'-decanedioylbis(piperidine-4,1- diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1- yl)-2-oxoethane-1,1-diyl))dicarbamate (600 mg, 417.92 umol, 1 eq) in DMF (2 mL) was added piperidine (106.75 mg, 1.25 mmol, 123.82 uL, 3 eq). The mixture was stirred at 15°C for 2 h after 10 which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was concentrated to give a crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30mm, 5um; mobile phase: [water(0.1%TFA)-MeOH]; B%: 45%-75%,10 min ) to give the title compound (190 mg, 156 umol, 37.3% yield, 2 TFA) was obtained as a white solid. 15 1H NMR (400MHz, DMSO-d6) δ = 8.17 (br s, 2H), 7.98 (d, J=2.4 Hz, 2H), 7.27 - 7.23 (m, 4H), 7.12 (t, J=8.9 Hz, 4H), 4.44 (br s, 4H), 4.10 (br s, 2H), 3.97 - 3.88 (m, 6H), 3.81 - 3.70 (m, 4H), 2.92 (br d, J=11.5 Hz, 2H), 2.69 - 2.63 (m, 1H), 2.34 - 2.31 (m, 1H), 2.28 - 2.21 (m, 4H), 2.05 (br s, 2H), 1.68 - 1.55 (m, 4H), 1.45 (br s, 4H), 1.31 (d, J=12.0 Hz, 12H), 1.23 (br s, 12H) LCMS (ES, m/z): 991.7 [M+H+]. 20 Step 5 of 6, Synthesis of Intermediate 77.5, di-tert-butyl ((2S,2'S)-(((1S,1'S)-(1,1'- decanedioylbis(piperidine-4,1-diyl))bis(2-(6-(4-fluorobenzyl)-33-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxo , y iyl))bis(1- oxobutane-2,1-diyl))bis(methylcarbamate). 25 To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (33.68 mg, 155.01 umol, 2.1 eq), DIEA (47.70 mg, 369.08 umol, 64.29 uL, 5 eq) in DMF (3 mL) was added HATU (56.13 mg, 147.63 umol, 2 eq) at 0°C. The mixture was stirred 2 h. 1,10-bis(4-((S)-1-amino-2-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2- oxoethyl)piperidin-1-yl)decane-1,10-dione (90 mg, 73.8 umol, 1 eq, 2 TFA) was added to the 30 mixture. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (15 mL) was added to the mixture and the mixture was extracted with EtOAc (10 mL * 3). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (100 mg, quantitative yield) as a yellow oil. 35 LCMS (ES, m/z): 1389.9 [M+H+]. 201 70226WO01 Step 6 of 6, Synthesis of Example 38, (2S,2'S)-N,N'-((1S,1'S)-(decanedioylbis(piperidine-1,4- diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-2-oxoethane-1,1-diyl))bis(2-( butanamide). 5 To a solution of di-tert-butyl ((2S,2'S)-(((1S,1'S)-(1,1'-decanedioylbis(piperidine-4,1-diyl))bis(2-(6- (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2- oxoethane-1,1-diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate) (100 mg, 71.96 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 3.00 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with 10 formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*40mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 15%-47%, 8 min) to give the title compound (61.2 mg, 43.2 umol, 60.0% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 595.5 [M/2+H+]. 15 1H NMR (400MHz, METHANOL-d4) δ = 8.18 (s, 2H), 7.25 (dd, J=5.5, 8.5 Hz, 4H), 6.98 (t, J=8.8 Hz, 4H), 4.64 - 4.50 (m, 4H), 4.31 - 4.23 (m, 2H), 4.06 - 3.95 (m, 4H), 3.82 - 3.76 (m, 6H), 3.06 (br t, J=12.0 Hz, 2H), 2.66 (s, 6H), 2.58 (br t, J=12.1 Hz, 2H), 2.43 - 2.31 (m, 4H), 2.11 (br d, J=11.4 Hz, 2H), 1.96 - 1.82 (m, 6H), 1.69 (br t, J=13.4 Hz, 2H), 1.57 (br s, 4H), 1.43 - 1.29 (m, 24H), 1.28 - 1.16 (m, 2H), 0.92 (t, J=7.4 Hz, 6H) 20 Example 39, (2S,2'S)-N,N'-((1S,1'S)-(([1,1'-biphenyl]-4,4'-dicarbonyl)bis(piperidine-1,4- diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-2-oxoethane-1,1-diyl))bis(2-(methylamino)butanamide). O O O Fmo O c O O c Fmo H F HN HN N H N N HO O HN 2 HN O 787-70-2 115 O F i ri in O F 25 Step 1 of 4: Synthesis of Intermediate 78.1, 9H-fluoren-9-ylmethyl N-[(1S)-1-[1-[4-[4-[4-[(1S)- 1-(9H-fluoren-9-ylmethoxycarbonylamino)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo- 202 70226WO01 2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]piperidine-1-carbonyl]phenyl]benzoyl]-4- piperidyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridin-1-yl]-2-oxo-ethyl]carbamate. Two batches were carried out in parallel: 5 To a solutio 4-(4-carboxyphenyl)benzoic acid (41.01 mg, 169.30 umol, 1 eq) in DMF (3 mL) was added DIEA (87.5 mg, 677 umol, 118 uL, 4 eq) and HATU (129 mg, 339 umol, 2 eq) at 0°C. The mixture was stirred 2 h, then (S)-(9H-fluoren-9-yl)methyl (2-(6-(4-fluorobenzyl)-3,3-dimethyl- 5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (250 mg, 372 umol, 2.2 eq, HCl) was added to the mixture. The mixture was stirred 10 at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (20 mL * 2) and saturated NH4Cl aq. (30 mL) was added to the mixture, and the mixture was extracted with EtOAc (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (400 mg, 271 umol, 80.1% yield) as a yellow oil. 15 LCMS (ES, m/z): 1475.8 [M+H+]. Step 2 of 4: Synthesis of Intermediate 78.2, 1-[(2S)-2-amino-2-[1-[4-[4-[4-[(1S)-1-amino-2-[6- [(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo- ethyl]piperidine-1-carbonyl]phenyl]benzoyl] iperidyl]acetyl]-6-[(4-fluorophenyl)methyl]- 20 3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one. To a solution of 9H-fluoren-9-ylmethyl N-[(1S)-1-[1-[4 ylmethoxycarbonylamino)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]piperidine-1-carbonyl]phenyl]benzoyl]-4- piperidyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1- 25 yl]-2-oxo-ethyl]carbamate (400 mg, 271 umol, 1 eq) in DMF (2 mL) was added piperidine (69.2 mg, 813 umol, 80.3 uL, 3 eq) . The mixture was stirred at 15°C for 2 h. LC-MS indicated complete conversion to a product of target mass. The mixture was filtered and the filtrate was concentrated to give a crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 15%- 30 45%, 8 min) to give the title compound (96 mg, 76.2 umol, 28.1% yield, 2 TFA) as a white solid. LCMS (ES, m/z): 516.5 [M/2+H+]. 1H NMR (400MHz, DMSO-d6) δ = 8.22 (br s, 4H), 7.99 (s, 2H), 7.78 (br d, J=8.1 Hz, 4H), 7.51 - 7.43 (m, 4H), 7.25 (dd, J=5.7, 8.4 Hz, 3H), 7.14 - 7.09 (m, 3H), 4.55 (br s, 2H), 4.14 (br s, 2H), 4.01 - 3.91 (m, 4H), 3.81 - 3.60 (m, 12H), 3.07 (br s, 2H), 2.82 - 2.68 (m, 2H), 2.15 (br s, 2H), 1.79 35 - 1.53 (m, 4H), 1.51 - 1.41 (m, 2H), 1.38 - 1.27 (m, 12H) 203 70226WO01 Step 3 of 4: Synthesis of Intermediate 78.3, tert-butyl N-[(1S)-1-[[(1S)-1-[1-[4-[4-[4-[(1S)-1- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-2-[6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]piperidine-1- 5 carbonyl]phenyl]benzoyl]-4-piperidyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate. To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]bu cid (26.92 mg, 123.88 umol, 2 eq) in DMF (3 mL) was added HATU (47.1 mg, 124 umol, 2 eq) and DIEA (40.0 mg, 310 umol, 54.0 uL, 5 eq) at 0°C. The mixture was stirred 2 h and 1-[(2S)-2-amino-2-[1-[4-[4-[4-[(1S)-1-10 amino-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]- 2-oxo-ethyl]piperidine-1-carbonyl]phenyl]benzoyl]-4-piperidyl]acetyl]-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one (78 mg, 61.9 umol, 1 eq, 2 TFA) was added to the mixture. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. H2O (20 15 mL) was added to the mixture, and the mixture was extracted with EtOAc (10 mL * 2) and DCM (10 mL* 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (100 mg, quantitative yield) as a yellow oil. LCMS (ES, m/z): 1430.8 [M+H+]. 20 Step 4 of 4: Synthesis of Example 39, (2S,2'S)-N,N'-((1S,1'S)-(([1,1'-biphenyl]-4,4'- dicarbonyl)bis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1-diyl))bis(2- (methylamino)butanamide). 25 To a solution of tert-bu y N-[(1S)-1-[[(1S)-1-[1-[4-[4-[4-[(1S)-1-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]piperidine-1-carbonyl]phenyl]benzoyl]-4- piperidyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1- yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (80 mg, 55.96 umol, 1 eq) in DCM (2 mL) 30 was added TFA (0.6 mL). The mixture was stirred at 15°C for 2 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 30%-70%, 8 min) to give the title compound (18.5 mg, 12.4 35 umol, 22.2% yield, 97.696% purity, 2 TFA) as a yellow solid. 204 70226WO01 LCMS (ES, m/z): 615.4 [M/2+H+]. 1H NMR (400MHz, METHANOL-d4) δ = 8.20 (br s, 2H), 7.73 (br s, 4H), 7.50 (br d, J=7.9 Hz, 4H), 7.24 (br s, 4H), 6.97 (br t, J=8.1 Hz, 4H), 4.68 (br s, 2H), 4.55 (br d, J=8.4 Hz, 2H), 4.43 (br s, 2H), 4.19 (br d, J=10.6 Hz, 2H), 4.01 (br s, 2H), 3.79 (br s, 6H), 3.12 (br s, 2H), 2.85 (br d, J=8.4 5 Hz, 6H), 2.17 (br d, J=8.5 Hz, 2H), 1.89 - 1.83 (m, 2H), 1.74 (br d, J=8.9 Hz, 4H), 1.47 (br s, 6H), 1.39 (br d, J=11.0 Hz, 18H), 0.89 (br s, 6H). Example 40, (2S,2'S)-N,N'-((1S,1'S)-(((perfluoro-1,4-phenylene)bis(methylene))bis(piperidine- 1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- 10 b]pyridin-1-yl)-2-oxoethane-1,1-diyl))bis(2-(methylamino)butanamide). F F O O F Fmoc Br Fmoc HN F Br HN HN H2N HN F N F N F F Step 1 of 4: Synthesis of Intermediate 79.1, bis((9H-fluoren-9-yl)methyl) ((1S,1'S)- (((perfluoro-1,4-phenylene)bis(methylene))bis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-15 33-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1- d y amate. Two batches were carried out in parallel: (S)-(9H-fluoren-9-yl)methyl (2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate (200 mg, 298 umol, 2.1 eq, 20 HCl), 1,4-bis(bromomethyl)-2,3,5,6-tetrafluoro-benzene (47.7 mg, 142 umol, 1 eq), and DIEA (73.4 mg, 568 umol, 98.9 uL, 4 eq) were combined in DMF (3 mL). The mixture was stirred at 30°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The two reactions were combined for work up. H2O (20 mL) was added to the mixture and the mixture was extracted with DCM (10 mL * 3). The combined organic 25 phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (400 mg, quantitative yield) as a yellow oil. LCMS (ES, m/z): 1443.6 [M+H+]. 205 70226WO01 Step 2 of 4: Synthesis of Intermediate 79.2, 1,1'-((2S,2'S)-2,2'-(((perfluoro-1,4- phenylene)bis(methylene))bis(piperidine-1,4-diyl))bis(2-aminoacetyl))bis(6-(4-fluorobenzyl)- 3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrol in-5-one). To a solution of bis((9H-fluoren-9-yl)methyl) ((1S,1'S)-(((perfluoro-1,4- 5 phenylene)bis(methylene))bis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1-diyl))dicarbamate (400 mg, 277.09 umol, 1 eq) in DMF (2 mL) was added piperidine (70.8 mg, 831 umol, 82.1 uL, 3 eq). The mixture was stirred at 15°C for 2h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was 10 concentrated to give a crude product. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-CH3CN], B%: 30%-55%, 8 min) to give the title compound (55 mg, 55.1 umol, 19.9% yield) as a white solid. LCMS (ES, m/z): 500.5 [M/2+H+]. 15 Step 3 of 4: Synthesis o f Intermediate 79.3, di-tert-butyl ((2S,2'S)-(((1S,1'S)-(((perfluoro-1,4- phenylene)bis(methylene))bis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1- diyl))bis(azanediyl))bis(1-oxobutane-1,2-diyl))bis(methylca 20 To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (22.83 mg, 105.10 umol, 2.1 eq), DIEA (25.87 mg, 200.18 umo , 4.87 uL, 4 eq) in DMF (3 mL) was added HATU (38.06 mg, 100.09 umol, 2 eq) at 0°C. The mixture was stirred 2 h and the 1,1'-((2S,2'S)-2,2'-(((perfluoro- 1,4-phenylene)bis(methylene))bis(piperidine-1,4-diyl))bis(2-aminoacetyl))bis(6-(4-fluorobenzyl)- 3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one) (50 mg, 50.1 umol, 1 eq) was 25 added to the mixture. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (15 mL) was added to the mixture, and the mixture was extracted with EtOAc (10 mL * 3). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (80 mg, crude) as a yellow oil. 30 LCMS (ES, m/z): 1397.9 [M+H+]. Step 4 of 4: Synthesis of Example 40, (2S,2'S)-N,N'-((1S,1'S)-(((perfluoro-1,4- phenylene)bis(methylene))bis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1-diyl))bis(2- 35 (methylamino)butanamide). 206 70226WO01 To a solution of di-tert-butyl ((2S,2'S)-(((1S,1'S)-(((perfluoro-1,4- phenylene)bis(methylene))bis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1-diyl))bis(azanediyl))bis(1- oxobutane-1,2-diyl))bis(methylcarbamate) (80 mg, 57.24 umol, 1 eq) in EtOAc (2 mL) was added 5 HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [water(0.05%NH3H2O+10mM NH4HCO3)-CH3CN], B%: 10%-60%, 8 min) to give the title 10 compound (22.1 mg, 18.5 umol, 32.2% yield, 100% purity) as a white solid. LCMS (ES, m/z): 599.4 [M/2+H+]. 1H NMR (400MHz, METHANOL-d4) δ = 8.18 (s, 2H), 7.29 - 7.20 (m, 4H), 6.97 (br t, J=8.8 Hz, 4H), 4.49 (br d, J=8.9 Hz, 2H), 4.27 (br d, J=10.5 Hz, 2H), 3.97 (br d, J=10.5 Hz, 2H), 3.83 - 3.69 (m, 8H), 3.01 - 2.90 (m, 6H), 2.35 - 2.24 (m, 6H), 2.17 - 2.04 (m, 4H), 1.89 - 1.72 (m, 4H), 1.66 - 15 1.54 (m, 6H), 1.47 - 1.40 (m, 4H), 1.37 (br d, J=4.5 Hz, 12H), 0.86 (t, J=7.4 Hz, 6H) Example 41, (2S,2'S)-N,N'-((1S,1'S)-(hexa-2,4-diyne-1,6-diylbis(piperidine-1,4-diyl))bis(2-(6- (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2- oxoethane-1,1-diyl))bis(2-(methylamino)butanamide). Boc Fmoc H2N O N F HN N N F Boc OH O Br O HN O Pyr. 20 Step 1 of 4: Synthesis of Intermediate 80.1, (S)-1-(2-amino-2-(1-(prop-2-yn-1-yl)piperidin-4- yl)acetyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5(4H)-one. Two batches were carried out in parallel: 25 To a solution of (S)-(9H-fluoren-9-yl)methyl (2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxo-1-(piperidin-4-yl)ethyl)carbamate hydrochloride (199 mg, 296 umol, 1.1 eq, HCl) and DIEA (139 mg, 1.08 mmol, 187 uL, 4 eq) in DMF (2 mL) 207 70226WO01 was added 3-bromoprop-1-yne (40 mg, 269 umol, 29.0 uL, 80% purity, 1 eq) in DMF (1 mL). The mixture was stirred at 30°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Two reactions were combined for work-up. Water (20 mL) was added to the mixture, and the mixture was extracted with EtOAc (15 mL * 3). The 5 combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (160 mg, 355 umol, 66.0% yield) as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.74 10 LCMS (ES, m/z): 451.3 [M+H+]. 1H NMR (400MHz, C RM-d) δ = 8.43 (s, 1H), 7.27 (s, 2H), 6.92 (br t, J=8.6 Hz, 2H), 3.93 - 3.87 (m, 1H), 3.8 - . (m, 2H), 3.32 (br s, 2H), 3.11 (q, J=7.4 Hz, 1H), 3.03 - 2.89 (m, 2H), 2.27 - 2.20 (m, 2H), 2.05 - 1.94 (m, 1H), 1.67 (br d, J=10.8 Hz, 2H), 1.62 - 1.44 (m, 4H), 1.44 - 1.40 (m, 6H) 15 Step 2 of 4: Synthesis of Intermediate 80.2, tert-butyl ((S)-1-(((S)-2-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxo-1-(1-(prop-2-yn-1- yl)piperidin-4-yl)ethyl)amino)-1-oxobutan-2-yl)(methyl)carbamate on of (S)-1-(2-amino-2-(1-(prop-2-yn-1-yl)piperidin-4-yl)acetyl)-6-( robenzyl)-3,3- 20 dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5(4H)-one (141.43 mg, 313.91 umol, 1.1 eq) and (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (62 mg, 285.37 umol, 1 eq) in DCM (3 mL) was added DIEA (111 mg, 856 umol, 149 uL, 3 eq) and HATU (163 mg, 428 umol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to 25 the mixture and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (100 mg, 154 umol, 53.9% yield) as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.42 30 LCMS (ES, m/z): 650.3 [M+H+]. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.33 (br s, 1H), 7.27 - 7.23 (m, 2H), 6.93 (t, J=8.7 Hz, 2H), 4.57 (br t, J=8.4 Hz, 1H), 4.44 (br s, 1H), 4.14 (d, J=10.4 Hz, 1H), 3.85 (br d, J=10.1 Hz, 1H), 3.80 (s, 2H), 3.42 (br s, 2H), 3.18 (br d, J=7.5 Hz, 1H), 3.07 - 2.95 (m, 2H), 2.79 (s, 3H), 2.34 (br s, 2H), 2.07 - 1.53 (m, 8H), 1.49 (s, 8H), 1.44 - 1.39 (m, 6H), 0.88 (t, J=7.4 Hz, 3H) 35 208 70226WO01 Step 3 of 4: Synthesis of Intermediate 80.3, di-tert-butyl ((2S,2'S)-(((1S,1'S)-(1,1'-(hexa-2,4- diyne-1,6-diyl)bis(piperidine-4,1-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1-diyl))bis(azanediyl))bis(1- oxobutane-2,1-diyl))bis(methylcarbamate). 5 To a solution of tert-butyl ((S)-1-(((S)-2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxo-1-(1-(prop-2-yn-1-yl)piperidin-4-yl)ethyl)amino)- 1-oxobutan-2-yl)(methyl)carbamate (90 mg, 139 umol, 1 eq) in CH3CN (3 mL) was added pyridine (65.7 mg, 831 umol, 67.1 uL, 6 eq) and Cu(OAc)2 (30.2 mg, 166 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting 10 material with formation of a single peak of target mass. NH3.H2O (10 mL) was added to the mixture, and the mixture was extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (55 mg, 42.3 umol, 61.2% yield) as a yellow 15 oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.28 LCMS (ES, m/z): 1297.9 [M+H+]. Step 4 of 4: Synthesis of Example 41, (2S,2'S)-N,N'-((1S,1'S)-(hexa-2,4-diyne-1,6-20 diylbis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro- To a solution of di-tert-butyl ((2S2'S)-(((1S1'S)-(1,1'-(hexa-2,4-diyne-1,6-diyl)bis(piperidine-4,1- diy , oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1- yl)-2-oxoethane-1,1-diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate) (55 mg, 25 42.39 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was blown to dryness by N2 stream to give a residue and the mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100*40mm, 5um; mobile 30 phase: [water(0.1%TFA)-CH3CN], B%: 1%-35%, 8 min) to give the title compound (26.2 mg, 19.77 umol, 46.64% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 549.4 [M/2+H+]. 1H NMR (400MHz, METHANOL-d4) δ = 8.17 (s, 2H), 7.28 - 7.20 (m, 4H), 7.02 - 6.94 (m, 4H), 4.64 (d, J=8.1 Hz, 2H), 4.28 - 4.19 (m, 6H), 4.00 (d, J=10.5 Hz, 2H), 3.85 - 3.76 (m, 6H), 3.65 (br 209 70226WO01 t, J=12.4 Hz, 4H), 3.14 - 3.01 (m, 4H), 2.66 (s, 6H), 2.23 - 2.09 (m, 4H), 1.98 - 1.84 (m, 6H), 1.75 (quin, J=12.2 Hz, 4H), 1.39 (d, J=14.4 Hz, 12H), 0.92 (t, J=7.6 Hz, 6H). Example 42, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(naphthalene-4,1- 5 diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- mino)butanamide). OBn Br 25.1 I ZnI Pd2(dba)3, SPhos OBn OH O Zn, Br(CH2)2Br, TMSCl DMF, 15-80°C, 12h Pd/C, H Br 2 B M B M F Step 1 of 10: Synthesis of Intermediate 81.1, (R)-(2-((tert-butoxycarbonyl)amino) -3- 10 methoxy-3-oxopropyl)zinc(II) iodide. Zinc powder (10.5 g, 161 mmol, 3.53 eq) was added to a rapidly stirring solution of 2% aqueous HCl (108 mL) and stirred for 3 minutes. The aqueous solution was decanted and the zinc was washed in rapid succession with EtOH (70 mL), acetone (2 * 35 mL), and MTBE (120 mL). The zinc was rapidly filtered, transferred to a 250 mL round bottomed flask and dried at 80°C under 15 vacuum for 2 h. The flask containing the zinc dust was backfilled with N2 and DMF (80 mL) was added followed by 1,2-dibromoethane (1.71 g, 9.11 mmol, 688 uL, 0.2 eq). The suspension was heated at 80°C for 30 minutes. After cooling to 15°C, chloro(trimethyl)silane (495 mg, 4.56 mmol, 578 uL, 0.1 eq) was added and the suspension was stirred an additional 30 minutes at 15°C. To this suspension was slowly added methyl (2R)-2-(tert-butoxycarbonylamino)-3-iodo-propanoate (15 g, 20 45.6 mmol, 1 eq) in DMF (20 mL) which resulted in an exotherm. After returning to 15°C, stirring was discontinued. TLC (Petroleum ether/EtOAc = 5:1) indicated complete consumption of starting material and formation of one new spot. The resulting (R)-(2-((tert-butoxycarbonyl)amino) -3- 210 70226WO01 methoxy-3-oxopropyl)zinc(II) iodide (18.0 g, quantitative yield) was obtained as a bright white solution and was used directly into the next step. Step 2 of 10, Synthesis of Intermediate 81.2, (S)-methyl 3-(4-(benzyloxy)naphthalen-1-yl)-2- 5 ((tert-butoxycarbonyl)amino)propanoate. To a solution of 1-benzyloxy-4-bromo-naphthalene (6 g, 19.2 mmol, 1 eq) and SPhos (393 mg, 958 , . ed Pd2(dba)3 (439 mg, 479 umol, 0.025 eq) and [(2R)-2- (tert-butoxycarbonylamino)-3- methoxy-3-oxo-propyl]-iodo-zinc (9.07 g, 23.0 mmol, 1.2 eq) was added to the mixture at 15°C under N2. The mixture was stirred at 80°C for 12 h. LC-MS 10 indicated complete conversion to a product of target mass. The reaction mixture was added into saturated NH4Cl aq. (100 mL) and extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 2:1) to give the title compound (7.2 g, 16.5 mmol, 86.3% yield) as 15 a white solid. TLC (Petroleum ether/EtOAc = 3:1) LCMS (ES, m/z): 336.1 [M-Boc+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.42 (br d, J = 8.1 Hz, 1H), 8.02 (br d, J = 8.4 Hz, 1H), 7.59 - 7.37 (m, 7H), 7.17 (br d, J = 7.8 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 5.25 (s, 2H), 5.12 - 20 4.95 (m, 1H), 4.82 - 4.59 (m, 1H), 3.71 - 3.60 (m, 3H), 3.58 - 3.34 (m, 2H), 1.60 - 1.31 (m, 9H) Step 3 of 10: Synthesis of Intermediate 81.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4- hydroxynaphthalen-1-yl)propanoate. To a solution of methyl (2S)-3-(4-benzyloxy-1-naphthyl)-2-(tert-butoxycarbonylamino) propanoate 25 (7.2 g, 16.5 mmol, 1 eq) in MeOH (200 mL) was added Pd/C (700 mg, 10% purity) under N2 atmosphere at 15°C. The mixture was stirred at 15°C for 12 h under H2 (15 psi) atmosphere. LC- MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was concentrated to give the title compound (5.7 g, 16.5 mmol, 99.8% yield) as a yellow solid. 30 LCMS (ES, m/z): 246.1 [M-Boc +H+] 1H NMR (400MHz, DMSO-d6) δ = 8.18 (d, J=8.3 Hz, 1H), 7.95 (br d, J=8.5 Hz, 1H), 7.56 (dt, J=1.3, 7.6 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.35 (br d, J=8.0 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 5.76 (s, 1H), 4.27 - 4.15 (m, 1H), 3.60 (s, 3H), 3.39 (dd, J=5.1, 14.1 Hz, 1H), 3.14 (br dd, J=9.6, 14.2 Hz, 1H), 1.31 (s, 9H) 35 211 70226WO01 Step 4 of 10: Synthesis of Intermediate 81.4, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4- (prop-2-yn-1-yloxy)naphthalen-1-yl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxy-1-naphthyl)propanoate (3 g, 8.69 mmol, 1 eq) and K2CO3 (1.20 g, 8.69 mmol, 1 eq) in DMF (40 mL) was added 3- 5 bromoprop-1-yne (1.55 g, 13.0 mmol, 1.12 mL, 1.5 eq) dropwise at 15°C. The mixture was stirred at 40°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (80 mL) was added to the mixture, then extracted with EtOAc (40 mL * 3). The combined organic phase was washed with brine (60 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was 10 purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (2.68 g, 6.99 mmol, 80.5% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.55 LCMS (ES, m/z): 284.2 [M-Boc+H+] 1H NMR (400MHz, CHLOROFORM-d) δ = 8.33 (br d, J=8.1 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 15 7.61 - 7.54 (m, 1H), 7.54 - 7.48 (m, 1H), 7.19 (d, J=7.9 Hz, 1H), 6.87 (d, J=7.9 Hz, 1H), 4.89 (d, J=2.4 Hz, 2H), 3.79 - 3.68 (m, 1H), 3.63 (s, 3H), 3.57 - 3.36 (m, 2H), 2.55 (t, J=2.3 Hz, 1H), 1.41 (s, 9H) Step 5 of 10: Synthesis of Intermediate 81.5, (S)-methyl 2-amino-3-(4-(prop-2-yn-1- 20 yloxy)naphthalen-1-yl)propanoate hydrochloride. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-prop-2-ynoxy-1- naphthyl)propanoate (2.68 g, 6.99 mmol, 1 eq) in EtOAc (25 mL) was added HCl/EtOAc (4 M, 25 mL, 14.3 eq). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The 25 mixture was filtered and the filter cake was dried to give the title compound (1.55 g, 4.85 mmol, 69.4% yield, HCl) as a yellow solid. LCMS (ES, m/z): 284.1 [M-Boc+H+] 1H NMR (400MHz, DMSO-d6) δ = 8.60 (br s, 2H), 8.21 (d, J=8.1 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.68 - 7.53 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.02 (d, J=7.9 Hz, 1H), 5.01 (d, J=2.3 Hz, 2H), 4.20 30 (br t, J=7.4 Hz, 1H), 3.64 (t, J=2.3 Hz, 1H), 3.55 (s, 3H), 3.44 (dd, J=8.2, 14.2 Hz, 1H) Step 6 of 10: Synthesis of Intermediate 81.6, (S)-methyl 2-((S)-2-((tert- butoxycarbonyl)(methyl) amino)butanamido)-3-(4-(prop-2-yn-1-yloxy)naphthalen-1- yl)propanoate. 212 70226WO01 To a solution of methyl (2S)-2-amino-3-(4-prop-2-ynoxy-1-naphthyl)propanoate (353 mg, 1.10 mmol, 1.2 eq, HCl) and DIEA (357 mg, 2.76 mmol, 481 uL, 3 eq) in DCM (6 mL) was added (2S)- 2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (200 mg, 921 umol, 1 eq) and HATU (525 mg, 1.38 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete 5 consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH4Cl aq. (30 mL) and extracted with DCM (30 mL * 3). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 1:1) to give the title compound (420 mg, 870 umol, 94.6% yield) as a yellow oil. 10 TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.57 LCMS (ES, m/z): 383.2 [M-Boc+H+]. Step 7 of 10: Synthesi s o Intermedate 81.7, (S)-2-((S)-2-((tert-butoxycarbonyl)(methyl) amino)butanamido)-3-(4-(prop-2-yn-1-yloxy)naphthalen-1-yl)propanoic acid. 15 To a solution of methyl (2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-(4- prop-2-ynoxy-1-naphthyl)propanoate (420 mg, 870 umol, 1 eq) in MeOH (2 mL)/H2O (2 mL)/THF (6 mL) was added LiOH (62.5 mg, 2.61 mmol, 3 eq). The mixture was stirred at 15°C for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The 20 residue was dissolved in H2O (15 mL), then extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1 M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (230 mg, 491 umol, 56.4% yield) as a yellow oil. 25 LCMS (ES, m/z): 369.1 [M-Boc+H+] 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.32 (d, J = 7.6 Hz, 1H), 8.13 (br d, J = 8.5 Hz, 1H), 7.60 (dt, J = 1.3, 7.6 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.21 (br d, J = 7.8 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 4.96 - 4.91 (m, 1H), 4.87 (d, J = 2.3 Hz, 2H), 4.59 - 4.42 (m, 1H), 3.64 (br dd, J = 5.9, 14.4 Hz, 1H), 3.47 - 3.34 (m, 1H), 2.54 (t, J = 2.4 Hz, 1H), 2.38 (br s, 3H), 1.54 (ddd, J = 7.3, 10.1, 14.4 30 Hz, 2H), 1.44 (s, 9H), 0.81 (br s, 3H) Step 8 of 10: Synthesis of Intermediate 81.8, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn-1-yloxy)naphthalen-1-yl)propan-2-yl)amino)-1- 35 oxobutan-2-yl)(methyl)carbamate. 213 70226WO01 To a solution of (2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-(4-prop-2- ynoxy-1-naphthyl)propanoic acid (102 mg, 217 umol, 1.2 eq) and DIEA (70.2 mg, 543 umol, 94.6 uL, 3 eq) in DCM (3 mL) was added tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2- dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (70 mg, 181 umol, 1 eq), HATU (103 mg, 5 272 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by 10 preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (60 mg, 71.7 umol, 39.6% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.57 LCMS (ES, m/z): 837.4 [M +H+]. 15 Step 9 of 10: Synthesis of Intermediate 81.9, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(naphthalene-4,1-diyl))bis(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4- fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate). To a solution of tert-butyl N-[(1S)-1-[[2-[5-[tert-butyl(dimethyl)silyl] -[(4-20 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxy-1- naphthyl)methyl]ethyl]carbamoyl]propyl]-N-methyl-carbamate (60 mg, 71.7 umol, 1 eq) in CH3CN (4 mL) was added Cu(OAc)2 (15.6 mg, 86.0 umol, 1.2 eq) and pyridine (34.0 mg, 430 umol, 34.7 uL, 6 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. 25 Saturated NH4Cl (20 mL) was added to the mixture, and the mixture was extracted with EtOAc (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (30 mg, 17.9 umol, 50.1% yield) as a yellow solid. 30 TLC (EtOAc) Rf = 0.57 LCMS (ES, m/z): 1558.0 [M-TBS+H+] Step 10 of 10: Synthesis of Example 42, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(naphthalene-4,1-diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- 214 70226WO01 tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). To a solution o -[(1S)-1-[[(1S)-1-[[4-[6-[[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- 5 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-1- naphthyl]oxy]hexa-2,4-diynoxy]-1-naphthyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- N-methyl-carbamate (30 mg, 17.94 umol, 1 eq) in EtOAc (2 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete 10 consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100*40mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 30%-69%, 8 min) to give the title compound (6.3 mg, 4.28 umol, 23.9% yield, 100% purity, 2 TFA) as a white solid. 15 LCMS (ES, m/z): 622.4 [M/2+H+] 1H NMR (400 MHz, METHANOL-d4) δ = 8.22 (br d, J = 8.4 Hz, 2H), 8.18 - 8.12 (m, 4H), 7.60 - 7.44 (m, 4H), 7.31 - 7.19 (m, 6H), 7.00 (t, J = 8.8 Hz, 4H), 6.78 (br d, J = 7.9 Hz, 2H), 5.03 - 4.93 (m, 4H), 4.87 - 4.81 (m, 2H), 3.82 (dd, J = 5.3, 6.8 Hz, 2H), 3.75 (s, 4H), 3.67 - 3.51 (m, 4H), 3.39 (br t, J = 12.3 Hz, 2H), 2.67 (s, 6H), 2.23 (d, J = 10.1 Hz, 2H), 2.02 - 1.84 (m, 4H), 1.07 (s, 6H), 20 0.99 (t, J = 7.5 Hz, 6H), 0.47 (s, 6H) Example 43, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dimethyl-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxo p pane-1,2-diyl))bis(2-(methylamino)butanamide). 215 70226WO01 Br OBn 26.1 ZnI OBn OH O O Pd2(dba)3, SPhos DMF, 15-8 Pd/C, H Br 2 LiOH Boc OMe 0°C, 12h N MeOH K2CO3, DMF MeOH, THF F O Step 1 of 10: Synthesis of Intermediate 82.1, (S)-methyl 3-(4-(benzyloxy)-2,3- dimethylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate. 5 To a solution of 1-benzyloxy-4-bromo-2,3-dimethyl-benzene (5 g, 17.2 mmol, 1 eq) and dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (352 mg, 859 umol, 0.05 eq) in DMF (50 mL) was added Pd2(dba)3 (393 mg, 429 umol, 0.025 eq) and [(2R)-2-(tert-butoxycarbonylamino)-3- methoxy-3-oxo-propyl]-iodo-zinc (8.13 g, 20.6 mmol, 1.2 eq) at 15°C under N2. The mixture was stirred at 15°C for 12 h, then at 80°C for 4 h. LC-MS indicated complete conversion to a product 10 of target mass. The reaction mixture was added into saturated NH4Cl aq. (150 mL) and extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 5:1) to give the title compound (3.31 g, 8.00 mmol, 46.6% yield) as a yellow solid. 15 TLC (Petroleum ether/EtOAc = 10:1) Rf = 0.24 LCMS (ES, m/z): 314.2 [M-Boc+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.48 - 7.36 (m, 4H), 7.36 - 7.30 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.05 (s, 2H), 4.50 (q, J = 6.8 Hz, 1H), 3.76 (s, 2H), 3.73 - 3.65 (m, 3H), 2.25 (d, J = 7.9 Hz, 6H), 1.42 - 1.37 (m, 9H). 20 Step 2 of 10: Synthesis of Intermediate 82.2, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4- hydroxy-2,3-dimethylphenyl)propanoate. 216 70226WO01 To a solution of methyl (2S)-3-(4-benzyloxy-2,3-dimethyl-phenyl)-2-(tert- butoxycarbonylamino)propanoate (3.31 g, 8.00 mmol, 1 eq) in MeOH (50 mL) was added Pd/C (1.5 g, 10% purity) under N2 atmosphere at 15°C. The suspension was degassed and purged with H2 three times. The mixture was stirred at 15°C for 2 h under H2 (15 psi) atmosphere. LC-MS 5 indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was concentrated to give the title compound (2.56 g, 7.92 mmol, 98.9% yield) as a yellow oil. LCMS (ES, m/z): 224.2 [M-Boc+H+] 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.76 (d, J = 8.1 Hz, 1H), 6.56 (br d, J = 8.1 Hz, 1H), 10 5.07 - 4.93 (m, 1H), 4.49 (q, J = 6.9 Hz, 1H), 4.38 - 4.25 (m, 1H), 3.73 - 3.65 (m, 3H), 3.11 (dd, J = 6.3, 14.1 Hz, 1H), 2.95 (br dd, J = 6.8, 13.9 Hz, 1H), 2.24 (s, 3H), 2.18 (s, 3H), 1.42 - 1.38 (m, 9H). Step 3 of 10: Synthesis of Intermediate 82.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3- (2,3-dimethyl-4-(prop-2-yn-1-yloxy)phenyl)propanoate. 15 To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxy-2,3-dimethyl- phenyl)propanoate (2.56 g, 7.92 mmol, 1 eq) in DMF (40 mL) was added K2CO3 (2.19 g, 15.8 mmol, 2 eq) and 3-bromoprop-1-yne (1.77 g, 11.9 mmol, 1.28 mL, 80% purity, 1.5 eq). The mixture was stirred at 60°C for 12 h followed by 80°C for 3 h. LC-MS indicated complete conversion to a product of target mass. The mixture was filtered, the filtrate added into NH4Cl aq. 20 (80 mL), then extracted with EtOAc (100 mL * 2). The combined organic phase was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (1.5 g, 4.15 mmol, 50.0% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.47 25 LCMS (ES, m/z): 262.2 [M-Boc+H+]. 1H NMR (400MHz, CHLOROFORM-d) δ = 6.87 (br d, J =8.4 Hz, 1H), 6.76 (d, J =8.5 Hz, 1H), 4.97 (br d, J =8.0 Hz, 1H), 4.67 (d, J =2.4 Hz, 2H), 4.50 (q, J =7.0 Hz, 1H), 3.69 (s, 3H), 3.13 (dd, J =6.1, 14.1 Hz, 1H), 2.96 (br dd, J =7.2, 14.1 Hz, 1H), 2.49 (t, J =2.3 Hz, 1H), 2.24 (s, 3H), 2.19 (s, 3H), 1.41 (s, 9H). 30 Step 4 of 10: Synthesis of Intermediate 82.4, (S)-2-((tert-butoxycarbonyl)amino)-3-(2,3- dimethyl-4-(prop-2-yn-1-yloxy)phenyl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2,3-dimethyl-4-prop-2-ynoxy- phenyl)propanoate (500 mg, 1.38 mmol, 1 eq) in THF (6 mL)/H2O (2 mL) was added LiOH (99.4 35 mg, 4.15 mmol, 3 eq). The mixture was stirred at 15°C for 2 h. LC-MS indicated complete 217 70226WO01 consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (15 mL), then extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the combined organic 5 phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (460 mg, 1.32 mmol, 95.7% yield) as a colorless oil. LCMS (ES, m/z): 248.2 [M-Boc+H+]. Step 5 of 10: Synthesis of Intermediate 82.5, (S)-tert-butyl (1-(5-((tert-10 butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2,3-dimethyl-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(2,3-dimethyl-4-prop-2-ynoxy- phenyl)propanoic acid (324 mg, 931 umol, 1.2 eq) and tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (300 mg, 776 umol, 1 eq) in 15 DCM (6 mL) was added DIEA (301 mg, 2.33 mmol, 406 uL, 3 eq) and HATU (443 mg, 1.16 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (15 mL), then extracted with DCM (10 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure 20 to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (390 mg, 545 umol, 70.2% yield) as a white solid. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.63 LCMS (ES, m/z): 716.4 [M+H+] 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.20 (s, 1H), 7.15 (dd, J = 5.6, 8.4 Hz, 2H), 6.99 - 25 6.90 (m, 3H), 6.65 (d, J = 8.4 Hz, 1H), 5.41 (br d, J = 8.8 Hz, 1H), 4.63 - 4.58 (m, 2H), 3.86 (q, J = 15.0 Hz, 2H), 3.71 (br d, J = 9.9 Hz, 1H), 3.50 (s, 1H), 3.17 - 3.09 (m, 1H), 3.03 - 2.94 (m, 1H), 2.81 (br d, J = 9.9 Hz, 1H), 2.29 (s, 3H), 2.13 (s, 3H), 1.44 (s, 9H), 1.19 (s, 3H), 0.93 - 0.91 (m, 9H), 0.82 (s, 3H), 0.27 (d, J = 6.9 Hz, 6H). 30 Step 6 of 10: Synthesis of Intermediate 82.6, (S)-1-(2-amino-3-(2,3-dimethyl-4-(prop-2-yn-1- yloxy)phenyl)propanoyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2,3-dimethyl-4-prop-2-ynoxy-phenyl)methyl]-2- 35 oxo-ethyl]carbamate (390 mg, 545 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 218 70226WO01 mL). The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give the title compound (290 mg, 539 umol, 99.0% yield, HCl) as a yellow solid. 5 LCMS (ES, m/z): 502.2 [M +H+]. Step 7 of 10: Synthesis of Intermediate 82.7, (S)-2-amino-1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(2,3-dimethyl- 4-(prop-2-yn-1-yloxy)phenyl)propan-1-one. 10 To a solution of 1-[(2S)-2-amino-3-(2,3-dimethyl-4-prop- oxy-phenyl)propanoyl]-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one (290 mg, 539 umol, 1 eq, HCl) in DCM (10 mL) was added imidazole (239 mg, 3.50 mmol, 6.5 eq) and tert-butyl-chloro- dimethyl-silane (203 mg, 1.35 mmol, 165 uL, 2.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak 15 of target mass. The reaction mixture was added into saturated NH4Cl aq. (15 mL), then extracted with DCM (15 mL * 2). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol/TEA = 20:2:1) to give the title compound (320 mg, 520 umol, 96.4% yield) as a yellow oil. 20 TLC (EtOAc/Methanol/TEA = 20:2:1) Rf = 0.53 LCMS (ES, m/z): 616.4 [M +H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.25 (s, 1H), 7.15 (dd, J = 5.6, 8.3 Hz, 2H), 6.98 - 6.90 (m, 3H), 6.68 (d, J = 8.4 Hz, 1H), 4.61 (d, J = 2.3 Hz, 2H), 3.94 - 3.81 (m, 3H), 3.68 (d, J = 9.8 Hz, 1H), 3.15 - 3.00 (m, 2H), 2.90 (br d, J = 9.8 Hz, 1H), 2.39 (t, J = 2.2 Hz, 1H), 2.25 (s, 3H), 25 2.13 (s, 3H), 1.24 - 1.16 (m, 3H), 0.96 - 0.87 (m, 12H), 0.31 - 0.25 (m, 6H). Step 8 of 10: Synthesis of Intermediate 82.8, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2,3-dimethyl-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- 30 oxobutan-2-yl)(methyl)carbamate. To a solution of (2S)-2-amino-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl) methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-(2,3-dimethyl-4-prop-2-ynoxy-phenyl)propan-1-one (120 mg, 195 umol, 1.1 eq) in DCM (5 mL) was added DIEA (68.7 mg, 531 umol, 92.6 uL, 3 eq), (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (38.5 mg, 177 umol, 1 eq) and HATU 35 (101 mg, 266 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated 219 70226WO01 complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (10 mL), extracted with DCM (10 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum 5 ether/EtOAc = 3:1) to give the title compound (90 mg, 110 umol, 62.3% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.43 LCMS (ES, m/z): 815.5 [M+H+] 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.19 (s, 1H), 7.15 (dd, J = 5.6, 8.4 Hz, 2H), 7.00 - 6.86 (m, 4H), 6.65 (d, J . Hz, 1H), 4.95 - 4.85 (m, 1H), 4.60 (d, J = 2.3 Hz, 2H), 3.96 - 3.78 (m, 10 2H), 3.73 - 3.66 (m, 1H), 3.11 (dd, J = 5.4, 13.3 Hz, 1H), 3.02 - 2.92 (m, 1H), 2.81 (d, J = 10.1 Hz, 1H), 2.74 (s, 3H), 2.37 (t, J = 2.3 Hz, 1H), 2.35 - 2.27 (m, 3H), 2.14 (s, 3H), 2.03 - 1.91 (m, 1H), 1.73 - 1.60 (m, 2H), 1.58 - 1.47 (m, 11H), 0.94 - 0.82 (m, 15H), 0.27 (d, J = 6.3 Hz, 6H). Step 9 of 10: Synthesis of Intermediate 82.9, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-15 diyne-1,6-diylbis(oxy))bis(2,3-dimethyl-4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane- 3,2-diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate). A mixture of tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2,3-dimethyl-4-prop-2- 20 ynoxy-phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (80 mg, 98.2 umol, 1 eq), pyridine (46.6 mg, 589 umol, 47.5 uL, 6 eq), and Cu(OAc)2 (21.4 mg, 118 umol, 1.2 eq) in CH3CN (4 mL) was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the mixture was added into saturated NH3.H2O aq. (10 mL), then extracted 25 with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (60 mg, 36.9 umol, 75.1% yield) as a yellow oil. TLC (EtOAc) Rf = 0.54 LCMS (ES, m/z): 1514.7 [M +H+], another peak of 1399.7 [M+H+] corresponding to TBS cleaved 30 product also noted. Step 10 of 10: Synthesis of Example 43, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(2,3-dimethyl-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- 35 (methylamino)butanamide). 220 70226WO01 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-2,3-dimethyl- phenoxy]hexa-2,4-diynoxy]-2,3-dimethyl-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- 5 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- N-methyl-carbamate (60 mg, 36.9 umol, 1 eq) in EtOAc (1 mL) was added HCl/dioxane (4 M, 1 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by10 preparative HPLC (column: Phenomenex Luna 80*30mm, 3um; mobile phase: [water(0.1%TFA)- CH3CN], B%: 25%-55%, 8 min) to give the title compound (25.7 mg, 18.0 umol, 48.8% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 600.4 [M/2+H+] 1H NMR (400 MHz, METHANOL-d4) δ = 8.20 (s, 2H), 7.24 (dd, J = 5.6, 8.4 Hz, 4H), 7.02 - 6.90 15 (m, 6H), 6.64 (d, J = 8.4 Hz, 2H), 4.76 - 4.68 (m, 4H), 4.65 - 4.59 (m, 2H), 3.83 - 3.77 (m, 6H), 3.21 - 3.12 (m, 2H), 3.10 - 3.01 (m, 2H), 2.73 (d, J = 10.0 Hz, 2H), 2.63 (s, 6H), 2.30 (s, 6H), 2.11 (s, 6H), 1.99 - 1.87 (m, 4H), 1.25 (s, 6H), 0.98 (t, J = 7.5 Hz, 6H), 0.85 (s, 6H). Example 44, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2-methoxy-4,1-20 phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). 221 70226WO01 O OBn Br 27.1 O OBn O OH O O O O ZnI Pd2(dba)3, SPhos DMF, 15-80°C, 12h Pd/C, H2 Br HCl/EtOAc Boc OMe NH Step 1 of 9: Synthesis of Intermediate 83.1, (S)-methyl 3-(4-(benzyloxy)-2-methoxyphenyl)-2- ((tert-butoxycarbonyl)amino)propanoate. 5 To a solution of 4-benzyloxy-1-bromo-2-methoxy-benzene (8 g, 27.3 mmol, 1 eq) and Sphos (560 mg, 1.36 mmol, 0.05 eq) in DMF (80 mL) was added Pd2(dba)3 (625 mg, 682 umol, 0.025 eq) and [(2R)-2-(tert-butoxycarbonylamino) -3-methoxy-3-oxo-propyl]-iodo-zinc (12.9 g, 32.8 mmol, 1.2 eq) at 15°C under N2. The mixture was stirred at 80°C for 12 h. LC-MS indicated complete conversion to a product of target mass. The reaction mixture was added into saturated NH4Cl aq. 10 (50 mL) and extracted with EtOAc (50 mL * 3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 2:1) to give the title compound (8.35 g, 20.1 mmol, 73.7% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.45 15 LCMS (ES, m/z): 316.2 [M-Boc+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.49 - 7.32 (m, 5H), 6.99 (d, J = 8.3 Hz, 1H), 6.58 - 6.47 (m, 2H), 5.19 (br d, J = 7.5 Hz, 1H), 5.05 (s, 2H), 4.47 (q, J = 6.8 Hz, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.08 - 2.89 (m, 2H), 1.40 (s, 9H). 20 Step 2 of 9: Synthesis of Intermediate 83.2, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4- hydroxy-2-methoxyphenyl)propanoate. 222 70226WO01 To a solution of methyl (2S)-3-(4-benzyloxy-2-methoxy-phenyl)-2-(tert-butoxycarbonyl amino)propanoate (8.35 g, 20.1 mmol, 1 eq) in MeOH (80 mL) was added Pd/C (4 g, 10% purity) under N2 atmosphere at 15°C. The mixture was stirred at 15°C for 12 h under H2 (15 psi) atmosphere. LC-MS indicated complete consumption of starting material with formation of a 5 single peak of target mass. The mixture was filtered and the filtrate was concentrated to give the title compound (6.4 g, 19.7 mmol, 97.9% yield) as a yellow solid. LCMS (ES, m/z): 226.2 [M-Boc +H+] 1H NMR (400 MHz, DMSO-d6) δ = 7.06 (br d, J = 7.9 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.36 (d, J = 1.9 Hz, 1H), 6.23 (dd, J = 2.1, 8.1 Hz, 1H), 5.75 (s, 1H), 4.15 - 4.06 (m, 1H), 3.72 (s, 3H), 3.56 10 (s, 3H), 2.92 - 2.85 (m, 1H), 2.63 (br dd, J = 9.3, 13.6 Hz, 1H), 1.32 (s, 9H). Step 3 of 9: Synthesis of Intermediate 83.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2- methoxy-4-(prop-2-yn-1-yloxy)phenyl)propanoate. A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxy-2-methoxy- 15 phenyl)propanoate (3.2 g, 9.84 mmol, 1 eq), 3-bromoprop-1-yne (1.76 g, 11.8 mmol, 1.27 mL, 80% purity, 1.2 eq), and K2CO3 (2.72 g, 19.7 mmol, 2 eq) in DMF (30 mL). The mixture was stirred at 60°C for 12 h. LC-MS indicated complete conversion to a product of target mass. The reaction mixture was added into H2O (40 mL) and saturated NH4Cl aq. (40 mL), then extracted with EtOAc (30 mL * 3). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, 20 filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (3.48 g, 9.58 mmol, 97.4% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.37 LCMS (ES, m/z): 264.0 [M-Boc+H+]. 25 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.00 (d, J = 8.1 Hz, 1H), 6.57 - 6.47 (m, 2H), 5.17 (br d, J = 7.1 Hz, 1H), 4.68 (d, J = 2.3 Hz, 2H), 4.47 (q, J = 6.7 Hz, 1H), 3.81 (s, 3H), 3.70 (s, 3H), 3.05 - 2.94 (m, 2H), 2.53 (t, J = 2.2 Hz, 1H), 1.39 (s, 9H). Step 4 of 9: Synthesis of Intermediate 83.4, (S)-methyl 2-amino-3-(2-methoxy-4-(prop-2-yn-1- 30 yloxy)phenyl)propanoate hydrochloride. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2-methoxy-4-prop-2-ynoxy- phenyl)propanoate (3.48 g, 9.58 mmol, 1 eq) in EtOAc (15 mL) was added HCl/EtOAc (4 M, 30 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was 223 70226WO01 concentrated under reduced pressure to give the title compound (2.6 g, 8.67 mmol, 90.6% yield, HCl) as a purple solid. LCMS (ES, m/z): 264.1 [M-Boc+H+]. 1H NMR (400 MHz, DMSO-d6) δ = 8.56 (br s, 2H), 7.08 (d, J = 8.4 Hz, 1H), 6.65 - 6.48 (m, 1H), 5 4.79 (d, J = 2.4 Hz, 2H), 4.10 - 4.00 (m, 1H), 3.76 (s, 3H), 3.63 (s, 3H), 3.58 (t, J = 2.4 Hz, 1H), 3.03 (d, J = 6.9 Hz, 2H). Step 5 of 9: Synthesis of Intermediate 83.5, (S)-methyl 2-((S)-2-((tert- butoxycarbonyl)(methyl) amino)butanamido)-3-(2-methoxy-4-(prop-2-yn-1- 10 yloxy)phenyl)propanoate. To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]buta cid (870 mg, 4.00 mmol, 1.2 eq), methyl (2S)-2-amino-3-(2-methoxy-4-prop-2-ynoxy-phenyl)propanoate (1 g, 3.34 mmol, 1 eq, HCl) and DIEA (1.29 g, 10.0 mmol, 1.74 mL, 3 eq) in DCM (20 mL) was added HATU (1.90 g, 5.00 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete 15 consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (20 mL) was added to the mixture and the mixture was extracted with DCM (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound 20 (1.45 g, 3.13 mmol, 94.0% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.48 LCMS (ES, m/z): 463.1 [M+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.72 (d, J = 8.3 Hz, 1H), 7.42 (br d, J = 6.4 Hz, 1H), 7.25 - 7.21 (m, 1H), 5.41 (d, J = 2.4 Hz, 2H), 5.29 - 5.11 (m, 1H), 4.58 (s, 3H), 4.46 (s, 3H), 3.56 25 (s, 5H), 3.29 - 3.24 (m, 3H), 2.77 - 2.74 (m, 1H), 2.71 - 2.61 (m, 1H), 2.21 (s, 9H), 1.59 (t, J = 7.4 Hz, 3H). Step 6 of 9: Synthesis of Intermediate 83.6, (S)-2-((S)-2-((tert-butoxycarbonyl)(methyl) amino)butanamido)-3-(2-methoxy-4-(prop-2-yn-1-yloxy)phenyl)propanoic acid. 30 To a solution of methyl (2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-(2- methoxy-4-prop-2-ynoxy-phenyl)propanoate (1.45 g, 3.13 mmol, 1 eq) in MeOH (6 mL)/H2O (6 mL)/THF (18 mL) was added LiOH (225 mg, 9.40 mmol, 3 eq). The mixture was stirred at 15°C for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to 35 give a residue. The residue was dissolved in H2O (15 mL), then extracted with EtOAc (15 mL * 2), 224 70226WO01 and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (20 mL * 3) and the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.4 g, 3.12 mmol, 99.6% yield) as a yellow oil. 5 LCMS (ES, m/z): 449.1 [M +H+] 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.03 (br d, J = 8.1 Hz, 1H), 6.85 (br s, 1H), 6.50 (br d, J = 8.3 Hz, 1H), 4.67 (d, J = 2.1 Hz, 3H), 4.53 - 4.40 (m, 1H), 3.83 (s, 3H), 3.19 - 2.97 (m, 2H), 2.82 (s, 3H), 2.53 (t, J = 1.9 Hz, 1H), 1.64 - 1.49 (m, 2H), 1.46 (s, 9H), 0.84 (t, J = 7.3 Hz, 3H). 10 Step 7 of 9: Synthesis of Intermediate 83.7, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2-methoxy-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- oxobutan-2-yl)(methyl)carbamate. To a solution of (2S)-2-[[(2S)-2-[tert-butoxyca l(methyl)amino]butanoyl]amino]-3- (2-15 methoxy-4-prop-2-ynoxy-phenyl)propanoic acid (522 mg, 1.16 mmol, 1.5 eq) tert-butyl-[[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (300 mg, 776 umol, 1 eq) and DIEA (300 mg, 2.33 mmol, 406 uL, 3 eq) in DCM (8 mL) was added HATU (443 mg, 1.16 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. 20 Saturated NH4Cl (20 mL) was added to the mixture, and the mixture was extracted with EtOAc (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (610 mg, 746 umol, 96.2% yield) as a yellow oil. 25 TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.44 LCMS (ES, m/z): 817.4 [M +H+]. Step 8 of 9: Synthesis of Intermediate 83.8, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-diyne- 1,6-diylbis(oxy))bis(2-methoxy-4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-30 fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate). To a solution of tert-butyl N-[(1S)-1-[[2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2-methoxy-4-prop-2-ynoxy- phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (200 mg, 245 umol, 1 eq) in 35 CH3CN (4 mL) was added Cu(OAc)2 (53.4 mg, 294 umol, 1.2 eq) and pyridine (116 mg, 1.47 225 70226WO01 mmol, 119 uL, 6 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete conversion to a product of target mass. The mixture was added into saturated NH3.H2O aq. (8 mL), then extracted with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (190 mg, 116 umol, 95.1% yield) 5 as a yellow solid. LCMS (ES, m/z): 1518.0 [M+H+], another peak of 1163.8 [M+H+] corresponding to TBS cleaved product also noted. Step 9 of 9: Synthesis of Example 44, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-10 diylbis(oxy))bis(2-methoxy-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin -3-oxopropane-1,2-diyl))bis(2- (meth ino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert-butoxy carbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-15 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3-methoxy- phenoxy]hexa-2,4-diynoxy]-2-methoxy-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- N-methyl-carbamate (180 mg, 110 umol, 1 eq) in EtOAc (2 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 15 °C for 0.5 h after which time LC-MS indicated complete 20 consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100*40mm, 5um; mobile phase: [water(0.1% TFA)- CH3CN]; B% : 20%-50%, 8 min) to give impure product. The crude product was repurified by preparative HPLC (column: Phenomenex Luna C18100*30mm, 5um; mobile phase: 25 [water(0.1%TFA)-MeOH]; B%: 55%-70%, 10 min) to give the title compound (4.9 mg, 3.42 umol, 3.10% yield, 100% purity, 2 TFA) as a yellow solid. LCMS (ES, m/z): 602.4 [M/2+H+] 1H NMR (400 MHz, METHANOL-d4) δ = 8.17 (s, 2H), 7.24 (dd, J = 5.6, 8.4 Hz, 4H), 7.05 - 6.96 (m, 6H), 6.56 (d, J = 2.1 Hz, 2H), 6.42 (dd, J = 2.1, 8.3 Hz, 2H), 4.82 - 4.69 (m, 6H), 3.96 (d, J = 30 10.3 Hz, 2H), 3.80 (s, 8H), 3.78 - 3.66 (m, 4H), 3.28 (br d, J = 10.4 Hz, 2H), 3.05 - 2.94 (m, 4H), 2.53 (s, 6H), 1.96 - 1.83 (m, 4H), 1.32 (s, 6H), 1.08 (s, 6H), 0.97 (t, J = 7.5 Hz, 6H). Example 45, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2-cyano-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4 trahydro-1H-pyrrolo[3,2- 35 b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). 226 70226WO01 Br OBn NC 28.1 NC OBn NC OH NC O NC O ZnI Pd2(dba)3, SPhos D Pd/C, H Br LiOH Boc OMe MF, 15-80°C, 12h 2 N Boc OMe MeOH Boc OM MeOH, THF H e K N N 2CO3, DMF Boc OMe Boc OH N N F O Step 1 of 10: Synthesis of Intermediate 84.1, (S)-methyl 3-(4-(benzyloxy)-2-cyanophenyl)-2- ((tert-butoxycarbonyl)amino)propanoate. 5 To a solution of SPhos (641 mg, 1.56 mmol, 0.05 eq), Pd2(dba)3 (715 mg, 781 umol, 0.025 eq), and 5-benzyloxy-2-bromo-benzonitrile (9 g, 31.2 mmol, 1 eq) in DMF (80 mL) under N2, was added [(2R)-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxo-propyl]-iodo-zinc (14.8 g, 37.5 mmol, 1.2 eq). The mixture was stirred at 15°C for 12 h followed by 80°C for 4 h after which time TLC (Petroleum ether/EtOAc = 2:1) indicated complete consumption of the starting material. The 10 reaction mixture was added into saturated NH4Cl aq. (150 mL), then extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: C1820-35um 100A 800 g; mobile phase: [water-CH3CN], B%: 0%-80%, 120 mL/min) to give the title compound (8 g, 17.5 mmol, 56.1% yield, FA) as a white 15 solid. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.43 LCMS (ES, m/z): 311.1 [M-Boc+H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.32 - 7.28 (m, 2H), 7.27 - 7.19 (m, 2H), 7.18 - 7.06 (m, 2H), 7.06 - 6.97 (m, 2H), 5.05 - 4.93 (m, 2H), 4.53 - 4.41 (m, 1H), 3.64 (s, 3H), 3.19 (br dd, J = 20 5.5, 14.1 Hz, 1H), 3.01 (br dd, J = 7.3, 14.0 Hz, 1H), 1.27 (s, 9H). Step 2 of 10: Synthesis of Intermediate 84.2, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2- cyano-4-hydroxyphenyl)propanoate 227 70226WO01 To a solution of methyl (2S)-3-(4-benzyloxy-2-cyano-phenyl)-2-(tert-butoxy carbonylamino)propanoate (8 g, 19.5 mmol, 1 eq) in MeOH (80 mL) was added Pd/C (8 g, 10% purity) under N2 atmosphere at 15°C. The suspension was degassed and purged with H2 three times. The mixture was stirred at 15°C for 12 h under H2 (15 psi) atmosphere. LC-MS indicated 5 complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was concentrated to give the title compound (6.2 g, 19.4 mmol, 99.3% yield) as a yellow oil. LCMS (ES, m/z): 319.1 [M-H+] 1H NMR (400MHz, CHLOROFORM-d) δ = 7.22 - 7.14 (m, 1H), 7.02 (br s, 1H), 6.93 (br d, J=7.3 10 Hz, 1H), 5.25 (br d, J=8.4 Hz, 1H), 4.63 - 4.52 (m, 1H), 3.80 (s, 3H), 3.37 - 2.96 (m, 2H), 1.41 (s, 9H). Step 3 of 10: Synthesis of Intermediate 84.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2- cyano-4-(prop-2-yn-1-yloxy)phenyl)propanoate. 15 To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2-cyano-4-hydroxy- phenyl)propanoate (3 g, 9.37 1 eq) in DMF (40 mL) was added K2CO3 (2.59 g, 18.7 mmol, 2 eq) and 3-bromoprop-1-yne (2.09 g, 14.1 mmol, 1.51 mL, 80% purity, 1.5 eq). The mixture was stirred at 60°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (40 mL) was added to the mixture, then extracted 20 with EtOAc (40 mL * 3). The combined organic phase was washed with brine (40 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (2.89 g, 8.06 mmol, 86.1% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.45 25 LCMS (ES, m/z): 259.2 [M-Boc+H+]. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.29 (br d, J=8.8 Hz, 1H), 7.20 (br d, J=2.3 Hz, 1H), 7.18 - 7.13 (m, 1H), 5.12 (br d, J=8.0 Hz, 1H), 4.70 (d, J=2.3 Hz, 2H), 4.66 - 4.56 (m, 1H), 3.78 (s, 3H), 3.40 - 3.08 (m, 2H), 2.56 (t, J=2.4 Hz, 1H), 1.40 (s, 9H). 30 Step 4 of 10: Synthesis of Intermediate 84.4, (S)-2-((tert-butoxycarbonyl)amino)-3-(2-cyano- 4-(prop-2-yn-1-yloxy)phenyl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2-cyano-4-prop-2-ynoxy- phenyl)propanoate (600 mg, 1.67 mmol, 1 eq) in THF (3 mL) and H2O (1 mL) was added LiOH (120 mg, 5.02 mmol, 3 eq). The mixture was stirred at 15°C for 2 h. LC-MS indicated complete 35 consumption of starting material with formation of a single peak of target mass. The mixture was 228 70226WO01 concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (15 mL), then extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced 5 pressure to give the title compound (500 mg, 1.45 mmol, 86.7% yield) as a yellow oil. LCMS (ES, m/z): 245.2 [M-Boc+H+]. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.37 - 7.29 (m, 1H), 7.26 - 7.15 (m, 2H), 4.72 (br s, 2H), 4.68 - 4.48 (m, 1H), 3.51 - 3.35 (m, 1H), 3.25 - 2.95 (m, 1H), 2.56 (s, 1H), 1.47 - 1.18 (m, 9H). 10 Step 5 of 10: Synthesis of Intermediate 84.5, (S)-tert-butyl (1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2-cyano-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(2-cyano-4-prop-2-ynoxy- phenyl)propanoic15 acid (200 mg, 581 umol, 1.2 eq) tert-butyl-[[6-[(4-fluorophenyl) methyl]-3,3-dimethyl-1,2- dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (187 mg, 484 umol, 1 eq) in DCM (3 mL) was added DIEA (188 mg, 1.45 mmol, 253 uL, 3 eq) and HATU (276 mg, 726 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was added to the 20 mixture, and the mixture was extracted with DCM (10 mL * 3). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (252 mg, 353 umol, 73.0% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.40 25 LCMS (ES, m/z): 713.5 [M+H+] 1H NMR (400MHz, CHLOROFORM-d) δ = 8.15 (s, 1H), 7.26 - 7.24 (m, 1H), 7.21 (br d, J=2.3 Hz, 1H), 7.18 - 7.07 (m, 4H), 6.97 - 6.91 (m, 2H), 5.37 (br d, J=9.0 Hz, 1H), 4.85 - 4.63 (m, 4H), 4.03 (br d, J=10.3 Hz, 1H), 3.96 - 3.83 (m, 4H), 3.25 (br dd, J=5.0, 13.9 Hz, 1H), 2.99 (br dd, J=9.0, 13.8 Hz, 1H), 2.52 (t, J=2.4 Hz, 1H), 1.32 (s, 12H), 0.92 (s, 9H), 0.30 (d, J=2.6 Hz, 6H). 30 Step 6 of 10: Synthesis of Intermediate 84.6, (S)-2-(2-amino-3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b idin-1-yl)-3-oxopropyl)-5-(prop-2-yn- 1-yloxy)benzonitrile. butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl) methyl]- 35 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2-cyano-4-prop-2-ynoxy-phenyl)methyl]-2-oxo- 229 70226WO01 ethyl]carbamate (252 mg, 353 umol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (3 M, 2 mL). The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give the title compound (170 mg, 318 umol, 89.9% yield, HCl) as a 5 yellow solid. LCMS (ES, m/z): 499.3 [M +H+]. Step 7 of 10: Synthesis of Intermediate 84.7, (S)-2-(2-amino-3-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- 10 b]pyridin-1-yl)-3-oxopropyl)-5-(prop-2-yn-1-yloxy)benzonitrile. To a solution of 2-[(2S)-2-amino-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2, 4- dihydropyrrolo[3, -1-yl]-3-oxo-propyl]-5-prop-2-ynoxy-benzonitrile (170 mg, 318 umol, 1 eq, HCl) in DCM (3 mL) was added imidazole (141 mg, 2.07 mmol, 6.5 eq) and TBSCl (120 mg, 794 umol, 97.3 uL, 2.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated 15 complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (20 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (150 20 mg, 245 umol, 77.0% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.50 LCMS (ES, m/z): 613.4 [M +H+]. 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.91 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.58 (br d, J = 6.3 Hz, 1H), 5.43 (br s, 1H), 5.01 (br d, J = 8.3 Hz, 1H), 4.51 (q, J = 7.2 Hz, 1H), 25 3.69 (s, 3H), 3.08 (dd, J = 6.3, 14.2 Hz, 1H), 2.92 (br dd, J = 7.1, 14.2 Hz, 1H), 2.65 - 2.55 (m, 2H), 1.44 - 1.35 (m, 9H), 1.20 (br t, J = 7.5 Hz, 3H). Step 8 of 10: Synthesis of Intermediate 84.8, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-30 b]pyridin-1-yl)-3-(2-cyano-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- oxobutan-2-yl)(methyl)carbamate. To a solution of 2-[(2S)-2-amino-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl) methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-5-prop-2-ynoxy-benzonitrile (140 mg, 228 umol, 1.1 eq) and (2S)-2-[tert-butoxycarbonyl(methyl)amino] butanoic acid (45 mg, 207 umol, 35 1 eq) in DCM (3 mL) was added DIEA (80.3 mg, 621 umol, 108 uL, 3 eq) and HATU (118 mg, 230 70226WO01 311 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The 5 filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (150 mg, 185 umol, 89.2% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.55 LCMS (ES, m/z): 616.5 [M +H+]. 10 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.19 - 8.12 (m, 1H), 7.22 - 7.06 (m, 5H), 6.95 (t, J = 8.8 Hz, 2H), 6.86 (br d, J = 1.8 Hz, 1H), 5.31 (s, 3H), 5.18 - 5.11 (m, 1H), 4.69 (d, J = 2.3 Hz, 2H), 4.03 (br s, 1H), 3.87 (br d, J= 4.6 Hz, 2H), 3.30 (dd, J = 5.3, 14.0 Hz, 1H), 2.99 (br dd, J = 9.1, 13.4 Hz, 1H), 2.58 - 2.52 (m, 3H), 1.81 (quind, J = 6.7, 13.8 Hz, 1H), 1.65 - 1.57 (m, 1H), 1.56 - 1.48 (m, 9H), 1.32 (s, 3H), 1.29 - 1.24 (m, 3H), 0.93 (s, 9H), 0.83 (t, J = 7.4 Hz, 3H), 0.30 (d, J = 3.0 15 Hz, 6H). Step 9 of 10: Synthesis of Intermediate 84.9, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-20 1-yl]-3-oxo-propyl]-3-cyano-phenoxy]hexa-2,4- yl]methyl]-2-[5-[tert- l]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- bamate. tyl(dimethyl)silyl]ox enyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2-cyano-4-prop-2-ynoxy- 25 phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (140 mg, 172 umol, 1 eq), pyridine (81.8 mg, 1.03 mmol, 83.5 uL, 6 eq), and Cu(OAc)2 (37.6 mg, 207 umol, 1.2 eq) in CH3CN (3 mL) was stirred at 85°C for 1.5 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the mixture was added into saturated NH3.H2O aq. (10 mL), then extracted 30 with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (115 mg, 70.9 umol, 82.2% yield) as a yellow oil. TLC (EtOAc) Rf = 0.57 LCMS (ES, m/z): 1408.8 [M+H+], another peak of 1293.8 [M+H+] corresponding to TBS cleaved 35 product also noted. 231 70226WO01 Step 10 of 10: Synthesis of Example 45, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(2-cyano-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- 5 (methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert-butoxy carbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3-cyano- phenoxy]hexa-2,4-diynoxy]-2-cyano-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-10 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- N-methyl-carbamate (100 mg, 61.7 umol, 1 eq) in EtOAc (2 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative 15 HPLC (column: Phenomenex Luna 80*30mm, 3um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 20%-50%, 8 min) to give the title compound (31.1 mg, 21.9 umol, 35.5% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 597.4 [M/2+H+] 1H NMR (400 MHz, METHANOL-d4) δ = 8.20 (s, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 2.6 20 Hz, 2H), 7.28 - 7.23 (m, 4H), 7.19 (dd, J = 2.8, 8.6 Hz, 2H), 7.02 - 6.96 (m, 4H), 4.99 (t, J = 7.6 Hz, 2H), 4.88 - 4.84 (m, 6H), 4.08 (d, J = 10.4 Hz, 2H), 3.80 (s, 4H), 3.74 (t, J = 6.0 Hz, 2H), 3.45 (d, J = 10.3 Hz, 2H), 3.34 (br d, J = 7.3 Hz, 2H), 3.24 - 3.17 (m, 2H), 2.54 (s, 6H), 1.97 - 1.84 (m, 4H), 1.33 (s, 6H), 1.16 (s, 6H), 0.96 (t, J = 7.5 Hz, 6H). 25 ,2- 232 70226WO01 Br OBn 29.2 OBn OH O O ZnI Pd2(dba)3, SPhos DMF, 15-80°C, 12h Pd/C, H Br 2 LiOH Boc OMe THF H F O Step 1 of 10: Synthesis of Intermediate 85.1, (S)-methyl 3-(4-(benzyloxy)-2-ethylphenyl)-2- ((tert-butoxycarbonyl)amino)propanoate. 5 To a solution of SPhos (557 mg, 1.36 mmol, 0.05 eq), Pd2(dba)3 (621 mg, 678 umol, 0.025 eq) and 4-benzyloxy-1-bromo-2-ethyl- benzene (7.9 g, 27.1 mmol, 1 eq) in DMF (80 mL) was added [(2R)- 2-(tert-butoxy carbonylamino)-3-methoxy-3-oxo-propyl]-iodo-zinc (12.8 g, 32.6 mmol, 1.2 eq) under N2. The mixture was stirred at 80°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added 10 into saturated NH4Cl aq. (150 mL) and extracted with EtOAc (100 mL * 3). The combined organic hase was washed with brine (200 mL) dried over Na SO filtered and concentrated under as (d, 9 (m, 70226WO01 Step 2 of 10: Synthesis of Intermediate 85.2, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2- ethyl-4-hydroxyphenyl)propanoate To a solution of methyl (2S)-3-(4-benzyloxy-2-ethyl-phenyl)-2-(tert- butoxycarbonylamino)propanoate (5.55 g, 13.4 mmol, 1 eq) in MeOH (50 mL) was added Pd/C 5 (2.5 g, 10% purity) under N2 atmosphere at 15°C. The suspension was degassed and purged with H2 three times. The mixture was stirred at 15°C for 12 h under H2 (15 psi) atmosphere. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was concentrated to give the title compound (4 g, 12.4 mmol, 92.2% yield) as a colorless oil. 10 LCMS (ES, m/z): 322.3 [M +H+] 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.91 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.58 (br d, J = 6.3 Hz, 1H), 5.43 (br s, 1H), 5.01 (br d, J = 8.3 Hz, 1H), 4.51 (q, J = 7.2 Hz, 1H), 3.69 (s, 3H), 3.08 (dd, J = 6.3, 14.2 Hz, 1H), 2.92 (br dd, J = 7.1, 14.2 Hz, 1H), 2.65 - 2.55 (m, 2H), 1.44 - 1.35 (m, 9H), 1.20 (br t, J = 7.5 Hz, 3H). 15 Step 3 of 10: Synthesis of Intermediate 85.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2- ethyl-4-(prop-2-yn-1-yloxy)phenyl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2-ethyl-4-hydroxy- phenyl)propanoate (3 g, 9.28 mmol, 1 eq) in DMF (50 mL) was added K2CO3 (2.56 g, 18.6 mmol, 20 2 eq), 3-bromoprop-1-yne (2.07 g, 13.9 mmol, 1.50 mL, 80% purity, 1.5 eq). The mixture was stirred at 80°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (80 mL), then extracted with EtOAc (100 mL * 2). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was 25 purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (2.76 g, 7.64 mmol, 82.3% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.54 LCMS (ES, m/z): 262.1 [M-Boc+H+]. 30 Step 4 of 10: Synthesis of Intermediate 85.4, (S)-2-((tert-butoxycarbonyl)amino)-3-(2-ethyl-4- (prop-2-yn-1-yloxy)phenyl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2-ethyl-4-prop-2-ynoxy- phenyl)propanoate (760 mg, 2.10 mmol, 1 eq) in THF (6 mL)/H2O (2 mL) was added LiOH (151 mg, 6.31 mmol, 3 eq). The mixture was stirred at 15°C for 2 h. LC-MS indicated complete 35 consumption of starting material with formation of a single peak of target mass. The mixture was 234 70226WO01 concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (15 mL), then extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced 5 pressure to give the title compound (730 mg, 2.10 mmol, 99.9% yield) as a yellow oil. LCMS (ES, m/z): 248.2 [M-Boc+H+]. Step 5 of 10: Synthesis of Intermediate 85.5, (S)-tert-butyl (1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- 10 b]pyridin-1-yl)-3-(2-ethyl-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(2-ethyl-4-prop-2-ynoxy-phenyl) propanoic acid (324 mg, 931 umol, 1.2 eq) in DCM (5 mL) was added DIEA (401 mg, 3.10 mmol, 541 uL, 4 eq), tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl- 1,2-dihydropyrrolo [3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (300 mg, 776 umol, 1 eq) and HATU 15 (443 mg, 1.16 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (10 mL) and extracted with DCM (8 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum 20 ether/EtOAc = 2:1) to give the title compound (330 mg, 461 umol, 59.4% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.63 LCMS (ES, m/z): 716.6 [M+H+]. Step 6 of 10: Synthesis of Intermediate 85.6, (S)-1-(2-amino-3-(2-ethyl-4-(prop-2-yn-1-25 yloxy)phenyl)propanoyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-5(4H)-one hydrochloride. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2-ethyl-4-prop-2-ynoxy-phenyl)methyl]-2-oxo- ethyl]carbamate (330 mg, 461 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). 30 The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give the title compound (230 mg, 428 umol, 92.7% yield, HCl) as a yellow solid. LCMS (ES, m/z): 502.3 [M +H+]. 35 235 70226WO01 Step 7 of 10: Synthesis of Intermediate 85.7, (S)-2-amino-1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(2-ethyl-4- (prop-2-yn-1-yloxy)phenyl)propan-1-one. To a solution of (S)-1-(2-amino-3-(2-ethyl-4-(prop-2-yn-1-yloxy)phenyl)propanoyl)-6-(4- 5 fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-5(4H)-one hydrochloride (230 mg, 427 umol, 1 eq, HCl) in DCM (10 mL) was added imidazole (189 mg, 2.78 mmol, 6.5 eq), tert- butyl-chloro-dimethyl-silane (161 mg, 1.07 mmol, 131 uL, 2.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (10 mL) and 10 extracted with DCM (8 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol/TEA = 20:2:1) to give the title compound (190 mg, 309 umol, 72.2% yield) as a yellow oil. TLC (EtOAc/Methanol/TEA = 20:2:1) Rf = 0.63 15 LCMS (ES, m/z): 616.5 [M +H+] 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.26 (s, 1H), 7.17 - 7.11 (m, 2H), 7.10 - 7.04 (m, 1H), 6.97 - 6.88 (m, 2H), 6.77 (d, J = 2.3 Hz, 1H), 6.66 (br dd, J = 2.3, 8.2 Hz, 1H), 4.64 - 4.57 (m, 2H), 3.83 (br s, 2H), 3.70 (br d, J = 9.9 Hz, 1H), 3.27 - 2.90 (m, 3H), 2.89 - 2.77 (m, 1H), 2.64 (br d, J = 7.3 Hz, 2H), 2.48 - 2.40 (m, 1H), 1.23 - 1.13 (m, 6H), 0.94 - 0.85 (m, 12H), 0.32 - 0.23 (m, 6H). 20 Step 8 of 10: Synthesis of Intermediate 85.8, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2-ethyl-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- oxobutan-2-yl)(methyl)carbamate. 25 To a solution of (2S)-2-amino-1-[5-[t -butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-(2-ethyl-4-prop-2-ynoxy-phenyl)propan-1-one (100 mg, 162 umol, 1.1 eq) in DCM (4 mL) was added DIEA (76.3 mg, 590 umol, 103 uL, 4 eq), (2S)-2- [tert-butoxycarbonyl(methyl)amino]butanoic acid (32.1 mg, 148 umol, 1 eq) and HATU (84.2 mg, 221 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete 30 conversion to a product of target mass. The reaction mixture was added into saturated NH4Cl aq. (10 mL) and extracted with DCM (8 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (120 mg, 147 umol, 99.7% yield) as a yellow oil. 35 TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.53 236 70226WO01 LCMS (ES, m/z): 815.5 [M+H+] Step 9 of 10: Synthesis of Intermediate 85.9, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(2-ethyl-4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4- 5 fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate). To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2-ethyl-4-prop-2-ynoxy- phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (110 mg, 135 umol, 1 eq) in 10 CH3CN (4 mL) was added Cu(OAc)2 (29.4 mg, 162 umol, 1.2 eq) and pyridine (64.1 mg, 810 umol, 65.4 uL, 6 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the mixture was added into NH3.H2O (10 mL), then extracted with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to 15 give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (100 mg, 61.4 umol, 91.0% yield) as a white solid. TLC (EtOAc) Rf = 0.63 LCMS (ES, m/z): 1514.7 [M+H+], another peak of 1399.7 [M+H+] corresponding to TBS cleaved product also noted. 20 Step 10 of 10: Synthesis of Example 46, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(2-ethyl-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). 25 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3-ethyl- phenoxy]hexa-2,4-diynoxy]-2-ethyl-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- 30 N-methyl-carbamate (100 mg, 61.4 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 20°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30mm, 3um; mobile phase: [water(0.1%TFA)- 237 70226WO01 CH3CN], B%: 20%-50%, 8 min) to give the title compound (59.7 mg, 41.8 umol, 68.1% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 600.4 [M/2+H+] 1H NMR (400 MHz, METHANOL-d4) δ = 8.18 (s, 2H), 7.27 - 7.20 (m, 4H), 7.10 (d, J = 8.4 Hz, 5 2H), 7.04 - 6.96 (m, 4H), 6.78 (d, J = 2.5 Hz, 2H), 6.66 (dd, J = 2.6, 8.5 Hz, 2H), 4.76 - 4.67 (m, 6H), 3.86 (d, J = 10.3 Hz, 2H), 3.81 - 3.73 (m, 6H), 3.11 - 3.05 (m, 4H), 2.82 (d, J = 10.1 Hz, 2H), 2.74 - 2.65 (m, 4H), 2.63 (s, 6H), 2.00 - 1.86 (m, 4H), 1.26 (s, 6H), 1.19 (t, J = 7.5 Hz, 6H), 1.00 - 0.92 (m, 12H). 10 Example 47, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-dimethyl-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). OBn OB ZnI Br n OH O O 30.1 Pd/C, H Br HCl/EtOAc Boc (R) N OMe 2 H Pd2(dba)3, SPhos Boc (S) OMe MeOH B (S) K2CO3, DMF EtOAc B (S) HCl (S) S) NH NH 15 Step 1 of 9: Synthesis of Intermediate 86.1, methyl (2S)-3-(4-benzyloxy-2,6-dimethyl-phenyl)- 2-(tert-butoxycarbonylamino)propanoate. To a so -di methyl-benzene (6.5 g, 22.3 mmol, 1 eq) and dicyclo hexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (458 mg, 1.12 mmol, 0.05 eq) in DMF (100 mL) was added Pd2(dba)3 (511 mg, 558 umol, 0.025 eq) and [(2R)-2-(tert- 20 butoxycarbonylamino)-3-methoxy- 3-oxo-propyl]-iodo-zinc (10.6 g, 26.8 mmol, 1.2 eq) at 15°C under N2. The mixture was stirred at 80°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction 238 70226WO01 mixture was added into saturated NH4Cl aq. (150 mL), then extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (6.4 g, 15.5 5 mmol, 69.3% yield) as a white solid. TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.73. LCMS (ES, m/z): 314.1 [M-Boc+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.44 - 7.33 (m, 5H), 6.67 (s, 2H), 5.06 - 4.98 (m, 3H), 3.65 (s, 3H), 3.07 - 2.98 (m, 2H), 2.33 (s, 6H), 1.42 - 1.35 (m, 9H). 10 Step 2 of 9: Synthesis of Intermediate 86.2, methyl (2S)-2-(tert-butoxycarbonylamino)- 3-(4- hydroxy-2,6-dimethyl-phenyl)propanoate. To a solution of methyl (2S)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-(tert- butoxycarbonylamino)propanoate (6.4 g, 15.5 mmol, 1 eq) in MeOH (200 mL) was added Pd/C 15 (2.5 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (5 g, 15.5 mmol, 99.9% yield) as a yellow oil. 20 LCMS (ES, m/z): 224.2 [M-Boc+H]+. 1H NMR (400 MHz, DMSO-d6) δ = 6.73 (s, 2H), 3.99 - 3.91 (m, 1H), 3.86 (s, 2H), 3.52 (s, 3H), 3.34 - 3.25 (m, 1H), 3.20 - 3.12 (m, 1H), 2.85 (td, J = 1.7, 3.6 Hz, 5H), 1.69 (s, 9H). Step 3 of 9: Synthesis of Intermediate 86.3, methyl (2S)-2-(tert-butoxycarbonylamino)- 3- 25 (2,6-dimethyl-4-prop-2-ynoxy-phenyl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxy-2,6-dimethyl- phenyl)propanoate (3 g, 9.28 mmol, 1 eq) in DMF (40 mL) was added K2CO3 (2.56 g, 18.6 mmol, 2 eq) and 3-bromoprop-1-yne (2.07 g, 13.9 mmol, 1.50 mL, 80% purity, 1.5 eq). The mixture was stirred at 80 °C for 12 h after which time LC-MS indicated complete consumption of starting 30 material with formation of a single peak of target mass. The mixture was filtered and the filtrate was added into saturated NH4Cl aq. (60 mL), then extracted with EtOAc (40 mL * 2). The combined organic phase was washed with brine (70 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (2.95 g, 35 8.16 mmol, 88.0% yield) as a yellow oil. 239 70226WO01 TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.53. LCMS (ES, m/z): 262.1 [M-Boc+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.65 (s, 2H), 4.65 (d, J = 2.3 Hz, 2H), 4.50 (q, J = 7.8 Hz, 1H), 3.65 (s, 3H), 3.02 (q, J = 6.6 Hz, 2H), 2.52 - 2.47 (m, 1H), 2.33 (s, 6H), 1.43 - 1.28 (m, 5 9H). Step 4 of 9: Synthesis of Intermediate 86.4, methyl (2S)-2-amino-3-(2,6-dimethyl-4- prop-2- ynoxy-phenyl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2,6-dimethyl- 4-prop-2-ynoxy- 10 p e y p opa oa e . g, 8.16 mmol, 1 eq) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 25 mL). The mixture was stirred at 15°C for 1 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give the title compound (2.1 g, 7.05 mmol, 86.4% yield, HCl) as a white solid. 15 LCMS (ES, m/z): 262.2 [M+H]+. 1H NMR (400 MHz, METHANOL-d4) δ = 6.70 (s, 2H), 4.68 (d, J = 2.4 Hz, 2H), 4.12 (dd, J = 7.4, 8.9 Hz, 1H), 3.66 (s, 3H), 3.29 - 3.24 (m, 1H), 3.18 - 3.12 (m, 1H), 2.93 (t, J = 2.4 Hz, 1H), 2.31 (s, 6H). 20 Step 5 of 9: Synthesis of Intermediate 86.5, methyl (2S)-2-[[(2S)-2-[tert-butoxycarbonyl (methyl)amino]butanoyl]amino]-3-(2,6-dimethyl-4-prop-2-ynoxy-phenyl)propanoate. To a solution of methyl (2S)-2-amino-3-(2,6-dimethyl-4-prop-2-ynoxy-phenyl)propanoate (1 g, 3.36 , q, HCl) in DCM (20 mL) was added DIEA (1.74 g, 13.4 mmol, 2.34 mL, 4 eq), (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (876 mg, 4.03 mmol, 1.2 eq) and HATU25 (1.92 g, 5.04 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC- MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was added into saturated NH4Cl aq. (20 mL), then extracted with DCM (20 mL * 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue 30 was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (1.44 g, 3.13 mmol, 93.1% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.53. LCMS (ES, m/z): 361.2 [M-Boc+H]+ 240 70226WO01 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.64 (s, 2H), 4.76 (q, J = 8.0 Hz, 1H), 4.64 (d, J = 2.3 Hz, 2H), 4.56 - 4.34 (m, 1H), 3.67 (s, 3H), 3.08 - 2.96 (m, 2H), 2.52 (s, 3H), 2.50 - 2.47 (m, 1H), 2.32 (s, 6H), 1.94 - 1.83 (m, 1H), 1.66 - 1.56 (m, 1H), 1.53 - 1.49 (m, 9H), 0.85 (t, J = 7.4 Hz, 3H). 5 Step 6 of 9: Synthesis of Intermediate 86.6, (2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl) amino]butanoyl]amino]-3-(2,6-dimethyl-4-prop-2-ynoxy-phenyl)propanoic acid. To a solution of methyl(2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]- 3- (2,6-dimethyl-4-prop-2-ynoxy-phenyl)propanoate (1.44 g, 3.13 mmol, 1 eq) in THF (15 mL)/MeOH (5 mL)/H2O (5 mL) was added LiOH (225 mg, 9.38 mmol, 3 eq). The mixture was 10 stirred at 15°C for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (20 mL), then extracted with EtOAc (20 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (20 mL * 3) and the combined organic phase was washed 15 with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (1.26 g, 2.82 mmol, 90.3% yield) as a yellow oil. LCMS (ES, m/z): 347.1 [M-Boc+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.63 (s, 2H), 4.95 - 4.78 (m, 1H), 4.64 (d, J = 2.2 Hz, 2H), 4.61 - 4.51 (m, 1H), 3.21 - 3.02 (m, 2H), 2.63 - 2.40 (m, 3H), 2.37 (s, 6H), 2.14 - 2.09 (m, 20 1H), 1.83 - 1.53 (m, 2H), 1.48 (s, 9H), 0.90 - 0.73 (m, 3H). Step 7 of 9: Synthesis of Intermediate 86.7, tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl (dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 1-[(26-dimeth l-4- ro -2- nox - hen l)meth l]-2-oxo-eth l]carbamo l] ro l]-N-methyl- 25 carbamate. To a solution of (2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3- (2,6- dimethyl-4-prop-2-ynoxy-phenyl)propanoic acid (520 mg, 1.16 mmol, 1.5 eq) and tert-butyl-[[6- [(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (300 mg, 776 umol, 1 eq) in DCM (5 mL) was added DIEA (301 mg, 2.33 mmol, 406 uL, 3 eq) and 30 HATU (443 mg, 1.16 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (20 mL) aq. was added to the mixture, and the mixture was extracted with DCM (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a 241 70226WO01 residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (329 mg, 404 umol, 52.0% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.51 LCMS (ES, m/z): 815.5 [M+H]+ 5 Step 8 of 9: Synthesis of Intermediate 86.8, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-diyne- 1,6-diylbis(oxy))bis(2,6-dimethyl-4,1-phenylene))bis(3-(5-((tert-butyldimethylsilyl)oxy)-6-(4- fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrr -oxopropane-1,2- diyl))bis(azanediyl))bis(1-oxobutane-1,2-diyl))bis(methylcarbamate). 10 To a solution of tert-butyl ((S)-1-(((S)-1-(5-((tert-butyldi ethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(2,6-dimethyl-4-(prop-2-yn-1- yloxy)phenyl)-1-oxopropan-2-yl)amino)-1-oxobutan-2-yl)(methyl)carbamate (160 mg, 196 umol, 1 eq) in CH3CN (3 mL) was added Cu(OAc)2 (42.8 mg, 236 umol, 1.2 eq) and pyridine (93.2 mg, 1.18 mmol, 95.1 uL, 6 eq). The mixture was stirred at 85°C for 1 h under air environment after 15 which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was added into NH3.H2O (10 mL), then extracted with EtOAc (15 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (150 mg, 92.1 umol, 93.8% yield) as a yellow oil. LCMS (ES, m/z): 1514.7 [M+H+], corresponding to TBS cleaved product. 20 Step 9 of 9: Synthesis of Example 47, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(2,6-dimethyl-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). 25 To a solution of di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6- dimethyl-4,1-phenylene))bis(3-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(azanediyl))bis(1- oxobutane-1,2-diyl))bis(methylcarbamate) (150 mg, 92.1 umol, 1 eq) in EtOAc (3 mL) was added HCl/dioxane (4 M, 3 mL). The mixture was stirred at 15°C for 0.5 h. LC-MS indicated complete 30 consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18100*30mm, 5um; mobile phase: [water(0.1%TFA)-MeOH]; B%: 60%-75%, 10 min) to give the title compound (6.5 mg, 4.52 umol, 4.91% yield, 99.3% purity, 2 TFA) as a white solid. 35 LCMS (ES, m/z): 600.4 [M+H]+ 242 70226WO01 1H NMR (400MHz, METHANOL-d4) δ = 8.20 (s, 2H), 7.23 (dd, J=5.5, 8.5 Hz, 4H), 6.99 (t, J=8.8 Hz, 4H), 6.59 (s, 4H), 4.79 - 4.62 (m, 6H), 3.82 - 3.75 (m, 8H), 3.26 (br d, J=11.9 Hz, 2H), 3.02 (dd, J=3.9, 13.7 Hz, 2H), 2.66 (s, 6H), 2.58 (d, J=10.0 Hz, 2H), 2.29 (s, 12H), 2.00 - 1.86 (m, 4H), 1.24 (s, 6H), 0.99 (t, J=7.5 Hz, 6H), 0.89 (s, 6H). 5 Example 48, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-dichloro-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). Cl I OBn Z I 314 l l Cl O Cl O H N O F 10 Step 1 of 10: Synthesis of Intermediate 87.1, (S)-methyl 3-(4-(benzyloxy)-2,6-dichlorophenyl)- 2-((tert-butoxycarbonyl)amino)propanoate. To a solution of SPhos (401 mg, 976 umol, 0.05 eq), Pd2(dba)3 (447 mg, 488 umol, 0.025 eq) and 5-benzyloxy-1,3-dichloro-2-iodo-benzene (7.4 g, 19.5 mmol, 1 eq) in DMF (50 mL) was added 15 [(2R)-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxo-propyl]-iodo-zinc (9.24 g, 23.4 mmol, 1.2 eq) under N2. The mixture was stirred at 80°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (100 mL) was added to the mixture, then extracted with EtOAc (60 mL * 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a 20 residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0: to 8:1) to give the title compound (5.14 g, 11.3 mmol, 57.9% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.40 LCMS (ES, m/z): 355.8 [M-Boc+H + 25 Step 2 of 10: Synthesis of Intermediate 87.2, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3- (2,6-dichloro-4-hydroxyphenyl)propanoate. 243 70226WO01 To a solution of methyl (2S)-3-(4-benzyloxy-2,6-dichloro-phenyl)-2-(tert- butoxycarbonylamino)propanoate (5.14 g, 11.3 mmol, 1 eq) in MeOH (50 mL) was added Pd/C (5 g, 10% purity) under N2 atmosphere at 0°C. The mixture was stirred at 20°C for 2 h under H2 (15 psi) atmosphere. The mixture was stirred at 20°C for 2 h under N2 after which time TLC 5 (Petroleum ether/EtOAc = 5:1) indicated complete consumption of starting material and formation of one new spot. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0: to 5:1) to give the title compound (2.47 g, 6.78 mmol, 59.9% yield) as a yellow oil. 10 TLC (Petroleum ether/EtOAc =3:1) Rf = 0.40 LCMS (ES, m/z): 264.0 [M-Boc+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 6.83 - 6.68 (m, 2H), 5.30 - 5.24 (m, 1H), 4.74 - 4.58 (m, 1H), 3.85 - 3.72 (m, 3H), 3.37 - 3.26 (m, 1H), 3.24 - 3.15 (m, 1H), 1.38 (s, 9H). 15 Step 3 of 10: Synthesis of Intermediate 87.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3- (2,6-dichloro-4-(prop-2-yn-1-yloxy)phenyl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2,6-dichloro-4-hydroxy- phenyl)propanoate (2.47 g, 6.78 mmol, 1 eq) in DMF (40 mL) was added K2CO3 (1.87 g, 13.6 mmol, 2 eq) and 3-bromoprop-1-yne (1.51 g, 10.2 mmol, 1.10 mL, 80% purity, 1.5 eq). The 20 mixture was stirred at 60°C for 12 h. LC-MS indicated complete conversion to a product of target mass. Water (30 mL) was added to the mixture, then extracted with EtOAc (30 mL * 3). The combined organic phase was washed with brine (40 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0: to 5:1) to give the title compound (2.51 g, 25 6.24 mmol, 92.0% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.60 LCMS (ES, m/z): 303.0 [M-Boc+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 6.96 (s, 2H), 5.15 (br d, J=9.0 Hz, 1H), 4.76 - 4.62 (m, 3H), 3.75 (s, 3H), 3.40 - 3.17 (m, 2H), 2.56 (t, J=2.4 Hz, 1H), 1.40 - 1.28 (m, 9H). 30 Step 4 of 10: Synthesis of Intermediate 87.4, (S)-2-((tert-butoxycarbonyl)amino)-3-(2,6- dichloro-4-(prop-2-yn-1-yloxy)phenyl)propanoic acid. ino)-3-(2,6-dichloro-4-prop-2-ynoxy- phenyl)propanoate (2.51 g, 6.24 mmol, 1 eq) in THF (24 mL)/H2O (8 mL) was added LiOH (448 35 mg, 18.7 mmol, 3 eq). The mixture was stirred at 20°C for 2 h. LC-MS indicated complete 244 70226WO01 consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (20 mL), then extracted with EtOAc (20 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (30 mL * 3) and the combined organic 5 phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2.12 g, 5.47 mmol, 87.6% yield) was obtained as a yellow oil. LCMS (ES, m/z): 388.0 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 6.98 (s, 2H), 5.15 (br d, J=8.6 Hz, 1H), 4.76 - 4.63 (m, 3H), 3.48 - 3.23 (m, 2H), 2.57 (br s, 1H), 1.36 (s, 6H), 1.22 (br s, 3H). 10 Step 5 of 10: Synthesis of Intermediate 87.5, (S)-tert-butyl (1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2,6-dichloro-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(2,6-dichloro-4-prop-2-ynoxy- 15 phenyl)propanoic acid (482 mg, 1.24 mmol, 1.2 eq) and DIEA (401 mg, 3.10 mmol, 541 uL, 3 eq) in DCM (10 mL) was added tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2- dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (400 mg, 1.03 mmol, 1 eq) and HATU (590 mg, 1.55 mmol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The 20 residue was added into saturated NH4Cl aq. (20 mL) and extracted with DCM (30 mL * 3). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0: to 5:1) to give the title compound (674 mg, 891 umol, 86.1% yield) as a yellow oil. 25 TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.60 LCMS (ES, m/z): 757.0 [M+H]+ Step 6 of 10: Synthesis of Intermediate 87.6, (S)-1-(2-amino-3-(2,6-dichloro-4-(prop-2-yn-1- yloxy)phenyl)propanoyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- 30 ridin-5(4H)-one hydrochloride. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2,6-dichloro-4-prop-2-ynoxy-phenyl)methyl]-2- oxo-ethyl]carbamate (674 mg, 891 umol, 1 eq) in EtOAc (4 mL) was added HCl/EtOAc (4 M, 8 mL). The mixture was stirred at 25°C for 0.5 h after which time LC-MS indicated complete 35 consumption of starting material with formation of a single peak of target mass. The mixture was 245 70226WO01 filtered and the filter cake was dried to give the title compound (337 mg, 582 umol, 65.4% yield, HCl) as a yellow solid. LCMS (ES, m/z): 542.2 [M+H]+ 5 Step 7 of 10: Synthesis of Intermediate 87.7, (S)-2-amino-1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(2,6-dichloro-4- (prop-2-yn-1-yloxy)phenyl)propan-1-one. To a solution of 1-[(2S)-2-amino-3-(2,6-dichloro-4-prop- oxy-phenyl)propanoyl]-6-[(4- fluorophenyl) l]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one (337 mg, 582 umol, 1 10 eq, HCl) and imidazole (258 mg, 3.78 mmol, 6.5 eq) in DCM (6 mL) was added TBSCl (219 mg, 1.46 mmol, 178 uL, 2.5 eq) at 0°C. The mixture was stirred at 25°C for 3 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (15 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and 15 filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 1:2) to give the title compound (260 mg, 396 umol, 68.0% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 1:2) Rf = 0.43 LCMS (ES, m/z): 656.2 [M+H]+ 20 Step 8 of 10: Synthesis of Intermediate 87.8, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2,6-dichloro-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- oxobutan-2- l)(meth l)carbamate 25 To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (95.3 mg, 439 umol, 1.2 eq), (2S)-2-amino-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H- pyrrolo[3,2-b]pyridin-1-yl]-3-(2,6-dichloro-4-prop-2-ynoxy-phenyl)propan-1-one (240 mg, 365 umol, 1 eq), and DIEA (142 mg, 1.10 mmol, 191 uL, 3 eq) in DCM (3 mL) was added HATU (208 mg, 548 umol, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated 30 complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (20 mL) was added to the mixture which was then extracted with DCM (15 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (260 35 mg, 304 umol, 83.1% yield) as a yellow solid. 246 70226WO01 TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.55 LCMS (ES, m/z): 855.3 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.20 (s, 1H), 7.20 - 7.12 (m, 2H), 6.99 - 6.91 (m, 4H), 5.20 (br d, J = 3.8 Hz, 1H), 4.66 (d, J = 2.4 Hz, 2H), 4.16 - 4.04 (m, 1H), 3.92 - 3.70 (m, 3H), 3.41 5 (dd, J = 9.9, 13.9 Hz, 1H), 3.19 (dd, J = 5.5, 14.0 Hz, 1H), 2.54 (t, J = 2.3 Hz, 1H), 2.50 (s, 3H), 1.81 (br dd, J = 6.2, 12.7 Hz, 1H), 1.63 (s, 2H), 1.51 (s, 9H), 1.33 (s, 3H), 1.28 - 1.22 (m, 3H), 0.93 (s, 9H), 0.82 (t, J = 7.4 Hz, 3H), 0.30 (d, J = 4.5 Hz, 6H). Step 9 of 10: Synthesis of Intermediate 87.9, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-10 diyne-1,6-diylbis(oxy))bis(2,6-dichloro-4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane- 3,2-diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate). To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2,6-dichloro-4-prop-2- 15 ynoxy-phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (100 mg, 117 umol, 1 eq) in CH3CN (3 mL) was added pyridine (55.5 mg, 701 umol, 56.6 uL, 6 eq) and Cu(OAc)2 (25.5 mg, 140 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the mixture was added into NH3.H2O (10 mL), then extracted 20 with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (80 mg, 46.8 umol, 80.1% yield) as a yellow oil. LCMS (ES, m/z): 1381.1 [M-2TBS-Boc+H]+ Step 10 of 10: Synthesis of Example 48, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-25 diylbis(oxy))bis(2,6-dichloro-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1- y)- -oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-30 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5-dichloro- phenoxy]hexa-2,4-diynoxy]-2,6-dichloro-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- N-methyl-carbamate (80 mg, 46.8 umol, 1 eq) in EtOAc (2 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 25°C for 0.5 h after which time LC-MS indicated complete 35 consumption of starting material with formation of a single peak of target mass. The mixture was 247 70226WO01 concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 30%-70%, 8 min) to give the title compound (31.8 mg, 21.1 umol, 45.0% yield, 100% purity, 2 TFA) as a white solid. 5 LCMS (ES, m/z): 641.3 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.18 (s, 2H), 7.24 (dd, J = 5.6, 8.4 Hz, 4H), 7.04 (s, 4H), 6.99 (t, J = 8.8 Hz, 4H), 4.97 (dd, J = 5.8, 9.5 Hz, 2H), 4.82 (br s, 4H), 3.94 (d, J = 10.3 Hz, 2H), 3.83 - 3.75 (m, 6H), 3.51 (dd, J = 9.6, 13.5 Hz, 2H), 3.28 (br d, J = 5.6 Hz, 2H), 3.06 (d, J = 10.1 Hz, 2H), 2.58 (s, 6H), 2.02 - 1.84 (m, 4H), 1.30 (s, 6H), 1.07 (s, 6H), 0.98 (t, J = 7.5 Hz, 6H). 10 Example 49, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-difluoro-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-ox ane-1,2-diyl))bis(2-(methylamino)butanamide). F Br OBn O S) OH N Boc F HN F F F N O N Boc OTBS (S) N TBSO O O (S ) Boc OH F O 15 Step 1 of 10: Synthesis of Intermediate 88.1, (S)-methyl 3-(4-(benzyloxy)-2,6-difluorophenyl)- 2-((tert-butoxycarbonyl)amino)propanoate. To a solution of dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (446 mg, 1.09 mmol, 0.05 eq), Pd2(dba)3 (497 mg, 543 umol, 0.025 eq) and 5-benzyloxy-2-bromo-1,3-difluoro-benzene20 (6.5 g, 21.7 mmol, 1 eq) in DMF (50 mL) was added [(2R)-2-(tert-butoxycarbonylamino)-3- methoxy-3-oxo-propyl]-iodo-zinc (10.3 g, 26.1 mmol, 1.2 eq) under N2 and the mixture was stirred at 80°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH 4 Cl aq. (80 mL) was added to the mixture which was then extracted with EtOAc (80 mL * 2). The combined organic phase was washed with brine (80 mL), 248 70226WO01 dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 0:1) to give the title compound (3.8 g, 9.02 mmol, 41.5% yield) as a yellow solid TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.43 5 LCMS (ES, m/z): 322.2 [M-Boc+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 7.23 (br s, 2H), 7.01 (br d, J = 3.3 Hz, 3H), 3.83 (s, 2H), 3.55 (br s, 2H), 1.48 (br s, 3H), 1.33 (br s, 6H), 1.27 (s, 6H). Step 2 of 10: Synthesis of Intermediate 88.2, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3- 10 (2,6-difluoro-4-hydroxyphenyl)propanoate. To a solution of methyl (2S)-3-(4-benzyloxy-2,6-difluoro-phenyl)-2-(tert-butoxy carbonylamino)propanoate (3.8 g, 9.02 mmol, 1 eq) in MeOH (40 mL) was added Pd/C (3.8 g, 10% purity, 1.00 eq) under N2 atmosphere at 20°C. The mixture was stirred at 20°C for 2 h under H2 (15 psi) atmosphere. The mixture was then stirred at 20°C for 10 h under H2 (15 psi) atmosphere. 15 The mixture was further stirred at 40°C for 2 h under H2 (15 psi) atmosphere. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was concentrated to give the title compound (2.5 g, 7.55 mmol, 83.7% yield) as a yellow oil. LCMS (ES, m/z): 232.0 [M-Boc+H]+ 20 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.36 (br d, J = 8.9 Hz, 2H), 4.51 (br d, J = 7.5 Hz, 1H), 4.30 (br d, J = 7.2 Hz, 1H), 3.74 (s, 3H), 3.19 - 3.09 (m, 1H), 2.94 (dd, J = 7.1, 14.1 Hz, 1H), 1.44 (s, 9H). Step 3 of 10: Synthesis of Intermediate 88.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3- 25 (2,6-difluoro-4-(prop-2-yn-1-yloxy)phenyl)propanoate. To a solution of methyl (2S)-2-(t rt-butoxycarbonylamino)-3-(2,6-difluoro-4-hydroxy- phenyl)propanoate (2.5 g, 7.5 mmol, 1 eq) in DMF (35 mL) was added K2CO3 (2.09 g, 15.1 mmol, 2 eq) and 3-bromoprop-1-yne (1.68 g, 11.3 mmol, 1.22 mL, 80% purity, 1.5 eq). The mixture was stirred at 60°C for 12 h. LC-MS indicated complete consumption of starting material 30 with formation of a single peak of target mass. Saturated NH4Cl aq. (40 mL) was added to the mixture, and the mixture was extracted with EtOAc (40 mL * 2). The combined organic phase was washed with brine (40 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 0:1) to give the title compound (1.7 g, 4.60 mmol, 61.0% yield) as 35 a yellow oil. 249 70226WO01 TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.53 LCMS (ES, m/z): 270.1 [M-Boc+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.53 (d, J = 9.0 Hz, 2H), 5.08 (br d, J = 8.0 Hz, 1H), 4.65 (d, J = 2.4 Hz, 2H), 4.55 (br d, J = 7.1 Hz, 1H), 3.75 (s, 3H), 3.17 (br d, J = 5.4 Hz, 1H), 2.97 5 (br dd, J = 6.9, 13.9 Hz, 1H), 2.56 (t, J = 2.4 Hz, 1H), 1.39 (s, 9H). Step 4 of 10: Synthesis of Intermediate 88.4, (S)-2-((tert-butoxycarbonyl)amino)-3-(2,6- difluoro-4-(prop-2-yn-1-yloxy)phenyl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2,6-difluoro-4-prop-2-ynoxy- 10 p e y p opa oa e g, . o , eq L)/H2O (3 mL) was added LiOH (195 mg, 8.12 mmol, 3 eq). The mixture was stirred at 15°C for 2 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (8mL), then extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1M KHSO4 to 15 pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (920 mg, 2.59 mmol, 95.6% yield) as a yellow oil. LCMS (ES, m/z): 256.1 [M-Boc+H]+ 20 Step 5 of 10: Synthesis of Intermediate 88.5, (S)-tert-butyl (1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2,6-difluoro-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)carbamate. To a solution of tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2- b]pyridin-5-yl]oxy]-dimethyl-silane (300 mg, 776 umol, 1 eq), (2S)-2-(tert-butoxycarbonylamino)- 25 3-(2,6-difluoro-4-prop-2-ynoxy-phenyl)propanoic acid (331 mg, 931 umol, 1.2 eq) and DIEA (301 mg, 2.33 mmol, 405.52 uL, 3 eq) in DCM (6 mL) was added HATU (443 mg, 1.16 mmol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete conversion to a product of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 30 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title comound (460 mg, 635 umol, 81.9% yield) as a yellow oil. TLC (Petroleum ether/EtOAc =3:1) Rf = 0.45 LCMS (ES, m/z): 724.8 [M+H]+ 250 70226WO01 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.17 (s, 1H), 7.16 (dd, J = 5.6, 8.3 Hz, 2H), 6.95 (t, J = 8.7 Hz, 2H), 6.53 (br d, J = 8.9 Hz, 2H), 5.36 (br d, J = 9.0 Hz, 1H), 5.31 (s, 1H), 4.81 - 4.71 (m, 1H), 4.64 (d, J = 2.0 Hz, 2H), 4.03 (br d, J = 10.1 Hz, 1H), 3.87 - 3.81 (m, 2H), 3.08 - 2.92 (m, 2H), 2.54 (t, J = 2.2 Hz, 1H), 1.37 - 1.27 (m, 15H), 0.94 (s, 9H), 0.31 (d, J = 3.0 Hz, 6H). 5 Step 6 of 10: Synthesis of Intermediate 88.6, (S)-1-(2-amino-3-(2,6-difluoro-4-(prop-2-yn-1- yloxy)phenyl)propanoyl)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-5(4H)-one. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-10 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2,6-difluoro-4-prop-2-ynoxy-phenyl)methyl]-2- oxo-ethyl]carbamate (460 mg, 635 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 20°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give the title compound (300 mg, 549 umol, 86.5% yield, 15 HCl) as a yellow solid. LCMS (ES, m/z): 510.3 [M+H]+ Step 7 of 10: Synthesis of Intermediate 88.7, (S)-2-amino-1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(2,6-difluoro-4- 20 (prop-2-yn-1-yloxy)phenyl)propan-1-one. To a -[(2S)-2-amino-3-(2,6-difluoro-4-prop-2-ynoxy-phenyl)propanoyl]-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one (300 mg, 549 umol, 1 eq, HCl) and imidazole (243 mg, 3.57 mmol, 6.5 eq) in DCM (6 mL) was added TBSCl (207 mg, 1.37 mmol, 168 uL, 2.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated 25 complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture which was then extracted with DCM (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (280 mg, 30 449 umol, 81.7% yield) as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.65 LCMS (ES, m/z): 624.3 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.24 (s, 1H), 7.17 (dd, J = 5.6, 8.3 Hz, 2H), 6.94 (t, J = 8.6 Hz, 2H), 6.56 (d, J = 9.0 Hz, 2H), 4.66 (d, J = 2.3 Hz, 2H), 3.95 - 3.84 (m, 4H), 3.75 (d, J = 35 10.1 Hz, 1H), 2.98 - 2.86 (m, 2H), 2.55 (t, J = 2.1 Hz, 1H), 1.26 (s, 6H), 0.94 (s, 9H), 0.31 (s, 6H). 251 70226WO01 Step 8 of 10: Synthesis of Intermediate 88.8, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2,6-difluoro-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- 5 oxobutan-2-yl)(methyl)carbamate. To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (108.67 mg, 500.18 umol, 1.2 eq), (2S)-2-amino-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-(2,6-difluoro-4-prop-2-ynoxy-phenyl)propan-1-one (260 mg, 417 umol, 1 eq), and DIEA (162 mg, 1.25 mmol, 218 uL, 3 eq) in DCM (6 mL) was 10 added HATU (238 mg, 625 umol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 3 h. LC-MS indicated complete conversion to a product of target mass. Saturated NH4Cl aq. (20 mL) was added to the mixture, and the mixture was extracted with DCM (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative 15 TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (230 mg, 279 umol, 67.1% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.55 LCMS (ES, m/z): 823.7 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.17 (br s, 1H), 7.16 (dd, J = 5.5, 8.4 Hz, 2H), 6.95 (t, 20 J = 8.7 Hz, 2H), 6.52 (br d, J = 8.8 Hz, 2H), 5.03 (br s, 1H), 4.65 (d, J = 2.3 Hz, 2H), 4.09 - 3.80 (m, 4H), 3.00 (br d, J = 6.6 Hz, 2H), 2.57 (s, 3H), 2.55 - 2.53 (m, 1H), 1.85 (br d, J = 1.5 Hz, 1H), 1.67 - 1.55 (m, 2H), 1.51 (s, 9H), 1.38 - 1.29 (m, 6H), 0.93 (s, 9H), 0.83 (t, J = 7.4 Hz, 3H), 0.31 (d, J = 2.8 Hz, 6H). 25 Step 9 of 10: Synthesis of Intermediate 88.9, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(2,6-difluoro-4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropan e- 3,2-diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate). To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-30 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2,6-difluoro-4-prop-2- ynoxy-phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (100 mg, 122 umol, 1 eq) in CH3CN (3 mL) was added pyridine (57.7 mg, 729 umol, 58.8 uL, 6 eq) and Cu(OAc)2 (26.48 mg, 145.80 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. 35 The reaction mixture was filtered and the mixture was added into NH3.H2O (10 mL), then extracted 252 70226WO01 with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (95 mg, 57.8 umol, 95.1% yield) as a yellow oil. LCMS (ES, m/z): 823.7 [M+H]+ 5 Step 10 of 10: Synthesis of Intermediate Example 49, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(2,6-difluoro-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl- 5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert-10 butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5-difluoro- phenoxy]hexa-2,4-diynoxy]-2,6-difluoro-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- N-methyl-carbamate (90 mg, 54.7 umol, 1 eq) in EtOAc (2 mL) was added HCl/dioxane (4 M, 4 15 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 25%-65%, 8 min) to give the title compound (41 mg, 28.4 umol, 51.9% yield, 100% purity, 2 TFA) as a white 20 solid. LCMS (ES, m/z): 608.3 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.16 (s, 2H), 7.24 (dd, J = 5.5, 8.4 Hz, 4H), 7.03 - 6.95 (m, 4H), 6.63 (br d, J = 9.3 Hz, 4H), 4.83 (br d, J = 6.9 Hz, 6H), 4.04 (d, J = 10.4 Hz, 2H), 3.82 - 3.73 (m, 6H), 3.46 (d, J = 10.1 Hz, 2H), 3.17 (br d, J = 8.1 Hz, 2H), 3.10 - 3.02 (m, 2H), 2.55 (s, 25 6H), 1.95 - 1.84 (m, 4H), 1.34 (s, 6H), 1.19 (s, 6H), 0.96 (t, J = 7.5 Hz, 6H). Example 50, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2-methyl-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). 253 70226WO01 OBn OBn OH I O O ZnI (R) 33.1 Pd/C, H2 Br LiOH Boc OMe N Pd (S) 2(dba)3, SPhos Boc O MeOH (S) K CO , DMF (S) MeOH, THF (S) H Me Boc OMe 2 3 O DMF, 15-80°C, 12h N N Boc OMe Boc OH H H N N F O Step 1 of 10: Synthesis of Intermediate 89.1, (S)-methyl 3-(4-(benzyloxy)-2-methylphenyl)-2- ((tert-butoxycarbonyl)amino)propanoate. 5 To a solution of SPhos (570 mg, 1.39 mmol, 0.05 eq), Pd2(dba)3 (636 mg, 694 umol, 0.025 eq) and 4-benzyloxy-1-iodo-2-methyl-benzene (9 g, 27.8 mmol, 1 eq) in DMF (10 mL) was added [(2R)-2- (tert-butoxycarbonylamino)-3-methoxy-3-oxo-propyl]-iodo-zinc (13.1 g, 33.3 mmol, 1.2 eq) and the mixture was stirred at 80°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into 10 saturated NH4Cl aq. (150 mL), then extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 0:1) to give the title compound (10.5 g, 26.3 mmol, 94.7% yield) as a yellow oil. 15 TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.41 LCMS (ES, m/z): 341.1 [M-Boc+H]+ Step 2 of 10: Synthesis of Intermediate 89.2, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4- hydroxy-2-methylphenyl)propanoate 20 To a solution of methyl (2S)-3-(4-benzyloxy-2-methyl-phenyl)-2-(tert-butoxycarbonylamino) propanoate (10.5 g, 26.3 mmol, 1 eq) in MeOH (100 mL) was added Pd/C (8 g, 10% purity) under N2 atmosphere at 15°C. The mixture was stirred at 15°C for 2 h under H2 (15 psi) atmosphere. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was concentrated to give the title compound 25 (8 g, 25.9 mmol, 98.4% yield) as a yellow oil. 254 70226WO01 LCMS (ES, m/z): 210.2 [M-Boc+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.88 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 2.1 Hz, 1H), 6.57 (br d, J = 7.6 Hz, 1H), 6.03 (br s, 1H), 5.06 (br d, J = 8.1 Hz, 1H), 4.52 (q, J = 7.1 Hz, 1H), 3.76 - 3.67 (m, 3H), 3.07 (dd, J = 6.1, 14.1 Hz, 1H), 2.89 (br dd, J = 7.1, 14.0 Hz, 1H), 2.26 (s, 3H), 5 1.44 - 1.32 (m, 9H). Step 3 of 10: Synthesis of Intermediate 89.3, (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(2- methyl-4-(prop-2-yn-1-yloxy)phenyl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxy-2-methyl- 10 phenyl)propanoate (4 g, 12.93 mmol, 1 eq) in DMF (40 mL) was added K2CO3 (3.57 g, 25.9 mmol, 2 eq) and 3-bromoprop-1-yne (2.88 g, 19.4 mmol, 2.09 mL, 80% purity, 1.5 eq). The mixture was stirred at 80°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (40 mL) was added to the mixture, and the mixture was extracted with EtOAc (40 mL * 2). The combined organic phase was washed 15 with brine (40 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 0:1) to give the title compound (3.2 g, 9.21 mmol, 71.2% yield) as a white solid. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.43 20 LCMS (ES, m/z): 248.2 [M-Boc+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.98 (d, J = 8.3 Hz, 1H), 6.81 - 6.70 (m, 2H), 4.99 (br d, J = 8.1 Hz, 1H), 4.66 (d, J = 2.4 Hz, 2H), 4.53 (q, J = 7.3 Hz, 1H), 3.70 (s, 3H), 3.13 - 3.03 (m, 1H), 2.93 (br dd, J = 7.1, 13.9 Hz, 1H), 2.51 (t, J = 2.3 Hz, 1H), 2.32 (s, 3H), 1.40 (s, 9H). 25 Step 4 of 10: Synthesis of Intermediate 89.4, (S)-2-((tert-butoxycarbonyl)amino)-3-(2-methyl- 4-(prop-2-yn-1-yloxy)phenyl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2-methyl-4-prop-2-ynoxy- phenyl)propanoate (3.2 g, 9.21 mmol, 1 eq) in THF (30 mL)/H2O (10 mL) was added LiOH (661 mg, 27.63 mmol, 3 eq). The mixture was stirred at 15°C for 2 h after which time TLC (Petroleum 30 ether/EtOAc = 3:1) indicated complete consumption of starting material and formation of one new spot. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (8 mL), then extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and 255 70226WO01 concentrated under reduced pressure to give the title compound (3 g, 9.00 mmol, 97.7% yield) as a colorless oil. LCMS (ES, m/z): 234.2 [M-Boc+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.08 (d, J = 8.4 Hz, 1H), 6.81 - 6.65 (m, 2H), 5.21 (br 5 d, J = 8.0 Hz, 1H), 4.63 (br s, 2H), 4.52 - 4.39 (m, 1H), 3.25 - 3.12 (m, 1H), 2.91 (br dd, J = 7.5, 14.1 Hz, 1H), 2.50 (s, 1H), 2.34 (s, 3H), 1.43 - 1.24 (m, 9H). Step 5 of 10: Synthesis of Intermediate 89.5, (S)-tert-butyl (1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- 10 b]pyridin-1-yl)-3-(2-methyl-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(2-methyl-4-prop-2-ynoxy- phenyl)propanoic acid (310 mg, 931 umol, 1.2 eq) and DIEA (301 mg, 2.33 mmol, 406 uL, 3 eq) in DCM (6 mL) was added tert-butyl-[[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-1,2- dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (300 mg, 776 umol, 1 eq) and HATU (443 15 mg, 1.16 mmol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete conversion to a product of target mass. Saturated NH4Cl aq. (15 mL) was added to the mixture, and the mixture was extracted with DCM (15 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum 20 ether/EtOAc = 3:1) to give the title compound (390 mg, 556 umol, 71.6% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.60 LCMS (ES, m/z): 702.4 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.16 (dd, J = 5.6, 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 1H), 6.98 - 6.92 (m, 2H), 6.75 (d, J = 2.4 Hz, 1H), 6.66 (dd, J = 2.4, 8.3 Hz, 1H), 5.41 (br d, J = 8.8 25 Hz, 1H), 5.31 (s, 1H), 4.60 (d, J = 2.3 Hz, 2H), 3.93 - 3.80 (m, 2H), 3.04 - 2.93 (m, 2H), 2.44 (t, J = 2.3 Hz, 1H), 2.36 (s, 3H), 1.43 (s, 9H), 1.21 (s, 3H), 0.95 - 0.88 (m, 15H), 0.28 (d, J = 8.1 Hz, 6H). Step 6 of 10: Synthesis of Intermediate 89.6, (S)-2-amino-1-(6-(4-fluorobenzyl)-5-hydroxy- 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(2-methyl-4-(prop-2-yn-1 - 30 yloxy)phenyl)propan-1-one hydrochloride. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl) methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2-methyl-4-prop-2-ynoxy-phenyl)methyl]-2-oxo- ethyl]carbamate (390 mg, 555.60 umol, 1 eq) in EtOAc (4 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete 35 consumption of starting material with formation of a single peak of target mass. The mixture was 256 70226WO01 concentrated under reduced pressure to give the title compound (240 mg, 458 umol, 82.4% yield, HCl) as a yellow solid. LCMS (ES, m/z): 488.2 [M+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.26 (s, 1H), 7.32 - 7.20 (m, 2H), 7.10 - 6.98 (m, 3H), 5 6.82 (d, J = 2.6 Hz, 1H), 6.73 (dd, J = 2.6, 8.4 Hz, 1H), 6.71 - 6.69 (m, 1H), 4.66 (d, J = 2.4 Hz, 2H), 4.28 (dd, J = 4.9, 11.0 Hz, 1H), 3.82 (d, J = 2.5 Hz, 2H), 3.69 (d, J = 10.3 Hz, 1H), 3.23 - 3.05 (m, 2H), 2.86 (t, J = 2.4 Hz, 1H), 2.48 (d, J = 10.3 Hz, 1H), 2.32 (s, 3H), 2.04 - 2.00 (m, 2H), 1.24 (s, 3H), 0.91 (d, J = 2.5 Hz, 3H). 10 Step 7 of 10: Synthesis of Intermediate 89.7, (S)-2-amino-1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(2-methyl-4- (prop-2-yn-1-yloxy)phenyl)propan-1-one. To a solution of (2S)-2-amino-1-[6-[(4-fluorophenyl)methyl]-5-hydroxy-3,3-dimethyl- 2H- pyrrolo[3,2-b]pyridin-1-yl]-3-(2-methyl-4-prop-2-ynoxy-phenyl)propan-1-one (240 mg, 458 umol, 15 1 eq, HCl) and imidazole (203 mg, 2.98 mmol, 6.5 eq) in DCM (4 mL) was added TBSCl (173 mg, 1.14 mmol, 140 uL, 2.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and 20 filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol/TEA = 20:2:1) to give the title compound (90 mg, 150 umol, 32.7% yield) as a yellow solid. TLC (EtOAc/Methanol/TEA = 20:2:1) Rf = 0.56 LCMS (ES, m/z): 602.8 [M+H]+ 25 Step 8 of 10: Synthesis of Intermediate 89.8, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(2-methyl-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- oxobutan-2-yl)(methyl)carbamate. 30 To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (34.7 mg, 160 umol, 1.2 eq), (2S)-2-amino-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H- pyrrolo[3,2-b]pyridin-1-yl]-3-(2-methyl-4-prop-2-ynoxy-phenyl)propan-1-one (80 mg, 133 umol, 1 eq) and DIEA (51.5 mg, 399 umol, 69.5 uL, 3 eq) in DCM (3 mL) was added HATU (75.8 mg, 199.39 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete 35 consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl 257 70226WO01 aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (15 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (90 mg, 112 5 umol, 84.5% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.40 LCMS (ES, m/z): 801.4 [M+H]+ Step 9 of 10: Synthesi ermediate 89.9, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-10 diyne-1,6-diylbis(oxy))bis(2-methyl-4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)-6- (4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate). To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2-methyl-4-prop-2-ynoxy- 15 phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (80 mg, 99.87 umol, 1 eq) in CH3CN (3 mL) was added pyridine (48.1 mg, 608 umol, 49.1 uL, 6 eq) and Cu(OAc)2 (22.1 mg, 122 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was added into saturated NH3.H2O aq. (10 mL), then extracted with EtOAc (8 mL * 20 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (80 mg, 50.0 umol, 98.6% yield) as a yellow solid. LCMS (ES, m/z): 1486.6 [M-TBS+H]+ Step 10 of 10: Synthesis of Example 50, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-25 diylbis(oxy))bis(2-methyl-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-o xopropane-1,2-diyl))bis(2- (methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-30 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3-methyl- phenoxy]hexa-2,4-diynoxy]-2-methyl-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- N-methyl-carbamate (70 mg, 43.8 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete consumption of 35 starting material with formation of a single peak of target mass. The mixture was filtered and the 258 70226WO01 filter cake was dried to give a crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 5%- 45%, 8 min) to give the title compound (42.5 mg, 29.9 umol, 68.3% yield, 98.399% purity, 2 TFA) as a white solid. 5 LCMS (ES, m/z): 586.5 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.18 (s, 2H), 7.23 (dd, J = 5.5, 8.5 Hz, 4H), 7.06 (d, J = 8.4 Hz, 2H), 6.99 (t, J = 8.8 Hz, 4H), 6.75 (d, J = 2.5 Hz, 2H), 6.65 (dd, J = 2.6, 8.4 Hz, 2H), 4.78 - 4.66 (m, 6H), 3.88 (d, J = 10.3 Hz, 2H), 3.82 - 3.71 (m, 6H), 3.10 - 3.04 (m, 4H), 2.86 (d, J = 10.1 Hz, 2H), 2.61 (s, 6H), 2.34 (s, 6H), 1.90 (s, 4H), 1.26 (s, 6H), 1.00 - 0.92 (m, 12H). 10 Example 51, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(5-methoxy-1H-indole-1,3- diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). ZnI O Br O Boc O O N OMe O OMe NHBoc N N O O OTBS O OH N N TBSCl, im N Boc OH N HCl/E idazole LiOH 2.11 tOAc F F HB F F O O O O , DCM 15 Step 1 of 12: Synthesis of Intermediate 90.1, 2-bromoethynyl(triethyl)silane. triethyl(ethynyl)silane (25 g, 178 mmol, 1 mL, 1 eq) and AgNO3 (5.88 g, 34.6 mmol, 0.2 eq) were dissolved in acetone (600 mL) under N2. The reaction mixture was stirred vigorously in the dark for 30 minutes at 15°C, after which time the reaction had turned a milky white color. NBS (34.9 g, 20 196 mmol, 1.1 eq) was added and the reaction was stirred for 3 h in the dark at 15°C after which time TLC (Petroleum ether/EtOAc = 1:0) indicated complete consumption of starting material and formation of a new product. The reaction mixture was filtered and the solvent was removed under reduced pressure to give a residue. The residue was added to petroleum ether (200 mL). The mixture was stirred at 15°C for 1 h, then the mixture was filtered and the filtrate was concentrated 25 to give the title compound (38 g, 173 mmol, 97.3% yield) as a yellow oil 1H NMR (400 MHz, CHLOROFORM-d) δ = 1.01 (t, J = 7.9 Hz, 9H), 0.69 - 0.57 (m, 6H). 259 70226WO01 Step 2 of 12: Synthesis of Intermediate 90.2, methyl (2S)-2-(tert-butoxycarbonylamino)-5- triethylsilyl-pent-4-ynoate. CuCN (7.15 g, 79.8 mmol, 17.4 mL, 0.9 eq) and LiCl (6.77 g, 159 mmol, 3.27 mL, 1.8 eq) were 5 dried together by heating under vacuum at 150°C for 2 h. After returning to 15°C, DMF (35 mL) was added to the mixture. The mixture was cooled -20°C, then a solution of [(2R)-2-(tert- butoxycarbonylamino)-3-methoxy-3-oxo-propyl]-iodo-zinc (35 g, 88.7 mmol, 1 eq) was added dropwise. After a period of 30 min, 2-bromoethynyl(triethyl)silane (23.3 g, 106 mmol, 1.2 eq) was added dropwise to the reaction mixture. The reaction mixture was then allowed to slowly warm to 10 15°C and stirred 12 h after which time TLC (Petroleum ether/EtOAc = 10:1) indicated complete consumption of starting material and formation of two new products. The reaction was quenched by the addition of water (400 mL) and extracted with EtOAc (3 * 300 mL). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 15 Petroleum ether/EtOAc = 1:0 to 8:1) to give the title compound (18.4 g, 53.9 mmol, 60.7% yield) as a white solid. LCMS (ES, m/z): 242.3 [M-Boc+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ = 5.32 (br d, J = 8.0 Hz, 1H), 4.52 - 4.41 (m, 1H), 3.76 (s, 3H), 2.87 - 2.69 (m, 2H), 1.45 (s, 9H), 0.97 (t, J = 7.9 Hz, 8H), 0.63 - 0.49 (m, 6H). 20 Step 3 of 12: Synthesis of Intermediate 90.3, methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5- methoxy-2-triethylsilyl-1H-indol-3-yl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-5-triethylsilyl-pent-4-ynoate (7 g, 20.5 mmol, 1.5 eq) and 2-bromo-4-methoxy-aniline (2.76 g, 13.7 mmol, 1 eq) in dioxane (100 mL) was25 added bis(tri-tert-butylphosphine)palladium(0) (349 mg, 683 umol, 0.05 eq) under N2. N- cyclohexyl-N-methyl-cyclohexanamine (6.67 g, 34.2 mmol, 7.25 mL, 2.5 eq) was added to the mixture at 15°C under N2 and the mixture was stirred at 60°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (50 mL) was added to the mixture which was then extracted with EtOAc (40 mL * 3). The 30 combined organic phase was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 5:1). The crude product was purified by reversed-phase MPLC (column: C1820-35um, 100A, 330g; mobile phase: [Water (1% TFA)-CH3CN], B%: 55%-85%, 70 mL/min) to give the title compound (1.1 g, 2.38 mmol, 17.4% 35 yield) as a yellow oil. 260 70226WO01 TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.43 LCMS (ES, m/z): 407.2 [M-Boc+H]+. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.91 (s, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.89 - 6.83 (m, 1H), 4.94 (br d, J=7.9 Hz, 1H), 4.59 - 4.44 (m, 1H), 3.87 (s, 3H), 3.71 - 3.61 5 (m, 3H), 3.28 - 3.18 (m, 2H), 1.43 - 1.29 (m, 8H), 1.04 - 0.98 (m, 9H), 0.97 - 0.87 (m, 6H). Step 4 of 12: Synthesis of Intermediate 90.4, methyl (2S)-2-(tert-butoxycarbonylamino)- 3-(5- methoxy-1H-indol-3-yl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-methoxy-2-triethylsilyl-1H-indol- 10 3-yl)propano g, 2.38 mmol, 1 eq) in THF (15 mL) was added TBAF (1 M, 7.13 mL, 3 eq) at 0°C. The mixture was stirred at 20°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. Water (20 mL) was added to the mixture which was then extracted with EtOAc (15 mL * 3). The combined organic phase was washed with 15 brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:2) to give the title compound (500 mg, 1.44 mmol, 60.4% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:2) Rf = 0.49. LCMS (ES, m/z): 293.1 [M-Boc+H]+. 20 Step 5 of 12: Synthesis of Intermediate 90.5, methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5- methoxy-1-prop-2-ynyl-indol-3-yl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-methoxy-1H-indol-3- yl)propano 00 mg, 1.44 mmol, 1 eq) in DMF (6 mL) was added t-BuOK (177 mg, 1.58 mmol, 25 1.1 eq) at 0°C. The mixture was stirred at 0°C for 0.5 h and 3-bromoprop-1-yne (277 mg, 1.87 mmol, 201 uL, 80% purity, 1.3 eq) was dissolved in DMF (1 mL) and added dropwise to the mixture at 0°C. The mixture was stirred at 20°C for 1 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (10 mL) was added to the mixture which was then extracted with EtOAc (10 mL * 3). The combined organic phase was 30 washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (310 mg, 802. umol, 55.9% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.45. LCMS (ES, m/z): 331.1 [M-Boc+H]+. 35 261 70226WO01 Step 6 of 12: Synthesis of Intermediate 90.6, (2S)-2-(tert-butoxycarbonylamino)-3-(5- methoxy-1-prop-2-ynyl-indol-3-yl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-methoxy-1-prop-2-ynyl-indol-3- yl)propanoate (310 mg, 802 umol, 1 eq) in THF (3 mL) and H2O (1 mL) was added LiOH (57.6 5 mg, 2.41 mmol, 3 eq). The mixture was stirred at 20°C for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (8 mL), then extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1 M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the 10 combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (250 mg, 671 umol, 83.7% yield) as a yellow oil. LCMS (ES, m/z): 317.1 [M-Boc+H]+. 15 Step 7 of 12: Synthesis of Intermediate 90.7, tert-butyl N-[(1S)-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-1-[(5-methoxy-1-prop-2-ynyl-indol-3-yl)methyl]-2-oxo-ethyl]carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(5-methoxy-1-prop-2-ynyl-i yl)propanoic acid (220 mg, 591 umol, 1.2 eq), tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3- 20 dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (190 mg, 492 umol, 1 eq) in DCM (4 mL) was added DIEA (191 mg, 1.48 mmol, 257 uL, 3 eq) and HATU (281 mg, 738 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was added to the mixture which was then extracted with DCM (10 mL * 2). The combined organic 25 phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (250 mg, 337 umol, 68.5% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.46 30 LCMS (ES, m/z): 741.4 [M+H]+ Step 8 of 12: Synthesis of Intermediate 90.8, 1-[(2S)-2-amino-3-(5-methoxy-1-prop-2-ynyl- indol-3-yl)propanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2- b]pyridin-5-one. 262 70226WO01 To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(5-methoxy-1-prop-2-ynyl-indol-3-yl)methyl]-2- oxo-ethyl]carbamate (250 mg, 337 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 15 °C for 12 h after which time LC-MS indicated complete 5 consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (147 mg, 261 umol, 77.4% yield, HCl) as a yellow solid. LCMS (ES, m/z): 527.2 [M+H]+ 10 Step 9 of 12: Synthesis of Intermediate 90.9, (2S)-2-amino-1-[5-[tert-butyl(dimethyl)silyl]oxy- 6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-(5-methoxy-1- prop-2-ynyl-indol-3-yl)propan-1-one. To a solution of 1-[(2S)-2-amino-3-(5-methoxy-1-prop-2-ynyl-indol-3-yl)propanoyl]-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one (147 mg, 261 umol, 1 15 eq, HCl) in DCM (3 mL) was added imidazole (116 mg, 1.70 mmol, 6.5 eq) and TBSCl (98.4 mg, 653 umol, 80.0 uL, 2.5 eq) at 0°C. The mixture was stirred at 15°C for 24 h after which time LC- MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over 20 Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (81 mg, 126 umol, 48.4% yield) as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.63. LCMS (ES, m/z): 641.4 [M+H]+, another peak of 527.3 [M+H]+ corresponding to TBS cleaved 25 product also noted. Step 10 of 12: Synthesis of Intermediate 90.10, tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl 2H pyrrolo[3,2-b]pyridin- 1-yl]-1-[(5-methoxy-1-prop-2-ynyl-indol-3-yl)methyl]-2-oxo-ethyl ]ca yl]propyl]-N- 30 methyl-carbamate. To a solution of (2S)-2-amino-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-(5-methoxy-1-prop-2-ynyl-indol-3-yl)propan-1-one (90 mg, 140 umol, 1.1 eq), (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (27.7 mg, 128 umol, 1 eq) in DCM (3 mL) was added DIEA (49.5 mg, 383 umol, 66.7 uL, 3 eq) and HATU (72.8 35 mg, 192 umol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h after which time LC-MS 263 70226WO01 indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was added to the mixture which was then extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, 5 Petroleum ether/EtOAc = 3:1) to give the title compound (100 mg, 119 umol, 93.2% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.38. LCMS (ES, m/z): 840.4 [M+H]+ 10 Step 11 of 12: Synthesis of Intermediate 90.11, tert-butyl N-[(1S)-1-[[(1S)-1-[[1-[6-[3-[(2S)-2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-3-oxo-propyl]-5-methoxy-indol-1-yl]hexa-2,4-diynyl]-5-methoxy-indol-3-yl]methyl]-2-[5- [tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2- 15 b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate. To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(5-methoxy-1-prop-2-ynyl- indol-3-yl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (90 mg, 107 umol, 1 eq) in CH3CN (4 mL) was added pyridine (50.8 mg, 643 umol, 51.9 uL, 6 eq) and Cu(OAc)2 (23.4 mg, 20 128 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the mixture was added into saturated NH3.H2O aq. (10 mL), then extracted with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (90 mg, crude) as a yellow oil. 25 LCMS (ES, m/z): 1564.5 [M-TBS+H]+, another peak of 1450.6 [M+H]+ corresponding to 2 TBS cleaved product also noted. Step 12 of 12: Synthesis of Example 51, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(5- methoxy-1H-indole-1,3-diyl))bis(3-(6-(4-fluorob l)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro- 30 1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1 ,2-diyl))bis(2-(methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[1-[6-[3-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-5-methoxy- indol-1-yl]hexa-2,4-diynyl]-5-methoxy-indol-3-yl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-35 [(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo- 264 70226WO01 ethyl]carbamoyl]propyl]-N-methyl-carbamate (90 mg, 53.6 umol, 1 eq) in EtOAc (3 mL) was added HCl/dioxane (4 M, 3 mL). The mixture was stirred at 20°C for 0.5 h after which time LC- MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a crude product. The residue 5 was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 22%-52%, 8 min) to give the title compound (19.8 mg, 13.4 umol, 24.1% yield, 100% purity, 2 TFA) as a yellow solid. LCMS (ES, m/z): 625.4 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 8.26 - 8.16 (m, 2H), 7.23 (td, J=4.4, 8.6 Hz, 6H), 7.10 - 10 6.96 (m, 8H), 6.84 - 6.75 (m, 2H), 5.01 - 4.91 (m, 4H), 3.84 - 3.75 (m, 8H), 3.73 (s, 2H), 3.67 (d, J=2.9 Hz, 4H), 3.28 - 3.13 (m, 4H), 2.93 - 2.78 (m, 2H), 2.69 - 2.61 (m, 6H), 2.00 - 1.85 (m, 4H), 1.24 - 1.15 (m, 6H), 1.05 - 1.05 (m, 1H), 1.05 - 0.96 (m, 6H), 0.63 - 0.44 (m, 6H). Example 52, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(5-cyano-1H-indole-1,3-15 diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). N Br N O O O O N O N N OMe OH NH2 OMe OMe TBAF Br N LiOH OMe HBoc NHBoc NHBoc NHBoc TE HB P P B M THF B K DMF THF, H2O O F Step 1 of 10: Synthesis of Intermediate 91.1, methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5- 20 cyano-2-triethylsilyl-1H-indol-3-yl)propanoate. Methyl (2S)-2-(tert-butoxycarbonylamino)-5-triethylsilyl-pent-4-ynoate (13.0 g, 38.1 mmol, 1.5 eq) and 4-amino-3-bromo-benzonitrile (5 g, 25.4 mmol, 1 eq) were added to a 250 mL round bottomed flask and dioxane (100 mL) was added to the mixture under N2 Bis(tri-tert- butylphosphine)palladium(0) (648 mg, 1.27 mmol, 0.05 eq) and N-cyclohexyl-N-methyl- 265 70226WO01 cyclohexanamine (12.4 g, 63.4 mmol, 13.5 mL, 2.5 eq) were added to the mixture at 15°C under N2. The mixture was stirred at 60°C for 12 h under N2 after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (50 mL) was added to the mixture which was then extracted with EtOAc (50 mL * 3). The 5 combined organic phase was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (8.3 g, 18.1 mmol, 71.5% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.48. 10 LCMS (ES, m/z): 402.2 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 8.40 (br s, 1H), 8.00 - 7.86 (m, 1H), 7.45 - 7.33 (m, 2H), 5.00 (br d, J=8.5 Hz, 1H), 4.61 - 4.48 (m, 1H), 3.67 (s, 3H), 3.32 - 3.16 (m, 2H), 1.42 - 1.30 (m, 9H), 1.03 - 0.92 (m, 15H). 15 Step 2 of 10: Synthesis of Intermediate 91.2, methyl (2S)-2-(tert-butoxycarbonylamino)- 3-(5- cyano-1H-indol-3-yl)propanoate To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-cyano-2-triethylsilyl-1H-indol-3- yl)propanoate (4 g, 8.74 mmol, 1 eq) in THF (40 mL) was added TBAF (1 M, 26.2 mL, 3 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete 20 consumption of starting material with formation of a single peak of target mass. Water (30 mL) was added to the mixture which was then extracted with EtOAc (20 mL * 3). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (1.5 g, 4.37 mmol, 50.0% yield) as a yellow 25 oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.46. LCMS (ES, m/z): 244.2 [M-Boc+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 8.45 (br s, 1H), 7.91 (s, 1H), 7.47 - 7.38 (m, 2H), 7.14 (d, J=1.6 Hz, 1H), 5.11 (br d, J=7.4 Hz, 1H), 4.71 - 4.62 (m, 1H), 3.72 (s, 3H), 3.39 - 3.22 (m, 2H), 30 1.45 (s, 9H). Step 3 of 10: Synthesis of Intermediate 91.3, methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5- cyano-1-prop-2-ynyl-indol-3-yl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-cyano-1H-indol-3-yl)propanoate 35 (1.5 g, 4.37 mmol, 1 eq) in DMF (20 mL) was added t-BuOK (539 mg, 4.81 mmol, 1.1 eq) at 0°C. 266 70226WO01 The mixture was stirred at 0°C for 0.5 h and then 3-bromoprop-1-yne (844 mg, 5.68 mmol, 612 uL, 80% purity, 1.3 eq) in DMF (1 mL) was added dropwise to the mixture at 0°C. The mixture was stirred at 15°C for 1 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (40 mL) was added to the mixture which was 5 then extracted with EtOAc (30 mL * 3). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1). The product was purified by reversed-phase MPLC (column: C18, 20-35um, 100A, 120g; mobile phase: [water- CH3CN-HCl]; B%: 35%- 65%, 50 mL/min) to give the title compound (500 mg, 1.31 mmol, 30.0% 10 yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.36. LCMS (ES, m/z): 282.2 [M-Boc+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 7.94 - 7.87 (m, 1H), 7.51 - 7.41 (m, 2H), 7.14 (s, 1H), 5.10 (br d, J=7.5 Hz, 1H), 4.87 (d, J=2.5 Hz, 2H), 4.71 - 4.62 (m, 1H), 3.73 (s, 3H), 3.39 - 3.19 (m, 15 2H), 2.46 (t, J=2.5 Hz, 1H), 1.46 (s, 9H). Step 4 of 10: Synthesis of Intermediate 91.4, (2S)-2-(tert-butoxycarbonylamino)-3-(5-cyano- 1-prop-2-ynyl-indol-3-yl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-cyano-1-prop-2-ynyl-indol-3-yl) 20 propanoate (500 mg, 1.31 mmol, 1 eq) in THF (6 mL)/H2O (2 mL) was added LiOH (94.2 mg, 3.93 mmol, 3 eq). The mixture was stirred at 15°C for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (15 mL), then extracted with EtOAc (15 mL * 2), and then the water phase was acidified with 1M KHSO4 to 25 pH 1-2. The acidic aqueous phase was extracted with DCM (15 mL * 3) and the combined organic phase was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (470 mg, 1.28 mmol, 97.6% yield) a yellow oil. LCMS (ES, m/z): 366.2 [M-H]- 1H NMR (400MHz, METHANOL-d4) δ = 8.05 (d, J=0.9 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.46 (dd, 30 J=1.1, 8.5 Hz, 1H), 7.35 (s, 1H), 5.02 (d, J=2.5 Hz, 2H), 4.41 (dd, J=4.9, 7.9 Hz, 1H), 3.35 (d, J=4.8 Hz, 1H), 3.14 (dd, J=8.1, 14.6 Hz, 1H), 2.88 (t, J=2.6 Hz, 1H), 1.37 (s, 9H). Step 5 of 10: Synthesis of Intermediate 91.5, tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl) silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(5-cyano- 35 1-prop-2-ynyl-indol-3-yl)methyl]-2-oxo-ethyl]carbamate. 267 70226WO01 To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(5-cyano-1-prop-2-ynyl-indol-3-yl) propanoic acid (440 mg, 1.20 mmol, 1.2 eq) and tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (386 mg, 998 umol, 1 eq) in DMF (4 mL) was added DIEA (387 mg, 2.99 mmol, 522 uL, 3 eq) and HATU (569 mg, 1.50 5 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (15 mL) was added to the mixture which was then extracted with DCM (15 mL * 2). The combined organic phase was washed with brine (15 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by 10 preparative TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (360 mg, 489 umol, 49.0% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.47. LCMS (ES, m/z): 736.4 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 8.17 (s, 1H), 7.99 (s, 1H), 7.45 - 7.37 (m, 2H), 7.20 - 15 7.15 (m, 3H), 6.96 (t, J=8.8 Hz, 2H), 5.42 (br d, J=8.8 Hz, 1H), 4.78 (d, J=2.5 Hz, 2H), 3.96 - 3.75 (m, 4H), 3.24 - 3.17 (m, 2H), 3.08 (d, J=10.1 Hz, 1H), 2.27 (t, J=2.4 Hz, 1H), 1.44 (s, 9H), 1.19 (s, 3H), 0.92 (s, 9H), 0.75 (s, 3H), 0.26 (d, J=2.9 Hz, 6H). Step 6 of 10: Synthesis of Intermediate 91.6, 3-[(2S)-2-amino-3-[6-[(4-fluorophenyl) methyl]-20 3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-1-prop-2-ynyl- indole-5-carbonitrile. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(5-cyano-1-prop-2-ynyl-indol-3-yl)methyl]-2-oxo- ethyl]carbamate (360 mg, 489 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 3 mL). 25 The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (220 mg, 394 umol, 80.6% yield, HCl) as a gray oil. LCMS (ES, m/z): 522.2 [M+H]+ 30 1H NMR (400MHz, METHANOL-d4) δ = 8.26 (s, 1H), 7.89 (s, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.55 (s, 1H), 7.43 (dd, J=1.3, 8.5 Hz, 1H), 7.28 (dd, J=5.5, 8.6 Hz, 2H), 7.03 (t, J=8.8 Hz, 2H), 5.04 (d, J=2.5 Hz, 2H), 4.43 (dd, J=5.2, 10.0 Hz, 1H), 3.94 - 3.79 (m, 2H), 3.76 (br d, J=10.2 Hz, 1H), 3.61 (q, J=7.0 Hz, 1H), 3.47 - 3.34 (m, 2H), 2.86 (t, J=2.5 Hz, 1H), 1.30 - 1.10 (m, 6H). 268 70226WO01 Step 7 of 10: Synthesis of Intermediate 91.7, 3-[(2S)-2-amino-3-[5-[tert-butyl(dimethyl) silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo- propyl]-1-prop-2-ynyl-indole-5-carbonitrile. To a solution of 3-[(2S)-2-amino-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- 5 dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-1-prop-2-ynyl-indole-5-carbonitrile (220 mg, 394 umol, 1 eq, HCl) in DCM (3 mL) was added TBSCl (149 mg, 986 umol, 121 uL, 2.5 eq) and imidazole (174 mg, 2.56 mmol, 6.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was added to the mixture which was then extracted 10 with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (170 mg, 267 umol, 67.8% yield) as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.68. 15 LCMS (ES, m/z): 626.4 [M+H]+, another peak of 522.2 [M+H]+ corresponding to TBS cleaved product also noted. 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.24 - 8.18 (m, 1H), 7.96 (s, 1H), 7.45 - 7.36 (m, 2H), 7.24 (br s, 1H), 7.19 - 7.11 (m, 2H), 6.93 (br t, J=8.6 Hz, 2H), 4.79 (br s, 2H), 4.02 (br s, 1H), 3.83 - 3.75 (m, 2H), 3.30 - 3.03 (m, 4H), 2.26 (br s, 1H), 1.23 - 1.16 (m, 3H), 0.91 (s, 9H), 0.85 - 0.78 20 (m, 3H), 0.26 (s, 6H). Step 8 of 10: Synthesis of Intermediate 91.8, tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1- l]-1-[(5-c ano-1- ro -2- n l-indol-3- l)meth l]-2-oxo-eth l]carbamo l] ro l]-N-methyl- 25 carbamate. To a solution of 3-[(2S)-2-amino-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-1-prop-2-ynyl-indole-5-carbonitrile (155 mg, 244 umol, 1.1 eq) and (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (48.2 mg, 222 umol, 1 eq) in DCM (3 mL) was added HATU (126 mg, 332 umol, 1.5 eq) and DIEA (85.930 mg, 665 umol, 116 uL, 3 eq) at 0°C. The mixture was stirred at 20°C for 12 h after which time LC- MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was added to the mixture which was then extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative 269 70226WO01 TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (180 mg, 216 umol, 97.3% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.43. LCMS (ES, m/z): 835.8 [M+H]+ 5 1H NMR (400MHz, CHLOROFORM-d) δ = 8.15 (br d, J=5.6 Hz, 1H), 7.98 (br s, 1H), 7.45 - 7.37 (m, 2H), 7.17 (br dd, J=5.5, 8.5 Hz, 3H), 7.02 - 6.89 (m, 3H), 5.07 - 4.97 (m, 1H), 4.79 (br s, 2H), 3.97 - 3.67 (m, 4H), 3.26 - 3.15 (m, 2H), 2.99 (br d, J=16.9 Hz, 1H), 2.77 - 2.70 (m, 3H), 2.27 (br s, 1H), 2.01 - 1.92 (m, 1H), 1.75 - 1.62 (m, 1H), 1.51 - 1.45 (m, 9H), 1.17 (s, 3H), 0.93 - 0.89 (m, 12H), 0.70 (br s, 3H), 0.26 (d, J=2.8 Hz, 6H). 10 Step 9 of 10: Synthesis of Intermediate 91.9, tert-butyl N-[(1S)-1-[[(1S)-1-[[1-[6-[3-[(2S)-2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl) silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo- propyl]-5-cyano-indol-1-yl]hexa-2,4-diynyl]-5-cyano-indol-3-yl]methyl]-2-[5-[tert-15 butyl(dimethyl)silyl] oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate. Two batches were carried out in parallel: To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(5-cyano-1-prop-2-ynyl- 20 indol-3-yl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (80 mg, 95.8 umol, 1 eq) in CH3CN (3 mL) was added Cu(OAc)2 (20.9 mg, 115 umol, 1.2 eq) and pyridine (45.5 mg, 575 umol, 46.4 uL, 6 eq). The mixture was stirred at 85°C for 1 h under air environment after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The two reactions were combined for workup. The reaction mixture was filtered 25 and the mixture was added into saturated NH3.H2O aq. (15 mL), then extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (155 mg, 92.9 umol, 97.0% yield) as a yellow oil. LCMS (ES, m/z): 834.9 [M/2+H]+, another peak of 1554.7 [M+H]+ corresponding to TBS cleaved 30 product also noted. Step 10 of 10: Synthesis of Example 52, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(5- cyano-1H-indole-1,3-diyl))bis(3-(6-(4-fluoroben 3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro- 1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). 270 70226WO01 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[1-[6-[3-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-5-cyano-indol-1- yl]hexa-2,4-diynyl]-5-cyano-indol-3-yl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- 5 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- N-methyl-carbamate (155 mg, 92.9 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a crude product. The residue was purified by 10 preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 20%-50%, 8 min) to give the title compound (40.1 mg, 27.3 umol, 29.4% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 620.4 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 8.18 - 8.14 (m, 2H), 8.12 - 8.06 (m, 2H), 7.57 - 7.51 (m, 15 2H), 7.47 - 7.40 (m, 2H), 7.34 (s, 2H), 7.24 (dd, J=5.5, 8.4 Hz, 4H), 7.03 - 6.95 (m, 4H), 5.14 - 5.05 (m, 4H), 3.89 - 3.74 (m, 8H), 3.27 (br d, J=8.9 Hz, 6H), 2.81 (d, J=10.4 Hz, 2H), 2.69 - 2.62 (m, 6H), 1.98 - 1.86 (m, 4H), 1.22 - 1.17 (m, 6H), 1.01 - 0.95 (m, 6H), 0.64 - 0.56 (m, 6H). Example 53, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(7-chloro-1H-indole-1,3-20 diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). Br O O NH2 O O OMe OH O Cl OMe OMe Br M TBAF NHBoc LiOH NHBoc H N O F 70226WO01 Step 1 of 10: Synthesis of Intermediate 92.1, methyl (2S)-2-(tert-butoxycarbonylamino)-3-(7- chloro-2-triethylsilyl-1H-indol-3-yl)propanoate. 5 Methyl (2S)-2-(tert-butoxycarbonylamino)-5-triethylsilyl-pent-4-ynoate (11.9 g, 34.9 mmol, 1.5 eq) and 2-bromo-6-chloro-aniline (4.8 g, 23.3 mmol, 1 eq) was added to a 250 mL round bottomed flask. Dioxane (80 mL) was added to the mixture under N2, then bis(tri-tert- butylphosphine)palladium(0) (594 mg, 1.16 mmol, 0.05 eq) and N-cyclohexyl-N-methyl- cyclohexanamine (11.4 g, 58.1 mmol, 12.3 mL, 2.5 eq) were added to the mixture at 15°C under 10 N2. The mixture was stirred at 60°C for 12 h under N2 after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (100 mL), then extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column 15 chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (9 g, 19.3 mmol, 82.9% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.40. LCMS (ES, m/z): 411.1 [M-Boc+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.08 (br s, 1H), 7.48 (br d, J = 7.8 Hz, 1H), 7.18 (d, J 20 = 7.5 Hz, 1H), 7.08 - 7.00 (m, 1H), 4.93 (br d, J = 7.7 Hz, 1H), 4.67 - 4.48 (m, 1H), 3.62 (s, 3H), 3.38 - 3.13 (m, 2H), 1.36 (s, 9H), 1.06 - 1.03 (m, 6H), 1.00 - 0.90 (m, 9H). Step 2 of 10: Synthesis of Intermediate 92.2, methyl (2S)-2-(tert-butoxycarbonylamino)- 3-(7- chloro-1H-indol-3-yl)propanoate. 25 To a solution of methyl (2S)-2-(tert-butoxycarbonylam o)-3-(7-chloro-2-triethylsilyl-1H-indol-3- yl)propanoate (4.5 g, 9.63 mmol, 1 eq) in THF (60 mL) was added TBAF (1 M, 28.9 mL, 3 eq) at 0 °C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was added into H2O (50 mL), then extracted with EtOAc (100 mL * 2). The combined organic phase was washed with brine (50 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (2.36 g, 6.69 mmol, 69.4% yield) as a yellow solid. TLC (Petroleum ether/ethyl acetate = 2:1) Rf = 0.31. LCMS (ES, m/z): 253.0 [M-Boc+H]+ 272 70226WO01 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.32 (br s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.11 - 7.01 (m, 2H), 5.08 (br d, J = 7.9 Hz, 1H), 4.74 - 4.59 (m, 1H), 3.68 (s, 3H), 3.35 - 3.21 (m, 2H), 1.44 (s, 9H). 5 Step 3 of 10: Synthesis of Intermediate 92.3, methyl (2S)-2-(tert-butoxycarbonylamino)-3-(7- chloro-1-prop-2-ynyl-indol-3-yl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(7-chloro-1H-indol-3-yl)propanoate (2.36 g, 6.69 mmol, 1 eq) in DMF (20 mL) was added t-BuOK (751 mg, 6.69 mmol, 1 eq) at 0°C. The mixture was stirred at 0 °C for 0.5 h and the 3-bromoprop-1-yne (1.29 g, 8.70 mmol, 937 uL, 10 80% purity, 1.3 eq) was added dropwise to the mixture at 0°C. The mixture was stirred at 15°C for 1 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (30 mL) was added to the mixture, and the mixture was extracted with EtOAc (30 mL * 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a 15 residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (2.33 g, 5.96 mmol, 89.1% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.55 LCMS (ES, m/z): 291.1 [M-Boc+H]+ 20 Step 4 of 10: Synthesis of Intermediate 92.4, (2S)-2-(tert-butoxycarbonylamino)-3-(7-chloro- 1-prop-2-ynyl-indol-3-yl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(7-chloro-1-prop-2-ynyl-indol-3-yl) propanoate (700 mg, 1.79 mmol, 1 eq) in THF (9 mL)/H2O (3 mL) was added LiOH (129 mg, 5.37 mmol, 3 eq). The mixture was stirred at 15°C for 2 h. LC-MS indicated complete consumption of 25 starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (15 mL), then extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced 30 pressure to give the title compound (570 mg, 1.51 mmol, 84.5% yield) as a yellow solid. LCMS (ES, m/z): 277.1 [M-Boc+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 7.48 (d, J=7.9 Hz, 1H), 7.18 (d, J =7.0 Hz, 1H), 7.12 - 7.10 (m, 1H), 7.05 - 6.99 (m, 1H), 5.31 (s, 2H), 5.03 (br d, J =7.5 Hz, 1H), 4.66 (br d, J =5.9 Hz, 1H), 3.40 - 3.20 (m, 2H), 2.43 (br s, 1H), 1.44 (br s, 9H). 35 273 70226WO01 Step 5 of 10: Synthesis of Intermediate 92.5, tert-butyl N-[(1S)-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-1-[(7-chloro-1-prop-2-ynyl-indol-3-yl)methyl]-2-ox hyl]carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(7-chloro-1-prop-2-ynyl-indol-3- 5 yl)propanoic acid (234 mg, 621 umol, 1.2 eq) and DIEA (201 mg, 1.55 mmol, 270 uL, 3 eq) in DCM (8 mL) was added tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo [3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (200 mg, 517 umol, 1 eq) and HATU (295 mg, 776 umol, 1.5 eq) at 0 °C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The 10 residue was added into saturated NH4Cl aq. (15 mL), then extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (271 mg, 364 umol, 70.3% yield) as a yellow solid. 15 TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.70 LCMS (ES, m/z): 745.4 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 7.53 (br d, J=8.0 Hz, 1H), 7.18 - 7.07 (m, 4H), 7.04 - 6.90 (m, 4H), 5.42 (br d, J =8.8 Hz, 1H), 5.20 (d, J =2.3 Hz, 2H), 4.86 - 4.76 (m, 1H), 3.85 (s, 2H), 3.72 (br d, J =10.1 Hz, 1H), 3.24 - 3.11 (m, 2H), 2.98 (d, J =10.1 Hz, 1H), 2.19 - 2.13 (m, 1H), 1.45 20 (s, 9H), 1.15 (s, 3H), 0.91 (s, 9H), 0.69 (s, 3H), 0.26 (d, J =4.6 Hz, 6H). Step 6 of 10: Synthesis of Intermediate 92.6, 1-[(2S)-2-amino-3-(7-chloro-1-prop-2-ynyl- indol-3-yl)propanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2- b] ridin-5-one 25 To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(7-chloro-1-prop-2-ynyl-indol-3-yl)methyl]-2-oxo- ethyl]carbamate (270 mg, 362 umol, 1 eq) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 5 mL). The mixture was stirred at 15°C for 1 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and 30 the filter cake was dried to give the title compound (129 mg, 227 umol, 62.8% yield, HCl) as a yellow solid. LCMS (ES, m/z): 531.3 [M+H]+ 274 70226WO01 Step 7 of 10: Synthesis of Intermediate 92.7, (2S)-2-amino-1-[5-[tert-butyl(dimethyl)silyl] oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-(7-chloro-1- prop-2-ynyl-indol-3-yl)propan-1-one. To a solution of 1-[(2S)-2-amino-3-(7-chloro-1-prop-2-ynyl-indol-3-yl)propanoyl]-6-[(4- 5 fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one (119 mg, 210 umol, 1 eq, HCl) in DCM (8 mL) was added imidazole (92.8 mg, 1.36 mmol, 6.5 eq) and TBSCl (79.0 mg, 524 umol, 64.2 uL, 2.5 eq) at 0 °C. The mixture was stirred at 15°C for 12 h after which time LC- MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH4Cl aq. (50 mL) and extracted with DCM (20 mL * 10 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (95 mg, 147 umol, 70.2% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.50. 15 LCMS (ES, m/z): 645.4 [M+H]+ Step 8 of 10: Synthesis of Intermediate 92.8, tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl (dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 1-[(7-chloro-1-prop-2-ynyl-indol-3-yl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl- 20 carbamate. To a solution of (2R)-2-amino-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-(7-chloro-1-prop-2-ynyl-indol-3-yl)propan-1-one (85.0 mg, 132 umol, 1.1 eq) and DIEA (46.4 mg, 359 umol, 62.6 uL, 3 eq) in DCM (4 mL) was added (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (26.0 mg, 120 umol, 1 eq) and HATU25 (68.3 mg, 180 umol, 1.5 eq) at 0 °C. The mixture was stirred at 15°C for 12 h after which time LC- MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH4Cl aq. (8 mL), then extracted with DCM (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative 30 TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (92 mg, 109 umol, 91.0% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.45. LCMS (ES, m/z): 844.4 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 7.56 (br d, J =5.6 Hz, 1H), 7.20 - 7.10 (m, 3H), 7.06 35 (s, 1H), 7.01 - 6.89 (m, 4H), 5.20 (d, J =2.0 Hz, 2H), 5.11 - 5.02 (m, 1H), 3.85 (s, 2H), 3.68 (br d, J 275 70226WO01 =9.7 Hz, 1H), 3.17 (br d, J =7.9 Hz, 2H), 2.75 (s, 3H), 2.18 (s, 1H), 1.88 - 1.53 (m, 4H), 1.49 (s, 9H), 1.14 (s, 3H), 0.90 (s, 12H), 0.70 (br s, 3H), 0.25 (d, J =4.5 Hz, 6H). Step 9 of 10: Synthesis of Intermediate 92.9, tert-butyl N-[(1S)-1-[[(1S)-1-[[1-[6-[3-[(2S)- 2- 5 [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3 yridin- 1-yl]-3-oxo-propyl]-4-chloro -yl]hexa-2,4-diynyl]-4-chloro-indol-3-yl]methyl]-2-[5- [tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2- b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate. 10 To a solution of tert-butyl N-[(1 (dimethyl)silyl]oxy-6-[(4-fluorophenyl) methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(7-chloro-1-prop-2-ynyl-indol-3- yl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (85 mg, 101 umol, 1 eq) in CH3CN (3 mL) was added Cu(OAc)2 (21.9 mg, 121 umol, 1.2 eq) and pyridine (47.8 mg, 601 umol, 48.7 uL, 6 eq). The mixture was stirred at 85 °C for 1 h under air environment after which time LC-MS 15 indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH3 aq. (20 mL), then extracted with EtOAc (15 mL * 3). The combined organic phase was washed with brine (15 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc/TEA = 60:60:1) to give the title compound (31 mg, 18.4 umol, 20 36.5% yield) as a yellow oil. TLC (Petroleum ether/EtOAc/TEA = 60:60:1) Rf = 0.7. LCMS (ES, m/z): 1573.9 [M-TBS+H]+ Step 10 of 10: Synthesis of Example 53, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(7-25 chloro-1H-indole-1,3-diyl))bis(3-(6-(4-fluorobenz l)-33-dimthl-5- x-2345-ttr hdro- 1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane- ,- y s - e ya o ua a e). T l ti f t tb tl N 1S 1 1S 1 163 2S 2 2S 2 t tbt b yl (met y)amno] utanoy]amno]--[5-[tert- uty( met y)s y]oxy- -[( - uoropeny)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-4-chloro-indol-1-yl]hexa-2,4-diynyl]-30 4-chloro-indol-3-yl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (31 mg, 18.4 umol, 1 eq) in EtOAc (2 mL) was added HCl/dioxane (4 M, 2 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under 35 reduced pressure to give a residue. The residue was purified by preparative HPLC (column: 276 70226WO01 Phenomenex Luna 80*30mm, 3um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 23%-53%, 8 min) to give the title compound (2.9 mg, 1.95 umol, 10.6% yield, 100% purity, 2 TFA) as a yellow solid. LCMS (ES, m/z): 630.0 [M/2+H]+ 5 1H NMR (400MHz, METHANOL-d4) δ = 8.20 (s, 2H), 7.56 (d, J =8.0 Hz, 2H), 7.25 (dd, J =5.4, 8.6 Hz, 4H), 7.19 - 7.10 (m, 4H), 7.04 - 6.91 (m, 6H), 5.45 (d, J =18.4 Hz, 2H), 5.20 (d, J =18.4 Hz, 2H), 3.86 - 3.74 (m, 8H), 3.26 - 3.17 (m, 4H), 2.81 (d, J =10.1 Hz, 2H), 2.64 (s, 6H), 2.04 - 1.82 (m, 4H), 1.17 (s, 6H), 0.98 (t, J =7.5 Hz, 6H), 0.60 (s, 6H). 10 Example 54, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(6-chloro-1H-indole-1,3- diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). Br O O O OMe O OMe OMe Cl NH2 Br TBAF NH HCl/EtOAc Cl Boc OMe Cl NHBoc Cl NHBoc THF EtOAc F c O F 15 Step 1 of 9: Synthesis of Intermediate 93.1, tert-butyl 6-(2-(benzyloxy)-4-chlorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate. 2-bromo-5-chloro-aniline (2 g, 9.69 mmol, 1 eq) and methyl (2S)-2-(tert-butoxycarbonylamino)- 5- triethylsilyl-pent-4-ynoate (4.96 g, 14.5 mmol, 1.5 eq) were added to a 100 mL round bottomed flask. Dioxane (40 mL) was added to the mixture under N2, then bis(tri-tert-20 butylphosphine)palladium(0) (247 mg, 484 umol, 0.05 eq) and N-cyclohexyl-N-methyl- cyclohexanamine (4.73 g, 24.2 mmol, 5.14 mL, 2.5 eq) were added to the mixture at 15°C under N2. The mixture was stirred at 60°C for 12 h under N2 after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction 277 70226WO01 mixture was added into saturated NH4Cl aq. (60 mL), then extracted with EtOAc (60 mL * 3). The combined organic phase was washed with brine (60 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 2:1) to give the title compound (2.7 g, 5.78 5 mmol, 59.68% yield) as a yellow oil. TLC ( Petroleum ether/EtOAc = 5:1) Rf = 0.47. LCMS (ES, m/z): 411.1 [M-Boc+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.99 (br s, 1H), 7.47 (br d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.05 (br d, J = 8.4 Hz, 1H), 4.93 (br d, J = 8.0 Hz, 1H), 4.56 (q, J = 7.1 Hz, 1H), 3.73 - 3.50 10 (m, 3H), 3.23 (br d, J = 6.8 Hz, 2H), 1.46 - 1.26 (m, 8H), 1.10 - 0.97 (m, 9H), 0.97 - 0.87 (m, 6H). Step 2 of 9: Synthesis of Intermediate 93.2, methyl (2S)-2-(tert-butoxycarbonylamino)- 3-(6- chloro-1H-indol-3-yl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(6- H- indol-3- 15 yl)propanoate (3 g, 6.42 mmol, 1 eq) in THF (30 mL) was added TBAF (1 M, 19.3 mL, 3 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was added into H2O (50 mL), then extracted with EtOAc (50 mL * 2). The combined organic phase was washed with brine (50 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (1.5 g, 4.25 mmol, 66.2% yield) as a yellow solid. TLC (Petroleum ether/ ethyl acetate = 2:1) Rf = 0.37. LCMS (ES, m/z): 253.0 [M-Boc+H]+ 25 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.26 (br s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 1.5 Hz, 1H), 7.13 - 6.89 (m, 2H), 5.09 (br d, J = 7.8 Hz, 1H), 4.85 - 4.44 (m, 1H), 3.68 (s, 3H), 3.26 (br t, J = 4.1 Hz, 2H), 1.44 (s, 8H). Step 3 of 9: Synthesis of Intermediate 93.3, methyl (2S)-2-(tert-butoxycarbonylamino)- 3-(6- 30 chloro-1-prop-2-ynyl-indol-3-yl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(6-chloro-1H-indol-3-yl) propanoate (1.45 g, 4.11 mmol, 1 eq) in DMF (15 mL) was added t-BuOK (507 mg, 4.52 mmol, 1.1 eq) at 0°C. The mixture was stirred at 0°C for 0.5 h and 3-bromoprop-1-yne (794 mg, 5.34 mmol, 576 uL, 80% purity, 1.3 eq) dissolved in DMF (5 mL) was added dropwise to the mixture at 0°C. The mixture 35 was stirred at 15°C for 2 h after which time LC-MS indicated complete consumption of starting 278 70226WO01 material with formation of a single peak of target mass. The mixture was quenched with H2O (10 mL), then extracted with EtOAc (30 mL * 3). The combined organic phase was washed with H2O (20 mL * 3), brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc 5 = 1:0 to 2:1) to give the title compound (1.2 g, 3.07 mmol, 74.7% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.61. LCMS (ES, m/z): 291.0 [M-Boc+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.45 (d, J = 8.5 Hz, 1H), 7.37 (s, 1H), 7.11 (dd, J = 1.3, 8.4 Hz, 1H), 7.00 (s, 1H), 5.07 (br d, J = 7.6 Hz, 1H), 4.79 (d, J = 2.5 Hz, 2H), 4.68 - 4.55 (m, 10 1H), 3.68 (s, 3H), 3.25 (br t, J = 4.9 Hz, 2H), 2.43 (t, J = 2.5 Hz, 1H), 1.44 (s, 9H). Step 4 of 9: Synthesis of Intermediate 93.4, methyl (2S)-2-amino-3-(6-chloro-1- prop-2-ynyl- indol-3-yl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(6-chloro-1-prop-2-ynyl-indol-3-yl) 15 propanoate (1.2 g, 3.07 mmol, 1 eq) in EtOAc (10 mL) was added HCl/EtOAc (4 M, 5 mL) at 0°C. The mixture was stirred at 40°C for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (820 mg, 2.51 mmol, 81.6% yield, HCl) as a white solid. 20 LCMS (ES, m/z): 291.1 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ = 8.68 (br s, 2H), 7.71 - 7.54 (m, 2H), 7.35 (s, 1H), 7.11 (dd, J = 1.6, 8.4 Hz, 1H), 5.08 (t, J = 2.3 Hz, 2H), 4.22 (br t, J = 6.1 Hz, 1H), 3.65 (s, 3H), 3.47 (t, J = 2.3 Hz, 1H), 3.34 - 3.22 (m, 2H). 25 Step 5 of 9: Synthesis of Intermediate 93.5, methyl (2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-(6-chloro-1-prop-2-ynyl-indol-3- l To a solution of methyl (2S)-2-amino-3-(6-chloro-1-prop-2-ynyl-indol-3-yl)propanoate (414 mg, 1.27 mmol, 1.1 eq, HCl), (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (250 mg, 1.15 30 mmol, 1 eq), and DIEA (446 mg, 3.45 mmol, 601 uL, 3 eq) in DCM (20 mL) was added HATU (569 mg, 1.50 mmol, 1.3 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC- MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (30 mL) and extracted with DCM (30 mL * 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, 35 filtered and concentrated under reduced pressure to give a residue. The residue was purified by 279 70226WO01 column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 2:1) to give the title compound (520 mg, 1.06 mmol, 92.2% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.50 LCMS (ES, m/z): 390.2 [M-Boc+H]+ 5 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.52 - 7.33 (m, 2H), 7.11 (dd, J = 1.6, 8.5 Hz, 1H), 7.06 - 6.82 (m, 1H), 4.83 - 4.73 (m, 2H), 4.57 - 4.27 (m, 1H), 3.68 (s, 3H), 3.25 (br d, J = 5.1 Hz, 2H), 2.69 - 2.50 (m, 3H), 2.45 - 2.37 (m, 1H), 2.03 - 1.91 (m, 1H), 1.79 - 1.49 (m, 2H), 1.41 (br s, 9H), 0.87 (t, J = 7.4 Hz, 3H). 10 Step 6 of 9: Synthesis of Intermediate 93.6, (2S)-2-[[(2S)-2-[tert-butoxycarbonyl (methyl)amino]butanoyl]amino]-3-(6-chloro-1-prop-2-ynyl-indol-3-yl)propanoic acid. To a solution of methyl (2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3- (6- 2-ynyl-indol-3-yl)propanoate (510 mg, 1.04 mmol, 1 eq) in MeOH (3 mL)/THF (9 mL)/H2O (3 mL) was added LiOH (74.8 mg, 3.12 mmol, 3 eq). The mixture was stirred at 15 °C 15 for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (15 mL), extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the combined organic phase was washed with brine (10 mL), 20 dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (370 mg, 777 umol, 74.7% yield) as a yellow oil. LCMS (ES, m/z): 376.1 [M-Boc+H]+ 1H NMR (400 MHz, DMSO-d6) δ = 8.22 - 7.83 (m, 1H), 7.65 - 7.50 (m, 2H), 7.21 (s, 1H), 7.06 (dd, J = 1.8, 8.5 Hz, 1H), 5.03 (br d, J = 1.8 Hz, 2H), 4.45 (br d, J = 4.1 Hz, 1H), 3.41 (br d, J = 2.4 Hz, 25 1H), 3.33 (s, 3H), 3.22 - 3.00 (m, 2H), 2.70 - 2.61 (m, 1H), 1.88 - 1.45 (m, 2H), 1.45 - 1.21 (m, 9H), 0.89 - 0.54 (m, 3H). Step 7 of 9: Synthesis of Intermediate 93.7, tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl (dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-30 1-[(6-chloro-1-prop-2-ynyl-indol-3-yl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl- carbamate. To a solution of (2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-(6- chloro- 1-prop-2-ynyl-indol-3-yl)propanoic acid (163 mg, 341 umol, 1.2 eq) tert-butyl- [[6-[(4- fluorophenyl) methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl- silane 35 (110 mg, 285 umol, 1 eq) and DIEA (110 mg, 854 umol, 149 uL, 3 eq) in DCM (6 mL) was added 280 70226WO01 HATU (141 mg, 370 umol, 1.3 eq) at 0°C. The mixture was stirred at 15°C for 5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (20 mL) and extracted with DCM (10 mL * 3). The combined organic phase was washed with brine (20 mL), dried over 5 Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (Petroleum ether/ ethyl acetate = 2:1) to give the title compound (160 mg, 189 umol, 66.6% yield) as a white solid. LCMS (ES, m/z): 844.2 [M+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.15 (br d, J = 7.1 Hz, 1H), 7.55 (br d, J = 6.6 Hz, 10 1H), 7.32 (s, 1H), 7.15 (dd, J = 5.7, 8.2 Hz, 2H), 7.05 - 6.91 (m, 4H), 5.14 - 4.98 (m, 1H), 4.70 (br s, 2H), 3.86 (s, 2H), 3.70 (br d, J = 7.9 Hz, 1H), 3.17 (br d, J = 7.0 Hz, 2H), 3.07 - 2.91 (m, 1H), 2.73 (s, 3H), 2.23 (s, 1H), 1.99 (br s, 1H), 1.77 - 1.50 (m, 2H), 1.50 - 1.36 (m, 9H), 1.15 (s, 3H), 0.93 - 0.85 (m, 12H), 0.69 (br s, 3H), 0.26 (d, J = 2.1 Hz, 6H). 15 Step 8 of 9: Synthesis of Intermediate 93.8, tert-butyl N-[(1S)-1-[[(1S)-1-[[1-[6-[3-[(2S)- 2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimet H-pyrrolo[3,2-b]pyridin- 1-yl]-3-oxo-propyl]-6-chloro-indol-1-yl]hexa-2,4-diynyl]-6-chloro-indol-3-yl]methyl]-2-[5- [tert ethyl]-3,3-dimethyl-2H-pyrrolo[3,2- 20 b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate. To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl) methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(6-chloro-1-prop-2-ynyl-indol-3- yl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (130 mg, 154 umol, 1 eq) in CH3CN (6 mL) was added Cu(OAc)2 (33.5 mg, 185 umol, 1.2 eq) and pyridine (73.1 mg, 924 25 umol, 74.6 uL, 6 eq). The mixture was stirred at 85°C for 2 h under air environment after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was added into saturated NH3.H2O aq. (5 mL), then extracted with EtOAc (10 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (110 mg, 65.2 umol, 84.7% yield) as a brown solid. 30 LCMS (ES, m/z): 1475.7 [M-2TBS+H]+ Step 9 of 9: Synthesis of Example 54, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(6- chloro-1H-indole-1,3-diyl))bis(3-(6-(4-fluoro -3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro- 1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). 281 70226WO01 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[1-[6-[3-[(2S)-2-[[(2S)-2-[tert-butoxycarbonyl (methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-6-chloro-indol-1-yl]hexa-2,4-diynyl]- 6-chloro-indol-3-yl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- 5 dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (90 mg, 53.4 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 2 mL) at 0°C. The mixture was stirred at 15°C for 1 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a crude product. The residue was purified by preparative HPLC (column: 10 Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(0.1%TFA)- CH3CN], B%: 25%- 55%, 8 min) to give the title compound (8.9 mg, 7.07 umol, 13.3% yield, 100% purity) as a yellow solid. LCMS (ES, m/z): 626.9 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.18 (s, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.49 - 7.37 (m, 15 2H), 7.24 (br dd, J = 5.5, 8.4 Hz, 4H), 7.14 (s, 2H), 7.06 - 6.91 (m, 6H), 4.97 (s, 4H), 3.90 - 3.72 (m, 8H), 3.35 (s, 4H), 3.22 (br d, J = 8.0 Hz, 4H), 2.87 (br d, J = 10.3 Hz, 2H), 2.63 (s, 6H), 1.99 - 1.84 (m, 4H), 1.19 (s, 6H), 0.98 (br t, J = 7.5 Hz, 6H), 0.62 (s, 6H). Example 55, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(4-chloro-1H-indole-1,3-20 diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-ox , is(2-(methylamino)butanamide). Cl O O Br O O O Cl (S Cl (S) OH (S) Cl ) OMe (S) OMe Cl (S) OMe NH Br OMe 2 NHBoc LiOH NHBoc TES NHBoc Pd[P(tBu)3]2, Cy2NMe NHBoc NHBoc t-BuOK, DMF THF, H2O N F Boc Step 1 of 10: Synthesis of Intermediate 94.1, methyl(2S)-2-(tert-butoxycarbonylamino)- 3-(4- 25 chloro-2-triethylsilyl-1H-indol-3-yl)propanoate. 282 70226WO01 2-bromo-3-chloro-aniline (2.82 g, 13.6 mmol, 1 eq), and methyl (2S)-2-(tert-butoxycarbonylamino) -5-triethylsilyl-pent-4-ynoate (7 g, 20.5 mmol, 1.5 eq) were added to a 250 mL round bottomed flask. Dioxane (120 mL), bis(tri-tert-butylphosphine)palladium(0) (349 mg, 683 umol, 0.05 eq) and N-cyclohexyl-N-methyl-cyclohexanamine (6.67 g, 34.1 mmol, 7.25 mL, 2.5 eq) were added to 5 the mixture at 15°C under N2. The mixture was stirred at 60°C for 12 h under N2 after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (80 mL), then extracted with EtOAc (60 mL * 3). The combined organic phase was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was 10 purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0: to 10:1) to give impure product. The crude product was purified by reversed-phase MPLC (column: 800g Agela C18; mobile phase: [water-THF-CH3CN]; B%:45-75% 30 min;75% 25min, 120 mL/min) to give the title compound (4.86 g, 10.4 mmol, 76.1% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.50. 15 LCMS (ES, m/z): 367.1 [M-Boc+H]+ Step 2 of 10: Synthesis of Intermediate 94.2, methyl(2S)-2-(tert-butoxycarbonylamino) -3-(4- chloro-1H-indol-3-yl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-chloro-2-triethylsilyl-1H-indol- 3- 20 yl)propanoate (4.86 g, 10.4 mmol, 1 eq) in THF (50 mL) was added TBAF (1 M, 31.2 mL, 3 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was added into H2O (15 mL), then extracted with EtOAc (30 mL * 2). The combined organic phase was washed with brine (30 mL), dried over 25 Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (885 mg, 2.51 mmol, 24.1% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.60. LCMS (ES, m/z): 253.1 [M-Boc+H]+ 30 Step 3 of 10: Synthesis of Intermediate 94.3, methyl(2S)-2-(tert-butoxycarbonylamino) -3-(4- chloro-1-prop-2-ynyl-indol-3-yl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-chloro-1H-indol-3-yl) propanoate (883 mg, 2.50 mmol, 1 eq) in DMF (10 mL) was added t-BuOK (309 mg, 2.75 mmol, 1.1 eq) at 35 0°C. The mixture was stirred at 0°C for 0.5 h and 3-bromoprop-1-yne (484 mg, 3.25 mmol, 350 283 70226WO01 uL, 80% purity, 1.3 eq) dissolved in DMF (1 mL) was added dropwise to the mixture at 0°C. The mixture was stirred at 15°C for 1 h after which time TLC (Petroleum ether/EtOAc = 1:1) indicated complete consumption of the starting material. The mixture was quenched with 15 mL H2O, then extracted with EtOAc (20 mL * 3). The combined organic phase was washed with H2O (30 mL * 5 5) and brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (539 mg, 1.38 mmol, 55.1% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.50. LCMS (ES, m/z): 391.1 [M-Boc+H]+ 10 Step 4 of 10: Synthesis of Intermediate 94.4, (2S)-2-(tert-butoxycarbonylamino)-3-(4- chloro- 1-prop-2-ynyl-indol-3-yl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-chloro- 1-prop-2-ynyl-indol- 3- yl)propanoate (535 mg, 1.37 mmol, 1 eq) in H2O (2 mL)/THF (6 mL) was added LiOH (98.3 mg, 15 4.11 mmol, 3 eq). The mixture was stirred at 15°C for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (8 mL), extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the 20 combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (446 mg, 1.18 mmol, 86.4% yield) as a yellow solid. LCMS (ES, m/z): 277.1 [M-Boc+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 7.14 (q, J = 7.6 Hz, 4H), 5.11 (br s, 1H), 4.80 - 4.57 25 (m, 2H), 3.94 - 3.64 (m, 2H), 3.41 (br d, J = 7.5 Hz, 1H), 2.42 (br s, 1H), 1.40 (br s, 8H). Step 5 of 10: Synthesis of Intermediate 94.5, tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl) silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(4- chloro-1-prop-2-ynyl-indol-3-yl)methyl]-2-oxo-ethyl]carbamate. 30 To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(4-chloro-1-prop-2-ynyl-indol-3-yl) propanoic acid (426 mg, 1.13 mmol, 1.2 eq) in DCM (6 mL) was added DIEA (365 mg, 2.83 mmol, 492 uL, 3 eq), tert-butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo [3,2- b]pyridin-5-yl]oxy]-dimethyl-silane (364 mg, 942 umol, 1 eq) and HATU (537 mg, 1.41 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of 35 starting material with formation of a single peak of target mass. The residue was added into 284 70226WO01 saturated NH4Cl aq. (12 mL), then extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (497 mg, 667 umol, 70.8% yield) as a yellow oil. 5 TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.60. LCMS (ES, m/z): 745.4 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 7.24 - 6.91 (m, 8H), 5.31 (br s, 2H), 4.68 (br s, 2H), 3.84 (br s, 2H), 3.53 (br s, 1H), 3.34 - 3.16 (m, 2H), 2.58 (br s, 1H), 2.16 - 2.02 (m, 1H), 1.41 (br s, 9H), 1.31 - 1.15 (m, 6H), 0.90 (br s, 9H), 0.25 (br s, 6H). 10 Step 6 of 10: Synthesis of Intermediate 94.6, 1-[(2S)-2-amino-3-(4-chloro-1-prop-2-ynyl - indol-3-yl)propanoyl]-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2- b]pyridin-5-one. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(d ]oxy-6-[(4-fluorophenyl)methyl] -15 3,3-dimet -pyrrolo[3,2-b]pyridin-1-yl]-1-[(4-chloro-1-prop-2-ynyl-indol-3-yl)methyl]-2-oxo- ethyl]carbamate (495 mg, 664 umol, 1 eq) in EtOAc (4 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 15°C for 5 h. LC-MS indicated complete conversion to a product of target mass. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (376 mg, 662 umol, 99.8% yield, HCl) as a yellow oil. 20 LCMS (ES, m/z): 531.3 [M+H]+ Step 7 of 10: Synthesis of Intermediate 94.7, 2S)-2-amino-1-[5-[tert-butyl(dimethyl)silyl] oxy- 6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-(4-chloro-1-prop-2- ynyl-indol-3-yl)propan-1-one. 25 To a solution of 1-[(2S)-2-amino-3-(4-chloro-1-prop-2-ynyl-indol-3-yl)propanoyl]-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one (376 mg, 663 umol, 1 eq, HCl) and imidazole (293 mg, 4.31 mmol, 6.5 eq) in DCM (8 mL) was added TBSCl (250 mg, 1.66 mmol, 203 uL, 2.5 eq) at 0°C. The mixture was stirred at 15°C for 5 h after which time LC- MS indicated complete consumption of starting material with formation of a single peak of target 30 mass. The residue was added into saturated NH4Cl aq. (20 mL) and extracted with DCM (30 mL * 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol/TEA = 20:2:1) to give the title compound (420 mg, 651 umol, 98.2% yield) as a yellow oil. 35 TLC (EtOAc/Methanol/TEA = 20:2:1) Rf = 0.60. 285 70226WO01 LCMS (ES, m/z): 645.3 [M+H]+ Step 8 of 10: Synthesis of Intermediate 94.8, tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl (dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 5 1-[(4-chloro-1-prop-2-ynyl-indol-3-yl)methyl]-2-oxo-e pyl]-N-methyl- carbamate. To a solution of (2S)-2-amino-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-(4-chloro-1-prop-2-ynyl-indol-3-yl)propan-1-one (380 mg, 589 umol, 1.1 eq) in DCM (6 mL) was added DIEA (207 mg, 1.61 mmol, 280 uL, 3 eq), (2S)- 10 2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (116 mg, 535 umol, 1 eq) and HATU (305 mg, 803 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH4Cl aq. (12 mL), then extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and 15 concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0: to 5:1) to give the title compound (450 mg, 533 umol, 99.5% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.45 LCMS (ES, m/z): 844.4 [M+H]+ 20 1H NMR (400MHz, CHLOROFORM-d) δ = 7.26 - 7.11 (m, 5H), 7.03 - 6.90 (m, 3H), 5.35 - 5.16 (m, 2H), 4.70 (br s, 2H), 4.62 - 4.27 (m, 1H), 4.00 - 3.80 (m, 3H), 3.61 - 3.16 (m, 3H), 2.67 (br s, 3H), 1.70 - 1.56 (m, 3H), 1.54 - 1.44 (m, 9H), 1.18 (br s, 3H), 0.90 (s, 9H), 0.89 - 0.83 (m, 3H), 0.79 - 0.53 (m, 3H), 0.25 (d, J=1.3 Hz, 6H). 25 Step 9 of 10: Synthesis of Intermediate 94.9, tert-butyl N-[(1S)-1-[[(1S)-1-[[1-[6-[3-[(2S)- 2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amin ]-3-[5-[t rt- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- e y- -py o o , - pyridin- 1-yl]-3-oxo-propyl]-4-chloro-indol-1-yl]hexa-2,4-diynyl]-4-chloro-indol-3-yl]methyl]-2-[5- l i h l il l]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2- 30 b]pyr d n- -y]- -oxo-ethyl]car yl-carbamate. To a solution of tert-butyl N-[(1S )-1-[[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl) methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(4-chloro-1-prop-2-ynyl-indol-3- yl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (250 mg, 296 umol, 1 eq) in CH3CN (6 mL) was added pyridine (140 mg, 1.78 mmol, 143 uL, 6 eq) and Cu(OAc)2 (64.5 mg, 35 355 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment after which time 286 70226WO01 LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH3 aq. (20 mL), then extracted with EtOAc (20 mL * 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue to give the title compound (245 mg, 145 5 umol, 98.1% yield) as a yellow oil. LCMS (ES, m/z): 1457.6 [M-2TBS+H]+ Step 10 of 10: Synthesis of Example 55, (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(4- chloro-1H-indole-1,3-diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro- 10 1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[1-[6-[3-[(2S)-2-[[(2S)-2-[tert-butoxycarbonyl butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-4-chloro-indol-1-yl]hexa-2,4-diynyl]- 4-chloro-indol-3-yl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- 15 dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (245 mg, 145 umol, 1 eq) in EtOAc (5 mL) was added HCl/dioxane (4 M, 5 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and to give crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna 20 80*30mm, 3um; mobile phase: [water(TFA)-CH3CN], B%: 25%-55%, 8 min) to give the title compound (89 mg, 59.9 umol, 41.2% yield, 100% purity, 2 TFA) as an off-white solid. LCMS (ES, m/z): 630.4 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 8.18 (s, 1H), 7.98 (s, 1H), 7.51 (d, J=7.3 Hz, 1H), 7.28 - 6.93 (m, 14H), 6.56 (s, 1H), 5.19 - 5.03 (m, 2H), 4.99 - 4.91 (m, 1H), 4.84 - 4.66 (m, 4H), 4.40 (br 25 s, 1H), 4.21 - 3.99 (m, 2H), 3.89 - 3.68 (m, 8H), 3.66 - 3.49 (m, 2H), 3.24 - 3.12 (m, 1H), 3.01 (br t, J=12.6 Hz, 1H), 2.90 - 2.83 (m, 1H), 2.74 (s, 1H), 2.72 (s, 3H), 2.66 (s, 3H), 2.07 - 1.79 (m, 4H), 1.20 (s, 3H), 1.10 - 0.89 (m, 9H), 0.65 (s, 2H), 0.16 (s, 2H). Example 56, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(3-methoxy-4,1-30 phenylene))bis(3-(6-( orobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxo propane-1,2-diyl))bis(2-(methylamino)butanamide). 287 70226WO01 MeO N O (R) MeO (S) O N N Boc OH (S) O O NaBH4 O OH SOCl2 O OMe Cl n-BuLi, THF O N (R) 2N HCl O OMe N NH DIEA, HATU, DCM MeOH DC 2 BnO BnO M BnO BnO BnO OMe F O Step 1 of 11: Synthesis of Intermediate 95.1, (4-(benzyloxy)-3-methoxyphenyl)methanol. To a solution of 4-benzyloxy-3-methoxy-benzaldehyde (5 g, 20.6 mmol, 1 eq) in MeOH (50 mL) 5 was added NaBH4 (1.08 g, 28.6 mmol, 1.38 eq) dropwise at 0°C. The mixture was stirred at 15°C for 2 h after which time TLC (Petroleum ether/EtOAc = 1:1) indicated complete consumption of starting material and formation of one new spot. The reaction was quenched with water (5 mL), cooled, stirred for 15 minutes, and the solvent was removed under reduced pressure. EtOAc (100 mL) and H2O (100 mL) were added to the crude compound and the layers were separated. The 10 aqueous layer was extracted with EtOAc (50 mL * 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:2) to give the title compound (4.7 g, 19.2 mmol, 93.2% yield) as a white solid. LCMS (ES, m/z): 243.1 [M-H+] 15 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.51 - 7.45 (m, 2H), 7.43 - 7.29 (m, 3H), 6.99 - 6.80 (m, 3H), 5.18 (s, 2H), 4.61 (s, 2H), 3.92 (s, 3H). Step 2 of 11: Synthesis of Intermediate 95.2, 1-(benzyloxy)-4-(chloromethyl)-2- methoxybenzene. 20 To a solution of (4-benzyloxy-3-methoxy-phenyl)methanol (3.8 g, 15.6 mmol, 1 eq) in DCM (40 mL) was added SOCl2 (2.22 g, 18.7 mmol, 1.35 mL, 1.2 eq) at 15°C under N2. The mixture was stirred at 60°C for 2 h after which time TLC (Petroleum ether/EtOAc = 2:1) indicated complete consumption of starting material and formation of a new product. The mixture was allowed to return to room temperature and then treated with ice-cold water (80 mL). Under stirring, sodium 25 hydrogencarbonate was added to the mixture until basic. The organic layer was separated and the 288 70226WO01 recovered aqueous layer extracted with dichloromethane (3 * 40 mL). The combined organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (2.64 g, 10.1 mmol, 64.6% yield) as a white solid. 5 TLC (Petroleum ether/EtOAc = 4:1) Rf = 0.35 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.47 - 7.30 (m, 5H), 6.95 (d, J = 1.5 Hz, 1H), 6.91 - 6.82 (m, 2H), 5.17 (s, 2H), 4.56 (s, 2H), 3.92 (s, 3H). Step 3 of 11: Synthesis of Intermediate 95.3, (5R)-2-(4-(benzyloxy)-3-methoxybenzyl)-5- 10 isopropyl-3,6-dimethoxy-2,5-dihydropyrazine. To a mixture of (2R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (0.62 g, 3.37 mmol, 602 uL, 1 eq) in THF (30 mL) at -78°C was added n-BuLi (2.5 M, 1.68 mL, 1.25 eq) under N2, then the mixture stirred at -78°C for 30 min. To the mixture was added 1-benzyloxy-4-(chloromethyl)-2- methoxy-benzene (1.15 g, 4.37 mmol, 1.3 eq) in THF (5 mL) dropwise at -78 °C and stirred at - 15 78°C for 6 h. The mixture was warmed to 15°C and stirred for 6 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into H2O (30 mL) and saturated NaHCO3 aq. (30 mL), then extracted with EtOAc (50 mL * 2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was 20 purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (1.1 g, 2.68 mmol, 79.6% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.53 LCMS (ES, m/z): 411.1 [M+H+] 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.45 - 7.41 (m, 2H), 7.39 - 7.33 (m, 2H), 7.32 - 7.29 25 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 1.8 Hz, 1H), 6.57 (dd, J = 1.9, 8.1 Hz, 1H), 5.11 (s, 2H), 4.31 (br d, J = 3.4 Hz, 1H), 3.83 (s, 3H), 3.75 - 3.67 (m, 6H), 3.31 (t, J = 3.1 Hz, 1H), 3.04 (br d, J = 4.6 Hz, 1H), 2.16 (dtd, J = 3.1, 6.7, 13.6 Hz, 1H), 1.55 (s, 1H), 0.96 (d, J = 6.9 Hz, 3H), 0.62 (d, J = 6.9 Hz, 3H). 30 Step 4 of 11: Synthesis of Intermediate 95.4, (S)-methyl 2-amino-3-(4-(benzyloxy)-3- methoxyphenyl)propanoate. To a solution of (5R)-2-[(4-benzyloxy-3-methoxy-phenyl)methyl]-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazine (710 mg, 1.73 mmol, 1 eq) in THF (12 mL) was added HCl (2 M, 4 mL) at 0°C. The mixture was stirred at 15°C for 1.5 h. LC-MS indicated complete consumption of starting 35 material with formation of a single peak of target mass. The reaction mixture was added into 289 70226WO01 NH3.H2O (15 mL), then the mixture was concentrated under reduced pressure to give a residue. The crude product was dissolved in NH3.H2O (15 mL), then extracted with DCM (15 mL * 2). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (500 mg, 1.59 mmol, 91.7% yield) as a yellow oil. 5 LCMS (ES, m/z): 316.2 [M+H+] Step 5 of 11: Synthesis of Intermediate 95.5, (S)-methyl 3-(4-(benzyloxy)-3-methoxyphenyl)- 2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)butanamido)propanoate. To a solution of methyl (2S)-2-amino-3-(4-benzyloxy-3-methoxy-phenyl)propanoate (500 mg, 1.59 10 mmol, 1 eq) and (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (448 mg, 2.06 mmol, 1.3 eq) in DCM (15 mL) was added DIEA (820 mg, 6.34 mmol, 1.10 mL, 4 eq) and HATU (904 mg, 2.38 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (15 mL), then extracted with DCM (15 mL * 3). The 15 combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (640 mg, 1.24 mmol, 78.4% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.33 LCMS (ES, m/z): 415.2 [M-Boc+H+] 20 Step 6 of 11: Synthesis of Intermediate 95.6, (S)-methyl 2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)butanamido)-3-(4-hydroxy-3-methoxyphenyl)propanoate. To a solution of methyl (2S)-3-(4-benzyloxy-3-methoxy-phenyl)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]propanoate (640 mg, 1.24 mmol, 1 eq) in MeOH 25 (50 mL) was added Pd/C (320 mg, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (520 mg, 1.23 mmol, 98.5% yield) as a yellow oil. 30 LCMS (ES, m/z): 425.1 [M+H+] Step 7 of 11: Synthesis of Intermediate 95.7, (S)-methyl 2-((S)-2-((tert- butoxycarbonyl)(methyl)amino)butanamido)-3-(3-methoxy-4-(prop-2-yn-1- yloxy)phenyl)propanoate. 90 70226WO01 A mixture of methyl (2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino] -3-(4- hydroxy-3-methoxy-phenyl)propanoate (490 mg, 1.15 mmol, 1 eq), 3-bromoprop -1-yne (223 mg, 1.50 mmol, 162 uL, 80% purity, 1.3 eq), and K2CO3 (319 mg, 2.31 mmol, 2 eq) in DMF (15 mL) was stirred at 60°C for 12 h. LC-MS indicated complete consumption of starting material with 5 formation of a single peak of target mass. The mixture was filtered and the filtrate was added into saturated NH4Cl aq. (25 mL), then extracted with EtOAc (20 mL * 2). The combined organic phase was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 1:1) to give the title compound (450 mg, 973 umol, 84.3% yield) as a yellow oil. 10 TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.43 LCMS (ES, m/z): 363.2 [M-Boc+H+]. Step 8 of 11: Synthesis of Intermediate 95.8, (S)-2-((S)-2-((tert-butoxycarbonyl) (methyl)amino)butanamido)-3-(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)propanoic acid.15 To a solution of methyl (2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-(3- p-2-ynoxy-phenyl)propanoate (450 mg, 973 umol, THF (9 mL)/MeOH (3 mL)/H2O (3 mL) was added LiOH (69.9 mg, 2.92 mmol, 3 eq). The mixture was stirred at 15°C for 2 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to 20 give a residue. The residue was dissolved in H2O (15 mL), then extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (430 mg, 959 umol, 98.5% yield) as a yellow oil. 25 LCMS (ES, m/z): 349.2 [M-Boc+H+]. Step 9 of 11: Synthesis of Intermediate 95.9, tert-butyl ((S)-1-(((S)-1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)amino)-1- 30 oxobutan-2-yl)(methyl)carbamate. To a solution of (2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-(3- methoxy-4-prop-2-ynoxy-phenyl)propanoic acid (200 mg, 446 umol, 1.2 eq) in DCM (5 mL) was added DIEA (192 mg, 1.49 mmol, 259 uL, 4 eq), tert-butyl-[[6-[(4-fluorophenyl) methyl]-3,3- dimethyl -1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (144 mg, 372 umol, 1 eq) 35 and HATU (212 mg, 557 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS 291 70226WO01 indicated complete conversion to a product of target mass. The reaction mixture was added into saturated NH4Cl aq. (10 mL) and extracted with DCM (8 mL * 3). The combined organic phase was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum 5 ether/EtOAc = 3:1) to give the title compound (150 mg, 184 umol, 49.4% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.34 LCMS (ES, m/z): 818.4 [M +H+]. Step 10 of 11: Synthe iate 95.10, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-10 diyne-1,6-diylbis(oxy))bis(3-methoxy-4,1-phenylene))bis(1-(5-((tert-butyldimethylsilyl)oxy)-6- (4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- diyl))bis(azanediyl))bis(1-oxobutane-2,1 methylcarbamate). To a solution of tert-butyl N-[(1S)-1-[[2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(3-methoxy-4-prop-2-ynoxy- 15 phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (140 mg, 171 umol, 1 eq) in CH3CN (5 mL) was added Cu(OAc)2 (37.4 mg, 206 umol, 1.2 eq) and pyridine (81.3 mg, 1.03 mmol, 83 uL, 6 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete conversion to a product of target mass. The reaction mixture was filtered and the mixture was added into NH3.H2O (8 mL), extracted with EtOAc (8 mL * 3), dried over Na2SO4, 20 filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (50 mg, 30.6 umol, 17.9% yield) as a yellow oil. TLC (EtOAc) Rf = 0.63 LCMS (ES, m/z): 1517.6 [M+H+] 25 Step 11 of 11: Synthesis of Example 56, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(3-methoxy-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). 30 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-2-methoxy- phenoxy]hexa-2,4-diynoxy]-3-methoxy-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- 35 N-methyl-carbamate (50 mg, 30.6 umol, 1 eq) in EtOAc (1.5 mL) was added HCl/dioxane (4 M, 3 292 70226WO01 mL). The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100*40mm, 5um; mobile phase: 5 [water(0.1%TFA)-CH3CN], B%: 20%-45%, 8 min) to give the title compound (6.4 mg, 4.36 umol, 14.2% yield, 97.492% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 602.4 [M/2+H+] 1H NMR (400 MHz, METHANOL-d4) δ = 8.24 - 8.20 (m, 2H), 7.25 (dd, J = 5.5, 8.6 Hz, 4H), 7.03 - 6.97 (m, 4H), 6.92 - 6.80 (m, 6H), 4.82 - 4.72 (m, 6H), 3.96 (d, J = 10.5 Hz, 2H), 3.83 - 3.72 (m, 10 6H), 3.66 - 3.60 (m, 6H), 3.08 - 2.99 (m, 6H), 2.63 - 2.59 (m, 6H), 1.99 - 1.83 (m, 4H), 1.31 - 1.25 (m, 6H), 1.03 - 0.92 (m, 12H). Example 57, (2S,2'S)-N,N'-((2S,2'S)-(adipoylbis(piperidine-1,4-diyl))bis(3-(6-(4-fluorobenzyl)- 3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2- 15 diyl))bis(2-( mide). Step 1 of 6: Synthesis of Intermediate 96.1, tert-butyl (S)-4-(2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- 20 dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropyl)piperidine-1-carboxylate. (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)piperidin-4- yl)propanoic acid (985 mg, 1 Eq, 1.99 mmol), 5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)- 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (770 mg, 1 Eq, 1.99 mmol) and DIPEA (309 mg, 416 μL, 1.2 Eq, 2.39 mmol) were combined in DMF (1.5 mL) and treated with HATU (909 25 mg, 1.2 Eq, 2.39 mmol) at ambient temperature overnight after which time TLC indicated complete conversion to a new spot. The mixture was diluted with EtOAc, washed twice with water, once with brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified on 293 70226WO01 40 g silica eluted with 20-35% EtOAc/hexanes to give the title compound (0.88 g, 1.0 mmol, 51 %) as a brown foam. Step 2 of 6: Synthesis of Intermediate 96.2, tert-butyl (S)-4-(2-amino-3-(5-((tert- 5 butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropyl)piperidine-1-carboxylate. A solution of tert-butyl (S)-4-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1- yl)-3-oxopropyl)piperidine-1-carboxylate (0.80 g, 1 Eq, 0.93 mmol) in DMF (3 mL) was treated 10 with piperidine (1.3 g, 1.5 mL, 16 Eq, 15 mmol) at ambient temperature for 15 min after which time the starting material had been consumed. Addition of water resulted in precipitation of a solid that was filtered off and discarded. The filtrate was extracted with EtOAc and the organic phase was isolated, washed twice with brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified on 40g silica eluted with 0-10% CH3OH in DCM to give the title 15 compound (0.43 g, 0.67 mmol, 72 %), as a pink oil. LCMS (ES, m/z): 527.29 [M-TBS+H+] Step 3 of 6: Synthesis of Intermediate 96.3, tert-butyl 4-((S)-2-((S)-2- (((benzyloxy)carbonyl)(methyl)amino)propanamido)-3-(5-((tert-butyldimethylsilyl)oxy)-6-(4-20 fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropyl)piperidine-1-carboxylate. Tert-butyl (S)-4-(2-amino-3-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3- dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropyl)piperidine-1-carboxylate (0.430 g, 1 Eq, 671 μmol), N-((benzyloxy)carbonyl)-N-methyl-L-alanine (159 mg, 1 Eq, 671 μmol), HOBt (123 mg, 25 1.2 Eq, 805 μmol), and DIPEA (217 mg, 292 μL, 2.5 Eq, 1.68 mmol) were combined in DCM and treated with EDC (154 mg, 1.2 Eq, 805 μmol) overnight at ambient temperature. The mixture was diluted with DCM, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 24 g silica eluted with 0-10% CH3OH/DCM to give the title compound (450 mg, 523 μmol, 78.0 %) as a tan foam. 30 LCMS (ES, m/z): 746.31 [M-TBS+H+] Step 4 of 6: Synthesis of Intermediate 96.4, benzyl ((S)-1-(((S)-1-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(piperidin-4- yl)propan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate. 294 70226WO01 tert-butyl 4-((S)-2-((S)-2-(((benzyloxy)carbonyl)(methyl)amino)propanamido)-3-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1- yl)-3-oxopropyl)piperidine-1-carboxylate (450 mg, 1 Eq, 523 μmol) was dissolved in DCM (5 mL) and treated with TFA (740 mg, 500 μL, 12.4 Eq, 6.49 mmol) for 30 min at ambient 5 temperature after which time TLC indicated complete consumption of starting material. The mixture was concentrated to dryness, dissolved in DCM, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated to dryness to give the crude title compound (333 mg, 516 μmol, 98.6 %). LCMS (ES, m/z): 647.14 [M+H]+ 10 Step 5 of 6: Synthesis of Intermediate 96.5, dibenzyl ((2S,2'S)-(((2S,2'S)- (adipoylbis(piperidine-1,4-diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl) ne-1,2-diyl))bis(azanediyl))bis(1- oxopropane-1,2-diyl))bis(methylcarbamate). 15 A solution of benzyl (( (S)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(piperidin-4-yl)propan-2-yl)amino)-1-oxopropan-2- yl)(methyl)carbamate (54.2 mg, 2 Eq, 84.0 μmol) in DCM (1 mL) was treated with DIPEA (16.3 mg, 21.9 μL, 3 Eq, 126 μmol) and adipoyl dichloride (7.69 mg, 1 Eq, 42.0 μmol) with stirring at ambient temperature overnight. The crude reaction mixture was purified on 12 g silica gel eluted 20 with 0-15% CH3OH/DCM to give the title compound (56.1 mg, 40.0 μmol, 95.3 %). LCMS (ES, m/z): 1401.7 [M+H]+ Step 6 of 6: Synthesis of Example 57, (2S,2'S)-N,N'-((2S,2'S)-(adipoylbis(piperidine-1,4- diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- 25 b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)propanamide). Dibenzyl ((2S,2'S)-(((2S,2'S)-(adip lbis(piperidine-1,4-diyl))bis(3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro- -pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2- diyl))bis(azanediyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (56.1 mg, 1 eq, 40.0 μmol) dissolved in a mixture of CH3OH (5 mL) and EtOH (5 mL) was treated with a catalytic 30 amount of 10% Pd/C under H2 (1 atm) with vigorous stirring for 16 h at ambient temperature after which time LCMS indicated formation of the desired product. The catalyst was removed by filtration through Celite and the filtrate was concentrated to dryness. The residue was purified on 12 g silica gel eluted with a gradient of CH3CH/H2O/NH4OH (94:3:3) to (90:5:5) to give the title compound (10.3 mg, 9.09 μmol, 22.7 %). 35 LCMS (ES, m/z): 567.12 [M/2+H]+ 295 70226WO01 1H NMR (600 MHz, Methanol-d4) δ 8.20 (d, J = 1.2 Hz, 2H), 7.27 (dd, J = 8.5, 5.5 Hz, 4H), 7.00 (t, J = 8.8 Hz, 4H), 4.78 (dd, J = 9.9, 3.4 Hz, 2H), 4.53 (t, J = 12.1 Hz, 2H), 4.19 (dd, J = 10.4, 1.9 Hz, 2H), 4.06 – 3.94 (m, 2H), 3.89 (dd, J = 10.3, 7.5 Hz, 2H), 3.82 (d, J = 3.0 Hz, 4H), 3.17 (q, J = 6.8 Hz, 2H), 3.11 – 2.97 (m, 2H), 2.65 – 2.50 (m, 2H), 2.42 (d, J = 6.1 Hz, 4H), 2.33 (s, 6H), 1.99 – 5 1.55 (m, 14H), 1.42 (d, J = 2.9 Hz, 6H), 1.40 (d, J = 1.4 Hz, 6H), 1.25 (d, J = 6.9 Hz, 6H), 1.23 – 1.01 (m, 4H). The following final compounds were prepared according to the same procedure as Example 57, replacing adipoyl dichloride with the appropriate bis-acid chloride: Examples 58-60. The 10 compounds were found to have characterizing data as set forth below. Example 58, (2S,2'S)-N,N'-((2S,2'S)-(octanedioylbis(piperidine-1,4-diyl))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide). 15 1H NMR (600 MHz, Methanol-d4) δ 8.18 (d, J = 1.4 Hz, 2H), 7.24 (dd, J = 8.5, 5.5 Hz, 4H), 6.98 (t, J = 8.8 Hz, 4H), 4.76 (dd, J = 10.2, 3.5 Hz, 2H), 4.51 (t, J = 12.4 Hz, 2H), 4.20 – 4.12 (m, 2H), 3.95 (t, J = 11.9 Hz, 2H), 3.87 (dd, J = 10.4, 6.9 Hz, 2H), 3.79 (d, J = 3.2 Hz, 4H), 3.17 (q, J = 6.7 20 Hz, 2H), 3.03 (dt, J = 29.4, 12.4 Hz, 2H), 2.62 – 2.48 (m, 2H), 2.37 (dt, J = 11.7, 6.5 Hz, 4H), 2.32 (s, 6H), 1.96 – 1.84 (m, 2H), 1.80 – 1.51 (m, 12H), 1.45 – 1.27 (m, 16H), 1.27 – 0.98 (m, 10H). Example 59, (2S,2'S)-N,N'-((2S,2'S)-(decanedioylbis(piperidine-1,4-diyl))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- 25 oxopropane-1,2-diyl))bis(2-(methylamino)propana i 70226WO01 1H NMR (600 MHz, Methanol-d4) δ 8.16 (d, J = 1.7 Hz, 2H), 7.24 (dd, J = 8.5, 5.6 Hz, 4H), 6.98 (t, J = 8.8 Hz, 4H), 4.77 – 4.69 (m, 2H), 4.56 – 4.47 (m, 2H), 4.18 (dd, J = 10.3, 5.8 Hz, 2H), 4.01 – 3.92 (m, 2H), 3.88 (dd, J = 10.3, 7.6 Hz, 2H), 3.80 (s, 4H), 3.76 – 3.66 (m, 2H), 3.12 – 2.98 (m, 2H), 2.64 – 2.50 (m, 8H), 2.37 (td, J = 7.7, 3.8 Hz, 4H), 1.89 (dd, J = 20.3, 13.1 Hz, 2H), 1.81 – 5 1.61 (m, 6H), 1.57 (t, J = 7.4 Hz, 6H), 1.45 (dd, J = 7.0, 3.2 Hz, 6H), 1.43 – 0.96 (m, 24H). 70226WO01 (16.3 mg, 21.9 μL, 3 Eq, 126 μmol) and bis(4-isocyanatophenyl)methane (10.5 mg, 1 Eq, 42.0 μmol) with stirring at ambient temperature overnight. The crude reaction mixture was purified on 12 g silica gel eluted with 0-15% CH3OH/DCM to give the title product (56.0 mg, 36.3 μmol, 86.5 %) 5 Step 2 of 2: Synthesis of Example 61, N,N'-(methylenebis(4,1-phenylene))bis(4-((S)-3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2- (methylamino)propanamido)-3-oxopropyl)piperidine-1-carboxamide). dibenzyl((2S,2'S)(((2S,2'S)((((methylenebis(4,1phenylene))bis(azanediyl))bis(carbonyl))bis(piperid10 ine-1,4-diyl))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(azanediyl))bis(1-oxopropane-1,2- diyl))bis(methylcarbamate) (56.0 mg, 1 Eq, 36.3 μmol) dissolved in a mixture of CH3OH (5 mL) and EtOH (5 mL) was treated with a catalytic amount of 10% Pd/C under H2 (1 atm) with vigorous stirring for 16 h at ambient temperature after which time LCMS indicated formation of the 15 desired product. The catalyst was removed by filtration through Celite and the filtrate was concentrated to dryness. The residue was purified on 12 g silica gel eluted with a gradient of CH3CH/H2O/NH4OH (94:3:3) to (90:5:5) to give the title product (22.3 mg, 17.5 μmol, 48.2 %). LCMS (ES, m/z): 637.20 [M/2+H]+ 1H NMR (600 MHz, Methanol-d4) δ 8.19 (s, 2H), 7.28 – 7.22 (m, 4H), 7.25 – 7.19 (m, 4H), 7.08 (d, 20 J = 8.4 Hz, 4H), 7.02 – 6.95 (m, 4H), 4.78 (dd, J = 10.2, 3.7 Hz, 2H), 4.18 (d, J = 10.4 Hz, 2H), 4.17 – 4.12 (m, 2H), 3.88 (d, J = 10.3 Hz, 2H), 3.85 (s, 2H), 3.80 (d, J = 2.4 Hz, 4H), 3.17 (q, J = 6.8 Hz, 2H), 2.83 (dtd, J = 26.2, 12.8, 2.7 Hz, 4H), 2.32 (s, 6H), 1.92 – 1.86 (m, 2H), 1.79 – 1.70 (m, 4H), 1.65 (dt, J = 12.9, 9.4 Hz, 4H), 1.41 (s, 6H), 1.39 (s, 6H), 1.25 (d, J = 6.9 Hz, 6H), 1.34 – 1.14 (m, 6H). 25 The following final compound was prepared according to the same two step procedure as Example 61, replacing bis(4-isocyanatophenyl)methane with 1,6-diisocyanatohexane: Example 62. The compound was found to have characterizing data as set forth below. 30 Example 62, N,N'-(hexane-1,6-diyl)bis(4-((S)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2-(methylamino)propanamido)-3- oxopropyl)piperidine-1-carboxamide). 298 70226WO01 , 4 . , , . , . , . , , . , . , 4H), 4.78 (dd, J = 10.1, 4.0 Hz, 2H), 4.19 (d, J = 10.3 Hz, 2H), 4.01 (d, J = 11.7 Hz, 4H), 3.89 (d, J 5 = 10.4 Hz, 2H), 3.86 – 3.78 (m, 4H), 3.15 (dt, J = 18.4, 7.0 Hz, 6H), 2.79 – 2.63 (m, 4H), 2.33 (s, 6H), 1.85 (d, J = 12.9 Hz, 2H), 1.76 – 1.55 (m, 6H), 1.55 – 1.45 (m, 6H), 1.42 (s, 6H), 1.41 (s, 6H), 1.34 (p, J = 3.4 Hz, 4H), 1.25 (d, J = 6.9 Hz, 6H), 1.24 – 1.02 (m, 4H). Example 63, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-10 phenylene))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxobutane-4,2-diyl))bis(2-(methylamino)propanamide). Step 1 of 6: Synthesis of Intermediate 102.1, (S)-2-((tert-butoxycarbonyl)amino)-4-(4-(prop-2- 15 yn-1-yloxy)phenyl)butanoic acid. (S)-2-((tert-butoxycarbonyl)amino)-4-(4-hydroxyphenyl)butanoic acid (2.00 g, 1 Eq, 6.77 mmol) and K2CO3 (2.81 g, 3 Eq, 20.3 mmol) were combined in DMF (13 mL) and treated with 3- bromoprop-1-yne (2.42 g, 2.21 mL, 9.2 molar, 3 Eq, 20.3 mmol) at ambient temperature overnight. The mixture was partitioned between EtOAc and water and the phases were 20 separated. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to dryness to give the crude intermediate product, prop-2-yn-1-yl (S)-2-((tert- butoxycarbonyl)amino)-4-(4-(prop-2-yn-1-yloxy)phenyl)butanoate (2.94 g) contaminated with 299 70226WO01 residual alkylating agent, as a yellow oil. The crude intermediate was treated with 1 M KOH in MeOH (13.5 mL, 2 eq) at ambient temperature for one hour. The reaction mixture was concentrated to dryness and the residue was redissolved in water. The aqueous solution was washed with Et2O to remove residual propargyl bromide and then combined with fresh 5 EtOAc. The pH of the biphasic mixture was acidified to pH ~ 2 by addition of 1 N KHSO4. The phases were isolated and the aqueous phase was extracted with EtOAc. The organics were combined, dried over MgSO4, filtered and concentrated to dryness to give the title compound (2.31 g, quantitative). 1H NMR (400 MHz, Chloroform-d) δ 10.00 (s, 1H), 7.16 – 7.08 (m, 2H), 6.89 (d, J = 8.6 Hz, 2H), 10 5.12 (d, J = 8.4 Hz, 1H), 4.66 (d, J = 2.4 Hz, 2H), 4.42 – 4.10 (m, 1H), 2.67 (q, J = 8.4 Hz, 2H), 2.51 (t, J = 2.4 Hz, 1H), 2.23 – 2.08 (m, 1H), 2.07 – 1.89 (m, 1H), 1.44 (s, 9H). Step of 6: Synthesis of Intermediate 102.2, tert-butyl (S)-(1-(5-((tert-butyldimethylsilyl)oxy)- 6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-4-(4-(prop- 15 2-yn-1-yloxy)phenyl)butan-2-yl)carbamate. (S)-2-((tert-butoxycarbonyl)amino)-4-(4-(prop-2-yn-1-yloxy)phenyl)butanoic acid (345 mg, 1 Eq, 1.03 mmol), 5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H- pyrrolo[3,2-b]pyridine (400 mg, 1 Eq, 1.03 mmol), and DIPEA (160 mg, 216 μL, 1.2 Eq, 1.24 mmol) were combined in DCM (4 mL) and treated with HATU (472 mg, 1.2 Eq, 1.24 mmol) at 20 ambient temperature for 1 h after which time TLC indicated complete conversion to a new spot. The mixture was diluted with DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 12 g silica eluted with 0-30% EtOAc/hexanes to give the title compound (542 mg, 772 μmol, 74.6 %), as a colorless oil. LCMS (ES, m/z): 702.38 [M+H]+ 25 Step 3 of 6: Synthesis of Intermediate 102.3, (S)-1-(2-amino-4-(4-(prop-2-yn-1- yloxy)phenyl)butanoyl)-6-(4-fluorobenzyl)-33 di thyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2- b]pyridin-5-one. Tert-butyl (S)-(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro- 30 1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-4-(4-(prop-2-yn-1-yloxy)phenyl)butan-2-yl)carbamate (542 mg, 1 Eq, 772 μmol) dissolved in DCM (4 mL) was treated with TFA (1 mL) at ambient temperature for 1 h. The reaction mixture was concentrated to dryness to give the TFA salt of the title compound (875 mg) as a colorless oil. LCMS (ES, m/z): 488.30 [M+H]+ 300 70226WO01 1H NMR (600 MHz, Methanol-d4) δ 8.14 (s, 1H), 7.29 – 7.22 (m, 2H), 7.22 – 7.15 (m, 2H), 6.99 (t, J = 8.8 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 4.67 (d, J = 2.4 Hz, 2H), 4.16 (dd, J = 7.3, 4.6 Hz, 1H), 3.80 (s, 2H), 3.67 (d, J = 10.4 Hz, 1H), 3.50 (d, J = 10.4 Hz, 1H), 2.92 (t, J = 2.4 Hz, 1H), 2.79 (ddd, J = 14.2, 8.3, 6.0 Hz, 1H), 2.75 – 2.65 (m, 1H), 2.16 (ddd, J = 14.4, 10.5, 7.3 Hz, 2H), 1.32 5 (d, J = 5.8 Hz, 6H). Step 4 of 6: Synthesis of Intermediate 102.4, tert-butyl ((S)-1-(((S)-1-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-4-(4-(prop-2-yn-1- yloxy)phenyl)butan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate. 10 (S)-1-(2-amino-4-(4-(prop-2-yn-1-yloxy)phenyl)butanoyl)-6-(4-fluorobenzyl)-3,3-dimethyl- 1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one, Trifluoracetate (445 mg, 1 Eq, 741 μmol), N- (tert-butoxycarbonyl)-N-methyl-L-alanine (151 mg, 1 Eq, 741 μmol), and DIPEA (239 mg, 323 μL, 2.5 Eq, 1.85 mmol) were combined in DMF (4 mL) and treated with HATU (338 mg, 1.2 Eq, 889 μmol) at ambient temperature overnight after which time TLC indicated complete conversion 15 to a new spot. The mixture was diluted with EtOAc, washed twice with water and once with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 24 g silica eluted with 40-90% EtOAc/hexanes to give the title compound (156 mg, 232 μmol, 31.3 %) as a colorless oil. LCMS (ES, m/z): 673.47 [M+H]+ 20 1H NMR (600 MHz, Chloroform-d) δ 8.35 (s, 1H), 7.27 – 7.20 (m, 2H), 7.14 (d, J = 8.1 Hz, 2H), 6.92 (t, J = 8.7 Hz, 4H), 4.67 (d, J = 2.5 Hz, 2H), 3.87 – 3.68 (m, 3H), 3.33 (d, J = 10.4 Hz, 1H), 2.83 (s, 3H), 2.74 – 2.63 (m, 1H), 2.58 (dt, J = 14.5, 7.8 Hz, 1H), 2.51 (t, J = 2.4 Hz, 1H), 1.96 (q, J = 7.3 Hz, 2H), 1.49 (s, 9H), 1.41 – 1.28 (m, 9H). 25 Step 5 of 6: Synthesis of Intermediate 102.5, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4-fluorobenzyl)-33-dimethyl-5-oxo-2,3,4,5- t t h d 1H l 32 b idi 1 l 1 b t 42 di l b di l bi 1 oxopropane-1,2-diyl))bis(methylcarbamate). Tert-butyl ((S)-1-(((S)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-30 pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-4-(4-(prop-2-yn-1-yloxy)phenyl)butan-2-yl)amino)-1- oxopropan-2-yl)(methyl)carbamate (162 mg, 2 Eq, 241 μmol) dissolved in CH3CN (5 mL) was treated with diacetoxycopper monohydrate (57.7 mg, 2.4 Eq, 289 μmol) and pyridine (114 mg, 116 μL, 12 Eq, 1.44 mmol) at 85 °C for 48 h. The reaction mixture was filtered through a plug of silica, eluted with CH3CN, and concentrated to dryness. The residue was purified on 24 g silica 301 70226WO01 eluted with 70-100% EtOAc/hexanes to give the title compound (44.6 mg, 33.2 μmol, 27.6 %), as a white solid. LCMS (ES, m/z): 1343.48 [M+H]+ 5 Step 6 of 6: Synthesis of Example 63, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 utane-4,2-diyl))bis(2- (methylamino)propanamide). Di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4-10 fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane- 4,2-diyl))bis(azanediyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (44.6 mg, 1 Eq, 33.2 μmol) dissolved in DCM (1 mL) was treated with TFA (378 mg, 256 μL, 100 Eq, 3.32 mmol) at ambient temperature for 2 h after which time LCMS indicated complete conversion. The mixture was concentrated to dryness to give the crude product as a yellow glass. The residue was combined 15 with a second batch of crude product and purified on 12 g silica gel eluted with a gradient of CH3CH/H2O/NH4OH (94:2:2) to (90:5:5) to give impure product. This material was repurified by RP-HPLC (column: Phenomenex Luna C18100*30mm, 5um; mobile phase: [water(0.1% TFA)- CH3CN], B%: 10%-100%, 13 min) to give the TFA salt of the title compound (43.3 mg, 37.9 μmol) as a clear glass. 20 LCMS (ES, m/z): 1143.54 [M+H]+ 1H NMR (600 MHz, Methanol-d4) δ 8.12 (s, 2H), 7.30 – 7.22 (m, 4H), 7.18 (d, J = 8.6 Hz, 4H), 6.99 (t, J = 8.8 Hz, 4H), 6.90 (d, J = 8.7 Hz, 4H), 4.80 (s, 4H), 4.52 (dd, J = 8.7, 4.7 Hz, 2H), 3.93 (q, J = 7.0 Hz, 2H), 3.86 – 3.71 (m, 6H), 3.38 (d, J = 10.4 Hz, 2H), 2.88 – 2.77 (m, 2H), 2.72 (s, 6H), 2.65 – 2.57 (m, 2H), 2.15 – 1.96 (m, 4H), 1.54 (d, J = 7.0 Hz, 6H), 1.30 (d, J = 7.9 Hz, 12H). 25 Example 64, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(1-(6-(4 fl orobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxo butane-4,2-diyl))bis(2-(methylamino)butanamide). 302 70226WO01 Step 1 of 3: Synthesis of Intermediate 103.1, tert-butyl ((S)-1-(((S)-1-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-4-(4-(prop-2-yn-1- 5 yloxy)phenyl)butan-2-yl)amino)-1-oxobutan-2-yl)(methyl)carbamate. (S)-1-(2-amino-4-(4-(prop-2-yn-1-yloxy)phenyl)butanoyl)-6-(4-fluorobenzyl)-3,3-dimethyl- 1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one, Trifluoracetate (230 mg, 1 Eq, 383 μmol), (S)- 2-((tert-butoxycarbonyl)(methyl)amino)butanoic acid (83.2 mg, 1 Eq, 383 μmol), and DIPEA (124 mg, 170 μL, 2.5 Eq, 957 μmol) were combined in DMF (4 mL) and treated with HATU (175 mg, 10 1.2 Eq, 460 μmol) at ambient temperature overnight after which time TLC indicated complete conversion to a new spot. The mixture was diluted with EtOAc, washed twice with water and once with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 24 g silica eluted with 40-90% EtOAc/hexanes to give the title compound (164 mg, 239 μmol, 62.4 %), as a colorless oil. 15 LCMS (ES, m/z): 687.40 [M+H]+ 1H NMR (600 MHz, Methanol-d4) δ 8.14 (s, 1H), 7.24 (dd, J = 8.5, 5.5 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.98 (t, J = 8.8 Hz, 2H), 6.94 – 6.87 (m, 2H), 4.69 (d, J = 2.5 Hz, 2H), 4.59 – 4.35 (m, 2H), 3.78 (s, 2H), 3.41 (dd, J = 19.0, 10.5 Hz, 1H), 2.92 (t, 1H), 2.87 (s, 3H), 2.80 – 2.65 (m, 1H), 2.63 – 2.50 (m, 1H), 2.12 – 1.84 (m, 3H), 1.84 – 1.65 (m, 1H), 1.49 (s, 9H), 1.29 (s, 6H), 0.93 (q, J 20 = 7.2, 5.8 Hz, 3H). Step 2 of 3: Synthesis of Intermediate 103.2, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- 70226WO01 tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-4,2-diyl))bis(azanediyl))bis(1- oxobutane-1,2-diyl))bis(methylcarbamate). Tert-butyl ((S)-1-(((S)- (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b] op-2-yn-1-yloxy)phenyl)butan-2-yl)amino)-1-oxobutan- 5 2-yl)(methyl)carbamate (164 mg, 2 Eq, 239 μmol) dissolved in CH3CN (5 mL) was treated with diacetoxycopper (47.7 mg, 2.2 Eq, 263 μmol) and pyridine (113 mg, 12 Eq, 1.43 mmol) at 85 °C for 24 h after which time LCMS indicated partial conversion. Additional diacetoxycopper (47.7 mg, 2.2 Eq, 263 μmol) was added and the mixture was stirred an additional 24 h at 85 °C. The reaction mixture was filtered through a plug of silica, eluted with CH3OH, and concentrated to 10 dryness. The residue was purified on 24 g silica eluted with 70-100% EtOAc to give the title compound as a white solid. LCMS (ES, m/z): 1371.62 [M+H]+ Step 3 of 3: Synthesis of Example 64, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-15 diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-4,2-diyl))bis(2- (methylamino)butanamide). Di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane- 20 4,2-diyl))bis(azanediyl))bis(1-oxobutane-1,2-diyl))bis(methylcarbamate) (1 Eq) dissolved in DCM (1 mL) was treated with 2,2,2-trifluoroacetic acid (excess) for 2 h. The mixture was concentrated to dryness and the crude product was purified by RP-HPLC (column: Phenomenex Luna C18 100*30mm, 5um; mobile phase: [water(0.1% TFA)-CH3CN], B%: 10%-100%, 13 min) to give the TFA salt of the title compound (47.6 mg, 34.1 μmol) as a clear glass. 25 LCMS (ES, m/z): 1171.95 [M+H]+ 1H NMR (600 MHz, Methanol-d4) δ 8.10 (s, 2H), 7.23 (dd, J = 8.5, 5.6 Hz, 4H), 7.20 – 7.12 (m, 4H), 6.97 (t, J = 8.8 Hz, 4H), 6.88 (d, J = 8.6 Hz, 4H), 4.77 (s, 4H), 4.53 (dd, J = 8.6, 5.0 Hz, 2H), 3.91 – 3.71 (m, 8H), 3.36 (d, J = 10.4 Hz, 2H), 2.80 (dt, J = 13.1, 6.1 Hz, 2H), 2.70 (s, 6H), 2.63 – 2.54 (m, 2H), 2.16 – 1.82 (m, 8H), 1.28 (d, J = 6.9 Hz, 12H), 0.98 (t, J = 7.5 Hz, 6H). 30 Example 65, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxopentane-5,2-diyl))bis(2-(methylamino)butanamide). 304 70226WO01 Step 1 of 11: Synthesis of Intermediate 104.1, 3-(4-(allyloxy)phenyl)propan-1-ol. 4-(3-hydroxypropyl)phenol (2000 mg, 13.14 mmol, 1 eq) and K2CO3 (2.724 g, 19.71 mmol, 1.5 5 eq) were combined in DMF (10 mL) and treated with 3-bromoprop-1-yne (2.345 g, 1.757 mL, 80% Wt, 15.77 mmol, 1.2 eq) at 80°C overnight. The mixture was partitioned between EtOAc and water and the phases were separated. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Hexane/EtOAc = 3:1) to the title compound (1.63 g, 8.60 mmol, 65.4 %) as 10 a transparent oil. TLC (Hexane/EtOAc = 1:1) Rf = 0.55. 1H NMR (600 MHz, Chloroform-d) δ 7.13 – 7.08 (m, 2H), 6.91 – 6.87 (m, 2H), 4.64 (d, J = 2.7 Hz, 2 (t, J = 6.5 Hz, 2H), 2.68 – 2.61 (m, 3H), 2.52 (t, J = 2.5 Hz, 1H), 1.91 – 1.79 (m, 2H). 15 Step 2 of 11: Synthesis of Intermediate 104.2, 1-(3-bromopropyl)-4-(prop-2-yn-1- yloxy)benzene. To a solution of 3-(4-(prop-2-yn-1-yloxy)phenyl)propan-1-ol (1636 mg, 8.600 mmol, 1 eq) in dry THF (10 mL) were added CBr4 (3.422 g, 10.32 mmol, 1.2 eq) and triphenylphosphine (2.707 g, 10.32 mmol, 1.2 eq). The mixture was stirred at 25°C for 1 h. The mixture was partitioned between 20 EtOAc and water and the phases were separated. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue. The residue was purified by 305 70226WO01 column chromatography (SiO2, 0-80% EtOAc/Hexane) to give the title compound (2.12 g, 8.38 mmol, 97.5 %) as a transparent oil. TLC (Hexane/EtOAc = 1:1) Rf = 0.68. 1H NMR (600 MHz, Chloroform-d) δ 7.16 – 7.12 (m, 2H), 6.95 – 6.90 (m, 2H), 4.67 (d, J = 2.6 Hz, 5 2H), 3.39 (t, J = 6.6 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 2.53 (t, J = 2.4 Hz, 1H), 2.14 (dq, J = 8.0, 6.6 Hz, 2H). Step 3 of 11: Synthesis of Intermediate 104.3, (2R,5S)-2-isopropyl-3,6-dimethoxy-5-(3-(4- (prop-2-yn-1-yloxy)phenyl)propyl)-2,5-dihydropyrazine. 10 A solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (500 mg, 486 μL, 2.71 mmol, 1 eq) in THF (20 mL) was placed in an oven-dried flask under argon, and cooled to -78°C. While stirring, n-butyllithium (243 mg, 1.52 mL, 2.5 molar, 3.80 mmol, 1.4 eq) in hexane was added via syringe. After stirring for 30 min at -78°C, 1-(3-bromopropyl)-4-(prop-2-yn-1-yloxy)benzene (756 mg, 2.99 mmol, 1.1 eq) dissolved in 1 mL of THF was added dropwise via cannula. The mixture 15 was stirred at -78 °C for 3 h, and then warmed to ambient temperature. After 8 h, the reaction was quenched with saturated NH4Cl. The volatiles were removed in vacuo, and the aqueous phase was extracted twice with EtOAc. The EtOAc extracts were combined and washed with water and brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by column chromatography (SiO2, 0-5% EtOAc/Hexane) to give the title compound (621 mg, 1.74 mmol, 64.2 20 %) as a transparent oil. LCMS (ES, m/z): 357.41 [M+H]+. Step 4 of 11: Synthesis of Intermediate 104.4, methyl (S)-2-amino-5-(4-(prop-2-yn-1- yloxy)phenyl)pentanoate. 25 To a solution of (2R,5S)-2-isopropyl-3,6-dime y p p y y y p yl)propyl)- 2,5-dihydropyrazine (621 mg, 1.74 mmol, 1 eq) in THF (5 mL) and methanol (2 mL) was added HCl in Methanol (4 g, 3 mL, 3 molar, 9 mmol, 5 eq) at 0°C. The mixture was stirred at 25°C overnight. The reaction mixture was added into NH4OH (5 mL), then the mixture was concentrated under reduced pressure to give a residue. The crude product was dissolved in NH4OH (5mL) and 30 H2O (10 mL), and then extracted twice with EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated to dryness to give the crude title compound (261 mg, 1000 μmol, 57.4 %) as a transparent oil. LCMS (ES, m/z): 262.02 [M+H]+. 306 70226WO01 Step 5 of 11: Synthesis of Intermediate 104.5, methyl (S)-2-((tert-butoxycarbonyl)amino)-5-(4- (prop-2-yn-1-yloxy)phenyl)pentanoate. To a solution of methyl (S)-2-amino-5-(4-(prop-2-yn-1-yloxy)phenyl)pentanoate (261.3 mg, 1.000 mmol, 1 eq) and Boc2O (480.2 mg, 505 μL, 2.200 mmol, 2.2 eq) in DCM (15 mL) was added TEA 5 (607.1 mg, 836 μL, 6.000 mmol, 6 eq) in portions at 0°C. The mixture was stirred at 25°C for 12 h after which time TLC (Hexane/EtOAc = 3:1) indicated complete consumption of the starting material. The mixture was partitioned between EtOAc and water and the phases were separated. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, 0-40% 10 EtOAc/hexanes) to give the title compound (65.3 mg, 181 μmol, 18.1 %) as a transparent oil. LCMS (ES, m/z): 362.23 [M+H]+. 1H NMR (600 MHz, Chloroform-d) δ 7.09 – 7.06 (m, 2H), 6.91 – 6.87 (m, 2H), 5.00 (d, J = 8.6 Hz, 1H), 4.66 (d, J = 2.5 Hz, 2H), 4.34 – 4.29 (m, 1H), 3.71 (s, 3H), 2.63 – 2.53 (m, 2H), 2.51 (t, J = 2.4 Hz, 1H), 1.86 – 1.77 (m, 1H), 1.70 – 1.57 (m, 3H), 1.43 (s, 9H). 15 Step 6 of 11: Synthesis of Intermediate 104.6, (S)-2-((tert-butoxycarbonyl)amino)-5-(4-(prop- 2-yn-1-yloxy)phenyl)pentanoic acid. methyl (S)-2-((tert-butoxycarbonyl)amino)-5-(4-(prop-2-yn-1-yloxy)phenyl)pentanoate (65.3 mg, 181 μmol, 1 eq) was dissolved in THF (10 mL) and Methanol (1 mL), combined with LiOH (24.0 20 mg, 500 μL, 2 molar, 1.00 mmol, 5.54 eq) and stirred at 25°C for 16 h. The mixture was concentrated to dryness, redissolved in water, and acidified to pH 4 with 1N HCl. The mixture was extracted with EtOAc (3 x 50 mL) and the combined organic phase was dried over Na2SO4, filtered and concentrated to dryness to give the title compound (76.9 mg, 221 μmol, quantitative) as a transparent oil. 25 LCMS (ES, m/z): 348.24 [M+H]+. Step 7 of 11: Synthesis of Intermediate 104.7, tert-butyl (S)-(1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxo-5-(4-(prop-2-yn-1-yloxy)phenyl)pentan-2-yl)carbamate 30 To a solution of (S)-2-((tert-butoxycarbonyl)amino)-5-(4-(prop-2-yn-1-yloxy)phenyl)pentanoic acid (76.9 mg, 221 μmol, 1 eq) and 5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (94.1 mg, 243 μmol, 1.1 eq) in DCM (10 mL) was added DIPEA (85.8 mg, 116 μL, 664 μmol, 3 eq) and dipropyldiphosphonic acid (153 mg, 143 μL, 50% wt, 332 μmol, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 12 h. Saturated NH4Cl (20 35 mL) was added to the mixture and the mixture was extracted with DCM (20 mL * 2). The 307 70226WO01 combined organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/Hexane) to give the title compound (96.8 mg, 135 μmol, 61.1 %) as a yellowish solid. LCMS (ES, m/z): 716.38 [M+H]+. 5 Step 8 of 11: Synthesis of Intermediate 104.8, (S)-2-amino-1-(6-(4-fluorobenzyl)-5-hydroxy- 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-(4-(prop-2-yn-1- yloxy)phenyl)pentan-1-one. To a solution of tert-butyl (S)-(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-10 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-5-(4-(prop-2-yn-1-yloxy)phenyl)pentan-2- yl)carbamate (96.8 mg, 135 μmol, 1 eq) in THF (5 mL) and Methanol (2 mL) was added HCl (1 g, 1 mL, 3 molar, 3 mmol, 20 eq) at 0°C. The mixture was stirred at 25°C overnight. The reaction mixture was added into NH4OH (5 mL), then the mixture was concentrated under reduced pressure to give a residue. The crude product was dissolved in NH4OH (5mL), H2O (10 mL), and extracted 15 twice with EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated to dryness to give the crude product, (S)-2-amino-1-(6-(4-fluorobenzyl)-5-hydroxy-3,3-dimethyl- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-(4-(prop-2-yn-1-yloxy)phenyl)pentan-1-one (70 mg, 0.14 mmol, 100 %) as a yellowish solid. LCMS (ES, m/z): 502.37 [M+H]+. 20 Step 9 of 11: Synthesis of Intermediate 104.9, tert-butyl ((S)-1-(((S)-1-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-5-(4-(prop-2-yn-1- yloxy)phenyl)pentan-2-yl)amino)-1-oxobutan-2-yl)(methyl)carbamate. To a solution of (S)-2-amino-1-(6-(4-fluorobenzyl)-5-hydroxy-3,3-dimethyl-2,3-dihydro-1H- 25 pyrrolo[3,2-b]pyridin-1-yl)-5-(4-(prop-2-yn-1-yloxy)phenyl)pentan-1-one (80 mg, 0.16 mmol, 1 eq) and (S)-2-((tert-butoxycarbonyl)(methyl)amino)butanoic acid (38 mg, 0.18 mmol, 1.1 eq) in DCM (10 mL) was added DIPEA (62 mg, 83 μL, 0.48 mmol, 3 eq) and dipropyldiphosphonic acid (0.11 g, 0.10 mL, 50% Wt, 0.24 mmol, 1.5 eq) at 0°C.The mixture was stirred at 25°C for 12 h. Saturated NH4Cl (20 mL) was added to the mixture and the mixture was extracted with DCM (20 30 mL * 2). The combined organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, 0-100% EtOAc/Hexanes) to give the title compound (61.5 mg, 87.8 μmol, 55 %), as a yellowish solid. LCMS (ES, m/z): 701.47 [M+H]+. 35 308 70226WO01 Step 10 of 11: Synthesis of Intermediate 104.10, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopentane-5,2-diyl))bis(azanediyl))bis(1- oxobutane-1,2-diyl))bis(methylcarbamate). 5 tert-butyl ((S)-1-(((S)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxo-5-(4-(prop-2-yn-1-yloxy)phenyl)pentan-2-yl)amino)-1-oxobutan-2- yl)(methyl)carbamate (61.5 mg, 87.8 μmol, 2 eq) dissolved in CH3CN (5 mL) was treated with diacetoxycopper, water (21.0 mg, 105 μmol, 2.4 eq) and pyridine (41.6 mg, 42.6 μL, 527 μmol, 12 eq) at 85 °C for 48 h. The reaction mixture was filtered through a plug of silica, eluted with 10 CH3CN, and concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100*30mm, 5um; mobile phase: [water(0.1% TFA)-CH3CN], B%: 10%- 100%, 13 min) to give the title compound (7.8 mg, 5.6 μmol, 13 %), as a white solid. LCMS (ES, m/z): 1400.05 [M+H]+ 15 Step 11 of 11: Synthesis of Example 65, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopentane-5,2-diyl))bis(2- (methylamino)butanamide). di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4-20 fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopentane- 5,2-diyl))bis(azanediyl))bis(1-oxobutane-1,2-diyl))bis(methylcarbamate) (7.8 mg, 5.6 μmol, 1 eq) dissolved in DCM (1 mL) was treated with TFA (3 g, 2 mL, 0.03 mol) at ambient temperature for 2 h after which time LCMS indicated complete conversion. The mixture was concentrated to dryness to give the crude product as a yellow glass. The residue was purified by preparative HPLC 25 (column: Phenomenex Luna C18100*30mm, 5um; mobile phase: [water(0.1% TFA)-CH3CN], B%: 10%-100%, 13 min) to give the title compound (1.02 mg, 0.715 μmol, 13 %) as a white solid. LCMS (ES, m/z): 1199.97 [M+H]+ 1H NMR (600 MHz, Methanol-d4) δ 8.14 (s, 2H), 7.23 (dd, J = 8.5, 5.5 Hz, 4H), 7.13 – 7.10 (m, 4H), 6.97 (t, J = 8.8 Hz, 4H), 6.84 (d, J = 8.6 Hz, 4H), 4.74 (s, 4H), 4.63 – 4.58 (m, 2H), 4.02 (d, J 30 = 10.5 Hz, 2H), 3.82 – 3.74 (m, 6H), 3.58 (d, J = 10.4 Hz, 2H), 2.66 (s, 6H), 2.65 – 2.59 (m, 4H), 1.96 – 1.87 (m, 4H), 1.86 – 1.76 (m, 4H), 1.74 – 1.67 (m, 4H), 1.35 (s, 6H), 1.29 (s, 2H), 1.25 (s, 6H), 0.97 (t, J = 7.5 Hz, 6H). 309 70226WO01 Example 66, (2S,2'S)-N,N'-((2S,2'S)-(buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1- oxobutane-4,2-diyl))bis(2-(methylamino)butanamide). A suspension of 2-(4-iodophenyl)ethan-1-ol (1000 mg, 4.031 mmol, 1 eq), ethynyltrimethylsilane (475.1 mg, 670 μL, 4.838 mmol, 1.2 eq), CuI (38.39 mg, 201.6 μmol, 0.05 eq), PdCl2(PPh3)2 (141.5 mg, 201.6 μmol, 0.05 eq), and TEA (1.224 g, 1.69 mL, 12.09 mmol, 3 eq) was stirred in THF (10 10 mL) at 55°C overnight. Upon completion, the mixture was partitioned between EtOAc and water and the phases were separated. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, 0-30% EtOAc/Hexane) to give the title compound (889 mg, 4.07 mmol, quantitative) as a white solid. 15 TLC (Hexane/EtOAc = 2:1) Rf = 0.44. Step 2 of 12: Synthesis of Intermediate 105.2, 2-(4-ethynylphenyl)ethan-1-ol. To a solution of 2-(4-((trimethylsilyl)ethynyl)phenyl)ethan-1-ol (889.2 mg, 4.072 mmol, 1 eq) in THF (10 mL) was added tetrabutylammonium fluoride (1.28 g, 4.88 mL, 1 molar, 4.89 mmol, 2.5 20 eq). The mixture was stirred at ambient temperature for 1 h. Upon completion, the mixture was 310 70226WO01 partitioned between EtOAc and water and the phases were separated. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, 0-40% EtOAc/Hexane) to give the title compound (490 mg, 3.35 mmol, 82.3 %) as brownish transparent oil. 5 TLC (Hexane/EtOAc = 1:1) Rf = 0.53. 1H NMR (600 MHz, Chloroform-d) δ 7.45 – 7.42 (m, 2H), 7.19 – 7.16 (m, 2H), 3.81 (t, J = 6.6 Hz, 2H), 3.06 (s, 1H), 2.84 (t, J = 6.6 Hz, 2H), 1.94 (d, J = 1.3 Hz, 1H). Step 3 of 12: Synthesis of Intermediate 105.3, 1-(2-bromoethyl)-4-ethynylbenzene. 10 To a solution of 2-(4-ethynylphenyl)ethan-1-ol (490 mg, 3.35 mmol, 1 eq) in dry THF (10 mL) were added CBr4 (1.33 g, 4.02 mmol, 1.2 eq) and triphenylphosphine (1.06 g, 4.02 mmol, 1.2 eq). The mixture was stirred at 25°C for 1 h. The mixture was partitioned between EtOAc and water and the phases were separated. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue. The residue was purified by column 15 chromatography (SiO2, 0-30% EtOAc/Hexane) to give the title compound (658 mg, 3.15 mmol, 93.9 %) as a transparent oil. TLC (Hexane/EtOAc = 8:1) Rf = 0.71. 1H NMR (600 MHz, Chloroform-d) δ 7.68 – 7.64 (m, 2H), 7.39 – 7.36 (m, 2H), 3.76 (t, J = 7.5 Hz, 2H), 3.37 (t, J = 7.5 Hz, 2H), 3.29 (s, 1H). 20 Step 4 of 12: Synthesis of Intermediate 105.4, (2S,5R)-2-(4-ethynylphenethyl)-5-isopropyl-3,6- dimethoxy-2,5-dihydropyrazine. A solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (580.2 mg, 564.3 μL, 3.149 mmol, 1 eq) in THF (6 mL) was placed in an oven-dried flask under argon, and cooled to -78°C. 25 While stirring, n-butyllithium (282.4 mg, 1.763 mL, 2.5 molar, 4.408 mmol, 1.4 eq) in hexane was added via syringe. After stirring for 30 min at -78°C, 1-(2-bromoethyl)-4-ethynylbenzene (658.4 mg, 3.149 mmol, 1 eq) dissolved in 1 mL of THF was added dropwise via cannula. The mixture was stirred at -78 °C for 3 h, and then warmed to ambient temperature. After 8 h, the reaction was quenched with saturated NH4Cl. The volatiles were removed in vacuo, and the aqueous phase was 30 extracted twice with EtOAc. The EtOAc extracts were combined and washed with water and brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by column chromatography (SiO2, 0-5% EtOAc/Hexane) to give the title compound (104.8 mg, 335.5 μmol, 10.65 %) as a pale yellow oil. LCMS (ES, m/z): 313.24 [M+H]+. 311 70226WO01 1H NMR (600 MHz, Chloroform-d) δ 7.39 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 4.03 (dt, J = 7.2, 3.9 Hz, 1H), 3.97 (t, J = 3.5 Hz, 1H), 3.69 (d, J = 1.8 Hz, 6H), 3.02 (s, 1H), 2.68 – 2.55 (m, 2H), 2.27 (ddh, J = 10.2, 6.8, 3.4 Hz, 1H), 2.15 (dddd, J = 13.9, 10.4, 6.7, 4.2 Hz, 1H), 2.02 – 1.92 (m, 1H), 1.04 (d, J = 7.0 Hz, 3H), 0.69 (d, J = 6.9 Hz, 3H). 5 Step 5 of 12: Synthesis of Intermediate 105.5, methyl (S)-2-amino-4-(4- ethynylphenyl)butanoate. To a solution of (2S,5R)-2-(4-ethynylphenethyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (164.2 mg, 525.6 μmol, 1 eq) in THF (5 mL) and Methanol (2 mL) was added HCl in Methanol (4 10 g, 3 mL, 3 molar, 9 mmol, 5 eq) at 0°C. The mixture was stirred at 25°C overnight. The reaction mixture was added into NH4OH (5 mL), then the mixture was concentrated under reduced pressure to give a residue. The crude product was dissolved in NH4OH (5mL) and H2O (10 mL), and then extracted twice with EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated to dryness to give the title compound (105 mg, 482 μmol, 91.7 %) as a transparent oil. 15 LCMS (ES, m/z): 218.15 [M+H]+. Step 6 of 12: Synthesis of Intermediate 105.6, methyl ((S)-2-((tert-butoxycarbonyl)amino)-4- (4-ethynylphenyl)butanoate. To a solution of methyl (S)-2-amino-4-(4-ethynylphenyl)butanoate (105 mg, 482 μmol, 1 eq) and 20 Boc2O (231 mg, 244 μL, 1.06 mmol, 2.2 eq) in DCM (15 mL) was added TEA (293 mg, 403 μL, 2.89 mmol, 6 eq) in portions at 0°C. The mixture was stirred at 25°C for 12 h after which time TLC (Hexane/EtOAc = 1:1) indicated complete consumption of the starting material. The mixture was partitioned between EtOAc and water and the phases were separated. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue. The 25 residue was purified by column chromatography (SiO2, 0-50% EtOAc/Hexanes) to give the title compound (98.2 mg, 309 μmol, 64.2 %) as a transparent oil. LCMS (ES, m/z): 318.21 [M+H]+. Step 7 of 12: Synthesis of Intermediate 105.7, S)-2-((tert-butoxycarbonyl)amino)-4-(4- 30 ethynylphenyl)butanoic acid. Methyl (S)-2-((tert-butoxycarbonyl)amino)-4-(4-ethynylphenyl)butanoate (98.2 mg, 309 μmol, 1 eq) was dissolved in THF (10 mL) and Methanol (1 mL), combined with LiOH (24.0 mg, 500 μL, 2 molar, 1.00 mmol, 3.23 eq) and stirred at 25°C for 16 h. Upon completion, the aqueous solution was acidified to pH 4 with 1N HCl and then extracted with EtOAc (3 x 50 mL). The combined 312 70226WO01 organic phase was dried over Na2SO4, filtered and concentrated to dryness to give the title compound as a transparent oil. LCMS (ES, m/z): 304.22 [M+H]+. 5 Step 8 of 12: Synthesis of Intermediate 105.8, tert-butyl (S)-(1-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-4-(4-ethynylphenyl)-1-oxobutan-2-yl)carbamate. To a solution of (S)-2-((tert-butoxycarbonyl)amino)-4-(4-ethynylphenyl)butanoic acid (80.5 mg, 265 μmol, 1 eq) and 5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro- 10 1H-pyrrolo[3,2-b]pyridine (113 mg, 292 μmol, 1.1 eq) in DCM (10 mL) was added DIPEA (103 mg, 139 μL, 796 μmol, 3 eq) and dipropyldiphosphonic acid (183 mg, 171 μL, 50% Wt, 398 μmol, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 12 h. Saturated NH4Cl (20 mL) was added to the mixture and the mixture was extracted with DCM (2 x 20 mL). The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue. The residue 15 was purified by column chromatography (SiO2, 0-10% EtOAc/Hexane) to give the title compound (78.1 mg, 116 μmol, 43.8 %) as a yellowish solid. LCMS (ES, m/z): 672.63 [M+H]+. Step 9 of 12: Synthesis of Intermediate 105.9, (S)-2-amino-4-(4-ethynylphenyl)-1-(6-(4-20 fluorobenzyl)-5-hydroxy-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)butan-1- one. To a solution of tert-butyl (S)-(1-(5-((tert-butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-(4-ethynylphenyl)-1-oxobutan-2-yl)carbamate (78.1 mg, 116 μmol, 1 eq) in THF (5 mL) and Methanol (2 mL) was added HCl (1 g, 1 mL, 3 molar, 3 25 mmol, 30 eq) at 0°C. The mixture was stirred at 25°C overnight. The reaction mixture was added into NH4OH (5 mL), then the mixture was concentrated under reduced pressure to give a residue. The crude product was dissolved in NH4OH (5mL) and H2O (10 mL), and extracted twice with EtOAc. The combined organic phase was dried over Na2SO4, filtered and concentrated to dryness to give the title compound (60 mg, 0.13 mmol, quantitative) as a yellowish solid. 30 LCMS (ES, m/z): 458.34 [M+H]+. Step 10 of 12: Synthesis of Intermediate 105.10, tert-butyl ((S)-1-(((S)-4-(4-ethynylphenyl)-1- (6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1- oxobutan-2-yl)amino)-1-oxobutan-2-yl)(methyl)carbamate. 313 70226WO01 To a solution of ((S)-1-(2-amino-4-(4-ethynylphenyl)butanoyl)-6-(4-fluorobenzyl)-3,3-dimethyl- 1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one (60 mg, 0.13 mmol, 1 eq) and (S)-2-((tert- butoxycarbonyl)(methyl)amino)butanoic acid (31 mg, 0.14 mmol, 1.1 eq) in DCM (10 mL) was added DIPEA (51 mg, 69 μL, 0.39 mmol, 3 eq) and dipropyldiphosphonic acid (91 mg, 85 μL, 5 50% Wt, 0.20 mmol, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 12 h. Saturated NH4Cl (20 mL) was added to the mixture and the mixture was extracted with DCM (2 x 20 mL). The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30mm, 5um; mobile phase: [water(0.1% TFA)-CH3CN], B%: 10%-100%, 13 min) to give the 10 desired product (28.5 mg, 43.4 μmol, 33 %), as a yellowish solid. LCMS (ES, m/z): 657.43 [M+H]+. Step 11 of 12: Synthesis o Intermediate 105.11, di-tert-butyl ((2S,2'S)-(((2S,2'S)-(buta-1,3- diyne-1,4-diylbis(4,1-phenylene))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-15 tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-4,2-diyl))bis(azanediyl))bis(1- oxobutane-1,2- )bis(methylcarbamate). Tert-butyl ((S)-1-(((S)-4-(4-ethynylphenyl)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H- lo[3,2-b]pyridin-1-yl)-1-oxobutan-2-yl)amino)-1-oxobutan-2- yl)(methyl)carbamate (28.5 mg, 43.4 μmol, 2 eq) dissolved in CH3CN (5 mL) was treated with 20 diacetoxycopper, water (20.8 mg, 104 μmol, 4.8 eq) and pyridine (41.2 mg, 42.1 μL, 521 μmol, 24 eq) at 85 °C for 48 h. The reaction mixture was filtered through a plug of silica, eluted with CH3CN, and concentrated to dryness. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100*30mm, 5um; mobile phase: [water(0.1% TFA)-CH3CN], B%: 10%- 100%, 13 min) to give the title product (5.8 mg, 4.4 μmol, 20 %) as a white solid. 25 LCMS (ES, m/z): 1312.05 [M+H]+ Step 12 of 12: Synthesis of Example 66, (2S,2'S)-N,N'-((2S,2'S)-(buta-1,3-diyne-1,4- diylbis(4,1-phenylene))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-4,2-diyl))bis(2-(methylamino)butanamide). 30 Di-tert-butyl ((2S,2'S)-(((2S,2'S)-(buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane- 4,2-diyl))bis(azanediyl))bis(1-oxobutane-1,2-diyl))bis(methylcarbamate) (5.8 mg, 4.4 μmol, 1eq) dissolved in DCM (1 mL) was treated with TFA (3 g, 2 mL, 0.03 mol) at ambient temperature for 2 h after which time LCMS indicated complete conversion. The mixture was concentrated to dryness 35 to give the crude product as a yellow glass. The residue was purified by preparative HPLC 314 70226WO01 (column: Phenomenex Luna C18100*30mm, 5um; mobile phase: [water(0.1% TFA)-CH3CN], B%: 10%-100%, 13 min) to give the title compound (0.43 mg, 0.32 μmol, 7.3 %) as a white solid. LCMS (ES, m/z): 556.41 [M/2+H]+ 1H NMR (600 MHz, Methanol-d4) δ 8.09 (s, 2H), 7.45 – 7.40 (m, 4H), 7.30 – 7.27 (m, 4H), 7.27 – 5 7.23 (m, 4H), 6.99 (td, J = 9.0, 2.6 Hz, 4H), 4.58 (dd, J = 8.1, 5.5 Hz, 2H), 3.98 (d, J = 10.4 Hz, 2H), 3.82 – 3.76 (m, 6H), 3.55 (d, J = 10.4 Hz, 2H), 2.88 (dt, J = 13.8, 6.9 Hz, 2H), 2.75 – 2.71 (m, 2H), 2.69 (s, 6H), 2.19 – 2.05 (m, 4H), 2.00 – 1.84 (m, 4H), 1.36 – 1.30 (m, 12H), 0.98 (t, J = 7.5 Hz, 6H). 10 Example 67, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(butane-1,4-diylbis(1H-1,2,3-triazole-4,1- diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- O F 15 20 To a solution of tert-butyl N-[(1S)-2-[[(1S,2S)-2-azido-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]propyl]amino]-1- methyl-2-oxo-ethyl]-N-methyl-carbamate (145 mg, 207 umol, 2.2 eq), octa-1,7-diyne (10 mg, 94.2 umol, 1eq) and DIEA (24.4 mg, 188 umol, 32.8 uL, 2 eq) in DMF (3 mL) was added CuI (25.1 mg, 25 132 umol, 1.4 eq) at 15°C. The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 70°C for 12 h under N2 atmosphere after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (10 mL) was added to the mixture, then extracted with EtOAc (15 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced 30 pressure to give the title compound (141 mg, 93.8 umol, 99.7% yield) as a yellow oil. LCMS (ES, m/z): 537.5 [(M-TBS-Boc)/2+H]+ 315 70226WO01 Step 2 of 2: Synthesis of Example 67, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(butane-1,4-diylbis(1H- 1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2-(methylamino)propanamide). To a solution of tert-butyl N-[(1S)-2-[[(1S,2S)-2-[4-[4-[1-[(1S,2S)-2-[[(2S)-2-[tert- 5 butoxycarbonyl(methyl)amino]propanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-methyl-3-oxo-propyl]triazol- 4-yl]butyl]triazol-1-yl]-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl- carbamate (110 mg, 73.2 umol, 1 eq) in EtOAc (3 mL) was added HCl/EtOAc (4 M, 3 mL, 164 eq). 10 The mixture was stirred at 15°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered to give the crude solid product. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100*40mm, 5um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 10%- 42%, 8 min) to give the title compound (67.4 mg, 51.8 umol, 70.7% yield, 100% purity, 2 TFA) as 15 an off-white solid. LCMS (ES, m/z): 537.4 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 8.04 (s, 2H), 7.64 (s, 2H), 7.18 (dd, J = 5.6, 8.7 Hz, 4H), 6.92 (t, J = 8.9 Hz, 4H), 5.20 (d, J = 9.6 Hz, 2H), 5.04 - 4.94 (m, 2H), 4.05 (d, J = 10.5 Hz, 2H), 3.92 (q, J = 7.2 Hz, 2H), 3.74 - 3.63 (m, 6H), 3.29 (td, J = 1.6, 3.3 Hz, 4H), 2.68 (s, 6H), 2.39 (br d, 20 J =2.6 Hz, 4H), 1.70 (d, J =6.8 Hz, 6H), 1.48 (d, J =7.2 Hz, 6H), 1.28 (s, 6H), 1.23 (s, 6H) The following final compounds were prepared according to the same procedure as Example 67: Examples 68-71. The compounds were found to have characterizing data as set forth below. 25 Example 68, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(hexane-1,6-diylbis(1H-1,2,3-triazole-4,1- diyl))bis(1-(6-(4-fluor b nzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxo utane-3,2-diyl))bis(2-(methylamino)propanamide). Boc N HN F H O F 70226WO01 1H NMR (400MHz, METHANOL-d4) δ = 8.09 (s, 2H), 7.66 (s, 2H), 7.22 (dd, J=5.5, 8.5 Hz, 4H), 6.97 (t, J=8.8 Hz, 4H), 5.18 (d, J=9.6 Hz, 2H), 5.06 - 4.96 (m, 2H), 4.08 (d, J=10.5 Hz, 2H), 3.94 (q, J=6.9 Hz, 2H), 3.79 - 3.70 (m, 4H), 3.62 (br d, J=10.4 Hz, 2H), 2.70 (s, 6H), 2.58 - 2.40 (m, 4H), 1.74 (d, J=6.8 Hz, 6H), 1.50 (d, J=7.0 Hz, 6H), 1.34 - 1.16 (m, 18H), 0.98 (br s, 4H) 5 Example 69, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(octane-1,8-diylbis(1H-1,2,3-triazole-4,1- O F O 70226WO01 4.05 (d, J=10.4 Hz, 2H), 3.93 (q, J=7.0 Hz, 2H), 3.79 - 3.59 (m, 6H), 2.70 (s, 6H), 1.76 (d, J=6.9 Hz, 6H), 1.50 (d, J=7.0 Hz, 6H), 1.30 (s, 6H), 1.22 - 1.11 (m, 6H) Example 71, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-((((propane-2,2-diylbis(4,1- 5 phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)- . Boc N H N N O O O O N O 351 HN O N F 10 1H NMR (400MHz, METHANOL-d4) δ = 8.07 (d, J=7.4 Hz, 4H), 7.16 (dd, J=5.6, 8.4 Hz, 4H), 7.04 (d, J=8.8 Hz, 4H), 6.89 (t, J=8.8 Hz, 4H), 6.72 (d, J=8.8 Hz, 4H), 5.23 (d, J=9.4 Hz, 2H), 5.15 - 5.00 (m, 6H), 4.07 (d, J=10.5 Hz, 2H), 4.00 - 3.87 (m, 2H), 3.72 (s, 4H), 3.61 (d, J=10.5 Hz, 2H), 2.70 (s, 6H), 1.77 (d, J=6.8 Hz, 6H), 1.55 (s, 6H), 1.50 (d, J=7.0 Hz, 6H), 1.31 (s, 6H), 1.21 (s, 6H). 15 Example 72, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-((((oxybis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)- 3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2- diyl))bis(2-(methylamino)propanamide). Boc O O N O H H N O F 20 Step 1 of 2: Synthesis of Intermediate 111.1, tert-butyl N-[(1S)-2-[[(1S,2S)-2-[4-[[4-[4-[[1- [(1S,2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-3- oxo-propyl]triazol-4-yl]methoxy]phenoxy]phenoxy]methyl]triazol-1-yl]-1-[6-[(4-25 fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridine-1- carbonyl]propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate. 318 70226WO01 To a solution of tert-butyl N-[(1S)-2-[[(1S,2S)-2-azido-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]propyl]amino]-1- methyl-2-oxo-ethyl]-N-methyl-carbamate (145 mg, 207 umol, 2.2 eq), octa-1,7-diyne (10 mg, 94.2 umol, 1eq), DIEA (24.4 mg, 188 umol, 32.8 uL, 2 eq) in DMF (3 mL) was added CuI (25.1 mg, 5 132 umol, 1.4 eq) at 15°C. The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 70°C for 12 h under N2 atmosphere after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (10 mL) was added to the mixture, then extracted with EtOAc (15 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced 10 pressure to give the title compound (141 mg, 93.8 umol, 99.7% yield) as a yellow oil. LCMS (ES, m/z): 537.5 [(M-TBS-Boc)/2+H]+ Step 2 of 2: Synthesis of Example 72, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-((((oxybis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-15 3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2- diyl))bis(2-(methylamino)propanamide). To a solution of tert-butyl N-[(1S)-2-[[(1S,2S)-2-[4-[[4-[4-[[1-[(1S,2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]propanoyl]amino]-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-3-oxo-propyl]triazol-4-yl]methoxy]phenoxy]20 phenoxy]methyl]triazol-1-yl]-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo [3,2-b]pyridine-1-carbonyl]propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (30 mg, 20.8 umol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 2 mL). The mixture was stirred at 25°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with 25 formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*40mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 25%-70%, 8 min) to give the title compound (7.7 mg, 5.23 umol, 25.2% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 623.4 [M/2+H]+ 30 1H NMR (400 MHz, METHANOL-d4) δ = 8.12 (s, 2H), 8.06 (s, 2H), 7.30 (dd, J = 5.4, 8.6 Hz, 4H), 6.99 - 6.90 (m, 4H), 6.63 (br d, J = 9.0 Hz, 4H), 6.41 (br d, J = 8.9 Hz, 4H), 5.22 - 5.15 (m, 4H), 5.13 - 5.06 (m, 8H), 4.07 (br d, J = 10.5 Hz, 2H), 3.90 (br s, 2H), 3.83 - 3.74 (m, 4H), 3.43 (br d, J = 10.3 Hz, 2H), 2.71 (s, 6H), 1.76 (d, J = 6.8 Hz, 6H), 1.50 (d, J = 7.0 Hz, 6H), 1.33 (s, 6H), 1.00 (s, 6H) 35 319 70226WO01 The following final compounds were prepared according to the same procedure as Example 72: Examples 73 and 74. The compounds were found to have characterizing data as set forth below. Example 73, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-((((methylenebis(4,1- 5 phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)- 3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2- . Boc N H (S) N N O O N O O O HN 37.1 (S) O (S) N H NH N N (S) F 10 1H NMR (400 MHz, METHANOL-d4) δ = 8.27 (s, 2H), 8.07 (s, 2H), 7.35 (dd, J = 5.5, 8.5 Hz, 5H), 6.93 (t, J = 8.8 Hz, 4H), 6.52 (d, J = 8.5 Hz, 4H), 6.24 (br d, J = 8.4 Hz, 4H), 5.25 (d, J = 10.5 Hz, 2H), 5.16 - 5.10 (m, 6H), 4.03 (br d, J = 10.4 Hz, 2H), 3.96 - 3.91 (m, 2H), 3.87 (br d, J = 14.3 Hz, 2H), 3.77 - 3.70 (m, 2H), 3.43 (br d, J = 10.4 Hz, 2H), 3.09 (s, 2H), 2.71 (s, 6H), 1.73 (d, J = 6.6 Hz, 6H), 1.50 (d, J = 7.0 Hz, 7H), 1.35 (s, 7H), 1.10 - 1.03 (m, 4H), 0.71 (s, 6H) 15 Example 74, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(((1,4-phenylenebis(oxy))bis(methylene))bis(1H- 1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2-(methylamino)propanamide). Boc O HN N (S) F 20 1H NMR (400MHz, METHANOL-d4) δ = 8.15 (s, 2H), 8.01 (s, 2H), 7.14 (dd, J=5.5, 8.4 Hz, 4H), 6.86 (t, J=8.8 Hz, 4H), 6.52 (s, 4H), 5.12 - 5.04 (m, 2H), 4.94 (br s, 12H), 4.03 (br d, J=10.4 Hz, 2H), 3.93 (q, J=6.9 Hz, 2H), 3.74 (br d, J=9.0 Hz, 4H), 3.42 (br d, J=10.6 Hz, 2H), 2.71 (s, 6H), 1.81 (d, J=6.5 Hz, 6H), 1.51 (d, J=7.0 Hz, 6H), 1.31 (s, 6H), 1.13 (s, 6H) 25 320 70226WO01 Example 75, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(octa-3,5-diyne-1,8-diylbis(1H-1,2,3-triazole-4,1- diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-ox ne-3,2-diyl))bis(2-(methylamino)propanamide). Boc N (S) O Boc N H N O (S) HN HN (S) (S) F O NH N N F ( DIEA , CuI , 85°C O NH N O S) N3 O N O N N (S (S)) F N DMF 70°C 12h (S (S)) 2) HCl/EtOAc N N O F butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- 1-carbonyl]-2-(4-but-3-ynyltriazol-1-yl)propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl- carbamate. 10 To a solution of tert-butyl N-[(1S)-2-[[(1S,2S)-2-azido-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]propyl]amino]-1- methyl-2-oxo-ethyl]-N-methyl-carbamate (79 mg, 113 umol, 1 eq), hexa-1,5-diyne (88.4 mg, 1.13 mmol, 10 eq), and DIEA (29.3 mg, 226 umol, 39.4 uL, 2 eq) in DMF (4 mL) was added CuI (21.6 mg, 113 umol, 1 eq) at 15°C. The mixture was degassed and purged with N2 three times, and then 15 the mixture was stirred at 70°C for 12 h under N2 atmosphere after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (20 mL) was added to the mixture, then extracted with EtOAc (20 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum 20 ether/EtOAc = 1:1) to give the title compound (85 mg, 109 umol, 96.8% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.50. LCMS (ES, m/z): 776.8 [M+H]+ Step 2 of 2: Synthesis of Example 75, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(octa-3,5-diyne-1,8-25 diylbis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2- (methylamino)propanamide). To a solution of tert-butyl N-[(1S)-2-[[(1S,2S)-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]-2-(4-but-3-ynyltriazol- 30 1-yl)propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (77 mg, 99.2 umol, 1 eq) in CH3CN (3 mL) was added pyridine (47.1 mg, 595 umol, 48.0 uL, 6 eq) and Cu(OAc)2 (21.6 mg, 119 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment after which time 321 70226WO01 LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH3 aq. (10 mL), then extracted with EtOAc (15 mL * 3). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the intermediate product (76 mg, 49.0 umol, 5 98.8% yield) as a yellow oil. To a solution of the intermediate product (76 mg, 49.0 umol, 1 eq) in EtOAc (3 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 20°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered to give the crude solid product. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile 10 phase: [water(TFA)-CH3CN], B%: 10%-55%, 8 min) to give the title compound (13.4 mg, 9.75 umol, 19.9% yield, 98.161% purity, 2 TFA) as an off-white solid. LCMS (ES, m/z): 561.4 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 8.05 (s, 2H), 7.79 (s, 2H), 7.22 (dd, J=5.5, 8.5 Hz, 4H), 6.98 (t, J=8.8 Hz, 4H), 5.23 (d, J=9.4 Hz, 2H), 5.09 - 4.99 (m, 2H), 4.10 (d, J=10.4 Hz, 2H), 3.92 15 (q, J=6.7 Hz, 2H), 3.76 (s, 4H), 3.70 (d, J=10.5 Hz, 2H), 2.77 (br t, J=7.1 Hz, 4H), 2.70 (s, 6H), 2.46 - 2.32 (m, 4H), 1.72 (d, J=6.9 Hz, 6H), 1.49 (d, J=7.0 Hz, 6H), 1.30 (d, J=14.8 Hz, 14H). The following final compounds were prepared according to the same procedure as Example 75: Examples 76 and 77. The compounds were found to have characterizing data as set forth below. 20 Example 76, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(deca-4,6-diyne-1,10-diylbis(1H-1,2,3-triazole-4,1- diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2-(methylamino)propanamide). Boc N (S) F HN H N O F 25 , . 1H NMR (400 MHz, METHANOL-d4) δ = 8.13 (s, 2H), 7.63 (s, 2H), 7.31 (br dd, J = 5.5, 8.1 Hz, 4H), 6.98 (br t, J = 8.6 Hz, 4H), 5.11 (br d, J = 10.3 Hz, 4H), 4.13 (br d, J = 10.4 Hz, 2H), 3.96 - 3.84 (m, 4H), 3.69 (br d,J = 14.6 Hz, 2H), 3.60 (br d, J = 10.5 Hz, 2H), 2.76 - 2.66 (m, 8H), 2.56 - 2.45 (m, 2H), 1.79 (br d, J = 6.6 Hz, 6H), 1.70 - 1.61 (m, 4H), 1.51 (br d, J = 6.9 Hz, 10H), 1.39 (s, 30 6H), 1.31 (s, 6H). 322 70226WO01 Example 77, (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(((hexa-2,4-diyne-1,6- diylbis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3- 5 O F 10 15 323 70226WO01 OH OH OH O O Boc NH (Boc)2O, NaHCO3 BnBr, NaHCO O 3 SOCl2, Py S NaN3 OH Boc OH Boc OBn O S O NaIO4, RuCl3 O OBn H N MeOH, H O N DMF N MeCN, - N N DMF O N3 2 2 H H 78 C to RT, 2 h 0 C to RT, 2 h Boc O OBn O O O Boc OBn 117.1 117.2 117.3 117.4 117.5 OTBS 2.11 EA lux OH DMF Step 1 of 11: Synthesis of Intermediate 117.1, (2S,3S)-2-(tert-butoxycarbonylamino)-3- hydroxy-butanoic acid. 5 NaHCO3 (15.9 g, 189 mmol, 7.35 mL, 1.5 eq) and (Boc)2O (41.2 g, 189 mmol, 43.4 mL, 1.5 eq) in MeOH (120 mL) were added to (2S,3S)-2-amino-3-hydroxy-butanoic acid (15 g, 126 mmol, 1 eq) in H2O (120 mL). The mixture was stirred at 15°C for 12 h after which time TLC (Dichloromethane/Methanol = 10:1) indicated complete consumption of starting material and formation of a new product. The reaction mixture was acidified to pH 2 using aqueous HCl (0.5 10 M) and extracted with EtOAc (3 * 100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (27 g, 123 mmol, 97.8% yield) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 5.66 (br d, J = 7.1 Hz, 1H), 4.36 (br d, J = 2.8 Hz, 1H), 4.18 (br s, 1H), 1.44 (s, 9H), 1.29 - 1.25 (m, 3H) 15 Step 2 of 11: Synthesis of Intermediate 117.2, benzyl (2S,3S)-2-(tert-butoxycarbonylamino)- 3-hydroxy-butanoate. To a solution of (2S,3S)-2-(tert-butoxycarbonylamino)-3-hydroxy-butanoic acid (35 g, 160 mmol, 1 eq) in DMF (400 mL) was added NaHCO3 (40.2 g, 479 mmol, 18.6 mL, 3 eq) and BnBr (137 g,20 798 mmol, 94.8 mL, 5 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC- 24 70226WO01 MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (200 mL) was added to the mixture, and the mixture was extracted with EtOAc (100 mL * 2). The combined organic phase was washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The crude product 5 was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (39 g, 126 mmol, 79.0% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.46. LCMS (ES, m/z): 210.1 [M-Boc+H]+ 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.39 - 7.34 (m, 5H), 5.46 (br d, J = 2.3 Hz, 1H), 5.21 10 (d, J = 4.4 Hz, 2H), 4.44 (br s, 1H), 4.20 - 4.13 (m, 1H), 2.05 (s, 1H), 1.45 (s, 9H), 1.15 (br d, J = 6.3 Hz, 3H) Step 3 of 11: Synthesis of Intermediate 117.3, 4-benzyl 3-(tert-butyl) (4S,5S)-5-methyl-1,2,3- oxathiazolidine-3,4-dicarboxylate 2-oxide. 15 A solution of SOCl2 (9.50 g, 79.8 mmol, 5.79 mL, 1.30 eq) in CH3CN ( L) was degassed and purged with N2 three times at -40°C, and then benzyl (2S,3S)-2-(tert-butoxycarbonylamino)-3- hydroxy-butanoate (19 g, 61.4 mmol, 1 eq) in CH3CN (180 mL) was added dropwise over 30 min at -40°C. The mixture was stirred at -40°C for 60 min and to the mixture was added pyridine (24.3 g, 307 mmol, 24.8 mL, 5.00 eq). The mixture was stirred at 0°C for 1 h after which time TLC 20 (Petroleum ether/EtOAc = 3:1) indicated complete consumption of starting material and formation of a new product. The reaction mixture was quenched by addition of H2O (400 mL), and extracted with EtOAc (200 mL * 3). The combined organic phase was washed with saturated aq. NaCl (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (22 g, quantitative yield) as a yellow oil. 25 Step 4 of 11: Synthesis of Intermediate 117.4, 4-benzyl 3-(tert-butyl) (4S,5S)-5-methyl-1,2,3- oxathiazolidine-3,4-dicarboxylate 2,2-dioxide. To a solution of 4-benzyl 3-(tert-butyl) (4S,5S)-5-methyl-1,2,3-oxathiazolidine-3,4-dicarboxylate 2-oxide (22 g, 61.9 mmol, 1 eq) in CH3CN (200 mL) was added RuCl3 (257 mg, 1.24 mmol, 82.6 30 uL, 0.02 eq) at 0°C. To the mixture was added NaIO4 (19.9 g, 92.9 mmol, 5.15 mL, 1.5 eq) in H2O (200 mL). The mixture was stirred at 0°C for 2 h after which time TLC (Petroleum ether/EtOAc = 5:1) indicated complete consumption of starting material and formation of a new product. The reaction mixture was added into saturated NaHCO3 aq. (200 mL), then extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, 35 filtered and concentrated under reduced pressure to give a residue. The residue was purified by 325 70226WO01 column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 3:1) to give the title compound (8 g, 21.5 mmol, 34.8% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.39. 1HNMR (400 MHz, CHLOROFORM-d) δ = 7.43 - 7.32 (m, 5H), 5.42 - 5.30 (m, 1H), 5.28 - 5.18 5 (m, 1H), 5.13 - 5.03 (m, 1H), 4.67 (br s, 1H), 1.64 - 1.34 (m, 12H) Step 5 of 11: Synthesis of Intermediate 117.5, benzyl (2S,3R)-3-azido-2-(tert- butoxycarbonylamino)butanoate. To a solution of 4-benzyl 3-(tert-butyl) (4S,5S)-5-methyl-1,2,3-oxathiazolidine-3,4-dicarboxylate 10 2,2-dioxide (1 g, 2.69 mmol, 1 eq) in DMF (12 mL) was added NaN3 (610 mg, 9.38 mmol, 3.48 eq) at 15°C with stirring. The mixture was stirred at 80°C for 1 h after which time TLC (Petroleum ether/EtOAc = 3:1) indicated complete consumption of starting material and formation of a new product. The reaction mixture was added into H2O (80 mL), then extracted with EtOAc (40 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced 15 pressure to give the title compound (900 mg, 2.69 mmol, quantitative yield) as a yellow oil. Step 6 of 11: Synthesis of Intermediate 117.6, benzyl (2S,3R)-3-[4-[[4-[1-[4-[[1-[(1R,2S)-3- benzyloxy-2-(tert-butoxycarbonylamino)-1-methyl-3-oxo-propyl]triazol-4- yl]methoxy]phenyl]-1-methyl-ethyl]phenoxy 20 butoxycarbonylamino)butanoate. To a solution of benzyl (2S,3R)-3-azido-2-(tert-butoxycarbonylamino)butanoate (900 mg, 2.69 mmol, 6 eq), 1-[1-methyl-1-(4-prop-2-ynoxyphenyl)ethyl]-4-prop-2-ynoxy-benzene (137 mg, 449 umol, 1 eq), and DIEA (116 mg, 897 umol, 156 uL, 2 eq) in DMF (12 mL) was added CuI (120 mg, 628 umol, 1.4 eq) at 15°C. The mixture was degassed and purged with N2 three times, and 25 then the mixture was stirred at 70°C for 12 h under N2 atmosphere. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (20 mL) was added to the mixture, then extracted with EtOAc (30 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in MeOH (5 mL), and the resulting solution 30 was loaded to a 120 g ISCO reverse phase (C18) flash column, eluted with 65% to 95% Acetonitrile in water. The product fraction was collected and evaporated under reduced pressure to give the title compound (357 mg, 367 umol, 81.8% yield) as a yellow solid. LCMS (ES, m/z): 973.5 [M +H]+ 326 70226WO01 Step 7 of 11: Synthesis of Intermediate 117.7, (2S,3R)-2-(tert-butoxycarbonylamino)-3-[4-[[4- [1-[4-[[1-[(1R,2S)-2-(tert-butoxycarbonylamino)-2-carboxy-1-methyl-ethyl]triazol-4- yl]methoxy]phenyl]-1-methyl-ethyl]phenoxy]methyl]triazol-1-yl]butanoic acid. To a solution of benzyl (2S,3R)-3-[4-[[4-[1-[4-[[1-[(1R,2S)-3-benzyloxy-2-(tert- 5 butoxycarbonylamino)-1-methyl-3-oxo-propyl]triazol-4-yl]methoxy]phenyl]-1-methyl-ethyl] phenoxy]methyl]triazol-1-yl]-2-(tert-butoxycarbonylamino)butanoate (357 mg, 367 umol, 1 eq) in MeOH (6 mL) was added Pd/C (350 mg, 10% purity) under N2 atmosphere at 15°C. The mixture was stirred at 15°C for 2 h under H2 (15 psi) atmosphere after which time TLC (Petroleum ether/EtOAc = 3:1) indicated conversion to a new product. The mixture was filtered and the filtrate 10 was concentrated under reduced pressure to give the title compound (290 mg, 366 umol, 99.7% yield) as a white solid. LCMS (ES, m/z): 793.5 [M +H]+ Step 8 of 11: Synthesis of Intermediate 117.8, tert-butyl N-[(1S,2R)-2-[4-[[4-[1-[4-[[1-15 [(1R,2S)-2-(tert-butoxycarbonylamino)-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyr l]-1-methyl-3-oxo- propyl]triazol-4-yl]methoxy]phenyl]-1-methyl-ethyl]phenoxy]methyl]triazol-1-yl]-1-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- 1-carbonyl]propyl]carbamate. 20 To a solution of (2S,3R)-2-(tert-butoxycarbonylamino)-3-[4-[[4-[1-[4-[[1-[(1R,2S)-2-(tert- butoxycarbonylamino)-2-carboxy-1-methyl-ethyl]triazol-4-yl]methoxy]phenyl]-1-methyl- ethyl]phenoxy]methyl]triazol-1-yl]butanoic acid (250 mg, 315 umol, 1 eq) and tert-butyl-[[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (305 mg, 788 umol, 2.5 eq) in DCM (6 mL) was added DIEA (245 mg, 1.89 mmol, 330 uL, 6 eq) 25 and HATU (360 mg, 946 umol, 3 eq) at 0°C. The mixture was stirred at 50°C for 4 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH4Cl aq. (12 mL), then extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (15 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative 30 TLC (SiO2, Petroleum ether/EtOAc = 1:1) to give the title compound (422 mg, 276 umol, 87.5% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.65. LCMS (ES, m/z): 765.8 [M/2+H]+. 327 70226WO01 Step 9 of 11: Synthesis of Intermediate 117.9, 1,1'-((2S,2'S,3R,3'R)-3,3'-((((propane-2,2- diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(2- aminobutanoyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2- b]pyridin-5-one). 5 To a solution of tert-butyl N-[(1S,2R)-2-[4-[[4-[1-[4-[[1-[(1R,2S)-2-(tert-butoxycarbonylamino)-3- [5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2- b]pyridin-1-yl]-1-methyl-3-oxo-propyl]triazol-4-yl]methoxy]phenyl]-1-methyl- ethyl]phenoxy]methyl]triazol-1-yl]-1-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]propyl]carbamate (420 mg, 275 umol, 1 eq) in 10 EtOAc (3 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 15°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the filter cake was dried to give the title compound (287 mg, 244 umol, 89.0% yield, 2 HCl) as a yellow solid. LCMS (ES, m/z): 1101.5 [M+H]+. 15 Step 10 of 11: Synthesis of Intermediate 117.10, di-tert-butyl ((2S,2'S)-(((2S,2'S,3R,3'R)- ((((propane-2,2-diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1- diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(azanediyl))bis(1-oxopr - 20 diyl))bis(methylcarbamate). (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (39.8 mg, 196 umol, 2 eq), DIEA (76.0 mg, 588 umol, 102 uL, 6 eq), and HATU (112 mg, 294 umol, 3 eq) were combined in DMF (5 mL) and stirred at 0°C for 30 min. 1,1'-((2S,2'S,3R,3'R)-3,3'-((((propane-2,2-diylbis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(2-aminobutanoyl))bis(6-(4- 25 fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-b]pyridin-5-one) (115 mg, 97.9 umol, 1 eq, 2 HCl) was added at 0°C. The mixture was stirred at 50°C for 5.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (10 mL) was added to the mixture, then extracted with EtOAc (20 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced 30 pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (135 mg, 91.7 umol, 93.7% yield) as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.60. LCMS (ES, m/z): 1471.7 [M+H]+ 328 70226WO01 Step 11 of 11: Synthesis of Example 78, (2S,2'S)-N,N'-((2S,2'S,3R,3'R)-((((propane-2,2- diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1- oxobutane-3,2-diyl))bis(2-(methylamino)propanamide). 5 To a solution of di-tert-butyl ((2S,2'S)-(((2S,2'S,3R,3'R)-((((propane-2,2-diylbis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2- diyl))bis(azanediyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (135 mg, 91.7 umol, 1 eq) in EtOAc (3 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 15°C for 0.5 h. 10 LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 10%-50%, 8 min) to give the title compound (25.9 mg, 17.3 umol, 18.7% yield, 99.3% purity, 2 TFA) as a white solid. 15 LCMS (ES, m/z): 636.5 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 8.22 (d, J=15.3 Hz, 4H), 7.25 (dd, J=5.4, 8.6 Hz, 4H), 7.19 - 7.14 (m, 4H), 7.02 - 6.94 (m, 4H), 6.90 (d, J=8.9 Hz, 4H), 5.33 (d, J=9.3 Hz, 2H), 5.25 - 5.14 (m, 2H), 5.10 (s, 4H), 4.11 - 4.03 (m, 4H), 3.86 - 3.75 (m, 4H), 3.63 (q, J=6.9 Hz, 2H), 2.37 (s, 6H), 1.68 (d, J=6.9 Hz, 6H), 1.63 (s, 6H), 1.44 - 1.37 (m, 12H), 1.35 (s, 6H) 20 Example 79, (2S,2'S)-N,N'-((2S,2'S)-((((propane-2,2-diylbis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(3-(6-(4-fluorobenzyl)- 3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2- diyl))bis(2-(methylamino)propanamid . 329 70226WO01 OH SOCl2, Py, MeCN O NaIO4, RuCl3 O Boc NH O O -78 C to RT, 2 h O NaN 35.1 O S 0 C to RT, 2 h S OB O OBn 3 Boc N OBn N n N DMF O N3 Bo DIEA, CuI, DMF H B c O OBn OH DCM Step 1 of 9: Synthesis of Intermediate 118.1, 4-benzyl 3-(tert-butyl) (4S)-1,2,3-oxathiazolidine- 3,4-dicarboxylate 2-oxide. 5 A solution of thionyl chloride (10.5 g, 88.0 mmol, 6.39 mL, 1.3 eq) i 3CN (270 mL) was degassed and purged with N2 three times at -40°C, and then benzyl (2S)-2-(tert- butoxycarbonylamino)-3-hydroxy-propanoate (20 g, 67.7 mmol, 1 eq) in CH3CN (180 mL) was added dropwise over 30 min at -40°C. The mixture was stirred at -40°C for 60 min and to the mixture was added pyridine (26.8 g, 339 mmol, 27.3 mL, 5 eq). The mixture was stirred at 0°C for 10 1 h after which time TLC (Petroleum ether/EtOAc = 3:1) indicated conversion to a new product. The reaction mixture was quenched by addition of H2O (400 mL), and then diluted with EtOAc (400 mL) and extracted with EtOAc (200 mL * 3). The combined organic phase was washed with saturated aq. NaCl (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (23.1 g, crude) as a yellow oil. 15 Step 2 of 9: Synthesis of Intermediate 118.2, 4-benzyl 3-(tert-butyl) (S)-1,2,3-oxathiazolidine- 3,4-dicarboxylate 2,2-dioxide. To a solution of 4-benzyl 3-(tert-butyl) (4S)-1,2,3-oxathiazolidine-3,4-dicarboxylate 2-oxide (23.1 g, 67.7 mmol, 1 eq) in CH3CN (200 mL) was added RuCl3 (281 mg, 1.35 mmol, 90.3 uL, 0.02 eq) 20 at 0°C. To the mixture was added NaIO4 (21.7 g, 102 mmol, 5.62 mL, 1.5 eq) in H2O (200 mL) 330 70226WO01 dropwise with stirring. The mixture was stirred at 0°C for 2 h after which time TLC (Petroleum ether/EtOAc = 5:1) indicated complete consumption of starting material and formation of a new product. The reaction mixture was added into saturated NaHCO3 aq. (200 mL), then extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (200 mL), dried over 5 Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 5:1) to give the title compound (11.7 g, 32.7 mmol, 48.4% yield) as a white solid. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.50. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.43 - 7.32 (m, 5H), 5.38 - 5.19 (m, 2H), 4.91 - 4.73 10 (m, 2H), 4.72 - 4.64 (m, 1H), 1.50 (br s, 9H) Step 3 of 9: Synthesis of Intermediate 118.3, benzyl (S)-3-azido-2-((tert- butoxycarbonyl)amino)propanoate. To a solution of 4-benzyl 3-(tert-butyl) (S)-1,2,3-oxathi azolidine-3,4-dicarboxylate 2,2-dioxide (2 15 g, 5.60 mmol, 1 eq) in DMF (20 mL) was added NaN3 (1.35 g, 20.8 mmol, 3.71 eq) at 15°C with stirring. The mixture was stirred at 80°C for 2 h after which time TLC (Petroleum ether/EtOAc = 3:1) indicated complete consumption of starting material and formation of a new product. The reaction mixture was added into H2O (80 mL), then extracted with EtOAc (50 mL * 3) and DCM (50 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under 20 reduced pressure to give the title compound (1.79 g, 5.59 mmol, quantitative yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.38 - 7.37 (m, 2H), 7.37 (d, J = 2.6 Hz, 3H), 5.24 - 5.21 (m, 3H), 4.52 (dd, J = 4.5, 9.0 Hz, 1H), 3.77 - 3.71 (m, 2H), 1.45 (s, 9H) Step 4 of 9: Synthesis of Intermediate 118.4, dibenzyl 3,3'-((((propane-2,2-diylbis(4,1-25 phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))(2S,2'S)-bis(2-((tert- butoxycarbonyl)amino)propanoate). To a solution of benzyl (S)-3-azido-2-((t ert- utoxycarbonyl)amino)propanoate (1.79 g, 5.59 mmol, 5 eq), 4,4'-(propane-2,2-diyl)bis((prop-2-yn-1-yloxy)benzene) (340 mg, 1.12 mmol, 1 eq), and DIEA (289 mg, 2.23 mmol, 389 uL, 2 eq) in DMF (20 mL) was added CuI (298 mg, 1.56 mmol, 30 1.4 eq) at 15°C. The mixture was degassed and purged with N2 three times, and then the mixture was stirred at 70°C for 12 h under N2 atmosphere after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (20 mL) was added to the mixture which was then extracted with EtOAc (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was 35 concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase 331 70226WO01 MPLC (column: C18, 20-35um, 100A, 120g; mobile phase: [Water (1% TFA)-CH3CN], B%: 55%- 85%, 50 mL/min) to give the title compound (620 mg, 656 umol, 58.7% yield) as a gray solid. LCMS (ES, m/z): 945.6 [M +H]+ 1HNMR (400 MHz, DMSO-d6) δ = 8.14 (s, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.35 (s, 8H), 7.11 (d, J = 5 8.8 Hz, 4H), 6.91 (d, J = 8.8 Hz, 4H), 5.20 - 5.10 (m, 4H), 5.09 - 5.04 (m, 4H), 4.83 - 4.75 (m, 2H), 4.70 - 4.53 (m, 4H), 1.58 (s, 6H), 1.32 (s, 18H). Step 5 of 9: Synthesis of Intermediate 118.5, (2S,2'S)-3,3'-((((propane-2,2-diylbis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(2-((tert- 10 butoxycarbonyl)amino)propanoic acid). To a solution of dibenzyl 3,3'-((((propane-2,2-diylbis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))(2S,2'S)-bis(2-((tert- butoxycarbonyl)amino)propanoate) (200 mg, 212 umol, 1 eq) in MeOH (3 mL) was added Pd/C (200 mg, 10% purity) under N2 atmosphere at 15°C. The mixture was stirred at 15°C for 2 h under 15 H2 (15 psi) atmosphere after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was concentrated to give the title compound (150 mg, 196 umol, 92.7% yield) as a yellow oil. LCMS (ES, m/z): 765.5 [M +H]+ 20 Step 6 of 9: Synthesis of Intermediate 118.6, di-tert-butyl ((2S,2'S)-((((propane-2,2- diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(3-(5-((tert- butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-23-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))dicarbam . To a solution of (2S,2'S)-3,3'-((((propane-2,2-diylbis(4,1-25 phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(2-((tert- butoxycarbonyl)amino)propanoic acid) (150 mg, 196 umol, 1 eq) and tert-butyl-[[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (189 mg, 490 umol, 2.5 eq) in DCM (3 mL) was added DIEA (152 mg, 1.18 mmol, 205 uL, 6 eq) and T3P (447 mg, 703 umol, 418 uL, 50% purity, 3.59 eq) at 0°C. The mixture was stirred at 50°C 30 for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (20 mL) was added to the mixture which was then extracted with DCM (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 1:2) to give the title 35 compound (180 mg, 120 umol, 61.1% yield) as a yellow solid. 332 70226WO01 TLC (Petroleum ether/EtOAc = 1:2) Rf = 0.61. LCMS (ES, m/z): 1387.8 [M-TBS+H]+ Step 7 of 9: Synthesis of Intermediate 118.7, 1,1'-((2S,2'S)-3,3'-((((propane-2,2-diylbis(4,1- 5 phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(2- aminopropanoyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H-pyrrolo[3,2- b]pyridin-5-one). To a solution of di-tert-butyl ((2S,2'S)-((((propane-2,2-diylbis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(3-(5-((tert-10 butyldimethylsilyl)oxy)-6-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1- yl)-3-oxopropane-1,2-diyl))dicarbamate (180 mg, 120 umol, 1 eq) in EtOAc (2 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 15°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give the title compound (110 mg, 96.0 umol, 80.1% yield, 2 15 HCl) as a yellow solid. LCMS (ES, m/z): 1073.5 [M+H]+ Step 8 of 9: Synthesis of Intermediate 118.8, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((((propane-2,2- diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(3-(6-(4-20 fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(azanediyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate). To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoic acid (39.0 mg, 192 umol, 2 eq) in DCM (4 mL) was added DIEA (74.4 mg, 576 umol, 100 uL, 6 eq), 1,1'-((2S,2'S)-3,3'- ((((propane-2,2-diylbis(4,1-phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-25 diyl))bis(2-aminopropanoyl))bis(6-(4-fluorobenzyl)-3,3-dimethyl-1,2,3,4-tetrahydro-5H- pyrrolo[3,2-b]pyridin-5-one) (110 mg, 96.0 umol, 1 eq, 2 HCl) and HATU (109 mg, 288 umol, 3 eq) at 0°C. The mixture was stirred at 15°C for 12 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (20 mL) was added to the mixture, and the mixture was extracted with DCM (15 mL * 2). The 30 combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (90 mg, 62.3 umol, 64.9% yield) as a yellow solid. TLC (EtOAc/Methanol = 10:1) Rf = 0.57. 35 LCMS (ES, m/z): 1443.6 [M+H]+. 333 70226WO01 Step 9 of 9: Synthesis of Example 79, (2S,2'S)-N,N'-((2S,2'S)-((((propane-2,2-diylbis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(3-(6-(4-fluorobenzyl)- 5 To a solution of di-tert-butyl ((2S,2'S)-(((2S,2'S)-((((propane-2,2-diylbis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2- diyl))bis(azanediyl))bis(1-oxopropane-1,2-diyl))bis(methylcarbamate) (90 mg, 62.3 umol, 1 eq) in 10 EtOAc (2 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 20°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30mm, 3um; mobile phase: [water(0.1%TFA)-CH3CN], B%: 20%-50%, 8 min) to give the title compound (7 15 mg, 4.76 umol, 7.63% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 622.4 [M/2+H]+. 1H NMR (400 MHz, METHANOL-d4) δ = 8.17 (s, 1H), 8.09 (s, 2H), 7.22 (dd, J = 5.6, 8.2 Hz, 4H), 7.12 (d, J = 8.8 Hz, 4H), 6.95 (t, J = 8.8 Hz, 4H), 6.83 (d, J = 8.9 Hz, 4H), 5.28 (br t, J = 6.9 Hz, 2H), 5.08 (s, 6H), 4.02 - 3.94 (m, 2H), 3.87 - 3.63 (m, 10H), 2.58 (s, 6H), 1.60 (s, 6H), 1.48 (d, J = 20 6.9 Hz, 6H), 1.33 (d, J = 7.4 Hz, 12H) Example 80, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(24-dichlorobenzyl)-33-dimethyl-5-oxo-2345-tetrahydro-1H- ide). HN N OTBS Cl Cl O HCl (S) N Cl N Cl 25 70226WO01 Step 1 of 5: Synthesis of Intermediate 119.1, (S)-tert-butyl (1-(5-((tert- butyldimethylsilyl)oxy)-6-(2,4-dichlorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn-1-yloxy)phenyl)propan-2-yl)carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(4-prop-2-ynoxyphenyl)propanoic acid (263 5 mg, 823 umol, 1.2 eq) and DIEA (266 mg, 2.06 mmol, 358 uL, 3 eq) in DCM (6 mL) was added tert-butyl-[[6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5- yl]oxy]-dimethyl-silane (300 mg, 686 umol, 1 eq) and HATU (391 mg, 1.03 mmol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (20 mL) was added to 10 the mixture and the mixture was extracted with DCM (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (360 mg, 487 umol, 71.1% yield) as a yellow oil. 15 TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.53 LCMS (ES, m/z): 739.3 [M+H+]. Step 2 of 5: Synthesis of Intermediate 119.2, (S)-1-(2-amino-3-(4-(prop-2-yn-1- yloxy)phenyl)propanoyl)-6-(2,4-dichlorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- 20 b]pyridin-5(4H)-one hydrochloride. To a solution N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(2,4- dichlorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2- ynoxyphenyl)methyl]ethyl]carbamate (360 mg, 487 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete 25 consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (260 mg, 464 umol, 95.1% yield, HCl) as a yellow solid. LCMS (ES, m/z): 524.1[M+H+]. 30 Step 3 of 5: Synthesis of Intermediate 119.3, tert-butyl ((S)-1-(((S)-1-(6-(2,4-dichlorobenzyl)- 3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn- 1-yloxy)phenyl)propan-2-yl)amino)-1-oxobutan-2-yl)(methyl)carbamate. To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (116 mg, 535 umol,1.2 eq), 1-[(2S)-2-amino-3-(4-prop-2-ynoxyphenyl)propanoyl]-6-[(2,4-dichlorophenyl) 335 70226WO01 methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one (250 mg, 446 umol, 1 eq, HCl), and DIEA (173 mg, 1.34 mmol, 233 uL, 3 eq) in DCM (4 mL) was added HATU (254 mg, 669 umol, 1.5 eq) at 0°C. The mixture was stirred at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) 5 was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (160 mg, 221 umol, 49.6% yield) as a yellow solid. TLC (EtOAc) Rf = 0.50 10 LCMS (ES, m/z): 722.2[M+H+]. Step 4 of 5: Synthesis of Intermediate 119.4, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-[(2,4- dichlorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydro -oxo-15 propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2- 4-dichlorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N- methyl-carbamate. To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-5-oxo- 2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamoyl] 20 propyl]-N-methyl-carbamate (160 mg, 221 umol, 1 eq) in CH3CN (4 mL) was added pyridine (105 mg, 1.33 mmol, 107 uL, 6 eq) and Cu(OAc)2 (48.2 mg, 265 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filtrate was added into NH3.H2O (10 mL), then extracted with EtOAc (8 mL * 3). The combined organic 25 phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (140 mg, 96.9 umol, 87.6% yield) as a yellow solid. LCMS (ES, m/z): 1443.4[M+H+]. Step 5 of 5: Synthesis of Example 80, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-30 diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(2,4-dichlorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert-butoxycarbonyl (methyl)amino]butanoyl]amino]-3-[6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-35 dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[6- 336 70226WO01 [(2,4-dichlorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo- ethyl]carbamoyl]propyl]-N-methyl-carbamate (130 mg, 89.9 umol, 1 eq) in EtOAc (1 mL) was added HCl/dioxane (4 M, 2 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The 5 mixture was filtered and the filter cake was dried to give a crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna C18100*40mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 15%-60%, 8 min) to give the title compound (57.4 mg, 38.9 umol, 43.3% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 1242.4[M+H+]. 10 1H NMR (400 MHz, METHANOL-d4) δ = 8.08 (s, 2H), 7.46 (d, J = 1.6 Hz, 2H), 7.31 - 7.25 (m, 4H), 7.19 (d, J = 8.6 Hz, 4H), 6.85 (d, J = 8.6 Hz, 4H), 4.75 (br d, J = 6.8 Hz, 6H), 3.98 - 3.89 (m, 6H), 3.73 (dd, J = 5.3, 6.8 Hz, 2H), 3.11 - 2.99 (m, 6H), 2.58 (s, 6H), 1.89 (br d, J = 7.0 Hz, 4H), 1.29 (s, 6H), 1.00 (s, 6H), 0.94 (s, 6H) 15 Example 81, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(4-chloro-2-cyanobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). HN N OTBS Cl Cl HCl O ( Cl 8.4 Boc S) N N NH NH Boc OH (S) 2 Boc CN 20 Step 1 of 5: Synthesis of Intermediate 120.1, tert-butyl N-[(1S)-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-chloro-2-cyano-phenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2- b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(4-prop-2-ynoxyphenyl)propanoic acid (246 mg, 771 umol, 1.1 eq) in DCM (4 mL) was added DIEA (272 mg, 2.10 mmol, 366 uL, 3 eq), 2-[[5-25 [tert-butyl(dimethyl)silyl]oxy-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-6-yl]methyl]-5- chloro-benzonitrile (300 mg, 701 umol, 1 eq) and HATU (399.74 mg, 1.05 mmol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to 337 70226WO01 the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (430 mg, 590 umol, 84.1% yield) as a 5 yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.53 LCMS (ES, m/z): 729.3[M+H+]. Step 2 of 5: Synthesis of Intermediate 120.2, 2-[[1-[(2S)-2-amino-3-(4-prop-2-10 ynoxyphenyl)propanoyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-6-yl]methyl]- 5-chloro-benzonitrile. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-chloro-2-cyano- phenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2- ynoxyphenyl)methyl]ethyl]carbamate (430 mg, 590 umol, 1 eq) in EtOAc (2 mL) was added 15 HCl/EtOAc (4 M, 6 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give the title compound (320 mg, 580 umol, 98.4% yield, HCl) as a yellow solid. LCMS (ES, m/z): 515.2 [M+H+]. 20 Step 3 of 5: Synthesis of Intermediate 120.3, tert-butylN-[(1S)-1-[[(1S)-2-[6-[(4-chloro-2- cyano-phenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4- prop-2-ynoxyphenyl)methyl]ethyl]carbamoyl]p thyl-carbamate. To a solution of 2-[[1-[(2S)-2-amino-3-(4-prop-2-ynoxyphenyl)propanoyl]-3,3-dimethyl-5-oxo-2,4- 25 dihydropyrrolo[3,2-b]pyridin-6-yl]methyl]-5-chloro-benzonitrile (168 mg, 304 umol, 1.1 eq, HCl) in DCM (4 mL) was added DIEA (143 mg, 1.10 mmol, 192 uL, 4 eq), (2S)-2-[tert-butoxycarbonyl (methyl)amino]butanoic acid (60 mg, 276 umol, 1 eq) and HATU (158 mg, 414 umol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into 30 saturated NH4Cl aq. (10 mL) and extracted with DCM (8 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (120 mg, 168 umol, 60.9% yield) as a yellow oil. TLC (EtOAc) Rf = 0.53 35 LCMS (ES, m/z): 714.4[M+H+]. 338 70226WO01 1H NMR (400 MHz, DMSO-d6) δ = 8.26 (br d, J = 6.8 Hz, 1H), 8.09 - 8.01 (m, 2H), 7.73 (dd, J = 2.3, 8.4 Hz, 1H), 7.41 (br d, J = 8.4 Hz, 1H), 7.17 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 4.71 (d, J = 2.3 Hz, 2H), 4.62 (br s, 1H), 4.41 (s, 1H), 3.99 - 3.87 (m, 3H), 3.58 - 3.40 (m, 2H), 3.01 - 2.75 (m, 3H), 2.57 (br s, 3H), 1.73 (tt, J = 6.6, 13.3 Hz, 1H), 1.42 - 1.34 (m, 9H), 1.24 (s, 6H), 0.77 5 (br s, 3H) Step 4 of 5: Synthesis of Intermediate 120.4, tert-butylN-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-[(4-chloro-2-cyano- phenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo o-10 propyl]phenoxy]hexa-2,4-di henyl]methyl]-2-[6-[(4-chloro-2-cyano-phenyl)methyl]- 3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N- methyl-carbamate. To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[6-[(4-chloro-2-cyano-phenyl)methyl]-3,3-dimethyl- 5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl] 15 carbamoyl]propyl]-N-methyl-carbamate (110 mg, 154 umol, 1 eq) in CH3CN (4 mL) was added Cu(OAc)2 (33.6 mg, 185 umol, 1.2 eq) and pyridine (73.1 mg, 924 umol, 74.6 uL, 6 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the filtrate was added into NH3.H2O (10 mL), then extracted with EtOAc 20 (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 10:1) to give the title compound (100 mg, 70.1 umol, 91.0% yield) as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.63 LCMS (ES, m/z): 1424.2[M+H+]. 25 Step 5 of 5: Synthesis of Example 81, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-chloro-2-cyanobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). 30 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-[(4-chloro-2-cyano-phenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4- diynoxy]phenyl]methyl]-2-[6-[(4-chloro-2-cyano-phenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (100 mg, 35 70.10 umol, 1 eq) in EtOAc (1 mL) was added HCl/dioxane (4 M, 2 mL). The mixture was stirred 339 70226WO01 at 20°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30mm, 3um; mobile phase: [water(TFA)-CH3CN], B%: 20%-50%, 8 min) to give the title compound (34.9 5 mg, 23.5 umol, 33.5% yield, 97.9% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 1225.4[M+H+]. 1H NMR (400 MHz, METHANOL-d4) δ = 8.25 (s, 2H), 7.75 (d, J = 2.3 Hz, 2H), 7.58 (dd, J = 2.3, 8.4 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.6 Hz, 4H), 6.86 (d, J = 8.6 Hz, 4H), 4.78 - 4.73 (m, 4H), 4.69 (s, 2H), 4.01 (s, 4H), 3.96 (d, J = 10.3 Hz, 2H), 3.73 (dd, J = 5.3, 6.9 Hz, 2H), 3.10 - 10 3.00 (m, 6H), 2.59 (s, 6H), 1.98 - 1.84 (m, 4H), 1.28 (s, 6H), 1.00 - 0.94 (m, 12H) Example 82, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(2,4-difluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). HN N F HCl O F (S) N N (S) O (S) NH2 O Boc OH Boc O O (S) NH F F N O HAT DIEA D M F F H N H N ( H 1.2 eq. Cu(OAc) S) 2, O Boc N O (S) O N O 6 e oq.Py,ACN, O (S) NH HCl/EtO O (S) NH 85 C. F O N Ac, EtOAc F O N F F 15 Step 1 of 5: Synthesis of Intermediate 121.1, tert-butylN-[(1S)-2-[5-[tert-butyl(dimethyl)silyl] oxy-6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4- prop-2-ynoxyphenyl)methyl]ethyl]carbamate. 20 To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(4-prop-2-ynoxyphenyl)propanoic acid (260 mg, 816 umol, 1.1 eq) and tert-butyl-[[6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-1,2- dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]-dimethyl-silane (300 mg, 742 umol, 1 eq) in DCM (4 mL) was added DIEA (288 mg, 2.22 mmol, 387 uL, 3 eq) and HATU (423 mg, 1.11 mmol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting 25 material with formation of a peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under 340 70226WO01 reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (420 mg, 595 umol, 80.2% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.47 LCMS (ES, m/z): 706.8 [M+H+]. 5 1H NMR (400MHz, CHLOROFORM-d) δ = 8.18 (s, 1H), 7.15 (d, J = 8.5 Hz, 2H), 7.09 - 7.01 (m, 1H), 6.89 - 6.73 (m, 4H), 5.37 (br d, J = 8.9 Hz, 1H), 4.69 - 4.60 (m, 3H), 3.94 - 3.78 (m, 3H), 3.09 (d, J = 10.0 Hz, 1H), 2.99 (br d, J = 7.3 Hz, 2H), 2.49 - 2.42 (m, 1H), 1.42 (s, 9H), 1.25 - 1.21 (m, 3H), 0.99 - 0.95 (m, 3H), 0.91 (s, 9H), 0.28 (d, J = 7.6 Hz, 6H) 10 Step 2 of 5: Synthesis of Intermediate 121.2, 1-[(2S)-2-amino-3-(4-prop-2-ynoxyphenyl) propanoyl]-6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5- one. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(2,4- difluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2- 15 ynoxyphenyl)methyl]ethyl] carbamate (420 mg, 595 umol, 1 eq) in EtOAc (4 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 20°C for 1 h. LC-MS indicated starting material remained. The mixture was stirred another for 4 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give the title compound (340 mg, quantitative yield, HCl) 20 as a yellow oil. LCMS (ES, m/z): 492.3[M+H+]. Step 3 of 5: Synthesis of Intermediate 121.3, tert-butyl N-[(1S)-1-[[(1S)-2-[6-[(2,4- difluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1- 25 [(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamoyl]propyl]-N-methyl-carbamate. To a solution of 1-[(2S)-2-amino-3-(4-prop-2-ynoxyphenyl)propanoyl]-6-[(2,4- difluorophenyl)methyl]-3,3-dimethyl-2,4-dihydropyrrolo[3,2-b]pyridin-5-one (174 mg, 329 umol, 1.10 eq, HCl) and (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (65 mg, 299 umol, 1 eq) in DCM (4 mL) was added DIEA (193 mg, 1.50 mmol, 261 uL, 5 eq) and HATU (171 mg, 449 30 umol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to 35 give the title compound (90 mg, 130 umol, 43.6% yield) as a yellow oil. 341 70226WO01 TLC (EtOAc) Rf = 0.69 LCMS (ES, m/z): 691.3 [M+H+]. Step 4 of 5: Synthesis of Intermediate 121.4, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2- 5 [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-[(2,4- difluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- -oxo- propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[6-[(2,4-difluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo yl]carbamoyl]propyl]-N- methyl-carbamate. 10 To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-5-oxo- 2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamoyl] propyl]-N-methyl-carbamate (80 mg, 116 umol, 1 eq) in CH3CN (4 mL) was added pyridine (55.0 mg, 695 umol, 56.1 uL, 6 eq) and Cu(OAc)2 (25.2 mg, 139 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting 15 material with formation of a single peak of target mass. The reaction mixture was filtered and the mixture was added into NH3.H2O (10 mL), then extracted with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (80 mg, quantitative yield) as a yellow oil. LCMS (ES, m/z): 1379.7[M+H+]. 20 Step 5 of 5: Synthesis of Example 82, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(2,4-difluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). 25 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4- diynoxy]phenyl]methyl]-2-[6-[(2,4-difluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (80 mg, 30 58.0 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm, 3um; mobile phase: [water(TFA)-CH3CN], B%: 20%-50%, 8 min) to give the title 35 compound (47.1 mg, 33.3 umol, 57.5% yield, 99.6% purity, 2 TFA) as a white solid. 342 70226WO01 LCMS (ES, m/z): 1179.5[M+H+]. 1H NMR (400MHz, METHANOL-d4) δ = 8.16 (s, 2H), 7.33 - 7.26 (m, 2H), 7.20 (d, J =8.6 Hz, 4H), 6.96 - 6.83 (m, 8H), 4.81 - 4.69 (m, 10H), 3.95 (d, J =10.4 Hz, 2H), 3.80 (s, 4H), 3.73 (dd, J =5.3, 6.8 Hz, 2H), 3.11 (d, J =10.4 Hz, 2H), 3.03 (br d, J =8.0 Hz, 4H), 2.57 (s, 6H), 1.97 - 1.83 (m, 5 4H), 1.29 (s, 6H), 1.00 (s, 6H), 0.96 (t, J =7.6 Hz, 6H) Example 83, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-dimethyl-4,1- phenylene))bis(3-(3,3-dimethyl-5-oxo-6-(2,4,5-trifluorobenzyl)-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). OBn OBn OH O ZnI Br 30.1 Pd/C, Br (R) H2 LiOH Boc OMe N H 2 3 s Boc (S) Bo (S) (S) Pd (dba) , SPho N OMe MeOH c N OMe K2CO3, DMF Boc N OMe THF, H2O H CM 10 Step 1 of 9: Synthesis of Intermediate 122.1, methyl (2S)-3-(4-benzyloxy-2,6-dimethyl- phenyl)-2-(tert-butoxycarbonylamino)propanoate. To a solution of 5-benzyloxy-2-bromo-1,3-dimethyl-benzene (6.5 g, 22.3 mmol, 1 eq) and 15 dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (458 mg, 1.12 mmol, 0.05 eq) in DMF (100 mL) was added Pd2(dba)3 (511 mg, 55 umol, 0.025 eq) at 15°C under N2. [(2R)-2-(tert- butoxycarbonylamino) -3-methoxy-3 -oxo-propyl]-iodo-zinc (10.6 g, 26.8 mmol, 1.2 eq) was added to the mixture at 15°C under N2 and the mixture was stirred at 80°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a peak of target mass. The reaction 343 70226WO01 mixture was added into saturated NH4Cl aq. (150 mL), then extracted with EtOAc (100 mL * 3). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 4:1) to give the title compound (6.4 g, 15.5 5 mmol, 69.3% yield) as a white solid. TLC (Petroleum ether/EtOAc = 5:1) Rf = 0.73. LCMS (ES, m/z): 314.1 [M-Boc+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.44 - 7.33 (m, 5H), 6.67 (s, 2H), 5.06 - 4.98 (m, 3H), 3.65 (s, 3H), 3.07 - 2.98 (m, 2H), 2.33 (s, 6H), 1.42 - 1.35 (m, 9H) 10 Step 2 of 9: Synthesis of Intermediate 122.2, methyl (2S)-2-(tert-butoxycarbonylamino)-3- (4- hydroxy-2,6-dimethyl-phenyl)propanoate. To a solution of methyl (2S)-3-(4-benzyloxy-2,6-dimethyl-phenyl)-2-(tert-butoxycarbonylamino) propanoate (6.4 g, 15.5 mmol, 1 eq) in MeOH (200 mL) was added Pd/C (5 g, 10% purity) under 15 N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 15°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (5 g, 15.46 mmol, 99.90% yield) as a yellow oil. 20 LCMS (ES, m/z): 224.2 [M-Boc+H]+. 1H NMR (400 MHz, DMSO-d6) δ = 6.73 (s, 2H), 3.99 - 3.91 (m, 1H), 3.86 (s, 2H), 3.52 (s, 3H), 3.34 - 3.25 (m, 1H), 3.20 - 3.12 (m, 1H), 2.85 (td, J = 1.7, 3.6 Hz, 5H), 1.69 (s, 9H) Step 3 of 9: Synthesis of Intermediate 122.3, methyl (2S)-2-(tert-butoxycarbonylamino)-3- 25 (2,6-dimethyl-4-prop-2-ynoxy-phenyl)propanoate. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxy-2,6-dimethyl-phenyl) propanoate (2.2 g, 6.80 mmol, 1 eq) and K2CO3 (1.88 g, 13.6 mmol, 2 eq) in DMF (40 mL) was added 3-bromoprop-1-yne (1.52 g, 10.2 mmol, 1.10 mL, 80% purity, 1.5 eq). The mixture was stirred at 80°C for 12 h. LC-MS indicated complete conversion to a product of target mass. 30 Saturated NH4Cl (30 mL) was added to the mixture which was then extracted with EtOAc (30 mL * 2). The combined organic phase was washed with brine (40 mL * 2), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/EtOAc = 1:0 to 1:1) to give the title compound (2.1 g, 5.81 mmol, 85.4% yield) as a colorless oil. 35 TLC (Petroleum ether/EtOAc = 2:1) Rf = 0.43 344 70226WO01 LCMS (ES, m/z): 262.2 [M-Boc+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 6.65 (s, 2H), 5.05 (br d, J = 8.8 Hz, 1H), 4.65 (d, J = 2.4 Hz, 2H), 4.53 - 4.45 (m, 1H), 3.65 (s, 3H), 3.04 - 2.98 (m, 2H), 2.50 (t, J = 2.4 Hz, 1H), 2.33 (s, 6H), 1.38 (s, 8H) 5 Step 4 of 9: Synthesis of Intermediate 122.4, (2S)-2-(tert-butoxycarbonylamino)-3- (2,6- dimethyl-4-prop-2-ynoxy-phenyl)propanoic acid. To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(2,6-dimethyl-4-prop-2-ynoxy - phenyl)propanoate (2.1 g, 5.81 mmol, 1 eq) in THF (18 mL)/H2O (6 mL) was added LiOH (417 10 mg, 17.4 mmol, 3 eq) and the mixture was stirred at 20°C for 2 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (10 mL), then extracted with EtOAc (10 mL * 2), and then the water phase was acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the combined organic 15 phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (2 g, 5.76 mmol, 99.1% yield) as a pink oil. LCMS (ES, m/z): 248.1 [M-Boc+H]+ Step 5 of 9: Synthesis of Intermediate 122.5, (S)-tert-butyl (1-(5-((tert-butyldimethylsilyl)20 oxy)-3,3-dimethyl-6-(2,4,5-trifluorobenzyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(2,6- dimethyl-4-(prop-2-yn-1-yloxy)phenyl)-1-oxopropan-2-yl)carbamate. To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(2,6-dimethyl-4-(prop-2-yn-1- yloxy)phenyl)propanoic acid (296 mg, 852 umol, 1.2 eq) and tert-butyl-[[3,3-dimethyl-6-[(2,4,5 - trifluorophenyl)methyl]- 1,2-dihydropyrrolo[3,2-b]pyridin- 5-yl]oxy]-dimethyl-silane (300 mg, 710 25 umol, 1 eq) in DCM (6 mL) was added DIEA (275 mg, 2.13 mmol, 371 uL, 3 eq) and HATU (297 mg, 781 umol, 1.1 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LCMS showed desired mass was detected. Saturated NH4Cl (10 mL) was added to the mixture which was then extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by 30 preparative TLC (SiO2, Petroleum ether/EtOAc = 4:1) to give the title compound (200 mg, 266 umol, 37.5% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 4:1) Rf = 0.63. LCMS (ES, m/z): 752.4 [M+H]+ 345 70226WO01 Step 6 of 9: Synthesis of Intermediate 122.6, 1-[(2S)-2-amino- 3-(2,6-dimethyl-4-prop-2- ynoxy-phenyl)propanoyl]-3,3-dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2,4- dihydropyrrolo[3,2-b]pyridin-5-one. To a solution of tert-butyl N-[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-3,3- dimethyl-6- [(2,4,5- 5 trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(2,6-dimethyl-4-prop-2-ynoxy- phenyl)methyl]-2-oxo-ethyl]carbamate (200 mg, 266 umol, 1 eq) in EtOAc (4 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 20°C for 3 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give the title compound (170 mg, quantitative yield, HCl) 10 as a yellow oil. LCMS (ES, m/z): 538.3 [M+H]+ Step 7 of 9: Synthesis of Intermediate 122.7, tert-butyl N-[(1S)-1-[[(1S)-2-[3,3- dimethyl -5- oxo-6-[(2,4,5-trifluorophenyl)methyl]-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[(2,6-15 dimethyl-4-prop-2-ynoxy-phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl- carbamate. To a solution of 1-[(2S)-2-amino-3-(2,6-dimethyl -3,3- dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2,4-dihydropyrrolo[3,2-b]pyridin-5-one (120 mg, 223.23 umol, 1 eq) and (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (58.20 mg, 267.87 20 umol, 1.2 eq) in DCM (3 mL) was added DIEA (86.55 mg, 669.68 umol, 116.64 uL, 3 eq) and T3P (106.54 mg, 334.84 umol, 99.57 uL, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC- MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was added to the mixture which was then extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was 25 concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 1:1) to give the title compound (150 mg, 204 umol, 91.2% yield) as an off-white oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.49. LCMS (ES, m/z): 637.3 [M-Boc+H]+ 30 Step 8 of 9: Synthesis of Intermediate 122.8, tert-butyl N-[(1S)-1-[[(1S)-1-[[4- [6-[4-[(2S) -2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino] -dimethyl-5-oxo-6-[(2,4,5- trifluorophenyl)methyl]-2,4-dihydropyrrolo[3,2-b]pyridin-1-y l]-3-oxo-propyl]-3,5-dimethyl- phenoxy]hexa-2,4-diynoxy]-2,6-dimethyl-phenyl]methyl]-2 ethyl-5-oxo-6-[(2,4,5- 346 70226WO01 trifluorophenyl)methyl]-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo- ethyl]carbamoyl]propyl]-N-methyl-carbamate. To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[3,3-dimethyl-5-oxo-6-[(2,4,5-trifluorophenyl) olo[3,2-b]pyridin-1-yl]-1-[(2,6-dimethyl-4-prop-2-ynoxy-phenyl)methyl]- 5 2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (100 mg, 136 umol, 1 eq) in CH3CN (4 mL) was added pyridine (64.4 mg, 814 umol, 65.7 uL, 6 eq) and Cu(OAc)2 (29.6 mg, 163 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass and the mixture was added into saturated NH3.H2O aq. (10 mL), then extracted with EtOAc (8 mL * 3), dried over 10 Na2SO4, filtered and concentrated under reduced pressure to give the title compound (100 mg, quantitative yield) as a yellow oil. LCMS (ES, m/z): 1472.0 [M+H]+ Step 9 of 9: Synthesis of Example 83, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-15 diylbis(oxy))bis(2,6-dimethyl-4,1-phenylene))bis(3-(3,3-dimethyl-5-oxo-6-(2,4,5- trifluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2- diyl))bis(2-(methylamino)bu To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2- [tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[3,3-dimethyl-5-oxo-6-[(2,4,5-20 trifluorophenyl)methyl]-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5-dimethyl- phenoxy]hexa-2,4-diynoxy]-2,6-dimethyl-phenyl]methyl]-2-[3,3-dimethyl-5-oxo-6-[(2,4,5- trifluorophenyl)methyl]-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N- methyl-carbamate (100 mg, 67.95 umol, 1 eq) in EtOAc (2 mL) was added HCl/dioxane (4 M, 3 mL). The mixture was stirred at 25°C for 0.5 h. LC-MS indicated complete consumption of 25 starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 25%-65%, 8 min) to give the title compound (53.6 mg, 35.7 umol, 52.6% yield, 100% purity, 2 TFA) as a yellow solid. 30 LCMS (ES, m/z): 636.3 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 8.23 (s, 2H), 7.23 - 7.09 (m, 4H), 6.60 (s, 4H), 4.76 - 4.65 (m, 4H), 3.82 - 3.76 (m, 8H), 3.30 - 3.23 (m, 4H), 3.03 (br dd, J = 4.0, 13.8 Hz, 2H), 2.66 (s, 6H), 2.58 (d, J = 10.1 Hz, 2H), 2.30 (s, 12H), 2.00 - 1.89 (m, 4H), 1.24 (s, 6H), 1.00 (t, J = 7.5 Hz, 6H), 0.89 (s, 6H) 35 347 70226WO01 Example 84, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-dimethyl-4,1- phenylene))bis(3-(3,3-dimethyl-6-(2,4,5-trifluorobenzyl)-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). HCl HN N F Boc F F F F O HCl O F N F N F 10.2 B H Boc OH N F F ynoxy-phenyl)methyl]-2-[3,3-dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2- b]pyridin-1-yl]-2-oxo-ethyl]carbamate. To a solution of 3,3-dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-1,2-dihydropyrrolo[3,2-b] pyridine 10 (500 mg, 1.52 mmol, 1 eq, HCl), (2S)-2-(tert-butoxycarbonylamino)-3- (2,6-dimethyl- 4-prop-2- ynoxy-phenyl)propanoic acid (634 mg, 1.83 mmol, 1.2 eq), and DIEA (590 mg, 4.56 mmol, 795 uL, 3 eq) in DCM (10 mL) was added HATU (867 mg, 2.28 mmol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (20 mL) was added to the mixture 15 which was then extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (20 mL) dried over Na2SO4 and filtered The filtrate was concentrated under reduced m (m, Hz, (s, 70226WO01 Step 2 of 5: Synthesis of Intermediate 123.2, (2S)-2-amino-3-(2,6-dimethyl-4-prop-2- ynoxy- phenyl)-1-[3,3-dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1- yl]propan-1-one. To a solution of tert-butyl N-[(1S)-1-[(2,6-dimethyl-4-prop-2-ynoxy-phenyl)methyl] -2-[3,3- 5 dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamate (670 mg, 1.08 mmol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete conversion to a product of target mass. The mixture was concentrated under reduced pressure to give the title compound (560 mg, 1.00 mmol, 93.12% yield, HCl) as a yellow solid. 10 LCMS (ES, m/z): 522.3 [M+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.79 (d, J = 1.1 Hz, 1H), 8.33 (d, J = 1.4 Hz, 1H), 7.38 (ddd, J = 7.1, 8.7, 10.7 Hz, 1H), 7.24 (dt, J = 6.7, 10.0 Hz, 1H), 6.65 (s, 2H), 4.64 (d, J = 2.4 Hz, 2H), 4.49 - 4.35 (m, 1H), 4.18 (s, 2H), 3.98 (d, J = 10.1 Hz, 1H), 3.29 - 3.20 (m, 1H), 2.91 (t, J = 2.4 Hz, 1H), 2.47 (d, J = 10.0 Hz, 1H), 2.36 - 2.17 (m, 6H), 2.02 (d, J = 3.5 Hz, 1H), 1.43 - 1.36 15 (m, 3H), 1.07 - 0.92 (m, 3H) Step 3 of 5: Synthesis of Intermediate 123.3, tert-butyl N-[(1S)-1-[[(1S)-1-[(2,6-dimethyl-4- prop-2-ynoxy-phenyl)methyl]-2-[3,3-dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2H- pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate. 20 To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (252 mg, 1.16 mmol, 1.2 eq), (2S)-2-amino-3-(2,6-dimethyl-4-prop-2-ynoxy-phenyl)-1-[3,3-dimethyl-6-[(2,4,5- trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1-yl]propan-1-one (540 mg, 967 umol, 1 eq, HCl), and DIEA (375 mg, 2.90 mmol, 505 uL, 3 eq) in DCM (8 mL) was added HATU (552 mg, 1.45 mmol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete 25 consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl (10 mL) was added to the mixture which was then extracted with DCM (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (520 mg, 721.40 30 umol, 74.55% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.30 LCMS (ES, m/z): 721.7 [M+H]+ Step 4 of 5: Synthesis of Intermediate 123.4, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S) -2-35 [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]a [(2,4,5- 349 70226WO01 trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5-dimethyl- phenoxy]hexa-2,4-diynoxy]-2,6-dimethyl-phenyl]methyl]-2-[3,3-dimethyl-6-[(2,4,5- trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N- methyl-carbamate. 5 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[(2,6-dimethyl-4-prop-2-ynoxy-phenyl)methyl]- 2- [3,3-dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo- ethyl]carbamoyl] propyl]-N-methyl-carbamate (100 mg, 138 umol, 1 eq) in CH3CN (3 mL) was added pyridine (65.8 mg, 832 umol, 67.2 uL, 6 eq) and Cu(OAc)2 (30.2 mg, 166 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete 10 consumption of starting material with formation of a single peak of target mass. The reaction mixture was filtered and the mixture was added into saturated NH3.H2O aq. (10 mL), then extracted with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (95 mg, 65.99 umol, 95.13% yield) as a yellow oil. LCMS (ES, m/z): 1440.0 [M+H]+ 15 Step 5 of 5: Synthesis of Example 84, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(2,6-dimethyl-4,1-phenylene))bis(3-(3,3-dimethyl-6-(2,4,5-trifluorobenzyl)-2,3- dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). 20 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert-butoxycarbonyl (methyl)amino]butanoyl]amino]-3-[3,3-dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2- b]pyridin-1-yl]-3-oxo-propyl]-3,5-dimethyl-phenoxy]hexa-2,4-diynoxy]-2,6-dimethyl- phenyl]methyl]-2-[3,3-dimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1-yl]- 2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (90 mg, 62.52 umol, 1 eq) in EtOAc (1 mL) 25 was added HCl/dioxane (4 M, 2 mL). The mixture was stirred at 20°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)- CH3CN], B%: 35%-75%, 8 min) to give the title compound (31.9 mg, 21.74 umol, 34.77% yield, 30 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z) 620.5 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.33 (d, J = 1.0 Hz, 2H), 8.07 (d, J = 1.3 Hz, 2H), 7.27 - 7.11 (m, 4H), 6.58 (s, 4H), 4.81 (br dd, J = 4.3, 11.5 Hz, 4H), 4.72 (s, 4H), 3.98 (s, 4H), 3.89 (d, J = 9.9 Hz, 2H), 3.82 (dd, J = 5.3, 6.8 Hz, 2H), 3.08 (br dd, J = 4.1, 13.8 Hz, 2H), 2.73 (d, J = 9.9 Hz, 350 70226WO01 2H), 2.65 (s, 6H), 2.28 (s, 12H), 1.91 (br d, J = 7.3 Hz, 4H), 1.26 (s, 6H), 0.99 (t, J = 7.6 Hz, 6H), 0.89 (s, 6H) Example 85, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-dimethyl-4,1- 5 phenylene))bis(3-oxo-3-(3,3,4-trimethyl-5-oxo-6-(2,4,5-trifluorobenzyl)-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)propane-1,2-diyl))bis(2-(methylamino)butanamide). HN N HCl Boc F O (S) N (S) O O N O O Cu(OAc) , Pyr. ACN O NH O (S) N O NH O (S) N 2 , 85°C F HCl/dioxane, EtOAc F F F F F Step 1 of 5: Synthesis of Intermediate 124.1, tert-butyl N-[(1S)-1-[(2,6-dimethyl-4-prop-2-10 ynoxy-phenyl)methyl]-2-oxo-2-[3,3,4-trimethyl-5-oxo-6-[(2,4,5-trifluorophenyl)methyl]-2H- pyrrolo[3,2-b]pyridin-1-yl]ethyl]carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(2,6-dimethyl-4-prop-2-ynoxy-phenyl) propanoic acid (348 mg, 1.00 mm in DCM (4 mL) was added DIEA (432 mg, 3.34 mmol, 582 uL, 4 eq), 3,3,4-trimethyl-6-[(2,4,5-trifluorophenyl)methyl]- 1,2-dihydropyrrolo [3,2- 15 b]pyridin-5-one (300 mg, 836 umol, 1 eq, HCl) and T3P (798 mg, 1.25 mmol, 746 uL, 50% purity, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (10 mL) and extracted with DCM (8 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. 20 The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 1:3) to give the title compound (430 mg, 659.80 umol, 78.91% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.40. LCMS (ES, m/z): 652.5 [M+H]+ 25 Step 2 of 5: Synthesis of Intermediate 124.2, 1-[(2S)-2-amino-3-(2,6-dimethyl-4-prop-2 - ynoxy-phenyl)propanoyl]-3,3,4-trimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2H rrolo[3,2- 70226WO01 To a solution of tert-butyl N-[(1S)-1-[(2,6-dimethyl-4-prop-2-ynoxy-phenyl)methyl]-2-oxo-2 - [3,3,4-trimethyl-5-oxo-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1- yl]ethyl]carbamate (430 mg, 660 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 5 mL). The mixture was stirred at 20°C for 1 h. LC-MS indicated complete conversion to a product of 5 target mass. The reaction mixture was concentrated under reduced pressure to give the title compound (330 mg, 561.17 umol, 85.05% yield, HCl) as a yellow oil. LCMS (ES, m/z): 522.2 [M+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.35 (s, 1H), 7.30 - 7.10 (m, 2H), 6.66 (s, 2H), 4.67 - 4.64 (m, 2H), 4.28 (dd, J = 3.8, 11.9 Hz, 1H), 3.81 (s, 2H), 3.54 (s, 3H), 3.37 - 3.33 (m, 3H), 2.89 10 (t, J = 2.4 Hz, 1H), 2.34 - 2.24 (m, 6H), 1.99 (s, 1H), 1.34 (s, 3H), 0.98 (s, 3H) Step 3 of 5: Synthesis of Intermediate 124.3, tert-butyl N-[(1S)-1-[[(1S)-1-[(2,6-dimethyl-4- prop-2-ynoxy-phenyl)methyl]-2-oxo-2-[3,3,4-trimethyl-5-oxo-6-[(2,4,5- trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1- pyl]-N-methyl- 15 carbamate. To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (52.3 mg, 2 l, 1 eq) in DCM (4 mL) was added DIEA (124 mg, 963 umol, 167 uL, 4 eq) and T3P (230 mg, 361 umol, 215 uL, 50% purity, 1.5 eq), and 1-[(2S)-2-amino-3-(2,6-dimethyl- 4-prop-2-ynoxy- phenyl)propanoyl]-3,3,4-trimethyl-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-5- 20 one (170 mg, 289 umol, 1.2 eq, HCl) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into saturated NH4Cl aq. (10 mL) and extracted with DCM (8 mL * 3). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc/Methanol = 25 10:1) to give the title compound (90 mg, 119 umol, 49.76% yield) as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.63 LCMS (ES, m/z): 751.5 [M+H]+ Step 4 of 5: Synthesis of Intermediate 124.4, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4- [(2S) -2-30 [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-oxo-3-[3,3,4-trimethyl-5-oxo- 6 ,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1-yl]propyl]-3,5-dimethyl- phenoxy]hexa-2,4-diynoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-2-[3,3, -oxo-6- [(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1-yl]ethyl]ca rbamoyl]propyl]-N- methyl-carbamate. 352 70226WO01 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[(2,6-dimethyl-4-prop-2-ynoxy-phenyl)methyl] -2- oxo-2-[3,3,4-trimethyl-5-oxo-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2-b]pyridin-1- yl]ethyl]carbamoyl]propyl]-N-methyl-carbamate (90 mg, 120 umol, 1 eq) in CH3CN (4 mL) was added Cu(OAc)2 (26.1 mg, 144 umol, 1.2 eq) and pyridine (56.9 mg, 719 umol, 58.0 uL, 6 eq). 5 The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into saturated NH3 aq. (12 mL), then extracted with EtOAc (20 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, 10 EtOAc/Methanol = 10:1) to give the title compound (80 mg, 53.34 umol, 89.01% yield) as a yellow oil. TLC (EtOAc/Methanol = 10:1) Rf = 0.63 LCMS (ES, m/z): 1500.0 [M+H]+ 15 Step 5 of 5: Synthesis o f Example 85, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(2,6-dimethyl-4,1-phenylene))bis(3-oxo-3-(3,3,4-trimethyl-5-oxo-6-(2,4,5- trifluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)propane-1,2-diyl))bis(2- (methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2- [tert-butoxycarbonyl20 (methyl)amino]butanoyl]amino]-3-oxo-3-[3,3,4-trimethyl-5-oxo-6-[(2,4,5-trifluorophenyl)methyl]- 2H-pyrrolo[3,2-b]pyridin-1-yl]propyl]-3,5-dimethyl-phenoxy]hexa-2,4-diynoxy]-2,6-dimethyl- phenyl]methyl]-2-oxo-2-[3,3,4-trimethyl-5-oxo-6-[(2,4,5-trifluorophenyl)methyl]-2H-pyrrolo[3,2- b]pyridin-1-yl]ethyl]carbamoyl]propyl]-N-methyl-carbamate (80 mg, 53.3 umol, 1 eq) in EtOAc (1 mL) was added HCl/dioxane (4 M, 2 mL). The mixture was stirred at 25°C for 0.5 h. LC-MS 25 indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 25%-65%, 8 min) to give the title compound (35.2 mg, 23.04 umol, 43.20% yield, 100% purity, 2 TFA) as a yellow solid. 30 LCMS (ES, m/z):650.4 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.30 (s, 2H), 7.28 - 7.08 (m, 4H), 6.62 (s, 4H), 4.77 - 4.70 (m, 6H), 3.85 - 3.75 (m, 8H), 3.53 (s, 6H), 3.26 (br s, 2H), 3.03 (br dd, J = 4.1, 13.8 Hz, 2H), 2.66 (s, 6H), 2.61 (br d, J = 9.9 Hz, 2H), 2.31 (s, 12H), 2.01 - 1.87 (m, 4H), 1.36 (s, 6H), 1.04 - 0.95 (m, 12H) 35 353 70226WO01 Example 86, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(2,4-dichlorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridi l)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). HCl HN N Cl Cl HCl O O Boc Cl H H N N B H B O Cl Cl trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn-1- yloxy)phenyl)propan-2-yl)carbamate. To a solution of 6-[(2,4-dichlorophenyl)methyl]-3,3,4-trimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-10 5-one (300 mg, 803 umol, 1 eq, HCl), (2S)-2-(tert-butoxycarbonylamino)-3-(4-prop-2- ynoxyphenyl)propanoic acid (308 mg, 963 umol, 1.2 eq), and DIEA (311.26 mg, 2.41 mmol, 419.49 uL, 3 eq) in DCM (6 mL) was added HATU (458 mg, 1.20 mmol, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 3 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the 15 mixture, and the mixture was extracted with DCM (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 1:1) to give the title compound (460 mg, 720 umol, 89.7% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.40 20 LCMS (ES, m/z): 638.4 [M+H]+ Step 2 of 5: Synthesis of Intermediate 125.2, (S)-1-(2-amino-3-(4-(prop-2-yn-1- yloxy)phenyl)propanoyl)-6-(2,4-dichlorobenzyl)-3,3,4-trimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-5(4H)-one. 25 T tert-butyl N-[(1S)-2-[6-[(2,4-dichlorophenyl)methyl]-3,3,4-trimethyl-5-oxo-2H- p yrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamate (460 mg, 720 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 20°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with 354 70226WO01 formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give the title compound (400 mg, 696 umol, 96.6% yield, HCl) as a yellow solid. LCMS (ES, m/z): 538.2 [M+H]+ 5 Step 3 of 5: Synthesis of Intermediate 125.3, tert-butyl ((S)-1-(((S)-1-(6-(2,4-dichlorobenzyl)- 3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2- yn-1-yloxy)phenyl)propan-2-yl)amino)-1-oxobutan-2-yl)(methyl)carbamate. To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (68.0 mg, 313 umol, 1.2 eq), 1-[(2S)-2-amino-3-(4-prop-2-ynoxyphenyl)propanoyl]-6-[(2,4-dichlorophenyl)methyl]-3,3,4- 10 trimethyl-2H-pyrrolo[3,2-b]pyridin-5-one (150 mg, 261 umol, 1 eq, HCl), and DIEA (101.16 mg, 783 umol, 136 uL, 3 eq) in DCM (3 mL) was added HATU (149 mg, 391 umol, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase 15 was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (150 mg, 203 umol, 77.9% yield) as a yellow solid. TLC (EtOAc) Rf = 0.57 LCMS (ES, m/z): 737.4 [M+H]+ 20 Step 4 of 5: Synthesis of Intermediate 125.4, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(2,4-dichlorobenzyl)-3,3,4-trimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate). 25 To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[6-[(2,4-dichlorophenyl)methyl]-3,3,4-trimethyl-5- oxo-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2- ynoxyphenyl)methyl]ethyl]carbamoyl]propyl]-N-methyl-carbamate (100 mg, 136 umol, 1 eq) in CH3CN (3 mL) was added pyridine (64.3 mg, 813 umol, 65.7 uL, 6 eq) and Cu(OAc)2 (29.6 mg, 163 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS 30 indicated complete conversion to a product of target mass. The reaction mixture was filtered and the mixture was added into NH3.H2O (10 mL), then extracted with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (90 mg, 61.1 umol, 90.1% yield) as a yellow solid. LCMS (ES, m/z): 1473.2 [M+H]+ 35 355 70226WO01 Step 5 of 5: Synthesis of Example 86, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(2,4-dichlorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). 5 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-[(2,4-dichlorophenyl)methyl]-3,3,4-trimethyl- 5-oxo-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2- [6-[(2,4-dichlorophenyl)methyl]-3,3,4-trimethyl-5-oxo-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo- ethyl]carbamoyl]propyl]-N-methyl-carbamate (90 mg, 61.1 umol, 1 eq) in EtOAc (2 mL) was 10 added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 25°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)- CH3CN], B%: 30%-70%, 8 min) to give the title compound (28.3 mg, 18.9 umol, 30.9% yield, 15 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 636.4 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.12 (s, 2H), 7.46 (d, J = 1.9 Hz, 2H), 7.33 - 7.26 (m, 4H), 7.19 (d, J = 8.5 Hz, 4H), 6.86 (d, J = 8.5 Hz, 4H), 4.80 - 4.73 (m, 6H), 3.97 (d, J = 10.3 Hz, 2H), 3.90 (s, 4H), 3.73 (dd, J = 5.3, 6.9 Hz, 2H), 3.56 (s, 6H), 3.14 (d, J = 10.3 Hz, 2H), 3.01 (br d, 20 J = 8.0 Hz, 4H), 2.58 (s, 6H), 1.96 - 1.80 (m, 4H), 1.39 (s, 6H), 1.09 (s, 6H), 0.93 (t, J = 7.5 Hz, 6H) Example 87, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(4-chloro-2-cyanobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H- 25 pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). HCl HN N Cl Cl O O HCl Cl Boc N N Cl 2 NH O NH2 O Boc OH Boc O CN Cl 70226WO01 Step 1 of 5: Synthesis of Intermediate 126.1, (S)-tert-butyl (1-(6-(4-chloro-2-cyanobenzyl)- 3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2- yn-1-yloxy)phenyl)propan-2-yl)carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(4-prop-2-ynoxyphenyl)propanoic acid (212 5 mg, 663 umol, 1 eq) and 5-chloro-2-[(3,3,4-trimethyl-5-oxo-1,2-dihydropyrrolo[3,2-b]pyridin-6- yl)methyl]benzonitrile (290 mg, 796.12 umol, 1.2 eq, HCl) in DCM (6 mL) was added DIEA (429 mg, 3.32 mmol, 578 uL, 5 eq) and T3P (317 mg, 995 umol, 296 uL, 1.5 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, 10 and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (390 mg, 619.89 umol, 93.44% yield) as a yellow oil. TLC (EtOAc) Rf = 0.57 15 LCMS (ES, m/z): 629.2 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 8.46 (s, 1H), 7.61 (s, 1H), 7.49 - 7.44 (m, 2H), 7.16 (br d, J=8.5 Hz, 2H), 6.87 (d, J=8.5 Hz, 2H), 5.35 (br d, J=8.9 Hz, 1H), 4.64 (d, J=2.3 Hz, 2H), 4.56 (q, J=8.0 Hz, 1H), 4.10 - 3.98 (m, 2H), 3.81 (br d, J=10.0 Hz, 1H), 3.52 (s, 3H), 3.01 - 2.93 (m, 3H), 1.43 (s, 9H), 1.36 (s, 3H), 1.08 (s, 3H) 20 Step 2 of 5: Synthesis of Intermediate 126.2, (S)-2-((1-(2-amino-3-(4-(prop-2-yn-1- yloxy)phenyl)propanoyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin- 6-yl)methyl)-5-chlorobenzonitrile hydrochloride. To a solution of tert-butyl N-[(1S)-2-[6-[(4-chloro-2-cyano-phenyl)methyl]-3,3,4-trimethyl-5-oxo- 25 2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamate (380 mg, 604. umol, 1 eq) in EtOAc (3 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 25°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give the title compound (360 mg, quantitative yield, HCl) as a yellow oil. 30 LCMS (ES, m/z): 529.1 [M+H]+ Step 3 of 5: Synthesis of Intermediate 126.3, tert-butyl ((S)-1-(((S)-1-(6-(4-chloro-2- cyanobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo- 3-(4-(prop-2-yn-1-yloxy)phenyl)propan-2-yl)amino)-1-oxobutan-2-yl)(methyl)carbamate. 357 70226WO01 To a solution of 2-[[1-[(2S)-2-amino-3-(4-prop-2-ynoxyphenyl)propanoyl]-3,3,4-trimethyl-5-oxo- 2H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-5-chloro-benzonitrile (160 mg, 283 umol, 1.1 eq, HCl) and (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (55.9 mg, 257 umol, 1 eq) in DCM (3 mL) was added DIEA (166 mg, 1.29 mmol, 224 uL, 5 eq) and T3P (196 mg, 309 umol, 184 uL, 5 50% purity, 1.2 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated complete conversion to a product of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, EtOAc) to give the title compound (85 mg, 117 10 umol, 45.4% yield) as a yellow oil. TLC (EtOAc) Rf = 0.53 LCMS (ES, m/z): 728.4 [M+H]+ Step 4 of 5: Synthesis of Intermediate 126.4, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4-15 diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4-chloro-2-cyanobenzyl)-3,3,4-trimethyl-5- oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2- diyl))bis(azanediyl))bis(1-oxobutane-2,1-diyl))bis(methylcarbamate) To on of tert-butyl N-[(1S)-1-[[(1S)-2-[6-[(4-chloro-2-cyano-phenyl)methyl]-3,3,4- trimethyl-5-oxo-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2- 20 ynoxyphenyl)methyl]ethyl]carbamoyl] propyl]-N-methyl-carbamate (85 mg, 117 umol, 1 eq) in CH3CN (4 mL) was added pyridine (55.4 mg, 700 umol, 56.5 uL, 6 eq) and Cu(OAc)2 (25.4 mg, 140 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was added into NH3.H2O (10 mL), then extracted with EtOAc (8 mL * 3), dried over 25 Na2SO4, filtered and concentrated under reduced pressure to give the title compound (85 mg, quantitative yield) as a yellow oil. LCMS (ES, m/z): 1453.4 [M+H]+ Step 5 of 5: Synthesis of Example 87, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-30 diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-chloro-2-cyanobenzyl)-3,3,4-trimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-[(4-chloro-2-cyano-phenyl)methyl]-3,3,4-35 trimethyl-5-oxo-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4- 358 70226WO01 diynoxy]phenyl]methyl]-2-[6-[(4-chloro-2-cyano-phenyl)methyl]-3,3,4-trimethyl-5-oxo-2H- pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (85 mg, 58.4 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 25°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with 5 formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*40mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 15%-60%, 8 min) to give the title compound (46 mg, 30.8 umol, 52.7% yield, 99.3% purity, 2 TFA) as a yellow solid. LCMS (ES, m/z): 627.3 [M/2+H]+ 10 1H NMR (400MHz, METHANOL-d4) δ = 8.31 (s, 2H), 7.76 (d, J=2.1 Hz, 2H), 7.59 (dd, J=2.1, 8.4 Hz, 2H), 7.45 (d, J=8.5 Hz, 2H), 7.22 (br d, J=8.5 Hz, 4H), 6.88 (d, J=8.6 Hz, 4H), 4.82 - 4.71 (m, 8H), 4.03 - 3.96 (m, 6H), 3.74 (br t, J=6.1 Hz, 2H), 3.54 (s, 6H), 3.11 (br d, J=10.3 Hz, 2H), 3.03 (br d, J=7.9 Hz, 4H), 2.59 (s, 6H), 1.97 - 1.84 (m, 4H), 1.39 (s, 6H), 1.10 (s, 6H), 0.96 (t, J=7.5 Hz, 6H) 15 Example 88, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(2,4-dichlorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin- 1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). O HCl Cl Cl O Cl Bo HCl N HN c N Boc O H HN O NH2 N O Boc OH Boc Cl 20 Step 1 of 5: Synthesis of Intermediate 127.1, (S)-tert-butyl (1-(6-(2,4-dichlorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn-1- yloxy)phenyl)propan-2-yl)carbamate. To a solution of 6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridine 25 (300 mg, 873 umol, 1 eq, HCl) in DCM (6 mL) was added DIEA (338.45 mg, 2.62 mmol, 456.14 uL, 3 eq), (2S)-2-(tert-butoxycarbonylamino)-3-(4-prop-2-ynoxyphenyl)propanoic acid (335 mg, 1.05 mmol, 1.2 eq) and HATU (497.86 mg, 1.31 mmol, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated complete conversion to a product of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 359 70226WO01 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title compound (420 mg, 690 umol, 79.1% yield) as a yellow oil. 5 TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.46 LCMS (ES, m/z): 608.3 [M+H]+ Step 2 of 5: Synthesis of Intermediate 127.2, (S)-2-amino-1-(6-(2,4-dichlorobenzyl)-3,3- dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(4-(prop-2-yn-1-yloxy)phenyl)propan- 10 1-one hydrochloride. tion of tert-butyl N-[(1S)-2-[6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2- b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamate (420 mg, 690 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 25°C for 0.5 h after which time LC-MS indicated complete consumption of starting material with formation of a 15 single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (300 mg, 551 umol, 79.8% yield, HCl) as a yellow solid. LCMS (ES, m/z): 508.1 [M+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.86 (s, 1H), 8.35 (s, 1H), 7.57 - 7.37 (m, 3H), 7.24 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 2H), 4.69 (d, J = 2.4 Hz, 2H), 4.53 (br dd, J = 6.2, 9.2 Hz, 1H), 20 4.34 (s, 2H), 4.15 (d, J = 10.3 Hz, 1H), 3.26 - 3.10 (m, 3H), 2.93 (t, J = 2.3 Hz, 1H), 1.50 (s, 3H), 1.20 (s, 3H) Step 3 of 5: Synthesis of Intermediate 127.3, tert-butyl ((S)-1-(((S)-1-(6-(2,4-dichlorobenzyl)- 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn-1- 25 yloxy)phenyl)propan-2-yl)amino)-1-oxobutan-2-yl)(methyl)carbamate. To a solution of (2S)-2-amino-1-[6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2- b]pyridin-1-yl]-3-(4-prop-2-ynoxyphenyl)propan-1-one (200 mg, 367 umol, 1 eq, HCl), (2S)-2- [tert-butoxycarbonyl(methyl)amino]butanoic acid (95.69 mg, 440.45 umol, 1.2 eq), and DIEA (142 mg, 1.10 mmol, 192 uL, 3 eq) in DCM (3 mL) was added HATU (209 mg, 551 umol, 1.5 eq) at 30 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, 360 70226WO01 Petroleum ether/EtOAc = 1:1) to give the title compound (200 mg, 283 umol, 77.0% yield) as a yellow solid. TLC (Petroleum ether/EtOAc =1:1) Rf = 0.54 LCMS (ES, m/z): 707.3 [M+H]+ 5 Step 4 of 5: Synthesis of Intermediate 127.4, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(2,4-dichlorobenzyl)-3,3-dimethyl-2,3- dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2-diyl))bis(azaned (1- oxobutane-2,1-diyl))bis(methylcarbamate). 10 To a solution of tert- l N-[(1S)-1-[[(1S)-2-[6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl-2H- pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamoyl]propyl]-N- methyl-carbamate (100 mg, 141 umol, 9.58e-1 eq) in CH3CN (3 mL) was added pyridine (70.0 mg, 885 umol, 71.5 uL, 6 eq) and Cu(OAc)2 (32.2 mg, 177 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material 15 with formation of a single peak of target mass and the mixture was added into saturated NH3.H2O aq. (10 mL), then extracted with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (100 mg, 70.8 umol, 95.9% yield) as a yellow solid LCMS (ES, m/z): 707.5 [M/2+H]+ 20 Step 5 of 5: Synthesis of Example 88, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(2,4-dichlorobenzyl)-3,3-dimethyl-2,3-dihydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide) To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- 25 butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-[(2,4-dichlorophenyl)methyl]-3,3-dimethyl- 2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[6- [(2,4-dichlorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo- ethyl]carbamoyl]propyl]-N-methyl-carbamate (100 mg, 70.75 umol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 2 mL). The mixture was stirred at 25°C for 0.5 h. LC-MS indicated 30 complete conversion to a product of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 40%-75%, 8 min) to give the title compound (55.2 mg, 38.30 umol, 54.1% yield, 100% purity, 2 TFA) as a white solid. LCMS (ES, m/z): 607.3 [M/2+H]+ 361 70226WO01 1H NMR (400 MHz, METHANOL-d4) δ = 8.26 (d, J = 1.5 Hz, 2H), 8.03 (d, J = 1.4 Hz, 2H), 7.46 (s, 2H), 7.30 (s, 4H), 7.20 (d, J = 8.5 Hz, 4H), 6.83 (d, J = 8.5 Hz, 4H), 4.73 (s, 6H), 4.12 - 4.02 (m, 6H), 3.73 (dd, J = 5.3, 6.9 Hz, 2H), 3.23 (d, J = 10.0 Hz, 2H), 3.11 - 3.02 (m, 4H), 2.56 (s, 6H), 1.98 - 1.80 (m, 4H), 1.28 (s, 6H), 1.01 (s, 6H), 0.95 (t, J = 7.6 Hz, 6H) 5 Example 89, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(4-chloro-2-cyanobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). O Cl 10 Step 1 of 5: Synthesis of Intermediate 128.1, (S)-tert-butyl (1-(6-(4-chloro-2-cyanobenzyl)- 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn-1- yloxy)phenyl)propan-2-yl)carbamate. To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-(4-prop-2-ynoxyphenyl)propanoic acid (43015 mg, 1.35 mmol, 1.5 eq), 5-chloro-2-[(3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-6- yl)methyl]benzonitrile (300 mg, 898 umol, 1 eq, HCl) and DIEA (348 mg, 2.69 mmol, 469 uL, 3 eq) in DCM (6 mL) was added T3P (685 mg, 1.08 mmol, 640 uL, 50% purity, 1.2 eq) at 0°C. The mixture was stirred at 50°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the 20 mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 1:1) to give the title compound (150 mg, 250 umol, 27.9% yield) as a yellow solid. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.43 25 LCMS (ES, m/z): 599.3 [M+H]+ Step 2 of 5: Synthesis of Intermediate 128.2, (S)-2-((1-(2-amino-3-(4-(prop-2-yn-1- yloxy)phenyl)propanoyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl)-5- nitrile hydrochloride. 362 70226WO01 To a solution of tert-butyl N-[(1S)-2-[6-[(4-chloro-2-cyano-phenyl)methyl]-3,3-dimethyl-2H- pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamate (150 mg, 250.37 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 25°C for 0.5 h. The mixture was stirred at 15°C for 1 h after which time LC-MS indicated 5 complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give the title compound (100 mg, 187 umol, 74.6% yield, HCl) as a yellow solid. LCMS (ES, m/z): 499.3 [M+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.77 (s, 1H), 8.33 (s, 1H), 7.89 - 7.83 (m, 1H), 7.72 (dd, 10 J = 2.3, 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.23 (br d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 4.68 (d, J = 2.4 Hz, 2H), 4.52 (br dd, J = 6.0, 9.1 Hz, 1H), 4.40 (s, 2H), 4.08 (br d, J = 10.4 Hz, 1H), 3.24 - 3.10 (m, 3H), 2.95 - 2.87 (m, 1H), 1.44 (s, 3H), 1.15 (s, 3H) Step 3 of 5: Synthesis of Intermediate 128.3, tert-butyl ((S)-1-(((S)-1-(6-(4-chloro-2-15 cyanobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn- 1-yloxy)phenyl)propan-2-yl)amino)-1-oxobutan-2-yl)( rbamate. To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (48.7 mg, 224 umol, 1.2 eq), 2-[[1-[(2S)-2-amino-3-(4-prop-2-ynoxyphenyl)propanoyl]-3,3-dimethyl-2H-pyrrolo[3,2- b]pyridin-6-yl]methyl]-5-chloro-benzonitrile (100 mg, 186.75 umol, 1 eq, HCl) and DIEA (72.4 20 mg, 560 umol, 97.6 uL, 3 eq) in DCM (3 mL) was added HATU (92.3 mg, 243 umol, 1.3 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated 25 under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (100 mg, 143 umol, 76.7% yield) as a yellow solid. TLC (Petroleum ether/EtOAc =2:1) Rf = 0.47 LCMS (ES, m/z): 698.3 [M+H]+ 30 Step 4 of 5: Synthesis of Intermediate 128.4, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4-chlor b ) 3,3 d thyl-2,3- dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2-diyl))bis(azanediyl))bis(1- oxobutane-2,1-diyl))bis(methylcarbamate) 363 70226WO01 To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[6-[(4-chloro-2-cyano-phenyl)methyl]-3,3-dimethyl- 2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamoyl]propyl]- N-methyl-carbamate (100 mg, 143 umol, 1 eq) in CH3CN (3 mL) was added pyridine (68.0 mg, 859 umol, 69.4 uL, 6 eq) and Cu(OAc)2 (31.2 mg, 172 umol, 1.2 eq). The mixture was stirred at 5 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was added into NH3.H2O (10 mL), then extracted with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (70 mg, 50.2 umol, 70.1% yield) as a yellow solid. LCMS (ES, m/z): 1395.2 [M+H]+ 10 Step 5 of 5: Synthesis of Example 89, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-chloro-2-cyanobenzyl)-3,3-dimethyl-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert-15 butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-[(4-chloro-2-cyano-phenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]- 2-[6-[(4-chloro-2-cyano-phenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo- ethyl]carbamoyl]propyl]-N-methyl-carbamate (70 mg, 50.2 umol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 2 mL). The mixture was stirred at 25°C for 0.5 h after which time LC-MS 20 indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 30%-70%, 8 min) to give the title compound (43.4 mg, 29.8 umol, 59.4% yield, 97.677% purity, 2 TFA) as a white solid. 25 LCMS (ES, m/z): 597.4 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.28 (d, J = 1.8 Hz, 1H), 8.09 (d, J = 1.8 Hz, 2H), 7.79 (d, J = 2.1 Hz, 2H), 7.65 (dd, J = 2.3, 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.6 Hz, 4H), 6.84 (d, J = 8.6 Hz, 4H), 4.81 - 4.66 (m, 6H), 4.20 (s, 4H), 4.05 (d, J = 10.1 Hz, 2H), 3.74 (dd, J = 5.3, 7.0 Hz, 2H), 3.23 (d, J = 10.1 Hz, 2H), 3.11 - 3.04 (m, 4H), 2.57 (s, 6H), 1.98 - 1.82 (m, 30 4H), 1.29 (s, 6H), 1.01 (s, 6H), 0.96 (t, J = 7.5 Hz, 6H) Example 90, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(2,4-dichlorophenoxy)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). 364 70226WO01 O Cl Cl HCl O Cl l HN Boc OH HN Bo N HC c N O NH2 O Boc OH Boc N N H O 19.2 O O HCl/EtOAc O O NH l l Cl O Cl tep o 5: ynt ess o nterme ate . , ( )-tert- uty ( -( -( , - c orop enoxy)- , - dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn-1- 5 yloxy)phenyl)propan-2-yl)carbamate. To a solution of 6-(2,4-dic lorophenoxy)-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridine (300 mg, 868 umol, 1 eq, HCl) and (2S)-2-(tert-butoxycarbonylamino)-3-(4-prop-2-ynoxyphenyl)propanoic acid (416 mg, 1.30 mmol, 1.5 eq) in DCM (6 mL) was added DIEA (561 mg, 4.34 mmol, 756 uL, 5 eq) and T3P (718 mg, 1.13 mmol, 671 uL, 50% purity, 1.3 eq) at 0°C. The mixture was stirred at 10 25°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title 15 compound (160 mg, 262 umol, 30.2% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) Rf = 0.30 LCMS (ES, m/z): 610.1 [M+H]+ Step 2 of 5: Synthesis of Intermediate 129.2, (S)-2-amino-1-(6-(2,4-dichlorophenoxy)-3,3-20 dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine 1 l 3-(4-(prop-2-yn-1- yloxy)phenyl)propan-1-one hydrochloride. T solution of tert-butyl N-[(1S)-2-[6-(2,4-dichlorophenoxy)-3,3-dimethyl-2H-pyrrolo[3,2- b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamate (160 mg, 262.07 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 25°C for 1.5 25 h after which time LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give the title compound (130 mg, 238 umol, 90.7% yield, HCl) as a white solid. LCMS (ES, m/z): 510.2 [M+H]+ 365 70226WO01 Step 3 of 5: Synthesis of Intermediate 129.3, tert-butyl ((S)-1-(((S)-1-(6-(2,4- dichlorophenoxy)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop- 2-yn-1-yloxy)phenyl)propan-2-yl)amino)-1-oxobutan-2-yl)(methyl)carbamate. To a solution of (2S)-2-amino-1-[6-(2,4-dichlorophenoxy)-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 5 1-yl]-3-(4-prop-2-ynoxyphenyl)propan-1-one (105 mg, 192 umol, 1 eq, HCl), (2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoic acid (50.1 mg, 230 umol, 1.2 eq) in DCM (3 mL) was added DIEA (124 mg, 960 umol, 167 uL, 5 eq) and HATU (110 mg, 288 umol, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated complete conversion to a product of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with 10 DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 2:1) to give the title compound (130 mg, 183 umol, 95.4% yield) as a colorless oil. TLC (Petroleum ether/EtOAc = 2:1) 15 LCMS (ES, m/z): 709.2 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 8.04 (d, J=2.4 Hz, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.50 (d, J=2.5 Hz, 1H), 7.24 (dd, J=2.5, 8.8 Hz, 1H), 7.12 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.8 Hz, 1H), 6.86 (d, J=8.6 Hz, 2H), 5.31 (s, 1H), 4.97 - 4.89 (m, 1H), 4.63 (d, J=2.3 Hz, 2H), 3.95 (br d, J=9.9 Hz, 1H), 3.23 (d, J=10.0 Hz, 1H), 3.05 - 2.92 (m, 2H), 2.81 (s, 2H), 2.68 (s, 3H), 2.46 (t, J=2.3 Hz, 20 1H), 1.50 (s, 9H), 1.33 (s, 3H), 1.08 (s, 3H), 0.87 (t, J=7.4 Hz, 3H) Step 4 of 5: Synthesis of Intermediate 129.4, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(2,4-dichlorophenoxy)-3,3-dimethyl-2,3- dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2-diyl))bis(azanediyl))bis(1- 25 oxobutane-2,1-diyl))bis(methylcarbamate). To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[6-(2,4-dichlorophenoxy)-3,3-dimethyl-2H- pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamoyl]propyl]-N- methyl-carbamate (130 mg, 183 umol, 1 eq) in CH3CN (4 mL) was added pyridine (86.9 mg, 1.10 mmol, 88.7 uL, 6 eq) and Cu(OAc)2 (39.9 mg, 220 umol, 1.2 eq). The mixture was stirred at 85 °C 30 for 1 h under air environment. LC-MS indicated complete conversion to a product of target mass. The mixture was added into NH3.H2O (10 mL), extracted with EtOAc (8 mL * 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (130 mg, quantitative yield) as a yellow oil. LCMS (ES, m/z): 1415.5 [M+H]+ 35 366 70226WO01 Step 5 of 5: Synthesis of Example 90, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(2,4-dichlorophenoxy)-3,3-dimethyl-2,3-dihydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- 5 butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-(2,4-dichlorophenoxy)-3,3-dimethyl-2H- pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[6-(2,4- dichlorophenoxy)-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N- methyl-carbamate (130 mg, 91.7 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 4 mL). The mixture was stirred at 25 °C for 1 h. LC-MS indicated complete consumption of starting 10 material with formation of a single peak of target mass. The mixture was filtered and the filter cake was dried to give a crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm, 5um; mobile phase: [water(TFA)-CH3CN], B%: 30%-60%, 8 min) to give the title compound (96.1 mg, 66.50 umol, 72.50% yield, 100% purity, 2 TFA) as a white solid. 15 LCMS (ES, m/z): 609.1 [M/2+H]+ 1H NMR (400MHz, METHANOL-d4) δ = 7.95 (d, J=2.5 Hz, 2H), 7.85 (d, J=2.6 Hz, 2H), 7.61 (d, J=2.5 Hz, 2H), 7.37 (dd, J=2.5, 8.8 Hz, 2H), 7.21 (d, J=8.5 Hz, 4H), 7.12 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.5 Hz, 4H), 4.76 (s, 4H), 4.08 (d, J=10.1 Hz, 2H), 3.74 (t, J=6.1 Hz, 2H), 3.27 (d, J=10.1 Hz, 2H), 3.06 (br d, J=7.9 Hz, 4H), 2.58 (s, 6H), 2.04 (s, 2H), 1.95 - 1.85 (m, 4H), 1.29 (s, 6H), 20 1.01 (s, 6H), 0.96 (t, J=7.5 Hz, 6H) Example 91, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1- phenylene))bis(3-(6-(4-chloro-2-cyanophenoxy)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). O Cl Cl HCl O Cl B N H l H H oc H N B O Cl 25 Step 1 of 5: Synthesis of Intermediate 130.1, (S)-tert-butyl (1-(6-(4-chloro-2-cyanophenoxy)- 3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2-yn-1- yloxy)phenyl)propan-2-yl)carbamate. 367 70226WO01 To a solution of 5-chloro-2-[(3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-6-yl)oxy]benzonitrile (250 mg, 834 umol, 1 eq) and (2S)-2-(tert-butoxycarbonylamino)-3-(4-prop-2- ynoxyphenyl)propanoic acid (346.25 mg, 1.08 mmol, 1.3 eq) in DCM (8 mL) was added DIEA (323 mg, 2.50 mmol, 436 uL, 3 eq) and HATU (476 mg, 1.25 mmol, 1.5 eq) at 0°C. The mixture 5 was stirred at 50°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc = 3:1) to give the title 10 compound (490 mg, 815.18 umol, 97.74% yield) as a yellow oil. TLC (Petroleum ether/EtOAc = 3:1) LCMS (ES, m/z): 601.4 [M+H]+ 1H NMR (400MHz, CHLOROFORM-d) δ = 8.14 (d, J=2.2 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.49 - 7.46 (m, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.90 - 6.85 (m, 3H), 5.32 - 5.27 (m, 15 1H), 4.78 (br s, 1H), 4.72 - 4.66 (m, 1H), 4.63 (d, J=2.2 Hz, 2H), 3.97 (br d, J=9.9 Hz, 1H), 3.18 (d, J=9.9 Hz, 1H), 3.05 - 2.94 (m, 2H), 1.43 (s, 9H), 1.34 (s, 3H), 1.04 (s, 3H) Step 2 of 5: Synthesis of Intermediate 130.2, (S)-2-((1-(2-amino-3-(4-(prop-2-yn-1- yloxy)phenyl)propanoyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)oxy)-5- 20 chlorobenzonitrile. To a solution of tert-butyl N-[(1S)-2-[6-(4-chloro-2-cyano-phenoxy)-3,3-dimethy olo[3,2- b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamate (490 mg, 815 umol, 1 eq) in EtOAc (3 mL) was added HCl/EtOAc (4 M, 6 mL). The mixture was stirred at 25°C for 1 h after which time LC-MS indicated complete consumption of starting material with formation of a 25 single peak of target mass. The mixture was concentrated under reduced pressure to give the title compound (470 mg, quantitative yield, HCl) as a yellow oil. LCMS (ES, m/z): 501.3 [M+H]+ Step 3 of 5: Synthesis of Intermediate 130.3, tert-butyl ((S)-1-(((S)-1-(6-(4-chloro-2-30 cyanophenoxy)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxo-3-(4-(prop-2- To a solution of 2-[[1-[(2S)-2-amino-3-(4-prop-2-ynoxyphenyl)propanoyl]-3,3-dimethyl-2H- pyrrolo[3,2-b]pyridin-6-yl]oxy]-5-chloro-benzonitrile (100 mg, 186 umol, 1 eq, HCl) and (2S)-2- [tert-butoxycarbonyl(methyl)amino]butanoic acid (48.5 mg, 223 umol, 1.2 eq) in DCM (4 mL) was 35 added DIEA (120 mg, 930 umol, 162 uL, 5 eq) and HATU (70.8 mg, 186 umol, 1 eq) at 0°C. The 368 70226WO01 mixture was stirred at 0°C for 0.5 h and 2-[[1-[(2S)-2-amino-3-(4-prop-2-ynoxyphenyl)propanoyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-6-yl]oxy]-5-chloro-benzonitrile (100 mg, 186 umol, 1 eq, HCl) was added to the mixture at 0°C. The mixture was stirred at 25°C for 3 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. 5 Saturated NH4Cl aq. (10 mL) was added to the mixture, and the mixture was extracted with DCM (10 mL * 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, Petroleum ether/EtOAc =1:1) to give the title compound (80 mg, 114 umol, 61.4% yield) as an off-white oil. 10 TLC (Petroleum ether/EtOAc = 1:1) Rf = 0.51 LCMS (ES, m/z): 700.4 [M+H]+ Step 4 of 5: Synthesis of Intermediate 130.4, di-tert-butyl ((2S,2'S)-(((2S,2'S)-((hexa-2,4- diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4-chloro-2-cyanophenoxy)-3,3-dimethyl-15 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopropane-3,2-diyl))bis(azanediyl))bis(1- oxobutane-2,1-diyl))bis(methylcarbamate). To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[6-(4-chloro-2-cyano-phenoxy)-3,3-dimethyl-2H- pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-1-[(4-prop-2-ynoxyphenyl)methyl]ethyl]carbamoyl]propyl]-N- methyl-carbamate (75 mg, 107.11 umol, 1 eq) in CH3CN (3 mL) was added pyridine (50.8 mg, 643 20 umol, 51.9 uL, 6 eq) and Cu(OAc)2 (23.4 mg, 129 umol, 1.2 eq). The mixture was stirred at 85°C for 1 h under air environment. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The residue was added into NH3.H2O (10 mL), then extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (70 25 mg, 50.1 umol, 93.5% yield) as a yellow solid. LCMS (ES, m/z): 1399.4 [M+H]+ Step 5 of 5: Synthesis of Example 91, (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6- diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4-chloro-2-cyanophenoxy)-3,3-dimethyl-2,3-dihydro- 30 1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide). To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[6-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[6-(4-chloro-2-cyano-phenoxy)-3,3-dimethyl- 2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]phenoxy]hexa-2,4-diynoxy]phenyl]methyl]-2-[6-(4- chloro-2-cyano-phenoxy)-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo- 35 ethyl]carbamoyl]propyl]-N-methyl-carbamate (65 mg, 46.48 umol, 1 eq) in EtOAc (1 mL) was 369 70226WO01 added HCl/EtOAc (4 M, 2 mL). The mixture was stirred at 25°C for 0.5 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C1875*30mm, 3um; mobile phase: 5 [water(NH3H2O+NH4HCO3)-CH3CN], B%: 10%-90%, 8 min) to give the title compound (10.5 mg, 8.76 umol, 18.9% yield, 100% purity) as a white solid. LCMS (ES, m/z): 599.5 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.12 (d, J = 2.5 Hz, 2H), 8.03 - 7.99 (m, 2H), 7.85 (d, J = 2.5 Hz, 2H), 7.64 (dd, J = 2.6, 9.1 Hz, 2H), 7.22 (d, J = 8.5 Hz, 4H), 7.03 (d, J = 9.0 Hz, 2H), 10 6.86 (d, J = 8.5 Hz, 4H), 4.77 (s, 4H), 4.58 (br s, 2H), 4.20 - 4.12 (m, 2H), 3.42 - 3.34 (m, 2H), 3.08 - 2.93 (m, 6H), 2.28 - 2.19 (m, 6H), 1.58 (s, 4H), 1.33 (s, 6H), 1.09 - 1.03 (m, 6H), 0.91 - 0.83 (m, 6H) 1H NMR (400MHz, CHLOROFORM-d) δ = 8.04 (d, J=2.4 Hz, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.50 (d, J=2.5 Hz, 1H), 7.24 (dd, J=2.5, 8.8 Hz, 1H), 7.12 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.8 Hz, 1H), 15 6.86 (d, J=8.6 Hz, 2H), 5.31 (s, 1H), 4.97 - 4.89 (m, 1H), 4.63 (d, J=2.3 Hz, 2H), 3.95 (br d, J=9.9 Hz, 1H), 3.23 (d, J=10.0 Hz, 1H), 3.05 - 2.92 (m, 2H), 2.81 (s, 2H), 2.68 (s, 3H), 2.46 (t, J=2.3 Hz, 1H), 1.50 (s, 9H), 1.33 (s, 3H), 1.08 (s, 3H), 0.87 (t, J=7.4 Hz, 3H) Example 92, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-20 dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[2-[4-[2-[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- yl]ethoxy]phenoxy]ethyl]triazol-1-yl]propyl]-2-(methylamino)propanamide. 70226WO01 Step 1 of 2: Synthesis of Intermediate 131.6, tert-butyl N-[(1S)-2-[[(1S,2S)-2- [4-[2- [4-[2-[1- [(1S,2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-3-[5-[tert- butyl(diphenyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- ridin-1- 5 yl]-1-methyl-3-oxo-propyl]triazol-4-yl]ethoxy]phenoxy]ethyl]triazol-1-yl]-1-[5-[tert- butyl(diphenyl)silyl]oxy-6-[(4-fluoropheny l]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine- 1-carbonyl]propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate. To a solution of 1,4-bis(but-3-ynoxy)benzene (24.8 mg, 116 umol, 1 eq), tert-butyl N-[(1S)-2- [[(1S,2S)-2-azido-1-[5-[tert-butyl(diphenyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H- 10 pyrrolo[3,2-b]pyridine-1-carbonyl]propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (200 mg, 243 umol, 2.1 eq) in DMF (2 mL) was added CuSO4.5H2O (5.79 mg, 23.2 umol, 0.2 eq) and SODIUM ASCORBATE (18.4 mg, 92.7 umol, 0.8 eq) under N2. The mixture was stirred at 120°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (2 mL) was added to the mixture, the mixture was extracted with 15 EtOAc (2 mL x 2). The combined organic layers were washed with brine (2 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE: EA = 1:3) to give the title compound (130 mg, 69.95 umol, 60.38% yield) as a yellow solid. TLC (Petroleum ether/Ethyl acetate = 1:3) Rf = 0.50. 20 LCMS (ES, m/z): 1381.5 [M-2TBDPS+H]+. Step 2 of 2: Synthesis of Example 92, (2S)-N-[(1S,2S)-1-[6- [(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[2-[4-[2-[1-[(1S,2S)-3-[6- [(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-25 methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- yl]ethoxy]pheno y e y]triazol-1-yl]propyl]-2-(methylamin )propanamide. To a solution of tert-butyl N-[(1S)-2-[[(1S,2S)-2-[4-[2-[4-[2 -[ -[( S,2S)-2-[[(2S)- 2-[tert- butoxycarbonyl(methyl)amino]propanoyl]amino]-3-[5-[tert-butyl(diphenyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-methyl-3-oxo-propyl]triazol-30 4-yl]ethoxy]phenoxy]ethyl]triazol-1-yl]-1-[5-[tert-butyl(diphenyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridine-1-carbonyl]propyl]amino]-1- methyl-2-oxo-ethyl]-N-methyl-carbamate (130 mg, 670 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 2 mL). The mixture was stirred at 25°C for 1 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was 35 filtered, the filter cake was concentrated under reduced pressure to give a residue. The residue was 371 70226WO01 purified by prep-HPLC (TFA condition; column: Phenomenex Luna C1875*30mm*3um; mobile phase: [water(TFA)-ACN]; B%: 20%-50%, 8min) to give the title compound (67 mg, 46.86 umol, 66.99% yield, 98.58% purity, 2TFA) as a white solid. LCMS (ES, m/z): 591.3 [M/2+H]+. 5 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.12 (s, 6H) 1.32 (s, 6H) 1.52 (d, J =7.00 Hz, 6H) 1.81 (d, J=6.63 Hz, 6H) 2.72 (s, 6H) 2.83 - 3.01 (m, 4H) 3.51 (d, J=10.51 Hz, 2H) 3.65 - 3.73 (m, 6H) 3.79 - 3.85 (m, 2H) 3.96 (q, J=6.96 Hz, 2H) 4.06 - 4.11 (m, 2H) 4.97 - 5.02 (m, 2H) 5.06 - 5.11 (m, 2H) 6.35 - 6.40 (m, 4H) 6.89 (t, J=8.76 Hz, 4H) 7.22 (dd, J=8.44, 5.57 Hz, 4H) 7.76 (s, 2H) 8.19 (s, 2H). 10 The following final compounds were prepared according to the same procedure as Example 92: Examples 93-108. The compounds were found to have characterizing data as set forth below. Example 93, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-15 dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[3-[4-[3-[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3- lo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- yl]propoxy]phenoxy]propyl]triazol-1-yl]propyl]-2-(methylamino)propenamide. LCMS (ES, m/z): 605.6 [M/2+H]+. 20 2H), 7.73 (s, 2H), 7.27 (dd, J=5.5, 8.5 Hz, 4H), 7.00 - 6.88 (m, 4H), 6.46 (s, 4H), 5.15 (d, J=10.1 Hz, 2H), 5.03 - 4.93 (m, 3H), 4.15 (d, J=10.5 Hz, 2H), 3.94 (q, J=7.1 Hz, 2H), 3.84 - 3.67 (m, 4H), 3.62 (d, J=10.5 Hz, 2H), 3.45 - 3.36 (m, 2H), 2.90 - 2.77 (m, 2H), 2.76 - 2.63 (m, 8H), 1.98 - 1.83 (m, 2H), 1.77 (d, J=6.8 Hz, 6H), 1.67 - 1.56 (m, 2H), 1.51 (d, J=7.1 Hz, 6H), 1.34 (s, 6H), 1.22 (s, 6H). 25 Example 94, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrr l 32 b idi 1 b l 2 4 4 4 4 1 1S2S 3 6 4 fluoropheny )met y]- , - met y-5-oxo- , - y ropyrro o[ , - ]pyr n- -y]-1-methyl-2- [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- 30 yl]butox tyl]triazol-1-yl]propyl]-2-(methylamino)propanamide. LCMS ( ES, m/z): 619.3 [M/2+H]+. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.24 - 1.38 (m, 14H) 1.47 - 1.54 (m, 8H) 1.60 - 1.69 (m, 2H) 1.78 (d, J=6.75 Hz, 6H) 2.63 - 2.76 (m, 10H) 3.19 - 3.26 (m, 2H) 3.36 - 3.43 (m, 2H) 3.58 - 3.78 (m, 6H) 3.95 (q, J=6.88 Hz, 2H) 4.19 (d, J=10.51 Hz, 2H) 4.98 - 5.07 (m, 4H) 5.19 (d, 372 70226WO01 J=10.26 Hz, 2H) 6.45 (s, 4H) 6.94 (t, J=8.76 Hz, 4H) 7.26 (dd, J=8.44, 5.57 Hz, 4H) 7.73 (s, 2H) 8.13 (s, 2H). Example 95, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- 5 dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[2-[4-[4-[2-[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dih rolo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- yl]ethoxy]phenoxy]phenoxy]ethyl]triazol-1-yl]propyl]-2-(methylamino)propanamide. LCMS (ES, m/z): 637.3 [M/2+H]+. 10 1H ANOL-d4) δ = 8.09 (s, 2H), 7.84 (s, 2H), 7.22 (dd, J=5.6, 8.4 Hz, 4H), 6.92 (t, J=8.8 Hz, 4H), 6.75 - 6.65 (m, 4H), 6.56 - 6.43 (m, 4H), 5.26 - 5.17 (m, 2H), 5.10 - 5.01 (m, 2H), 4.08 - 3.90 (m, 8H), 3.80 - 3.66 (m, 4H), 3.53 (d, J=10.5 Hz, 2H), 3.05 (t, J=6.0 Hz, 4H), 2.71 (s, 6H), 1.74 (d, J=6.8 Hz, 6H), 1.49 (d, J=7.1 Hz, 6H), 1.23 (s, 6H), 1.06 (s, 6H). 15 Example 96, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[3-[4-[4-[3-[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- yl]propoxy]phenoxy]phenoxy]pro e. 20 LCMS (ES, m/z): 651.3 [M/2+H]+. 1H NMR (400 MHz, METHANOL-d4) δ = 8.03 (s, 2H), 7.77 (s, 2H), 7.25 - 7.16 (m, 4H), 7.00 - 6.90 (m, 4H), 6.84 - 6.78 (m, 4H), 6.76 - 6.68 (m, 4H), 5.23 (d, J=9.6 Hz, 2H), 5.02 (br dd, J=6.8, 9.6 Hz, 2H), 4.11 (d, J=10.5 Hz, 2H), 3.97 - 3.87 (m, 2H), 3.77 - 3.67 (m, 10H), 2.79 (br d, J=7.0 Hz, 4H), 2.70 (s, 6H), 1.92 (td, J=6.5, 13.2 Hz, 4H), 1.72 (d, J=6.8 Hz, 6H), 1.49 (d, J=7.0 Hz, 6H), 25 1.31 - 1.27 (m, 6H), 1.24 (s, 6H). Example 97, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[4-[4-[4-[4-[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-30 [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- yl]butoxy]phenoxy]phenoxy]but ol-1-yl]propyl]-2-(methylamino)propanamide. LCMS (ES, m/z): 665.3 [M/2+H]+. 1H NMR (400 MHz, METHANOL-d4) δ = 8.05 (s, 2H), 7.73 (s, 2H), 7.19 (dd, J=5.4, 8.6 Hz, 4H), 6.93 (t, J=8.8 Hz, 4H), 6.87 - 6.73 (m, 8H), 5.21 (d, J=9.5 Hz, 2H), 5.00 (br dd, J=6.9, 9.5 Hz, 2H), 35 4.10 (d, J=10.5 Hz, 2H), 3.92 (d, J=7.0 Hz, 2H), 3.78 - 3.61 (m, 10H), 2.70 (s, 6H), 2.68 - 2.60 (m, 373 70226WO01 4H), 1.73 (d, J=6.8 Hz, 6H), 1.69 - 1.60 (m, 4H), 1.59 - 1.51 (m, 4H), 1.49 (d, J=7.0 Hz, 6H), 1.28 (d, J=9.8 Hz, 12H). Example 98, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- 5 dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[3-[[4-[[3-[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- yl]propanoylamino]methyl]phenyl]methylamino]-3-oxo-propyl]triazol-1-yl]propyl]-2- (methylamino)propanamide. 10 , : . 1H NMR (400 MHz, METHANOL-d4) δ = 8.07 (s, 2H) 7.66 (s, 2H) 7.13 - 7.23 (m, 8H) 6.90 - 6.99 (m, 4H) 5.26 (d, J=9.38 Hz, 2H) 4.97 - 5.02 (m, 2H) 4.26 (q, J=14.93 Hz, 4H) 4.08 (d, J=10.51 Hz, 2H) 3.95 (q, J=7.00 Hz, 2H) 3.68 - 3.78 (m, 6H) 3.31 (s, 4H) 2.88 - 2.97 (m, 4H) 2.70 (s, 6H) 2.50 (t, J=7.38 Hz, 4H) 1.65 (d, J=6.75 Hz, 6H) 1.46 - 1.53 (m, 6H) 1.29 (d, J=13.26 Hz, 12H). 15 Example 99, 4-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]-3- oxo-propyl]triazol-4-yl]-N-[[4-[[4-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-20 (methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- yl]butanoylamino]methyl]phenyl]methyl]butanamide. LCMS (ES, m/z): 646.7 [M/2+H]+. 1H NMR (400 MHz, METHANOL-d4) δ = 8.02 (s, 2H), 7.73 (s, 2H), 7.24 - 7.16 (m, 8H), 6.96 (t, J = 8.8 Hz, 4H), 5.23 (d, J = 9.3 Hz, 2H), 5.01 (dd, J = 6.9, 9.1 Hz, 2H), 4.31 (s, 4H), 4.07 (d, J = 25 10.5 Hz, 2H), 3.91 (d, J = 7.0 Hz, 2H), 3.81 - 3.65 (m, 6H), 2.68 (s, 6H), 2.61 (s, 4H), 2.18 - 2.12 (m, 4H), 1.83 (t, J = 7.5 Hz, 4H), 1.70 (d, J = 6.8 Hz, 6H), 1.48 (d, J = 7.0 Hz, 6H), 1.29 (d, J = 11.1 Hz, 12H). Example 100, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-30 dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[[4-[4-[[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- yl]methoxy]phenyl]phenoxy]methyl]triazol-1-yl]propyl]-2-(methylamino)propan amide. LCMS (ES, m/z): 615.5 [M/2+H]+ 374 70226WO01 1H NMR (400 MHz, METHANOL-d4) δ = 8.07 (d, J = 10.9 Hz, 4H), 7.24 - 7.12 (m, 8H), 6.87 (t, J = 8.8 Hz, 4H), 6.75 (d, J = 8.8 Hz, 4H), 5.16 - 5.05 (m, 10H), 4.08 (d, J = 10.4 Hz, 2H), 3.93 (d, J = 7.0 Hz, 2H), 3.71 (s, 4H), 3.44 (d, J = 10.5 Hz, 2H), 2.71 (s, 6H), 1.81 (d, J = 6.6 Hz, 6H), 1.50 (d, J = 7.0 Hz, 6H), 1.27 (s, 6H), 1.19 (s, 6H). 5 Example 101, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[[6-[[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2S)-2-(methylamino)propanoyl]amino]-3-ox yl]triazol-4-yl]methoxy]-2- 10 naphthyl]oxymethyl]triazol-1-yl]propyl]-2-(methylamino)propanamide. LCMS (ES, m/z): 602.3 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.11 (s, 2H), 8.07 (s, 2H), 7.26 (d, J = 8.8 Hz, 2H), 7.21 - 7.11 (m, 4H), 7.02 (d, J = 2.2 Hz, 2H), 6.93 - 6.77 (m, 6H), 5.18 - 5.08 (m, 8H), 4.05 (d, J = 10.5 Hz, 2H), 3.95 (q, J = 7.2 Hz, 2H), 3.78 - 3.64 (m, 4H), 3.47 (d, J = 10.5 Hz, 2H), 2.71 (s, 6H), 1.80 15 (d, J = 6.6 Hz, 6H), 1.51 (d, J = 7.0 Hz, 6H), 1.29 (s, 6H), 1.03 (s, 6H). Example 102, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[[5-[[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-20 [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4-yl]methoxy]-1- naphthyl]oxymethyl]triazol-1-yl]propyl]-2-(methylamino)propanamide. LCMS (ES, m/z): 602.4 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.15 (s, 2H), 8.10 (s, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.05 (dd, J = 5.4, 8.6 Hz, 4H), 6.98 (t, J = 8.1 Hz, 2H), 6.78 - 6.66 (m, 6H), 5.25 - 5.18 (m, 6H), 5.13 - 25 5.05 (m, 2H), 4.09 (d, J = 10.5 Hz, 2H), 3.94 (d, J = 7.0 Hz, 2H), 3.75 - 3.66 (m, 4H), 3.65 - 3.60 (m, 2H), 2.72 (s, 6H), 1.81 (d, J = 6.6 Hz, 6H), 1.51 (d, J = 7.0 Hz, 6H), 1.31 (s, 6H), 1.02 (s, 6H). Example 103, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[[7-[[1-[(1S,2S)-3-[6-[(4-30 fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4-yl]methoxy]-2- naphthyl]oxymethyl]triazol-1-yl]propyl]-2-(methylamino)propanamide LCMS (ES, m/z): 602.3 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.08 (s, 2H), 8.02 (s, 2H), 7.52 (d, J = 8.9 Hz, 2H), 7.14 35 (dd, J = 5.5, 8.5 Hz, 4H), 7.08 (d, J = 2.0 Hz, 2H), 6.86 (s, 6H), 5.26 (d, J = 9.9 Hz, 2H), 5.16 - 5.08 375 70226WO01 (m, 6H), 4.05 (d, J = 10.4 Hz, 2H), 3.68 (q, J = 15.3 Hz, 4H), 3.57 (d, J = 10.5 Hz, 2H), 3.18 (d, J = 6.9 Hz, 2H), 2.31 (s, 6H), 1.73 (d, J = 6.8 Hz, 6H), 1.28 (s, 6H), 1.23 (d, J = 6.9 Hz, 6H), 1.15 (s, 6H). 5 Example 104, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[[4-[2,2,2-trifluoro-1-[4-[[1-[(1S,2S)-3-[6-[(4- fluorophenyl 1-methyl-2- [[(2S)-2-(methylamino)propano triazol-4-yl]methoxy]phenyl]-1- (trifluoromethyl)ethyl]phenoxy]methyl] no)propanamide. 10 LCMS (ES, m/z): 690.3 [M/2+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.09 (d, J = 4.9 Hz, 4H), 7.28 - 7.14 (m, 8H), 6.95 - 6.86 (m, 8H), 5.22 (d, J = 9.5 Hz, 2H), 5.14 - 5.07 (m, 6H), 4.07 (d, J = 10.5 Hz, 2H), 3.94 (q, J = 6.8 Hz, 2H), 3.72 (s, 4H), 3.60 (d, J = 10.4 Hz, 2H), 2.70 (s, 6H), 1.79 (d, J = 6.8 Hz, 6H), 1.53 - 1.48 (m, 6H), 1.30 (s, 6H), 1.23 (s, 6H). 15 Example 105, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[[[2-[4-[2-[[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2S)-2-(methylamino)propano 3-oxo-propyl]triazol-4-yl]methylamino]-2-oxo- 20 ethyl]phenyl]acetyl]amino]methyl]triazol-1-yl]propyl]-2-(methylamino)propanamide. LCMS (ES m/z): 618.4 [M/2+H]+ 1H N , 8.08 (s, 2H), 7.80 (s, 2H), 7.21 (dd, J = 5.5, 8.6 Hz, 4H), 7.12 (s, 4H), 6.94 (t, J = 8.8 Hz, 4H), 5.28 (d, J = 9.0 Hz, 2H), 5.07 (br d, J = 2.0 Hz, 2H), 4.32 (s, 4H), 4.03 (s, 2H), 3.88 (br d, J = 6.9 Hz, 2H), 3.82 - 3.73 (m, 6H), 3.37 (br d, J = 13.8 Hz, 6H), 25 2.65 (s, 6H), 1.66 (d, J = 6.9 Hz, 6H), 1.48 (d, J = 7.0 Hz, 6H), 1.32 (s, 6H), 1.24 (s, 6H). Example 106, (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[2-[[2-[4-[2-[2-[1-[(1R,2R)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-30 [[(2R)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4-yl]ethylamino]-2-oxo- m, d, J 70226WO01 = 7.1 Hz, 2H), 3.81 - 3.70 (m, 6H), 3.42 (s, 4H), 3.37 - 3.33 (m, 4H), 2.78 (t, J = 7.1 Hz, 4H), 2.68 (s, 6H), 1.66 (d, J = 6.8 Hz, 6H), 1.48 (d, J = 7.0 Hz, 6H), 1.30 (d, J = 14.4 Hz, 12H). Example 107, N4-[[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- 5 dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]-3- oxo-propyl]triazol-4-yl]methyl]-N1-[[1-[(1R,2R)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl- 5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2R)-2- (methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4-yl]methyl]terephthalamide. 10 ), .05 - (s, 15 -3- hyl- 20 (m, 4H), 6.99 - 6.92 (m, 4H), 5.26 (d, J = 9.1 Hz, 2H), 5.06 (br dd, J = 6.9, 8.9 Hz, 2H), 4.07 (d, J = 10.4 Hz, 2H), 3.92 (q, J = 7.0 Hz, 2H), 3.79 - 3.70 (m, 6H), 3.59 - 3.48 (m, 4H), 2.94 (br t, J = 7.1 25 Hz, 4H), 2.70 (s, 6H), 1.70 (d, J = 6.8 Hz, 6H), 1.49 (d, J = 7.0 Hz, 6H), 1.31 (s, 6H), 1.26 (s, 6H). Example 109, (2S)-N-[(1S)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[[4-[2-[2-[[2-[4-[(2S)-3-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2-30 (methylamino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl- phenoxy]acetyl]amino]ethylamino]-2-oxo-ethoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-ethyl]- 2-(methylamino)butanamide. 377 70226WO01 Step 1 of 4: Synthesis of intermediate 132.1, benzyl 2-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- 5 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5- dimethyl-phenoxy]acetate. Two batches were carried out in parallel: To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 1-[(4-hydroxy-2,6-dimethyl-phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate 10 (500 mg, 643.46 umol, 1 eq) in ACN (10 mL) was added K2CO3 (142.29 mg, 1.03 mmol, 1.6 eq) and benzyl 2-bromoacetate (206.36 mg, 900.84 umol, 141.34 uL, 1.4 eq) at 0°C. The mixture was stirred at 60°C for 12 hr. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Two reactions were combined for work-up. Water (20 mL) was added to the mixture, the mixture was extracted with EtOAc (20 mL x 3). The combined 15 organic layers were washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/0 to 6/1) to give the title compound (710 mg, 767.40 umol, 59.63% yield) as a colorless oil. TLC (Petroleum ether : Ethyl acetate = 3:1) Rf = 0.52 20 LCMS (ES, m/z): 825.5 [M-Boc+H]+. Step 2 of 4: Synthesis of Intermediate 132.2, 2-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- 378 70226WO01 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5- dimethyl-phenoxy]acetic acid. oyl]amino]- 3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2- 5 b]pyridin-1-yl]-3-oxo-propyl]-3,5-dimethyl-phenoxy]acetate (710 mg, 767.40 umol, 1 eq) in EtOAc (20 mL) was added Pd/C (350 mg, 10% purity) at N2 atmosphere. The suspension was degassed and purged with H2 for three times. The mixture was stirred under H2 (15Psi) at 25°C for 1 hr. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered, the filtrate was concentrated to give the title compound 10 (545 mg, 652.63 umol, 85.04% yield) as white solid. LCMS (ES, m/z): 835.4 [M+H]+. Step 3 of 4: Synthesis of Intermediate 132.3, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[2-[2-[[2-[4- [(2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-15 butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- propyl]-3,5-dimethyl-phenoxy]acetyl]amino]ethylamino]-2-oxo-ethoxy]-2,6- dimethyl-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl- carbamate. 20 To a solution of 2-[4-[(2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5- [tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-3-oxo-propyl]-3,5-dimethyl-phenoxy]acetic acid (150 mg, 179.62 umol, 3 eq) ethane-1,2- diamine (7.96 mg, 59.87 umol, 8.87 uL, 1 eq, 2HCl) in DCM (3 mL) was added DIEA (46.43 mg, 359.24 umol, 62.57 uL, 6 eq) and T3P (380 mg, 597.14 umol, 355.14 uL, 50% purity, 9.97 eq) at 25 0°C. The mixture was stirred at 25°C for 12 hr. LC-MS indicated complete conversion to a product of target mass. Water (5 mL) was added to the mixture, the mixture was extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18200*40mm*10um;mobile 30 phase: [water(TFA)-ACN]; B%: 60%-95%,8 min) to give the title compound (54 mg, 28.09 umol, 46.92% yield, 2 TFA) as a yellow solid. LCMS (ES, m/z): 1467.0 [M-2TBS+H]+. Step 4 of 4: Synthesis of example 109, (2S)-N-[(1S)-2-[6-[(4-fluorophenyl)methyl]-3,3-35 dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[[4-[2-[2-[[2-[4-[(2S)-3-[6-[(4- 379 70226WO01 fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2- (methylamino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl- phenoxy]acetyl]amino]ethylamino]-2-oxo-ethoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-ethyl]- 5 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[2-[2-[[2-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5-dimethyl- phenoxy]acetyl]amino]ethylamino]-2-oxo-ethoxy]-2,6-dimethyl-phenyl]methyl]-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 10 2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (48 mg, 28.33 umol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 1 mL). The mixture was stirred at 25°C for 1 hr. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was blown to dryness by N2 stream and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18 15 75*30mm*3um; mobile phase: [water(FA)-ACN]; B%: 20%-55%,8 min) to give the title compound (14.3 mg, 10.27 umol, 36.27% yield, 97.54% purity, 2 FA) as a white solid. LCMS (ES, m/z): 1265.4 [M+H]+ 1H NMR (400 MHz, METHANOL-d4) δ = 8.21 (s, 2H), 7.24 (dd, J = 5.5, 8.4 Hz, 4H), 7.00 (t, J = 8.8 Hz, 4H), 6.62 (s, 4H), 4.75 (br dd, J = 4.3, 11.1 Hz, 2H), 4.35 (s, 4H), 3.82 (br d, J = 10.3 Hz, 20 2H), 3.79 (s, 4H), 3.39 (s, 4H), 3.27 - 3.10 (m, 4H), 2.98 (br dd, J = 4.3, 13.7 Hz, 2H), 2.63 (d, J = 10.1 Hz, 2H), 2.36 (s, 6H), 2.28 (s, 12H), 1.68 (br t, J = 7.2 Hz, 4H), 1.24 (s, 6H), 0.97 - 0.86 (m, 12H). The following final compounds were prepared according to the same procedure as Example 109: 25 Examples 110 and 111. The yield, HNMR and QC data are shown below. Example 110, (2S)-N-[(1S)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydrop l 32 b idi 1 l 1 4 2 4 2 4 (2S)-3-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl -5-oxo- , -d ydropyrroo[3, -b]pyr d n- -y ]-2-[[(2S)-2-30 (methylamino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl- phenoxy]acetyl]amino]butylamino]-2-oxo-ethoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-ethyl]- 2-(methylamino)butanamide. LCMS (ES, m/z): 1293.5 [M+H]+ 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.89 - 0.95 (m, 12H) 1.24 (s, 6H) 1.50 (br s, 4H) 1.61 35 - 1.68 (m, 4H) 2.29 (s, 12H) 2.33 (s, 6H) 2.62 (d, J=10.13 Hz, 2H) 2.96 - 3.06 (m, 4H) 3.20 - 3.27 380 70226WO01 (m, 6H) 3.78 (s, 4H) 3.82 (d, J=10.13 Hz, 2H) 4.39 (s, 4H) 4.74 (br d, J=4.50 Hz, 1H) 4.76 (br d, J=4.25 Hz, 1H) 6.64 (s, 4H) 6.97 - 7.04 (m, 4H) 7.24 (dd, J=8.57, 5.44 Hz, 4H) 8.22 (s, 2 H) 8.57 (s, 1H) 5 Example 111, (2S,2'S)-N,N'-((2S,2'S)-(((((1,4-phenylenebis(methylene))bis(azanediyl))bis(2- oxoethane-2,1-diyl))bis(oxy))bis(2,6-dimethyl-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-o yrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2- diyl))bis(2-(methylamino)butanamide). LCMS (ES, m/z): 1341.4 [M+H]+. 10 1H NMR ( HANOL-d4) δ = 8.21 (s, 2H), 7.23 (dd, J = 5.6, 8.7 Hz, 4H), 7.18 (s, 4H), 7.03 - 6.95 (m, 4H), 6.63 (s, 4H), 4.75 (d, J = 3.9 Hz, 1H), 4.72 (br d, J = 4.2 Hz, 1H), 4.47 (s, 4H), 4.39 (d, J = 4.6 Hz, 4H), 3.81 (s, 2H), 3.77 (s, 4H), 3.27 - 3.21 (m, 2H), 3.15 - 3.10 (m, 2H), 2.99 (dd, J = 4.2, 13.6 Hz, 2H), 2.60 (d, J = 10.3 Hz, 2H), 2.36 (s, 6H), 2.27 (s, 12H), 1.67 (t, J = 7.1 Hz, 4H), 1.23 - 1.19 (m, 6H), 0.92 (t, J = 7.5 Hz, 6H), 0.85 (s, 6H). 15 Example 112, (2S)-N-[(1S)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[[4-[[4-[[4-[(2S)-3-[6-[(4-fluorophenyl)methyl]-3,3- 20 381 70226WO01 TBSO OTBS N Boc N Br N F O (S) NH Br S Step 1 of 2: Synthesis of intermediate 134.2, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[[4-[[4-[(2S)-2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert- 5 butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-3-oxo-propyl]-35-dimethyl-phenoxy]methyl]phenyl]methoxy]-2,6-dimethyl- rt-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl- 2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate. To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-10 fluoropheny ethyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-1-[(4-hydroxy-2,6-dimethyl- phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (35.33 mg, 45.46 umol, 2.4 eq) in DMF (4 mL) was added K2CO3 (10.47 mg, 75.77 umol, 4 eq) at 80°C . The mixture was stirred at 80°C for 0.5 hr. Then 1,4-bis(bromomethyl)benzene (5 mg, 18.94 umol, 1 eq) was added dropwise at 80°C. The mixture was stirred at 80°C for 12 hr. LC-MS indicated complete 15 conversion to a product of target mass. Water (5 mL) was added to the mixture, the mixture was extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether: Ethyl acetate = 1:1) to give the title compound (23 mg, 13.89 umol, 73.31% yield) as a yellow oil. 20 TLC (Petroleum ether/Ethyl acetate = 1:1) Rf=0.47 82 70226WO01 Step 2 of 2: Synthesis Example 112, (2S)-N-[(1S)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl- 5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[[4-[[4-[[4-[(2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2- 5 (methylamino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl- phenoxy]methyl]phenyl]methoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-ethyl]-2- y butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-10 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5-dimethyl- phenoxy]methyl]phenyl]methoxy]-2,6-dimethyl-phenyl]methyl]-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (46 mg, 27.77 umol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 1 mL, 144.02 eq). The mixture was stirred at 25°C for 1 hr. LC-MS 15 indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered, the filter cake was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex luna C18 100*40mm*3 um; mobile phase: [water(TFA)-ACN]; B%: 35%-78%,8 min) to give the title compound (3.2 mg, 2.18 umol, 7.85% yield, 99.2% purity, 2 TFA) as a white solid. 20 LCMS (ES, m/z): 1227.4 [M+H]+. 1H NMR (400 MHz, METHANOL-d4) δ = 8.19 (s, 2H), 7.26 (s, 4H), 7.13 (dd, J = 5.5, 8.5 Hz, 4H), 6.91 (t, J = 8.8 Hz, 4H), 6.40 (s, 4H), 5.33 (s, 4H), 3.88 (s, 4H), 3.81 - 3.76 (m, 4H), 3.30 - 3.21 (m, 4H), 3.01 (dd, J = 4.1, 13.6 Hz, 2H), 2.70 (d, J = 10.0 Hz, 2H), 2.64 (s, 6H), 2.23 (s, 12H), 1.98 - 1.85 (m, 4H), 1.19 (s, 6H), 0.99 (t, J = 7.5 Hz, 6H), 0.90 (s, 6H). 25 Example 113, N1,N4-bis[2-[4-[(2S)-3-[6-[(4-fluorophenyl)methyl]- 3,3- dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2-(methylamino)butanoyl]amino]-3-oxo-propyl]- 3,5-dimethyl-phenoxy]ethyl]terephthalamide. 383 70226WO01 Step 1 of 4: Synthesis of Intermediate 135.2, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[2- (benzyloxycarbonylamino)ethoxy]-2,6-dimethyl-phenyl]methyl]-2-[5-[tert- 5 butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate. To a solution of benzyl N-(2-bromoethyl)carbamate (60 mg, 232 umol, 1 eq) tert-butyl N-[(1S)-1- [[(1S)-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H- pyrrolo[3,2-b]pyridin-1-yl]-1-[(4-hydroxy-2,6-dimethyl-phenyl)methyl]-2-oxo- 10 ethyl]carbamoyl]propyl]-N-methyl-carbamate (199 mg, 256 umol, 1.1 eq) in DMF (4 mL) was added K2CO3 (38.6 mg, 279 umol, 1.2 eq). The mixture was stirred at 80°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (10 mL) was added to the mixture, the mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10mL), dried over Na2SO4 and filtered. The 15 filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate= 1:1) to give the title compound (140 mg, 147 umol, 63.1% yield) as a yellow oil. TLC (Petroleum ether/Ethyl acetate = 1:1) Rf = 0.42. LCMS (ES, m/z): 840.7 [M-TBS+H]+. 20 Step 2 of 4: Synthesis of Intermediate 135.3, tert-butyl N-[(1S)-1-[[(1S)-1-[[4- (2- aminoethoxy)-2,6-dimethyl-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo- ethyl]carbamoyl]propyl]-N-methyl-carbamate. 25 To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[2-(benzyloxycarbonylamino)ethoxy] -2,6- dimethyl-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- 384 70226WO01 dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (120 mg, 126 umol, 1 eq) in MEOH (4 mL) was added 10% Pd/C (200 mg, 50% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15Psi) at 25°C for12 h. LC-MS indicated complete consumption of starting 5 material with formation of a single peak of target mass. The mixture was filtered, the filtrate was concentrated to give the title compound (90 mg, 110 umol, 87.3% yield) as a yellow solid. LCMS (ES, m/z): 706.7 [M-TBS+H]+. Step 3 of 4: Synthesis of Intermediate 135.4, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[2-[[4-[2- [4-10 [(2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-3-oxo-propyl]-3,5-dimethyl-phenoxy]ethylcarbamoyl]b amino]ethoxy]-2,6- ethyl-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- d thyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo hyl- 15 carbamate. To a solution of terephthalic acid (6 mg, 36.1 umol, 1 eq) tert-butyl N-[(1S)-1-[[(1S)-1- [[4-(2- aminoethoxy)-2,6-dimethyl-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- N-methyl-carbamate (62.2 mg, 75.8 umol, 2.1 eq) in DMF (2 mL) was added DIEA (18.7 mg, 144 20 umol, 25.2 uL, 4 eq) and HATU (27.5 mg, 72.2 umol, 2 eq) at 0°C. The mixture was stirred at 80°C for 12 h. LC-MS indicated complete conversion to a product of target mass. Water (15 mL) was added to the mixture. The mixture was extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC 25 (SiO2, Petroleum ether : Ethyl acetate= 1:1) to give the title compound (50 mg, 28.2 umol, 78.2% yield) as a yellow solid. TLC (Petroleum ether : Ethyl acetate=1:1) Rf = 0. LCMS (ES, m/z): 1442.5 [M-2TBS-BOC+H]+. 30 Step 4 of 4: Synthesis of Example 113, N1,N4-bis[2-[4-[(2S)-3-[6 -[(4-fluorophenyl)methyl]- 3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2- (methylamino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl-phenoxy]ethyl]terephthalamide. To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[2-[[4-[2-[4-[(2S)-2-[[(2S)-2 -[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-35 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5-dimethyl- 385 70226WO01 phenoxy]ethylcarbamoyl]benzoyl]amino]ethoxy]-2,6-dimethyl-phenyl]methyl]-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (40 mg, 22.6 umol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 1 mL). The mixture was stirred at 25°C for 1 h. LC-MS indicated 5 complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition column: Phenomenex Luna 80*30mm*3um; mobile phase: [water(TFA)-ACN]; B%: 25%-55%, 8min) to give the title compound (17.9 mg, 10.90 umol, 48.23% yield, 95.567% purity, 2TFA) as a white solid. 10 LCMS (ES, m/z): 1341.5 [M+H]+. 1H NMR (400 MHz, METHANOL-d4) δ = 8.63 (s, 1H), 8.16 (s, 2H), 7.83 (s, 4H), 7.22 - 7.11 (m, 4H), 6.91 - 6.80 (m, 4H), 6.40 (s, 4H), 4.79 (dd, J = 4.3, 11.4 Hz, 2H), 4.53 (dt, J = 2.3, 5.3 Hz, 4H), 3.88 (s, 4H), 3.83 - 3.75 (m, 8H), 3.26 (dd, J = 11.5, 13.5 Hz, 2H), 3.01 (dd, J = 4.2, 13.7 Hz, 2H), 2.69 (d, J = 9.9 Hz, 2H), 2.65 (s, 6H), 2.22 (s, 12H), 2.02 - 1.84 (m, 4H), 1.19 (s, 6H), 1.00 (t, 15 J = 7.6 Hz, 6H), 0.90 (s, 6H). Example 114, N,N'-bis[2-[4-[(2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl -5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2-(methylamino)butanoyl]amino]-3-oxo-propyl]- 3,5-dimethyl-phenoxy]ethyl]butanediamide. OTBS OTBS Boc 20 Step 1 of 2: Synthesis of Intermediate 136.2, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[2- [[4-[2-[4- [(2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert- 386 70226WO01 butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-3-oxo-propyl]-3,5-dimethyl-phenoxy]ethylamino]-4-oxo-butanoyl]amino]ethoxy]-2,6- ,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carba 5 carbamate. To a solution of succinic acid (5.6 mg, 47.4 umol, 1 eq) tert-butyl N-[(1S)-1-[[(1S)-1-[[4-(2- aminoethoxy)-2,6-dimethyl-phenyl]methyl] -2-[5-[tert-butyl (dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- N-methyl-carbamate (79.7 mg, 97.2 umol, 2.05 eq) in DMF (3 mL) was added DIEA (24.5 mg, 190 10 umol, 33.0 uL, 4 eq) and HATU (36.1 mg, 94.8 umol, 2 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (5 mL) was added to the mixture, the mixture was extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The 15 residue was purified by prep-TLC (SiO2, PE: EA = 0:1) to give the title compound (55.6 mg, 32.3 umol, 68.1% yield) as a yellow oil. TLC (Petroleum ether : Ethyl acetate=0:1) Rf = 0.6. LCMS (ES, m/z): 1494.1 [M-2TBS+H]+. 20 Step 2 of 2: Synthesis of Example 114, N,N'-bis[2-[4-[(2S)-3-[6 -[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2- (methylamino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl-phenoxy]ethyl]butanediamide. To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[2-[ 2S)-2-[[(2S)-2- [tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-25 fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5-dimethyl- phenoxy]ethylamino]-4-oxo-butanoyl]amino]ethoxy]-2,6-dimethyl-phenyl]methyl]-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (50 mg, 29.0 umol, 1 eq) in EtOAc (2 mL) was added HCl/EtOAc (4 M, 2 mL). The mixture was stirred at 25°C for 1 h. LC-MS indicated 30 complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered, the filter cake was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition; column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [water(TFA)-ACN];B%: 20%-45%,8min) to give the title compound (24.3 mg, 15.13 umol, 52.12% yield, 94.745% purity, 2TFA) as a white solid. 35 LCMS (ES, m/z): 1293.4 [M+H]+. 387 70226WO01 1H NMR (400 MHz, METHANOL-d4) δ = 8.15 (s, 2H), 7.23 - 7.18 (m, 4H), 7.02 - 6.95 (m, 4H), 6.40 (s, 4H), 4.37 - 4.29 (m, 4H), 3.88 (s, 4H), 3.81 - 3.77 (m, 4H), 3.52 (t, J = 5.6 Hz, 4H), 3.28 - 3.21 (m, 2H), 3.01 (dd, J = 4.1, 13.6 Hz, 2H), 2.72 - 2.59 (m, 10H), 2.46 (s, 4H), 2.22 (s, 12H), 1.98 - 1.87 (m, 4H), 1.19 (s, 6H), 1.00 (t, J = 7.6 Hz, 6H), 0.89 (s, 6H). 5 Example 115, (2S)-N-[(1S)-2 -[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[[4-[2-[[2-[4-[2-[2-[4-[(2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2- (methylamino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl-phenoxy]ethylamino]-2-oxo-10 ethyl]phenyl]acetyl]amino]ethoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-ethyl]-2- (methylamino)butanamide. Step 1 of 2: Synthesis of Intermediate 137.2, tert-butyl N-[(1S)-1-[[(1S)-1-[[4- [2-[[2-[4-[2-[2-15 [4-[(2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-3-oxo-propyl]-3,5-dimethyl-phenoxy]ethylamino]-2-oxo- ethyl]phenyl]acetyl]amino]ethoxy]-2,6-dimethyl-phenyl]methyl]-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 20 1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate. To a solution of 2-[4-(carboxymethyl)phenyl]acetic acid (13 mg, 67.0 umol, 1 eq) and tert-butyl N- [(1S)-1-[[(1S)-1-[[4-(2-aminoethoxy)-2,6-dimethyl-phenyl]methyl]-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (115 mg, 141 umol, 2.1 eq) in DMF (2 mL) 388 70226WO01 was added DIEA (34.6 mg, 268 umol, 46.6 uL, 4 eq) and HATU (50.9 mg, 134 umol, 2 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated complete conversion to a product of target mass. Water (10 mL) was added to the mixture, the mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and 5 filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate= 0:1) to give the title compound (81 mg, 45.0 umol, 67.3% yield) as a white solid. TLC (Petroleum ether : Ethyl acetate=0:1) Rf = 0.58. LCMS (ES, m/z): 1470.3 [M-2TBS-BOC+H]+. 10 Step 2 of 2: Synthesis of Example 115, (2S)-N-[(1S)-2 -[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[[4-[2-[[2-[4-[2-[2-[4-[(2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2- mino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl-phenoxy]ethylamino]-2-oxo-15 ethyl]phenyl]acetyl]amino]ethoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-ethyl]-2- (methylamino)butanamide. To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4- )-2-[[(2S)- 2-[tert - butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5-dimethyl-20 phenoxy]ethylamino]-2-oxo-ethyl]phenyl]acetyl]amino]ethoxy]-2,6-dimethyl-phenyl]methyl]-2-[5- [tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin- 1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (71 mg, 39.5 umol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 1 mL). The mixture was stirred at 25°C for 1 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. 25 The mixture was blown to dryness by N2 stream and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA condition;column: Phenomenex Luna 80*30mm*3um;mobile phase: [water(TFA)-ACN]; B%: 25%-70%,8min) to give the title compound (25.8 mg, 15.29 umol, 38.72% yield, 94.661% purity, 2TFA) as a white solid. LCMS (ES, m/z): 1369.5 [M+H]+. 30 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.89 (s, 6H) 0.99 (t, J =7.50 Hz, 6H) 1.18 (s, 6H) 1.85 - 1.98 (m, 4H) 2.22 (s, 12H) 2.64 (s, 6H) 2.69 (d, J =10.01 Hz, 2H) 3.01 (dd, J =13.63, 4.25 Hz, 2H) 3.25 (br dd, J =13.51, 11.63 Hz, 4H) 3.43 (s, 4H) 3.52 (br t, J =5.32 Hz, 4H) 3.78 (s, 4H) 4.33 - 4.38 (m, 4H) 4.77 - 4.82 (m, 4H) 6.40 (s, 4H) 6.93 - 6.99 (m, 4H) 7.11 - 7.21 (m, 8H) 7.96 - 8.06 (m, 1H) 8.12 (s, 2H). 35 389 70226WO01 Example 116, (2S)-N-[(1S)-2-[6- [(4-fluorophenyl) methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo [3,2-b] pyridin-1-yl]- 1-[[4-[4-[1-[4-[4-[(2S)-3-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2- (methylamino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl-phenoxy]butyl]triazol-4- 5 yl]butoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-ethyl]-2-(methylamino)butanamide. Step 1 of 8: Synthesis of Intermediate 138.2, methyl (2S)-3-[4-(4-bromobutoxy)- 2,6- dimethyl-phenyl]-2-(tert-butoxycarbonylamino)propanoate. 10 To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxy- 2,6-dimethyl-phenyl) propanoate (100 mg, 309 umol, 1 eq), 1,4-dibromobutane (73.44 mg, 340.15 umol, 41.03 uL, 1.1 eq) in DMF (4 mL) was added K2CO3 (64.1 mg, 464 umol, 1.5 eq). The mixture was stirred at 25°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (10 mL) was added to the mixture, the mixture was extracted 15 with EtOAc (10 mL x 2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate= 2:1) to give the title compound (660 mg, 1.44 mmol, 51.74% yield) as a white solid. TLC (Petroleum ether : Ethyl acetate =2:1) Rf = 0.58. 20 LCMS (ES, m/z): 358.0 [M-Boc+H]+. Step 2 of 8: Synthesis of Intermediate 138.3, methyl (2S)-3-[4-(4-azidobutoxy)-2,6-dimethyl - phenyl]-2-(tert-butoxycarbonylamino)propanoate. To a solution of methyl (2S)-3-[4-(4-bromobutoxy)-2,6-dimethyl-phenyl]-2-(tert- 25 butoxycarbonylamino)propanoate (660 mg, 1.44 mmol, 1 eq) in DMF (8 mL) was added one portion NaN3 (310 mg, 4.77 mmol, 3.31 eq). The mixture was stirred at 80°C for 2 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The reaction mixture was added into H2O 20 mL, then extracted with EtOAc (20 mL * 3), the 390 70226WO01 combined organic phase dried over Na2SO4, filtered and filtrate was concentrated under reduced pressure to give the title compound (560 mg, quantitative yield) as a yellow oil. LCMS (ES, m/z): 321.3 [M-Boc+H]+. 5 Step 3 of 8: Synthesis of Intermediate 138.4, methyl (2S)-2-amino-3-[4-(4-azidobutoxy) -2,6- dimethyl-phenyl]propanoate. To a solution of methyl (2S)-3-[4-(4-azidobutoxy)-2,6-dimethyl-phen -2- (tert- rbonylamino)propanoate (560 mg, 1.33 mmol, 1 eq) in EtOAc (3 mL) was added HCl/EtOAc (4 M, 3 mL). The mixture was stirred at 25°C for 1 h. LC-MS indicated complete 10 conversion to a product of target mass. The reaction mixture was concentrated under reduced pressure to give the title compound (450 mg, quantitative yield, HCl) as a white solid. LCMS (ES, m/z): 321.1 [M+H]+. Step 4 of 8: Synthesis of Intermediate 138.5, methyl (2S)-3-[4-(4-azidobutoxy)-2,6-dimethyl- 15 phenyl]-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]propanoate. To a solution of (2S)-2-[tert-butoxycarbonyl(methyl)amino] butanoic acid (301.37 mg, 1.39 mmol, -amino-3-[4- (4-azidobutoxy)-2,6-dimethyl-phenyl]propanoate (450 mg, 1.26 mmol, 1 eq, HCl) and DIEA (652 mg, 5.04 mmol, 878.61 μL, 4 eq) at 0°C. The mixture was stirred at 20°C for 12 h. LC-MS 20 indicated complete consumption of starting material with formation of a single peak of target mass. Water (20 mL) was added to the mixture, the mixture was extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate= 1.5:1) to give the title compound (610 mg, 1.17 25 mmol, 93.09% yield) as a yellow oil. TLC (Petroleum ether : Ethyl acetate =1.5:1) Rf = 0.52. LCMS (ES, m/z): 420.3 [M-Boc+H]+. Step 5 of 8: Synthesis of Intermediate 138.6, (2S)-3-[4-(4-azidobutoxy)-2,6- dimethyl-phenyl] 30 -2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]propanoic acid. To a solution of methyl (2S)-3-[4-(4-azidobutoxy)-2,6-dimethyl-phenyl]- 2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]propanoate (570 mg, 1.10 mmol, 1 eq) in THF (6 mL) H2O (2 mL) was added LiOH (78.8 mg, 3.29 mmol, 3 eq). The mixture was stirred at 20°C for 2 h. LC-MS indicated complete conversion to a product of target mass. The mixture was 35 concentrated under reduced pressure to give a residue, the residue was dissolved in H2O (15 mL), 391 70226WO01 then extracted with EtOAC (10 mL * 2), then the water phase acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase was extracted with DCM (10 mL * 3) and the organic phase were washed with brine (10 mL). Then dried over Na2SO4, filtered and filtrate was concentrated under reduced pressure to give the title compound (510 mg, 1.01 mmol, 91.96% yield) as a yellow solid. 5 LCMS (ES, m/z): 528.3 [M+23]+. Step 6 of 8: Synthesis of Intermediate 138.7, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-(4-azidobutoxy) -2,6-dimethyl-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl- 10 carbamate. To a solution of (2S)-3-[4-(4-azidobutoxy)-2,6-dimethyl-phenyl]-2 -[[(2S)-2- [tert- butoxycarbonyl(methyl)amino]butanoyl]amino]propanoic acid (200 mg, 395.57 μmol, 1 eq), tert- butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl] oxy]- dimethyl-silane (168 mg, 435 μmol, 1.1 eq) in DCM (4 mL) was added DIEA (153 mg, 1.19 mmol, 15 206 μL, 3 eq) and T3P (610 mg, 959 μmol, 570 μL, 50% purity, 2.42 eq) at 0°C. The mixture was stirred at 20°C for 12h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water (20 mL) was added to the mixture, the mixture was extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give 20 a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate= 3:1) to give the title compound (160 mg, 183.03 μmol, 46.27% yield) as a yellow solid. TLC (Petroleum ether : Ethyl acetate =3:1) Rf = 0.53. LCMS (ES, m/z): 874.4 [M+H]+. 25 Step 7 of 8: Synthesis of Intermediate 138.8, tert-butyl N-[(1S)-1-[[(1S)-1 -[[4-[4-[1-[4-[4- [(2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]but n yl]amino]-3-[5-[tert- b t l di th l il l 6 4 fl h l th l 33 th l 2H lo[3,2-b]pyridin- 1-yl]-3-oxo-propyl]-3,5-dimethyl-phenoxy]butyl]triazol-4-yl]butoxy]-2,6-dimethyl- phenyl]methyl]-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- 30 b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate. Three batches was carried out in parallel: To a solution of tert-butyl N-[(1S)-1-[[(1S)-2-[6- [(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[(4-hex-5- ynoxy-2,6-dimethyl-phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (17.3 mg, 23.3 μmol, 1 eq), tert-butyl N-[(1S)-1-[[(1S)-1-[[4-(4-azidobutoxy)-2,6-dimethyl-35 phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H- 392 70226WO01 pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (20.4 mg, 23.3 μmol, 1 eq) in THF (1 mL) H2O (1 mL) was added CuSO4.5H2O (1.75 mg, 7.00 μmol, 0.3 eq) sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (1.39 mg, 7.00 μmol, 0.3 eq) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20°C for 2 5 h under N2 atmosphere. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Three reactions were combined for work-up. The reaction mixture was added into H2O 10 mL, then extracted with EtOAc (10 mL * 3), the combined organic phase dried over Na2SO4, filtered and filtrate was concentrated under reduced pressure to give the title compound (100 mg, quantitative yield) as a yellow solid. 10 Step 8 of 8: Synthesis of Intermediate example 116, (2S)-N-[(1S)-2-[6-[(4-fluorophenyl) methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[[4-[4-[1-[4-[4-[(2S)-3- [6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2- [[(2S)-2-(methylamino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl-phenoxy]butyl]triazol-4- 15 yl]butoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-ethyl]-2-(methylamino)butanamide. To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[4-[1-[4-[4-[(2S)-2-[[(2S)-2- [tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5-dimethyl- phenoxy]butyl]triazol-4-yl]butoxy]-2,6-dimethyl-phenyl]methyl]-2-[6-[(4-fluorophenyl)methyl]-20 3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N- methyl-carbamate (100 mg, 61.8 μmol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 1 mL). The mixture was stirred at 20°C for 0.5h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC(TFA condition25 column: column: 3_Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.1% TFA)- ACN];gradient:35%-65% B over 8.0 min to give the title compound (47.8 mg, 30.61 μmol, 49.50% yield, 98.029% purity, 2TFA) as a gray solid. LCMS (ES, m/z): 651.9 [M/2+H]+. 1H NMR (400 MHz, METHANOL-d4) δ = 8.19 (s, 2H), 7.75 (s, 1H), 7.27 - 7.20 (m, 4H), 7.05 - 30 6.96 (m, 4H), 6.54 (s, 4H), 4.73 - 4.62 (m, 2H), 4.40 (br d, J = 3.1 Hz, 2H), 3.88 (br d, J = 4.4 Hz, 4H), 3.79 (s, 8H), 3.27 - 3.20 (m, 2H), 3.01 (br dd, J = 3.3, 13.5 Hz, 2H), 2.73 (br t, J = 6.9 Hz, 2H), 2.68 - 2.62 (m, 6H), 2.57 (br d, J = 9.9 Hz, 2H), 2.31 - 2.22 (m, 12H), 2.07 - 1.99 (m, 2H), 1.98 - 1.86 (m, 4H), 1.83 - 1.66 (m, 6H), 1.23 (s, 6H), 1.05 - 0.95 (m, 6H), 0.87 (s, 6H). 393 70226WO01 Example 117, (2S)-N-[(1S)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[[4-[3-[1-[3-[4-[(2S)-3-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2- (methylamino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl-phenoxy]propyl]triazol-4- 5 yl]propoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-ethyl]-2-(methylamino)butanamid. Synthesis of Intermediate 139.2, methyl (2S)-3-[4-(3-bromopropoxy)-2,6-dimethyl-phenyl]-2- (tert-butoxycarbonylamino)propanoate. 10 To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(4-hydroxy-2, 6-dimethyl-phenyl) propanoate (500 mg, 1.55 mmol, 1 eq), 3-bromopropan-1-ol (236.39 mg, 1.70 mmol, 153.50 uL, 1.1 eq) in Tol. (10 mL) was added 2-(tributyl-λ5-phosphanylidene) acetonitrile (447.80 mg, 1.86 mmol, 1.2 eq) at 25°C under N2. The mixture was stirred at 80°C for 12 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. Water 15 (20 mL) was added to the mixture, the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate= 80:40) to give the title compound (0.5 g, 1.13 mmol, 50.00% yield) as a white solid. 20 LCMS (ES, m/z): 468.0 [M +Na]+. -2- 70226WO01 To a solution of methyl (2S)-3-[4-(3-bromopropoxy)-2, 6-dimethyl-phenyl]-2-(tert- butoxycarbonylamino) propanoate (500 mg, 1.13 mmol, 1 eq) in DMF (8 mL) was added NaN3 (310 mg, 4.77 mmol, 4.24 eq) at 0°C. The mixture was stirred at 80°C for 2 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The 5 reaction mixture was added into H2O 20 mL, then extracted with EtOAc (20 mL * 3), the combined organic phase dried over Na2SO4, filtered and filtrate was concentrated under reduced pressure to give the title compound (497 mg, quantitative yield) as a yellow oil. LCMS (ES, m/z): 307.2 [M-Boc+H]+. 10 Synthesis of Intermediate 139.4, methyl (2R)-2-amino-3-[4-(3-azidopropoxy)-2,6-dimethyl- phenyl]propanoate. To a solution of methyl (2S)-3-[4-(3-azidopropoxy)-2,6-dimethyl-phenyl]-2-(tert- butoxycarbonylamino)propanoate (497 mg, 1.22 mmol, 1 eq) in EtOAc (4 mL) was added HCl/EtOAc (4 M, 4 mL, 13.09 eq). The mixture was stirred at 25°C for 1 h. LC-MS indicated 15 complete consumption of starting material with formation of a single peak of target mass. The mixture was filtered, the filter cake was concentrated under reduced pressure to give the title compound (630 mg, quantitative yield, HCl) as a yellow solid. LCMS (ES, m/z): 307.2 [M+H]+. 20 Synthesis of Intermediate 139.5, methyl (2S)-3-[4-(3-azidopropoxy)-2,6-dimethyl-phenyl]-2- [[(2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoyl]amino]propanoate. To a solution of methyl (2R)-2-amino-3-[4-(3-azidopropoxy)-26-dimethyl-phenyl]propanoate (580 mg, 1.69 mmol, 1 eq, HCl) in DCM (2 . , 6.77 mmol, 1.18 mL, 4 eq) (2S)-2-[tert-butoxycarbonyl(methyl)amino]butanoic acid (404.33 mg, 1.86 mmol, 1.1 eq) and 25 HATU (964.94 mg, 2.54 mmol, 1.5 eq) at 0°C. The mixture was stirred at 25°C for 12 h. LC-MS indicated complete conversion to a product of target mass. Water (50 mL) was added to the mixture, the mixture was extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, 30 Petroleum ether/Ethyl acetate=1/0 to 0/1) to give the title compound (398 mg, 787.17 μmol, 46.53% yield) as a yellow oil. LCMS (ES, m/z): 528.2 [M+Na]+ TLC (Petroleum ether/Ethyl acetate = 1:1) Rf = 0.72. 395 70226WO01 Synthesis of Intermediate 139.6, (2S)-3-[4-(3-azidopropoxy)-2,6-dimethyl-phenyl]-2-[[(2S)-2- [tert-butoxycarbonyl(methyl)amino]butanoyl]amino]propanoic acid. To a solution of methyl (2S)-3-[4-(3-azidopropoxy)-2, 6-dimethyl-phenyl]-2-[[(2S)-2-[tert- butoxycarbonyl (methyl) amino] butanoyl ] amino ]propanoate (398 mg, 787.17 μmol, 1 eq) in 5 THF (3 mL), H2O (1 mL), MeOH (1 mL) was added LiOH (56.55 mg, 2.36 mmol, 3 eq). The mixture was stirred at 15°C for 2 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The mixture was concentrated under reduced pressure to give a residue, the residue was dissolved in H2O (10 mL), then extracted with EtOAC ( 8 mL * 2), then the water phase acidified with 1M KHSO4 to pH 1-2. The acidic aqueous phase 10 was extracted with DCM (8 mL *3) and the organic phase were washed with brine (10 mL), then dried over Na2SO4, filtered and filtrate was concentrated under reduced pressure to give the titile compound (400 mg, quantitative yield) as a yellow oil. LCMS (ES, m/z): 392.2[M-Boc+H]+. 15 Synthesis of Intermediate 139.7, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-(3-azidopropoxy)-2,6- dimethyl-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3- dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl- carbamate. To a solution of (2S)-3-[4-(3-azidopropoxy)-2,6-dimethyl-phenyl]-2-[[(2S)-2-[tert-20 butoxycarbonyl(methyl)amino]butanoyl]amino]propanoic acid (180 mg, 366.17 μmol, 1 eq) tert- butyl-[[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-1,2-dihydropyrrolo[3,2-b]pyridin-5-yl]oxy]- dimethyl-silane (155.71 mg, 402.78 μmol, 1.1 eq) in DCM (5 mL) was added DIEA (141.97 mg, 1.10 mmol, 191.34 μL, 3 eq) and T3P (570 mg, 895.72 μmol, 533.21 μL, 50% purity, 2.45 eq) at 0°C. The mixture was stirred at 20°C for 12h. LC-MS indicated complete consumption of starting 25 material with formation of a single peak of target mass. Water (10 mL) was added to the mixture, the mixture was extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, Petroleum ether : Ethyl acetate = 3:1 RF=0.43) to give the title compound (230 mg, 267.40 μmol, 65.71% yield) as a 30 yellow oil. LCMS (ES, m/z):860.5[M+H]+. TLC (Petroleum ether : Ethyl acetate = 3:1) Rf = 0.43. Synthesis of Intermediate 139.8, tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[3-[1-[3-[4-[(2S)-2-[[(2S)-2-35 [tert-butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6- 396 70226WO01 [(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5- dimethyl-phenoxy]propyl]triazol-4-yl]propoxy]-2,6-dimethyl-phenyl]methyl]-2-[5-[tert- ridin- 1-yl]-2-o pyl]-N-methyl-carbamate. 5 a propoxy)-2,6-dimethyl-phenyl]methyl]-2-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl]carbamoyl]propyl]- N-methyl-carbamate (30.60 mg, 35.58 μmol, 1 eq) and tert-butyl N-[(1S)-1-[[(1S)-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-10 1-[(2,6-dimethyl-4-pent-4-ynoxy-phenyl)methyl]-2-oxo-ethyl]carbamoyl]propyl]-N-methyl- carbamate (30 mg, 35.58 μmol, 1 eq) in THF (1 mL) and H2O (1 mL) was added CuSO4.5H2O (2.67 mg, 10.67 μmol, 0.3 eq) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H- furan-3-olate (2.11 mg, 10.67 μmol, 0.3 eq) was degassed and purged with N2 for 3 times. The mixture was stirred at 25°C for 2 h under N2 atmosphere. LC-MS indicated complete conversion to 15 a product of target mass. Three reactions were combined for work-up. Water (10 mL) was added to the mixture, the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the title compound (120 mg, 70.45 μmol, 66.00% yield) as a yellow oil. 20 LCMS (ES, m/z): 751.4 [M/2-Boc+H]+. Synthesis of Example 117, (2S)-N-[(1S)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-1-[[4-[3-[1-[3-[4-[(2S)-3-[6-[(4-fluorophenyl)methyl]-3,3- dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2-25 (methylamino)butanoyl]amino]-3-oxo-propyl]-3,5-dimethyl-phenoxy]propyl]triazol-4- yl]propoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-ethyl]-2-(methylamino)butanamide. To a solution of tert-butyl N-[(1S)-1-[[(1S)-1-[[4-[3-[1-[3-[4-[(2S)-2-[[(2S)-2-[tert- butoxycarbonyl(methyl)amino]butanoyl]amino]-3-[5-[tert-butyl(dimethyl)silyl]oxy-6-[(4- fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]-3-oxo-propyl]-3,5-dimethyl-30 phenoxy]propyl]triazol-4-yl]propoxy]-2,6-dimethyl-phenyl]methyl]-2-[5-[tert- butyl(dimethyl)silyl]oxy-6-[(4-fluorophenyl)methyl]-3,3-dimethyl-2H-pyrrolo[3,2-b]pyridin-1-yl]- 2-oxo-ethyl]carbamoyl]propyl]-N-methyl-carbamate (110 mg, 64.58 μmol, 1 eq) in EtOAc (1 mL) was added HCl/EtOAc (4 M, 1 mL). The mixture was stirred at 25°C for 1 h. LC-MS indicated complete consumption of starting material with formation of a single peak of target mass. The 35 mixture was blown to dryness by N2 stream and concentrated under reduced pressure to give a 397 70226WO01 residue. The residue was purified by prep-HPLC (TFA condition;column: Phenomenex luna C18 100*40mm*3 um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:15%-45% B over 8.0 min ) to give the title compound (66.9 mg, 44.20 μmol, 68.44% yield, 99.267% purity, 2TFA) as a white solid. 5 LCMS (ES, m/z): 637.9[M/2+H]+. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.87 (d, J=2.13 Hz, 6H) 0.99 (t, J=7.50 Hz, 6H) 1.24 (d, J=1.75 Hz, 6H) 1.86 - 1.96 (m, 3H) 1.96 - 2.08 (m, 3H) 2.24 - 2.27 (m, 12H) 2.30 (br s, 2H) 2.61 (br d, J=12.88 Hz, 2H) 2.65 (d, J=3.50 Hz, 6H) 2.82 (t, J=7.50 Hz, 2H) 3.01 (dd, J=13.63, 4.13 Hz, 2H) 3.25 (s, 2H) 3.77 - 3.83 (m, 8H) 3.85 - 3.92 (m, 4H) 4.52 (s, 2H) 4.71 (br d, J=11.51 Hz, 10 2H) 6.53 (d, J=4.50 Hz, 4H) 7.00 (t, J=8.63 Hz, 4H) 7.21 - 7.26 (m, 4H) 7.74 (s, 1H) 8.20 (s, 2H). Jurkat latency reversal assay. Jurkat HIV-luciferase clones were maintained in RPMI medium 1640 (Gibco by Life Technologies) containing 10% (vol/vol) fetal bovine serum (SAFC/Sigma-Aldrich) and 25 15 units/mL penicillin, 25 units/mL streptomycin (Gibco by Life Technologies), and were split 1:4 every 3 to 4 days to maintain a cell density of ~0.3 to 1 million cells/mL. The Jurkat clones were maintained with the addition of 500nM EFV in the medium. Three Jurkat cell clones (C16, I15, and N6), each harboring one or two integrated HIV proviruses expressing the luciferase reporter gene, were added at equal amounts for a total of 5,000 cells per well to 384-well plates containing 20 compound titrations. Dose-response testing was performed on compounds dissolved in dimethyl sulfoxide (DMSO; Fisher Scientific, Merelbeke, Belgium) dispensed in duplicate serial 3-fold, 14- point titrations using a D300e Digital Droplet Dispenser (Hewlett-Packard) to give final assay concentrations of 10 μM to 2.1 pM in 50 μL of medium at 0.5% DMSO (vol/vol) final concentration. Cells and compound were incubated at 37°C for 48 hours, unless otherwise 25 indicated, followed by the addition of 20 μL of Steady-Glo® Luciferase (Promega). Luminescence resulting from the induction of the virally expressed luciferase was measured using an EnVision 2102 Multilabel Plate Reader (Perkin Elmer). Dose-response relationships were analyzed with GraphPad PRISM 6 using a four-parameter logistic regression model to calculate the concentration of compound that gives half-maximal response (EC50) and the maximal percent activation 30 compared to the vehicle control. Jurkat cytotoxicity assay Cell viability of Jurkat cells was determined using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega), a homogeneous method to determine the ATP levels in a culture well, which corresponds to the presence of metabolically active cells in culture. Cells were cultured as 35 indicated elsewhere for the Jurkat assays. A proportion of cells was removed and 30 μL of Promega 398 70226WO01 CellTiter-Glo® reagent was added to each well containing cells and luminescence was measured using a Perkin Elmer EnVision plate reader. Dose-response relationships were analyzed with GraphPad PRISM 6 using a four-parameter model logistic regression model to calculate the concentration of compound that reduces cell viability by 50% when compared to untreated controls 5 (CC50). BIR Binding Assay The BIR domain binding assays are FRET based competition assays that utilize His-tagged versions of each of the BIR2 and BIR3 domains from cIAP1, cIAP2, and XIAP (each domain assayed separately) each at a custom optimal concentration and a probe, 200nM SMAC/DIABLO 10 peptide AVPIAQKSE labelled with AlexaFluor647 (part# crb1110326h, Discovery Peptides). The assay is conducted in 50mM HEPES, 150nM NaCl, 1mM CHAPS, 5% Glycerol, 1mM DTT, in dI water with a final pH of 7.4 and final volume of 20uL. Final protein domain concentrations are: 50nM cIAP1-BIR3 (Part # APT-11-370 Reaction Biology), 100nM XIAP-BIR3 (Part # APT-11- 351 Reaction Biology), 200nM XIAP-BIR2 (Part # APT-11-470 Reaction Biology), 325nM cIAP2- 15 BIR2 (Part # APT-11-489 Reaction Biology), 50nM cIAP2-BIR3 (Part # APT-11-372 Reaction Biology), 325nM cIAP1-BIR2 (Part # APT-11-487 Reaction Biology). Compounds were plated using a HP Tecan D300 printer in a final total volume of 202nl and DMSO concentration normalized across the 15-point, 3-fold dilution series. Peptide and probe were prepared at 2x relative to the concentrations above in binding buffer, 10uL added to the prepared compound 20 plates, and incubated for 60 minutes. LANCE Eu-W1024 (part# AD0401 Perkin Elmer#, vendor) was prepared at 2x concentration in binding buffer for final concentration of 2nM, 10uL added to each well, and plates incubated for 30 minutes. Plates were read on an ENVISION multifunction plate reader with 320nM laser excitation to obtain the 615nm/665nm emission ratio as indicative of probe:protein proximity. Data was analyzed using GraphPad PRISM and curves fit using 25 log(inhibitor) vs. response -- Variable slope (four parametersXXX method to obtain IC50 and pIC50 values. The assay results are set forth in Table 4, with desired properties denoted with “+” symbols as defined below and assays without data are represented by “-”. Compounds were o timized to 30 have potency in the Jurkat latency reversal assay, limited or no cytotoxicity, and increased fold separation between BIR3 and BIR2 binding activity for cIAP1 and cIAP2 over XIAP. a Jurkat assay potency. ++++: 9.31 > pEC50 >= 7.90; +++: 7.90 > pEC50 >= 7.20; ++: <= 70226WO01 c BIR3 and BIR2 binding assays. +++++: 9.50 > pIC50 >= 8.00; ++++: 8.00 > pIC50 >= 7.00; +++: 7.00 > pIC50 >= 6.00; ++: 6.00 > pIC50 >= 5.00; +: 5.00 > pIC50. d cIAP1_BIR3 or cIAP2_BIR3 versus XIAP_BIR3 binding assay window (fold separation (FS)). +++++: FS > 10,000; ++++: 10,000 > FS > 1,000; +++: 1000 > FS >100; ++: 100 > FS > 5 10; +: 10 > FS >1. c P1_BIR2 or cIAP2_BIR2 versus XIAP_XIAP binding assay window (fold separation (FS)). +++++: FS > 10,000; ++++: 10,000 > FS > 1,000; +++: 1000 > FS >100; ++: 100 > FS > 10; +: 10 > FS >1. Table 4 Ex. # pEC50 a pCC50 cIAP1 cIAP2 XIAP cIAP1 BIR3/ cIAP2 BIR3 cIAP1 cIAP2 XIAP cIAP1 BIR2/ cIAP2 BIR2/ Average Averageb BIR3c BIR3c BIR3c XIAP BIR3d /XIAP BIR3d BIR2c BIR2c BIR2c XIAP BIR2e XIAP BIR2e 1 + ++++ - - - - - - - - - - 70226WO01 Ex. # pEC50 ragea pCC50 cIAP1 cIAP2 XIAP cIAP1 BIR3/ cIAP2 BIR3 cIAP1 cIAP2 XIAP cIAP1 BIR2/ cIAP2 BIR2/ Ave Averageb BIR3c BIR3c BIR3c XIAP BIR3d /XIAP BIR3d BIR2c BIR2c BIR2c XIAP BIR2e XIAP BIR2e 30 + ++++ +++++ +++++ +++++ + + +++ +++ + +++ +++ 70226WO01 Ex. # pEC50 eragea pCC50 cIAP1 cIAP2 XIAP cIAP1 BIR3/ cIAP2 BIR3 cIAP1 cIAP2 XIAP cIAP1 BIR2/ cIAP2 BIR2/ Av Averageb BIR3c BIR3c BIR3c XIAP BIR3d /XIAP BIR3d BIR2c BIR2c BIR2c XIAP BIR2e XIAP BIR2e 70 +++ ++++ ++++ ++++ +++ ++ + +++ +++ + ++ ++ 70226WO01 Ex. # pEC50 pCC50 cIAP1 cIAP2 XIAP cIAP1 BIR3/ cIAP2 BIR3 cIAP1 cIAP2 XIAP cIAP1 BIR2/ cIAP2 BIR2/ Averagea Averageb BIR3c BIR3c BIR3c XIAP BIR3d /XIAP BIR3d BIR2c BIR2c BIR2c XIAP BIR2e XIAP BIR2e 114 +++ ++ +++++ +++++ ++ +++ +++ - - - - - activity of SMACm can also promote cell death in otherwise sensitive cells. Degradation of cIAP1/2 also affects intracellular signaling from TNFR family members, such as occurs after TNFa 5 engagement with TNFR1. cIAP1/2 attach K48-linked ubiquitin chains to RIPK1 to facilitate recruitment of NEMO, which promotes activation of the canonical NFkB pathway. In the absence of cIAP1/2, TNFa ligation to TNFR1 instead leads to activation of the kinase activity of RIPK1, which leads to apoptosis or necroptosis. Binding of SMAC to the BIR domains of XIAP and ML- IAP antagonizes the caspase inhibition activities of these molecules, often overexpressed in tumor 10 cells, leading to potentiation of apoptosis. Most SMACm compounds developed over the past 20 years in the oncology space have been designed to kill tumor cells by specifically binding to and inhibiting XIAP by binding to the BIR2 and BIR3 domains in XIAP and in some cases have attempted to limit cIAP1/2 engagement. However, for the purposes of HIV latency reversal through the activation of ncNF-kB, cIAP1/2 15 binding is the preferred activity and XIAP inhibition is an off-target and may contribute in heretofore unknown mechanisms to potential cytotoxicity or in vivo toxicity. It is noted that bivalent SMACm can more optimally activate ncNF-kB than monovalent compounds, perhaps through bridging cIAP1 and cIAP2 together in a ternary complex where each SMACm motif in the bivalent molecule interacts with one BIR domain from each of cIAP1 and cIAP2, mostly likely the 20 BIR3 domain, leading to the efficient degradation of both cIAP1 and cIAP2. The bivalent molecules of this application are optimized to bind to BIR3 of cIAP1 and cIAP2 more potently than BIR3 within XIAP and as such may form the ternary complex between cIAP1 and/or cIAP2 molecules as opposed to the intramolecular binding to BIR2 and BIR3, thereby favoring the depletion of cIAP1 and cIAP2 over inhibition of XIAP. 25 In some embodiments, the compounds were optimized to have potency in the Jurkat latency reversal assay presented in Table 4 indicated by the Jurkat assay potency pEC50 values. In some embodiments, the compound or pharmaceutically acceptable salt or stereoisomer thereof is selected from the group consisting of Compounds 12, 14, 16, 19, 20, 25, 34, 35, 36, 37, 40, 43, 44, 45, 46, 47, 48, 49, 50, 56, 63, 64, 65, 68, 69, 70, 71, 72, 73, 74, 76, 77, 78, 79, 80, 81, 82, 83, 85, 30 92, 94, 95, 96, 97, 100, 104, 105, 113, 114, 115, 116, and 117. 403 70226WO01 In some embodiments, the compounds were optimized to have limited or no cytotoxicity as presented in Table 4 indicated by the Jurkat assay toxicity pCC50. In some embodiments, the compound or pharmaceutically acceptable salt or stereoisomer thereof is selected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 17, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 5 33, 34, 35, 38, 39, 41, 44, 45, 51, 52, 53, 54, 56, 57, 58, 59, 60, 61, 62, 66, 67, 68, 69, 70, 71, 73, 74, 75, 76, 77, 78, 79, 93, 94, 95, 98, 99, 101, 102, 103, 105, 106, 107, and 108. In some embodiments, the compounds were optimized to increase fold separation for BIR3 as presented in Table 4 indicated by cIAP1 BIR3 binding assays pIC50. In some embodiments, the compound or pharmaceutically acceptable salt or stereoisomer thereof is selected from the group 10 consisting of Compounds 3, 4, 7, 9, 12, 14, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 28, 30, 35, 36, 37, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 85, 86, 87, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 113, 114, 115, 116, and 117. In some embodiments, the compounds were optimized to increase fold separation for BIR3 15 as presented in Table 4 indicated by cIAP2 BIR3 binding assays pIC50. In some embodiments, the compound or pharmaceutically acceptable salt or stereoisomer thereof is selected from the group consisting of Compounds 3, 4, 7, 9, 12, 14, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 30, 35, 36, 37, 38, 40, 41, 42, 44, 45, 46, 47, 48, 49, 50, 52, 53, 54, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 85, 86, 87, 92, 93, 94, 95, 96, 97, 98, 99, 100, 20 101, 102, 103, 104, 105, 106, 107, 108, 113, 114, 115, 116, and 117. In some embodiments, the compounds were optimized to increase fold separation for BIR3 binding activity as presented in Table 4 indicated by cIAP1 BIR3 vs XIAP BIR3 separation window. In some embodiments, the compound or pharmaceutically acceptable salt or stereoisomer thereof is selected from the group consisting of Compounds 16, 21, 22, 28, 55, 80, and 81. 25 In some embodiments, the compounds were optimized to increase fold separation for BIR3 binding activity as presented in Table 4 indicated by cIAP2 BIR3 vs XIAP BIR3 separation window. In some embodiments, the compound or pharmaceutically acceptable salt or stereoisomer thereof is selected from the group consisting of Compounds 16, 21, 22, 80, and 81. In some embodiments, the compounds were optimized to increase fold separation for BIR3 30 as presented in Table 4 indicated by XIAP BIR3 binding assays pIC50. In some embodiments, the compound or pharmaceutically acceptable salt or stereoisomer thereof is selected from the group consisting of Compounds 3, 7, 12, 17, 19, 20, 23, 24, 26, 30, 35, 41, 44, 45, 49, 52, 57, 58, 60, 61, 62, 72, 74, 75, 77, 79, 82, 92, 93, 94, 98, 99, 100, 101, 102, 103, , 105, 106, 107, and 108. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, 35 temperature, etc.) but some experimental errors and deviations should be accounted for. 404 70226WO01 One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practicing the subject matter described herein. The present disclosure is in no way limited to just the methods and materials described. Unless defined otherwise, technical and scientific terms used herein have the same 5 meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs, and are consistent with: Singleton et al (1994) Dictionary of Microbiology and Molecular Biology, 2nd Ed., J. Wiley & Sons, New York, NY; and Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immunobiology, 5th Ed., Garland Publishing, New York. Throughout this specification and the claims, the words “comprise,” “comprises,” and 10 “comprising” are used in a non-exclusive sense, except where the context requires otherwise. It is understood that embodiments described herein include “consisting of” and/or “consisting essentially of” embodiments. As used herein, the term “about,” when referring to a value is meant to encompass variations of, in some embodiments ± 50%, in some embodiments ± 20%, in some embodiments ± 15 10%, in some embodiments ± 5%, in some embodiments ± 1%, in some embodiments ± 0.5%, and in some embodiments ± 0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictates otherwise, between the upper 20 and lower limit of the range and any other stated or intervening value in that stated range, is encompassed. The upper and lower limits of these small ranges which may independently be included in the smaller rangers is also encompassed, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included. 25 Many modifications and other embodiments set forth herein will come to mind to one skilled in the art to which this subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although 30 specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. 405

Claims

70226WO01 WHAT IS CLAIMED IS: 1. A compound of Formula (I): each R1 and R2 is -H or -CH3; each R3 is -H, -CH3, -CH2CH3, cyclopropyl, -CH2-OH, or -CH(OH)CH3; each R4 is -H, -F, -Cl, -CH3, -CF3, -CN, -OH, -OCH3, -C(O)N(CH3)2, -CH(CH3)2, or -C(O)OCH3; each R5 is -H or -F; each R6 is -H, -F, -Cl, -Br, -CN, -CH3, -CHF2, or -CF3; each R7 is -H; each R8 is -H, -F, -Cl, or -CN; each R9 is -H or -CH3; each R10 is -H or -CH3; each X is -CH2- or -O-; each Y1 is -CH- or -C(O)-; each Y2 is -N-, -NH-, or -NCH3-; each represents a single bond or a double bond, wherein when Y1 is -CH-, Y2 is -N- and represents a double bond and when Y1 is -C(O)-, Y2 is -NH- or -NCH3-, and represents a single bond; L is a linker selected from the group consisting of -(C≡C)2-, a C1-C8 alkylene, - C(O)NHCH2-, -NHC(O)CH2-, -C(O)NH-U-NHC(O)-, -NHC(O)-U-C(O)NH-, -C(O)NH-U-Ar1-U- 406 70226WO01 NHC(O)-, -NHC(O)-U-Ar1-U-C(O)NH-, an optionally substituted C5-C12 arylene including from 0- 3 heteroatoms, -Ar2-Ar3-, -Ar4-T-Ar5-, -T-Ar6-T-, and -T-Ar7-T-Ar8-T- wherein -Ar1-, -Ar2-, -Ar3-, -Ar4-, -Ar5-, -Ar6-, -Ar7-, and -Ar8- are each a C6 arylene; -T- is -O-, -CH2-, -C(CH3)(CH3)-, or -C(CF3)(CF3)-; and -U- is a C1-C4 alkylene or a direct bond; Z1 is a C1-C4 alkylene or a direct bond; Z2 is a C1-C4 alkylene or a direct bond; W1 is -(CH2)nNHC(O)-, -C(O)NH(CH2)n-, -O-, -C(O)-, -(CH2)m-O-, -O-(CH2)m-, or a direct bond where n is from 0 to 3 and m is from 1 to 4; W2 is -(CH2)nNHC(O)-, -C(O)NH(CH2)n-, -O-, -C(O)-, -(CH2)m-O-, -O-(CH2)m-, or a direct bond where n is from 0 to 3 and m is from 1 to 4; V1 is an optionally substituted C1-C4 alkylene, a heterocycloalkylene, an optionally substituted arylene, or a combination thereof; V2 is an optionally substituted C1-C4 alkylene, a heterocycloalkylene, an optionally substituted arylene, or a combination thereof; Q1 is an optionally substituted C1-C4 alkylene or a direct bond; and Q2 is an optionally substituted C1-C4 alkylene or a direct bond. 2. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any preceding claim, wherein R1 and R2 in each instance are each -CH3. 3. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any preceding claim, wherein each R3 is -CH3 or -CH2CH3. 4. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any preceding claim, wherein each R9 is -H and each R10 is -CH3. 5. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-4, wherein each R6 is -F and each of R4, R5, R7, and R8 is -H. 6. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-4, (a) wherein each R6 is -Cl and each of R5 and R7 is -H and (b) wherein each R8 is -H, each R4 is -Cl or -CN or wherein each R4 is -H, each R8 is -Cl or -CN. 7. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any preceding claim, wherein each X is -CH2-. 407 70226WO01 8. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any preceding claim, wherein Z1 and Z2 are each a C1-C4 alkylene. 9. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any preceding claim, wherein W1 and W2 are each -O-. 10. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-9, wherein V1 and V2 are each an optionally substituted C1-C4 alkylene. 11. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-9, wherein V1 and V2 are each a combination of an optionally substituted C1-C4 alkylene and an optionally substituted arylene. 12. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to , 13. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-9, wherein V2 is selected from the group consisting , . 14. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-13, wherein each Y1 is -C(O)-, each Y2 is -NH- or -NCH3-, and each represents a single bond. 408 70226WO01 15. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-13, wherein each Y1 is -C(H)-, each Y2 is -N-, and each represents a double bond. 16. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-15, wherein L is -(C≡C)2-. 17. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-15, wherein L is a C1-C8 alkylene. 18. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1-15, wherein L is -NHC(O)-U-C(O)NH- or -NHC(O)-U-Ar1-U-C(O)NH-. 19. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 having the following formula: 20. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 having the following formula: 409 70226WO01 wherein W, Z, L, Z, W, each R, each R5, each R6, each R7, and each R8 are as defined above. 21. A compound selected from the group consisting of: , , , 70226WO01 nd . or a pharmace 22. A compound which is or a pharmaceut 23. A compound selected from the group consisting of: nd . 70226WO01 or a pharmaceutically acceptable salt thereof. 24. A compound selected from the group consisting of: , , , , 70226WO01 70226WO01 nd . or a pharmace 25. A compound selected from the group consisting of: and or a pharmace 26. A compound selected from the group consisting of 414 70226WO01 N1,N10-bis((S)-5-((S)-2-aminopropanamido)-6-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6-oxohexyl)deca-4,6-diynediamide; N1,N10-bis((S)-5-((S)-2-aminobutanamido)-6-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6-oxohexyl)deca-4,6-diynediamide; N1,N10-bis((S)-6-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-5-((S)-2-(methylamino)propanamido)-6-oxohexyl)deca-4,6- diynediamide; N1,N10-bis((S)-6-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-5-((S)-2-(methylamino)butanamido)-6-oxohexyl)deca-4,6- diynediamide; N1,N10-bis((S)-5-((R)-2-aminopropanamido)-6-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-6-oxohexyl)deca-4,6-diynediamide; (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(4-((S)-2-aminopropanamido)-5-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5- oxopentanamide); (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(5-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-((S)-2-(methylamino)propanamido)-5- oxopentanamide); (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(4-((S)-2-aminobutanamido)-5-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5- oxopentanamide); (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(5-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-((S)-2-(methylamino)butanamido)-5- oxopentanamide); (4S,4'S)-N,N'-(hexa-2,4-diyne-1,6-diyl)bis(5-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-((R)-2-(methylamino)propanamido)-5- oxopentanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-aminopropanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-aminobutanamide); 415 70226WO01 (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2R,2'R)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-aminopropanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-cyclopropyl-2-(methylamino)acetamide); (2R,2'R)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(3-hydroxy-2-(methylamino)propanamide); (2R,2'R,3S,3'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3- (6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(3-hydroxy-2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((octa-3,5-diyne-1,8-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-((octa-3,5-diyne-1,8-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((butane-1,4-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexane-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide); (S)-N-((S)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(4-((1-(2-(4-((S)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro- 1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2-(methylamino)propanamido)-3-oxopropyl)phenoxy)ethyl)- 1H-1,2,3-triazol-4-yl)methoxy)phenyl)-1-oxopropan-2-yl)-2-(methylamino)propanamide; (S)-N-((S)-1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-(4-(2-((2-(4-((S)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro- 1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2-(methylamino)propanamido)-3- oxopropyl)phenoxy)ethyl)amino)-2-oxoethoxy)phenyl)-1-oxopropan-2-yl)-2- (methylamino)propanamide; 416 70226WO01 (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(1H-indole-1,3-diyl))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(1H-indole-1,3-diyl))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide); (2R,2'R)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(1H-indole-1,3-diyl))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(1H-indole-1,3-diyl))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-cyclopropyl-2-(methylamino)acetamide); (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- aminobutanamide); (2S,2'S)-N,N'-((2S,2'S,3R,3'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(1-(6-(4-fluorobenzyl)- 3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2- aminopropanamide); (2S,2'S)-N,N'-((2S,2'S,3R,3'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(1-(6-(4-fluorobenzyl)- 3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2- aminobutanamide); (2S,2'S)-N,N'-((2S,2'S,3R,3'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(1-(6-(4-fluorobenzyl)- 3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2- (methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S,3R,3'R)-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(1-(6-(4-fluorobenzyl)- 3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2- (methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(3,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)propanamide); 417 70226WO01 (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(3,1-phenylene))bis(3-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((1S,1'S)-(decanedioylbis(piperidine-1,4-diyl))bis(2-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane-1,1-diyl))bis(2- (methylamino)butanamide); (2S,2'S)-N,N'-((1S,1'S)-(([1,1'-biphenyl]-4,4'-dicarbonyl)bis(piperidine-1,4-diyl))bis(2-(6- (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2- oxoethane-1,1-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((1S,1'S)-(((perfluoro-1,4-phenylene)bis(methylene))bis(piperidine-1,4- diyl))bis(2-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1- yl)-2-oxoethane-1,1-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((1S,1'S)-(hexa-2,4-diyne-1,6-diylbis(piperidine-1,4-diyl))bis(2-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-oxoethane- 1,1-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(naphthalene-4,1-diyl))bis(3- (6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dimethyl-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2-methoxy-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2-cyano-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2-ethyl-4,1-phenylene))bis(3- (6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-dimethyl-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-dichloro-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); 418 70226WO01 (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-difluoro-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2-methyl-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(5-methoxy-1H-indole-1,3-diyl))bis(3- (6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(5-cyano-1H-indole-1,3-diyl))bis(3-(6- (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(7-chloro-1H-indole-1,3-diyl))bis(3-(6- (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(6-chloro-1H-indole-1,3-diyl))bis(3-(6- (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-(hexa-2,4-diyne-1,6-diylbis(4-chloro-1H-indole-1,3-diyl))bis(3-(6- (4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(3-methoxy-4,1- phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-(adipoylbis(piperidine-1,4-diyl))bis(3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-(octanedioylbis(piperidine-1,4-diyl))bis(3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-(decanedioylbis(piperidine-1,4-diyl))bis(3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-(terephthaloylbis(piperidine-1,4-diyl))bis(3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)propanamide); 419 70226WO01 N,N'-(methylenebis(4,1-phenylene))bis(4-((S)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2-(methylamino)propanamido)-3- oxopropyl)piperidine-1-carboxamide); N,N'-(hexane-1,6-diyl)bis(4-((S)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5- tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2-(methylamino)propanamido)-3- oxopropyl)piperidine-1-carboxamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane- 4,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane- 4,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxopentane- 5,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-(buta-1,3-diyne-1,4-diylbis(4,1-phenylene))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane- 4,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(butane-1,4-diylbis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane- 3,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(hexane-1,6-diylbis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane- 3,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(octane-1,8-diylbis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4- fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane- 3,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(((1,3-phenylenebis(oxy))bis(methylene))bis(1H-1,2,3- triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-((((propane-2,2-diylbis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2- (methylamino)propanamide); 420 70226WO01 (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-((((oxybis(4,1-phenylene))bis(oxy))bis(methylene))bis(1H- 1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-((((methylenebis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2- (methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(((1,4-phenylenebis(oxy))bis(methylene))bis(1H-1,2,3- triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(octa-3,5-diyne-1,8-diylbis(1H-1,2,3-triazole-4,1-diyl))bis(1- (6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1- oxobutane-3,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(deca-4,6-diyne-1,10-diylbis(1H-1,2,3-triazole-4,1- diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1- yl)-1-oxobutane-3,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S,3S,3'S)-(((hexa-2,4-diyne-1,6-diylbis(oxy))bis(methylene))bis(1H- 1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2-(methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S,3R,3'R)-((((propane-2,2-diylbis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(1-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-oxobutane-3,2-diyl))bis(2- (methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-((((propane-2,2-diylbis(4,1- phenylene))bis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))bis(3-(6-(4-fluorobenzyl)-3,3- dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)propanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(2,4- dichlorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- chloro-2-cyanobenzyl)-3,3-dimethyl- -3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(2,4- difluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); 421 70226WO01 (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-dimethyl-4,1- phenylene))bis(3-(3,3-dimethyl-5-oxo-6-(2,4,5-trifluorobenzyl)-2,3,4,5-tetrahydro-1H-pyrrolo[3,2- b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-dimethyl-4,1- phenylene))bis(3-(3,3-dimethyl-6-(2,4,5-trifluorobenzyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1- yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,6-dimethyl-4,1- phenylene))bis(3-oxo-3-(3,3,4-trimethyl-5-oxo-6-(2,4,5-trifluorobenzyl)-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)propane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(2,4- dichlorobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- chloro-2-cyanobenzyl)-3,3,4-trimethyl-5-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3- oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(2,4- dichlorobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2- diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- chloro-2-cyanobenzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane- 1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(2,4- dichlorophenoxy)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2- diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((hexa-2,4-diyne-1,6-diylbis(oxy))bis(4,1-phenylene))bis(3-(6-(4- chloro-2-cyanophenoxy)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane- 1,2-diyl))bis(2-(methylamino)butanamide); (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]-2-[4-[2-[4-[2-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]- 3-oxo-propyl]triazol-4-yl]ethoxy]phenoxy]ethyl]triazol-1-yl]propyl]-2-(methylamino)propanamide; (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]-2-[4-[3-[4-[3-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]- 3-oxo-propyl]triazol-4-yl]propoxy]phenoxy]propyl]triazol-1-yl]propyl]-2- (methylamino)propanamide; 422 70226WO01 (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]-2-[4-[4-[4-[4-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]- 3-oxo-propyl]triazol-4-yl]butoxy]phenoxy]butyl]triazol-1-yl]propyl]-2- (methylamino)propanamide; (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]-2-[4-[2-[4-[4-[2-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]- 3-oxo-propyl]triazol-4-yl]ethoxy]phenoxy]phenoxy]ethyl]triazol-1-yl]propyl]-2- (methylamino)propanamide; (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]-2-[4-[3-[4-[4-[3-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]- 3-oxo-propyl]triazol-4-yl]propoxy]phenoxy]phenoxy]propyl]triazol-1-yl]propyl]-2- (methylamino)propanamide; (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]-2-[4-[4-[4-[4-[4-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]- 3-oxo-propyl]triazol-4-yl]butoxy]phenoxy]phenoxy]butyl]triazol-1-yl]propyl]-2- (methylamino)propanamide; (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]-2-[4-[3-[[4-[[3-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5- oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]- 3-oxo-propyl]triazol-4-yl]propanoylamino]methyl]phenyl]methylamino]-3-oxo-propyl]triazol-1- yl]propyl]-2-(methylamino)propanamide; 4-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4-yl]-N- [[4-[[4-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- yl]butanoylamino]methyl]phenyl]methyl]butanamide; (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]-2-[4-[[4-[4-[[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo- 2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]-3- oxo-propyl]triazol-4-yl]methoxy]phenyl]phenoxy]methyl]triazol-1-yl]propyl]-2- (methylamino)propanamide; 423 70226WO01 (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridine-1-carbonyl]-2-[4-[[6-[[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo- 2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]-3- oxo-propyl]triazol-4-yl]methoxy]-2-naphthyl]oxymethyl]triazol-1-yl]propyl]-2- (methylamino)propanamide; (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[[5-[[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2- (methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4-yl]methoxy]-1- naphthyl]oxymethyl]triazol-1-yl]propyl]-2-(methylamino)propanamide; (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[[7-[[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]- 3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2- (methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4-yl]methoxy]-2- naphthyl]oxymethyl]triazol-1-yl]propyl]-2-(methylamino)propanamide; (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[[4-[2,2,2-trifluoro-1-[4-[[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4-yl]methoxy]phenyl]-1- (trifluoromethyl)ethyl]phenoxy]methyl]triazol-1-yl]propyl]-2-(methylamino)propanamide; (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[[[2-[4-[2-[[1-[(1S,2S)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4-yl]methylamino]-2-oxo- ethyl]phenyl]acetyl]amino]methyl]triazol-1-yl]propyl]-2-(methylamino)propanamide; (2S)-N-[(1S,2S)-1-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridine-1-carbonyl]-2-[4-[2-[[2-[4-[2-[2-[1-[(1R,2R)-3-[6-[(4- fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2- [[(2R)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4-yl]ethylamino]-2-oxo- ethyl]phenyl]acetyl]amino]ethyl]triazol-1-yl]propyl]-2-(methylamino)propanamide; N4-[[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]-3-oxo-propyl]triazol-4- yl]methyl]-N1-[[1-[(1R,2R)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2R)-2-(methylamino)propanoyl]amino]-3-oxo- propyl]triazol-4-yl]methyl]terephthalamide; 424 70226WO01 N4-[2-[1-[(1S,2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2S)-2-(methylamino)propanoyl]amino]-3-oxo- propyl]triazol-4-yl]ethyl]-N1-[2-[1-[(1R,2R)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo- 2,4-dihydropyrrolo[3,2-b]pyridin-1-yl]-1-methyl-2-[[(2R)-2-(methylamino)propanoyl]amino]-3- oxo-propyl]triazol-4-yl]ethyl]terephthalamide; (2S)-N-[(1S)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridin-1-yl]-1-[[4-[2-[2-[[2-[4-[(2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2-(methylamino)butanoyl]amino]-3-oxo-propyl]-3,5- dimethyl-phenoxy]acetyl]amino]ethylamino]-2-oxo-ethoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo- ethyl]-2-(methylamino)butanamide; (2S)-N-[(1S)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridin-1-yl]-1-[[4-[2-[4-[[2-[4-[(2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2-(methylamino)butanoyl]amino]-3-oxo-propyl]-3,5- dimethyl-phenoxy]acetyl]amino]butylamino]-2-oxo-ethoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo- ethyl]-2-(methylamino)butanamide; (2S,2'S)-N,N'-((2S,2'S)-(((((1,4-phenylenebis(methylene))bis(azanediyl))bis(2-oxoethane- 2,1-diyl))bis(oxy))bis(2,6-dimethyl-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide); (2S)-N-[(1S)-2-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4-dihydropyrrolo[3,2- b]pyridin-1-yl]-1-[[4-[[4-[[4-[(2S)-3-[6-[(4-fluorophenyl)methyl]-3,3-dimethyl-5-oxo-2,4- dihydropyrrolo[3,2-b]pyridin-1-yl]-2-[[(2S)-2-(methylamino)butanoyl]amino]-3-oxo-propyl]-3,5- dimethyl-phenoxy]methyl]phenyl]methoxy]-2,6-dimethyl-phenyl]methyl]-2-oxo-ethyl]-2- (methylamino)butanamide; N1,N4-bis(2-(4-((S)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2-(methylamino)butanamido)-3-oxopropyl)-3,5- dimethylphenoxy)ethyl)terephthalamide; N1,N4-bis(2-(4-((S)-3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-2-((S)-2-(methylamino)butanamido)-3-oxopropyl)-3,5- dimethylphenoxy)ethyl)succinamide; (2S,2'S)-N,N'-((2S,2'S)-(((((2,2'-(1,4-phenylene)bis(acetyl))bis(azanediyl))bis(ethane-2,1- diyl))bis(oxy))bis(2,6-dimethyl-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide); 425 70226WO01 (2S,2'S)-N,N'-((2S,2'S)-((((1H-1,2,3-triazole-1,4-diyl)bis(butane-4,1-diyl))bis(oxy))bis(2,6- dimethyl-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2-(methylamino)butanamide); (2S,2'S)-N,N'-((2S,2'S)-((((1H-1,2,3-triazole-1,4-diyl)bis(propane-3,1- diyl))bis(oxy))bis(2,6-dimethyl-4,1-phenylene))bis(3-(6-(4-fluorobenzyl)-3,3-dimethyl-5-oxo- 2,3,4,5-tetrahydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-oxopropane-1,2-diyl))bis(2- (methylamino)butanamide);or a pharmaceutically acceptable salt or stereoisomer thereof. 27. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt or stereoisomer thereof according to any of claims 1-26, and a pharmaceutically acceptable excipient. 28. A method of treating an HIV infection in a human comprising administering to the human a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer thereof according to any of claims 1-26 or the pharmaceutical composition according to claim 27. 29. The compound or pharmaceutically acceptable salt or stereoisomer thereof according to any of claims 1-26 or the pharmaceutical composition according to claim 27, for use in treating an HIV infection. 30. Use of the compound or pharmaceutically acceptable salt or stereoisomer thereof according to any of claims 1-26 or the pharmaceutical composition according to claim 27, in the manufacture of a medicament for treating an HIV infection. 31. A method of treating cancer and pre-cancerous syndromes, in a human in need thereof, which comprises administering to the human a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer thereof according to any of claims 1-26 or the pharmaceutical composition according to claim 27. 32. A method of depleting latent HIV infected cells in a human comprising administering to the human a therapeutically effective amount of the compound or pharmaceutically acceptable salt or stereoisomer thereof according to any of claims 1-26 or the pharmaceutical composition according to claim 27. 33. A combination comprising the compound or pharmaceutically acceptable salt or stereoisomer thereof according to any of claims 1-26 and one or more pharmaceutical agents active against HIV. 426 70226WO01 34. The combination according to claim 33 wherein the one or more pharmaceutical agents active against HIV is selected from the group consisting of nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, attachment and fusion inhibitors, integrase inhibitors, maturation inhibitors, CXCR4 and/or CCR5 inhibitors, histone deacetylase inhibitors, histone crotonyl transferase inhibitors, protein kinase C agonists, proteasome inhibitors, TLR7 agonists, bromodomain inhibitors, and antibodies for clearance therapy. 35. A method of treating an HIV infection in a human comprising administering to the human a therapeutically effective amount of the combination according to claim 33 or claim 34. 36. A method of depleting latent HIV infected cells in a human comprising administering to the human a therapeutically effective amount of the combination according to claim 33 or claim 34. 427
PCT/US2025/028330 2024-05-08 2025-05-08 Dimeric smac mimetics useful in hiv therapy Pending WO2025235719A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463643956P 2024-05-08 2024-05-08
US63/643,956 2024-05-08

Publications (1)

Publication Number Publication Date
WO2025235719A1 true WO2025235719A1 (en) 2025-11-13

Family

ID=96344568

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/028330 Pending WO2025235719A1 (en) 2024-05-08 2025-05-08 Dimeric smac mimetics useful in hiv therapy

Country Status (1)

Country Link
WO (1) WO2025235719A1 (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015092420A1 (en) * 2013-12-20 2015-06-25 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015092420A1 (en) * 2013-12-20 2015-06-25 Astex Therapeutics Limited Bicyclic heterocycle compounds and their uses in therapy

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HIRD ALEXANDER W ET AL: "Small molecule inhibitor of apoptosis proteins antagonists: a patent review", EXPERT OPINION ON THERAPEUTIC PATIENTS, vol. 25, no. 7, 18 May 2015 (2015-05-18), GB, pages 755 - 774, XP093278414, ISSN: 1354-3776, DOI: 10.1517/13543776.2015.1041922 *

Similar Documents

Publication Publication Date Title
AU2019390729B2 (en) Compounds useful in HIV therapy
JP2020536106A (en) Interferon gene stimulator (STING) regulator useful for the treatment of HIV
US10604531B2 (en) Enhancer of zeste homolog 2 inhibitors
EA034571B1 (en) Prodrugs of glutamine analogs
EP3317271B1 (en) Inhibitors of ezh2 (enhancer of zeste homolog 2)
US20240051972A1 (en) Compounds Useful in HIV Therapy
WO2025235719A1 (en) Dimeric smac mimetics useful in hiv therapy
US20250326771A1 (en) Piperazine derivatives useful in hiv therapy
KR102717168B1 (en) Target protein degradation inducing compound, preparation method thereof and pharmaceutical composition for preventing or treating targeted protein related diseases containing the same as an active ingredient
HK40102082A (en) Compounds useful in hiv therapy
EP3524608B1 (en) Novel pyrimidine derivative compound or pharmaceutically acceptable salts thereof, preparation method thereof, and pharmaceutical composition using same
RU2806030C2 (en) Compounds suitable for therapy against hiv
BR122023027623A2 (en) COMPOUNDS AND SALTS, THEIR USES IN HIV TREATMENT, PHARMACEUTICAL COMPOSITION, COMBINATION AND KIT THEREOF
HK1261043B (en) Enhancer of zeste homolog 2 inhibitors
HK1261043A1 (en) Enhancer of zeste homolog 2 inhibitors